1-(2,3,4,5,6-penta'ACH'benzyl)piperazine Sort by Number of References by Asch

Query Query

Results

Date

493 reactions in Reaxys

2016-06-04 13h:58m:27s (EST)

ACH ACH N

1. Query

NH ACH

ACH ACH

Search as: As drawn

1/195

2016-06-04 14:03:19

N H

Rx-ID: 5440184 View in Reaxys 1/493 Yield

Conditions & References Irikura; Masuzawa; Nishino; Kitagawa; Uchida; Ichinoseki; Ito; Journal of medicinal chemistry; vol. 11; nb. 4; (1968); p. 801 - 804 View in Reaxys Rylski et al.; Acta Poloniae Pharmaceutica; vol. 28; (1971); p. 267,268 View in Reaxys Rylski et al.; Acta Poloniae Pharmaceutica; vol. 27; (1970); p. 357,359 View in Reaxys Mndzhoyan et al.; Armyanskii Khimicheskii Zhurnal; vol. 21; nb. 7; (1968); p. 603,604-614; ; vol. 70; nb. 96754t; (1969) View in Reaxys Sacha; Acta Poloniae Pharmaceutica; vol. 21; (1964); p. 369,373,376 View in Reaxys Ikeda; Yakugaku Zasshi; vol. 89; (1969); p. 677,685; ; vol. 71; nb. 61339; (1969) View in Reaxys Menaux et al.; Ingenieur Chimiste (Brussels); vol. 54; (1973); p. 54 View in Reaxys Mndzhoyan et al.; Armyanskii Khimicheskii Zhurnal; vol. 20; nb. 4; (1967); p. 289,290-295; ; vol. 68; nb. 29674n; (1968) View in Reaxys PROCEDURE A solution of this salt in 50 ml of water is made alkaline (pH>12) with about 60 ml of 5N sodium hydroxide, then extracted twelve times with 20 ml portions of chloroform. The combined extracts are dried over anhydrous sodium sulfate, and the pale brown oil remaining after removal of solvent is distilled at reduced pres in a Claisen flask. The yield of pure 1-benzylpiperazine, bp 122-124° C./2.5 mmHg, is 14.3-16.5 g. (65-75percent). Patent; Valent, Bryant G.; US2002/156084; (2002); (A1) English View in Reaxys ...nds, the plate was treated with gaseous HF at room temperature for 2 hours. ... 2-fluorophenethylamine N-(3-trifluoromethylphenyl)piperazine 3,3,5-trimethylcyclohexylamine 1-benzylpiperazine 2-(2-methylaminoethyl)pyridine 2-(2-aminoethyl)pyridine 4-amino-1-benzylpiperidine ... Patent; Lion Bioscience AG; US6515122; (2003); (B1) English View in Reaxys 15 : 1-[2S-Amino-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropyl]-4-(phenylmethyl)piperazine, dihydrochloride STR30 To a solution of 2 g of Boc-DMT in 25 mL of THF at -23° C. was added 0.71 mL of NMM followed by 0.84 mL of IBCF. To this was added a solution of 1.13 mL of N-benzylpiperazine in 5 mL of THF. The mixture was stirred for 16 hours and concentrated in vacuo. The residue was taken up in EtOAc and water. The organic phase was washed with saturated Na2 CO3, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel using 60percent EtOAc in hexane containing 2percent triethylamine to give 3 g of a white solid (Compound A, the Boc precursor of the title compound). 0.2 g of this solid was dissolved in a mixture of 5 mL each of CH2 Cl2 and 7N HCl in dioxane.

2/195

2016-06-04 14:03:19

The solution was allowed to stand at room temperature for 15 minutes. The volatiles were removed in vacuo to give the title compound as a white solid. Patent; G. D. Searle and Co.; US5389645; (1995); (A1) English View in Reaxys Specific examples of such compounds are ... 1-(4-chlorobenzoyl)-piperazine 4-phenyl-piperidine 4-benzyl-piperidine 1-phenyl-piperazine 1-benzyl-piperazine 4-(4-fluorophenyl)-piperidine 1-(4-fluorophenyl)-piperazine Patent; Zambon Group S.p.A.; US4983606; (1991); (A1) English View in Reaxys 1 : 3-(4-Benzylpiperazin-1-yl)propanethiol dihydrochloride (a) 31.5 g of 1-bromo-3-chloropropane were added to a mixture of 35 g of 1-benzylpiperazine, 150 ml of dimethyl sulfoxide and 25 g of potassium hydroxide. EXAMPLE 1 3-(4-Benzylpiperazin-1-yl)propanethiol dihydrochloride (a) 31.5 g of 1-bromo-3-chloropropane were added to a mixture of 35 g of 1-benzylpiperazine, 150 ml of dimethyl sulfoxide and 25 g of potassium hydroxide. The resulting mixture was stirred at room temperature for 3 hours. Water was added to the resulting solution, the reaction product was extracted with ether, dried (magnesium sulfate), and the salt was precipitated with ethereal hydrochloric acid to give 35.6 g (55percent of theory) of 1-benzyl-4-(3chloropropyl)piperazine dihydrochloride as a white crystalline solid. Patent; Boehringer Ingelheim Limited; US4618677; (1986); (A1) English View in Reaxys In a preferred embodiment of the process of preparing the compounds according to the invention, the compounds of formula: STR115 are preferably selected from among: morpholine, piperidine, piperazine, homopiperazine, N(2-hydroxy)ethyl piperazine, N-benzylpiperazine, 1-(4-fluoro phenyl)piperazine, 1-(2,3-dihydroxy propyl)piperazine, N-methyl piperazine, N-carbethoxypiperazine, ... Patent; DROPIC, Societe Civile de gestion de droits de Propriete Industrielle; US4760062; (1988); (A1) English View in Reaxys Utilizing Method B and the procedure of Jensen, et al., Acta Chem. Scand., 22, 37 (1968) and reacting the following: (a) dimethylamine, ... (c) morpholine, (d) N-methylcyclohexylamine, (e) N-methylcyclopentylamine, (f) 1-phenylpiperazine, (g) 1-benzylpiperazine, (h) pyrrolidine, (i) piperidine, and (j) homopiperidine Patent; A. H. Robins Company, Incorporated; US4826866; (1989); (A1) English View in Reaxys Additional primary amines suitable for the process of the invention are those represented by the following formulae:

3/195

2016-06-04 14:03:19

... 1-ethoxycarbonylpiperazine 1-(4-chlorobenzhydryl)piperazine n-methylpiperazine 1-benzylpiperazine 1-(pyrrolidinocarbonylmethyl)piperazine n-isopropyl-l-piperazineacetamide n-beta-hydroxyethylpiperazine ... Patent; ELI LILLY AND COMPANY; EP825164; (1998); (A2) English View in Reaxys

H N Cl

N H

Rx-ID: 16518 View in Reaxys 2/493 Yield 70 %

Conditions & References 5.1.3. General procedure for the synthesis of various substituted benzylpiperazines (3a-s) General procedure: Anhydrous piperazine (6.89 g, 80 mmol) was dissolved in 40 mL of freshly distilled THF. Once the piperazine was fully dissolved, 2.303 mL (20 mmol) of benzyl chloride was added dropwise. The reaction mixture was then refluxed for about 4 h until benzyl chloride disappeared, as assessed by TLC. The stirring mixture was allowed to cool, and then filtered. The filtrate was concentrated in a rotary evaporator and then diluted with EtOAc (100 mL) and water (50 mL), which was then made basic (pH>12) with a saturated 1 N NaOH aqueous solution and separated. The organic phase was washed with water (4 .x. 100 mL), brine (2 .x. 100 mL), dried over Na2SO4 and concentrated to yield an oil. Column chromatography (PE/EtOAc = 1:1 to EtOAc/MeOH = 5:1) afforded a pale yellow liquid. in tetrahydrofuran, Time= 4h, Reflux Zhang, Cunlong; Tan, Chunyan; Zu, Xuyu; Zhai, Xin; Liu, Feng; Chu, Bizhu; Ma, Xiaohua; Chen, Yuzong; Gong, Ping; Jiang, Yuyang; European Journal of Medicinal Chemistry; vol. 46; nb. 4; (2011); p. 1404 - 1414 View in Reaxys

60.5 %

in ethanol, T= 20 °C Bali, Alka; Sharma, Komal; Bhalla, Abhishek; Bala, Suman; Reddy, Dinesh; Singh, Anant; Kumar, Anil; European Journal of Medicinal Chemistry; vol. 45; nb. 6; (2010); p. 2656 - 2662 View in Reaxys

60.5 %

in ethanol, T= 20 °C Bali, Alka; Reddy, A. C. Dinesh Kumar; Medicinal Chemistry Research; vol. 22; nb. 1; (2013); p. 382 - 391 View in Reaxys

41 %

With hydrogenchloride in ethanol, water, Reflux Wang, Bao-Lei; Liu, Xing-Hai; Zhang, Xiu-Lan; Zhang, Ji-Feng; Song, Hai-Bin; Li, Zheng-Ming; Chemical Biology and Drug Design; vol. 78; nb. 1; (2011); p. 42 - 49 View in Reaxys

41 %

With hydrogenchloride in ethanol, water, Reflux Wang, Baolei; Shi, Yanxia; Zhan, Yizhou; Zhang, Liyuan; Zhang, Yan; Wang, Lizhong; Zhang, Xiao; Li, Yonghong; Li, Zhengming; Li, Baoju; Chinese Journal of Chemistry; vol. 33; nb. 10; (2015); p. 1124 - 1134 View in Reaxys

41 %

4/195

2016-06-04 14:03:19

stirred under reflux, and substituted benzyl chlorine(25 mmol) was added dropwise for over 5 min. The mixture wasrefluxed for 4e8 h with TLC monitoring, then left to stand overnightat room temperature. The solid precipitated was filtered andwashed with ethanol, the filtrate was evaporated in vacuum, andthe residuewas dissolved in 30 mL of saturated K2CO3 aq., extractedwith chloroform (8 mL 5). The chloroform solution was driedwith anhydrous Na2SO4 and evaporated in vacuum. The residuewas then distilled under reduced pressure to give compound as acolorless liquid. With hydrogenchloride in ethanol, T= 20 °C , Reflux Wang, Bao-Lei; Shi, Yan-Xia; Zhang, Shu-Jun; Ma, Yi; Wang, Hong-Xue; Zhang, Li-Yuan; Wei, Wei; Liu, XingHai; Li, Yong-Hong; Li, Zheng-Ming; Li, Bao-Ju; European Journal of Medicinal Chemistry; vol. 117; (2016); p. 167 - 178 View in Reaxys 38 %

in toluene, Time= 2h, T= 85 °C Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys With ethanol Baltzly et al.; Journal of the American Chemical Society; vol. 66; (1944); p. 263,265 View in Reaxys in ethanol, Heating He, Feng-Qi; Liu, Xing-Hai; Wang, Bao-Lei; Li, Zheng-Ming; Journal of Chemical Research; nb. 12; (2006); p. 809 - 811 View in Reaxys With N-ethyl-N,N-diisopropylamine in dichloromethane Xie, Yun Feng; Lake, Kirk; Ligsay, Kathleen; Komandla, Mallareddy; Sircar, Ila; Nagarajan, Gobi; Li, Jian; Xu, Kui; Parise, Jason; Schneider, Lisa; Huang, Ding; Liu, Juping; Dines, Kevin; Sakurai, Naoki; Barbosa, Miguel; Jack, Rick; Bioorganic and Medicinal Chemistry Letters; vol. 17; nb. 12; (2007); p. 3367 - 3372 View in Reaxys With triethylamine in ethanol, Time= 12h, T= 55 °C Cai, Mingyi; Li, Zhong; Fan, Feng; Huang, Qingchun; Shao, Xusheng; Song, Gonghua; Journal of Agricultural and Food Chemistry; vol. 58; nb. 5; (2010); p. 2624 - 2629 View in Reaxys in ethanol Bali, Alka; Bhalla, Abhishek; Bala, Suman; Kumar, Rajesh; Letters in Drug Design and Discovery; vol. 9; nb. 2; (2012); p. 218 - 224 View in Reaxys in acetonitrile, T= 20 °C Ren, Yu; Zhang, Hui Zhen; Zhang, Shao Lin; Luo, Yun Lei; Zhang, Ling; Zhou, Cheng He; Geng, Rong Xia; Journal of Chemical Sciences; vol. 127; nb. 12; (2015); p. 2251 - 2260 View in Reaxys The preparation of 1-benzylpiperazine General procedure: A 500 mL round-bottom flask was charged with38.7 g (0.45 mol)anhydrous piperazine, dissolved in 240 mL freshly distilled THF.The solution was heated to reflux. Once the piperazine (2) was fully dissolved, 9.5 g (0.075 mol)of benzyl chloride was added dropwise over 5 min. A whitesediment was immediately observed. The reaction mixture was then refluxed for 3h with stirring until no benzylchloride remained, as assessed by TLC. Thestirring mixture was allowed to cool, and then was filtered. The solids werewashed with 50 mL of THF, followed by 50 mL of EtOAc. The filtrate and the washer liquid were pooled and concentratedto 10percent of its original volume in a rotary evaporator. The concentrate waspoured into a separating funnel containing 50 mL of deionized water with 5percent KOH(pH>12). The aqueous layer was maintained at pH>12 during extraction withthree 50 mL portions of CH2Cl2 followed by two 50 mLportions of EtOAc. The organic layers were pooled, concentrated, and purifiedby flash

5/195

2016-06-04 14:03:19

chromatography on SiO2 (gradient, 1:4 to 2:1 MeOH:EtOAc) toobtain 11.22 g (85percent) of 1-benzylpiperazine as a pale yellowliquid. in tetrahydrofuran, Time= 3h, Reflux Si, Weijie; Zhang, Tao; Zhang, Lanxiang; Mei, Xiangdong; Dong, Mengya; Zhang, Kaixin; Ning, Jun; Bioorganic and Medicinal Chemistry Letters; vol. 26; nb. 9; (2016); p. 2380 - 2382 View in Reaxys

H N Cl

N H

Rx-ID: 1495652 View in Reaxys 3/493 Yield 91 %

Conditions & References in tetrahydrofuran, Time= 2.5h, Reflux Peterson, Quinn P.; Hsu, Danny C.; Goode, David R.; Novotny, Chris J.; Totten, Ryan K.; Hergenrother, Paul J.; Journal of Medicinal Chemistry; vol. 52; nb. 18; (2009); p. 5721 - 5731 View in Reaxys

90 %

2; 1 in tetrahydrofuran, Heating / reflux, Product distribution / selectivity Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS; WO2006/128173; (2006); (A2) English View in Reaxys

90 %

2 in tetrahydrofuran, Time= 2.5h, Reflux Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS; HERGENROTHER, Paul Joseph; PETERSON, Quinn Patrick; HSU, Danny Chung; WEST, Diana C.; FAN, Timothy M.; NOVOTNY, Chris J.; WO2010/91382; (2010); (A1) English View in Reaxys

85.8 %

5.1.3. General procedure for the synthesis of various substituted benzylpiperazines (3a-s) General procedure: Anhydrous piperazine (6.89 g, 80 mmol) was dissolved in 40 mL of freshly distilled THF. Once the piperazine was fully dissolved, 2.303 mL (20 mmol) of benzyl chloride was added dropwise. The reaction mixture was then refluxed for about 4 h until benzyl chloride disappeared, as assessed by TLC. The stirring mixture was allowed to cool, and then filtered. The filtrate was concentrated in a rotary evaporator and then diluted with EtOAc (100 mL) and water (50 mL), which was then made basic (pH>12) with a saturated 1 N NaOH aqueous solution and separated. The organic phase was washed with water (4 .x. 100 mL), brine (2 .x. 100 mL), dried over Na2SO4 and concentrated to yield an oil. Column chromatography (PE/EtOAc = 1:1 to EtOAc/MeOH = 5:1) afforded a pale yellow liquid. in tetrahydrofuran, Time= 4h, Reflux Zhang, Cunlong; Tan, Chunyan; Zu, Xuyu; Zhai, Xin; Liu, Feng; Chu, Bizhu; Ma, Xiaohua; Chen, Yuzong; Gong, Ping; Jiang, Yuyang; European Journal of Medicinal Chemistry; vol. 46; nb. 4; (2011); p. 1404 - 1414 View in Reaxys

85 %

The preparation of 1-benzylpiperazine A 500 mL round-bottom flask was charged with38.7 g (0.45 mol)anhydrous piperazine, dissolved in 240 mL freshly distilled THF.The solution was heated to reflux. Once the piperazine (2) was fully dissolved, 9.5 g (0.075 mol)of benzyl chloride was added dropwise over 5 min. A whitesediment was immediately observed. The reaction mixture was then refluxed for 3h with stirring until no benzylchloride remained, as assessed by TLC. Thestirring mixture was allowed to cool, and then was filtered. The solids werewashed with 50 mL of THF, followed by 50 mL of EtOAc. The filtrate and the washer liquid were pooled and concentratedto 10percent of its original volume in a rotary evaporator. The concentrate waspoured into a separating funnel containing 50 mL of deionized water with 5percent

6/195

2016-06-04 14:03:19

KOH(pH>12). The aqueous layer was maintained at pH>12 during extraction withthree 50 mL portions of CH2Cl2 followed by two 50 mLportions of EtOAc. The organic layers were pooled, concentrated, and purifiedby flash chromatography on SiO2 (gradient, 1:4 to 2:1 MeOH:EtOAc) toobtain 11.22 g (85percent) of 1-benzylpiperazine as a pale yellowliquid. The NMR data of compound 1-benzylpiperazine(3a)1H NMR(300 MHz), CDCl3 ) δ: 7.23-7.31 (m,5H), 3.48 (s, 2H), 2.87 (t, 4H,J=4.8 Hz),2.40 (br, 4H), 1.90 (s, 1H). IR 3903, 3304, 3027, 2939, 2811,1958, 1659, 1454, 1319, 1074, 1029, 915, 797, 742, 613 cm-1. in tetrahydrofuran, Time= 3h, Reflux Si, Weijie; Zhang, Tao; Zhang, Lanxiang; Mei, Xiangdong; Dong, Mengya; Zhang, Kaixin; Ning, Jun; Bioorganic and Medicinal Chemistry Letters; vol. 26; nb. 9; (2016); p. 2380 - 2382 View in Reaxys 82 %

in tetrahydrofuran, Reflux Zhu, Jieming; Zhang, Wei; Zhang, Laijun; Liu, Jun; Zheng, Ji; Hu, Jinbo; Journal of Organic Chemistry; vol. 75; nb. 16; (2010); p. 5505 - 5512 View in Reaxys

60 %

With sodium hydrogencarbonate in water, T= 55 - 60 °C Petrova, L. S.; Davidenkov, L. R.; Medved', S. S.; J. Appl. Chem. USSR (Engl. Transl.); vol. 53; nb. 1; (1980); p. 199 - 203,174 - 178 View in Reaxys

58 %

Synthesis of the intermediates 4-(substituted)benzylpiperazine 1 General procedure: Referring to the literature23 method, to a solution of anhydrouspiperazine (50 mmol) in 95percent ethanol (20 mL) was added 36percenthydrochloric acid (25 mmol). The mixture was stirred underrefluxing and substituted benzyl chlorine (25 mmol) addeddropwise over 5 min. The mixture was refluxed for 4–8 h withthin layer chromatography (TLC) monitoring, then left standingovernight at room temperature. The solid precipitate wasfiltered and washed with ethanol, the filtrate was evaporated invacuum and the residue was dissolved in saturated K2CO3 aq.(30 mL), extracted with chloroform (5 £ 8 mL). The chloroformsolution was dried with anhydrous Na2SO4 and evaporatedin vacuum. The residue was then distilled under reducedpressure to give compound 1 as a colorless liquid.1a: yield 58percent, bp 131–134C/10 mmHg; 1b: yield 36percent, bp147–150C/6 mmHg. With hydrogenchloride in ethanol, Reflux Wang, Bao-Lei; Zhan, Yi-Zhou; Zhang, Li-Yuan; Zhang, Yan; Zhang, Xiao; Li, Zheng-Ming; Phosphorus, Sulfur and Silicon and the Related Elements; vol. 191; nb. 1; (2016); p. 48 - 54 View in Reaxys

58 %

7/195

2016-06-04 14:03:19

Wang, Bao-Lei; Shi, Yan-Xia; Zhang, Shu-Jun; Ma, Yi; Wang, Hong-Xue; Zhang, Li-Yuan; Wei, Wei; Liu, XingHai; Li, Yong-Hong; Li, Zheng-Ming; Li, Bao-Ju; European Journal of Medicinal Chemistry; vol. 117; (2016); p. 167 - 178 View in Reaxys in 1,4-dioxane, Time= 7h, Heating Suzuki, Tsuneji; Fukazawa, Nobuyuki; San-nohe, Kunio; Sato, Wakao; Yano, Osamu; Tsuruo, Takashi; Journal of Medicinal Chemistry; vol. 40; nb. 13; (1997); p. 2047 - 2052 View in Reaxys in ethanol, Heating He, Feng-Qi; Liu, Xing-Hai; Wang, Bao-Lei; Li, Zheng-Ming; Journal of Chemical Research; nb. 12; (2006); p. 809 - 811 View in Reaxys 63 %Chromat.

in water, Time= 0.5h, T= 160 °C , p= 5171.62Torr , Flow reactor Borukhova, Svetlana; Nol, Timothy; Hessel, Volker; ChemSusChem; vol. 9; nb. 1; (2016); p. 67 - 74 View in Reaxys

H N

N H

Cl N

Cl N H

Rx-ID: 16520 View in Reaxys 4/493 Yield 81 %

66.7 %

in ethanol, T= 20 °C Bali, Alka; Reddy, A. C. Dinesh Kumar; Medicinal Chemistry Research; vol. 22; nb. 1; (2013); p. 382 - 391 View in Reaxys

64 %

in toluene, Time= 2h, T= 85 °C Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys With ethanol

8/195

2016-06-04 14:03:19

Baltzly et al.; Journal of the American Chemical Society; vol. 77; (1955); p. 4809 View in Reaxys With triethylamine in ethanol, Time= 12h, T= 55 °C Cai, Mingyi; Li, Zhong; Fan, Feng; Huang, Qingchun; Shao, Xusheng; Song, Gonghua; Journal of Agricultural and Food Chemistry; vol. 58; nb. 5; (2010); p. 2624 - 2629 View in Reaxys in ethanol Bali, Alka; Bhalla, Abhishek; Bala, Suman; Kumar, Rajesh; Letters in Drug Design and Discovery; vol. 9; nb. 2; (2012); p. 218 - 224 View in Reaxys in acetonitrile, T= 20 °C Ren, Yu; Zhang, Hui Zhen; Zhang, Shao Lin; Luo, Yun Lei; Zhang, Ling; Zhou, Cheng He; Geng, Rong Xia; Journal of Chemical Sciences; vol. 127; nb. 12; (2015); p. 2251 - 2260 View in Reaxys

N H

Rx-ID: 5462527 View in Reaxys 5/493 Yield 70%

Conditions & References XVI : 2-(4'-p-Methoxybenzyl-piperazino)-5 -oxo-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine-6-carboxylic acid. SPC23 EXAMPLE XVI 2-(4'-p-Methoxybenzyl-piperazino)-5 -oxo-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine-6-carboxylic acid. SPC23 By condensing 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine with 1-p-methoxybenzyl-piperazine, following the procedure described in Example VII, 2-(p-methoxybenzyl-piperazino)-5-oxo-6-carbethoxy-8ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine is obtained and is purified by recrystallisation from a mixture of isopropyl ether (1 volume) and benzene (1 volume); melting point 136°C; yield 70percent. Analysis for C24 H29 N5 O4 (molecular weight 451.51): Calculated percent: C, 63.84; H, 6.47; N, 15.51. Found percent: C, 63.75; H, 6.41; N, 15.31. Patent; Laboratoire Roger Bellon; US3950338; (1976); (A1) English View in Reaxys Pesson et al.; European Journal of Medicinal Chemistry; vol. 10; (1975); p. 567,570 View in Reaxys Mndzhoyan et al.; Armyanskii Khimicheskii Zhurnal; vol. 21; nb. 7; (1968); p. 603,604-614; ; vol. 70; nb. 96754t; (1969) View in Reaxys Ikeda; Yakugaku Zasshi; vol. 89; (1969); p. 677,685; ; vol. 71; nb. 61339; (1969) View in Reaxys Vejdelek et al.; Collection of Czechoslovak Chemical Communications; vol. 39; (1974); p. 2276,2277,2280 View in Reaxys Patent; US Vit. Pharm.; BE617599; (1962); ; vol. 59; nb. 646; (1963) View in Reaxys 1 : Synthesis of the Compounds of the Invention. 1-(4-Methoxybenzyl) piperazine. A solution of 1.077(12.5mM) of piperazine in 20 mL of absolute ethanol was prepared in a 125-mL of Erlenmeyer flask, and was warmed in a bath at 65° C. 1.988 g(12.5 mM) of piperazine dihydrochloride hydrate was dissolved in the solution, by swirling. Under continuous heat at 65° C. 1.958(12.5 mM) of 4-methoxybenzyl chloride was added with vigorous stirring, for five minutes. The separation of white needles commenced almost immediately.

