* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6938 - 6942,5
2
[ 24228-40-8 ]
[ 115-46-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1989, vol. 32, # 1, p. 105 - 118
3
[ 24228-40-8 ]
[ 10315-07-8 ]
Yield
Reaction Conditions
Operation in experiment
95%
With sodium hydroxide; water In tetrahydrofuran; 1,4-dioxane at 20℃;
(b) Synthesis of 1-benzyl-4-piperidinecarboxylic acid A 4N-aqueous sodium hydroxide solution (35 ml) was added to a solution of ethyl 1-benzyl-4-piperidinecarboxylate (16.1 g, 65.1 mmol) in a tetrahydrofuran (70 ml)/1,4-dioxane (70 ml) mixture at room temperature and stirred overnight. Then, the pH was adjusted to 7 with 2N-hydrochloric acid and the solvent was distilled off under reduced pressure. The resulting residue was suspended in ethanol and the suspension was filtered. The filtrate was concentrated under reduced pressure to obtain 1-benzyl-4-piperidinecarboxylic acid (13.6 g, 95percent).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 17, p. 4980 - 4983
[2] Patent: EP1500643, 2005, A1, . Location in patent: Page 18
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 20, p. 6491 - 6503
[4] Helvetica Chimica Acta, 1997, vol. 80, # 5, p. 1528 - 1551
[5] Patent: US6020368, 2000, A,
[6] Patent: US2009/209578, 2009, A1, . Location in patent: Page/Page column 25
[7] Patent: WO2004/33427, 2004, A1, . Location in patent: Page 102
[8] Scientia Pharmaceutica, 2018, vol. 86, # 1,
4
[ 123-91-1 ]
[ 24228-40-8 ]
[ 10315-07-8 ]
Reference：
[1] Patent: US5753679, 1998, A,
5
[ 1126-09-6 ]
[ 100-39-0 ]
[ 24228-40-8 ]
Yield
Reaction Conditions
Operation in experiment
86%
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 18 h;
2f) Ethyl 4-benzylisonipecotateA mixture of ethyl isonipecotate (65 mmol; 10.2 g), anhydrous potassium carbonate (195 mmol; 26.9 g) and benzyl bromide (78 mmol; 13.36 g) in anhydrous Λ/,Λ/-dimethylformamide (100 ml) was stirred at 700C for 18 hours. After cooling, the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (3 * 200 ml). The combined organic phases were washed with saturated NaCI solution (3 x 100 ml), dried over sodium sulfate and evaporated under reduced pressure. A crude product was obtained, which was purified on a column of alumina (eluting with chloroform) to give 13.84 g (86percent) of pure product as a yellow oil.1H NMR (CDCI3, δ ppm): 1.28-1.32 (t, 3H); 1.81 (m, 4H); 2.07-2.12 (m, 2H); 2.34 (m, 1 H); 2.91 (m, 2H); 3.55 (m, 2H); 4.15-4.21 (m, 2H); 7.31 -7.38 (m, 5H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6938 - 6942,5
[2] Journal of medicinal chemistry, 1980, vol. 23, # 8, p. 848 - 851
[3] Patent: WO2010/12611, 2010, A1, . Location in patent: Page/Page column 28
[4] Journal of Medicinal Chemistry, 1996, vol. 39, # 3, p. 749 - 756
[5] Organic Preparations and Procedures International, 1994, vol. 26, # 3, p. 421 - 428
[6] Journal of Medicinal Chemistry, 1992, vol. 35, # 13, p. 2392 - 2406
[7] Patent: US5753679, 1998, A,
[8] Patent: WO2006/46031, 2006, A1, . Location in patent: Page/Page column 69-70
[9] Patent: US2009/62277, 2009, A1, . Location in patent: Page/Page column 14
[10] Patent: US2009/62291, 2009, A1, . Location in patent: Page/Page column 13
[11] Patent: US2011/230459, 2011, A1, . Location in patent: Page/Page column 19-20
[12] Patent: WO2018/93818, 2018, A1, . Location in patent: Paragraph 0388
6
[ 1126-09-6 ]
[ 100-44-7 ]
[ 24228-40-8 ]
Yield
Reaction Conditions
Operation in experiment
91%
Stage #1: With potassium carbonate In toluene for 0.25 h; Stage #2: at 100℃; for 4 h;
Ethyl isonipecotate (1, 50 g, 0.31 mol) was dissolved in toluene (150 mL) in a round bottom flask, charged with potassium carbonate (60 g, 0.43 mol) and stirred for 15 min. Benzyl chloride (42 g, 0.31 mol) was charged and the reaction mass was refluxed for 4 h at 100 °C. Upon completion of the reaction as marked by TLC (hexane:ethyl acetate; 2:1), the reaction mass was cooled to room temperature and quenched with water (100 mL), stirred and the organic phase was separated. The aqueous phase was again extracted with toluene (100 mL). Combined organic phase was washed twice with saturated brine solution (50 mL). Remove toluene in vacuo to obtain N-benzyl ethyl isonipecotate (2, 6.97 g, 91 percent) as a yellow liquid.
75%
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20 - 120℃; for 1.5 h;
(a) Synthesis of ethyl 1-benzyl-4-piperidinecarboxylate Benzyl chloride (13.2 ml, 115 mmol) and potassium carbonate (19.8 g, 143 mmol) were added to a solution of ethyl 4-piperidinecarboxylate (15.0 g, 95.4 mmol) in N,N-dimethylformamide (50 ml) at room temperature and stirred at 120°C for 1.5 hours. Then, the reaction suspension was filtered and the solvent of the filtrate was distilled off under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 4/1) to obtain ethyl 1-benzyl-4-piperidinecarboxylate (17.7 g, 75percent).
Reference：
[1] Chemistry - A European Journal, 2013, vol. 19, # 45, p. 15281 - 15289
[2] Farmaco, 1993, vol. 48, # 10, p. 1439 - 1445
[3] Organic Process Research and Development, 2008, vol. 12, # 4, p. 731 - 735
[4] Tetrahedron, 2001, vol. 57, # 14, p. 2701 - 2710
[5] Journal of Medicinal Chemistry, 2005, vol. 48, # 20, p. 6491 - 6503
[6] Asian Journal of Chemistry, 2017, vol. 29, # 9, p. 1999 - 2004
[7] Scientia Pharmaceutica, 2018, vol. 86, # 1,
[8] Journal of Medicinal Chemistry, 1992, vol. 35, # 23, p. 4344 - 4361
[9] Patent: EP1500643, 2005, A1, . Location in patent: Page 18
[10] Helvetica Chimica Acta, 1997, vol. 80, # 5, p. 1528 - 1551
[11] European Journal of Medicinal Chemistry, 1994, vol. 29, # 1, p. 115 - 120
[12] Patent: US2004/29880, 2004, A1,
[13] Patent: WO2009/39431, 2009, A2, . Location in patent: Page/Page column 36
7
[ 100-44-7 ]
[ 24228-40-8 ]
Yield
Reaction Conditions
Operation in experiment
93.8%
With sodium hydrogencarbonate In ethanol for 3 h; Reflux
The 18.4g4- isonipecotate hydrochloride, 12.7g of benzyl chloride, 21.0 g of sodium bicarbonate and 40ml of absolute ethanol was added to a 100ml reaction flask, was heated to reflux and maintained at reflux the reaction 3h, cooled to an internal temperature 30 about, filtering, washing the filter cake with 20ml ethanol, and the filtrate was concentrated to a paste, added 40ml of toluene and 40ml of water, stirred and dispersed organic layer was separated, the toluene was concentrated to give 1-benzyl-4-piperidinecarboxylic acid ethyl ester 23.2g, as a pale yellow oily liquid. Yield: 93.8percent (in terms benzyl chloride). HPLC: 98.74percent
Reference：
[1] Patent: CN105693596, 2016, A, . Location in patent: Paragraph 0044; 0045; 0046; 0047
[2] European Journal of Medicinal Chemistry, 2000, vol. 35, # 7-8, p. 699 - 706
8
[ 136081-74-8 ]
[ 24228-40-8 ]
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 1, p. 18 - 19
9
[ 1126-09-6 ]
[ 100-52-7 ]
[ 24228-40-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 4, p. 1084 - 1088
[2] Patent: EP1553074, 2005, A1, . Location in patent: Page/Page column 48
Reference：
[1] Organic Process Research and Development, 2008, vol. 12, # 4, p. 731 - 735
[2] Asian Journal of Chemistry, 2017, vol. 29, # 9, p. 1999 - 2004
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 18h;
2f) Ethyl 4-benzylisonipecotateA mixture of ethyl isonipecotate (65 mmol; 10.2 g), anhydrous potassium carbonate (195 mmol; 26.9 g) and benzyl bromide (78 mmol; 13.36 g) in anhydrous Lambda/,Lambda/-dimethylformamide (100 ml) was stirred at 700C for 18 hours. After cooling, the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (3 * 200 ml). The combined organic phases were washed with saturated NaCI solution (3 x 100 ml), dried over sodium sulfate and evaporated under reduced pressure. A crude product was obtained, which was purified on a column of alumina (eluting with chloroform) to give 13.84 g (86%) of pure product as a yellow oil.1H NMR (CDCI3, delta ppm): 1.28-1.32 (t, 3H); 1.81 (m, 4H); 2.07-2.12 (m, 2H); 2.34 (m, 1 H); 2.91 (m, 2H); 3.55 (m, 2H); 4.15-4.21 (m, 2H); 7.31 -7.38 (m, 5H).
With triethylamine; In N-methyl-acetamide; water;
a) 4.62 ml (0.03 mol) of ethyl piperidine-4-carboxylate were dissolved in 50 ml of dimethylformamide and treated with 4.98 ml (0.036 mol) of triethylamine. 3.9 ml (0.033 mol) of benzyl bromide were added while cooling with ice and the mixture was stirred for 10 min., warmed to 40 and stirred under an argon atmosphere for 18 hrs. The solvent was then distilled off, the residue was added to 100 ml of water, extracted three times with 100 ml of ether each time and the organic phase was dried over magnesium sulfate. 5.33 g (72%) of ethyl 1-benzyl-piperidine-4-carboxylate were obtained as a yellow oil. MS: me/e=248 (C15 H22 NO2+).
