(2S,3S)-2-苯基哌啶-3-胺

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium triacetoxyborohydride (411 mg, 1.94 mmol) was added to a mixture of 2-cyclopropoxy-5-(trifluoromethoxy)benzaldehyde (Description 9, 159 mg, 0.646 mmol), (2S3S)-2-phenylpiperidin-3-amine (prepared by the method described in WO 95/08549, 171 mg, 0.97 mmol) and acetic acid, (111 μl, 1.94 mmol) in 1,2-dichloroethane (5 mL) and the mixture was stirred at room temperature for 2.5 h. The mixture was poured into aqueous sodium hydrogen carbonate (satd., 50 mL) and extracted with ethyl acetate. The combined organic fractions were washed with aqueous sodium hydrogen carbonate (satd., 2×50 mL) and brine (50 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (97:3:0.3). The residue was dissolved in ethanol (2 mL) and ethanolic hydrogen chloride (5M, 0.5 mL) was added. The solid was collected and recrystallised from ethanol. The solid was collected and dried in vacuo to give the title compound as a yellow solid (144 mg, 46%). m.p. 168-171° C. 1H NMR (360 MHz, CD3OD) δ0.66-0.67 (1H, m), 0.80-0.82 (3H, m), 1.99-2.03 (1H, m), 2.27-2.35 (1H, m), 2.43-2.54 (2H, m), 3.30 (1H, m), 3.57-3.68 (1H, m), 3.75-3.80 (2H, m), 4.06-4.14 (2H, m), 5.05-5.06 (1H, d, J 2.7 Hz), 7.26 (1H, d, J 2.0 Hz), 7.30-7.39 (2H, m), 7.50-7.57 (3H, m), and 7.61 (2H, m). m/z (ES+) 407 (M+1). prepared by the method extracted with ethyl acetate The combined organic fractions were washed with aqueous sodium hydrogen carbonate (satd., 2×50 mL) and brine (50 mL) dried (Na2SO4) the solvent was evaporated under reduced pressure The residue was purified by MPLC on silica gel eluting with CH2Cl2/MeOH/NH3(Aq.) (97:3:0.3) The residue was dissolved in ethanol (2 mL) ethanolic hydrogen chloride (5M, 0.5 mL) was added The solid was collected recrystallised from ethanol The solid was collected dried in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (2S,3S)-(−)-3-amino-2-phenylpiperidine (152 mg, 0.86 mmole) (L-tartaric acid salt, [a]D=−57.1 (EtOH, c=0.1138)) in methylene chloride (10 mL) at room temperature was added benzyl chloroformate (0.123 mL, 0.86 mmole) and diisopropylethylamine (0.45 mL, 2.58 mmole). The reaction was stirred for 16 hours and was then diluted with methylene chloride and quenched by addition of water. The mixture was separated and the aqueous was reextracted with 2 additional aliquots of methylene chloride. The organic layers were successively washed with a portion of brine, dried over sodium sulfate, combined and evaporated. The residue was purified by flash chromatography (5% methanol in methylene chloride) to afford 214 mg (80%) of the title compound. NMR (CDCl3): δ 1.55 (br, d, J=9 Hz, 1 H), 1.6-1.9 (m, 2 H), 2.02 (br. d, J=9 Hz, 1 H), 2.79 (dd, J=9 and 10 Hz, 1 H), 3.22 (dd, J=1 and 10 Hz, 1 H), 3.91 (br. s, 1 H), 4.01 (dd, J=1 and 8 Hz, 1 H), 4.89 (s, 2 H), 5.65 and 5.88 (2 br. s, 1 H), 7.1-7.4 (m, 10 H). quenched by addition of water The mixture was separated The organic layers were successively washed with a portion of brine dried over sodium sulfate evaporated The residue was purified by flash chromatography (5% methanol in methylene chloride)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (2S,3S)-(−)-3-amino-2-phenylpiperidine (152 mg, 0.86 mmole) (L-tartaric acid salt, [a]D=−57.1 (EtOH, c=0.1138)) in methylene chloride (10 mL) at room temperature was added benzyl chloroformate (0.123 mL, 0.86 mmole) and diisopropylethylamine (0.45 mL, 2.58 mmole). The reaction was stirred for 16 hours and was then diluted with methylene chloride and quenched by addition of water. The mixture was separated and the aqueous was reextracted with 2 additional aliquots of methylene chloride. The organic layers were successively washed with a portion of brine, dried over sodium sulfate, combined and evaporated. The residue was purified by flash chromatography (5% methanol in methylene chloride) to afford 214 mg (80%) of the title compound. NMR (CDCl3): δ 1.55 (br. d, J=9 Hz, 1H), 1.6-1.9 (m, 2H), 2.02 (br. d, J=9 Hz, 