9/195

2016-06-04 14:03:19

After the solution had been stirred for an additional 25 minutes at 65° C., it was cooled, and kept in an ice bath for about 30 minutes. The crystals of piperazine dihydrochloride hydrate were collected by suction filtration, washed with three 5 mL portions of ice-cold absolute ethanol, then dried. Recovery of the dihydrochloride was 1.748 g(88percent). Filtrate from this solution was evaporated to dryness at reduced pressure, and crude 1-(4-methoxybenzyl)-4-piperazinium chloride remained as a residue. In order to remove any piperazine dihydrochloride, the material was heated in about 20 ml of absolute ethanol to produce crystals which were rapidly filtered. Concentration of the filtrate followed by cooling produced 2.629 g(87percent) of 1-(4-methoxybenzyl)-4-piperazinium chloride in the form of a white crystal having a melting point of 154-157° C. A solution of this salt in 20 ml of water was made alkaline (pH>12) with about 20 ml of 5N sodium hydroxide solution, extracted with CH2Cl2 and then dried over MgSO4 for 30 minutes. Filtration, followed by solvent evaporation at reduced pressure, produced a white solid which was crystallized from petroleum ether to give (1.393 g, 54percent) of the product having a melting point of 99-101° C. and the following specifications: IR(KBr) 3392 cm-1, 2943 cm-1, 1509 cm-1, 1301 cm-1, 1034 cm-1, 991 cm-1. NMR(CDCl3)2.12(s,1H), 2.23-2.46(m,4H), 2.53-2.98(m,4H), 3.40(s,2H), 3.73(s,3H), 6.73-7.29(m,4H). Patent; Massachusetts College of Pharmacy; US2002/115655; (2002); (A1) English View in Reaxys 6 : 1-[(4-Methoxyphenyl)methyl]piperazine A 377 g (1.35 mole) amount of the preceding product comprised of 307.5 g (1.10 moles) of crude product and 69.5 g (0.25 moles) of purified product was refluxed with 435 ml of 12N hydrochloric acid for 6 hours then was mixed with an equal volume of ice and allowed to stand for 16 hours in the cold. The mixture was made basic with 535 ml of 10N sodium hydroxide and extracted with 200 ml of diethyl ether. The aqueous layer was removed and the etheral layer was extracted with 100 ml of water. This bottom layer (aqueous) was mixed with sodium carbonate then extracted with 150 ml of dichlorothane. The dichloromethane extract was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo and gave an oil. The oil was Kugelrohr distilled bp 94° C./0.5 mm of mercury and gave 22.4 of the desired product as an oil. Patent; American Cyanamid Company; US4562189; (1985); (A1) English View in Reaxys

H N O Cl

N H

Rx-ID: 9177090 View in Reaxys 6/493 Yield 90 %

Conditions & References 11 in tetrahydrofuran, Time= 2.5h, Heating / reflux Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS; WO2008/134474; (2008); (A2) English View in Reaxys

88 %

in tetrahydrofuran, Inert atmosphere, Reflux Peterson, Quinn P.; Hsu, Danny C.; Goode, David R.; Novotny, Chris J.; Totten, Ryan K.; Hergenrother, Paul J.; Journal of Medicinal Chemistry; vol. 52; nb. 18; (2009); p. 5721 - 5731 View in Reaxys

71.1 %

10/195

2016-06-04 14:03:19

mL) and water (50 mL), which was then made basic (pH>12) with a saturated 1 N NaOH aqueous solution and separated. The organic phase was washed with water (4 .x. 100 mL), brine (2 .x. 100 mL), dried over Na2SO4 and concentrated to yield an oil. Column chromatography (PE/EtOAc = 1:1 to EtOAc/MeOH = 5:1) afforded a pale yellow liquid. in tetrahydrofuran, Time= 4h, Reflux Zhang, Cunlong; Tan, Chunyan; Zu, Xuyu; Zhai, Xin; Liu, Feng; Chu, Bizhu; Ma, Xiaohua; Chen, Yuzong; Gong, Ping; Jiang, Yuyang; European Journal of Medicinal Chemistry; vol. 46; nb. 4; (2011); p. 1404 - 1414 View in Reaxys 37 %

in toluene, Time= 2h, T= 85 °C Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys 4 : Preparation of 1-(4-methoxyphenylmethyl)piperazine (Intermediate 15) EXAMPLE 4 Preparation of 1-(4-methoxyphenylmethyl)piperazine (Intermediate 15) 4-Methoxyphenylmethylchloride (3.9 g; 25 mmoles) (Aldrich) was added to a solution of piperazine (21.5 g; 250 mmoles), triethylamine (3 g; 30 mmoles) and potassium iodide (4.1 g; 25 mmoles) in DMF (150 ml). After 5 hours the reaction mixture was poured into water and extracted 3 times with ethyl ether. The aqueous phase was concentrated to small volume by evaporating the solvents under reduced pressure and extracted again 3 times with ethyl ether. The organic phases were collected to the previous ones, dried on Na2 SO4 and evaporated to dryness under reduced pressure. The crude was purified by chromatography (eluent CH2 Cl2:CH3 OH:ammonia 30percent=90:10:1) obtaining Intermediate 15 (4.4 g) as an oil. 1 H-NMR (200 MHz; CDCl ): δ(ppm): 1.74 (s, 1H); 2.36 (m, 4H); 2.84 (m, 4H); 3.40 (s, 2H); 3.77 (s, 3H); 6.82 (m, 3 2H); 7.20 (m, 2H). Mass: 207 [M+1]. With potassium iodide, triethylamine in N,N-dimethyl-formamide Patent; Zambon Group; US5674909; (1997); (A1) English View in Reaxys 4 : Preparation of 1-(4-methoxyphenylmethyl)piperazine (Intermediate 15) Example 4 Preparation of 1-(4-methoxyphenylmethyl)piperazine (Intermediate 15) 4-Methoxyphenylmethylchloride (3.9 g; 25 mmoles) (Aldrich) was added to a solution of piperazine (21.5 g; 250 mmoles), triethylamine (3 g; 30 mmoles) and potassium iodide (4.1 g; 25 mmoles) in DMF (150 ml). After 5 hours the reaction mixture was poured into water and extracted 3 times with ethyl ether. The aqueous phase was concentrated to small volume by evaporating the solvents under reduced pressure and extracted again 3 times with ethyl ether. The organic phases were collected to the previous ones, dried on Na2SO4 and evaporated to dryness under reduced pressure. The crude was purified by chromatography (eluent CH2Cl2:CH3OH:ammonia 30percent=90:10:1) obtaining Intermediate 15 (4.4 g) as an oil. 1H-NMR (200 MHz; CDCl ): δ (ppm): 1.74 (s, 1H); 2.36 (m, 4H); 2.84 (m, 4H); 3.40 (s, 2H); 3.77 (s, 3H); 6.82 (m, 3 2H); 7.20 (m, 2H). Mass: 207 [M+1]. With potassium iodide, triethylamine in N,N-dimethyl-formamide Patent; ZAMBON GROUP S.p.A.; EP781126; (2001); (B1) English View in Reaxys in acetonitrile, T= 20 °C Ren, Yu; Zhang, Hui Zhen; Zhang, Shao Lin; Luo, Yun Lei; Zhang, Ling; Zhou, Cheng He; Geng, Rong Xia; Journal of Chemical Sciences; vol. 127; nb. 12; (2015); p. 2251 - 2260

11/195

2016-06-04 14:03:19

View in Reaxys The preparation of 1-benzylpiperazine General procedure: A 500 mL round-bottom flask was charged with38.7 g (0.45 mol)anhydrous piperazine, dissolved in 240 mL freshly distilled THF.The solution was heated to reflux. Once the piperazine (2) was fully dissolved, 9.5 g (0.075 mol)of benzyl chloride was added dropwise over 5 min. A whitesediment was immediately observed. The reaction mixture was then refluxed for 3h with stirring until no benzylchloride remained, as assessed by TLC. Thestirring mixture was allowed to cool, and then was filtered. The solids werewashed with 50 mL of THF, followed by 50 mL of EtOAc. The filtrate and the washer liquid were pooled and concentratedto 10percent of its original volume in a rotary evaporator. The concentrate waspoured into a separating funnel containing 50 mL of deionized water with 5percent KOH(pH>12). The aqueous layer was maintained at pH>12 during extraction withthree 50 mL portions of CH2Cl2 followed by two 50 mLportions of EtOAc. The organic layers were pooled, concentrated, and purifiedby flash chromatography on SiO2 (gradient, 1:4 to 2:1 MeOH:EtOAc) toobtain 11.22 g (85percent) of 1-benzylpiperazine as a pale yellowliquid. in tetrahydrofuran, Time= 3h, Reflux Si, Weijie; Zhang, Tao; Zhang, Lanxiang; Mei, Xiangdong; Dong, Mengya; Zhang, Kaixin; Ning, Jun; Bioorganic and Medicinal Chemistry Letters; vol. 26; nb. 9; (2016); p. 2380 - 2382 View in Reaxys

H N

N H

Cl Cl

N Cl

N H

Rx-ID: 10455658 View in Reaxys 7/493 Yield 97 %

36 %

12/195

2016-06-04 14:03:19

aq.(30 mL), extracted with chloroform (5 £ 8 mL). The chloroformsolution was dried with anhydrous Na2SO4 and evaporatedin vacuum. The residue was then distilled under reducedpressure to give compound 1 as a colorless liquid.1a: yield 58percent, bp 131–134C/10 mmHg; 1b: yield 36percent, bp147–150C/6 mmHg. With hydrogenchloride in ethanol, Reflux Wang, Bao-Lei; Zhan, Yi-Zhou; Zhang, Li-Yuan; Zhang, Yan; Zhang, Xiao; Li, Zheng-Ming; Phosphorus, Sulfur and Silicon and the Related Elements; vol. 191; nb. 1; (2016); p. 48 - 54 View in Reaxys 36 %

4.2.2. Synthetic procedure of intermediates 4-(substituted)benzylpiperazine (15a-c) General procedure: The procedures are similar to that described previously (32). Toa solution of anhydrous piperazine (50 mmol) in 20 mL 95percent ofethanol was added concentrated hydrochloric acid (25 mmol). Themixture was stirred under reflux, and substituted benzyl chlorine(25 mmol) was added dropwise for over 5 min. The mixture wasrefluxed for 4e8 h with TLC monitoring, then left to stand overnightat room temperature. The solid precipitated was filtered andwashed with ethanol, the filtrate was evaporated in vacuum, andthe residuewas dissolved in 30 mL of saturated K2CO3 aq., extractedwith chloroform (8 mL 5). The chloroform solution was driedwith anhydrous Na2SO4 and evaporated in vacuum. The residuewas then distilled under reduced pressure to give compound as acolorless liquid. With hydrogenchloride in ethanol, T= 20 °C , Reflux Wang, Bao-Lei; Shi, Yan-Xia; Zhang, Shu-Jun; Ma, Yi; Wang, Hong-Xue; Zhang, Li-Yuan; Wei, Wei; Liu, XingHai; Li, Yong-Hong; Li, Zheng-Ming; Li, Bao-Ju; European Journal of Medicinal Chemistry; vol. 117; (2016); p. 167 - 178 View in Reaxys in ethanol, Heating He, Feng-Qi; Liu, Xing-Hai; Wang, Bao-Lei; Li, Zheng-Ming; Journal of Chemical Research; nb. 12; (2006); p. 809 - 811 View in Reaxys With triethylamine in ethanol, Time= 12h, T= 55 °C Cai, Mingyi; Li, Zhong; Fan, Feng; Huang, Qingchun; Shao, Xusheng; Song, Gonghua; Journal of Agricultural and Food Chemistry; vol. 58; nb. 5; (2010); p. 2624 - 2629 View in Reaxys in acetonitrile, T= 20 °C Ren, Yu; Zhang, Hui Zhen; Zhang, Shao Lin; Luo, Yun Lei; Zhang, Ling; Zhou, Cheng He; Geng, Rong Xia; Journal of Chemical Sciences; vol. 127; nb. 12; (2015); p. 2251 - 2260 View in Reaxys

N H

Rx-ID: 5444518 View in Reaxys 8/493 Yield

Conditions & References Piperazin, o-Chlor-benzyl-halogenid, Erhitzen Ikeda; Yakugaku Zasshi; vol. 89; (1969); p. 677,685; ; vol. 71; nb. 61339; (1969) View in Reaxys Formylpiperazin, 2-Chlorbenzylchlorid Patent; Kyorin Pharm. Co., Ltd.; JP6829142; (1966); ; vol. 70; nb. 87853x; (1969) View in Reaxys 2-Chlorbenzylchlorid, 1) Formylpiperazin, EtN3, 2) Hydrolyse

13/195

2016-06-04 14:03:19

Patent; Kyorin Pharm. Co., Ltd.; JP1783067; (1965); ; vol. 68; nb. 114642v; (1968) View in Reaxys Piperazin, 2-Chlor-benzylchlorid Patent; U.S. Vit. Pharm.; BE617599; (1962); ; vol. 59; nb. 646; (1963) View in Reaxys N-Formyl-piperazin, 2-Chlor-benzylchlorid, (C2H5)3N Patent; Kerin Seijaku Kabusihi Kaisja; JP29142; (1968); Ref. Zh., Khim.; vol. 8; nb. N420; (1970) View in Reaxys 1-Formyl-4-(o-Chlor-benzyl)-piperazin, NaH Irikura; Masuzawa; Nishino; Kitagawa; Uchida; Ichinoseki; Ito; Journal of medicinal chemistry; vol. 11; nb. 4; (1968); p. 801 - 804 View in Reaxys Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 1-(3-bromobenzyl)piperazine; 1-(4-bromobenzyl)piperazine; 1-(4-bromo-2-fluorobenzyl)piperazine; 1-(4-tert-butylbenzyl)piperazine; 1-(2-chlorobenzyl)piperazine; 1-(3-chlorobenzyl)piperazine; 1-(4-chlorobenzyl)piperazine; 1-(2-chloro-benzyl)-piperazine hydrochloride; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys

N H

Rx-ID: 5450086 View in Reaxys 9/493 Yield 50%

Conditions & References 1 : Synthesis of the Compounds of the Invention. A solution of this salt was prepared in 15 mL of water and was mixed with about 40 mL of 5 N sodium hydroxide solution. The product was extracted with CH2Cl2 and dried over MgSO4 for 30 minute. The product was then filtered and the solvent evaporated at reduced pressure to give the 1-(4-Chlorobenzyl) piperazine (2.627 g, 50percent). NMR (CDCl3)2.4(s,1H), 2.5-83(m, 4H), 3.0-3.38(m, 4H), 3.45(s,2H),7.5-7.8(m, 4H). Patent; Massachusetts College of Pharmacy; US2002/115655; (2002); (A1) English View in Reaxys Pesson et al.; European Journal of Medicinal Chemistry; vol. 10; (1975); p. 567,570 View in Reaxys Patent; U.S. Vit. Pharm.; BE617599; (1962); ; vol. 59; nb. 646; (1963) View in Reaxys Ikeda; Yakugaku Zasshi; vol. 89; (1969); p. 677,685; ; vol. 71; nb. 61339; (1969) View in Reaxys Vejdelek et al.; Collection of Czechoslovak Chemical Communications; vol. 39; (1974); p. 2276,2277,2280 View in Reaxys

14/195

2016-06-04 14:03:19

4.B : Step B Step B 1-(4-Chlorobenzyl)-piperazine To a solution of the foregoing protected piperazine (3 g, 9.7 mmol) in dichloromethane (30 ml) was added trifluoroacetic acid (7.7 ml, 97 mmol). The solution was stirred at ambient temperature overnight, evaporated and the residue partitioned between a 10percent solution of potassium carbonate in water (50 ml) and ethyl acetate (50 ml). The organic layer was decanted and the aqueous phase was extracted with ethyl acetate (3*50 ml). The combined organics were dried (sodium sulphate) and evaporated to give the title product as a low melting solid (2 g, 98percent). 1 H NMR (250 MHz, CDCl ) δ 2.46-2.62 (4H, m), 2.99-3.12 (4H, m), 3.51 (2H, s), 7.20-7.35 (4H, m). 3 Patent; Merck, Sharp and Dohme, Ltd.; US5684006; (1997); (A1) English View in Reaxys Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 1-(4-bromo-2-fluorobenzyl)piperazine; 1-(4-tert-butylbenzyl)piperazine; 1-(2-chlorobenzyl)piperazine; 1-(3-chlorobenzyl)piperazine; 1-(4-chlorobenzyl)piperazine; 1-(2-chloro-benzyl)-piperazine hydrochloride; 1-(4-chloro-benzyl)-piperazine hydrochloride; 1-(2-chloro-4-fluoro-benzyl)-piperazine; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys O N

H N

O N

N H

Rx-ID: 8665059 View in Reaxys 10/493 Yield 92 %

Conditions & References With potassium carbonate in ethanol, Time= 1h, T= 0 °C Zhao, Yan-Fang; Liu, Zi-Jian; Zhai, Xin; Ge, Dan-Dan; Huang, Qiang; Gong, Ping; Chinese Chemical Letters; vol. 24; nb. 5; (2013); p. 386 - 388 View in Reaxys

22 %

General procedure for the synthesis of 2a–2d General procedure: Anhydrous piperazine (18.0 g, 0.21 mol) was dissolved in chloroform (60 mL). Benzyl bromide 1a–1d (0.05 mol) in chloroform (30 mL) was added dropwise to the solution at 0 °C. The reaction mixture was stirred for about 6 h at room temperature. Then, the mixture was washed with 5percent K2CO3 solution (80 mL × 2) and water (80 mL × 4). The organic layer was dried over anhydrous Na2SO4. The filtrate was evaporated in vacuo and the residue was recrystallized from n-hexane to give the desired products 2a–2d. in chloroform, Time= 6h, T= 0 - 20 °C Zhou, An; Wu, Hongfei; Pan, Jian; Wang, Xuncui; Li, Jiaming; Wu, Zeyu; Hui, Ailing; Molecules; vol. 20; nb. 1; (2015); p. 1304 - 1318 View in Reaxys in ethanol, Time= 1h, Heating

15/195

2016-06-04 14:03:19

Dannhardt, Gerd; Gruchalla, Markus V.; Kohl, Beate K.; Parsons; Archiv der Pharmazie; vol. 333; nb. 8; (2000); p. 267 - 274 View in Reaxys in ethanol, Isopropyl acetate, Time= 0.5h, T= 20 °C Kuethe, Jeffrey T.; Wong, Audrey; Davies, Ian W.; Journal of Organic Chemistry; vol. 69; nb. 22; (2004); p. 7752 7754 View in Reaxys in ethanol, Isopropyl acetate, Time= 0.5h, T= 20 °C Kuethe, Jeffrey T.; Wong, Audrey; Qu, Chuanxing; Smitrovich, Jacqueline; Davies, Ian W.; Hughes, David L.; Journal of Organic Chemistry; vol. 70; nb. 7; (2005); p. 2555 - 2567 View in Reaxys Koufaki, Maria; Kiziridi, Christina; Papazafiri, Panagiota; Vassilopoulos, Athanasios; Varro, Andras; Nagy, Zsolt; Farkas, Attila; Makriyannis, Alexandros; Bioorganic and Medicinal Chemistry; vol. 14; nb. 19; (2006); p. 6666 - 6678 View in Reaxys General procedure for the preparation of compounds 11-16, 18-25 and 28 General procedure: Piperazine (3.0 equiv.) and K2CO3 (1.0 equiv) were mixed in THF (50 mL) under reflux condition. Subsequently, 68-82 (1.0 equiv) were added, and refluxing was continued for another three hours.The reaction mixture was concentrated in vacuo and partitioned between water and DCM. Theorganic phase was washed with brine and dried over Na2SO4. Products were purified by flash chromatography (DCM : MeOH = 8:1). With potassium carbonate in tetrahydrofuran, Time= 3h, Reflux Obreque-Balboa, Jos Esteban; Sun, Qiu; Bernhardt, Günther; König, Burkhard; Buschauer, Armin; European Journal of Medicinal Chemistry; vol. 109; (2016); p. 124 - 133 View in Reaxys

O HO

O N

N HO

NH O

N H

Rx-ID: 23997443 View in Reaxys 11/493 Yield

Conditions & References 1.1 : 8 Step 1: 4-Piperazin-1-ylmethyl-benzoic acid (4c) To a solution of 4-bromomethyl-benzoic acid (4a) and 1-t-butoxycarbonyl piperazine(5.95 g, 26.84 mmol) (4b) in ethanol (80 mL) was added potassium carbonate (3.71 g, 26.84 mmol). The resulting reaction mixture was refluxed for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue from the filtrate was dissolved in 25percent sodium hydroxide. This aqueous solution was washed with ether (3*50 mL) and cooled. This upon acidification with conc. HCl to pH 2.00 gave a fluffy white solid which was cooled in ice for 30 minutes and filtered. The white solid was washed carefully with ice-water (3*10 mL) and dried in vacuo for 24 h over P2O5. The solid was pure enough to be used as such, m.p, 253° C. (N-Boc.derivative). 1H NMR (300 MHz, DMSO-d6) δ (ppm)): 1.33 (s, 9H), 2.29 and 3.39 (each bs, each 4H), 3.49 (s, 3H), 7.27 (d, J=8.12 Hz, 2H), 7.81 (d, J=8.1 Hz, 2H). With potassium carbonate in sodium hydroxide, ethanol Patent; ARIAD PHARMACEUTICALS,INC.; US2003/100572; (2003); (A1) English View in Reaxys 1.1 : 8

16/195

2016-06-04 14:03:19

Step 1: 4-Piperazin-1-ylmethyl-benzoic Acid (4c) To a solution of 4-bromomethyl-benzoic acid (4a) and 1-t-butoxycarbonyl piperazine(5.95 g, 26.84 mmol) (4b) in ethanol (80 mL) was added potassium carbonate (3.71 g, 26.84 mmol). The resulting reaction mixture was refluxed for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue from the filtrate was dissolved in 25percent sodium hydroxide. This aqueous solution was washed with ether (3*50 mL) and cooled. This upon acidification with conc. HCl to pH 2.00 gave a fluffy white solid which was cooled in ice for 30 minutes and filtered. The white solid was washed carefully with ice-water (3*10 mL) and dried in vacuo for 24 h over P2O5. The solid was pure enough to be used as such, m.p, 253° C. (N-Boc.derivative). 1H NMR (300 MHz, DMSO-d ) δ (ppm)): 1.33 (s, 9H), 2.29 and 3.39 (each bs, each 4H), 3.49 (s, 3H), 7.27 (d, 6 J=8.12 Hz, 2H), 7.81(d, J=8.1 Hz, 2H). With potassium carbonate in sodium hydroxide, ethanol Patent; Shakespeare, William C.; Sawyer, Tomi K.; Metcalf III, Chester A.; Wang, Yihan; Bohacek, Regine; Sundaramoorthi, Rajeswari; US2003/114467; (2003); (A1) English View in Reaxys 1.8.1 : 8) Step 1: 4-Piperazin-1-ylmethyl-benzoic acid (4c) To a solution of 4-bromomethyl-benzoic acid (4a) and 1-t-butoxycarbonyl piperazine(5.95 g, 26.84 mmol) (4b) in ethanol (80 mL) was added potassium carbonate (3.71 g, 26.84 mmol). The resulting reaction mixture was refluxed for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue from the filtrate was dissolved in 25percent sodium hydroxide. This aqueous solution was washed with ether (3*50 mL) and cooled. This upon acidification with conc. HCl to pH 2.00 gave a fluffy white solid which was cooled in ice for 30 minutes and filtered. The white solid was washed carefully with ice-water (3*10 mL) and dried in vacuo for 24 h over P2O5. The solid was pure enough to be used as such, m.p, 253° C. (N-Boc.derivative). 1H NMR (300 MHz, DMSO-d6) δ (ppm)): 1.33 (s, 9H), 2.29 and 3.39 (each bs, each 4H), 3.49 (s, 3H), 7.27 (d, J=8.12 Hz, 2H), 7.81(d, J=8.1 Hz, 2H). With potassium carbonate in sodium hydroxide, ethanol Patent; Metcalf III, Chester A.; Shakespeare, William C.; Sawyer, Tomi K.; Wang, Yihan; Bohacek, Regine; US2003/114486; (2003); (A1) English View in Reaxys 1.8.1 : 8) Step 1: 4-Piperazin-1-ylmethyl-benzoic acid (4c) To a solution of 4-bromomethyl-benzoic acid (4a) and 1-t-butoxycarbonyl piperazine(5.95 g, 26.84 mmol) (4b) in ethanol (80 mL) was added potassium carbonate (3.71 g, 26.84 mmol). The resulting reaction mixture was refluxed for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue from the filtrate was dissolved in 25percent sodium hydroxide. This aqueous solution was washed with ether (3*50 mL) and cooled. This upon acidification with conc. HCl to pH 2.00 gave a fluffy white solid which was cooled in ice for 30 minutes and filtered. The white solid was washed carefully with ice-water (3*10 mL) and dried in vacuo for 24 h over P2O5. The solid was pure enough to be used as such, m.p, 253° C. (N-Boc.derivative). 1H NMR (300 MHz, DMSO-d6) δ(ppm)): 1.33 (s, 9H), 2.29 and 3.39 (each bs, each 4H), 3.49 (s, 3H), 7.27 (d, J=8.12 Hz, 2H), 7.81(d, J=8.1 Hz, 2H). With potassium carbonate in sodium hydroxide, ethanol

17/195

2016-06-04 14:03:19

Patent; Shakespeare, William C.; Sawyer, Tomi K.; Metcalf III, Chester A.; Wang, Yihan; Bohacek, Regine; US2003/130234; (2003); (A1) English View in Reaxys 1 : 8) Step 1: 4-Piperazin-1-ylmethyl-benzoic acid (4c) To a solution of 4-bromomethyl-benzoic acid (4a) and 1-t-butoxycarbonyl piperazine(5.95 g, 26.84 mmol) (4b) in ethanol (80 mL) was added potassium carbonate (3.71 g, 26.84 mmol). The resulting reaction mixture was refluxed for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue from the filtrate was dissolved in 25percent sodium hydroxide. This aqueous solution was washed with ether (3*50 mL) and cooled. This upon acidification with conc. HCl to pH 2.00 gave a fluffy white solid which was cooled in ice for 30 minutes and filtered. The white solid was washed carefully with ice-water (3*10 mL) and dried in vacuo for 24 h over P2O5. The solid was pure enough to be used as such, m.p, 253° C. (N-Boc.derivative). 1H NMR (300 MHz, DMSO-d6) δ(ppm)): 1.33 (s, 9H), 2.29 and 3.39 (each bs, each 4H), 3.49 (s, 3H), 7.27 (d, J=8.12 Hz, 2H), 7.81(d, J=8.1 Hz, 2H). With potassium carbonate in sodium hydroxide, ethanol Patent; Metcalf III, Chester A.; Shakespeare, William C.; Sawyer, Tomi K.; Wang, Yihan; Bohacek, Regine; US2003/105115; (2003); (A1) English View in Reaxys 1:8 Step 1: 4-Piperazin-1-ylmethyl-benzoic Acid (4c) To a solution of 4-bromomethyl-benzoic acid (4a) and 1-t-butoxycarbonyl piperazine (5.95 g, 26.84 mmol) (4b) in ethanol (80 mL) was added potassium carbonate (3.71 g, 26.84 mmol). The resulting reaction mixture was refluxed for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue from the filtrate was dissolved in 25percent sodium hydroxide. This aqueous solution was washed with ether (3*50 mL) and cooled. This upon acidification with conc. HCl to pH 2.00 gave a fluffy white solid which was cooled in ice for 30 minutes and filtered. The white solid was washed carefully with ice-water (3*10 mL) and dried in vacuo for 24 h over P2O5. The solid was pure enough to be used as such, m.p, 253° C. (N-Boc.derivative). 1H NMR (300 MHz, DMSO-d6) δ (ppm)): 1.33 (s, 9H), 2.29 and 3.39 (each bs, each 4H), 3.49 (s, 3H), 7.27 (d, J=8.12 Hz, 2H), 7.81(d, J=8.1 Hz, 2H). With potassium carbonate in sodium hydroxide, ethanol Patent; Wang, Yihan; Metcalf III, Chester A.; Shakespeare, William C.; Sawyer, Tomi K.; Bohacek, Regine; US2003/105065; (2003); (A1) English View in Reaxys 4.8.1 : 8) Step 1: 4-Piperazin-1-ylmethyl-benzoic acid (4c) To a solution of 4-bromomethyl-benzoic acid (4a) and 1-t-butoxycarbonyl piperazine(5.95 g, 26.84 mmol) (4b) in ethanol (80 mL) was added potassium carbonate (3.71 g, 26.84 mmol). The resulting reaction mixture was refluxed for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue from the filtrate was dissolved in 25percent sodium hydroxide. This aqueous solution was washed with ether (3*50 mL) and cooled. This upon acidification with conc. HCl to pH 2.00 gave a fluffy white solid which was cooled in ice for 30 minutes and filtered. The white solid was washed carefully with ice-water (3*10 mL) and dried in vacuo for 24 h over P2O5. The solid was pure enough to be used as such, m.p, 253° C. (N-Boc.derivative). 1H NMR (300 MHz, DMSO-d6) δ(ppm)): 1.33 (s, 9H), 2.29 and 3.39 (each bs, each 4H), 3.49 (s, 3H), 7.27 (d, J=8.12 Hz, 2H), 7.81(d, J=8.1 Hz, 2H).

18/195

2016-06-04 14:03:19

With potassium carbonate in sodium hydroxide, ethanol Patent; Wang, Yihan; Metcalf III, Chester A.; Shakespeare, William C.; Sawyer, Tomi K.; Bohacek, Regine; US2003/100573; (2003); (A1) English View in Reaxys

F H N

F Cl

N H

Rx-ID: 9177101 View in Reaxys 12/493 Yield 88 %

88 %

74 %

44 %

in toluene, Time= 2h, T= 85 °C Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

29%.