With potassium acetate; In acetonitrile; at 78℃; for 3h;
138 2-(1-[2-(I H-Indazol-4- ylV4-morpholin-4- yl-thieno[3 ,2-dlp yrimidin-6- ylmethyl"|-piperidin-4-yl|-propan-2-olVia 2-[l-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)- piperidin-4-yl]-propan-2-ol, prepared from 2-piperidin-4-yl-propan-2-ol.Amine preparation: To a solution of piperidine-4-carboxylic acid ethyl ester (3.0g) stirring in dry MeCN (3OmL) was added potassium carbonate (2.9Og) followed by benzyl bromide (2.5mL). The mixture was warmed to 78C. After 3 h the mixture was cooled, poured into water (10OmL) and extracted into ethyl acetate, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to give l-benzyl-piperidine-4-carboxylic acid ethyl ester(2.17g) as a pale yellow oil. EPO <DP n="72"/>To a solution of l-benzyl-piperidine-4-carboxylic acid ethyl ester (1.Og) stirring in dry THF (15mL) under a nitrogen atmosphere at 0C, was added methyl magnesium bromide (3.0M solution in diethyl ether; 8.1OmL) and stirred for 2 h at O0C. The reaction mixture was quenched with saturated ammonium chloride solution and extracted into ethyl acetate, dried (MgSO4) and the solvents removed in vacuo to give 2-(l-benzyl-piperidine-4-yl)-propan-2-ol (1.1 Ig) as a white solid.To a suspension of 10% palladium on charcoal (40mg) stirring in dry MeOH (1OmL) under a nitrogen atmosphere was added 2-(l-benzyl-piperidine-4-yl)-propan- 2-ol (0.25g) and the mixture warmed to 60C.After 3 h the mixture was cooled, filtered through a celite bed and the solvents removed in vacuo to yield the desired amine (153mg) as a colourless oil.1H NMR (400 MHz, J6-DMSO) 1.03 (s, 6H), 1.09 (m, IH), 1.23 (m, 2H), 1.66 (m, 2H), 1.98 (m, 2H), 2.97 (m, 2H), 3.83 (m, CH2 x 2 + CH2), 4.00 (m, 4H), 7.46 (t, 2H, J=7.3Hz), 7.65 (d, 1H, J=8.2 Hz), 8.21 (d, lh, J=7.1 Hz), 8.87 (s, IH), 13.15 (br s, IH); MS (ESf) 493.2 (MH+).
To a 50 mL round-bottomed flask was added ethyl isonipecotate (5.0 g, 32 mmol) in dimethylformamide at 0 C. Sodium hydroxide (0.86 g, 35 mmol) was added and the reaction mixture was allowed to stir for 15 minutes. 1-(Bromomethyl)benzene (4.2 ml, 35 mmol) was then added and the reaction mixture was allowed to stir slowly warming to room temperature. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, saturated sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. The ethyl 1-benzylpiperidine-4-carboxylate product (5.8 g, 23.3 mmol) was then added to a 500 mL round-bottomed flask in THF at -78 C. Methyllithium (18.7 ml, 46.7 mmol) was added and allowed to stir slowly warming to room temperature overnight. Upon completion, the reaction mixture was concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated sodium carbonate solution, saturated sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M) X2, eluting with a gradient of 1% to 10% methanol in dichloromethane, to provide 2-(1-benzylpiperidin-4-yl)propan-2-ol. To a solution of 2-(1-benzylpiperidin-4-yl)propan-2-ol in methanol was added palladium, 10 wt. % on activated carbon. A hydrogen balloon was attached to the reaction vessel and the reaction mixture was stirred overnight. Upon completion, the reaction mixture was filtered through Celite. The filtrate was concentrated to produce 2-(piperidin-4-yl)propan-2-ol.
To a 50 mL round-bottomed flask was added ethyl isonipecotate (5.0042 g, 32 mmol) in dimethylformamide at 0 C. Sodium hydroxide (0.8624 g, 35 mmol) was added and was allowed to stir for 15 minutes. 1-(Bromomethyl)benzene (4.2 ml, 35 mmol) was then added and the reaction mixture was allowed to stir slowly warming to room temperature. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, saturated sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; Cooling with ice;
Ethyl isonipecotate (40.0 mL, 0.26 mol), K2CO3, (55 g, 0.4 mol) and N,N-dimethylformamide (200 mL) were combined under nitrogen. The resulting mixture was cooled in an ice bath and benzyl bromide (31.0 mL, 0.26 mol) was added. The reaction mixture was allowed to stir overnight with warming to ambient temperature. A saturated aqueous solution of NH4Cl (500 mL) was added, and the product was extracted twice with ethyl acetate (1 L and 0.5 L). The combined organic layers were washed with saturated aqueous NH4Cl (500 mL) and brine (500 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude product was purified by flash chromatography on silica gel (400 g) eluting with hexane/ethyl acetate (1:0 to 4:1) to obtain 1-benzyl-piperidine-4-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) delta ppm 1.24 (t, J=7.07 Hz, 3H) 1.69-1.82 (m, 2H) 1.82-1.92 (m, 2H) 1.96-2.10 (m, 2H) 2.20-2.34 (m, 1H) 2.79-2.91 (m, 2H) 3.48 (s, 2H) 4.12 (q, J=7.14 Hz, 2H) 7.20-7.32 (m, 5H).
With triethylamine; In ethanol; at 0 - 20℃;
To a solution of ethyl piperidine-4-carboxylate (5.0 g, 31.8 mmol, 1.0 eq) and ethanol (15.0 mL), benzyl bromide (7.07 g, mmol, 1.3 eq) was added dropwise at 0 C. Following, triethylamine (1.06 g, 10.5 mmol, 1.5 eq) was added in one portion while at 0 C. The resulting mixture was allowed to warm to RT and stir overnight. The reaction was concentrated in vacuo to remove the presence of ethanol. The resulting residue was suspended in a mixture of ethyl acetate: D.I. water (20 mL:20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined extract was dried over Na2S04, then filtered through a plug of silica gel and washed with ethyl acetate. The filtrated was concentrated in vacuo to give product that was used in the next step without further purification. 1H NMR (400 MHz, CDC13) delta 7.41-7.20 (m, 5H), 4.14 (q, J = 7.2 Hz, 2H), 3.51 (s, 2H), 2.87 (dt, J = 3.5, 11.8 Hz, 2H), 2.29 (m, 1H), 2.04 (td, J= 2.5, 11.4 Hz, 2H), 1.95-1.85 (m, 2H), 1.85- 1.70 (m, 2H), 1.26 (t, J= 7.1 Hz, 3H).
Ethyl isonipecotate (1, 50 g, 0.31 mol) was dissolved in toluene (150 mL) in a round bottom flask, charged with potassium carbonate (60 g, 0.43 mol) and stirred for 15 min. Benzyl chloride (42 g, 0.31 mol) was charged and the reaction mass was refluxed for 4 h at 100 C. Upon completion of the reaction as marked by TLC (hexane:ethyl acetate; 2:1), the reaction mass was cooled to room temperature and quenched with water (100 mL), stirred and the organic phase was separated. The aqueous phase was again extracted with toluene (100 mL). Combined organic phase was washed twice with saturated brine solution (50 mL). Remove toluene in vacuo to obtain N-benzyl ethyl isonipecotate (2, 6.97 g, 91 %) as a yellow liquid.
88%
With triethylamine; In acetonitrile; for 3h;Reflux;
A mixture of ethyl isonipecotate 7 (10.00 g, 63.61 mmol, 1 eq.),benzyl chloride (7.69 mL, 66.79 mmol, 1.05 eq.) and triethylamine(26.45 mL, 190.8 mmol, 3 eq.) in anhydrous acetonitrile (100 mL)were refluxed for 3 h after which time the reaction mixturewas leftto cool to room temperature and the solvent was evaporated invacuo. The obtained oil was diluted with ethyl acetate (100 mL) andwashed with a 10% aqueous solution of sodium hydroxide(3 50 mL) and water (50 mL). The organic layer was dried(Na2SO4), filtered and evaporated in vacuo to afford ethyl 1-benzylpiperidine-4-carboxylate 8 as an orange oil (88%) whichwas used as is without any further purification; Rf 0.42 (1:3 ethylacetate: hexane); nmax (neat)/cm1 2944, 2801, 2760, 1728, 1448,1168,1046, 736, 698; 1H NMR (300 MHz, CDCl3); d 7.41e7.15 (m, 5H,ArH's), 4.13 (t, 2H, J 7.1 Hz, OCH2CH3), 3.51 (s, 2H, CH2Ph), 2.87 (dt,2H, J 11.4, 3.1 Hz, CH2N), 2.30 (tt, 1H, J 10.9, 4.2 Hz, CHCO), 2.05(td, 2H, J 11.3, 2.7 Hz, CH2N), 1.95e1.71 (m, 4H, CH2), 1.26 (t,J 7.1 Hz, OCH2CH3); 13C NMR (75 MHz, CDCl3); d 175.33, 138.49,129.16, 128.28, 127.07, 63.35, 60.33, 53.02, 41.32, 28.39, 14.32;HRMS m/z (ESI) 248.1682 ([M H] requires 248.1645).
75%
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20 - 120℃; for 1.5h;
(a) Synthesis of ethyl 1-benzyl-4-piperidinecarboxylate Benzyl chloride (13.2 ml, 115 mmol) and potassium carbonate (19.8 g, 143 mmol) were added to a solution of ethyl 4-piperidinecarboxylate (15.0 g, 95.4 mmol) in N,N-dimethylformamide (50 ml) at room temperature and stirred at 120C for 1.5 hours. Then, the reaction suspension was filtered and the solvent of the filtrate was distilled off under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 4/1) to obtain ethyl 1-benzyl-4-piperidinecarboxylate (17.7 g, 75%).