1H), 2.79 (dd, J=9 and 10 Hz, 1H), 3.22 (dd, J=1 and 10 Hz, 1H), 3.91 (br. s, 1H), 4.01 (dd, J=1 and 8 Hz, 1H), 4.89 (s, 2H), 5.65 and 5.88 (2br. s, 1H), 7.1-7.4 (m, 10H). quenched by addition of water The mixture was separated The organic layers were successively washed with a portion of brine dried over sodium sulfate evaporated The residue was purified by flash chromatography (5% methanol in methylene chloride)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (2S,3S)-(−)-3-amino-2-phenylpiperidine (152 mg, 0.86 mmole) (L-tartaric acid salt, [a]D=−57.1 (EtOH, c=0.1138)) in methylene chloride (10 mL) at room temperature was added benzyl chloroformate (0.123 mL, 0.86 mmole) and diisopropylethylamine (0.45 mL, 2.58 mmole). The reaction was stirred for 16 hours and was then diluted with methylene chloride and quenched by addition of water. The mixture was separated and the aqueous was reextracted with 2 additional aliquots of methylene chloride. The organic layers were successively washed with a portion of brine, dried over sodium sulfate, combined and evaporated. The residue was purified by flash chromatography (5% methanol in methylene chloride) to afford 214 mg (80%) of the title compound. NMR (CDCl3): δ 1.55 (br. d, J=9 Hz, 1H), 1.6-1.9 (m, 2H), 2.02 (br. d, J=9 Hz, 1H), 2.79 (dd, J=9 and 10 Hz, 1H), 3.22 (dd, J=1 and 10 Hz, 1H), 3.91 (br. s, 1H), 4.01 (dd, J=1 and 8 Hz, 1H), 4.89 (s, 2H), 5.65 and 5.88 (2br. s, 1H), 7.1-7.4 (m, 10H). quenched by addition of water The mixture was separated The organic layers were successively washed with a portion of brine dried over sodium sulfate evaporated The residue was purified by flash chromatography (5% methanol in methylene chloride)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a bottle were placed 9 g of 10% palladium-carbon, 180 ml of methanol, 275 ml of ethanol, 6.5 ml of concentrated hydrochloric acid and 9 g of the hydrochloride salt of (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine. The mixture was shaken under hydrogen (40 p.s.i.) overnight, after which 9 g of additional catalyst were added to the system and the mixture was shaken under hydrogen for 1 day. The mixture was diluted with water (250 mL), filtered through diatomaceous earth (Celite (trademark)) and the Celite was rinsed well with water. The filtrate was concentrated to a volume of ca. 600-700 mL, made basic with concentrated aqueous sodium hydroxide and extracted with chloroform. The chloroform extracts were dried (sodium sulfate) and concentrated to obtain 4.4 g of the title compound as a colorless oil. the mixture was shaken under hydrogen for 1 day filtered through diatomaceous earth (Celite (trademark)) the Celite was rinsed well with water The filtrate was concentrated to a volume of ca. 600-700 mL extracted with chloroform The chloroform extracts were dried (sodium sulfate) concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a bottle were placed 9 g of 10% palladium-carbon, 180 ml of methanol, 275 ml of ethanol, 6.5 ml of concentrated hydrochloric acid and 9 g of the hydrochloride salt of (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine. The mixture was shaken under hydrogen (40 p.s.i.) overnight, after which 9 g of additional catalyst were added to the system and the mixture was shaken under hydrogen for 1 day. The mixture was diluted with water (250 mL), filtered through diatomaceous earth (Celite (trademark)) and the Celite was rinsed well with water. The filtrate was concentrated to a volume of ca. 600-700 mL, made basic with concentrated aqueous sodium hydroxide and extracted with chloroform. The chloroform extracts were dried (sodium sulfate) and concentrated to obtain 4.4 g of the title compound as a colorless oil. the mixture was shaken under hydrogen for 1 day filtered through diatomaceous earth (Celite (trademark)) the Celite was rinsed well with water The filtrate was concentrated to a volume of ca. 600-700 mL extracted with chloroform The chloroform extracts were dried (sodium