P.19 : 1-(p-Fluorobenzyl)piperazine STR59 PREPARATION EXAMPLE 19 1-(p-Fluorobenzyl)piperazine STR59 To a solution of piperazine (86 g, 1.00 mol) in ethanol (500 ml) was added under ice-cooling a solution of p-fluorobenzyl chloride (12 ml, 0.77 mol) in ethanol (200 ml) and the mixture was stirred at room temperature for 12 hours. After the so separated substance was filtered off, the filtrate was distilled off under reduced pressure. The residue was mixed with 45percent sodium hydroxide (200 ml) and extracted with diethyl ether (400 ml*3). The ether layer was dried over potassium hydroxide and distilled off under reduced pressure. The oily substance thus obtained was distilled under reduced pressure to give 56.1 g of the title compound as colorless crystals. Yield=29percent. b.p. 293° C. 1 H-NMR(CDCl )δ2.39(bs,4H), 2.88(t,J=5 Hz,4H), 3.45(s,2H), 6.99(t,J=8 Hz,2H), 7.28(dd,J=5 Hz,8 Hz,2H) 3

19/195

2016-06-04 14:03:19

With sodium hydroxide in ethanol Patent; Nisshin Flour Milling Co., Ltd.; US5736550; (1998); (A1) English View in Reaxys in acetonitrile, T= 20 °C Ren, Yu; Zhang, Hui Zhen; Zhang, Shao Lin; Luo, Yun Lei; Zhang, Ling; Zhou, Cheng He; Geng, Rong Xia; Journal of Chemical Sciences; vol. 127; nb. 12; (2015); p. 2251 - 2260 View in Reaxys

O N

N H

Rx-ID: 5019256 View in Reaxys 13/493 Yield

Conditions & References With trifluoroacetic acid in dichloromethane, Ambient temperature Bourrain, Sylvie; Collins, Ian; Neduvelil, Joseph G.; Rowley, Michael; Leeson, Paul D.; Patel, Smita; Patel, Shil; Emms, Frances; Marwood, Rosemarie; Chapman, Kerry L.; Fletcher, Alan E.; Showell, Graham A.; Bioorganic and Medicinal Chemistry; vol. 6; nb. 10; (1998); p. 1731 - 1743 View in Reaxys With trifluoroacetic acid, Time= 0.5h, T= 0 °C Gitto, Rosaria; De Luca, Laura; Ferro, Stefania; De Grazia, Sara; Di Giorgio, Rosa Maria; Festa, Filomena; De Luca, Grazia; Journal of Heterocyclic Chemistry; vol. 47; nb. 1; (2010); p. 54 - 62 View in Reaxys With trifluoroacetic acid in dichloromethane, Time= 2h, Inert atmosphere Long, Jonathan Z.; Jin, Xin; Adibekian, Alexander; Li, Weiwei; Cravatt, Benjamin F.; Journal of Medicinal Chemistry; vol. 53; nb. 4; (2010); p. 1830 - 1842 View in Reaxys With trifluoroacetic acid in dichloromethane Dong, Ming-Xin; Lu, Lu; Li, Haitao; Wang, Xiaohua; Lu, Hong; Jiang, Shibo; Dai, Qiu-Yun; Bioorganic and Medicinal Chemistry Letters; vol. 22; nb. 9; (2012); p. 3284 - 3286 View in Reaxys 4.1.2 General procedure for the synthesis of 1-(3-substituted benzyl)piperazines 4a–g General procedure: These compounds were prepared by means of the previously reported methods [44]. To a solution of tert-butyl piperazine-1-carboxylate (0.559g, 3.0mmol) and triethylamine (0.63mL, 3.3mmol) in CH2Cl2 (15mL) appropriate substituted benzyl chlorides or benzyl bromides 2a–g (3.6mmol) were added. After stirring the mixture at room temperature overnight, it was then diluted with H2O and the organics extracted with CH2Cl2 (2×20mL), dried over MgSO4, and concentrated under reduced pressure. Purification of the crude material by flash column chromatography (SiO2, PE/AcOEt, 60/40) gave the corresponding intermediates. These intermediates (2.49mmol) were then treated with TFA (5.75mL, 76.8mmol) in toluene (15mL) and stirred for 80min at room temperature. After the removal of the solvent under reduced pressure, the residue was diluted with aqueous NaOH (1N) and the organics extracted with CH2Cl2 (2×20mL), dried over MgSO4, and concentrated under reduced pressure to give the desired compounds 4a–g (72–89percent). With trifluoroacetic acid in toluene, Time= 1.33333h, T= 20 °C Sadeghzadeh, Masoud; Sheibani, Shahab; Ghandi, Mehdi; Daha, Fariba Johari; Amanlou, Massoud; Arjmand, Mohammad; Hasani Bozcheloie, Abolfazl; European Journal of Medicinal Chemistry; vol. 64; (2013); p. 488 - 497

20/195

2016-06-04 14:03:19

View in Reaxys

N H

Rx-ID: 5437046 View in Reaxys 14/493 Yield

Conditions & References Steck,E.A.; Journal of Organic Chemistry; vol. 27; (1962); p. 306 - 308 View in Reaxys Patent; Morren; BE549420; ; nb. 12169; (1960) View in Reaxys Sacha; Acta Poloniae Pharmaceutica; vol. 21; (1964); p. 369,373,376 View in Reaxys Patent; Inst. Farm.; PL50668; (1966); ; vol. 66; nb. 76035 View in Reaxys Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 1-(2-fluoro-benzyl)-piper-azine hydrochloride; 1-(2-iodobenzyl)piperazine; 1-(3-iodobenzyl)piperazine; 1-(4-iodobenzyl)-piperazine; 1-(2-methylbenzyl)piperazine; 1-(3-methylbenzyl)piperazine; 1-(4-methylbenzyl)piper-azine; 1-(3-methyl-benzyl)-piperazine dihydrochloride; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys

N H

Rx-ID: 5444018 View in Reaxys 15/493 Yield 96 %

Conditions & References 2 : General Procedure A: Synthesis of 1-benzylpiperazines. General procedure: General Procedure A: Synthesis of 1-benzylpiperazines.[0088]Anhydrous piperazine (6.0 equiv.) was suspended in THF (0.45 M benzyl halide). The mixture was heated to reflux until piperazine fully dissolved. Upon dissolution, the substituted benzyl halide (1.0 equiv.) was added to the reaction mixture. A white solid immediately formed. The reaction mixture was stirred at reflux for 2.5 hours. The mixture was cooled to room temperature. The solid was filtered and washed with THF and EtOAc. The combined filtrates were concentrated to 10percent of the original volume. The concentrate was poured into a separatory funnel with 5percent brine/H2O made basic (pH>12) with KOH. The aqueous layer was extracted with DCM and EtOAc. The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography to yield pure 1-benzylpiperazine in tetrahydrofuran, Time= 2.5h, Reflux Patent; The Board of Trustees of the University lllinois; HERGENROTHER, Paul J.; US2013/96133; (2013); (A1) English View in Reaxys

21/195

2016-06-04 14:03:19

Steck,E.A.; Journal of Organic Chemistry; vol. 27; (1962); p. 306 - 308 View in Reaxys Ikeda; Yakugaku Zasshi; vol. 89; (1969); p. 677,685; ; vol. 71; nb. 61339; (1969) View in Reaxys 2.88 g (35%)

2.b : (b) (b) N-(4-methylbenzyl)piperazine The above ester (13 g; 0.0435 mole), sodium hydroxide solution (20percent w/v, 100 ml) and 2-ethoxyethanol (25 ml) were stirred at reflux for 18 hours, cooled to 70° C. and acidified with concentrated hydrochloric acid. After the vigorous effervescence ceased the mixture was cooled, rebasified and extracted with ether. The dried extracts were evaporated to an oily solid which was chromatographed to give 2.88 g (35percent) of title compound as an homogeneous oil. Patent; Beecham Group Limited; US4405620; (1983); (A1) English View in Reaxys 1 : 1-p-Methylbenzyl)piperazine A mixture of 25.4 g. of the above syrup in 200 ml. of dry tetrahydrofuran was stirred under nitrogen as 100 ml. of a 1 M solution of diborane in tetrahydrofuran was added over 15 minutes. The mixture was allowed to stand 18 hours, then 150 ml. of 12 N hydrochloric acid was added. The tetrahydrofuran was removed by distillation and then the mixture was refluxed for 4 hours, evaporated and 10 N sodium hydroxide is added to pH>7. The mixture was extracted with chloroform. The extracts were dried and evaporated to an oil which may be crystallized from n-hexane, giving 1-(p-methylbenzyl)piperazine. Patent; American Cyanamid Company; US4421753; (1983); (A1) English View in Reaxys

O N

N H F

Rx-ID: 9749609 View in Reaxys 16/493 Yield 99 %

95 %

4 :To a solution of 4-(4-fluoro-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (1.6 g, 5.4 mmol) in DCM was added trifluoroacetic acid (4.16 ml, 54 mmol). The resulting mixture was stirred for about 5 h. The reaction mass was concentrated and the residue was washed with dry ether. The TFA salt was diluted with minimum volume of water and neutralized with aq. NaOH solution at 5-10° C. Extraction of the aqueous solution with ethyl acetate followed by concentration of the combined organic phases under reduced pressure afforded 1 g (95percent) of 1-(4-Fluoro-benzyl)-piperazine. LC/MS [M+H]: 195.2. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.33-7.10 (m, 4 Ar H), 3.4 (s, 2H), 2.70 (t, J=4.8 Hz, 4H), 2.30 (t, J=1.6 Hz, 4 H). Stage 1: With trifluoroacetic acid in dichloromethane, Time= 5h Stage 2: With sodium hydroxide in water, T= 5 - 10 °C Patent; KHAMRAI, Uttam; Ronsheim, Matthew; Karak, Sumit Kumar; US2010/152160; (2010); (A1) English View in Reaxys

22/195

2016-06-04 14:03:19

90 %

1.B :Example IB: -4- (4-Fluoro-benzyl) -piperazine4- (4-Fluoro-benzyl) -piperazine-1-carboxylic acid tert- butyl ester (7.03 g, 23.8 mmol) in solution in toluene (300 ml) is treated with trifluoroacetic acid (53.2 ml, 716 mmol) at room temperature. After 2 hours of agitation the reaction mixture is diluted with dichloromethane, washed with 1 N soda and then with water. The organic phase is dried on MgSO4, filtered and evaporated to dryness. The crude product is isolated for the following reaction (4.2 g, 90percent) . With trifluoroacetic acid in toluene, Time= 2h, T= 20 °C Patent; PIERRE FABRE MEDICAMENT; WO2007/147824; (2007); (A1) English View in Reaxys

34.8 %

With trifluoroacetic acid in dichloromethane, Time= 4h, T= 20 °C Oh, Seung-Jun; Lee, Kyo Chul; Lee, Sang-Yoon; Ryu, Eun Kyoung; Saji, Hideo; Choe, Yearn Seong; Chi, Dae Yoon; Kim, Sang Eun; Lee, Jeewoo; Kim, Byung-Tae; Bioorganic and Medicinal Chemistry; vol. 12; nb. 21; (2004); p. 5505 - 5513 View in Reaxys With trifluoroacetic acid in dichloromethane Dong, Ming-Xin; Lu, Lu; Li, Haitao; Wang, Xiaohua; Lu, Hong; Jiang, Shibo; Dai, Qiu-Yun; Bioorganic and Medicinal Chemistry Letters; vol. 22; nb. 9; (2012); p. 3284 - 3286 View in Reaxys

H N

N H

Rx-ID: 30665786 View in Reaxys 17/493 Yield 77 %

63 %

in dichloromethane, Time= 1h, T= 0 °C , Inert atmosphere Biannic, Berenger; Bozell, Joseph J.; Organic Letters; vol. 15; nb. 11; (2013); p. 2730 - 2733 View in Reaxys

34 %

in dichloromethane, T= 20 °C , Cooling with ice Myochin, Takuya; Kiyose, Kazuki; Hanaoka, Kenjiro; Kojima, Hirotatsu; Terai, Takuya; Nagano, Tetsuo; Journal of the American Chemical Society; vol. 133; nb. 10; (2011); p. 3401 - 3409 View in Reaxys

850 mg

1.A : Synthesis of Compound 6 Anhydrous piperazine (2.2 g, 26 mmol) was dissolved in dichloromethane (20 mL). Under ice cooling, this solution was added drop wise with a solution of benzyl bromide (3.4 g, 13 mmol) in dichloromethane (20 mL). After completion of the addition, the mixture was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain Compound 6 (850 mg).

23/195

2016-06-04 14:03:19

in dichloromethane, Time= 6h, T= 20 °C , Cooling with ice Patent; The University of Tokyo; Nagano, Tetsuo; Kojima, Hirotatsu; Kiyose, Kazuki; US8507677; (2013); (B2) English View in Reaxys General procedure for the preparation of compounds 11-16, 18-25 and 28 General procedure: Piperazine (3.0 equiv.) and K2CO3 (1.0 equiv) were mixed in THF (50 mL) under reflux condition. Subsequently, 68-82 (1.0 equiv) were added, and refluxing was continued for another three hours.The reaction mixture was concentrated in vacuo and partitioned between water and DCM. Theorganic phase was washed with brine and dried over Na2SO4. Products were purified by flash chromatography (DCM : MeOH = 8:1). With potassium carbonate in tetrahydrofuran, Time= 3h, Reflux Obreque-Balboa, Jos Esteban; Sun, Qiu; Bernhardt, Günther; König, Burkhard; Buschauer, Armin; European Journal of Medicinal Chemistry; vol. 109; (2016); p. 124 - 133 View in Reaxys

N N N O

N H

Rx-ID: 294835 View in Reaxys 18/493 Yield

Conditions & References

69 %

With potassium hydroxide in methanol, Heating Bergbreiter, David E.; Osburn, Philip L.; Li, Chunmei; Organic Letters; vol. 4; nb. 5; (2002); p. 737 - 740 View in Reaxys With potassium hydroxide Horrom et al.; Journal of the American Chemical Society; vol. 77; (1955); p. 753 View in Reaxys With sodium hydroxide in 2-ethoxy-ethanol, Time= 18h, Heating Buckle, Derek R.; Outred, D. James; Smith, Harry; Spicer, Barbara A.; Journal of Medicinal Chemistry; vol. 27; nb. 11; (1984); p. 1452 - 1457 View in Reaxys With potassium hydroxide in ethanol, Time= 2.5h, T= 130 °C Ferte, Jacques; Kuehnel, Jean-Marc; Chapuis, Genevieve; Rolland, Yves; Lewin, Guy; Schwaller, Marc A.; Journal of Medicinal Chemistry; vol. 42; nb. 3; (1999); p. 478 - 489 View in Reaxys

H N Cl N H

N H

Rx-ID: 605033 View in Reaxys 19/493 Yield

Conditions & References With ethanol, T= 65 °C Craig; Young; ; <1973> 88 View in Reaxys

24/195

2016-06-04 14:03:19

Craig; Journal of the Chemical Society; (1959); p. 3634 View in Reaxys Cymerman-Craig et al.; Australian Journal of Chemistry; vol. 9; (1956); p. 397,402 View in Reaxys 18.4 g

Synthesis of N-Benzylpiperazine A solution of anhydrous piperazine (1, 9.5 g, 0.11 mol) and piperazine dihydrochloride(2, 31.8 g 0.2 mol) in ethanol (80 ml) were placed in a three necked flask equipped witha magnetic stir bar and reflux condenser was heated with vigorous stirring at 75 °C for3 h. Then a solution benzyl chloride 13.9 (0.11 mol) was added dropwise over a period of 30 minutes to the hot solution. The reaction mixture was refluxed for another 2 h. or until benzyl chloride had been completely consumed (the progress of the reaction was monitored by TLC). The mixture was cooled and the precipitated piperazine dihydrochloride (2) was collected and washed three times with ethanol. The filtrate combined with the washes was concentrated in vacuo to give the N-benzylpiperazine hydrochloride which was then treated with 6 M NaOH to pH >12. The aqueous layer of crude N-benzylpiperazine was extracted into CH2Cl2 (3 × 50 ml). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude oily product was purified by flash column chromatography on silica gel (1:3 MeOH-CH2Cl2) to give 18.4 g. (95percent) of N-benzylpiperazine as a colorless oil.141H NMR (500 MHz, CDCl3): δ 7.34-7.28 (m, 5H), 3.57 (s,2H), 3.23 (s,4H), 2.77(s,4H). MS (ESI): m/z = 177 (M++H) Stage 1: in ethanol, Time= 2.5h, Reflux Stage 2: With sodium hydroxide Wang, Jin; Li, Shuo; Hu, Xiao; Yang, Jian; Organic Preparations and Procedures International; vol. 46; nb. 5; (2014); p. 469 - 474 View in Reaxys Cl

N H

Rx-ID: 5935834 View in Reaxys 20/493 Yield 65 %

25/195

2016-06-04 14:03:19

1-(4-tert-butylbenzyl)piperazine; 1-(2-chlorobenzyl)piperazine; 1-(3-chlorobenzyl)piperazine; 1-(4-chlorobenzyl)piperazine; 1-(2-chloro-benzyl)-piperazine hydrochloride; 1-(4-chloro-benzyl)-piperazine hydrochloride; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys

H N

N H

F N

Cl N H

Rx-ID: 9177083 View in Reaxys 21/493 Yield 80 %

41 %

H N

N H

Rx-ID: 9177085 View in Reaxys 22/493

26/195

2016-06-04 14:03:19

Yield 62 %

36 %

in toluene, Time= 2h, T= 85 °C Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys in ethanol, Heating He, Feng-Qi; Liu, Xing-Hai; Wang, Bao-Lei; Li, Zheng-Ming; Journal of Chemical Research; nb. 12; (2006); p. 809 - 811 View in Reaxys 36 :Piperazine (170 g, 2.0 mol) was suspended in toluene (800 mL) and warmed to 85°C. The mixture was dissolved while stirring for 10 minutes. To the solution was added 4-methylbenzyl chloride (53 mL, 0.4 mol), and the mixture was stirred at 85°C for 2 hours and then left to stand for cooling to 50°C. A 1 N aqueous sodium hydroxide solution (440 mL) and ethyl acetate (100 mL) were added thereto, and the process of phase separation was performed. The resulting organic layer was washed with a 1 N aqueous sodium hydroxide solution (400 mL) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (420 mL). Triethylamine (84 mL, 0.6 mol) was added thereto, and the resulting mixture was ice cooled. t-Butyl dicabonate (97 mL, 0.42 mol) was added thereto, and the mixture was stirred overnight while elevating the temperature to room temperature. The solvent was distilled off under reduced pressure. A 4 N aqueous sodium hydroxide solution (200 mL) and ethyl acetate (300 mL) were added thereto, and the process of phase separation was performed. The resulting organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution (400 mL) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. To the residue was added a small amount of hexane, and the mixture was ice cooled. The obtained crystals were collected by filtration and washed with ice-cooled hexane to obtain the title compound (70 g, yield 60percent). The mother liquor was concentrated under reduced pressure, and then the residue was purified with silica gel column chromatography (hexane to hexane: ethyl acetate = 3: 1). The resulting oily matter was left to stand at room temperature. The obtained crystals were collected by filtration and washed with ice-cooled hexane to obtain the title compound (22 g, yield 19percent). Melting point 61-62°C. 1H NMR (CDCl ) δ 1.47 (9H, s), 2.34-2.38 (7H, m), 3.41-3.48 (6H, m), 7.12-7.27 (4H, m). 3 in toluene, Time= 2h, T= 85 °C Patent; Takeda Pharmaceutical Company Limited; EP1661898; (2006); (A1) English View in Reaxys

27/195

2016-06-04 14:03:19

H N

N H

Rx-ID: 9177100 View in Reaxys 23/493 Yield

Conditions & References

74 %

73 %

in toluene, Time= 2h, T= 85 °C Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys With triethylamine in ethanol, Time= 12h, T= 55 °C Cai, Mingyi; Li, Zhong; Fan, Feng; Huang, Qingchun; Shao, Xusheng; Song, Gonghua; Journal of Agricultural and Food Chemistry; vol. 58; nb. 5; (2010); p. 2624 - 2629 View in Reaxys in acetonitrile, T= 20 °C Ren, Yu; Zhang, Hui Zhen; Zhang, Shao Lin; Luo, Yun Lei; Zhang, Ling; Zhou, Cheng He; Geng, Rong Xia; Journal of Chemical Sciences; vol. 127; nb. 12; (2015); p. 2251 - 2260 View in Reaxys F N

Rx-ID: 24602242 View in Reaxys 24/493 Yield 43%

Conditions & References 49.n : EXAMPLE 49 (n) 2,3-Difluorobenzylpiperazine Using the product from Example 49f (1.14 g) and the procedure of Example 49m gave the desired product (0.45 g; 43percent yield). M+ 212. 1 H NMR (300 MHz, CDCl3) δ 7.20-6.97 (m, 2 H), 3.60 (s, 2 H), 2.90 (t, 4 H), 2.55-2.35 (brs, 4 H), 1.67 (s, 1 H). Patent; Molecular Geriatrics Corporation; US5658909; (1997); (A1) English View in Reaxys

43%

49.n : EXAMPLE 49 (n) 2,3-Difluorobenzylpiperazine

28/195

2016-06-04 14:03:19

Using the product from Example 49f (1.14 g) and the procedure of Example 49m gave the desired product (0.45 g; 43percent yield). M+ 212. 1 NMR (300 MHz, CDCl3) δ 7.20-6.97 (m, 2 H), 3.60 (s, 2 H), 2.90 (t, 4 H), 2.55-2.35 (brs, 4 H), 1.67 (s, 1 H). Patent; Molecular Geriatrics Corporation; US5693804; (1997); (A1) English View in Reaxys 43%

49.n : EXAMPLE 49 (n) 2,3-Difluorobenzylpiperazine Using the product from Example 49f (1.14 g) and the procedure of Example 49m gave the desired product (0.45 g; 43percent yield). M+ 212. 1H NMR (300 MHz, CDCl3) δ7.20-6.97 (m, 2H), 3.60 (s, 2H), 2.90 (t, 4H), 2.55-2.35 (brs, 4H), 1.67 (s, 1H). Patent; Molecular Geriatrics Corporation; US6214994; (2001); (B1) English View in Reaxys Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 1-(3-cyanobenzyl)piperazine; 1-(2,4-dichlorobenzyl)piperaz-ine; 1-(2,6-dichlorobenzyl)piperazine; 1-(3,4-dichlorobenzyl)piperazine; 1-(2,3-difluoro-benzyl)-piperazine; 1-(2,4-difluorobenzyl)piperazine; 1-(2,5-difluorobenzyl)piperazine; 1-(2,6-difluorobenz-yl)piperazine; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys F N HN F

Rx-ID: 24602244 View in Reaxys 25/493 Yield 83%

Conditions & References 49.p : EXAMPLE 49 (p) 2,5-Difluorobenzylpiperazine Using the compound of Example 49d (2.90 g) and the procedure of Example 49m gave the desired product (2.30 g; 83percent yield). M+ 212. 1 H NMR (300 MHz, CDCl3) δ 7.36-7.22 (m, 1 H), 7.10-6.90 (m, 3 H), 3.55 (s, 2 H), 3.30-3.10 9m, 4 H), 2.85-2.65 (m, 4 H). Patent; Molecular Geriatrics Corporation; US5658909; (1997); (A1) English View in Reaxys

83%

49.p : EXAMPLE 49 (p) 2,5-Difluorobenzylpiperazine Using the compound of Example 49d (2.90 g) and the procedure of Example 49m gave the desired product (2.30 g; 83percent yield). M+ 212. 1 NMR (300 MHz, CDCl3) δ 7.36-7.22 (m, 1 H), 7.10-6.90 (m, 3 H), 3.55 (s, 2 H), 3.30-3.10 9m, 4 H), 2.85-2.65 (m, 4 H). Patent; Molecular Geriatrics Corporation; US5693804; (1997); (A1) English View in Reaxys

83%

49.p : EXAMPLE 49 (p)

29/195

2016-06-04 14:03:19

2,5-Difluorobenzylpiperazine Using the compound of Example 49d (2.90 g) and the procedure of Example 49m gave the desired product (2.30 g; 83percent yield). M+ 212. 1H NMR (300 MHz, CDCl3) δ7.36-7.22 (m, 1H), 7.10-6.90 (m, 3H), 3.55 (s, 2H), 3.30-3.10 9m, 4H), 2.85-2.65 (m, 4H). Patent; Molecular Geriatrics Corporation; US6214994; (2001); (B1) English View in Reaxys Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 1-(2,6-dichlorobenzyl)piperazine; 1-(3,4-dichlorobenzyl)piperazine; 1-(2,3-difluoro-benzyl)-piperazine; 1-(2,4-difluorobenzyl)piperazine; 1-(2,5-difluorobenzyl)piperazine; 1-(2,6-difluorobenz-yl)piperazine; 1 -(3,4-difluorobenzyl)piperazine; 1 -(3,5-difluorobenzyl)piperazine; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys

N H

Rx-ID: 24643104 View in Reaxys 26/493 Yield 75%

Conditions & References 49.q : EXAMPLE 49 (q) 4-Fluorobenzylpiperazine Using the compound of Example 49a (5.25 g) and the procedure of Example 49m gave the desired product (4.35 g; 75percent yield). M+ 194. 1 H NMR (300 MHz, CDCl3) δ 8.95-8.70 (brs, 1 H), 7.40-7.25 (m, 2 H), 7.25-7.05 (m, 2 H), 3.50 (s, 2 H), 3.15-2.95 (brs, 2 H), 2.65-2.35 (m, 2 H). Patent; Molecular Geriatrics Corporation; US5658909; (1997); (A1) English View in Reaxys

75%

49.q : EXAMPLE 49 (q) 4-Fluorobenzylpiperazine Using the compound of Example 49a (5.25 g) and the procedure of Example 49m gave the desired product (4.35 g; 75percent yield). M+ 194. 1 NMR (300 MHz, CDCl3) δ 8.95-8.70 (brs, 1 H), 7.40-7.25 (m, 2 H), 7.25-7.05 (m, 2 H), 3.50 (s, 2 H), 3.15-2.95 (brs, 2 H), 2.65-2.35 (m, 2 H). Patent; Molecular Geriatrics Corporation; US5693804; (1997); (A1) English View in Reaxys

75%

49.q : EXAMPLE 49 (q) 4-Fluorobenzylpiperazine Using the compound of Example 49a (5.25 g) and the procedure of Example 49m gave the desired product (4.35 g; 75percent yield). M+ 194. 1H NMR (300 MHz, CDCl3) δ8.95-8.70 (brs, 1H), 7.40-7.25 (m, 2H), 7.25-7.05 (m, 2H), 3.50 (s, 2H), 3.15-2.95 (brs, 2H), 2.65-2.35 (m, 2H). Patent; Molecular Geriatrics Corporation; US6214994; (2001); (B1) English

30/195

2016-06-04 14:03:19

View in Reaxys Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 1-(4-ethyl-benzyl)-piperazine; 1-(4-ethyl-benzyl)-piperazine hydrochloride; 1 -(2-fluorobenzyl)piperazine; 1-(3-fluorobenzyl)piperazine; 1-(4-fluorobenzyl)piperazine; 1-(3-fluoro-benzyl)-piperazine hydrochloride; 1-(2-fluoro-benzyl)-piper-azine hydrochloride; 1-(2-iodobenzyl)piperazine; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys

Cl H N Cl

N H

Rx-ID: 621724 View in Reaxys 27/493 Yield 50 %

Conditions & References Time= 0.416667h, T= 65 °C Mehanna, Ahmed S.; Jin, Yung Kim; Bioorganic and Medicinal Chemistry; vol. 13; nb. 13; (2005); p. 4323 - 4331 View in Reaxys With ethanol Patent; Brit. Drug Houses Ltd.; GB840358; (1957) View in Reaxys in ethanol Witte; Arzneimittel-Forschung/Drug Research; vol. 39; nb. 10 A; (1989); p. 1309 - 1309 View in Reaxys

H N

F F

N H

F F F

Rx-ID: 1496075 View in Reaxys 28/493 Yield 96 %

31/195

2016-06-04 14:03:19

Zhang, Cunlong; Tan, Chunyan; Zu, Xuyu; Zhai, Xin; Liu, Feng; Chu, Bizhu; Ma, Xiaohua; Chen, Yuzong; Gong, Ping; Jiang, Yuyang; European Journal of Medicinal Chemistry; vol. 46; nb. 4; (2011); p. 1404 - 1414 View in Reaxys 75 %

in toluene, Time= 2h, T= 85 °C Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

72 %

With potassium carbonate in xylene, Time= 1h, Heating Scotto di Tella; Dessaigne; Boyer; et al.; European Journal of Medicinal Chemistry; vol. 19; nb. 2; (1984); p. 131 135 View in Reaxys

N H Cl

Rx-ID: 3078885 View in Reaxys 29/493 Yield 85 %

Conditions & References With sodium hydroxide in 2-ethoxy-ethanol, Time= 18h, Heating Buckle, Derek R.; Outred, D. James; Smith, Harry; Spicer, Barbara A.; Journal of Medicinal Chemistry; vol. 27; nb. 11; (1984); p. 1452 - 1457 View in Reaxys With potassium hydroxide in ethanol, Time= 2.5h, T= 130 °C Ferte, Jacques; Kuehnel, Jean-Marc; Chapuis, Genevieve; Rolland, Yves; Lewin, Guy; Schwaller, Marc A.; Journal of Medicinal Chemistry; vol. 42; nb. 3; (1999); p. 478 - 489 View in Reaxys 1.b : (b) (b) 1-(4-Chlorobenzyl)piperazine A mixture of 1-carboethoxy-4-(4-chlorobenzyl) piperazine (3.2 g) and 2.5 N sodium hydroxide solution (100 ml) was refluxed overnight and the turbid solution clarified by addition of a minimum of ethanol. After a further 6 hours at reflux, the solution was acidified hot whereby vigorous decarboxylation ensued. The cooled mixture was basified with dilute sodium hydroxide, extracted with ether and the dried extracts evaporated to a colourless oil. Distillation gave the title compound b.p.0.2 95° in quantitative yield. (Found; C, 63.02; H, 7.36; Cl, 16.60; N, 13.41; C11 H15 ClN2 requires; C, 62.70; H, 7.18; Cl, 16.83; N, 13.30percent). With sodium hydroxide Patent; Beecham Group Limited; US4263299; (1981); (A1) English View in Reaxys

32/195

2016-06-04 14:03:19

N N

N H Cl

Rx-ID: 5025238 View in Reaxys 30/493 Yield

Conditions & References

With trifluoroacetic acid in dichloromethane, Ambient temperature Bourrain, Sylvie; Collins, Ian; Neduvelil, Joseph G.; Rowley, Michael; Leeson, Paul D.; Patel, Smita; Patel, Shil; Emms, Frances; Marwood, Rosemarie; Chapman, Kerry L.; Fletcher, Alan E.; Showell, Graham A.; Bioorganic and Medicinal Chemistry; vol. 6; nb. 10; (1998); p. 1731 - 1743 View in Reaxys With trifluoroacetic acid in dichloromethane Dong, Ming-Xin; Lu, Lu; Li, Haitao; Wang, Xiaohua; Lu, Hong; Jiang, Shibo; Dai, Qiu-Yun; Bioorganic and Medicinal Chemistry Letters; vol. 22; nb. 9; (2012); p. 3284 - 3286 View in Reaxys A solution of tert-butyl piperazine-1-carboxylate (62) (2.0g, 10.8mmol) and 4-chlorobenzaldehyde (67) (1.28g, 9.08mmol) in DCE (30mL) were treated with NaBH(OAc)3(3.12g, 14.7mmol) and the mixure was stirred at 20°C under N2for 6h, then diluted with DCM and washed with 1N aqueous NaOH. The organic layer was dried and evaporated, and the residue was filtered through a short column of silica gel. The crude product was dissolved in DCM/TFA (1:1, 40mL) and kept at 20°C for 1h, then evaporated. The residue was dissolved in DCM and washed with 4N NH4OH, dried and evaporated. The residue was redissolved in 2N aqueous AcOH, and the aqueous layer was basified with concd NH4OH to give crude 1-(4-chlorobenzyl)piperazine (68). A cold solution of68(100mg, 0.47mmol) and DIPEA (20μL, 2 equiv) in DCM (3mL) was treated with morpholine-4-carbonyl chloride (63) (110mg, 0.74mmol). The mixture was stirred at 20°C for 30min, then diluted with DCM, washed with Na2CO3, dried and evaporated. Chromatography on silica gel, eluting with EtOAc/MeOH (from 95:5) containing 0.5percent concd NH4OH gave41, With trifluoroacetic acid in dichloromethane, Time= 1h, T= 20 °C Flanagan, Jack U.; Atwell, Graham J.; Heinrich, Daniel M.; Brooke, Darby G.; Silva, Shevan; Rigoreau, Laurent J.M.; Trivier, Elisabeth; Turnbull, Andrew P.; Raynham, Tony; Jamieson, Stephen M.F.; Denny, William A.; Bioorganic and Medicinal Chemistry; vol. 22; nb. 3; (2014); p. 967 - 977 View in Reaxys

