1-(4-fluorobenzyl) piperazine

Query Query N

1. Query

NH

Results

Date

18 reactions in Reaxys

2016-05-20 11h:03m:57s (EST)

F

Search as: As drawn

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O

F

O N N

N

N H F

Rx-ID: 9749609 View in Reaxys 1/18 Yield 99 %

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

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

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

2 HCl

F N H

Cl

N HN

F

Rx-ID: 23654328 View in Reaxys 2/18

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Yield 67 %

Conditions & References 6 :A mixture of 4-fluorobenzylchlorine and piperazine was treated according to the general preparation 1 to obtain N(4-fluorobenzyl) piperazine dihydrochloride (67percent), mp, 282-284° C. The N1-(4-fluorobenzyl)-N4-phenacyl piperazine dihydrochloride could be preparated according to the general preparation 2, which was reduced with KHCO3 (0.65 g, 6.5 mmol) and KBH4 (0.59 g, 10.4 mmol) in methanol (40 ml) according to the general preparation 3 to obtain 0.72 g of the title compound as white solid. Elementary analysis: C19H23FN2O.2HCl. Found: (percent C, 58.81; H, 6.35; N, 7.28); theoretical value (percent C, 58.92; H, 6.51; N, 7.23). MS: m/z 314 (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

F H N

F Cl

N H

N

N H

Rx-ID: 9177101 View in Reaxys 3/18 Yield 88 %

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

88 %

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

74 %

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

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

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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 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

F H N

Cl

F Cl

N H

N

N H

Rx-ID: 25032228 View in Reaxys 4/18 Yield

Conditions & References

56%

5.a : 1,3-Bis[4-(4-fluorobenzyl)-1-piperazinyl]propane tetrahydrochloride (a) A solution of 29 g of p-fluorobenzyl chloride in 50 g of reagent ethanol was added dropwise to a stirred solution of 34.5 g of piperazine in 150 g of reagent ethanol. A cold water bath was used to maintain the reaction temperature at 20° C. during the addition. The reaction mixture was stirred for an additional 11/2 hours and then added to 2 liters of ether. Precipitated piperazine hydrochloride was filtered off. The filtrate was concentrated to an oil, which was chromatographed on a silica column, the eluant being a mixture of CH2 Cl2 /methanol/ammonium hydroxide in the ratio of 45:5:1. After concentration of appropriate fractions, 21.7 g of 1-(4-fluorobenzyl)piperazine were isolated as a colorless liquid (56percent of theory). With ammonium hydroxide in methanol, ethanol Patent; Boehringer Ingelheim Ltd.; US4725597; (1988); (A1) English View in Reaxys

O

F

N

N H F

Rx-ID: 2663598 View in Reaxys 5/18 Yield 72 %

Conditions & References 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

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View in Reaxys H N

N

18F

O

N H

NH

18F

Rx-ID: 34571170 View in Reaxys 6/18 Yield

Conditions & References

70 %

With sodium cyanoborohydride, acetic acid in methanol, T= 100 - 175 °C Dahl, Kenneth; Schou, Magnus; Halldin, Christer; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 55; nb. 13; (2012); p. 455 - 459 View in Reaxys

F

H N

Cl 2 H

N H

H

N H O

Cl

N

H

N H

Rx-ID: 24138088 View in Reaxys 7/18 Yield

Conditions & References

5.248 g(91%)

1 : Synthesis of the Compounds of the Invention. 1-(4-Fluorobenzyl) piperazine hydrochloride. A solution of 2.154 g(25 mM) of piperazine in 25 mL of absolute ethanol, was warmed in a bath at 65° C. Piperazine dihydrochloride hydrate (3.9765 g(25 mM)) was dissolved in the solution, by swirling. In the bath at 65° C. 3.6145 g(25 mM) of 4-fluorobenzyl chloride was added to the solution with vigorous stirring. The separation of white needles commenced almost immediately. After the solution had been stirred for an additional 25 minutes at 65° C., it was cooled, and the unstirred solution was 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, and then dried. Approximately 3.989 g (100.3percent) of the dihydrochloride was recovered. Filtrate from this solution was evaporated to dryness at reduced pressure and crude 1-(4-methoxybenzyl)-4-piperazinium chloride was left as a residue. For removal of any piperazine dihydrochloride, the chloride may be crystallized after rapidly filtering a hot solution in about 20 mL of absolute ethanol. Concentration of the filtrate followed by cooling gave 5.248 g(91percent) of 1-(4-fluorobenzyl)-4-piperazinium chloride. 1-(4-Chlorobenzyl) piperazine. in ethanol, 1-chloromethyl-4-fluorobenzene Patent; Massachusetts College of Pharmacy; US2002/115655; (2002); (A1) English View in Reaxys

F H N Cl N H

F

H

Cl

N

Cl

H

N H

Rx-ID: 10229844 View in Reaxys 8/18 Yield 91 %

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

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F

methyl-<2-fluoro-benzyl>-carbamonitrile

Br

H

Br

N

N H

Rx-ID: 16226109 View in Reaxys 9/18 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

F

N

O

N H

Rx-ID: 13388753 View in Reaxys 10/18 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 View in Reaxys

O

F

N Br

H

N

N H

F

Rx-ID: 5206666 View in Reaxys 11/18 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

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F

N

HO

N H

Rx-ID: 16867739 View in Reaxys 12/18 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

F

N

Br

N H

Rx-ID: 21353276 View in Reaxys 13/18 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

O–

F

S

F F

O

N

N+

O

NH

18F

Rx-ID: 34571168 View in Reaxys 14/18 Yield

Conditions & References Reaction Steps: 2 1: C22H36N2O6*K(1+)*(18)F(1-) / acetonitrile; methanol / 100 - 200 °C 2: sodium cyanoborohydride; acetic acid / methanol / 100 - 175 °C With C22H36N2O6*K(1+)*(18)F(1-), sodium cyanoborohydride, acetic acid in methanol, acetonitrile Dahl, Kenneth; Schou, Magnus; Halldin, Christer; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 55; nb. 13; (2012); p. 455 - 459 View in Reaxys

F H N F

N H

O

N

N H

Rx-ID: 4856029 View in Reaxys 15/18 Yield

Conditions & References With polymer supported cyanoborohydride in methanol, toluene, Time= 72h, Ambient temperature, Yield given

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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

F H N

H N

N H

Cl 2 H

F

N

Cl

N H

Rx-ID: 28643308 View in Reaxys 16/18 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

F H N

F Br

N H

N

N H

Rx-ID: 31795371 View in Reaxys 17/18 Yield

Conditions & References Chai, Yunfeng; Jiang, Kezhi; Sun, Cuirong; Pan, Yuanjiang; Chemistry - A European Journal; vol. 17; nb. 39; (2011); p. 10820 - 10824 View in Reaxys

F

N

N H

Rx-ID: 24643104 View in Reaxys 18/18 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

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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 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

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