With potassium carbonate; In ethanol; water; ethyl acetate;
C. N-Benzylpiperidine-4-carboxylic Acid Ethyl Ester 1 g (6.4 mmol) of piperidine-4-carboxylic acid ethyl ester is mixed in 10 ml of absolute ethanol with 0.75 ml (6.4 mmol) of benzyl chloride and 1.52 g (11 mmol) of potassium carbonate. The batch is stirred for 30 hours at room temperature. It is then dispersed in ethyl acetate/water. The combined organic phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with hexane:ethyl acetate=1:1 as an eluant. 991 mg (64% of theory) of N-benzylpiperidine-4-carboxylic acid ethyl ester is obtained.
With sodium hydrogencarbonate; In ethanol; water; at 40 - 80℃; for 3h;
To a mixture of ethyl piperidine-4-carboxylate (50 g) and NaHCO3 in 50% EtOH (100 mL) at 4O0C, benzyl chloride (40.3 g) is added drop wise within one hour. The resulting mixture is stirred at 8O0C for 2 h. The mixture is cooled to rt. Hexane (50 mL) and water (50 mL) are added to the above mixture. The organic layer is separated and washed with water (50 mL). The mixture is dried (Na2SO4), and the solvent is evaporated to provide the title compound as an oil, which is used in the next step without purification.
General procedure: Ethyl nipecotate/Ethyl isonipecotate (0.014 mol/0.03 mol) andtriethylamine (0.014 mol/0.06 mol) were dissolved in 30 mL acetonitrileand stirred for 5-10 min in an ice bath under argon gas. Benzylchloride (0.007 mol/0.02 mol) was added in one portion to this mixtureand then the resulting mixture was stirred at room temperature for8-48 h under argon gas. The precipitate was removed, acetonitrile wasevaporated under reduced pressure and the organic layer was extractedwith diethyl ether. The combined organic extracts were dried overanhydrous sodium sulfate and concentrated in vacuo. The crude productwas purified by column chromatography (ethyl acetate/n-hexane)to give ethyl 1-benzylpiperidine-3-carboxylate as a yellowish oil. Ethyl1-benzylpiperidine-4-carboxylate was obtained as a pure yellowish oilafter vacuo without further purification.
[0361] To a solution of diisopropylamine (153 mg, 1.5 mmol) in THF (20 mL) was added nBuLi(2.5 M, 0.6 mL) at -75 C under N2? After 5 min, ethyl1-benzylpiperidine-4-carboxylate(247 mg, 1.0 mmol) was added and the resulting mixture then stirred at -70 oc for 10 min,before adding di-tert-butyl azodicarboxylate (345 mg, 1.5 mmol). The reaction was stirred for 30min, then quenched with aqueous N~Cl (10 mL) and extracted with EA (10 mL x 3). Thecombined organic layers were dried over Na2S04 and concentrated to give the crude product(350 mg, 72%) as an off-white solid. MS (ESI, m/e) [M+1t 478.3.
With n-butyllithium; diisopropylamine; In tetrahydrofuran; at -75 - -70℃; for 0.666667h;Inert atmosphere;
Under nitrogen protection, temperature control -75C,To a solution of diisopropylamine (153 mg, 1.5 mmol) in THF (20 mL) was slowly added n-BuLi (2.5 M, 0.6 mL).After 5 min, 1-benzyl-4-piperidinecarboxylic acid ethyl ester (247 mg, 1.0 mmol) was added.The mixture was stirred at -70 C for 10 min,Di-tert-butyl azodicarboxylate (345 mg, 1.5 mmol) was then added and stirring was continued for 30 min.The reaction was quenched with aqueous NH4Cl (10 mL) and then extracted with ethyl acetate (10 mL x 3). The organic phases are combined, dried over Na2SO4, and concentrated.An off-white solid crude product was obtained (350 mg, 72%).
With red-aluminum/N-methylpiperazine complex; In toluene; at -5 - 0℃; for 5h;Inert atmosphere;
Dried 500ml reaction flask to slowly purged with nitrogen, the 24.7g1- benzyl-4-piperidine carboxylic acid ethyl ester (0.1mol) and 24ml toluene was added to the reaction vessel, with stirring, cooled until the internal temperature at about -5 . The resulting red aluminum / N- methyl piperazine complex (about 0.26mol) dropwise to control the reaction temperature between -5 ~ 0 . 3h addition was complete, the reaction was continued insulation 2h. Was added slowly prepared 4N sodium hydroxide solution (containing 36gNaOH), control the internal temperature not higher than 20 , the addition was completed, stirring was stopped, the organic layer was washed with water (150ml / times, 4 times), the organic layer was concentrated at 75 concentrated under reduced pressure until no solvent was evaporated to give 1-benzyl-4-piperidine methanol, 19.61g, as a pale yellow oily liquid. Yield: 95.5percent. HPLC: 99.00percent
91%
In diethyl ether;
EXAMPLE 8 1-Benzyl-4-hydroxymethylpiperidine A solution of 1-benzyl-4-carboethoxypiperidine (74.3 g, 0.300 mole) in anhydrous Et2 O (740 mL) was stirred at 0° C. under N2. Lithium aluminum hydride (11.4 g, 0.300 mole) was added in small portions over 0.5 hours. After an additional 2.5 hours, the reaction was carefully quenched with H2 O (740 mL). The mixture was filtered through a Celite pad and rinsed with ethyl acetate (EtOAc), then the layers were separated. The aqueous layer was saturated with NaCl, then extracted with EtOAc (3*100 mL). The combined organics were extracted with brine, dried (MgSO4), and concentrated in vacuo. The resulting crude product was vacuum distilled, bp ~144° C. at 0.1 mm Hg, to yield the alcohol (55.8 g,91percent) as a colorless, viscous oil. Analysis: Calculated for C13 H19 NO: C,76.06; H,9.33; N,6.82; found: C,75.87; H,9.16; N,6.55.
90.5%
2g) (1-Benzyl-4-piperidyl)methanol(Compound Vl)To a solution of lithium aluminium hydride (72 mmol; 2.7 g) in anhydrous THF (40 ml) at 00C was added dropwise a solution of ethyl4-benzylisonipecotate (55 mmol; 13.7 g) in the same solvent (130 ml). The reaction mixture was stirred at room temperature for 20 minutes. After cooling to 00C, ice was added cautiously and the hydroxides thus formed were removed by filtration. After removing the tetrahydrofuran under reduced pressure, the aqueous phase was extracted with ethyl acetate (3 * 100 ml). The combined organic phases were washed with saturated NaCI solution (3 x 100 ml), dried over sodium sulfate and evaporated under reduced pressure. A crude product was obtained, which was purified on a column of alumina (eluting with ethyl acetate) to give 10.25 g (90.5percent) of pure product as an oil.1H NMR (CDCI3, delta ppm): 1.29-1.39 (m, 2H); 1.53-1.56 (m, 1 H); 1.74- 1.78 (m, 2H); 1.86 (s, 1 H); 1.99-2.05 (m, 2H); 2.94-2.98 (m, 2H); 3.52- 3.56 (m, 4H); 7.30-7.38 (m, 5H).
82%
With sodium bis(2-methoxyethoxy)aluminium dihydride; In toluene; at 20℃; for 2h;Inert atmosphere;
Charge toluene (100 mL) in a round bottom flask along with vitride (26 g, 0.12 mol) in an inert atmosphere. N-Benzyl ethyl isonipecotate (2, 40 g, 0.16 mol) was added slowly in portions to the reaction mass. The mixture was stirred at room temperature for 2 h. After completion of the reaction the mass was quenched with chilled water. Toluene phase was separated and dried over anhydrous sodium sulfate. Toluene was removed under vacuum to get N-benzyl piperidine alcohol (3, 26.9 g, 82 percent).
40%
With lithium aluminium tetrahydride; In tetrahydrofuran; for 0.0833333h;Cooling with ice;
(1-Benzylpiperidin-4-yl)methanol. The title compound was prepared by a modification of the procedure reported by Dutta et al. (J. Med. Chem. 1996, 39, 749?756). To a 500 mL round bottom flask equipped with magnetic stirring was added ethyl 1-benzylpiperidine-4-carboxylate (10 g, 40.4 mmol) and tetrahydrofuran (THF, 136 mL). The ester was allowed to dissolve and the solution was cooled to 0 oC in an ice bath. To this solution was added lithium aluminumhydride (81 mL, 81 mmol, 1M in THF) at 0 oC by syringe. The reaction was monitored by thin layer chromatography (TLC) developed with neat EtOAc. After 5 min the reaction was quenched with water (3.2 mL) and 15percent sodium hydroxide solution. The mixture was filtered through a layer of Celite and extracted with EtOAc (3 x). The organic extracts were combined and dried (Na2SO4). Removal of solvent gave the title compound (3.3 g, 40percent). Proton NMR ofthe product was consistent with the above literature reference. The compound was used in the next step without further purification.
With sodium hydroxide; In tetrahydrofuran; water; ethyl acetate;
a) 1.42 g (0.0375 mol) of lithium aluminium hydride were suspended in 20 ml of THF. 1.548 g (0.00623 mol) of ethyl 1-benzylpiperidine-4-carboxylate were slowly added dropwise at 0°. The mixture was heated to 70° and boiled at reflux for 16 hrs. The reaction mixture was treated with 70 ml of ethyl acetate, 6.5 ml of water and 1.5 ml of 2N aqueous NaOH. The mixture was stirred for 1 hr., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed on silica gel with methanol/dichloromethane (1:9) as the eluent. 1.16 g (91percent) of 1-benzyl-4-hydroxymethylpiperidine were obtained.