N H O

Rx-ID: 5025391 View in Reaxys 31/493 Yield

33/195

2016-06-04 14:03:19

Long, Jonathan Z.; Jin, Xin; Adibekian, Alexander; Li, Weiwei; Cravatt, Benjamin F.; Journal of Medicinal Chemistry; vol. 53; nb. 4; (2010); p. 1830 - 1842 View in Reaxys 4.1.2 General procedure for the synthesis of 1-(3-substituted benzyl)piperazines 4a–g General procedure: These compounds were prepared by means of the previously reported methods [44]. To a solution of tert-butyl piperazine-1-carboxylate (0.559g, 3.0mmol) and triethylamine (0.63mL, 3.3mmol) in CH2Cl2 (15mL) appropriate substituted benzyl chlorides or benzyl bromides 2a–g (3.6mmol) were added. After stirring the mixture at room temperature overnight, it was then diluted with H2O and the organics extracted with CH2Cl2 (2×20mL), dried over MgSO4, and concentrated under reduced pressure. Purification of the crude material by flash column chromatography (SiO2, PE/AcOEt, 60/40) gave the corresponding intermediates. These intermediates (2.49mmol) were then treated with TFA (5.75mL, 76.8mmol) in toluene (15mL) and stirred for 80min at room temperature. After the removal of the solvent under reduced pressure, the residue was diluted with aqueous NaOH (1N) and the organics extracted with CH2Cl2 (2×20mL), dried over MgSO4, and concentrated under reduced pressure to give the desired compounds 4a–g (72–89percent). With trifluoroacetic acid in toluene, Time= 1.33333h, T= 20 °C Sadeghzadeh, Masoud; Sheibani, Shahab; Ghandi, Mehdi; Daha, Fariba Johari; Amanlou, Massoud; Arjmand, Mohammad; Hasani Bozcheloie, Abolfazl; European Journal of Medicinal Chemistry; vol. 64; (2013); p. 488 - 497 View in Reaxys

N H

Rx-ID: 5450791 View in Reaxys 32/493 Yield 94 %

34/195

2016-06-04 14:03:19

1-(4-chlorobenzyl)piperazine; 1-(2-chloro-benzyl)-piperazine hydrochloride; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys

N NH

Rx-ID: 5453073 View in Reaxys 33/493 Yield

Conditions & References

73 %

2 : General Procedure A: Synthesis of 1-benzylpiperazines. General procedure: General Procedure A: Synthesis of 1-benzylpiperazines.[0088]Anhydrous piperazine (6.0 equiv.) was suspended in THF (0.45 M benzyl halide). The mixture was heated to reflux until piperazine fully dissolved. Upon dissolution, the substituted benzyl halide (1.0 equiv.) was added to the reaction mixture. A white solid immediately formed. The reaction mixture was stirred at reflux for 2.5 hours. The mixture was cooled to room temperature. The solid was filtered and washed with THF and EtOAc. The combined filtrates were concentrated to 10percent of the original volume. The concentrate was poured into a separatory funnel with 5percent brine/H2O made basic (pH>12) with KOH. The aqueous layer was extracted with DCM and EtOAc. The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography to yield pure 1-benzylpiperazine in tetrahydrofuran, Time= 2.5h, Reflux Patent; The Board of Trustees of the University lllinois; HERGENROTHER, Paul J.; US2013/96133; (2013); (A1) English View in Reaxys p-tert-Butylbenzylchlorid Lui et al.; Yaoxue Xuebao; vol. 11; nb. 8; (1964); p. 317,318-320; ; vol. 62; nb. 2776b; (1965) View in Reaxys Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA 1-(2-Bromobenzyl)piperazine; 1-(3-bromobenzyl)piperazine; 1-(4-bromobenzyl)piperazine; 1-(4-bromo-2-fluorobenzyl)piperazine; 1-(4-tert-butylbenzyl)piperazine; 1-(2-chlorobenzyl)piperazine; 1-(3-chlorobenzyl)piperazine; 1-(4-chlorobenzyl)piperazine; 1-(2-chloro-benzyl)-piperazine hydrochloride; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys

O O

N H

Rx-ID: 5939268 View in Reaxys 34/493

35/195

2016-06-04 14:03:19

Yield

Conditions & References Pesson et al.; European Journal of Medicinal Chemistry; vol. 10; (1975); p. 567,570 View in Reaxys Boissier et al.; Journal of Medicinal Chemistry; vol. 6; (1963); p. 541,542 View in Reaxys Patent; Servier; FR1191668; (1958); ; vol. 56; nb. 1463; (1962) View in Reaxys

O O

O N NH

Rx-ID: 5940663 View in Reaxys 35/493 Yield

Conditions & References Patent; Biofarma SA; FRM805; (1961); ; vol. 58; nb. 3442g; (1963) View in Reaxys Patent; Sci. Union et Cie Soc. Franc. de Rech. Med.; FR1302958; (1961); ; vol. 58; nb. 6844d; (1963) View in Reaxys EXAMPLES 27 AND 28 Following the procedure of Example 26 but replacing morpholine in step II with 1-benzylpiperazine and then with 1(2,3,4-trimethoxybenzyl)piperazine, the compounds of the following Examples are obtained in succession: Patent; Adir et Compagnie; US5276051; (1994); (A1) English View in Reaxys

N H

Rx-ID: 6165762 View in Reaxys 36/493 Yield

Conditions & References Vejdelek et al.; Collection of Czechoslovak Chemical Communications; vol. 39; (1974); p. 2276,2277,2280 View in Reaxys Patent; Boehringer Mannheim G.m.b.H.; FR2334361; (1977); DE2555290; ; vol. 85; nb. 102383 View in Reaxys 17.b : (b) (b) 1-(2-Methoxybenzyl)-piperazine The N-carboxylic acid ester obtained according to Example 17a is heated under reflux for 70 hours with 105 g potassium hydroxide in 1000 ml ethanol. The still warm reaction mixture is acidified with concentrated hydrochloric acid and thereafter stirred for 30 minutes. Subsequently, the bulk of the ethanol is evaporated off, the residue is mixed with 10N aqueous sodium hydroxide solution and the oil obtained is isolated and distilled in a vacuum. Patent; Boehringer Mannheim GmbH; US4092416; (1978); (A1) English View in Reaxys

HO O

NH N

Rx-ID: 6168174 View in Reaxys 37/493

36/195

2016-06-04 14:03:19

Yield

Conditions & References Piperazin, 5-Chlormethyl-2-hydroxy-benzoesaeure-methylester Patent; Sci.-Un. et Cie.-Soc. Franc. Rech. Med.; BE630639; (1962); ; vol. 61; nb. 9509f; (1964) View in Reaxys 5-Chlormethyl-salicylsaeure-methylester, Piperazin *6H2O/HCl (D= 1.19) Regnier et al.; Bulletin de la Societe Chimique de France; (1966); p. 2821,2825 View in Reaxys Piperazin, 5-Halogenmethyl-salicylsaeure-methylester Patent; Science Union and Cie.; BE630639; (1963); ; vol. 61; nb. 668; (1964) View in Reaxys

N OH

Rx-ID: 6168819 View in Reaxys 38/493 Yield

Conditions & References Piperazin, 5-Chlormethyl-2-hydroxy-benzoesaeure Patent; Sci.-Un. et Cie.-Soc. Franc. Rech. Med.; BE630639; (1962); ; vol. 61; nb. 9509f; (1964) View in Reaxys 1-<4-Hydroxy-3-carbomethoxy-benzyl>-4-formyl-piperazin in 6n-HCl Regnier et al.; Bulletin de la Societe Chimique de France; (1966); p. 2821,2825 View in Reaxys Piperazin, 5-Halogenmethyl-salicylsaeure Patent; Science Union and Cie.; BE630639; (1963); ; vol. 61; nb. 668; (1964) View in Reaxys

O O

NH N

Rx-ID: 6169689 View in Reaxys 39/493 Yield

Conditions & References Piperazin, 2-Aethoxy-5-brommethyl-benzoesaeure-methylester Patent; Sci.-Un. et Cie.-Soc. Franc. Rech. Med.; BE630639; (1962); ; vol. 61; nb. 9509f; (1964) View in Reaxys 2-Aethoxy-5-brommethyl-benzoesaeure-methylester, Piperazin *6H2O/HCl (D= 1.19) Regnier et al.; Bulletin de la Societe Chimique de France; (1966); p. 2821,2825 View in Reaxys Piperazin, 5-Halogenmethyl-2-aethoxy-benzoesaeure-methylester Patent; Science Union and Cie.; BE630639; (1963); ; vol. 61; nb. 668; (1964) View in Reaxys

37/195

2016-06-04 14:03:19

N O

Rx-ID: 6170831 View in Reaxys 40/493 Yield

Conditions & References Piperazin, 5-Chlormethyl-2-hydroxy-benzoesaeure-butylester Patent; Sci.-Un. et Cie.-Soc. Franc. Rech. Med.; BE630639; (1962); ; vol. 61; nb. 9509f; (1964) View in Reaxys 1-<4-Hydroxy-3-carboxy-benzyl>-piperazin * 2HCl, n-Butanol/ HCl Regnier et al.; Bulletin de la Societe Chimique de France; (1966); p. 2821,2825 View in Reaxys Piperazin,5-Halogenmethyl-salicylsaeure-butylester Patent; Science Union and Cie.; BE630639; (1963); ; vol. 61; nb. 668; (1964) View in Reaxys NH 2 I

N H

Rx-ID: 6171101 View in Reaxys 41/493 Yield

Conditions & References Aus dem Chlorid I und Piperazin Hebky,J. et al.; Collection of Czechoslovak Chemical Communications; vol. 35; (1970); p. 867 - 881 View in Reaxys entspr.Benzyl-halid, Amin Patent; SPOFA United Pharmaceutical Works; NL6516674; (1964); ; vol. 65; nb. 15270c; (1966) View in Reaxys Aus dem entspr. Benzylhalogenid (Cl,I) mit Piperazin Patent; Hebky et al.; CS121655; (1964); ; vol. 68; nb. 2696j; (1968) View in Reaxys O O O

NH N

Rx-ID: 6174889 View in Reaxys 42/493 Yield

Conditions & References 5-Chlormethyl-2-acetoxy-benzoesaeure-methylester, Piperazin, anschl. Methansulfonsaeure Regnier et al.; Bulletin de la Societe Chimique de France; (1966); p. 2821,2825 View in Reaxys Piperazin, 2-Acetoxy-5-chlormethyl-benzoesaeure-methylester Patent; Sci.-Un. et Cie.-Soc. Franc. Rech. Med.; BE630639; (1962); ; vol. 61; nb. 9509f; (1964)

38/195

2016-06-04 14:03:19

View in Reaxys Piperazin, 2-Acetoxy-5-halogenmethyl-benzoesaeure-methylester Patent; Science Union and Cie.; BE630639; (1963); ; vol. 61; nb. 668; (1964) View in Reaxys

H N Br

N H

Rx-ID: 9177089 View in Reaxys 43/493 Yield 38 %

Conditions & References in toluene, Time= 2h, T= 85 °C Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys Chai, Yunfeng; Jiang, Kezhi; Sun, Cuirong; Pan, Yuanjiang; Chemistry - A European Journal; vol. 17; nb. 39; (2011); p. 10820 - 10824 View in Reaxys in tetrahydrofuran Kapanda, Coco N.; Masquelier, Julien; Labar, Geoffray; Muccioli, Giulio G.; Poupaert, Jacques H.; Lambert, Didier M.; Journal of Medicinal Chemistry; vol. 55; nb. 12; (2012); p. 5774 - 5783 View in Reaxys F

H N

F N

N H

Rx-ID: 9177099 View in Reaxys 44/493 Yield 88 %

74 %

39/195

2016-06-04 14:03:19

Ren, Yu; Zhang, Hui Zhen; Zhang, Shao Lin; Luo, Yun Lei; Zhang, Ling; Zhou, Cheng He; Geng, Rong Xia; Journal of Chemical Sciences; vol. 127; nb. 12; (2015); p. 2251 - 2260 View in Reaxys

HN N OH

Rx-ID: 11956951 View in Reaxys 45/493 Yield

Conditions & References Reaction Steps: 2 1: 98 percent / HBr; H2SO4; water / 20 h / 70 °C 2: Et3N / CH2Cl2 / 20 °C With sulfuric acid, water, hydrogen bromide, triethylamine in dichloromethane Wang, Qiang; Wilson, Claire; Blake, Alexander J.; Collinson, Simon R.; Tasker, Peter A.; Schroeder, Martin; Tetrahedron Letters; vol. 47; nb. 50; (2006); p. 8983 - 8987 View in Reaxys Reaction Steps: 3 1: 98 percent / HBr; H2SO4; water / 20 h / 70 °C 2: 85 percent / KHCO3 / acetonitrile / 6 h / Heating 3: 83 percent / aq. HCl / 96 h / 100 °C With hydrogenchloride, sulfuric acid, water, hydrogen bromide, potassium hydrogencarbonate in acetonitrile Wang, Qiang; Wilson, Claire; Blake, Alexander J.; Collinson, Simon R.; Tasker, Peter A.; Schroeder, Martin; Tetrahedron Letters; vol. 47; nb. 50; (2006); p. 8983 - 8987 View in Reaxys Reaction Steps: 2 1: 41 percent / ethanol / 72 h / Heating 2: 97 percent / trifluoroacetic acid / CH2Cl2 / 20 h / 20 °C With trifluoroacetic acid in ethanol, dichloromethane, 1: Mannich reaction Fennie, Michael W.; DiMauro, Erin F.; O'Brien, Erin M.; Annamalai, Venkatachalam; Kozlowski, Marisa C.; Tetrahedron; vol. 61; nb. 26; (2005); p. 6249 - 6265 View in Reaxys Reaction Steps: 3 1: hydrogenchloride / water / 48 h / 20 °C / |Inert atmosphere 2: potassium iodide / ethyl acetate / 1 h / 20 °C / |Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C / |Inert atmosphere With hydrogenchloride, trifluoroacetic acid, potassium iodide in dichloromethane, water, ethyl acetate Biannic, Berenger; Bozell, Joseph J.; Organic Letters; vol. 15; nb. 11; (2013); p. 2730 - 2733 View in Reaxys

H O

N H

Rx-ID: 22350133 View in Reaxys 46/493 Yield

Conditions & References Reaction Steps: 2 1: formic acid 2: aqueous HCl

40/195

2016-06-04 14:03:19

With hydrochlorid acid, formic acid Fujii et al.; Yakugaku Zasshi; vol. 74; (1954); p. 1049; ; (1955); p. 11666 View in Reaxys Reaction Steps: 2 1: palladium; ethanol / Hydrogenation 2: methanol. KOH-solution With potassium hydroxide, ethanol, palladium Horrom et al.; Journal of the American Chemical Society; vol. 77; (1955); p. 753 View in Reaxys Reaction Steps: 2 1.1: acetic acid / methanol / 0.33 h / 20 °C / |Molecular sieve; |Inert atmosphere 1.2: 14 h / 20 °C / |Molecular sieve; |Inert atmosphere 2.1: palladium 10 on activated carbon; hydrogen / ethanol; tetrahydrofuran / 3 h / 20 °C With palladium 10 on activated carbon, hydrogen, acetic acid in tetrahydrofuran, methanol, ethanol Juki, Marko; Frlan, Rok; Chan, Fiona; Kirby, Robert W.; Madge, David J.; Tytgat, Jan; Peigneur, Steve; Anderluh, Marko; Kikelj, Danijel; Medicinal Chemistry Research; vol. 24; nb. 6; (2015); p. 2366 - 2380 View in Reaxys

O N

N O

Cl N

N H

Rx-ID: 22867143 View in Reaxys 47/493 Yield 50 %

Conditions & References 6 : Example 6 1-[N-(2-nitrophenyl)-N-cyclohexylcarbonyl-2-aminoethyl]-4-(2,5-dichlorobenzyl)-piperazine 2,5-Dichlorobenzyl chloride (2.01 g) was added to a mixture of 1.94 g of 1-ethoxycarbonyl-piperazine and 3.45 g of anhydrous potassium carbonate in 20 ml of dimethylformamide stirred at room temperature under a nitrogen atmosphere. After 24 h of stirring at the same temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase, which was dried on anhydrous sodium sulphate, was evaporated to dryness under vacuum. The oily residue was purified via flash chromatography (petroleum ether : ethyl acetate 85:15) giving 2 g (63percent) of 1-(2,5-dichlorobenzyl)-4-ethoxycarbonyl-piperazine.1H-NMR (CDCl3, δ): 7.50 (d, 1H, aromatic H6), 7.27 (d, 1H, aromatic H3), 7.15 (dd, 1H, aromatic H4), 4.13 (q, 2H, CH3CH2O), 3.58 (s, 2H, benzyl CH2), 3.55-3.45 (m, 4H, piperazine protons), 2.50-2.42 (m, 4H, piperazine protons), 1.26 (t, 3H, CH3CH2O). A solution containing 13 g of 1-(2,5-dichlorobenzyl)-4-ethoxycarbonyl-piperazine, prepared as above described, in 35 ml of 37percent hydrochloric acid was stirred for 40 h at reflux. Subsequently, 30 ml of water and 30 ml of ethyl acetate were added at room temperature, adjusting the pH to 11 via addition of 35percent sodium hydroxide. The organic phase was dried on anhydrous sodium sulphate and evaporated to dryness under vacuum. The crude was purified via flash chromatography (chloroform : methanol 7:3) giving 4.46 g (50percent) of 1-(2,5-dichlorobenzyl)-piperazine.1H-NMR (CDCl3, δ): 7.50 (d, 1H, aromatic H6), 7.26 (d, 1H, aromatic H3), 7.14 (dd, 1H, aromatic H4), 3.55 (s, 2H, benzyl CH2), 3.00-2.85 (m, 4H, piperazine protons), 2.55-2.48 (m, 4H, piperazine protons), 1.76 (s, 1H, NH). 1-[N-(2-nitrophenyl)-2-aminoethyl)-4-(2,5-dichlorobenzyl)-piperazine was prepared and purified following the method described in Example 5, first step, but using 1-(2,5-dichlorobenzyl)-piperazine, prepared as above described, in place of 1-(4-indolyl)-piperazine and using 4-dimethylaminopyridine in place of triethylamine and carrying out the reaction at 120°C for 8 h. Yield: 35percent.1H-NMR (CDCl3, δ): 8.45 (bs, 1H, NH), 8.10 (d, 1H, aniline H3), 7.45 (d, 1H, dichlorophenyl ring H6), 7.38 (dd, 1H, aniline H5), 7.25 (d, 1H, dichlorophenyl ring H3), 7.10 (dd, 1H, dichlorophenyl ring H4), 6.77 (d, 1H, aniline H6), 6.55 (dd, 1H, aniline H4), 3.59 (s, 2H, benzyl CH2), 3.35 (dt, 2H, NHCH2CH2), 2.73 (t, 2H, NHCH2CH2), 2.70-2.38 (m, 8H, piperazine protons). The title compound was prepared following the procedure described in Example 1, second step, except that 1-[N-(2-nitrophenyl)-2-aminoethyl)-4-(2,5-dichlorobenzyl)-piperazine, prepared as described above, was used in place of 1-[N-(2-nitrophenyl)-2-aminoethyl]-4-(2-methoxyphenyl)-piperazine, and heating was 12 h at reflux. The crude was purified via flash chromatography (ethyl acetate : petroleum ether 4:6). Yield: 22percent.1H-NMR (CDCl3, δ): 8.03 (dd, 1H, nitrophenyl ring H3), 7.75-7.40 (m, 4H, dichlorophenyl ring H6 and nitrophenyl ring H4,5,6), 7.25 (d, 1H, dichlorophenyl ring H3), 7.10 (dd, 1H, dichlorophenyl ring H4), 4.05-3.90 (m, 1H, C(O)NC(H)HCH2), 3.65-3.50 (m, 1H, C(O)NC(H)HCH2, 3.52 (s, 2H, benzyl CH2), 2.70-2.20 (m, 10H, C(O)NCH2CH2, piperazine protons), 2.00-0.70 (m, 11H, cyclohexyl protons).

41/195

2016-06-04 14:03:19

Stage 1: With hydrogenchloride in water, Time= 40h, Nitrogen atmosphere Stage 2: With sodium hydroxide in water, ethyl acetate, T= 20 °C , pH= 11 Patent; RECORDATI S.A.; RECORDATI INDUSTRIA CHIMICA E FARMACEUTICA S.p.a.; EP1000047; (2003); (B1) English View in Reaxys 14 : Preparation of 1-(2,5-dichlorobenzyl)piperazine (Compound 14B) Preparation of 1-(2,5-dichlorobenzyl)piperazine (Compound 14B) A solution containing 13 g of 1-(2,5-dichlorobenzyl)-4-ethoxycarbonylpiperazine in 35 mL of 37percent HCl was stirred for 40 h at reflux. Subsequently, 30 mL of water and 30 mL of EtOAc were added at room temperature, adjusting the pH to 11 via addition of 35percent NaOH. The organic phase, which was dried on anhydrous sodium sulphate, was evaporated to dryness under vacuum. The crude was purified via flash chromatography (CHCl3-MeOH 7:3) giving 4.46 g (50percent) of the title compound. 1H-NMR

(CDCl3, δ): 7.50 (d, 1H, aromatic H6), 7.26 (d, 1H, aromatic H3), 7.14 (dd, 1H, aromatic H4), 3.55 (s, 2H,

benzyl CH2), 3.00-2.85 (m, 4H, piperazine protons), 2.55-2.48 (m, 4H, piperazine protons), 1.76 (s, 1H, NH). With sodium hydroxide in hydrogenchloride, water, ethyl acetate Patent; Recordati S.A. Chemical and Pharmaceutical Company; US6399614; (2002); (B1) English View in Reaxys 14 : Preparation of 1-(2,5-dichlorobenzyl)piperazine (Compound 14B) Preparation of 1-(2,5-dichlorobenzyl)piperazine (Compound 14B) A solution containing 13 g of 1-(2,5-dichlorobenzyl)-4-ethoxycarbonylpiperazine in 35 mL of 37percent HCl was stirred for 40 h at reflux. Subsequently, 30 mL of water and 30 mL of EtOAc were added at room temperature, adjusting the pH to 11 via addition of 35percent NaOH. The organic phase, which was dried on anhydrous sodium sulphate, was evaporated to dryness under vacuum. The crude was purified via flash chromatography (CHCl3 --MeOH 7:3) giving 4.46 g (50percent) of the title compound. H-NMR (CDCl3, δ): 7.50 (d, 1H, aromatic H6), 7.26 (d, 1H, aromatic H3), 7.14 (dd, 1H, aromatic H4), 3.55 (s, 2H,

O N

O Cl Cl

N H

Rx-ID: 22966115 View in Reaxys 48/493 Yield

Conditions & References 1.2 : Step 2 Step 2 Trifluoroacetic acid (75 ml, 974 mmol) was added to a solution 1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzyl)piperazine (45 g, 130 mmol) in chloroform (75 ml). The reaction mixture was stirred for 1 h at room temperature and then made basic with a sodium hydroxide solution. The product was extracted into ethyl acetate and the organic layer was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo to give 1-(3,4-dichlorobenzyl)piperazine (35.8 g) as a solid. With trifluoroacetic acid in chloroform Patent; Syntex (U.S.A.) LLC; US6323223; (2001); (B1) English View in Reaxys

42/195

2016-06-04 14:03:19

1.2 : Step 2 Trifluoroacetic acid (75 ml, 974 mmol) was added to a solution 1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzyl)piperazine (45 g, 130 mmol) in chloroform (75 ml).. The reaction mixture was stirred for 1 h at room temperature and then made basic with a sodium hydroxide solution.. The product was extracted into ethyl acetate and the organic layer was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo to give 1-(3,4-dichlorobenzyl)piperazine (35.8 g) as a solid. With trifluoroacetic acid in chloroform, Time= 1h, T= 20 °C Patent; Syntex (U.S.A.) LLC; US6339087; (2002); (B1) English View in Reaxys 3.2 :TFA (75 mL, 0.97 mol) was added to a solution of 1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzyl)piperazine (45 g, 0.13 mol) in DCM (75 mL). The mixture was stirred for 1 h at room temperature and then made basic with a sodium hydroxide solution. The product was extracted into EtOAc and the organic layer was washed with sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo to give 1-(3,4-dichlorobenyl)piperazine (35.8 g) as a solid. Stage 1: With trifluoroacetic acid in dichloromethane, Time= 1h, T= 20 °C Stage 2: With sodium hydroxide in dichloromethane, water Patent; Gong, Leyi; Wilhelm, Robert Stephen; US2005/90504; (2005); (A1) English View in Reaxys O

2 HCl

N N

Rx-ID: 23246248 View in Reaxys 49/493 Yield 93 %

Conditions & References C : 5-Piperazio-1-ylmethyl-benzene-1,3-diol dihydrochloride 5-Piperazio-1-ylmethyl-benzene-1,3-diol dihydrochloride A solution of 4M hydrogen chloride in dioxan (10ml) was added to a solution of 4-(3,5-dihydroxy-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (2.21g, 7.2mmol) in methanol and the mixture was stirred for 1h. The mixture was reduced in vacuo and azeotroped with toluene to afford a white solid identified as 5-piperazin-1ylmethyl-benzene-1,3-diol dihydrochloride (1.88g, 93percent). With hydrochlorid acid in 1,4-dioxane, methanol, Time= 1h Patent; Ferring B.V.; EP1512687; (2005); (A1) English View in Reaxys

83 %

5-(Piperazin-1-ylmethyl)benzene-1,3-diol dihydrochloride (19) Step ii: A solution of boc-protected 19 (2.30 g, 7.47 mmol) in methanol (25 mL) wastreated with HCl (10.2 mL of a 4 M solution in 1,4-dioxane, 41.1 mmol) and stirredmagnetically for 1 h. The resulting mixture was concentrated under reduced pressurethen treated with toluene (5 mL) which was then removed under reduced pressure togive the title compound 19 (1.74 g, 83percent) as a white powder, m.p. 278-280 °C, (Rf =0.0 in 1:9 v/v methanol/dichloromethane). With hydrochlorid acid in 1,4-dioxane, methanol, Time= 1h, Inert atmosphere Reekie, Tristan A.; McGregor, Iain S.; Kassiou, Michael; Tetrahedron Letters; vol. 55; nb. 33; (2014); p. 4568 4571 View in Reaxys

2.91 g

5-(Piperazin-1-ylmethyl)benzene-1,3-diol dihydrochloride (15a) General procedure: Step ii: A solution of the appropriate tert-butyl carboxylate (5mmol) in methanol (15mL) was treated with HCl (5.0mL of a 4M solution in 1,4-dioxane, 20.3mmol) and stirred magnetically for 1h. The resulting mixture was concentrated under reduced pressure and azeotroped with toluene (10mL) to give The title compound was obtained as a white powder (2.91g, 75percent over two steps), m.p. 278–280°C, (Rf=0.0 in 1:9 v/v methanol/dichloromethane). (0034) 1H NMR (DMSO-d6, 300MHz): δ 9.87–9.57 (complex m, 4H), 6.44 (s, 2H), 6.36 (s, 1H), 5.36 (s, 1H), 4.16 (s, 2H), 3.55–3.24 (complex m, 8H). 13C NMR (DMSO-d6, 75MHz): δ 158.7, 130.4, 109.4, 103.8, 58.6,

43/195

2016-06-04 14:03:19

47.1, 39.5ppm. IR (diamond cell, thin film) νmax: 3330, 2970, 1738, 1598, 1365, 1216, 1175, 1009, 946, 859cm−1. LRMS (+ESI) m/z: 209 [(M+H)+ as a free base, 100percent With hydrochlorid acid in 1,4-dioxane, methanol, Time= 1h, Inert atmosphere Jorgensen, William T.; Gulliver, Damien W.; Werry, Eryn L.; Reekie, Tristan; Connor, Mark; Kassiou, Michael; European Journal of Medicinal Chemistry; vol. 108; (2016); p. 730 - 740 View in Reaxys O N

N H

Rx-ID: 24602243 View in Reaxys 50/493 Yield 59%

Conditions & References 49.o : EXAMPLE 49 (o) 4-Nitrobenzylpiperazine Using the product from Example 49h (0.50 g) and the procedure of Example 49m gave the desired product (0.28 g; 59percent yield). M+ 221. 1 H NMR (300 MHz, CDCl3) δ 8.27 (d, 2 H), 7.15 (d, 2 H), 3.75 (s, 2 H), 3.30-3.15 (m, 4 H), 2.85-2.70 (m, 4 H). Patent; Molecular Geriatrics Corporation; US5658909; (1997); (A1) English View in Reaxys

59%

49.o : EXAMPLE 49 (o) 4-Nitrobenzylpiperazine Using the product from Example 49h (0.50 g) and the procedure of Example 49m gave the desired product (0.28 g; 59percent yield). M+ 221. 1 NMR (300 MHz, CDCl3) δ 8.27 (d, 2 H), 7.15 (d, 2 H), 3.75 (s, 2 H), 3.30-3.15 (m, 4 H), 2.85-2.70 (m, 4 H). Patent; Molecular Geriatrics Corporation; US5693804; (1997); (A1) English View in Reaxys

