1-(4-chlorobenzyl)piperazine

Query Query N

1. Query

NH

Results

Date

15 reactions in Reaxys

2016-05-20 11h:17m:54s (EST)

Cl

Search as: As drawn

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Cl H N Cl

N H

Cl

Cl 2 H

N

N H

Rx-ID: 23667075 View in Reaxys 1/15 Yield 65%

Conditions & References 2 :First of all, a mixture of 4-chlorobenzylchlorine and piperazine was treated according to the general preparation 1 to obtain N-(4-chlorobenzyl) piperazine dihydrochloride, yield 65percent, mp 278-280° C. Then, a mixture of the above product (5 g, 20 mmol), KHCO3 (70 mmol) and 2-bromo-1-phenylpropan-1-one (3.96 ml, 26 mmol) in 40 ml of ethanol was refluxed for 8 hours, and then treated according to the general preparation 2 to obtain 6.1 g of N1-(4chlorobenzyl)-N4-(1-benzoylethyl) piperazine dihydrochloride, yield 59.51percent, mp 260-262° C. Finally, a mixture of above compound (1.5 g, 3.45 mmol) and KBH4 (0.74 g, 14 mmol) was treated according to the general preparation 3 to obtain the title compound, yield 65percent, mp. 240° C.). Elementary analysis: C20H25ClN2O.2HCl.2H2O. Found: (percent C, 54.74; H, 6.71; N, 6.34); theoretical value (percent C, 55.12; H, 6.71; N, 6.43). MS: m/z 344 (M)+ Stage 1: With potassium hydroxide, N-hexadecyl-N,N,N-trimethylammonium bromide in water, benzene, Time= 1 3h, T= 70 °C , Heating / reflux Stage 2: With hydrogenchloride in ethanol, pH= 3 Patent; Shanghai Institute of Pharmaceutical Industry; US2005/267121; (2005); (A1) English View in Reaxys

Cl

H N Cl

N H

Br

N

N H

Rx-ID: 31795369 View in Reaxys 2/15 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

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Cl

H N Cl

N H

Cl

N

N H

Rx-ID: 16518 View in Reaxys 3/15 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

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

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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 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

O

Cl

N

N H Cl

Rx-ID: 5025238 View in Reaxys 4/15 Yield 2g

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

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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

O

Cl

N

N H Cl

Rx-ID: 3078885 View in Reaxys 5/15 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

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Cl

H N

Cl

N

O

N H

Rx-ID: 5046349 View in Reaxys 6/15 Yield

Conditions & References

43 %

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 sodium tetrahydroborate in methanol, reductive alkylation 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

Cl Cl

N

O O

O

N H

Rx-ID: 25274456 View in Reaxys 7/15 Yield

Conditions & References

74%

XV : 2-(4'-p-Chlorobenzyl-piperazino)-5-oxo-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine-6-carboxylic acid. SPC22 EXAMPLE XV 2-(4'-p-Chlorobenzyl-piperazino)-5-oxo-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine-6-carboxylic acid. SPC22 Condensation of 1-p-chlorobenzyl-piperazine with 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido-(2,3-d)pyrimidine, as described in Example VII, gives, in a yield of 74percent, 2-(4'-p-chlorobenzyl-piperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine; melting point 150°C, after recrystallisation from ethyl acetate. Analysis for C23 H26 ClN5 O3 (molecular weight 455.5): Calculated percent: C, 60.59; H, 5.70; N, 15.36; Cl, 7.79. Found percent: C, 60.29; H, 5.72; N, 15.38; Cl, 7.76. Patent; Laboratoire Roger Bellon; US3950338; (1976); (A1) English View in Reaxys

Cl H N Cl N H

Cl

H

Cl

N

N H

Rx-ID: 621724 View in Reaxys 8/15 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

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Witte; Arzneimittel-Forschung/Drug Research; vol. 39; nb. 10 A; (1989); p. 1309 - 1309 View in Reaxys

Cl

p-chlorophenyl-(N-morpholino)methylbenzotriazole

O

N

N H

Rx-ID: 16351575 View in Reaxys 9/15 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

Cl

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

Cl

N

N H

Rx-ID: 16708152 View in Reaxys 10/15 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

Cl

Cl O

N

N H

Rx-ID: 37196497 View in Reaxys 11/15 Yield

Conditions & References Reaction Steps: 2 1: sodium tris(acetoxy)borohydride / 1,2-dichloro-ethane / 6 h / 20 °C / |Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C With sodium tris(acetoxy)borohydride, trifluoroacetic acid in dichloromethane, 1,2-dichloro-ethane 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

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Cl

H N

N H

Cl 2 H

Cl Cl

N

N H

Rx-ID: 28643306 View in Reaxys 12/15 Yield

Conditions & References Stage 1: in ethanol, Time= 1h, T= 65 °C Stage 2: in ethanol, Time= 2h, T= 78 °C Cunico, Wilson; Gomes, Claudia R.B.; Moreth, Marcele; Manhanini, Diogo P.; Figueiredo, Isabela H.; Penido, Carmen; Henriques, Maria G.M.O.; Varotti, Fernando P.; Krettli, Antoniana U.; European Journal of Medicinal Chemistry; vol. 44; nb. 3; (2009); p. 1363 - 1368 View in Reaxys

Cl

N

N H

Rx-ID: 5450086 View in Reaxys 13/15 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 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

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... 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

N

HCl

HN

Cl

Rx-ID: 28443478 View in Reaxys 14/15 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-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; 1-(2-chloro-6-fluorobenzyl)piperazine; 1-(3-cyanobenzyl)piperazine; ... Patent; Gillespie, Paul; Goodnow, JR., Robert Alan; Erickson, Shawn David; Jones, Richard; US2009/149466; (2009); (A1) English View in Reaxys

Cl O S HO

O

N

N H

Rx-ID: 8359700 View in Reaxys 15/15 Yield

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

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