With ammonium chloride; magnesium; In tetrahydrofuran;
PREPARATION 4 alpha,alpha-Bis-(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol To a 6.08 g (0.25 mole) of magnesium turnings and an iodine crystal in 600 ml of dry tetrahydrofuran and under an atmosphere of nitrogen was added, dropwise, a solution of p-bromofluorobenzene in 125 ml of tetrahydrofuran. The temperature of the reaction was kept below 10 C. by cooling in an ice-methanol bath. The mixture was stirred at room temperature for 1.5 hours. A solution of 24.7 g (0.10 mole) of 1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ester in tetrahydrofuran was added, and the mixture was stirred at room temperature for 17 hours. The reaction was poured into an icy, aqueous solution of ammonium chloride, and the resulting solution was extracted with methylene chloride. The methylene chloride solution was extracted with dilute sodium hydroxide and was dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. This was crystallized from ether-hexane to give 19.87 g (51%) of the title compound, m.p. 113-15 C. Analysis: Calculated for C25 H25 F2 NO: C, 76.31;H, 6.40;N,3.56. Found: C,76.24;H,6.38;N,3.50.
19.87 g (51%)
With ammonium chloride; In tetrahydrofuran;
PREPARATION 2 alpha,alpha-bis-(4-Fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol To a dry 2 liter round bottom flask containing magnesium turnings (6.08 g, 0.25 mole) and an iodine crystal in 600 ml of dry tetrahydrofuran (distilled from lithium aluminum hydride) and under an atmosphere of nitrogen was added, dropwise, a solution of 52.5 g (0.30 mole) of p-bromofluorobenzene in 125 ml of tetrahydrofuran. The temperature of the reaction mixture was kept below 10 C. by cooling in an ice-methanol bath. The mixture was stirred at room temperature for 1.5 hours. A solution of 1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ester (24.7 g, 0.1 mole) in tetrahydrofuran was added, and the mixture was stirred at room temperature for 17 hours. The reaction was poured into an icy, aqueous solution of ammonium chloride, and the resulting solution was extracted with methylene chloride. The methylene chloride solution was extracted with dilute sodium hydroxide and was dried (magnesium sulfate). The solvent was removed in vacuo to give an oil. This was crystallized from ether-hexane to give 19.87 g (51%) of the title compound, mp 113-115 C. Analysis: calculated for C25 H25 F2 NO: C, 76.31; H, 6.40; N, 3.56. Found: C, 76.24; H, 6.38; N, 3.50.
With magnesium; In tetrahydrofuran;
(a) To a stirred and refluxing Grignard-complex, previously prepared starting from 70 parts of 1-bromo-4-fluorobenzene and 10 parts of magnesium in 270 parts of tetrahydrofuran, was added dropwise a solution of 25 parts of ethyl 1-(phenylmethyl)-4-piperidinecarboxylate in 90 parts of tetrahydrofuran. Upon completion, stirring was continued for 2 hours at reflux temperature. The reaction mixture was cooled and poured onto a saturate ammonium chloride solution. The organic phase was separated, dried, filtered and evaporated, yielding 40 parts of alpha,alpha-bis(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol as a residue (intermediate 12).
19.87 g (51%)
With ammonium chloride; magnesium; In tetrahydrofuran;
PREPARATION 10 alpha,alpha-bis-(4-Fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol To magnesium turnings (6.08 g, 0.25 mole) and an iodine crystal in 600 ml of dry tetrahydrofuran (THF) (distilled from lithium aluminum hydride) and under an atmosphere of nitrogen was added dropwise a solution of p-bromofluorobenzene in 125 ml of THF. The temperature of the reaction mixture was kept below 10 C. by cooling in an ice-methanol bath. The mixture was stirred at room temperature for 1.5 hr. A solution of 1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ester (24.7 g, 0.10 mole) in THF was added, and the mixture was stirred at room temperature for 17 hr. The reaction mixture was poured into an icy, aqueous solution of ammonium chloride, and the resulting solution was extracted with methylene chloride. The solution was extracted with dilute sodium hydroxide and was dried (magnesium sulfate). The solvent was removed in vacuo to give an oil. This was crystallized from ether-hexane to give 19.87 g (51%) of title compound, m.p. 113-115 C. Analysis: Calculated for C25 H25 NOF2: C,76.31; H,6.40; N,3.56. Found: C,76.24; H,6.38; N,3.50.
With sodium hydroxide; In methanol; for 24h;Reflux;
To a stirring solution of sodium hydroxide (3.44 g, 86.02 mmol, 2eq.) in methanol (100 mL) at room temperature was added ethyl 1-benzylpiperidine-4-carboxylate 8 (10.01 g, 41.82 mmol, 1 eq.) inone portion. The resulting mixture was heated to reflux temperatureand left to stir overnight. The resulting solution was cooled toroom temperature and the solvent was evaporated in vacuo toafford a yellow solid. The solid was re-dissolved in distilled water(100 mL) and the pH adjusted to 5.5. The solvent was removed invacuo to afford a yellow solid. A pre-mixed solution of ethanol:chloroform (1:1, 200 mL) was added and the mixturewas left to stirfor 1 h after which time the solids were collected by filtration andwashed with chloroform(10 mL). The filtratewas collected, and thesolvent was evaporated in vacuo to afford 1-benzylpiperidine-4-carboxylic acid 9, as an off-white solid (98%) which was used as iswithout any further purification. (Yield 98%); Rf 0.07 (4:1dichloromethane: methanol); mp 168 C; nmax (neat)/cm1 2969,2864, 1602, 1448, 1382, 921, 756, 702, 659; 1H NMR (300 MHz,CDCl3); d 10.71 (s, 1H, OH), 7.38e7.27 (m, 5H, ArH's), 3.89 (s, 2H,CH2Ph), 3.14 (d, 2H, J 11.2 Hz, CH2N), 2.46 (t, 2H, J 8.9 Hz, CH2N),2.34e2.21 (m, 1H, CHCO), 2.07e1.82 (m, 4H, CH2); 13C NMR(75 MHz, CDCl3); d 178.88, 132.25, 130.75, 128.74, 60.81, 51.50,40.68, 26.72; HRMS m/z (ESI) 220.1353 ([M H] requires220.1332).
95%
With sodium hydroxide; water; In tetrahydrofuran; 1,4-dioxane; at 20℃;
(b) Synthesis of 1-benzyl-4-piperidinecarboxylic acid A 4N-aqueous sodium hydroxide solution (35 ml) was added to a solution of ethyl 1-benzyl-4-piperidinecarboxylate (16.1 g, 65.1 mmol) in a tetrahydrofuran (70 ml)/1,4-dioxane (70 ml) mixture at room temperature and stirred overnight. Then, the pH was adjusted to 7 with 2N-hydrochloric acid and the solvent was distilled off under reduced pressure. The resulting residue was suspended in ethanol and the suspension was filtered. The filtrate was concentrated under reduced pressure to obtain 1-benzyl-4-piperidinecarboxylic acid (13.6 g, 95%).
With sodium hydroxide; In methanol; dichloromethane; water;
Step 1. 1-Benzylpiperidine-4-carboxylic acid Ethyl 1-benzylpiperidine-4-carboxylate (13.73 g) in methanol (100 ml) was treated with 40% aqueous sodium hydroxide (8.3 ml) at room temperature 16 h. The solvent was removed in vacuo and the residue re-dissolved in water (100 ml), acidified with dilute hydrochloric acid to pH 4 and concentrated. The residue was extracted with hot ethanol (200 ml), filtered and concentrated again. Addition of dichloromethane resulted in crystallization giving the title compound as a colourless crystaline solid, (3.24 g, 27%). Removal of solvent from the filtrate and trituration with ether gave a second batch as an amorphous white solid, (9.24 g, 73%); numax (CH2 Cl2) 2496 (vbr), 1720 and 1604 (br) cm-1.
Preparation 28; 1-Benzylpiperidine-4-carboxylic acid; Sodium hydroxide solution (4.12 ml of a 1N solution, 4.12 mmol) was added to a stirring solution of ethyl 1-benzylpiperidine-4-carboxylate (1 g, 4.04 mmol) in ethanol (6 mL). After 24 hours, extra sodium hydroxide solution (4 mL) was added and the mixture was stirred for a further 24 hours. Dilute hydrochloric acid (4.06 ml of a 2N solution) was added to the mixture and the solvent was removed in vacuo. The residue was extracted with hot isopropyl alcohol (20 mL) and the solvent was evaporated in vacuo to low volume and allowed to stand at room temperature. The resulting solid was filtered off, washed with isopropyl alcohol and dried in vacuo to give the title compound as a white solid, 337 mg.LRMS: m/z ES 220 [MH]+
To a stirred solution of ethyl-N-benzyl isonipecotate (5.7g, 24. [2MMOL)] in methanol [(60ML)] was added a 1M solution of [NAOH] [(60ML,] [60MMOL).] The resulting mixture was stirred for 4 hours. The solution was neutralised by the addition of 2M HCI solution [(30ML,] [60MMOL)] then the solvent was removed in vacuo. The residue was triturated with THF [(3XLOOML),] the triturates were combined and evaporated to give 4.12g of N-benzylisonipecotic acid which was used without further purification. The N-benzylisonipecotic acid (3.94g, [18.] [0MMOL)] was suspended in THF (100ml) under Argon then cooled [TO-78C.] A 2M solution of lithium diisopropylamide was then added dropwise with stirring (22. [5ML,] 45mmol). The reaction was then allowed to warm to room temperature followed by refluxing under argon for a further hour (oil bath temperature [50C).] This solution was then allowed to cool back to room temperature. In a separate flask 4-bromobenzoyl chloride (5.93g, 27mmol) was dissolved in THF (100ml) and cooled [TO-78C.] The dianion solution was added dropwise to the acid chloride solution over 30 minutes. The reaction mixture was stirred at-78C for a further 30 minutes then allowed to warm to room temperature over night. The reaction was quenched by the addition of 2M HCI [(36ML,] 72mmol) in 100g of crushed ice. The product was extracted with 3x200ml DCM, dried over MgS04 and then evaporated to give a brown oil. Flash column chromatography was performed, eluting with 0 to 5% MeOH in DCM. 1.7g of pure material was obtained as an orange solid. M/z 358.
piperidine-4-carboxylic acid ethyl ester hydrochloride[ No CAS ]
[ 24228-40-8 ]
Yield
Reaction Conditions
Operation in experiment
93.8%
With sodium hydrogencarbonate; In ethanol; for 3h;Reflux;
The 18.4g4- isonipecotate hydrochloride, 12.7g of benzyl chloride, 21.0 g of sodium bicarbonate and 40ml of absolute ethanol was added to a 100ml reaction flask, was heated to reflux and maintained at reflux the reaction 3h, cooled to an internal temperature 30 about, filtering, washing the filter cake with 20ml ethanol, and the filtrate was concentrated to a paste, added 40ml of toluene and 40ml of water, stirred and dispersed organic layer was separated, the toluene was concentrated to give 1-benzyl-4-piperidinecarboxylic acid ethyl ester 23.2g, as a pale yellow oily liquid. Yield: 93.8% (in terms benzyl chloride). HPLC: 98.74%
A dry and argon-flushed flask, equipped with a magnetic stirring bar and a septum, was charged with morpholine (0.18mL, 2.1mmol) and 10mL THF. After cooling to 0C, DIBALH (2.0mL, 1.0M in hexane, 2.0 mmol) was added dropwise and stirred for 3h at same temperature. To a reaction mixture was slowly added ethyl N-benzylpiperidine-4-carboxylate (0.247g, 1.0mmol) and stirred for 10min. Then, LDBMA (2.8mL, 0.46M in hexane-THF, 1.3mmol) was added and the mixture was stirred for 10min again. The reaction was stopped by the aqueous 1N HCl (10mL) and extracted with diethyl ether (2×10mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel yielded N-benzyl-4-formylpiperidine (191mg, 94%).