sulfate) concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium triacetoxyborohydride (411 mg, 1.94 mmol) was added to a mixture of 2-cyclopropoxy-5-(trifluoromethoxy)benzaldehyde (Description 9, 159 mg, 0.646 mmol), (2S3S)-2-phenylpiperidin-3-amine (prepared by the method described in WO 95/08549, 171 mg, 0.97 mmol) and acetic acid, (111 μl, 1.94 mmol) in 1,2-dichloroethane (5 mL) and the mixture was stirred at room temperature for 2.5 h. The mixture was poured into aqueous sodium hydrogen carbonate (satd., 50 mL) and extracted with ethyl acetate. The combined organic fractions were washed with aqueous sodium hydrogen carbonate (satd., 2×50 mL) and brine (50 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (97:3:0.3). The residue was dissolved in ethanol (2 mL) and ethanolic hydrogen chloride (5M, 0.5 mL) was added. The solid was collected and recrystallised from ethanol. The solid was collected and dried in vacuo to give the title compound as a yellow solid (144 mg, 46%). m.p. 168-171° C. 1H NMR (360 MHz, CD3OD) δ0.66-0.67 (1H, m), 0.80-0.82 (3H, m), 1.99-2.03 (1H, m), 2.27-2.35 (1H, m), 2.43-2.54 (2H, m), 3.30 (1H, m), 3.57-3.68 (1H, m), 3.75-3.80 (2H, m), 4.06-4.14 (2H, m), 5.05-5.06 (1H, d, J 2.7 Hz), 7.26 (1H, d, J 2.0 Hz), 7.30-7.39 (2H, m), 7.50-7.57 (3H, m), and 7.61 (2H, m). m/z (ES+) 407 (M+1). prepared by the method extracted with ethyl acetate The combined organic fractions were washed with aqueous sodium hydrogen carbonate (satd., 2×50 mL) and brine (50 mL) dried (Na2SO4) the solvent was evaporated under reduced pressure The residue was purified by MPLC on silica gel eluting with CH2Cl2/MeOH/NH3(Aq.) (97:3:0.3) The residue was dissolved in ethanol (2 mL) ethanolic hydrogen chloride (5M, 0.5 mL) was added The solid was collected recrystallised from ethanol The solid was collected dried in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium triacetoxyborohydride (411 mg, 1.94 mmol) was added to a mixture of 2-cyclopropoxy-5-(trifluoromethoxy)benzaldehyde (Description 9, 159 mg, 0.646 mmol), (2S3S)-2-phenylpiperidin-3-amine (prepared by the method described in WO 95/08549, 171 mg, 0.97 mmol) and acetic acid, (111 μl, 1.94 mmol) in 1,2-dichloroethane (5 mL) and the mixture was stirred at room temperature for 2.5 h. The mixture was poured into aqueous sodium hydrogen carbonate (satd., 50 mL) and extracted with ethyl acetate. The combined organic fractions were washed with aqueous sodium hydrogen carbonate (satd., 2×50 mL) and brine (50 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (97:3:0.3). The residue was dissolved in ethanol (2 mL) and ethanolic hydrogen chloride (5M, 0.5 mL) was added. The solid was collected and recrystallised from ethanol. The solid was collected and dried in vacuo to give the title compound as a yellow solid (144 mg, 46%). m.p. 168-171° C. 1H NMR (360 MHz, CD3OD) δ0.66-0.67 (1H, m), 0.80-0.82 (3H, m), 1.99-2.03 (1H, m), 2.27-2.35 (1H, m), 2.43-2.54 (2H, m), 3.30 (1H, m), 3.57-3.68 (1H, m), 3.75-3.80 (2H, m), 4.06-4.14 (2H, m), 5.05-5.06 (1H, d, J 2.7 Hz), 7.26 (1H, d, J 2.0 Hz), 7.30-7.39 (2H, m), 7.50-7.57 (3H, m), and 7.61 (2H, m). m/z (ES+) 407 (M+1). prepared by the method extracted with ethyl acetate The combined organic fractions were washed with aqueous sodium hydrogen carbonate (satd., 2×50 mL) and brine (50 mL) dried (Na2SO4) the solvent was evaporated under reduced pressure The residue was purified by MPLC on silica gel eluting with CH2Cl2/MeOH/NH3(Aq.) (97:3:0.3) The residue was dissolved in ethanol (2 mL) ethanolic hydrogen chloride (5M, 0.5 mL) was added The solid was collected recrystallised from ethanol The solid was collected dried in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A magnetically stirred 1L erlenmeyer flask was charged with 20 grams (0.06 mol.) of the (+)-(2S,3S)-3-amino-2-phenylpiperidine mandelate salt (1 equivalent), 200 ml CH2Cl2 (10 vol.) and 200 ml of water (10 vol.). The pH of this slurry was adjusted from 5.1 to a stable 12 with 25% NaOH. The layers were separated and the