59%

49.o : EXAMPLE 49 (o) 4-Nitrobenzylpiperazine Using the product from Example 49h (0.50 g) and the procedure of Example 49m gave the desired product (0.28 g; 59percent yield). M+ 221. 1H NMR (300 MHz, CDCl3) δ8.27 (d, 2H), 7.15 (d, 2H), 3.75 (s, 2H), 3.30-3.15 (m, 4H), 2.85-2.70 (m, 4H). Patent; Molecular Geriatrics Corporation; US6214994; (2001); (B1) English View in Reaxys N

H N

N N H

N H

Rx-ID: 25405465 View in Reaxys 51/493 Yield 43 %

Conditions & References [00334] To a solution of piperazine (5.17 g, 60 mmol, 2 equiv) in EtOH (40 mL) was added 1 M HCl-EtOH (60 mL) dropwise over 1 h and the suspension was heated to 70° C. for 1 h. α-Bromo-p-tolunitrile (5.88 g, 30 mmol, 1 equiv) was added and the reaction was heated to reflux for 16 h. After cooling the solvent was removed by rotary evaporation and the residue was partitioned between CH2Cl2 (70 mL) and 2N aqueous KOH (70 mL) and the combined or-

44/195

2016-06-04 14:03:19

ganic phase was washed with saturated aqueous NaCl (100 mL) and dried (MgSO4). Chromatography (SiO2, 20percent CH3OH-5percent Et3N-CH2Cl2) afforded the monoalkylated material (2.6 g, 6.0 g theoretical, 43percent) as an amber oil Stage 1: With hydrogenchloride in ethanol, Time= 2h, T= 70 °C Stage 2: in ethanol, Time= 16h, Heating / reflux Stage 3: With potassium hydroxide in dichloromethane, water Patent; Teijin Intellectual Property Center Limited; Combichem, Inc.; US6686353; (2004); (B1) English View in Reaxys 19.151 : Preparation of 1-(4-Cyanobenzyl)piperazine. Preparation of 1-(4-Cyanobenzyl)piperazine. To a solution of piperazine (5.17 g, 60 mmol, 2 equiv) in EtOH (40 mL) was added 1 M HCl-EtOR (60 mL) dropwise over 1 h and the suspension was heated to 70 °C for 1 h. α-Bromo-p-tolunitrile (5.88 g, 30 mmol, 1 equiv) was added and the reaction was heated to reflux for 16 h. After cooling the solvent was removed by rotary evaporation and the residue was partitioned between CH2Cl2 (70 mL) and 2N aqueous KOH (70 mL) and the combined organic phase was washed with saturated aqueous NaCl (100 mL) and dried (MgSO4). Chromatography (SiO2, 20percent CH3OH-5percent Et3N-CH2Cl2) afforded the monoalkylated material (2.6 g, 6.0 g theoretical, 43percent) as an amber oil. in ethanol Patent; TEIJIN LIMITED; EP914319; (2001); (B1) English View in Reaxys General procedure for the preparation of compounds 11-16, 18-25 and 28 General procedure: Piperazine (3.0 equiv.) and K2CO3 (1.0 equiv) were mixed in THF (50 mL) under reflux condition. Subsequently, 68-82 (1.0 equiv) were added, and refluxing was continued for another three hours.The reaction mixture was concentrated in vacuo and partitioned between water and DCM. Theorganic phase was washed with brine and dried over Na2SO4. Products were purified by flash chromatography (DCM : MeOH = 8:1). With potassium carbonate in tetrahydrofuran, Time= 3h, Reflux Obreque-Balboa, Jos Esteban; Sun, Qiu; Bernhardt, Günther; König, Burkhard; Buschauer, Armin; European Journal of Medicinal Chemistry; vol. 109; (2016); p. 124 - 133 View in Reaxys

H N

N NH

N H

Rx-ID: 29752491 View in Reaxys 52/493 Yield 90 %

Conditions & References With potassium carbonate in dichloromethane, T= 0 - 20 °C Nalluri, Siva Krishna Mohan; Ravoo, Bart Jan; Angewandte Chemie - International Edition; vol. 49; nb. 31; (2010); p. 5371 - 5374 View in Reaxys

73%

2 : 1-( 4-(tert-butyl)benzyl)piperazine (5 { 20}) General procedure: General Procedure A: Synthesis of 1-benzylpiperazines. Anhydrous piperazine(6.0 equiv.) was suspended in THF (0.45 M benzyl halide). The mixture was heated to reflux until piperazine fully dissolved. Upon dissolution, the substituted benzyl halide (1.0 equiv.)was added to the reaction mixture. A white solid immediately formed. The reaction mixturewas stirred at reflux for 2.5 hours. The mixture was cooled to room temperature. The solidwas filtered and washed with THF and EtOAc. The combined filtrates were concentrated to10percent of the original volume. The concentrate was poured into a separatory funnel with 5percent brine/H20 made basic (pH > 12) with KOH. The aqueous layer was extracted with DCM andEtOAc. The organic layers were combined, dried over Na2S04 , and concentrated. The crudeproduct was purified by silica gel column chromatography to yield pure 1-benzylpiperazine. Synthesized according to General Procedure A: 4-tert-butylbenzyl bromide (4{20}, 4.05 mL, 22.0 mmol, 1 equiv.), piperazine (11.4 g, 132.1 mmol, 6 equiv.), THF (48.1 mL). Purificationwith flash column chromatog-

45/195

2016-06-04 14:03:19

raphy on silica gel (4:1 EtOAc:MeOH) afforded 5{20} (3.75 g,73percent) as a beige solid. 1H-NMR (500 MHz, CDCb): 8 7.30 (d, 2H, J = 8.5 Hz), 7.22 (d, 2H, J= 8.5 Hz), 3.44 (s, 2H), 2.85 (t, 4H, J = 5.0 Hz), 2.38 (br s, 4H), 1.54 (br s, 1H), 1.29 (s, 9H).13C-NMR (125 MHz, CDCb): 8 149.6, 134.7, 128.7, 124.8, 63.1, 54.3, 45.9, 34.2, 31.2. Stage 1: in tetrahydrofuran, Reflux Stage 2: in tetrahydrofuran, Time= 2.5h, Reflux Patent; HERGENROTHER, Paul J.; ROTH, Howard Steven; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS; WO2014/22858; (2014); (A1) English View in Reaxys in tetrahydrofuran Kapanda, Coco N.; Masquelier, Julien; Labar, Geoffray; Muccioli, Giulio G.; Poupaert, Jacques H.; Lambert, Didier M.; Journal of Medicinal Chemistry; vol. 55; nb. 12; (2012); p. 5774 - 5783 View in Reaxys

H N

Cl N H

F N H

Rx-ID: 30462550 View in Reaxys 53/493 Yield 87 %

77 %

2 : General Procedure A: Synthesis of 1-benzylpiperazines. General procedure: General Procedure A: Synthesis of 1-benzylpiperazines.[0088]Anhydrous piperazine (6.0 equiv.) was suspended in THF (0.45 M benzyl halide). The mixture was heated to reflux until piperazine fully dissolved. Upon dissolution, the substituted benzyl halide (1.0 equiv.) was added to the reaction mixture. A white solid immediately formed. The reaction mixture was stirred at reflux for 2.5 hours. The mixture was cooled to room temperature. The solid was filtered and washed with THF and EtOAc. The combined filtrates were concentrated to 10percent of the original volume. The concentrate was poured into a separatory funnel with 5percent brine/H2O made basic (pH>12) with KOH. The aqueous layer was extracted with DCM and EtOAc. The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography to yield pure 1-benzylpiperazine in tetrahydrofuran, Time= 2.5h, Reflux Patent; The Board of Trustees of the University lllinois; HERGENROTHER, Paul J.; US2013/96133; (2013); (A1) English View in Reaxys With triethylamine in ethanol, Time= 12h, T= 55 °C Cai, Mingyi; Li, Zhong; Fan, Feng; Huang, Qingchun; Shao, Xusheng; Song, Gonghua; Journal of Agricultural and Food Chemistry; vol. 58; nb. 5; (2010); p. 2624 - 2629

46/195

2016-06-04 14:03:19

View in Reaxys

H N Cl

N H

Rx-ID: 31795369 View in Reaxys 54/493 Yield 53 %

Conditions & References General procedure for the synthesis of 2a–2d General procedure: Anhydrous piperazine (18.0 g, 0.21 mol) was dissolved in chloroform (60 mL). Benzyl bromide 1a–1d (0.05 mol) in chloroform (30 mL) was added dropwise to the solution at 0 °C. The reaction mixture was stirred for about 6 h at room temperature. Then, the mixture was washed with 5percent K2CO3 solution (80 mL × 2) and water (80 mL × 4). The organic layer was dried over anhydrous Na2SO4. The filtrate was evaporated in vacuo and the residue was recrystallized from n-hexane to give the desired products 2a–2d. in chloroform, Time= 6h, T= 0 - 20 °C Zhou, An; Wu, Hongfei; Pan, Jian; Wang, Xuncui; Li, Jiaming; Wu, Zeyu; Hui, Ailing; Molecules; vol. 20; nb. 1; (2015); p. 1304 - 1318 View in Reaxys Chai, Yunfeng; Jiang, Kezhi; Sun, Cuirong; Pan, Yuanjiang; Chemistry - A European Journal; vol. 17; nb. 39; (2011); p. 10820 - 10824 View in Reaxys With potassium carbonate in tetrahydrofuran, T= 20 °C Chai, Yunfeng; Wang, Lin; Sun, Hezhi; Guo, Cheng; Pan, Yuanjiang; Journal of the American Society for Mass Spectrometry; vol. 23; nb. 5; (2012); p. 823 - 833 View in Reaxys

H N

N H

Cl F F

N F

Rx-ID: 40236787 View in Reaxys 55/493 Yield 92 %

Conditions & References 13 : Preparation 13 1-(2,4-difluorobenzyl)piperazine Preparation 13 1-(2,4-difluorobenzyl)piperazine [0163] A mixture of piperazine (26.5 g, 308 mmol) in THF (350 mL) was heated to 70° C. and 1-(chloromethyl)-2,4-difluorobenzene (5 g, 30.8 mmol) was added. The suspension was heated at 70° C. overnight. The solid (piperazine) was filtered off, and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was dried and concentrated to give the title compound (6 g, 92percent). ESI-MS m/z [M+H]+ 213.04 in tetrahydrofuran, T= 70 °C Patent; TAKEDA PHARMACEUTICAL COMPANY LIMITED; Brown, Jason; Hitchcock, Steve; Hopkins, Maria; Kikuchi, Shota; Monenschein, Holger; Reichard, Holly; Schleicher, Kristin; Sun, Huikai; Macklin, Todd; US2015/175602; (2015); (A1) English View in Reaxys

92 %

12 :A mixture of piperazine (26.5 g, 308 mmol) in THF (350 mL) was heated to 70 °C and 1-(chloromethyl)-2,4-difluorobenzene (5 g, 30.8 mmol) was added. The suspension was heated at 70 °C overnight. The solid (piperazine) was filtered off, and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was dried and concentrated to give the title compound (6 g, 92percent). ESI-MS mlz[M +H]+ 213.04. in tetrahydrofuran, T= 70 °C

47/195

2016-06-04 14:03:19

Patent; TAKEDA PHARMACEUTICAL COMPANY LIMITED; HITCHCOCK, Stephen; HOPKINS, Maria; KIKUCHI, Shota; MONENSCHEIN, Holger; REICHARD, Holly; SUN, Huikai; MACKLIN, Todd; WO2015/123505; (2015); (A1) English View in Reaxys 92 %

11 : Preparation 111 -(2,4-difluorobenzyl)piperazine j0145j A mixture of piperazine (26.5 g, 308 mmol) in THF (350 mL) was heated to 70 °C and 1-(chloromethyl)-2,4difluorobenzene (5 g, 30.8 mmol) was added. The suspension was heated at 70 °C overnight. The solid (piperazine) was filtered off, and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was dried and concentrated to give the title compound (6 g, 92percent). ESI-MS mlz[M +H]+ 213.04. in tetrahydrofuran, T= 70 °C Patent; TAKEDA PHARMACEUTICAL COMPANY LIMITED; ADAMS, Mark E.; BROWN, Jason W.; HITCHCOCK, Stephen; HOPKINS, Maria; KIKUCHI, Shota; LAM, Betty; MONENSCHEIN, Holger; REICHARD, Holly; SUN, Huikai; WO2015/123533; (2015); (A1) English View in Reaxys

H N

Br N

N H

Rx-ID: 16448 View in Reaxys 56/493 Yield

Conditions & References Patent; Brit. Drug Houses Ltd.; GB840358; (1957) View in Reaxys Morren; Strubbe; ; vol. 10; (1955); p. 239,242 View in Reaxys

H N

NH Br

N H

Rx-ID: 622722 View in Reaxys 57/493 Yield

Conditions & References With ethanol Patent; Brit. Drug Houses Ltd.; GB840358; (1957) View in Reaxys With ethanol Morren; Strubbe; ; vol. 10; (1955); p. 239,242 View in Reaxys

O H N Cl

O Cl

N H

Rx-ID: 728232 View in Reaxys 58/493 Yield

Conditions & References With ethanol Patent; Brit. Drug Houses Ltd.; GB840358; (1957)

48/195

2016-06-04 14:03:19

View in Reaxys Baltzly et al.; Journal of the American Chemical Society; vol. 66; (1944); p. 263,265 View in Reaxys F F

O F N

N H

Rx-ID: 2141134 View in Reaxys 59/493 Yield 70 mg

Conditions & References With potassium carbonate in methanol, water, Time= 20h Kawaguchi, Mamoru; Hayashi, Osamu; Kanamoto, Masahiro; Hamada, Masayuki; Yamamoto, Yukio; Oda, Jun'ichi; Agricultural and Biological Chemistry; vol. 51; nb. 2; (1987); p. 435 - 440 View in Reaxys With sodium hydroxide in methanol, Yield given Miller, Michael W.; Vice, Susan F.; McCombie, Stuart W.; Tetrahedron Letters; vol. 39; nb. 21; (1998); p. 3429 3432 View in Reaxys O N

H N

O N

N H

Rx-ID: 4856030 View in Reaxys 60/493 Yield 31 %

Conditions & References With sodium tris(acetoxy)borohydride in dichloromethane, Time= 18h, T= 20 °C Delarue; Girault; Maes; Debreu-Fontaine; Labaeid; Grellier; Sergheraert; Journal of Medicinal Chemistry; vol. 44; nb. 17; (2001); p. 2827 - 2833 View in Reaxys With polymer supported cyanoborohydride in methanol, toluene, Time= 72h, Ambient temperature, Yield given Ley, Steven V.; Bolli, Martin H.; Hinzen, Berthold; Gervois, Anne-Geraldine; Hall, Beverley J.; Journal of the Chemical Society - Perkin Transactions 1; nb. 15; (1998); p. 2239 - 2241 View in Reaxys

H N

O N H

N H

Rx-ID: 4856037 View in Reaxys 61/493 Yield 49 %

49/195

2016-06-04 14:03:19

With polymer supported cyanoborohydride in methanol, toluene, Time= 72h, Ambient temperature, Yield given Ley, Steven V.; Bolli, Martin H.; Hinzen, Berthold; Gervois, Anne-Geraldine; Hall, Beverley J.; Journal of the Chemical Society - Perkin Transactions 1; nb. 15; (1998); p. 2239 - 2241 View in Reaxys

O N

N H Cl

Rx-ID: 5025237 View in Reaxys 62/493 Yield

Conditions & References With trifluoroacetic acid in dichloromethane, Ambient temperature Bourrain, Sylvie; Collins, Ian; Neduvelil, Joseph G.; Rowley, Michael; Leeson, Paul D.; Patel, Smita; Patel, Shil; Emms, Frances; Marwood, Rosemarie; Chapman, Kerry L.; Fletcher, Alan E.; Showell, Graham A.; Bioorganic and Medicinal Chemistry; vol. 6; nb. 10; (1998); p. 1731 - 1743 View in Reaxys 4.1.2 General procedure for the synthesis of 1-(3-substituted benzyl)piperazines 4a–g General procedure: These compounds were prepared by means of the previously reported methods [44]. To a solution of tert-butyl piperazine-1-carboxylate (0.559g, 3.0mmol) and triethylamine (0.63mL, 3.3mmol) in CH2Cl2 (15mL) appropriate substituted benzyl chlorides or benzyl bromides 2a–g (3.6mmol) were added. After stirring the mixture at room temperature overnight, it was then diluted with H2O and the organics extracted with CH2Cl2 (2×20mL), dried over MgSO4, and concentrated under reduced pressure. Purification of the crude material by flash column chromatography (SiO2, PE/AcOEt, 60/40) gave the corresponding intermediates. These intermediates (2.49mmol) were then treated with TFA (5.75mL, 76.8mmol) in toluene (15mL) and stirred for 80min at room temperature. After the removal of the solvent under reduced pressure, the residue was diluted with aqueous NaOH (1N) and the organics extracted with CH2Cl2 (2×20mL), dried over MgSO4, and concentrated under reduced pressure to give the desired compounds 4a–g (72–89percent). With trifluoroacetic acid in toluene, Time= 1.33333h, T= 20 °C Sadeghzadeh, Masoud; Sheibani, Shahab; Ghandi, Mehdi; Daha, Fariba Johari; Amanlou, Massoud; Arjmand, Mohammad; Hasani Bozcheloie, Abolfazl; European Journal of Medicinal Chemistry; vol. 64; (2013); p. 488 - 497 View in Reaxys

H N

Cl N H

N H

Rx-ID: 5046349 View in Reaxys 63/493 Yield 43 %

50/195

2016-06-04 14:03:19

Pavlov, Andrei Y.; Preobrazhenskaya, Maria N.; Malabarba, Adriano; Ciabatti, Romeo; Colombo, Luigi; Journal of Antibiotics; vol. 51; nb. 1; (1998); p. 73 - 81 View in Reaxys

N H

Rx-ID: 5444134 View in Reaxys 64/493 Yield

Conditions & References Sacha; Acta Poloniae Pharmaceutica; vol. 21; (1964); p. 369,373,376 View in Reaxys Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 1-(2-iodobenzyl)piperazine; 1-(3-iodobenzyl)piperazine; 1-(4-iodobenzyl)-piperazine; 1-(2-methylbenzyl)piperazine; 1-(3-methylbenzyl)piperazine; 1-(4-methylbenzyl)piper-azine; 1-(3-methyl-benzyl)-piperazine dihydrochloride; 1-(2-methyl-benzyl)-piperazine hydrochloride; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys Cl Cl

N H

Rx-ID: 5470899 View in Reaxys 65/493 Yield

Conditions & References Patent; U.S. Vit. Pharm.; BE617599; (1962); ; vol. 59; nb. 646; (1963) View in Reaxys Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 1-(2-chloro-6-fluorobenzyl)piperazine; 1-(3-cyanobenzyl)piperazine; 1-(2,4-dichlorobenzyl)piperaz-ine; 1-(2,6-dichlorobenzyl)piperazine; 1-(3,4-dichlorobenzyl)piperazine; 1-(2,3-difluoro-benzyl)-piperazine; 1-(2,4-difluorobenzyl)piperazine; 1-(2,5-difluorobenzyl)piperazine; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys

51/195

2016-06-04 14:03:19

N H

Rx-ID: 5864347 View in Reaxys 66/493 Yield

Conditions & References Piperazinderivat IV, KOH Protiva et al.; Collection of Czechoslovak Chemical Communications; vol. 41; (1976); p. 1034,1037, 1040 View in Reaxys Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 1-(4-methyl-benzyl)-piperazine hydrochloride; 1 -(2-nitrobenzyl)piperazine dihydrochloride; 1-(3-nitrobenzyl)piperazine dihydrochloride; 1-[3-(trifluoromethyl)benzyl]piperazine; 1-(2,4,6-trimethylbenzyl)piperazine. Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys

N H

Rx-ID: 5867533 View in Reaxys 67/493 Yield

Conditions & References 4-Formylpiperazin Patent; Rhone-Poulenc; FRM104; (1960); ; vol. 58; nb. 10211g; (1963) View in Reaxys Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 1-(2-chloro-4-fluoro-benzyl)-piperazine; 1-(2-chloro-6-fluorobenzyl)piperazine; 1-(3-cyanobenzyl)piperazine; 1-(2,4-dichlorobenzyl)piperaz-ine; 1-(2,6-dichlorobenzyl)piperazine; 1-(3,4-dichlorobenzyl)piperazine; 1-(2,3-difluoro-benzyl)-piperazine; 1-(2,4-difluorobenzyl)piperazine; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys

52/195

2016-06-04 14:03:19

O O

N H

Rx-ID: 6168175 View in Reaxys 68/493 Yield

Conditions & References 4-Brommethyl-2-acetoxy-benzoesaeure-methylester, Piperazin Patent; Sci.-Un. et Cie.-Soc. Franc. Rech. Med.; BE630639; (1962); ; vol. 61; nb. 9509f; (1964) View in Reaxys 2-Acetoxy-4-brommethyl-benzoesaeure-methylester, Piperazin * 6H2O/ konz. HCl (D= 1.19) Regnier et al.; Bulletin de la Societe Chimique de France; (1966); p. 2821,2825 View in Reaxys

NH N HO O O

Rx-ID: 6169262 View in Reaxys 69/493 Yield

Conditions & References 3-Brommethyl-2-acetoxy-benzoesaeure-methylester, Piperazin * 6H2O/ konz. HCl (D= 1.19) Regnier et al.; Bulletin de la Societe Chimique de France; (1966); p. 2821,2825 View in Reaxys Piperazin, 2-Acetoxy-3-brommethyl-benzoesaeure-methylester Patent; Sci.-Un. et Cie.-Soc. Franc. Rech. Med.; BE630639; (1962); ; vol. 61; nb. 9509f; (1964) View in Reaxys O

OH N

N H

Rx-ID: 6171665 View in Reaxys 70/493 Yield

Conditions & References 1-Formyl-piperazin, Formaldehyd, Gentisinsaeure; Hydrolyse der nicht beschriebenen Formylverbdg. Patent; Sci.-Un. et Cie.-Soc. Franc. Rech. Med.; BE630639; (1962); ; vol. 61; nb. 9509f; (1964) View in Reaxys N-Formyl-N'-<3-carboxy-2.5-dihydroxy-benzyl>-piperazin Patent; Science Union and Cie.; BE630639; (1963); ; vol. 61; nb. 668; (1964) View in Reaxys

53/195

2016-06-04 14:03:19

NH N

Rx-ID: 6172505 View in Reaxys 71/493 Yield

Conditions & References α,α'-<1,4-Piperazindiyl>-bis-<2,6-di-tert.-butyl-p-cresol>, Schwefel Patent; Ethyl Corp.; US3218322; (1962); ; vol. 64; nb. 6666; (1966) View in Reaxys α,α-Piperazindiylverb., S Patent; Ethyl Corp.; US3186993; (1965); ; vol. 63; nb. 16368e; (1965) View in Reaxys

H N

Cl N

N H

Rx-ID: 9177071 View in Reaxys 72/493 Yield 68 %

30 %

in toluene, Time= 2h, T= 85 °C Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

H N

Cl N

N H

Rx-ID: 9177092 View in Reaxys 73/493 Yield 80 %

Conditions & References in toluene, Time= 2h, T= 85 °C Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576

54/195

2016-06-04 14:03:19

View in Reaxys 74 %

H N

F N H

F F

Rx-ID: 9177093 View in Reaxys 74/493 Yield

Conditions & References

80 %

in toluene, Time= 2h, T= 85 °C Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys General procedure for the preparation of compounds 11-16, 18-25 and 28 General procedure: Piperazine (3.0 equiv.) and K2CO3 (1.0 equiv) were mixed in THF (50 mL) under reflux condition. Subsequently, 68-82 (1.0 equiv) were added, and refluxing was continued for another three hours.The reaction mixture was concentrated in vacuo and partitioned between water and DCM. Theorganic phase was washed with brine and dried over Na2SO4. Products were purified by flash chromatography (DCM : MeOH = 8:1). With potassium carbonate in tetrahydrofuran, Time= 3h, Reflux Obreque-Balboa, Jos Esteban; Sun, Qiu; Bernhardt, Günther; König, Burkhard; Buschauer, Armin; European Journal of Medicinal Chemistry; vol. 109; (2016); p. 124 - 133 View in Reaxys

N OH

N O

Rx-ID: 9919519 View in Reaxys 75/493 Yield 97 %

Conditions & References With trifluoroacetic acid in dichloromethane, Time= 20h, T= 20 °C Fennie, Michael W.; DiMauro, Erin F.; O'Brien, Erin M.; Annamalai, Venkatachalam; Kozlowski, Marisa C.; Tetrahedron; vol. 61; nb. 26; (2005); p. 6249 - 6265 View in Reaxys

212.3 mg

With trifluoroacetic acid in dichloromethane, Time= 2h, T= 0 - 20 °C , Inert atmosphere

55/195

2016-06-04 14:03:19

Biannic, Berenger; Bozell, Joseph J.; Organic Letters; vol. 15; nb. 11; (2013); p. 2730 - 2733 View in Reaxys Z

Z O

O Z

O N

Rx-ID: 10098214 View in Reaxys 76/493 Yield

Conditions & References

90 %

With hydrogenchloride in ethyl acetate, Time= 0.5h, T= 20 °C Wang, Yuqiang; Li, Lianfa; Jiang, Wei; Larrick, James W.; Bioorganic and Medicinal Chemistry; vol. 13; nb. 19; (2005); p. 5592 - 5599 View in Reaxys

90 %

3 : Synthesis of Compound 6 Example 3 Synthesis of Compound 6 1-[4-(cis-4,7,10,13,16,19-Docosahexenoyl)amino]benzylpiperazine (6). Compound 5 (0.85 g, 1.4 mmol) was dissolved in ethyl acetate (10 mL), and saturated anhydrous HCl in ethyl acetate (7 mL) was added. The reaction mixture was stirred at room temperature for 30 min. The precipitate was filtered and washed with ethyl ether to afford 6 (0.68 g, 90percent yield). The product was used for the next reaction without further purification. With hydrogenchloride in ethyl acetate, Time= 0.5h, T= 20 °C Patent; Wang, Yuqiang; US2004/34033; (2004); (A1) English View in Reaxys

HN N

OH O N

N O

Rx-ID: 10469475 View in Reaxys 77/493 Yield 83 %

Conditions & References With hydrogenchloride, Time= 96h, T= 100 °C Wang, Qiang; Wilson, Claire; Blake, Alexander J.; Collinson, Simon R.; Tasker, Peter A.; Schroeder, Martin; Tetrahedron Letters; vol. 47; nb. 50; (2006); p. 8983 - 8987 View in Reaxys

70 %

With hydrogenchloride, Time= 48h, Heating Galbraith, Stuart G.; Wang, Qiang; Li, Li; Blake, Alexanders; Wilson, Claire; Collinson, Simon R.; Lindoy, Leonard F.; Plieger, Paul G.; Schroeder, Martin; Tasker, Peter A.; Chemistry - A European Journal; vol. 13; nb. 21; (2007); p. 6090 - 6107 View in Reaxys

56/195

2016-06-04 14:03:19

HN N

O O

Rx-ID: 11299177 View in Reaxys 78/493 Yield

Conditions & References Reaction Steps: 2 1: 85 percent / KHCO3 / acetonitrile / 6 h / Heating 2: 70 percent / aq. HCl / 48 h / Heating With hydrogenchloride, potassium hydrogencarbonate in acetonitrile Galbraith, Stuart G.; Wang, Qiang; Li, Li; Blake, Alexanders; Wilson, Claire; Collinson, Simon R.; Lindoy, Leonard F.; Plieger, Paul G.; Schroeder, Martin; Tasker, Peter A.; Chemistry - A European Journal; vol. 13; nb. 21; (2007); p. 6090 - 6107 View in Reaxys Reaction Steps: 2 1: 85 percent / KHCO3 / acetonitrile / 6 h / Heating 2: 83 percent / aq. HCl / 96 h / 100 °C With hydrogenchloride, potassium hydrogencarbonate in acetonitrile Wang, Qiang; Wilson, Claire; Blake, Alexander J.; Collinson, Simon R.; Tasker, Peter A.; Schroeder, Martin; Tetrahedron Letters; vol. 47; nb. 50; (2006); p. 8983 - 8987 View in Reaxys

B2 H6 THF

Cl F

N H

Rx-ID: 24645108 View in Reaxys 79/493 Yield 41%

Conditions & References 49.m : EXAMPLE 49 (m) 2-Fluorobenzylpiperazine The product from Example 49c (3.10 g) was dissolved in dry THF (75 mL) then a 1M B2 H6 THF solution (45 mL) was added dropwise over ca. 15 min. under N2. Upon complete addition, the solution was refluxed under N2 for 3 hrs. The reaction was cooled to 0° C. in an ice bath and then 1N HCl (ca. 70 mL) was carefully added dropwise. Upon complete addition, the reaction was allowed to warm to room temperature followed by extraction with EtOAc (2*100 mL). The organic layer was discarded and the acidic layer made basic with KOH. This was extracted with CH2 Cl2 (2*150 mL). The organic extracts were combined, dried (Na2 SO4), filtered and evaporated giving an oil that began to solidify upon standing. This was dissolved in 1N HCl (75 mL) then refluxed 1.5 hrs. The reaction was cooled to 0° C. then made basic with KOH followed by CH2 Cl2 extraction (2*100 mL). The organic extracts were combined, dried (Na2 SO4), filtered and evaporated affording a pale yellow oil (1.2 g; 41percent yield). M+ 194. 1 H NMR of the dihydrochloride salt (300 MHz, CDCl3) δ 10.00-9.30 (brs, 2 H), 7.15-6.85 (m, 4 H), 3.62 (s, 2 H), 3.35-3.15 (m, 2 H), 2.90-2.70 (m, 2 H). With potassium hydroxide in tetrahydrofuran, hydrogenchloride Patent; Molecular Geriatrics Corporation; US5658909; (1997); (A1) English View in Reaxys