94.3%
With red-aluminum/morpholine complex; In cyclohexane; at 0℃; for 3h;Inert atmosphere;
3L reaction flask to dry slowly purged with nitrogen, the 197.9g1- benzyl-4-piperidine carboxylic acid ethyl ester (0.8mol) and 230ml of cyclohexane added to the reaction flask, stirred and cooled to an internal temperature of between 0 . The red aluminum obtained - morpholine complex (0.88mol) dropwise to control the reaction temperature at about 0 . 2h addition was complete the addition was complete, 0 reaction was continued for 60min. Was added slowly prepared 4N sodium hydroxide solution (containing 110gNaOH), control the internal temperature not higher than 20 , the addition was completed, stirring was stopped, the organic layer was washed with water (1.1L / times, 4 times), the organic layer concentrated 75 concentrated under reduced pressure until no solvent was evaporated to give 1-benzyl-4-piperidine carbaldehyde 153.4g, as a pale yellow oily liquid. Yield: 94.3%. HPLC: 98.74%
6.91 g (92%)
With diisobutylaluminium hydride; In methanol; toluene;
EXAMPLE 2 1-benzypiperidine-4-carboxaldehyde To a solution of ethyl 1-benzylpiperidine-4-carboxylate (9.2 g, 0.037 mol) in 400 ml of toluene was added 1.5M diisobutylaluminum hydride in toluene (28 ml, 0. 042 mol) at -78 C. The mixture was stirred at -78 C. for 1 hr and quenched with 150 ml of MeOH and the dry ice bath was removed. After stirring for 2 hr at r.t., the mixture was filtered through diatomaceous earth (Celite (trademark)) and washed with methanol. The filtrate was concentrated to dryness to give 6.91 g (92%) of 1-benzylpiperidine-4-carboxaldehyde which can be used directly or purified by vacuum distillation, bp 93-97 C./1 mmHg. H-NMR (CDCl3)delta 1.6-1.8 (m, 2H), 1.8-1.9 (m, 2H), 2.05-2.17 (m, 2H), 2.17-2.3 (m, 1H), 2.75-2.9 (m, 2H), 3.5 (s, 2H), 7.2-7.4 (m, 5H), 9.6 (s, 1H) ppm.
With diisobutylaluminium hydride; In toluene; at -30℃; under 600.06 - 750.075 Torr;Thin film fluid;
A 1 mol/L toluene solution of diisobutylaluminum hydride was sent as a first fluid from the center at a ratio of supply pressure/back pressure of 0.10 MPa/0.08 MPa, a rotation speed of 2000 rpm, and a sending temperature of -30C, and a 0.92 mol/L ethyl N-benzyl isonipecotate/toluene solution was introduced as a second fluid into a space between the processing surfaces at 15 mL/min. The first fluid and the second fluid were mixed in a thin film fluid, and then a solution obtained after processing was discharged from the space between the processing surfaces at 30 mL/min. The discharged solution was collected into methanol. The thus obtained slurry solution was filtered under a reduced pressure to obtain a filtrate, and the filtrate was analyzed by gas chromatography. As a result, the reaction rate was 89%, and the ratio of N-benzylisonipecotinyl aldehyde (2) as a target substance contained in a reaction product was 97%, and the ratio of N-benzyl-4-pyperidyl methanol (3) as a side-product was only 3%.
An LDA (14 mmol) solution was prepared by treating diisopropylamine (1.37 g, 14 mmol) with BuLi (1.6 M, 8.5 mL, 14 mmol) at -78 C. in dry THF (10 mL) under Argon and allowing to warm up to -20 C. This solution was then cooled to -60 C. added to a solution of 1-benzyl-piperidine-4-ethyl carboxylate (3.05 g, 12 ramol) at -60 C. and allowed to warm up to -40 C. over 1 h whereupon a solution of trans-beta-nitrostyrene (1.93 g, 13 mmol) was added dropwise. The reaction mixture was allowed to warm up to room temperature over 1 h and then quenched with ammonium chloride (saturated, 40 mL) and the product extracted with ethyl acetate (2×40 mL). The combined organic extracts were then washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography on silica gel eluting with DCM: MeOH (9:1) afforded the title compound (4.1 g, 84%) as a light yellow gum. MS: m/e=397.4 (M+H).
84%
a) An LDA (14 mmol) solution was prepared by treating diisopropylamine (1.37 g, 14 mmol) with BuLi (1.6 M, 8.5 mL, 14 mmol) at -78 C. in dry THF (10 mL) under argon and allowing to warm up to -20 C. This solution was then cooled to -60 C. added to a solution of 1-benzyl-piperidine-4-ethyl carboxylate (3.05 g, 12 mmol) in THF (8 mL) at -60 C. and allowed to warm up to -40 C. over 1 h whereupon a solution of trans-beta-nitrostyrene (1.93 g, 13 mmol) in THF (8 mL) was added dropwise. The reaction mixture was allowed to warm up to room temperature over 1 h and then quenched with ammonium chloride (saturated, 40 mL) and the product extracted with ethyl acetate (2×40 mL). The combined organic extracts were then washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography on silica gel eluting with DCM:MeOH (9:1) afforded the title compound (4.1 g, 84%) as a light yellow gum. MS: m/e=397.4 (M+H).
With lithium diisopropyl amide; In tetrahydrofuran; at -78℃; for 1.25h;
To a solution OF N-BENZYLPIPERIDINE-4-CARBOXYLIC acid ethyl ester (6.1 g, 24.7 mmol) in 100 mL THF AT-78C was added LDA (14.2 mL of 2M in THF, 28.4 mmol) over 15 minutes. The solution was stirred AT-78C for another 15 minutes, followed by addition of a solution of 3,4- difluorobenzotrifluoride (4.5 g, 24. 7MMOL) in 20 mL THF over 15 minutes. The solution was stirred AT-78C for 30 minutes, and then the flask was immersed in an ice-water bath and slowly warmed to rt overnight, followed by treatment of saturated NH4C1 at 0C. The mixture was extracted by ethyl acetate (3x). The extracts were combined, washed with water and brine, dried over MGS04, and concentrated IRA vacuo. The residue was purified by column chromatography (77% hexane/18% EtOAc/5% MeOH) to afford pure desired product (3.52g, 35 %). LC-MS M+H 396.
With sodium cyanoborohydride; In ethanol; at 20℃; for 3h;
Reference Example 65 To a mixture of ethyl isonipecotate (10.0 g), benzaldehyde (6.75 g), and ethanol (100 mL) was added sodium cyanotrihydroborate (4.00 g) at room temperature. After stirring for 3 hours, the mixture was concentrated and distributed into hexane and water. The organic layer was extracted with 1 N hydrochloric acid, the aqueous layer was alkalified with sodium hydrogen carbonate, and then the reactant was extracted with hexane. The extracts were washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain ethyl 1-benzyl-4-piperidinecarboxylate (2.34 g). 1H-NMR (300 MHz, CDCl3) delta: 1.24 (3H, t, J=7.2 Hz), 1.68-1.91 (5H, m), 2.02 (2H, td, J=11.4 and 2.7 Hz), 2.27 (2H, tt, J=10.8 and 4.2 Hz), 2.82-2.88 (2H, m), 3.49 (2H, s), 4.12 (2H, q, J=7.2 Hz), 7.25-7.38 (5H, m).
In tetrahydrofuran; diethyl ether; at 0℃; for 2.0h;
138 2-(1-[2-(I H-Indazol-4- ylV4-morpholin-4- yl-thieno[3 ,2-dlp yrimidin-6- ylmethyl"|-piperidin-4-yl|-propan-2-olVia 2-[l-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)- piperidin-4-yl]-propan-2-ol, prepared from 2-piperidin-4-yl-propan-2-ol.Amine preparation: To a solution of piperidine-4-carboxylic acid ethyl ester (3.0g) stirring in dry MeCN (3OmL) was added potassium carbonate (2.9Og) followed by benzyl bromide (2.5mL). The mixture was warmed to 78C. After 3 h the mixture was cooled, poured into water (10OmL) and extracted into ethyl acetate, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to give l-benzyl-piperidine-4-carboxylic acid ethyl ester(2.17g) as a pale yellow oil. EPO <DP n="72"/>To a solution of l-benzyl-piperidine-4-carboxylic acid ethyl ester (1.Og) stirring in dry THF (15mL) under a nitrogen atmosphere at 0C, was added methyl magnesium bromide (3.0M solution in diethyl ether; 8.1OmL) and stirred for 2 h at O0C. The reaction mixture was quenched with saturated ammonium chloride solution and extracted into ethyl acetate, dried (MgSO4) and the solvents removed in vacuo to give 2-(l-benzyl-piperidine-4-yl)-propan-2-ol (1.1 Ig) as a white solid.To a suspension of 10% palladium on charcoal (40mg) stirring in dry MeOH (1OmL) under a nitrogen atmosphere was added 2-(l-benzyl-piperidine-4-yl)-propan- 2-ol (0.25g) and the mixture warmed to 60C.After 3 h the mixture was cooled, filtered through a celite bed and the solvents removed in vacuo to yield the desired amine (153mg) as a colourless oil.1H NMR (400 MHz, J6-DMSO) 1.03 (s, 6H), 1.09 (m, IH), 1.23 (m, 2H), 1.66 (m, 2H), 1.98 (m, 2H), 2.97 (m, 2H), 3.83 (m, CH2 x 2 + CH2), 4.00 (m, 4H), 7.46 (t, 2H, J=7.3Hz), 7.65 (d, 1H, J=8.2 Hz), 8.21 (d, lh, J=7.1 Hz), 8.87 (s, IH), 13.15 (br s, IH); MS (ESf) 493.2 (MH+).