aqueous layer was extracted once with 200 ml of CH2Cl2. The combined organic extracts were treated with 1 gram (5% by wt.) of Darco® G-60 for 15 minutes then dried with MgSO4 for 30 minutes. The Darco® and MgSO4 were removed by filtration and the filtrate was concentrated atmospherically to yield 7.36 grams of the title compound. Oil, 67.8% yield. The layers were separated the aqueous layer was extracted once with 200 ml of CH2Cl2 The combined organic extracts were treated with 1 gram (5% by wt.) of Darco® G-60 for 15 minutes then dried with MgSO4 for 30 minutes The Darco® and MgSO4 were removed by filtration the filtrate was concentrated atmospherically

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a bottle were placed 31 g of 10% palladium-carbon, 50 mL of water, 300 mL of methanol, 450 mL of ethanol, 20 mL of concentrated aqueous hydrochloric acid and 15 g (0.04 mole) of the hydrochloride salt of (2S,3S)-3-(2-methoxybenzyl)amino-2-phenylpiperdine. The mixture was shaken under hydrogen (40 p.s.i.) for 1 day and filtered through a pad of diatomaceous earth. The pad was rinsed with 2N aqueous hydrochloric acid (HCl), water, ethanol and water and concentrated with a rotary evaporator. Water was added to the residue and the mixture was made basic using 4N aqueous sodium hydroxide (NaOH). The mixture was extracted with four portions of dichloromethane, and the extracts were dried over magnesium sulfate (MgSO4) and concentrated to obtain 2.23 g of the title compound. The aqueous fraction was concentrated to dryness and triturated with chloroform. Concentration of the chloroform solution afforded an additional 4.15 g of title compound. The product obtained in this manner had spectral properties identical to those of the product of Example 1. filtered through a pad of diatomaceous earth The pad was rinsed with 2N aqueous hydrochloric acid (HCl), water, ethanol and water concentrated with a rotary evaporator Water was added to the residue The mixture was extracted with four portions of dichloromethane the extracts were dried over magnesium sulfate (MgSO4) concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a bottle were placed 2.65 g (15.6 mmol) of 3-amino-2-phenylpyridine, 10.6 g of 5% platinum/carbon and 106 mL of 1.5 M HCl in methanol. The mixture was shaken under an atmosphere (ca. 40 p.s.i.) of hydrogen for 2.5 hours. Water was added to the system, the mixture was filtered through a pad of diatomaceous earth and the pad was rinsed with ca. 700 mL of water. The filtrate was made basic with solid sodium hydroxide and extracted with two portions of dichloromethane. The combined organic fractions were washed with water, dried (sodium sulfate) and concentrated with a rotary evaporator to obtain 2.4 g of the title compound as a yellow oil. the mixture was filtered through a pad of diatomaceous earth the pad was rinsed with ca. 700 mL of water extracted with two portions of dichloromethane The combined organic fractions were washed with water dried (sodium sulfate) concentrated with a rotary evaporator

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a bottle were placed 2.65 g (15.6 mmol) of 3-amino-2-phenylpyridine, 10.6 g of 5% platinum/carbon and 106 mL of 1.5 M HCl in methanol. The mixture was shaken under an atmosphere (ca. 40 p.s.i.) of hydrogen for 2.5 hours. Water was added to the system, the mixture was filtered through a pad of diatomaceous earth and the pad was rinsed with ca. 700 mL of water. The filtrate was made basic with solid sodium hydroxide and extracted with two portions of dichloromethane. The combined organic fractions were washed with water, dried (sodium sulfate) and concentrated with a rotary evaporator to obtain 2.4 g of the title compound as a yellow oil. the mixture was filtered through a pad of diatomaceous earth the pad was rinsed with ca. 700 mL of water extracted with two portions of dichloromethane The combined organic fractions were washed with water dried (sodium sulfate) concentrated with a rotary evaporator