57/195

2016-06-04 14:03:19

41%

49.m : EXAMPLE 49 (m) 2-Fluorobenzylpiperazine The product from Example 49c (3.10 g) was dissolved in dry THF (75 mL) then a 1M B2 H6 THF solution (45 mL) was added dropwise over ca. 15 min. under N2. Upon complete addition, the solution was refluxed under N2 for 3 hrs. The reaction was cooled to 0° C. in an ice bath and then 1N HCl (ca. 70 mL) was carefully added dropwise. Upon complete addition, the reaction was allowed to warm to room temperature followed by extraction with EtOAc (2*100 mL). The organic layer was discarded and the acidic layer made basic with KOH. This was extracted with CH2 Cl2 (2*150 mL). The organic extracts were combined, dried (Na2 SO4), filtered and evaporated giving an oil that began to solidify upon standing. This was dissolved in 1N HCl (75 mL) then refluxed 1.5 hrs. The reaction was cooled to 0° C. then made basic with KOH followed by CH2 Cl2 extraction (2*100 mL). The organic extracts were combined, dried (Na2 SO4), filtered and evaporated affording a pale yellow oil (1.2 g; 41percent yield). M+ 194. 1 NMR of the dihydrochloride salt (300 MHz, CDCl3) δ 10.00-9.30 (brs, 2 H), 7.15-6.85 (m, 4 H), 3.62 (s, 2 H), 3.35-3.15 (m, 2 H), 2.90-2.70 (m, 2 H). With potassium hydroxide in tetrahydrofuran, hydrogenchloride Patent; Molecular Geriatrics Corporation; US5693804; (1997); (A1) English View in Reaxys

H N

N O

N H

Rx-ID: 24892303 View in Reaxys 80/493 Yield

Conditions & References 91 :4-Piperazin-l-ylmethylbenzoic acid methyl ester was made by the nucleophilic substitution between piperazine (18.80 g, 218.3 mmol, 5 equiv.) and methyl 4-(bromomethyl)benzoate (10.0 g, 43.6 mmol) in 60 mL of acetonitrile in the presence of sodium carbonate (23.18 g, 218.3 mmol). With sodium carbonate in acetonitrile Patent; ARDENT PHARMACEUTICALS, INC.; WO2006/113468; (2006); (A2) English View in Reaxys General procedure for the preparation of compounds 11-16, 18-25 and 28 General procedure: Piperazine (3.0 equiv.) and K2CO3 (1.0 equiv) were mixed in THF (50 mL) under reflux condition. Subsequently, 68-82 (1.0 equiv) were added, and refluxing was continued for another three hours.The reaction mixture was concentrated in vacuo and partitioned between water and DCM. Theorganic phase was washed with brine and dried over Na2SO4. Products were purified by flash chromatography (DCM : MeOH = 8:1). With potassium carbonate in tetrahydrofuran, Time= 3h, Reflux Obreque-Balboa, Jos Esteban; Sun, Qiu; Bernhardt, Günther; König, Burkhard; Buschauer, Armin; European Journal of Medicinal Chemistry; vol. 109; (2016); p. 124 - 133 View in Reaxys Cl Cl

N Cl

N H

Rx-ID: 25187150 View in Reaxys 81/493

58/195

2016-06-04 14:03:19

Yield

Conditions & References 1 : 1-(3,4-Dichlorobenzyl)piperazine EXAMPLE 1 1-(3,4-Dichlorobenzyl)piperazine A mixture of 39.0 g (0.2 moles) of 3,4-dichlorobenzyl chloride, 31.6 g (0.2 moles) of ethyl N-piperazinocarboxylate, 22.0 g (0.21 moles) of anhydrous sodium carbonate and 200 ml of xylene was refluxed for 3 hours using a DeanStark trap. Then the mixture was stirred at room temperature for 16 hours, filtered and washed with xylene. The filtrate was evaporated in vacuo and gave a syrup. A 750 ml amount of 4N potassium hydroxide in 95percent ethanol was added to the syrup and the mixture was refluxed for 18 hours. The reaction mixture was evaporated to a paste and 250 ml of water was added. The solution was extracted twice with 250 ml of chloroform. The extracts were combined, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and gave a syrup. The syrup was distilled, bp 132°-135° C./0.05 mm of mercury and gave 9.3 g of 1-(3,4-dichlorobenzyl)piperazine as a colorless liquid. With potassium hydroxide, sodium carbonate, mercury in anhydrous xylene, ethanol, water Patent; American Cyanamid Company; US4562189; (1985); (A1) English View in Reaxys 5 : 1-(5-Amino-4H-1,2,4-triazol-3-yl)-4-(3,4-dichlorobenzyl)piperazine EXAMPLE 5 1-(5-Amino-4H-1,2,4-triazol-3-yl)-4-(3,4-dichlorobenzyl)piperazine A mixture of 39.0 g (0.2 moles) of 3,4-dichlorobenzyl chloride, 31.6 g (0.2 moles) of ethyl N-piperazinocarboxylate, 22.0 g (0.21 moles) of anhydrous sodium carbonate and 200 ml of xylene was refluxed for 3 hours using a DeanStark trap. Then the mixture was stirred at room temperature for 16 hours, filtered and washed with xylene. The filtrate was evaporated in vacuo to give a syrup. A 750 ml amount of 4N potassium hydroxide in 95percent ethanol was added to the syrup and the mixture was refluxed for 18 hours. The reaction mixture was evaporated to a paste and 250 ml of water was added. The solution was extracted twice with 250 ml of chloroform. The extracts were combined, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and gave a syrup. The syrup was distilled, bp 132°-135° C./0.05 mm of mercury and gave 9.3 g of 1-(3,4-dichlorobenzyl)piperazine as a colorless liquid. With potassium hydroxide, sodium carbonate, mercury in anhydrous xylene, ethanol, water Patent; American Cyanamid Company; US4582833; (1986); (A1) English View in Reaxys

NH N

F F F

Rx-ID: 25858155 View in Reaxys 82/493 Yield 50%

Conditions & References 268.2 : Step 2. Step 2. 1-(3-Trifluoromethylbenzyl)piperazine. To a solution of 139 (1.4 g, 4.2 mmol) in CH2Cl2 (15 ml) was added TFA (1.3 ml, 17 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction was mixed with water (10 ml), brine (3.0 ml), made basic with 2N NaOH (2.0 ml), and extracted with CH2Cl2 (3*20 ml).

59/195

2016-06-04 14:03:19

The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give product 140 as an off-white solid (0.5 g, 50percent). Patent; Wu, Chengde; Anderson, C. Eric; Bui, Huong; Dupre, Brian; Gao, Daxin; Holland, George W.; Kassir, Jamal; Li, Wen; Wang, Junmei; US2005/54850; (2005); (A1) English View in Reaxys Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 1-(2-methyl-benzyl)-piperazine hydrochloride; 1-(4-methyl-benzyl)-piperazine hydrochloride; 1 -(2-nitrobenzyl)piperazine dihydrochloride; 1-(3-nitrobenzyl)piperazine dihydrochloride; 1-[3-(trifluoromethyl)benzyl]piperazine; 1-(2,4,6-trimethylbenzyl)piperazine. Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys

N NH I

Rx-ID: 28136252 View in Reaxys 83/493 Yield

Conditions & References Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 1-(4-fluorobenzyl)piperazine; 1-(3-fluoro-benzyl)-piperazine hydrochloride; 1-(2-fluoro-benzyl)-piper-azine hydrochloride; 1-(2-iodobenzyl)piperazine; 1-(3-iodobenzyl)piperazine; 1-(4-iodobenzyl)-piperazine; 1-(2-methylbenzyl)piperazine; 1-(3-methylbenzyl)piperazine; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys 63.A Patent; JANSSEN PHARMACEUTICA N.V.; WO2008/153752; (2008); (A2) English View in Reaxys

F N

O O

F F

HN F

2 HO

F O

Rx-ID: 28301712 View in Reaxys 84/493 Yield

Conditions & References 43.A :Tert-butyl 4-(3-(methoxycarbonyl)benzyl)piperazine-1-carboxylate (1.25g, 3.74mmol) was stirred with a 4 / 1 solution of dichloromethane / trifluoroacetic acid (2OmL) for 1 hour at room temperature. The solution was then concentrated under vacuum to afford the title compound (1.73g). MS (ESI) m/z 235.1 [M+H]+ in dichloromethane, Time= 1h, T= 20 °C

60/195

2016-06-04 14:03:19

Patent; N.V. ORGANON; WO2009/24550; (2009); (A1) English View in Reaxys 43.A : A: Methyl 3-(piperazin-1-ylmethyl)benzoate bis(2,2,2-trifluoroacetate) Tert-butyl 4-(3-(methoxycarbonyl)benzyl)piperazine-1-carboxylate (1.25 g, 3.74 mmol) was stirred with a 4/1 solution of dichloromethane/trifluoroacetic acid (20 mL) for 1 hour at room temperature. The solution was then concentrated under vacuum to afford the title compound (1.73 g). MS (ESI) m/z 235.1 [M+H]+ in dichloromethane, Time= 1h, T= 20 °C Patent; N.V. Organon and pharmacopeia, Inc.; US2009/264416; (2009); (A1) English View in Reaxys O N

Rx-ID: 28301843 View in Reaxys 85/493 Yield

Conditions & References 40.B :To a stirred mixture of tert-butyl 4-(3-(tert-butylcarbamoyl)-2-fluorobenzyl)piperazine-1- carboxylate (2.54mmol, 1g) in dichloromethane at room temperature was added trifluoroacetic acid (53.9mmol, 4mL, 6.14g). After 3 hours stirring the reaction was concentrated under reduced pressure. The residue was taken up in dichloromethane/methanol and loaded on to strong cation exchange column (10g) and washed with dichloromethane- <n="76"/>/methanol. Elution of the column with 2M ammonia in methanol gave the title compound(636mg). MS (ESI) m/z 294.4 [M+H]+ Stage 1: With trifluoroacetic acid in dichloromethane, Time= 3h, T= 20 °C Stage 2: With ammonia in methanol, dichloromethane Patent; N.V. ORGANON; WO2009/24550; (2009); (A1) English View in Reaxys 40.B : B: N-tert-Butyl-2-fluoro-3-(piperazin-1-ylmethyl)benzamide To a stirred mixture of tert-butyl 4-(3-(tert-butylcarbamoyl)-2-fluorobenzyl)piperazine-1-carboxylate (2.54 mmol, 1 g) in dichloromethane at room temperature was added trifluoro-acetic acid (53.9 mmol, 4 mL, 6.14 g). After 3 hours stirring the reaction was concentrated under reduced pressure. The residue was taken up in dichloromethane/methanol and loaded on to strong cation exchange column (10 g) and washed with dichloromethane/methanol. Elution of the column with 2M ammonia in methanol gave the title compound (636 mg). MS (ESI) m/z 294.4 [M+H]+ Stage 1: With trifluoroacetic acid in dichloromethane, Time= 3h, T= 20 °C Stage 2: With ammonia in methanol Patent; N.V. Organon and pharmacopeia, Inc.; US2009/264416; (2009); (A1) English View in Reaxys

O O

H N

F F F

Rx-ID: 28301850 View in Reaxys 86/493 Yield

Conditions & References 45.B :tert-Butyl 4-(3-(1 ,1 ,1 -trifluoro-2-methylpropan-2-ylcarbamoyl)benzyl)piperazine-1 - carboxylate (0.792mmol, 340mg) wsa dissolved in dichloromethane (3ml_) and trifluoroacetic acid (7.92mmol, 0.588ml_, 903mg) added. After 2 hours stirring, the mixture was taken up in dichloromethane, loaded on to a strong cation exchange column (5g) and washed with dichloromethane/methanol. Elution of the column with 2M ammonia in methanol gave the title compound (260mg). MS (ESI) m/z 330.3 [M+H]+ Stage 1: With trifluoroacetic acid in dichloromethane, Time= 2h Stage 2: With ammonia in methanol, dichloromethane

61/195

2016-06-04 14:03:19

Patent; N.V. ORGANON; WO2009/24550; (2009); (A1) English View in Reaxys 45.B : B: 3-(Piperazin-1-ylmethyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide tert-Butyl 4-(3-(1,1,1-trifluoro-2-methylpropan-2-ylcarbamoyl)benzyl)piperazine-1-carboxylate (0.792 mmol, 340 mg) wsa dissolved in dichloromethane (3 mL) and trifluoroacetic acid (7.92 mmol, 0.588 ml, 903 mg) added. After 2 hours stirring, the mixture was taken up in dichloromethane, loaded on to a strong cation exchange column (5 g) and washed with dichloromethane/methanol. Elution of the column with 2M ammonia in methanol gave the title compound (260 mg). MS (ESI) m/z 330.3 [M+H]+ Stage 1: With trifluoroacetic acid in dichloromethane, Time= 2h Stage 2: With ammonia in methanol, dichloromethane Patent; N.V. Organon and pharmacopeia, Inc.; US2009/264416; (2009); (A1) English View in Reaxys

O O

HN N N

H N

Rx-ID: 28301852 View in Reaxys 87/493 Yield

Conditions & References 48.C :To a stirred solution of (R)-tert-butyl 4-(3-(sec-butylcarbamoyl)benzyl)piperazine- 1-carboxylate (5.33mmol, 2g) in dichloromethane (1OmL) was added trifluoroacetic acid (5mL). The reaction mixture was stirred for 24 hours then was concentrated under reduced pressure. Purification by strong cation exchange column chromatography gave the title compound (1.4g). MS (ESI) m/z 276.3 ([M+H]+). With trifluoroacetic acid in dichloromethane, Time= 24h Patent; N.V. ORGANON; WO2009/24550; (2009); (A1) English View in Reaxys 48.C : C: (R)-N-sec-Butyl-3-(piperazin-1-ylmethyl)benzamide To a stirred solution of (R)-tert-butyl 4-(3-(sec-butylcarbamoyl)benzyl)piperazine-1-carboxylate (5.33 mmol, 2 g) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred for 24 hours then was concentrated under reduced pressure. Purification by strong cation exchange column chromatography gave the title compound (1.4 g). MS (ESI) m/z 276.3 ([M+H]+). With trifluoroacetic acid in dichloromethane, Time= 24h Patent; N.V. Organon and pharmacopeia, Inc.; US2009/264416; (2009); (A1) English View in Reaxys O N O

N H

2 HCl

O N H

N NH

Rx-ID: 28301856 View in Reaxys 88/493 Yield

Conditions & References 1.A.3 :The intermediate tert-butyl 4-(3-(tert-butylcarbamoyl)benzyl)piperazine-1- carboxylate (5g, 13.3mmol) was stirred with a 14percent wt./wt. solution of dry hydrochloric acid in anhydrous ethanol (2OmL) for 4 hours at room temperature. The solution was then concentrated under vacuum to afford the title compound (4.66g). MS (ESI) m/z 276.2 [M+H]+ With hydrogenchloride in ethanol, Time= 4h, T= 20 °C Patent; N.V. ORGANON; WO2009/24550; (2009); (A1) English

62/195

2016-06-04 14:03:19

View in Reaxys 1.A.3 :The intermediate tert-butyl 4-(3-(tert-butylcarbamoyl)benzyl)piperazine-1-carboxylate (5 g, 13.3 mmol) was stirred with a 14percent wt./wt. solution of dry hydrochloric acid in anhydrous ethanol (20 mL) for 4 hours at room temperature. The solution was then concentrated under vacuum to afford the title compound (4.66 g).MS (ESI) m/z 276.2 [M+H]+ With hydrogenchloride in ethanol, Time= 4h, T= 20 °C Patent; N.V. Organon and pharmacopeia, Inc.; US2009/264416; (2009); (A1) English View in Reaxys N

N H

Rx-ID: 28443466 View in Reaxys 89/493 Yield

Conditions & References Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 1-(2-chloro-benzyl)-piperazine hydrochloride; 1-(4-chloro-benzyl)-piperazine hydrochloride; 1-(2-chloro-4-fluoro-benzyl)-piperazine; 1-(2-chloro-6-fluorobenzyl)piperazine; 1-(3-cyanobenzyl)piperazine; 1-(2,4-dichlorobenzyl)piperaz-ine; 1-(2,6-dichlorobenzyl)piperazine; 1-(3,4-dichlorobenzyl)piperazine; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys 43 Patent; GRUENENTHAL GmbH; US2010/152158; (2010); (A1) English View in Reaxys

N H

Rx-ID: 28443487 View in Reaxys 90/493 Yield 88 %

63/195

2016-06-04 14:03:19

dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography to yield pure 1-benzylpiperazine in tetrahydrofuran, Time= 2.5h, Reflux Patent; The Board of Trustees of the University lllinois; HERGENROTHER, Paul J.; US2013/96133; (2013); (A1) English View in Reaxys Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 1-(3-fluorobenzyl)piperazine; 1-(4-fluorobenzyl)piperazine; 1-(3-fluoro-benzyl)-piperazine hydrochloride; 1-(2-fluoro-benzyl)-piper-azine hydrochloride; 1-(2-iodobenzyl)piperazine; 1-(3-iodobenzyl)piperazine; 1-(4-iodobenzyl)-piperazine; 1-(2-methylbenzyl)piperazine; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys

N O

N H

Rx-ID: 29108473 View in Reaxys 91/493 Yield

Conditions & References With trifluoroacetic acid in toluene, Time= 1.2h, T= 20 °C Perez, Michel; Lamothe, Marie; Maraval, Catherine; Mirabel, Etienne; Loubat, Chantal; Planty, Bruno; Horn, Clemens; Michaux, Julien; Marrot, Sebastien; Letienne, Robert; Pignier, Christophe; Bocquet, Arnaud; Nadal-Wollbold, Florence; Cussac, Didier; De Vries, Luc; Le Grand, Bruno; Journal of Medicinal Chemistry; vol. 52; nb. 19; (2009); p. 5826 - 5836 View in Reaxys 4.1.2 General procedure for the synthesis of 1-(3-substituted benzyl)piperazines 4a–g General procedure: These compounds were prepared by means of the previously reported methods [44]. To a solution of tert-butyl piperazine-1-carboxylate (0.559g, 3.0mmol) and triethylamine (0.63mL, 3.3mmol) in CH2Cl2 (15mL) appropriate substituted benzyl chlorides or benzyl bromides 2a–g (3.6mmol) were added. After stirring the mixture at room temperature overnight, it was then diluted with H2O and the organics extracted with CH2Cl2 (2×20mL), dried over MgSO4, and concentrated under reduced pressure. Purification of the crude material by flash column chromatography (SiO2, PE/AcOEt, 60/40) gave the corresponding intermediates. These intermediates (2.49mmol) were then treated with TFA (5.75mL, 76.8mmol) in toluene (15mL) and stirred for 80min at room temperature. After the removal of the solvent under reduced pressure, the residue was diluted with aqueous NaOH (1N) and the organics extracted with CH2Cl2 (2×20mL), dried over MgSO4, and concentrated under reduced pressure to give the desired compounds 4a–g (72–89percent). With trifluoroacetic acid in toluene, Time= 1.33333h, T= 20 °C Sadeghzadeh, Masoud; Sheibani, Shahab; Ghandi, Mehdi; Daha, Fariba Johari; Amanlou, Massoud; Arjmand, Mohammad; Hasani Bozcheloie, Abolfazl; European Journal of Medicinal Chemistry; vol. 64; (2013); p. 488 - 497 View in Reaxys

64/195

2016-06-04 14:03:19

NH 2

N H

Rx-ID: 29457861 View in Reaxys 92/493 Yield

Conditions & References

97 %

With [Pd(η3-1-Ph-allyl)(μ-Cl)]2, (Mor-DalPhos), ammonia, sodium t-butanolate in 1,4-dioxane, Time= 20h, T= 110 °C , Inert atmosphere, chemoselective reaction Lundgren, Rylan J.; Peters, Brendan D.; Alsabeh, Pamela G.; Stradiotto, Mark; Angewandte Chemie - International Edition; vol. 49; nb. 24; (2010); p. 4071 - 4074 View in Reaxys

68%

With bis(1,5-cyclooctadiene)nickel (0), Josiphos SL-J003-1, ammonia, lithium tert-butylate in 1,4-dioxane, toluene, Time= 16h, T= 110 °C , Sealed tube, chemoselective reaction Borzenko, Andrey; Rotta-Loria, Nicolas L.; Macqueen, Preston M.; Lavoie, Christopher M.; McDonald, Robert; Stradiotto, Mark; Angewandte Chemie - International Edition; vol. 54; nb. 12; (2015); p. 3773 - 3777; Angew. Chem.; vol. 127; nb. 12; (2015); p. 3844 - 3848,5 View in Reaxys

O E

N O

Rx-ID: 30315121 View in Reaxys 93/493 Yield 80 %

Conditions & References 52.A : Step A: Step A: preparation of (E)-3-(4-piperazin-1-ylmethyl-phenyl)-acrylic acid methyl ester To a stirred solution of 4-[4-((E)-2-methoxycarbonyl-vinyl)-benzyl]-piperazine-1-carboxylic acid tent-butyl ester (11.17 g, 29.4 mmol) in dichloromethane (100 mL) is added 4 N HCl in dioxane (200 mL). The reaction mixture is stirred for 4 h, concentrated in vacuo, triturated with ether, and filtered to yield 10.3 g of a white solid. The solid is suspended in 500 mL dichloromethane and washed with saturated sodium bicarbonate (2*250 mL), dried with magnesium sulfate, filtered and concentrated in vacuo to provide (E)-3-(4-piperazin-1-ylmethyl-phenyl)acrylic acid methyl ester as a white solid (6.52 g, 80percent yield). With hydrogenchloride in 1,4-dioxane, dichloromethane, Time= 4h Patent; Novartis AG; US2011/53925; (2011); (A1) English View in Reaxys

80 %

52.A :To a stirred solution of 4-[4-((E)-2-methoxycarbonyl-vinyl)-benzyl]-piperazine- l - carboxy.ic acid er -butyl ester ( 1 1 . 17 g, 29.4 mmol) in dichloromethane ( 100 mL) is added 4 N HC1 in dioxane (200 mL). The reaction mixture is stirred for 4 h, concentrated in vacuo, triturated with ether, and filtered to yield 10.3 g of a white solid. The solid is suspended in 500 mL dichloromethane and washed with saturated sodium bicarbonate (2 x 250 mL), dried with magnesium sulfate, filtered and concentrated in vacuo to provide (E)-3-(4-piperazin- l - ylmethyl-phenyi)-acrylic acid methyl ester as a white solid (6.52 g, 80percent yield). With hydrogenchloride in 1,4-dioxane, dichloromethane, Time= 4h

65/195

2016-06-04 14:03:19

Patent; NOVARTIS AG; CHO, Young Shin; JIANG, Lei; SHULTZ, Michael; CHEN, Christine Hiu-Tung; LIU, Gang; LI, Jianke; WO2012/25155; (2012); (A1) English View in Reaxys

H N N

N H

Rx-ID: 31310176 View in Reaxys 94/493 Yield

Conditions & References

81 %

in tetrahydrofuran, Reflux Hsu, Danny C.; Roth, Howard S.; West, Diana C.; Botham, Rachel C.; Novotny, Chris J.; Schmid, Steven C.; Hergenrother, Paul J.; ACS Combinatorial Science; vol. 14; nb. 1; (2012); p. 44 - 50 View in Reaxys in tetrahydrofuran, Time= 3h, Reflux Lu, Jinni; Toy, Patrick H.; Synlett; nb. 12; (2011); p. 1723 - 1726 View in Reaxys

N O F F

F F

Rx-ID: 35080428 View in Reaxys 95/493 Yield

Conditions & References Reaction Steps: 2 1: sodium iodide / tetrahydrofuran / 1 h / 20 °C 2: trifluoroacetic acid; water / 0.5 h / 20 °C With water, trifluoroacetic acid, sodium iodide in tetrahydrofuran Patent; Shanghai Sun-Sail Pharmaceutical Science and Technology Co., Ltd; WANG, Tiancai; XIN, Ting; FAN, Houxing; CHEN, Yilang; EP2573090; (2013); (A1) English View in Reaxys Reaction Steps: 2 1: sodium iodide / tetrahydrofuran / 12 h / 20 °C 2: trifluoroacetic acid / 0.5 h / 20 °C With trifluoroacetic acid, sodium iodide in tetrahydrofuran Patent; Wang, Tiancai; Xin, Ting; Fan, Houxing; Chen, Yilang; US2013/143864; (2013); (A1) English View in Reaxys OH O

HBr N NH

N H

Rx-ID: 36852121 View in Reaxys 96/493 Yield

Conditions & References 1 : Example -1 Example -1 Preparation 4-hydroxybenzylpiperazine 2 To a solution of hydrobromic acid 48percent in water (100ml) was added 4-methoxybenzylpiperazine hydrochloride 1 (10g, 41.2 mM) and the suspension was heated at reflux for 4 hours.