In tetrahydrofuran; at -78 - 20℃; for 21.0h;
Reference Example 66 To a mixture of ethyl 1-benzyl-4-piperidinecarboxylate and tetrahydrofuran (50 mL) was added at -78C for 1 hour a 1 M methyl magnesium bromide - tetrahydrofuran solution (1.2 mL). After stirring for 6 hours, the temperature was elevated to room temperature, and the mixture was stirred for 14 hours. The reactant was poured into an ammonium chloride solution and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 2-(1-benzyl-4-piperidinyl)-2-propanol (820 mg). 1H-NMR (300 MHz, CDCl3) delta: 1.16-1.45 (4H, m), 1.17 (6H, s), 1.68-1.73 (2H, m), 1.87-1.95 (2H, m), 2.94-2.99 (2H, m), 3.49 (2H, s), 7.24-7.32 (5H, m).
A mixture of ammonium chloride (216 mg, 4.04 mmol), trimethylaluminium (2.02 mL, 2.0M/toluene, 4.04 mmol), in toluene (5 mL) was stirred at rt for 30 min. Ethyl 1-benzylpiperidine-4-carboxylate (500 mg, 2.02 mmol) was added and mixture was stirred for 18 h at 80 C. The reaction mixture was cooled down and 1N sodium potassium tartrate solution was added. The reaction mixture was extracted with ethyl acetate, the organic phase was separated, dried (MgSO4), filtered and evaporated. The crude material was purified by preparative HPLC to give Example 126a (I120 mg) as a white solid. (M+H)+=218.
With sodium hydroxide; In water; isopropyl alcohol;
b) 0.8 g (0.00323 mol) of ethyl 1-benzylpiperidine-4-carboxylate was dissolved in a mixture of 5 ml of dioxan, 2 ml of water and 3.5 ml (0.0035 mol) of 1N aqueous NaOH. After stirring for 15 min. 3.5 ml (0.0035 mol) of 1N aqueous HCI were added, the mixture was diluted with 20 ml of water, the dioxan was removed by distillation and the residue which remained was lyophilized. The residue was boiled twice with 100 ml of isopropanol each time and the combined organic phases were filtered and concentrated. The product crystallized out in the cold. 0.586 g (83%) of 1-benzylpiperidine-4-carboxylic acid was obtained as white crystals; m.p. 167-168.
ethyl 1-benzyl-4-(4-chloro-2-(3,3,3-triethoxyprop-1-ynyl)phenyl)piperidine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With lithium dicyclohexylamide;palladium diacetate; tri-tert-butyl phosphine; In toluene; at 100℃; for 0.666667h;
Step E: Preparation of Ethyl l-benzyl-4-(4-chloro-2-(3,3,3- triethoxyprop-l-ynyl)phenyl)piperidine-4-carboxylate; [0837] In a glovebox, ethyl l-benzylpiperidine-4-carboxylate (2.0 g, 8.1 mmol), LiNCy2 (1.55g, 8.3 mmol), and toluene (10 mL) were loaded sequentially into a 40 mL vial. In a separate vial, Pd(OAc)2 (22 mg, 0.1 mmol), P(t-Bu)3 (44 mg, 0.22 mmol), l-bromo-4-chloro-2-(3,3,3-triethoxyprop-l- ynyl)benzene (1.5 g, 4.1 mmol), and toluene (10 mL) were loaded sequentially and were then heated at 1000C for 1 minute. The enolate solution in vial 1 was then added to the reaction mixture in vial 2 via a syringe. The combined mixture was heated at 1000C for 40 minutes. The reaction mixture was cooled to 23C and passed through a short plug of silica gel eluting with EtOAc (20 mL). The filtrate was concentrated in vacuo and purified by silica gel chromatography (eluant: 5-20% EtOlambdac/hexa?e + 2%TEA), affording 833 mg <n="190"/>of ethyl l-benzyl-4-(4-chloro-2-(3,3,3-triethoxyprop-l-ynyl)phenyl)piperidine- 4-carboxylate.
Step A: Preparation of Ethyl 1 -benzyl-4-(2-(2-(triethylsilyI)ethynyl)-phenyl)piperidine-4- carboxylate; [0810] At 00C, n-BuLi (1.6N, 2 mL, 3.2 mmol, 1.6 eq.) was syringed into a solution of HNCy2 (615 mg, 3.4 mmol, 1.7 eq.) in toluene (6 mL) in a N2- filled 40 mL vial equipped with a stirbar, an open-top cap and an I-Chem septum. The solution was warmed to room temperature, and ethyl 1 - benzylpiperidine carboxylate (840 mg, 3.4 mmol, 1.7 eq.) was then syringed into the mixture. <n="184"/>[081 1] [PdBrP(t-Bu)3]2 (15 mg, 0.02 mmol, 1 %) was weighed into a separate 20 mL vial containing a stir bar. The vial was then capped with an I- Chem septum cap, and evacuated/refilled with N2'(repeated twice). With N2 needled into the vial, toluene (4 mL) was syringed in, followed by (2-(2-bromo- phenyl) ethynyl)triethylsilane (590 mg, 2.0 mmol). The needle was then removed from the vial, and the vial was heated at 1000C for 2 minutes with stirring. The vial was allowed to cool for about 1 minute. The whole solution was then pulled into a 10 mL syringe before it completely cooled. The solution was then syringed into the above vial containing the lithium/anion with N2 needled in. The needle was removed. The whole solution was heated at 100C and monitored using GC. No (2-(2-bromo-phenyl) ethynyl)triethylsilane remained after 20 minutes. The reaction was cooled to room temperature and filtered through a silica gel plug, elutcd with EtOAc (30 mL). The resulting solution was concentrated, absorbed on silica gel and purified by silica flash chromatography (10-30% EtOAc/hexanes) to afford the title compound as a pale-yellow oil (533 mg). MS m/e = 462 (M+H)+.
Ethyl 1-benzylpiperidine-4-carboxylate (2.47 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to -78C. Lithium bis(trimethylsilyl) amide (11 mL, 1.0 M in tetrahydrofuran) was added slowly, and stirred for 30 minutes. 2-fluorobenzylbromide (1.34 mL, 11 mmol) in 5 mL tetrahydrofuran was added slowly. The resulting solution was allowed to reach room temperature and stirred over night. The reaction was quenched with ammonium chloride (aq, sat) and partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulphate, filtrated and concentrated. The crude material was purified on silica (heptane/ethyl acetate), to give 2.7 g (77%) the subtitle compound as a colourless oil. APCI-MS: m/z 356 [MH+]
75%
Ethyl 1-benzylpiperidine-4-carboxylate (10.0 g, 40.5 mmol) was dissolved in tetrahydrofuran (80 mL), cooled to -78[deg.] C., and LiHMDS (42.0 mL, 44.5 mmol) was slowly added dropwise thereto. After the solution was stirred at -78C for 30 minutes, o-fluorobenzyl bromide (8.37 g, 44.5 mmol) was slowly added dropwise and allowed to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (250 mL), extracted with ethyl acetate (100 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluent: petroleum ether/acetic acid) Ethyl ether = 10:1 to 5:1) as a pale yellow oil 49-f (10.8 g, 75%).
With methyllithium; In tetrahydrofuran; at -78 - 20℃;
To a 50 mL round-bottomed flask was added ethyl isonipecotate (5.0 g, 32 mmol) in dimethylformamide at 0 C. Sodium hydroxide (0.86 g, 35 mmol) was added and the reaction mixture was allowed to stir for 15 minutes. 1-(Bromomethyl)benzene (4.2 ml, 35 mmol) was then added and the reaction mixture was allowed to stir slowly warming to room temperature. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, saturated sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. The ethyl 1-benzylpiperidine-4-carboxylate product (5.8 g, 23.3 mmol) was then added to a 500 mL round-bottomed flask in THF at -78 C. Methyllithium (18.7 ml, 46.7 mmol) was added and allowed to stir slowly warming to room temperature overnight. Upon completion, the reaction mixture was concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated sodium carbonate solution, saturated sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M) X2, eluting with a gradient of 1% to 10% methanol in dichloromethane, to provide 2-(1-benzylpiperidin-4-yl)propan-2-ol. To a solution of 2-(1-benzylpiperidin-4-yl)propan-2-ol in methanol was added palladium, 10 wt. % on activated carbon. A hydrogen balloon was attached to the reaction vessel and the reaction mixture was stirred overnight. Upon completion, the reaction mixture was filtered through Celite. The filtrate was concentrated to produce 2-(piperidin-4-yl)propan-2-ol.
The produced ethyl 1-benzylpiperidine-4-carboxylate (5.7701 g, 23.3 mmol) was then added to a 500 mL round-bottomed flask in THF at -78 C. Methyllithium (18.7 ml, 46.7 mmol) was added and allowed to stir slowly warming to room temperature overnight. Upon completion, the reaction was concentrated. The residue was diluted with water) and extracted with ethyl acetate. The organic extract was washed with saturated sodium carbonate solution, saturated sodium chloride solution), dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40 M)×2, eluting with a gradient of 1% to 10% methanol in dichloromethane, to provide 2-(1-benzylpiperidin-4-yl)propan-2-ol (m+1=234.1).
To a solution of ethyl l-benzylpiperidine-4-carboxylate (4.94 g) in THF (20 mL) at - 780C, LDA (IM in THF) (1.1 eq) is added drop wise over 30 min. The resulting mixture is stirred at -780C for one hour. A solution of 4-methoxybenzyl chloride (3.13 g) in THF (10 mL) is added dropwise over 30 min. The mixture is allowed to warm to rt overnight. The reaction is quenched with water (20 mL) and the mixture is extracted with EtOAc (50 mL). The organic layer is separated and dried (Na2SO4), and the solvent is removed. Flash column purification of the residue with hexane/ethyl acetate (3:1) provides the title compound as a white solid.
To a solution consisting of ethyl 1-benzylpiperidine-4-carboxylate (500 mg, 2.02 mmol) in ethanol (10 mL) was added 1 N sodium hydroxide (2.02 mL, 2.02 mmol) and the reaction mixture was stirred at room temperature overnight. Most of the ethanol was removed under reduced pressure and stirring was continued for six hours. Toluene was added to remove most of the water by azeotrope and the material was dried under high vacuum overnight to provide the title intermediate as a white solid.
Diisopropylamine (3.14 inL; 22.23 mmol; 1.1 eq.) was dissolved in THF (60 mL) and cooled to -78 C. Butyl lithium (2.5 M in hexane; 8.89 mL; 22.23 mmol; 1.1 eq.) was then added and the solution was stirred for 30 minutes at -78 C. Ethyl l-benzylpiperidine-4-carboxylate (5 g; 20.21 mmol; 1 eq.) was dissolved in THF (40 mL) and added to the LDA solution at -78 C. The solution was stirred at -78 C for 30 minutes and iodomethane (1.32 mL; 21.22 mmol; 1.05 eq.) was added. The solution was slowly warmed to room temperature and stirred at room temperature for 1 hour. Water (100 mL) was then added to the reaction followed by EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure to afford the product (5.0 g, 94% yield) as an oil. The product was analytically pure and used without further purification. LC/MS m/z (M+l) 262.0, Retention time 1.78 minutes; (10-99% CH3CN-H20 gradient with 0.03% TFA, 5 min). .H NMR (400 MHz, CDC13) 8 7.24-7.14 (m, 5H), 4.08 (q, J = 7.1 Hz, 2H), 3.40 (s, 2H), 2.60-2.57 (m, 2H), 2.08-2.02 (m, 4H), 1.47-1.40 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H), 1.10 (s, 3H). [0210] l-Benzyl-4-methylpiperidine-4-carboxylate (5.0 g; 19.15 mmol) was dissolved in Et20 (50 mL) and cooled to 0 C. L1AIH4 (1.0 g; 26.3 mmol) was slowly added portion-wise to the solution. After the addition was complete, the solution was slowly warmed to room temperature and stirred for 1 h. The solution was then cooled to 0 C and slowly quenched with IN NaOH (6 mL). The resultant white precipitates were filtered and washed with EtOAc (100 mL). The combined organic layers were concentrated under reduced pressure to provide the product (3.9 g, 90% yield) as an oil which was used without further purification. LC/MS m/z M+l 220.0, retention time 0.64 minutes; (10-99% CH3CN-H20 gradient with 0.03% TFA, 5 min). .H NMR (400 MHz, CDCI3) 8 7.25-7.16 (m, 5H), 3.46 (s, 2H), 3.30 (d, J= 3.9 Hz, 2H), 2.51-2.46 (m, 2H), 2.26-2.20 (m, 2H), 1.52-1.45 (m, 3H), 1.30-1.25 (m, 2H), 0.87 (s, 3H). (l-benzyl-4-methylpiperidin-4-yl)methanol (3.9 g; 17.8 mmol) was dissolved in MeOH (50 mL) and NH4CO2H (12.5 g; 178.0 mmol) was added. Pd/C (10% by weight, wet; 5.5 g) was then added and the system was flushed with nitrogen and then with hydrogen. The reaction was stirred at room temperature overnight (18 h) and then filtered through a pad of Celite. The solvent was removed under high vacuum to provide a solid that was a mixture of the amino alcohol and NH4CO2H. The crude product (2.4 g as a mixture with NH4COOH) was used in the next step without further purification. LC/MS m/z (M+l) 130.0, retention time 0.35 min; (10-99% CH3CN-H2O gradient with 0.03% TFA, 5 min). .H NMR (400 MHz, CDCI3) 5 3.17 (s, 2H), 3.03-2.98 (m, 2H), 2.95-2.88 (m, 2H), 1.64-1.57 (m, 2H), 1.36-1.31 (m, 2H), 0.89 (s, 3H). [0212] (4-methylpiperidin-4-yl)methanol (2.4 g, a mixture of the amino alcohol andNELtCC^H) was suspended in DCM (70 mL). Et3N (5 mL; 37.2 mmol) was then added followed by the drop-wise addition of ethyl chloroformate (1.05 mL, 13 mmol, 1.4 eq.). After 1 hour at room temperature, IN HC1 (70 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (70 mL) and the combined organic layers were dried over Na2S04, filtered, and concentrated under high vacuum. The product (1.7 g, 47% yield over 2 steps) is obtained analytically pure as an oil and used without further purification. LC/MS m/z (M+l) 202.2, retention time 1.89 minutes; (10-99% CH3CN-H2O gradient with 0.03% TFA, 5 min). .H NMR (400 MHz, DMSC-d6) 8 4.05 (q, J= 7.1 Hz, 2H), 3.66 (dt, J = 13.6,4.7 Hz, 2H), 3.32 (s, 2H), 3.11 (t, .7=5.2 Hz, 1H),3.11 (dd, .7=23.9, 3.5 Hz, 1H), 1.44-1.37 (m, 3H), 1.26-1.22 (m, 2H), 1.19 (t, J= 7.1 Hz, 3H), 0.93 (s, 3H).[0213] To a 100 mL round bottom flask was added DCM (30 mL) and oxalyl chloride (0.88 mL; 10.13 mmol). The solution was cooled to -78 C and treated with DMSO (1.19 mL; 16.88 mmol). The solution was stirred at -78 C for 20 minutes and then treated with ethyl 4-(hydroxymethyl)-4-methylpiperidine-l-carboxylate (1.7 g; 8.44 mmol, dissolved in 10 mL of DCM). The solution was stirred for 30 minutes at -78 C and then treated with Et3N (3.53 mL; 25.32 mmol). The solution was stirred at -78 C for 20 min and then slowly warmed to room temperature and stirred at room temperature for an additional 2 h. The solution was then treated with saturated aqueous NaHCC>3 (50 mL), diluted with DCM (50 mL), and the layers were separated. The organic layer was washed with brine (50 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure to afford 1.6 g (95% yield) of the product as an oil which was used without further purification. LC/MS m/z (M+l) 200.0, retention time 2.23 minutes; (10-99% CH3CN-H2O gradient with 0.03% TFA, 5 min). .H NMR (400 MHz, CDC13) 5 9.40 (s, 1H), 4.06 (q, J= 7.1 Hz, 2H), 3.66 (dt, J...
89%
To a -78 C solution of N V-diisopropylamine (8.4 mL, 60 mmol) in anhydrous tetrahydrofuran was added a 1.6 M solution of H-butyllithium in hexanes (37.5 mL, 60 mmol). The solution was stirred at -78 C for 10 minutes, warmed to 0 C for 15 minutes, then cooled to -78 C. To this was added a solution of ethyl l-benzylpiperidine-4-carboxylate (8.74 g, 35.4 mmol) in anhydrous tetrahydrofuran (30 mL) dropwise over 10 minutes. The solution was stirred at -78 C for 0.5 h, then warmed to 0 C for 30 minutes, then cooled to -78 C. To this was added a solution of iodomethane (3.7 mL, 59 mmol) in anhydrous tetrahydrofuran (20 mL). The solution was warm to ambient temperature over 18 h and quenched with saturated aqueous ammonium chloride (10 mL). The solution was diluted with ethyl acetate (300 mL), washed with a 3:1 mixture of saturated aqueous ammonium chloride and water (2 x 400 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound as a light brown oil (8.21 g, 89% yield): 1H NMR (300 MHz, CDC13) 6 7.29-7.22 (m, 5H), 4.13 (q, J= 7.1 Hz, 2H), 3.44 (s, 2H), 2.66-2.60 (m, 2H), 2.13-2.07 (m, 4H), 1.52-1.42 (m, 2H), 1.22 (t, J= 7.1 Hz, 3H), 1.15 (s, 3H); MS (ES+) m/z 262.5 (M + 1).
Preparation B; Synthesis of ethyl 4-formyl-4-methylpiperidine-l-carboxylate; [00197] Diisopropylamine (3.14 mL; 22.23 mmol; 1.1 eq.) was dissolved in THF (60 mL) and cooled to -78 C. Butyl lithium (2.5 M in hexane; 8.89 mL; 22.23 mmol; 1.1 eq.) was then added and the solution was stirred for 30 minutes at -78 C. Ethyl l-benzylpiperidine-4- carboxylate (5 g; 20.21 mmol; 1 eq.) was dissolved in THF (40 mL) and added to the LDA solution at -78 C. The solution was stirred at -78 C for 30 minutes and iodomethane (1.32 mL; 21.22 mmol; 1.05 eq.) was added. The solution was slowly warmed to room EPO <DP n="70"/>temperature and stirred at room temperature for 1 hour. Water (100 mL) was then added to the reaction followed by EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the product (5.Og) as an oil. The product was analytically pure and used without further purification.