66/195

2016-06-04 14:03:19

The solution was then cooled to room temperature and concentrated to dryness to give a solid. Water was then added to the solid and the solution was stirred for 1 hour. The solid was then filtered, washed by water and dried at high vacuum to give the 4-hydroxybenzylpiperazine dihydrobromide 2 (6.3g, 43.2percent) With hydrogen bromide in water Patent; Randox Laboratories Ltd.; Benchikh, Elouard; Fitzgerald, Peter; Lowry, Philip; McConnell, Ivan; EP2679241; (2014); (A1) English View in Reaxys 1 : Preparation of 4-hydroxybenzylpiperazine dihydrobromide 2 Example-1 Preparation of 4-hydroxybenzylpiperazine dihydrobromide 2 To a solution of hydrobromic acid 48percent in water (100 ml) was added 4-methoxybenzylpiperazine hydrochloride 1 (10 g, 41.2 mM) and the suspension was heated at reflux for 4 hours. The solution was then cooled to room temperature and concentrated to dryness to give a solid. Water was then added to the solid and the solution was stirred for 1 hour. The solid was then filtered, washed by water and dried at high vacuum to give the 4-hydroxybenzylpiperazine dihydrobromide 2 (6.3 g, 43.2percent) With hydrogen bromide in water Patent; BENCHIKH, Elouard; McCONNELL, Ivan; LOWRY, Philip; FITZGERALD, Peter; US2014/4623; (2014); (A1) English View in Reaxys

2 HCl

N NH OH

Rx-ID: 39103131 View in Reaxys 97/493 Yield

Conditions & References Reaction Steps: 2 1.1: acetic acid / methanol / 1 h / 20 °C / |Inert atmosphere 1.2: 18 h / |Inert atmosphere 2.1: hydrochlorid acid / methanol; 1,4-dioxane / 1 h / |Inert atmosphere With hydrochlorid acid, acetic acid in 1,4-dioxane, methanol Reekie, Tristan A.; McGregor, Iain S.; Kassiou, Michael; Tetrahedron Letters; vol. 55; nb. 33; (2014); p. 4568 4571 View in Reaxys Jorgensen, William T.; Gulliver, Damien W.; Werry, Eryn L.; Reekie, Tristan; Connor, Mark; Kassiou, Michael; European Journal of Medicinal Chemistry; vol. 108; (2016); p. 730 - 740 View in Reaxys

N O

Rx-ID: 39245994 View in Reaxys 98/493 Yield 100 %

Conditions & References Methyl 4-(piperazin-1-ylmethyl)benzoate Methyl 4-(piperazin-l-ylmethyl)benzoate tert-butyl 4-(4-(methoxycarbonyl)benzyl)piperazine-l-carboxylate (1.5 g, 4.49 mmol) was dissolved in a mixture of trifluoroacetic acid (4.0 mL) and DCM (13.5 mL). The solution was stirred at

67/195

2016-06-04 14:03:19

room temperature overnight, and then was evaporated to dryness in vacuum to give the product as colourless oil. (1.0 g, quant.VH MN (300MHz, CDC ) δ 7.95 (d, J = 8.3 Hz, 2H, Har), 7.37 (d, J = 8.3 Hz, 2H, Har), 3.87 (s, 3H, CH3), 3.50 (s,2H, CH2), 2.86 (t, J = 5.0 Hz, 4H, 2xCH2), 2.38 (t, J = 5.0 Hz, 4H, 2xCH2), 1.89 (s, 1H, NH). 13C RMN (75 MHz, CDCb) δ 167.3 (C), 144.0 (2xC), 129.8 (2xCH), 129.2 (2xCH), 63.5 (CH2), 54.7 (2xCH2), 52.3 (CH3), 46.3 (2xCH2). With trifluoroacetic acid in dichloromethane, T= 20 °C Patent; UNIVERSITA' DEGLI STUDI DI MILANO - BICOCCA; UNIVERSITÉ DE GENÈVE; UNIVERSITÉ CLAUDE BERNARD LYON 1; GAMBACORTI-PASSERINI, Carlo; MOLOGNI, Luca; SCAPOZZA, Leonardo; BISSON, William; GOEKJIAN, Peter; BENOIT, Joseph; WO2015/1024; (2015); (A1) English View in Reaxys 95 %

With trifluoroacetic acid in dichloromethane, T= 25 °C Wang, Modi; Mao, Zhifeng; Kang, Tian-Shu; Wong, Chun-Yuen; Mergny, Jean-Louis; Leung, Chung-Hang; Ma, Dik-Lung; Chemical Science; vol. 7; nb. 4; (2016); p. 2516 - 2523 View in Reaxys

H N N

N H

Br N H

Rx-ID: 16583 View in Reaxys 99/493 Yield

Conditions & References With xylene Morren et al.; Industrie Chimique Belge; vol. 22; (1957); p. 409,416 View in Reaxys

H N Cl

N H

Rx-ID: 16616 View in Reaxys 100/493 Yield

Conditions & References T= 130 °C Patent; Monsanto Chem. Co.; US2451645; (1947) View in Reaxys Cl Cl

Cl 2 H

N Cl

N H

Rx-ID: 113246 View in Reaxys 101/493 Yield

Conditions & References With ethanol, sodium carbonate, benzene, anschl. Erh. mit wss. HCl Baltzly et al.; Journal of the American Chemical Society; vol. 76; (1954); p. 1165 View in Reaxys

68/195

2016-06-04 14:03:19

N H

Rx-ID: 158897 View in Reaxys 102/493 Yield

Conditions & References With hydrogenchloride Fujii et al.; Yakugaku Zasshi; vol. 74; (1954); p. 1049; ; (1955); p. 11666 View in Reaxys O NH N

N N H

Rx-ID: 320798 View in Reaxys 103/493 Yield

Conditions & References With nickel, platinum, benzene, Hydrogenation Mosher et al.; Journal of the American Chemical Society; vol. 75; (1953); p. 4949 View in Reaxys

N H

Rx-ID: 340989 View in Reaxys 104/493 Yield

Conditions & References With acetyl chloride, zinc(II) chloride, anschl. mit Piperazin und Methanol Patent; Miles Labor. Inc.; US2792398; (1954) View in Reaxys

Cl 2 H

N H Br

Rx-ID: 350134 View in Reaxys 105/493 Yield

Conditions & References With hydrogenchloride Baltzly et al.; Journal of the American Chemical Society; vol. 76; (1954); p. 1165 View in Reaxys

69/195

2016-06-04 14:03:19

N N

N H O

Rx-ID: 360346 View in Reaxys 106/493 Yield

Conditions & References With potassium hydroxide Morren et al.; Bulletin des Societes Chimiques Belges; vol. 60; (1951); p. 282,288 View in Reaxys

6 H

N H

Rx-ID: 662129 View in Reaxys 107/493 Yield

Conditions & References With ethanol Morren et al.; Bulletin des Societes Chimiques Belges; vol. 60; (1951); p. 282,288 View in Reaxys

H N Cl

N H

Br N H

Rx-ID: 759273 View in Reaxys 108/493 Yield

Conditions & References With ethanol Patent; Brit. Drug Houses Ltd.; GB840358; (1957) View in Reaxys

H N

Cl 2 H

O N H

Rx-ID: 1495420 View in Reaxys 109/493 Yield 36 %

Conditions & References With sodium hydroxide in formic acid, 1.) 100 deg C, 5 h; 2.) reflux, 2 h Ohtaka; Fujimoto; Yoshida; Kanazawa; Ito; Tsukamoto; Chemical and Pharmaceutical Bulletin; vol. 35; nb. 7; (1987); p. 2782 - 2791 View in Reaxys

70/195

2016-06-04 14:03:19

H N

Cl 8 H

N H

Rx-ID: 1495426 View in Reaxys 110/493 Yield 35 %

O O

H N

N H

Cl 2 H

O N H

Rx-ID: 1495537 View in Reaxys 111/493 Yield 47 %

H N

Cl 2 H

N H

Rx-ID: 1495653 View in Reaxys 112/493 Yield 27 %

O O H N

N H

O 4

O O

Cl 8 H N

N H

Rx-ID: 1495659 View in Reaxys 113/493 Yield 34 %

Conditions & References With sodium hydroxide in formic acid, 1.) 100 deg C, 5 h; 2.) reflux, 2 h

71/195

2016-06-04 14:03:19

Ohtaka; Fujimoto; Yoshida; Kanazawa; Ito; Tsukamoto; Chemical and Pharmaceutical Bulletin; vol. 35; nb. 7; (1987); p. 2782 - 2791 View in Reaxys

H N

Cl 2 H N

N H

Rx-ID: 1495918 View in Reaxys 114/493 Yield 35 %

H N Cl 2 H

N H

O N H

Rx-ID: 1495919 View in Reaxys 115/493 Yield 35 %

O H N

O 4

Cl 8 H N

N H

O N H

Rx-ID: 1495928 View in Reaxys 116/493 Yield 34 %

O O

H N

N H

Cl 2 H

O O

N H

Rx-ID: 1496102 View in Reaxys 117/493

72/195

2016-06-04 14:03:19

Yield

Conditions & References

32 %

With sodium hydroxide in formic acid, 1.) 100 deg C, 5 h; 2.) reflux, 2 h Ohtaka; Fujimoto; Yoshida; Kanazawa; Ito; Tsukamoto; Chemical and Pharmaceutical Bulletin; vol. 35; nb. 7; (1987); p. 2782 - 2791 View in Reaxys

O O

H N

O Cl

N H

Cl 2 H

O N H

Rx-ID: 1496108 View in Reaxys 118/493 Yield

Conditions & References

38.5 g

in ethanol, Time= 2h, T= 60 °C Ohtaka; Fujimoto; Yoshida; Kanazawa; Ito; Tsukamoto; Chemical and Pharmaceutical Bulletin; vol. 35; nb. 7; (1987); p. 2782 - 2791 View in Reaxys

O N

N H

Rx-ID: 2582575 View in Reaxys 119/493 Yield

Conditions & References With hydrogenchloride in methanol, Time= 2h, Heating Carpino, Louis A.; Mansour, E. M. E.; Knapczyk, Jerome; Journal of Organic Chemistry; vol. 48; nb. 5; (1983); p. 666 - 669 View in Reaxys

N H

Rx-ID: 2616907 View in Reaxys 120/493 Yield

Conditions & References With NaCHO3 Carpino, Louis A.; Mansour, E. M. E.; Knapczyk, Jerome; Journal of Organic Chemistry; vol. 48; nb. 5; (1983); p. 666 - 669 View in Reaxys

73/195

2016-06-04 14:03:19

N N

N H F

Rx-ID: 2663598 View in Reaxys 121/493 Yield

Conditions & References

72 %

With potassium hydroxide in ethanol, Time= 3h, T= 120 °C Bartl; Dlabac; Protiva; Collection of Czechoslovak Chemical Communications; vol. 45; nb. 11; (1980); p. 3182 3189 View in Reaxys

N H

Rx-ID: 3577488 View in Reaxys 122/493 Yield

Conditions & References With sodium hydroxide, Yield given Meyer; Tomcufcik; Chan; Haug; Journal of Medicinal Chemistry; vol. 32; nb. 3; (1989); p. 593 - 597 View in Reaxys

N H

Rx-ID: 3579577 View in Reaxys 123/493 Yield

Conditions & References With sodium hydroxide, Yield given Meyer; Tomcufcik; Chan; Haug; Journal of Medicinal Chemistry; vol. 32; nb. 3; (1989); p. 593 - 597 View in Reaxys Br

N N N

O O

N H

Rx-ID: 3584575 View in Reaxys 124/493 Yield

Conditions & References With sodium hydroxide, Time= 3h, Yield given Meyer; Tomcufcik; Chan; Haug; Journal of Medicinal Chemistry; vol. 32; nb. 3; (1989); p. 593 - 597 View in Reaxys

74/195

2016-06-04 14:03:19

H N

O O N

N H

Br N H

Rx-ID: 4604405 View in Reaxys 125/493 Yield

Conditions & References

66 %

With potassium carbonate, potassium iodide in various solvent(s), Time= 20h, Heating Masaguer, Christian F.; Ravina, Enrique; Tetrahedron Letters; vol. 37; nb. 29; (1996); p. 5171 - 5174 View in Reaxys

N H

Rx-ID: 4657296 View in Reaxys 126/493 Yield 82 %

Conditions & References With lithium aluminium tetrahydride in tetrahydrofuran, Time= 12h, Ambient temperature Masaguer, Christian F.; Ravina, Enrique; Tetrahedron Letters; vol. 37; nb. 29; (1996); p. 5171 - 5174 View in Reaxys

H N

N H

F F

Rx-ID: 4856005 View in Reaxys 127/493 Yield

Conditions & References With polymer supported cyanoborohydride in methanol, toluene, Time= 72h, Ambient temperature, Yield given Ley, Steven V.; Bolli, Martin H.; Hinzen, Berthold; Gervois, Anne-Geraldine; Hall, Beverley J.; Journal of the Chemical Society - Perkin Transactions 1; nb. 15; (1998); p. 2239 - 2241 View in Reaxys

H N

N H

Rx-ID: 4856016 View in Reaxys 128/493 Yield

75/195

2016-06-04 14:03:19

F H N F

N H

Rx-ID: 4856029 View in Reaxys 129/493 Yield

H N

N H

H N

N H

Rx-ID: 4856036 View in Reaxys 130/493 Yield

O O

H N

O O

N H

Rx-ID: 4856040 View in Reaxys 131/493 Yield

H N

N H

Rx-ID: 4856047 View in Reaxys 132/493 Yield

76/195

2016-06-04 14:03:19

NH 2

H N

NH 2

N H

Rx-ID: 4856068 View in Reaxys 133/493 Yield

N F

F F

Rx-ID: 4904772 View in Reaxys 134/493 Yield

Conditions & References With sodium hydroxide in methanol, Time= 24h, Heating Baziard-Mouysset, Genevieve; Younes, Salouma; Labssita, Youssef; Payard, Marc; Caignard, Daniel-Henri; Rettori, Marie-Claire; Renard, Pierre; Pfeiffer, Bruno; Guardiola-Lemaitre, Beatrice; European Journal of Medicinal Chemistry; vol. 33; nb. 5; (1998); p. 339 - 347 View in Reaxys

O N

N H

Rx-ID: 5024731 View in Reaxys 135/493 Yield

O O

S N

N H

Rx-ID: 5147205 View in Reaxys 136/493 Yield 74 %

Conditions & References With chloro-trimethyl-silane, sodium iodide in acetonitrile, Time= 3h, Heating

77/195

2016-06-04 14:03:19

Sabitha, Gowravaram; Subba Reddy; Abraham, Sunny; Yadav; Tetrahedron Letters; vol. 40; nb. 8; (1999); p. 1569 - 1570 View in Reaxys

Cl Cl

N N

N O

N H

Rx-ID: 5164306 View in Reaxys 137/493 Yield

Conditions & References With potassium hydroxide in ethanol, Time= 2.5h, T= 130 °C Ferte, Jacques; Kuehnel, Jean-Marc; Chapuis, Genevieve; Rolland, Yves; Lewin, Guy; Schwaller, Marc A.; Journal of Medicinal Chemistry; vol. 42; nb. 3; (1999); p. 478 - 489 View in Reaxys

O O

N N

N O

N H

Rx-ID: 5169989 View in Reaxys 138/493 Yield

O O

N N O

N H

Rx-ID: 5170063 View in Reaxys 139/493 Yield

78/195

2016-06-04 14:03:19

O O

O N

NH O

Rx-ID: 5171322 View in Reaxys 140/493 Yield

O O

O N

N O

N H

Rx-ID: 5171325 View in Reaxys 141/493 Yield

N Br

N H

Rx-ID: 5206666 View in Reaxys 142/493 Yield

Conditions & References With hydrogen bromide, Time= 1h, Heating Tapia, Ines; Alonso-Cires, Luisa; Lopez-Tudanca, Pedro Luis; Mosquera, Ramon; Labeaga, Luis; Innerarity, Ana; Orjales, Aurelio; Journal of Medicinal Chemistry; vol. 42; nb. 15; (1999); p. 2870 - 2880 View in Reaxys

79/195

2016-06-04 14:03:19

O S

N N

N H

Rx-ID: 5280785 View in Reaxys 143/493 Yield

Conditions & References

80 %

With potassium fluoride on basic alumina, Time= 0.1h, microwave irradiation, Substitution Sabitha, Gowravaram; Abraham, Sunny; Reddy, B. V. Subba; Yadav; Synlett; nb. 11; (1999); p. 1745 - 1746 View in Reaxys

H N

N H

N N

N H

Rx-ID: 5313630 View in Reaxys 144/493 Yield

Conditions & References in ethanol, Time= 24h, Alkylation Cuppoletti, Andrea; Dagostin, Claudio; Florea, Cristina; Galli, Carlo; Gentili, Patrizia; Lanzalunga, Osvaldo; Petride, Aurica; Petride, Horia; Chemistry - A European Journal; vol. 5; nb. 10; (1999); p. 2993 - 2999 View in Reaxys

H N

N H

B H

H N

N H

Rx-ID: 5318205 View in Reaxys 145/493 Yield 100 %

Conditions & References With sodium tetrahydroborate, triethyl amine hydrochloride, acetic acid in dichloromethane, Complex formation Perrio-Huard, Cecile; Aubert, Catherine; Lasne, Marie-Claire; Journal of the Chemical Society, Perkin Transactions 1; nb. 3; (2000); p. 311 - 316 View in Reaxys

H N

C6H5CH2NX (X-halogen)

N H

Rx-ID: 5440185 View in Reaxys 146/493 Yield 78 %

Conditions & References With conc. HX in ethanol, Heating Zlatoidsky; Maliar; European Journal of Medicinal Chemistry; vol. 31; nb. 9; (1996); p. 669 - 673

80/195

2016-06-04 14:03:19

View in Reaxys

3-methyl-benzyl halide

N H

Rx-ID: 5444135 View in Reaxys 147/493 Yield

Conditions & References Morren; Strubbe; ; vol. 10; (1955); p. 239,242 View in Reaxys

N H

Rx-ID: 5864502 View in Reaxys 148/493 Yield

Conditions & References Piperazin*6H2O, p-Isopropyl-benzylhalogenid, A. Ikeda; Yakugaku Zasshi; vol. 89; (1969); p. 677,685; ; vol. 71; nb. 61339; (1969) View in Reaxys

N H

Rx-ID: 5865655 View in Reaxys 149/493 Yield

Conditions & References Patent; U.S. Vit. Pharm.; BE617599; (1962); ; vol. 59; nb. 646; (1963) View in Reaxys OH O

N H

Rx-ID: 5872913 View in Reaxys 150/493 Yield

Conditions & References Trimetazidin*2HCl, AlCl3 Naito; Osumi; Kitao; Tetsuo; Kitaura; Fujita; Journal of pharmaceutical sciences; vol. 60; nb. 8; (1971); p. 1257 1259 View in Reaxys

81/195

2016-06-04 14:03:19

O Cl

N H

Rx-ID: 5880858 View in Reaxys 151/493 Yield

Conditions & References Formylpiperazin, 1) Benzylchlorid IV, 2) HCl, Erhitzen Patent; Rhone-Poulenc S.A.; FRM23; (1960); ; vol. 58; nb. 3444e; (1963) View in Reaxys

H 2N

N H

Rx-ID: 6080216 View in Reaxys 152/493 Yield

Conditions & References Aus der entspr. N4-(2-nitrobenzyl)piperazin, Ra/Ni, Hydrazinhydrat Patent; Takeda Chem. Ind.; FR2291757; (1976); DE2551355; (1976); ; vol. 85; nb. 94405 View in Reaxys

N H

Rx-ID: 6085369 View in Reaxys 153/493 Yield

Conditions & References entspr. Formylpiperazin Ii, HCl Mndzhoyan et al.; Armyanskii Khimicheskii Zhurnal; vol. 21; nb. 7; (1968); p. 603,604-614; ; vol. 70; nb. 96754t; (1969) View in Reaxys

N H

Rx-ID: 6088222 View in Reaxys 154/493 Yield

Conditions & References Mndzhoyan et al.; Armyanskii Khimicheskii Zhurnal; vol. 21; nb. 7; (1968); p. 603,604-614; ; vol. 70; nb. 96754t; (1969) View in Reaxys

82/195

2016-06-04 14:03:19

N H

Rx-ID: 6088467 View in Reaxys 155/493 Yield

Conditions & References entspr. Formylpiperazin Ij, HCl Mndzhoyan et al.; Armyanskii Khimicheskii Zhurnal; vol. 21; nb. 7; (1968); p. 603,604-614; ; vol. 70; nb. 96754t; (1969) View in Reaxys Br H 2N

Br N

N H

Rx-ID: 6088492 View in Reaxys 156/493 Yield

Conditions & References N1-Hydro-N4-(2-aminobenzyl)piperazin, 1) Br2, 2) ethanol. HCl Patent; Takeda Chem. Ind.; FR2291757; (1976); DE2551355; (1976); ; vol. 85; nb. 94405 View in Reaxys

N H

Rx-ID: 6089083 View in Reaxys 157/493 Yield

Conditions & References entspr. Formylpiperazin Im, HCl Mndzhoyan et al.; Armyanskii Khimicheskii Zhurnal; vol. 21; nb. 7; (1968); p. 603,604-614; ; vol. 70; nb. 96754t; (1969) View in Reaxys

N H

Rx-ID: 6089105 View in Reaxys 158/493 Yield

Conditions & References entspr. Formylpiperazin Il, HCl Mndzhoyan et al.; Armyanskii Khimicheskii Zhurnal; vol. 21; nb. 7; (1968); p. 603,604-614; ; vol. 70; nb. 96754t; (1969) View in Reaxys

83/195

2016-06-04 14:03:19

O OH

N H

Rx-ID: 6092046 View in Reaxys 159/493 Yield

Conditions & References Piperazin, 4-Halogenmethyl-salicylsaeure Patent; Science Union and Cie.; BE630639; (1963); ; vol. 61; nb. 668; (1964) View in Reaxys

N N

N H

Rx-ID: 8235136 View in Reaxys 160/493 Yield

Conditions & References Craig; Journal of the Chemical Society; (1959); p. 3634 View in Reaxys

Cl O S HO

N H

Rx-ID: 8359700 View in Reaxys 161/493 Yield

Conditions & References Piperazin XXI, Methansulfonat Vejdelek et al.; Collection of Czechoslovak Chemical Communications; vol. 39; (1974); p. 2276,2277,2280 View in Reaxys

Z O

N H

Rx-ID: 8361971 View in Reaxys 162/493 Yield

Conditions & References 1-(2,4,6-Trimethylbenzyl)-piperazin, Maleinsaeure Protiva et al.; Collection of Czechoslovak Chemical Communications; vol. 41; (1976); p. 1034,1037, 1040 View in Reaxys

84/195

2016-06-04 14:03:19

N N N N H

Rx-ID: 8373275 View in Reaxys 163/493 Yield

Conditions & References 1-Benzylpiperazin, CS2, H2O Florvall; Corrodi; Acta Pharmaceutica Suecica; vol. 7; (1970); p. 7,15 View in Reaxys

H N

Rx-ID: 8384992 View in Reaxys 164/493 Yield

Conditions & References Benzylchlorid, 1) Piperazin, 2) Tartrat Vejdelek et al.; Collection of Czechoslovak Chemical Communications; vol. 39; (1974); p. 2276,2277,2280 View in Reaxys

2 HCl

N H Cl

Rx-ID: 8596970 View in Reaxys 165/493 Yield 67 %

Conditions & References With hydrogenchloride, Time= 18h, Heating, Decarboxylation, hydrolysis Radl, Stanislav; Hezky, Petr; Proska, Jan; Hejnova, Lucie; Krejci, Ivan; Archiv der Pharmazie; vol. 333; nb. 5; (2000); p. 107 - 112 View in Reaxys

H N

N N

N H

Rx-ID: 8928736 View in Reaxys 166/493 Yield 45 %

85/195

2016-06-04 14:03:19

H N N

N H

Rx-ID: 8928743 View in Reaxys 167/493 Yield 18 %

H N

N H

Rx-ID: 9177072 View in Reaxys 168/493 Yield 79 %

H N

N O F

N H

F F

Rx-ID: 9177078 View in Reaxys 169/493 Yield 78 %

H N

O N

N H

Rx-ID: 9177081 View in Reaxys 170/493 Yield 61 %

86/195

2016-06-04 14:03:19

F F

H N

N H

F F

N H

Rx-ID: 9177094 View in Reaxys 171/493 Yield

Conditions & References

59 %

in toluene, Time= 2h, T= 85 °C Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

H N

Br N

N H

Br N H

Rx-ID: 9177154 View in Reaxys 172/493 Yield

Conditions & References

75 %

in toluene, Time= 2h, T= 85 °C Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys O NH N

O N 2H

2H 2H

N H

Rx-ID: 9234385 View in Reaxys 173/493 Yield 77 %

Conditions & References With lithium aluminium deuteride in tetrahydrofuran, T= 70 °C Wiegerinck, Peter; Post, Olaf; Hofstede, Leontine; Heuvel, Marcel van den; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 45; nb. 13; (2002); p. 1169 - 1171 View in Reaxys

H N

N H

F O

O N H

Rx-ID: 9236222 View in Reaxys 174/493 Yield 50 %

Conditions & References With sodium cyanoborohydride in ethanol, Time= 18h, Heating Mattson, Ronald J.; Catt, John D.; Keavy, Daniel; Sloan, Charles P.; Epperson, James; Gao, Qi; Hodges, Donald B.; Iben, Lawrence; Mahle, Cathy D.; Ryan, Elaine; Yocca, Frank D.; Bioorganic and Medicinal Chemistry Letters; vol. 13; nb. 6; (2003); p. 1199 - 1202 View in Reaxys

87/195

2016-06-04 14:03:19

HO HO

H N

N H

Rx-ID: 9294017 View in Reaxys 175/493 Yield

Conditions & References

58 %

Time= 24h, T= 140 °C Page, Philip C. Bulman; Heaney, Harry; McGrath, Matthew J.; Sampler, Edward P.; Wilkins, Robert F.; Tetrahedron Letters; vol. 44; nb. 14; (2003); p. 2965 - 2970 View in Reaxys

N N

N H Br

Rx-ID: 9426521 View in Reaxys 176/493 Yield

Conditions & References

77 %

With trifluoroacetic acid in chloroform, Time= 3h, T= 20 °C Bolognesi, Maria Laura; Cavalli, Andrea; Andrisano, Vincenza; Bartolini, Manuela; Banzi, Rita; Antonello, Alessandra; Rosini, Michela; Melchiorre, Carlo; Farmaco; vol. 58; nb. 9; (2003); p. 917 - 928 View in Reaxys

N N

N H

Rx-ID: 9481068 View in Reaxys 177/493 Yield

Conditions & References With 2,3-dicyano-5,6-dichloro-p-benzoquinone in methanol, dichloromethane, Time= 3h, T= 20 °C Godin, Guillaume; Compain, Philippe; Martin, Olivier R.; Synlett; nb. 13; (2003); p. 2065 - 2067 View in Reaxys O N H N Cl N H

N O

N H

Rx-ID: 10211327 View in Reaxys 178/493 Yield 26 %

Conditions & References Time= 0.416667h, T= 65 °C Mehanna, Ahmed S.; Jin, Yung Kim; Bioorganic and Medicinal Chemistry; vol. 13; nb. 13; (2005); p. 4323 - 4331 View in Reaxys

88/195

2016-06-04 14:03:19

O H N Cl

N H

Rx-ID: 10224573 View in Reaxys 179/493 Yield

Conditions & References

87 %

Time= 0.416667h, T= 65 °C Mehanna, Ahmed S.; Jin, Yung Kim; Bioorganic and Medicinal Chemistry; vol. 13; nb. 13; (2005); p. 4323 - 4331 View in Reaxys

F H N Cl

N H

Rx-ID: 10229844 View in Reaxys 180/493 Yield

Conditions & References

91 %

Time= 0.416667h, T= 65 °C Mehanna, Ahmed S.; Jin, Yung Kim; Bioorganic and Medicinal Chemistry; vol. 13; nb. 13; (2005); p. 4323 - 4331 View in Reaxys O

H N

N H

N HO

O O

Rx-ID: 10455629 View in Reaxys 181/493 Yield

Conditions & References With triethylamine in dichloromethane, T= 20 °C Wang, Qiang; Wilson, Claire; Blake, Alexander J.; Collinson, Simon R.; Tasker, Peter A.; Schroeder, Martin; Tetrahedron Letters; vol. 47; nb. 50; (2006); p. 8983 - 8987 View in Reaxys

N O

F HCl

Rx-ID: 11139042 View in Reaxys 182/493 Yield 1.04 g

Conditions & References With hydrogenchloride in 1,4-dioxane, Time= 3h, T= 20 °C Liu, Gang; Lynch, John K.; Freeman, Jennifer; Liu, Bo; Xin, Zhili; Zhao, Hongyu; Serby, Michael D.; Kym, Philip R.; Suhar, Tom S.; Smith, Harriet T.; Cao, Ning; Yang, Ruojing; Janis, Rich S.; Krauser, Joel A.; Cepa, Steven P.; Beno, David W. A.; Sham, Hing L.; Collins, Christine A.; Surowy, Teresa K.; Camp, Heidi S.; Journal of Medicinal Chemistry; vol. 50; nb. 13; (2007); p. 3086 - 3100 View in Reaxys

89/195

2016-06-04 14:03:19

N H

N O

Rx-ID: 11231249 View in Reaxys 183/493 Yield

Conditions & References With trifluoroacetic acid in dichloromethane, Time= 3h, T= 20 °C Palimkar, Sanjay S.; More, Vijaykumar S.; Kumar, P. Harish; Srinivasan, Kumar V.; Tetrahedron; vol. 63; nb. 51; (2007); p. 12786 - 12790 View in Reaxys

HCl

Rx-ID: 11420453 View in Reaxys 184/493 Yield

Conditions & References Reaction Steps: 2 1: Et3N / tetrahydrofuran / 72 h / 20 °C 2: 1.04 g / HCl / dioxane / 3 h / 20 °C With hydrogenchloride, triethylamine in tetrahydrofuran, 1,4-dioxane Liu, Gang; Lynch, John K.; Freeman, Jennifer; Liu, Bo; Xin, Zhili; Zhao, Hongyu; Serby, Michael D.; Kym, Philip R.; Suhar, Tom S.; Smith, Harriet T.; Cao, Ning; Yang, Ruojing; Janis, Rich S.; Krauser, Joel A.; Cepa, Steven P.; Beno, David W. A.; Sham, Hing L.; Collins, Christine A.; Surowy, Teresa K.; Camp, Heidi S.; Journal of Medicinal Chemistry; vol. 50; nb. 13; (2007); p. 3086 - 3100 View in Reaxys Z Z

O O

N Br

O N NH

Rx-ID: 12660077 View in Reaxys 185/493 Yield

Conditions & References Reaction Steps: 4 1: 95 percent / potassium carbonate / dimethylformamide / 4 h / 20 °C 2: 97 percent / H2 / Pd/C / ethyl acetate / 2 h 3: 73 percent / 2-(1-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium*PF6; N,N-diisopropylethylamine / acetonitrile 4: 90 percent / HCl / ethyl acetate / 0.5 h / 20 °C With hydrogenchloride, hydrogen, potassium carbonate, O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N-ethyl-N,N-diisopropylamine, palladium on activated charcoal in ethyl acetate, N,N-dimethyl-formamide, acetonitrile Wang, Yuqiang; Li, Lianfa; Jiang, Wei; Larrick, James W.; Bioorganic and Medicinal Chemistry; vol. 13; nb. 19; (2005); p. 5592 - 5599 View in Reaxys

90/195

2016-06-04 14:03:19

O Z

N Z

HN O

N N

H 2N

Rx-ID: 12662279 View in Reaxys 186/493 Yield

Conditions & References Reaction Steps: 2 1: 73 percent / 2-(1-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium*PF6; N,N-diisopropylethylamine / acetonitrile 2: 90 percent / HCl / ethyl acetate / 0.5 h / 20 °C With hydrogenchloride, O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N-ethyl-N,Ndiisopropylamine in ethyl acetate, acetonitrile Wang, Yuqiang; Li, Lianfa; Jiang, Wei; Larrick, James W.; Bioorganic and Medicinal Chemistry; vol. 13; nb. 19; (2005); p. 5592 - 5599 View in Reaxys

Z O

Z N

HN N

O N NH

N O

Rx-ID: 12662281 View in Reaxys 187/493 Yield

Conditions & References Reaction Steps: 3 1: 97 percent / H2 / Pd/C / ethyl acetate / 2 h 2: 73 percent / 2-(1-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium*PF6; N,N-diisopropylethylamine / acetonitrile 3: 90 percent / HCl / ethyl acetate / 0.5 h / 20 °C With hydrogenchloride, hydrogen, O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Nethyl-N,N-diisopropylamine, palladium on activated charcoal in ethyl acetate, acetonitrile Wang, Yuqiang; Li, Lianfa; Jiang, Wei; Larrick, James W.; Bioorganic and Medicinal Chemistry; vol. 13; nb. 19; (2005); p. 5592 - 5599 View in Reaxys