Diisopropylamine (3.14 mL; 22.23 mmol; 1.1 eq.) was dissolved in THF (60 mL) and cooled to -78 C. Butyl lithium (2.5 M in hexane; 8.89 mL; 22.23 mmol; 1.1 eq.) was then added and the solution was stirred for 30 minutes at -78 C. Ethyl 1-benzylpiperidine-4-carboxylate (E1) (5 g; 20.21 mmol; 1 eq.) was dissolved in THF (40 mL) and added to the LDA solution at -78 C. The solution was stirred at -78 C. for 30 min and iodomethane (1.32 mL; 21.22 mmol; 1.05 eq.) was added. The solution was slowly warmed to room temperature and stirred at room temperature for 1 h. Water (100 mL) was then added to the reaction followed by EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the product (E2) (5.0 g) as an oil. The product was analytically pure and used without further purification. LC/MS m/z (M+1) 262.0, Retention time 1.78 minutes; (10-99% CH3CN-H2O gradient with 0.03% TFA, 5 min). 1H NMR (400 MHz, CDCl3) delta 7.24-7.14 (m, 5H), 4.08 (q, J=7.1 Hz, 2H), 3.40 (s, 2H), 2.60-2.57 (m, 2H), 2.08-2.02 (m, 4H), 1.47-1.40 (m, 2H), 1.17 (t, J=7.1 Hz, 3H), 1.10 (s, 3H).
Preparation 98: 1-Benzyl-4-(2-fluoro-3-methyl-benzyl)-piperidine-4-carboxylic acid ethyl esterTo a solution of "l-benzyl-piperdine-4-carboxylic acid ethyl ester (15g, 60.64mmol) in THF (5OmL) at -780C was added a 1.8M solution of LDA in THF (37mL, 66.60mmol) over 10 minutes. The resulting mixture was stirred at -780C for 1 hour and then a solution of 2-fluoro-3-methylbenzyl bromide (13.5g, 66.48mmol) in THF (2OmL) was added. The resulting mixture was stirred at - 780C for 30 minutes then at room temperature for 18 hours. The reaction was poured into water (5OmL), and the mixture extracted with EtOAc (2x50mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to afford the title compound, 22.1 g. LRMS APCI m/z 370 [M+H]+
Step A: 1-Benzyl-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester To a solution of diisopropylamine (5.68 mL, 0.040 mol) in 100 ml THF at -78 C. was added nBuli (1.6M solution in hexane, 25.9 mL, 0.041 mol) drop-wise. The reaction mixture was warmed to -5 C. and stirring was continued for 30 mins. A solution of 1-benzylpiperidine-4-carboxylic acid ethyl ester (5.00 g, 0.020 mol) in THF (20 mL) was added drop wise and stirring was continued for a further 3 hr followed by the addition of a solution of 1-bromo-2-methoxy-ethane (3.82 g, 0.040 mol) in THF (20 mL) at -5 C. The reaction mixture was then allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was quenched with water and concentrated in vacuo to give a brown residue which was diluted with ethyl acetate and extracted 1NHCl. The aqueous layers were then combined, made basic (with 1N NaOH) and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (1:1 AcOEt/heptane) to give 1-benzyl-4-(2-methoxyethyl)-piperidine-4-carboxylic acid ethyl ester (5.2 g, 84%) as a brown oil. MS (ESI): 306.3 (MH+).
84%
To a solution of diisopropylamine (5.68 mL, 0.040 mol) in 100ml THF at -78C was added nBuli (1.6M solution in hexane, 25.9 mL, 0.041 mol) drop-wise. The reaction mixture was warmed to -5C and stirring was continued for 30mins. A solution of 1-benzylpiperidine- 4-carboxylic acid ethyl ester (5.00 g, 0.020 mol) in THF (20 mL) was added drop wise and stirring was continued for a further 3hr followed by the addition of a solution of 1-bromo- 2-methoxy-ethane (3.82 g, 0.040 mol) in THF (20 mL) at -5C. The reaction mixture was then allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was quenched with water and concentrated in vacuo to give a brown residue which was diluted with ethyl acetate and extracted 1NHC1. The aqueous layers were then combined, made basic (with IN NaOH) and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2S04), filtered andconcentrated in vacuo to give a crude residue which was purified by flash column chromatography (1: 1 AcOEt/heptane) to give l-benzyl-4-(2-methoxyethyl)-piperidine-4- carboxylic acid ethyl ester (5.2 g, 84%) as a brown oil. MS (ESI): 306.3 (MH+).
84%
To a solution of diisopropylamine (5.68 ml, 0.040 mol) in 100ml THF at -78C was added ?Buli (1.6M solution in hexane, 25.9 ml, 0.041 mol) drop-wise. The reaction mixture was warmed to -5C and stirring was continued for 30mins. A solution of 1-benzylpiperidine- 4-carboxylic acid ethyl ester (5.00 g, 0.020 mol) in THF (20 ml) was added drop wise and stirring was continued for a further 3hr followed by the addition of a solution of 1-bromo- 2-methoxy-ethane (3.82 g, 0.040 mol) in THF (20 ml) at -5C. The reaction mixture was then allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was quenched with water and concentrated in vacuo to give a brown residue which was diluted with ethyl acetate and extracted INHCl. The aqueous layers were then combined, made basic (with IN NaOH) and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (1:1 AcOEt/heptane) to give l-benzyl-4-(2-methoxyethyl)-piperidine-4- carboxylic acid ethyl ester (5.2 g, 84%) as a brown oil. MS (ESI): 306.3 (MH+).
General Procedure X: Nucleophilic fluorination at the a-position of an esterA flask is charged with a base (such as LDA, LiHMDS, NaHMDS, NaOEt, NaOMe, KOtBu, or NaNH2, preferably LDA) (1 to 3 equiv, preferably 1.5 equiv) in an organic solvent (such as THF, 1 ,4-dioxane, Et20 or DMF, preferably THF). The temperature of the mixture is adjusted to about -78 to -30 C (preferably about -40 C) and a solution of an ester (preferably 1 equiv) in an organic solvent (such as 1,4-dioxane, THF, Et20, or DMF preferably THF) is added slowly so as to maintain the temperature of the mixture within about +/- 10 C. The mixture is stirred at about -40 to 0 C (preferably about -15 to -10 C) for about 30 min to 2 h (preferably about 1 h), and is then cooled to about -78 to -40 C (preferably about -78 C). To the mixture is slowly added a solution of A^-fluoro-A^-(phenylsulfonyl)benzenesulfonamide (1-2 equiv, preferably 1.05 equiv) in an organic solvent (such as 1,4-dioxane, THF, Et20 or DMF, preferably THF) to maintain the temperature of the mixture within about +/- 15 C. The resulting mixture is stirred at about -78 to 0 C (preferably about -78 C) for about 30 min to 4 h (preferably about 1 h). The mixture is poured into ice water and extracted with an organic solvent (such as DCM or EtOAc). The combined extracts are optionally washed with water and/or brine, dried over anhydrous Na2S04 or MgS04, filtered or decanted and concentrated under reduced pressure. The crude material is optionally purified by silica gel chromatography. Illustration of General Procedure XPreparation No.X.l: Ethyl l-benzyl-4-fluoropiperidine-4-carboxylateA flask was charged with DIEA (8.64 mL, 60.6 mmol) and THF (100 mL). The mixture was cooled to about -78 C followed by the addition of «-BuLi (24.3 mL, 60.6 mmol) over about 5 min. The mixture was warmed to about 0 C and stirred for about 30 min and then cooled to about -40 C. To the mixture was added a solution of ethyl l-benzylpiperidine-4-carboxylate (10.0 g, 40.4 mmol, Oakwood) in THF (75 mL) over about 10 min such that the solution is kept between -40 to -30 C. The mixture was stirred for about 1 h at about -10 C before being cooled to about -78 C. A solution of A^-fluoro-A^-(phenylsulfonyl)benzenesulfonamide (14.0 g, 44.5 mmol) in THF (75 mL) was added over about 20 min while keeping the mixture between about - 65 and -78 C. The mixture was then stirred for about 1 h at about -78 C. The mixture was poured into a separatory funnel containing ice water (30 mL) and EtOAc (30 mL) was added. The aqueous layer was extracted with EtOAc (3 x 25 mL) and the combined organic extracts were washed with brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The resulting mixture was adsorbed onto silica gel and purified by flash silica gel chromatography eluting with hexanes/EtOAc (10:1) to afford ethyl l-benzyl-4-fluoropiperidine-4- carboxylate (7.13 g, 66 %): LC/MS (Table 2, Method h) Rt = 2.21 min; MS m/z: 266 (M+H)+.
General procedure: To a stirred solution of the carboxylate (1.50 g, 7.85 mmol, 1.0eq.) in toluene (25 ml), was added Red-Al (65 wt % in toluene,3.66 g, 3.54 ml, 11.8 mmol, 1.5 eq.) at 15-20 C. The contents were stirred overnight at rt. The reaction was quenched by the slowaddition of 10% sodium hydroxide (~1 ml) and then the addition ofwater. The contents were stirred for 30 min, and the toluene layerwas separated, washed with a saturated solution of sodium chloride.The organic layer was dried (anhydrous sodium sulfate), filtered and evaporated in vacuo to yield the alcohol which was used without any further purification
ethyl 1-benzyl-4-(cyanomethyl)piperidine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With lithium diisopropyl amide; In tetrahydrofuran; at -78℃; for 3h;
Step 15 A: Ethyl l-benzyl-4-(cvanomethyl)piperidine-4-carboxylate (0742) Ethyl l-benzylpiperidine-4-carboxylate (2.0 g, 8.1 mmol, 1.0 eq) was dissolved in anhydrous THF (20 mL) and cooled to -78 C. Next, LDA (2.0M in THF, 8.1 mL, 2.0 eq) was added dropwise and stirred for one hour at -78 C. A solution of bromoacetonitrile (1.9 g, 16.2 mmol, 2.0 eq) in THF (10 mL) was added dropwise at - 78 C and stirred at this temperature for 3 hours then warmed to room temperature. The reaction mixture was diluted with EtOAc and washed with sat. NH4C1 and brine. The organic layer was dried over MgSC>4, filtered and concentrated. The crude product was purified via ISCO silica chromatography eluting with an increasing gradient of EtOAc (0% to 100%) in hexanes to give ethyl l-benzyl-4-(cyanomethyl)piperidine-4- carboxylate 15a (1.3 g, 4.5 mmol) in a 56% yield.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