F O

N H

Rx-ID: 13388753 View in Reaxys 188/493 Yield

Conditions & References Reaction Steps: 2 1: 56.5 percent / NaBH3CN; acetic acid / methanol / 12 h / 80 °C / pH 5 2: 34.8 percent / trifluoroacetic acid / CH2Cl2 / 4 h / 20 °C With sodium cyanoborohydride, acetic acid, trifluoroacetic acid in methanol, dichloromethane Oh, Seung-Jun; Lee, Kyo Chul; Lee, Sang-Yoon; Ryu, Eun Kyoung; Saji, Hideo; Choe, Yearn Seong; Chi, Dae Yoon; Kim, Sang Eun; Lee, Jeewoo; Kim, Byung-Tae; Bioorganic and Medicinal Chemistry; vol. 12; nb. 21; (2004); p. 5505 - 5513

91/195

2016-06-04 14:03:19

View in Reaxys

Br N

Br N H

Rx-ID: 14072449 View in Reaxys 189/493 Yield

Conditions & References Reaction Steps: 2 1: 85 percent / Et3N; KI / ethanol / 16 h / Heating 2: 77 percent / TFA / CHCl3 / 3 h / 20 °C With triethylamine, trifluoroacetic acid, potassium iodide in ethanol, chloroform Bolognesi, Maria Laura; Cavalli, Andrea; Andrisano, Vincenza; Bartolini, Manuela; Banzi, Rita; Antonello, Alessandra; Rosini, Michela; Melchiorre, Carlo; Farmaco; vol. 58; nb. 9; (2003); p. 917 - 928 View in Reaxys

O N

O HO

2H 2H

N H

Rx-ID: 14519781 View in Reaxys 190/493 Yield

Conditions & References Reaction Steps: 2 1: 31 percent / urea / 0.33 h / 176 °C 2: 77 percent / LiAlD4 / tetrahydrofuran / 70 °C With lithium aluminium deuteride, urea in tetrahydrofuran Wiegerinck, Peter; Post, Olaf; Hofstede, Leontine; Heuvel, Marcel van den; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 45; nb. 13; (2002); p. 1169 - 1171 View in Reaxys

N-acetyl-N'-(3,4-dichlorophenylhaloacetyl)-hydrazide

H 2N 2H

2H 2H

N H

Rx-ID: 14527937 View in Reaxys 191/493 Yield

Conditions & References Reaction Steps: 3 1: 78 percent / NaOH / H2O 2: 31 percent / urea / 0.33 h / 176 °C 3: 77 percent / LiAlD4 / tetrahydrofuran / 70 °C With sodium hydroxide, lithium aluminium deuteride, urea in tetrahydrofuran, water Wiegerinck, Peter; Post, Olaf; Hofstede, Leontine; Heuvel, Marcel van den; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 45; nb. 13; (2002); p. 1169 - 1171 View in Reaxys

92/195

2016-06-04 14:03:19

sodium-compound of pentadiene-(1.3)

3-chlorobenzyl halide

N H

Rx-ID: 14828997 View in Reaxys 192/493 Yield

Conditions & References Reaction Steps: 2 1: 99 percent / NaHCO3 / aq. ethanol / 18 h / Heating 2: 69 percent / KOH / methanol / Heating With potassium hydroxide, sodium hydrogencarbonate in methanol, ethanol Bergbreiter, David E.; Osburn, Philip L.; Li, Chunmei; Organic Letters; vol. 4; nb. 5; (2002); p. 737 - 740 View in Reaxys

methyl-<2-fluoro-benzyl>-carbamonitrile

N H

Rx-ID: 16226109 View in Reaxys 193/493 Yield

Conditions & References Reaction Steps: 2 1: K2CO3 / acetonitrile / Heating 2: 45 percent HBr / 1 h / Heating With hydrogen bromide, potassium carbonate in acetonitrile Tapia, Ines; Alonso-Cires, Luisa; Lopez-Tudanca, Pedro Luis; Mosquera, Ramon; Labeaga, Luis; Innerarity, Ana; Orjales, Aurelio; Journal of Medicinal Chemistry; vol. 42; nb. 15; (1999); p. 2870 - 2880 View in Reaxys

p-chlorophenyl-(N-morpholino)methylbenzotriazole

N H

Rx-ID: 16351575 View in Reaxys 194/493 Yield

Conditions & References Reaction Steps: 2 1: NaBH3CN, AcOH / 16 h / Ambient temperature 2: aq. KOH / ethanol / 2.5 h / 130 °C With potassium hydroxide, sodium cyanoborohydride, acetic acid in ethanol Ferte, Jacques; Kuehnel, Jean-Marc; Chapuis, Genevieve; Rolland, Yves; Lewin, Guy; Schwaller, Marc A.; Journal of Medicinal Chemistry; vol. 42; nb. 3; (1999); p. 478 - 489 View in Reaxys

iPr2NH, 1.6 M nBuLi

O N H

Rx-ID: 16351594 View in Reaxys 195/493

93/195

2016-06-04 14:03:19

Yield

O O

O N H

Rx-ID: 16351893 View in Reaxys 196/493 Yield

HI, I2

Wang resin-OH

N H

Rx-ID: 16353314 View in Reaxys 197/493 Yield

O O

iBuMgHal O

N H

Rx-ID: 16353938 View in Reaxys 198/493 Yield

94/195

2016-06-04 14:03:19

Ferte, Jacques; Kuehnel, Jean-Marc; Chapuis, Genevieve; Rolland, Yves; Lewin, Guy; Schwaller, Marc A.; Journal of Medicinal Chemistry; vol. 42; nb. 3; (1999); p. 478 - 489 View in Reaxys

O O

butanedione-mono-<(E?)-O-methyl oxime > N

N H

Rx-ID: 16385585 View in Reaxys 199/493 Yield

O O O O O

N NH

Rx-ID: 16385813 View in Reaxys 200/493 Yield

Cl N H

Rx-ID: 16706139 View in Reaxys 201/493 Yield

Conditions & References Reaction Steps: 2 1: K2CO3 / ethanol / Heating 2: TFA / CH2Cl2 / Ambient temperature With potassium carbonate, trifluoroacetic acid in ethanol, dichloromethane Bourrain, Sylvie; Collins, Ian; Neduvelil, Joseph G.; Rowley, Michael; Leeson, Paul D.; Patel, Smita; Patel, Shil; Emms, Frances; Marwood, Rosemarie; Chapman, Kerry L.; Fletcher, Alan E.; Showell, Graham A.; Bioorganic and Medicinal Chemistry; vol. 6; nb. 10; (1998); p. 1731 - 1743 View in Reaxys

95/195

2016-06-04 14:03:19

sodium-compound of 1-cyclopentyl-ethanone

N H

Rx-ID: 16707968 View in Reaxys 202/493 Yield

potassium-<3-(4-chloro-phenoxy)-propane-1-thiolate>

Cl Cl

N H

Rx-ID: 16708152 View in Reaxys 203/493 Yield

Conditions & References Reaction Steps: 2 1: K2CO3 / ethanol / Heating 2: 2 g / TFA / CH2Cl2 / Ambient temperature With potassium carbonate, trifluoroacetic acid in ethanol, dichloromethane Bourrain, Sylvie; Collins, Ian; Neduvelil, Joseph G.; Rowley, Michael; Leeson, Paul D.; Patel, Smita; Patel, Shil; Emms, Frances; Marwood, Rosemarie; Chapman, Kerry L.; Fletcher, Alan E.; Showell, Graham A.; Bioorganic and Medicinal Chemistry; vol. 6; nb. 10; (1998); p. 1731 - 1743 View in Reaxys

O Cl

Na2S+9H2O

N H

Rx-ID: 16711162 View in Reaxys 204/493 Yield

96/195

2016-06-04 14:03:19

N H

Rx-ID: 16713987 View in Reaxys 205/493 Yield

N N

N N H

Rx-ID: 16767337 View in Reaxys 206/493 Yield

Conditions & References Reaction Steps: 2 1: Et3N / CH2Cl2 / 2 h 2: 1 N NaOH / methanol With triethylamine, sodium hydroxide in methanol, dichloromethane Miller, Michael W.; Vice, Susan F.; McCombie, Stuart W.; Tetrahedron Letters; vol. 39; nb. 21; (1998); p. 3429 3432 View in Reaxys

N N

N N H

Rx-ID: 16767945 View in Reaxys 207/493 Yield

97/195

2016-06-04 14:03:19

O N

O N O

N H

Rx-ID: 16867530 View in Reaxys 208/493 Yield

Conditions & References Reaction Steps: 2 1: polymer supported perruthenate / toluene / 2 h / 80 °C 2: polymer supported cyanoborohydride / methanol; toluene / 72 h / Ambient temperature With polymer supported cyanoborohydride, polymer supported perruthenate in methanol, toluene Ley, Steven V.; Bolli, Martin H.; Hinzen, Berthold; Gervois, Anne-Geraldine; Hall, Beverley J.; Journal of the Chemical Society - Perkin Transactions 1; nb. 15; (1998); p. 2239 - 2241 View in Reaxys

N H

Rx-ID: 16867739 View in Reaxys 209/493 Yield

F F

Rx-ID: 16867773 View in Reaxys 210/493 Yield

N H

Rx-ID: 16870401 View in Reaxys 211/493

98/195

2016-06-04 14:03:19

Yield

Cl OH

N H

Rx-ID: 16871509 View in Reaxys 212/493 Yield

NH 2

N H

Rx-ID: 16871885 View in Reaxys 213/493 Yield

(+-)-4-diethylamino-2-phenyl-butyric acid methyl ester

O OH

N H

Rx-ID: 16882318 View in Reaxys 214/493 Yield

99/195

2016-06-04 14:03:19

Ley, Steven V.; Bolli, Martin H.; Hinzen, Berthold; Gervois, Anne-Geraldine; Hall, Beverley J.; Journal of the Chemical Society - Perkin Transactions 1; nb. 15; (1998); p. 2239 - 2241 View in Reaxys

O O

OH O O

N H

Rx-ID: 16882388 View in Reaxys 215/493 Yield

F F

Rx-ID: 16962747 View in Reaxys 216/493 Yield

Conditions & References Reaction Steps: 2 1: 2) K2CO3 / tetrahydrofuran / 12.5 h / Heating 2: aq. NaOH / methanol / 24 h / Heating With sodium hydroxide, potassium carbonate in tetrahydrofuran, methanol Baziard-Mouysset, Genevieve; Younes, Salouma; Labssita, Youssef; Payard, Marc; Caignard, Daniel-Henri; Rettori, Marie-Claire; Renard, Pierre; Pfeiffer, Bruno; Guardiola-Lemaitre, Beatrice; European Journal of Medicinal Chemistry; vol. 33; nb. 5; (1998); p. 339 - 347 View in Reaxys

O O

O O N OH N H

Rx-ID: 17459829 View in Reaxys 217/493 Yield

Conditions & References Reaction Steps: 2 1: 95 percent / carbon tetrabromide, triphenylphosphine / CH2Cl2 / 24 h / Ambient temperature 2: 66 percent / potassium carbonate, potassium iodide / various solvent(s) / 20 h / Heating With carbon tetrabromide, potassium carbonate, triphenylphosphine, potassium iodide in dichloromethane Masaguer, Christian F.; Ravina, Enrique; Tetrahedron Letters; vol. 37; nb. 29; (1996); p. 5171 - 5174 View in Reaxys

100/195

2016-06-04 14:03:19

O O O

O HO

N O

N H

Rx-ID: 17468870 View in Reaxys 218/493 Yield

Conditions & References Reaction Steps: 2 1: 1,3-dicyclohexylcarbodiimide, 1-hydroxybenztriazole / CH2Cl2 / 6 h / Ambient temperature 2: 82 percent / lithium aluminum hydride / tetrahydrofuran / 12 h / Ambient temperature With lithium aluminium tetrahydride, benzotriazol-1-ol, dicyclohexyl-carbodiimide in tetrahydrofuran, dichloromethane Masaguer, Christian F.; Ravina, Enrique; Tetrahedron Letters; vol. 37; nb. 29; (1996); p. 5171 - 5174 View in Reaxys Reaction Steps: 3 1: 97 percent / lithium aluminum hydride / tetrahydrofuran / 12 h / Ambient temperature 2: 95 percent / carbon tetrabromide, triphenylphosphine / CH2Cl2 / 24 h / Ambient temperature 3: 66 percent / potassium carbonate, potassium iodide / various solvent(s) / 20 h / Heating With lithium aluminium tetrahydride, carbon tetrabromide, potassium carbonate, triphenylphosphine, potassium iodide in tetrahydrofuran, dichloromethane Masaguer, Christian F.; Ravina, Enrique; Tetrahedron Letters; vol. 37; nb. 29; (1996); p. 5171 - 5174 View in Reaxys

5-imino-<1.2.4>dithiazolidinethione-(3)

H 2N

(+-)-3-chloro-benzhydryl halide

N H

Rx-ID: 18551396 View in Reaxys 219/493 Yield

Conditions & References Reaction Steps: 2 1: 1.) O3 2.) NaBH3CN, CH3COOH / 1.)MeOH, CH2Cl2; -60 deg C; 2.) MeOH, -60 deg C, 10 min; 0 deg C for 20 h 2: 70 mg / K2CO3 / methanol; H2O / 20 h With sodium cyanoborohydride, potassium carbonate, ozone, acetic acid in methanol, water Kawaguchi, Mamoru; Hayashi, Osamu; Kanamoto, Masahiro; Hamada, Masayuki; Yamamoto, Yukio; Oda, Jun'ichi; Agricultural and Biological Chemistry; vol. 51; nb. 2; (1987); p. 435 - 440 View in Reaxys Br N

O N N

Br N H

Rx-ID: 18980132 View in Reaxys 220/493 Yield

Conditions & References Reaction Steps: 2 1: 2.) 99 percent formic acid / 1.) r.t., 20 h, 2.) 100 deg C, 2 h 2: 5 N aq. NaOH / 3 h With sodium hydroxide, formic acid Meyer; Tomcufcik; Chan; Haug; Journal of Medicinal Chemistry; vol. 32; nb. 3; (1989); p. 593 - 597

101/195

2016-06-04 14:03:19

View in Reaxys

Cl N

O N H

Rx-ID: 18984756 View in Reaxys 221/493 Yield

Conditions & References Reaction Steps: 2 1: 2.) 99 percent formic acid / 1.) r.t., 2.) 100 deg C 2: 5 N aq. NaOH With sodium hydroxide, formic acid Meyer; Tomcufcik; Chan; Haug; Journal of Medicinal Chemistry; vol. 32; nb. 3; (1989); p. 593 - 597 View in Reaxys

O F

N Cl

N H

Rx-ID: 18987065 View in Reaxys 222/493 Yield

Conditions & References Reaction Steps: 2 1: 2.) 99 percent formic acid / 1.) r.t., 2.) 100 deg C 2: 5 N NaOH With sodium hydroxide, formic acid Meyer; Tomcufcik; Chan; Haug; Journal of Medicinal Chemistry; vol. 32; nb. 3; (1989); p. 593 - 597 View in Reaxys

disodium-compound of 1,1,2,2-tetraphenyl-ethane Cl

4-methoxy-4'-methyl-benzhydryl bromide

N H

Rx-ID: 19852269 View in Reaxys 223/493 Yield

Conditions & References Reaction Steps: 2 1: ethanol / 5 h / Heating 2: 20percent w/v aq. NaOH / 2-ethoxy-ethanol / 18 h / Heating With sodium hydroxide in 2-ethoxy-ethanol, ethanol Buckle, Derek R.; Outred, D. James; Smith, Harry; Spicer, Barbara A.; Journal of Medicinal Chemistry; vol. 27; nb. 11; (1984); p. 1452 - 1457 View in Reaxys

102/195

2016-06-04 14:03:19

O N

N H

Rx-ID: 21126661 View in Reaxys 224/493 Yield

Conditions & References Reaction Steps: 2 1: HCl, conc. / methanol / 2 h / Heating 2: NaCHO3 With hydrogenchloride in methanol Carpino, Louis A.; Mansour, E. M. E.; Knapczyk, Jerome; Journal of Organic Chemistry; vol. 48; nb. 5; (1983); p. 666 - 669 View in Reaxys

N H

Rx-ID: 21151360 View in Reaxys 225/493 Yield

Conditions & References Reaction Steps: 3 1: diisopropylethylamine / CH2Cl2 / Heating 2: HCl, conc. / methanol / 2 h / Heating 3: NaCHO3 With hydrogenchloride, N-ethyl-N,N-diisopropylamine in methanol, dichloromethane Carpino, Louis A.; Mansour, E. M. E.; Knapczyk, Jerome; Journal of Organic Chemistry; vol. 48; nb. 5; (1983); p. 666 - 669 View in Reaxys

Cl Cl

N H

Rx-ID: 21151362 View in Reaxys 226/493 Yield

Conditions & References Reaction Steps: 2 1: diisopropylethylamine / CH2Cl2 / Heating 2: HCl, conc. / methanol / 2 h / Heating With hydrogenchloride, N-ethyl-N,N-diisopropylamine in methanol, dichloromethane Carpino, Louis A.; Mansour, E. M. E.; Knapczyk, Jerome; Journal of Organic Chemistry; vol. 48; nb. 5; (1983); p. 666 - 669 View in Reaxys

103/195

2016-06-04 14:03:19

N H

Rx-ID: 21353276 View in Reaxys 227/493 Yield

Conditions & References Reaction Steps: 2 1: 2 h / 90 °C 2: 72 percent / KOH / ethanol / 3 h / 120 °C With potassium hydroxide in ethanol Bartl; Dlabac; Protiva; Collection of Czechoslovak Chemical Communications; vol. 45; nb. 11; (1980); p. 3182 3189 View in Reaxys

N H

Rx-ID: 22350390 View in Reaxys 228/493 Yield

Conditions & References Reaction Steps: 2 1: Na2CO3; ethanol 2: aqueous HCl With hydrogenchloride, ethanol, sodium carbonate Fujii et al.; Yakugaku Zasshi; vol. 74; (1954); p. 1049; ; (1955); p. 11666 View in Reaxys

N H

Rx-ID: 22350503 View in Reaxys 229/493 Yield

Conditions & References Reaction Steps: 2 1: ethanol / Hydrogenation.an Raney-Nickel 2: ethanolic KOH With potassium hydroxide, ethanol Morren et al.; Bulletin des Societes Chimiques Belges; vol. 60; (1951); p. 282,288 View in Reaxys

Br Br

Cl 2 H

N H

Rx-ID: 22353694 View in Reaxys 230/493 Yield

Conditions & References Reaction Steps: 2

104/195

2016-06-04 14:03:19

1: Na2CO3; ethanol 2: aqueous HCl With hydrogenchloride, ethanol, sodium carbonate Baltzly et al.; Journal of the American Chemical Society; vol. 76; (1954); p. 1165 View in Reaxys O

N N

N H

Rx-ID: 22864971 View in Reaxys 231/493 Yield

Conditions & References 5.A : EXAMPLE 5 Preparation of 4-(4-methylthiobenzyl)-piperazinyl-benzimidazole-5-carboxamide The 4-BOC-1-(4-methylthio)-benzylpiperazine was taken in 10 mL 1:1 TFA/methylene chloride and stirred for 1 h at room temperature. The solvents were removed in vacuo and the residue was used without purification for coupling with benzimidazole-5-carboxylic acid. With trifluoroacetic acid in dichloromethane, Time= 1h, T= 20 °C Patent; Scios, Inc.; US6340685; (2002); (B1) English View in Reaxys

H N

(v1)

Pol

N H

NH N

Rx-ID: 22879894 View in Reaxys 232/493 Yield

Conditions & References 3 : REFERENCE EXAMPLE 3; Production of Piperazine-1-yl Methyl Resin Chloromethyl polystyrene resin (Merrifield resin) (20 g) was swollen in dry dioxane (200 ml), and piperazine (10.3 g, 0.12 mol) was added thereto, and the mixture was stirred at 70° C. for 16 hours. The resin was filtered off and washed with THF, 1 N NaOH-THF, water, THF, and diethyl ether in this order and dried in vacuo whereby the title resin, 20.1 g, was obtained. Anal. N, 2.65. in 1,4-dioxane Solid phase= Polystyrene, Time= 16h, T= 70 °C Patent; Takeda Chemical Industires, Ltd.; US6388022; (2002); (B1) English View in Reaxys

H N

2 HCl

N N

Cl Cl

Rx-ID: 22972045 View in Reaxys 233/493 Yield 92 %

Conditions & References 4 : Intermediate 4; N-(2,3-Dichlorophenylmethyl)piperazine, dihydrochloride salt To a solution of N-[(tert-butyloxycarbonyl]-N'-(2,3-dichlorobenzyl)piperazine [Intermediate 3, (8.25 g, 24 mmol)] in MeOH (200 mL) was added concentrated aqueous HCl solution (15 mL) slowly in portions. The reaction was stirred overnight and the first crop of product crystallized out. The reaction mixture was filtered and the filter cake was rinsed with Et2O to afford a white crystalline solid (4.1 g). The filtrate was concentrated to about of the original volume and a second crop of crystalline product was collected by filtration (2.9 g). The combined yield of the title prod-

105/195

2016-06-04 14:03:19

uct was 92percent. 1H NMR (DMSO-d6) δ9.81 (br, 2H), 7.87 (d, J=7.5 Hz, 1H), 7.75 (d, J=8.0 Hz), 7.47 (t, J=7.9 Hz), 4.45 (s, 2H), 3.40 (s, 4H), 3.16 (s, 1H); 13C NMR (DMSO-d6) δ133.0, 132.6, 132.5, 131.9, 128.7, 56.9, 48.2, 40.6; MS Calcd for [C11H14Cl2N2+H]+: 245, found: 245; Anal Calcd for C11H14Cl2N2 * 2HCl: C, 41.54; H, 5.07; N, 8.81. Found: C, 41.29; H, 5.34; N, 8.47. With hydrogenchloride in methanol, water Patent; Poindexter, Graham S.; Luo, Guanglin; Chen, Ling; US2003/232807; (2003); (A1) English View in Reaxys O N

2 OHHCl

O OH

Rx-ID: 23153022 View in Reaxys 234/493 Yield

Conditions & References

63 %

17.D : 17D: 1-(3-Hydroxybenzyl)piperazine dihydrochloride A solution of tert-butyl 4-(3-hydroxybenzyl)piperazine-1-carboxylate (1.94 g, 6.60 mmol) in 4N HCl/dioxan (10ml) was stirred at room temperature for 30 min then concentrated in vacuo. The residue was triturated with diethyl ether to give a white solid identified as 1-(3-hydroxybenzyl)piperazine dihydrochloride (1.10 g, 63percent). With hydrochlorid acid in 1,4-dioxane, Time= 0.5h, T= 20 °C Patent; Ferring B.V.; EP1449844; (2004); (A1) English View in Reaxys O N

2 HCl OH

Rx-ID: 23153025 View in Reaxys 235/493 Yield

Conditions & References

75 %

18.D : 18D: 1-(3-(Hydroxymethyl)benzyl)piperazine dihydrochloride A solution of tert-butyl 4-(3-(hydroxymethyl)benzyl)piperazine-1-carboxylate (230mg, 0.75mmol) in 4N HCl/dioxan (10ml) was stirred at room temperature for 45min then concentrated in vacuo. The residue was azeotroped with toluene to give a white solid identified as 1-(3-(hydroxymethyl)benzyl)-piperazine dihydrochloride (158 mg, 75percent). With hydrochlorid acid in 1,4-dioxane, Time= 0.75h, T= 20 °C Patent; Ferring B.V.; EP1449844; (2004); (A1) English View in Reaxys

N O

N H

Rx-ID: 23162096 View in Reaxys 236/493 Yield

Conditions & References 440 : 1-(3-Methoxybenzyl)piperazine A mixture of 2.0 g 3-methoxy benzylchloride, 2.9 g 1-Boc piperazine, 5 mL triethylamine, and 20 mL tetrahydrofuran was stirred at room temperature for 20 minutes. The mixture was concentrated, and the residue was added to 20 mL trifluoroacetic acid and stirred at room temperature for 20 minutes. The trifluoroacetic acid was evaporated, and the residue was suspended in methanol and neutralized with an aqueous saturated sodium bicarbonate solution. The solvent was evaporated, and the residue was suspended in dichloromethane and purified by NH silica gel chromatography to give 2.4 g of the title compound as a white solid.1H-NMR (CDCl3) δ: 2.68 (m, 4H), 3.15(m, 4H), 3.81(s, 3H), 4.20(s, 2H), 6.80-6.90s(m, 3H), 7.24(t, J=8.0Hz, 1H)

106/195

2016-06-04 14:03:19

Stage 1: With trifluoroacetic acid, Time= 0.333333h, T= 20 °C Stage 2: With sodium hydrogencarbonate in methanol, water Patent; Eisai Co., Ltd.; EP1382603; (2004); (A1) English View in Reaxys

N O

HCl

NH N

Rx-ID: 23246250 View in Reaxys 237/493 Yield

Conditions & References

82 %

G : N,N-Dimethyl-3-piperazin-1-ylmethyl-benzamide dihydrochloride N,N-Dimethyl-3-piperazin-1-ylmethyl-benzamide dihydrochloride 4-(3-Dimethylcarbamoyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (322mg, 0.93mmol) was dissolved in a solution of 4M hydrogen chloride in dioxan (10ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 1h. The mixture was reduced invacuo to afford N,N dimethyl-3-piperazin-1-ylmethyl-benzamide dihydrochloride, yield 244mg, 82percent. With hydrogenchloride in 1,4-dioxane, Time= 1h, T= 0 - 20 °C Patent; Ferring B.V.; EP1512687; (2005); (A1) English View in Reaxys

N O

HCl

N NH

Rx-ID: 23246252 View in Reaxys 238/493 Yield

Conditions & References

96 %

G : N,N-Dimethyl-3-piperazin-1-ylmethyl-thiobenzamide dihydrochloride N,N-Dimethyl-3-piperazin-1-ylmethyl-thiobenzamide dihydrochloride 4-(3-Dimethylthiocarbamoyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (1 10mg, 0.30mmol) was dissolved in a solution of 4N hydrogen chloride in dioxan (8ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 1h. The mixture was reduced invacuo and azeotroped with toluene and diethyl ether to afford N,N-dimethyl-3-piperazin-1-ylmethyl-thiobenzamide dihydrochloride, yield 97mg, 96percent. With hydrogenchloride in 1,4-dioxane, Time= 1h, T= 0 - 20 °C Patent; Ferring B.V.; EP1512687; (2005); (A1) English View in Reaxys O E

Rx-ID: 23301053 View in Reaxys 239/493 Yield

Conditions & References 33 Patent; S*BIO PTE LTD; WO2005/40101; (2005); (A1) English View in Reaxys

107/195

2016-06-04 14:03:19

H N

2 O

N H

F HN OH

O N

Rx-ID: 23308785 View in Reaxys 240/493 Yield 42 %

Conditions & References 32 :To a solution of 4-Formyl-benzoic acid methyl ester (0.167 g, 1.02 mmoL) and piperazin (0.557 g, 6.47 mmoL) in mixed solvent of MeOH (5 mL) and DCM (5 mL), was added NaBH3CN (0.111 g, 1.76 mmoL) and followed by acetic acid (0.75 mL, 13.1 mmoL). After being stirred at room temperature for 1 h, the reaction mixture was basified with aqueous Na2CO3 and extracted with DCM (x2). After workup, the residue was purified by preparative reverse-phase HPLC and the title compound was obtained as 2*TFA salt (0.195 g, 42percent). HPLC purity (254 nm) = 98percent; LC-MS (ESI, positive mode) m/z 235 ([M+H]+). 'H NMR (CD30D) 8 8. 01 (d, 2H, J=8.3 Hz), 7.58 (d, 2H, J = 8. 3 Hz), 4.39 (s, 2H), 3. 84 (s, 3H, OCH3), 3.52-3. 47 (m, 8H) ; 13C NMR (CD30D) 6 167.7, 135.3, 132.4, 131.2, 61.1, 52.9, 49.5, 42.2. Stage 1: With sodium cyanoborohydride in methanol, dichloromethane, Time= 1h, T= 20 °C Stage 2: With water, sodium carbonate in methanol, 4-(dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4Hpyran Patent; S*BIO PTE LTD; WO2005/40101; (2005); (A1) English View in Reaxys

H N

N H

Cl 2 H

N H

Rx-ID: 23487592 View in Reaxys 241/493 Yield 70 %

Conditions & References 3 :General preparation 3: N1-benzyl-N4-aralkyl formyl alkyl piperazine dihydro chloride (VI).; A mixture of piperazine (350mmol), KOH (100mmol) and hexadecyl-trimethyl ammonium bromide (CTAB, lmmol) in water (18ml) was heated to get a solution. Thereafter, benzyl chloride (100mmol) in 140ml of benzene was added to the solution dropwise at 70°C, and refluxed for 1h. The organic layer was washed with water and saline, dried (MgSO4), filtered and evaporated, the residue was dissolved by 50ml of ethanol and adjusted to a PH of 2 by HCl/C2H5OH (5N), the resulting precipitate was recrystallized from ethanol to obtain N-benzyl piperazine dihydrochloride (55-86percent). Stage 1: With potassium hydroxide, N-hexadecyl-N,N,N-trimethylammonium bromide in water, benzene, Time= 1h, T= 70 °C , Heating / reflux Stage 2: With hydrogenchloride in ethanol, pH= 2 Patent; Shanghai Institute of Pharmaceutical Industry; EP1553092; (2005); (A1) English View in Reaxys

NH N

O O

Rx-ID: 23520413 View in Reaxys 242/493 Yield