维格列汀杂质62

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

实验步骤: The standard procedure was followed using N-(4-cyano-2-t-butyldimethylsilanoxyphenyl)-N′-(2-bromophenyl)carbodiimide (54 mg, 0.13 mmol), diisopropylethylamine (32 μL, 0.29 mmol), L-proline benzylester hydro chloride (34 mg, 0.14 mmol) and TBAF (0.16 mL, 0.16 mmol) in THF (2 mL) and methanol (0.1 mL) to give 36 mg (67%) of 4-[[(7aS)-2-(2-bromophenyl)-hexahydro-1-oxo-3H-pyrrolo[1,2-c]imidazol-3-ylidene]amino]-3-hydroxybenzonitrile as a tan powder. 1H NMR (400 MHz, MeOD) δ 7.6 (2H, m), 7.35 (3H, m), 7.15 (1H, m), 7.0 (1H, m), 4.5 (1H, t), 3.0 (1H, m), 2.4 (1H, m), 2.2 (1H, m), 2.05 (2H, m); MS(EI) m/e 412 (M+).

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

实验步骤: The title compound was prepared by a similar method to Example 1 from L-proline benzyl ester hydrochloride and 4-fluorobenzenesulphonyl chloride. The crude product was purified by column chromatography on silica gel eluting with dichloromethane to afford benzyl (2S)-1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinecarboxylate as a clear oil. The crude product was purified by column chromatography on silica gel eluting with dichloromethane

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred suspension of (S)-benzyl pyrrolidine-2-carboxylate hydrochloride (5.63 g, 23.3 mmol), (R)-tetrahydrofuran-2-carboxylic acid (2.24 mL, 23.3 mmol), DIPEA (10.2 mL, 58.3 mmol), and HOBt (3.15 g, 23.3 mmol) in dry dichloromethane (100 mL) at 25° C. was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (4.45 g, 23.3 mmol) in one portion. The mixture was stirred at 25° C. for 16 h then 1N HCl (50 mL) was added. The organic phase was separated, washed with saturated sodium bicarbonate solution, dried with Na2SO4, filtered and concentrated to afford intermediate (S)-benzyl 1-((R)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate as a yellow oil which was carried forward directly. The organic phase was separated washed with saturated sodium bicarbonate solution dried with Na2SO4 filtered concentrated

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

实验步骤: Diisopropylethylamine (39.6 mmoles, 5.1 g) was added to a solution of L-proline benzyl ester hydrochloride (39.6 mmoles, 10.1 g) in 20 ml DMF at 0° and stirred for 1 hour. The solution was added to 2-(4-nitro-1H-imidazol-1-yl) octanoic acid (39.6 mmoles, 10.1 g) and hydroxybenzotriazole (43 mmoles, 5.8 g) in 10 ml DMF, and stirred for 30 minutes. Dicyclohexylcarbodiimide (43 mmoles, 8.97 g) was added portionwise over 2 hours. Ethyl acetate (50 ml) was added. The solution was filtered, dried over sodium sulfate and concentrated. The oil was chromatographed over silica gel eluted with 40% ethyl acetate in hexane to yield 5.32 g of 1-[1-oxo-2-(4-Nitro-1H-imidazol-1-yl)octyl]-L-proline benzyl ester. stirred for 30 minutes The solution was filtered dried over sodium sulfate concentrated The oil was chromatographed over silica gel eluted with 40% ethyl acetate in hexane

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

实验步骤: To a stirring solution of EtOCO-D,L-Phe(αMe)-OH (10.3 g, 41 mmol), HOBT (5.5 g, 41 mmol), Pro-OBzl·HCl (9.9 g, 41 mmol) and N,N-diisopropylethylamine (15.9 g, 123 mmol) in dimethylformamide (200 mL) at 0° C., was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide·HCl (8.6 g, 45 mmol). After stirring for 16 h, the solvents were removed in vacuo and the residue was dissolved in ethyl acetate (500 mL). The organic phase was washed three times with 0.1N HCl, three times with saturated aqueous NaHCO3, and once with brine. The organic phase was then dried (Na2SO4), filtered and concentrated in vacuo. The residue was chromatographed over silica gel eluting with 1:1 ethyl acetate:hexanes and the product containing fractions (as judged by TLC) were combined and concentrated in vacuo to give 13.5 g (75% yield) of a white foam. the solvents were removed in vacuo the residue was dissolved in ethyl acetate (500 mL) The organic phase was washed three times with 0.1N HCl, three times with saturated aqueous NaHCO3 The organic phase was then dried (Na2SO4) filtered concentrated in vacuo The residue was chromatographed over silica gel eluting with 1:1 ethyl acetate hexanes and the product containing fractions (as judged by TLC) concentrated in vacuo

反应条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Boc-L-alanine (19.5 g, 0.10 mol) was dissolved in dry tetrahydrofuran (90 ml) under an argon atmosphere in a flask fitted with an overhead stirrer and an internal thermometer. The solution was cooled to -15° C. and N-methylmorpholine (11.4 ml, 0.10 mol) was added followed by isobutylchloroformate (13.4 ml, 0.10 mol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. Five minutes after the addition was completed, a solution of L-proline benzyl ester hydrochloride (25.2 g, 0.10 mol) and N-methylmorpholine (11.4 ml, 0.10 mol) in chloroform (90 ml) was added dropwise at such a rate as to maintain the internal reaction temperature at -10° to -15° C. After the addition was completed, the reaction mixture was allowed to slowly warm to room temperature and then stirred at room temperature overnight. The reaction mixture was concentrated using a rotary evaporator, the residue diluted with ethyl acetate (500 ml)/0.2N hydrochloric acid (100 ml) and poured into a separatory funnel. The layers were separated and the aqueous phase extracted with a further 150 ml ethyl acetate. The combined organics were washed with 0.2 N hydrochloric acid (2×100 ml), water (100 ml), saturated sodium bicarbonate (2×100 ml), again with water (100 ml) and finally brine (100 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. Chromatography using ethyl acetate-hexane as the eluent gave Boc-L-alanyl-L-proline benzyl ester, Rf: 0.15 (EtOAc/hexane--30:70). fitted with an overhead stirrer to maintain the internal reaction temperature at -10° to -15° C Five minutes after the addition to maintain the internal reaction temperature at -10° to -15° C After the addition to slowly warm to room temperature The reaction mixture was concentrated a rotary evaporator the residue diluted with ethyl acetate (500 ml)/0.2N hydrochloric acid (100 ml) poured into a separatory funnel The layers were separated the aqueous phase extracted with a further 150 ml ethyl acetate The combined organics were washed with 0.2 N hydrochloric acid (2×100 ml), water (100 ml), saturated sodium bicarbonate (2×100 ml), again with water (100 ml) and finally brine (100 ml) The organic phase was dried over magnesium sulfate filtered concentrated on a rotary evaporator

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

实验步骤: To a suspension of N-Boc-L-phenylalanine (1.000 g, 3.77 mmol) in acetonitrile (25 ml) at room temperature was added L-proline benzyl ester HCl (1.002 g, 4.15 mmol), PyBOP (2.060 g, 3.96 mmol) followed by DIPEA (1.382 ml, 7.92 mmol). The reaction turned to clear and was stirred at room temperature for 1 hour. The reaction was quenched by brine and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 30 to 50% EtOAc/HEP) and gave the title compound: 1.6 g (yield: 97%). LCMS (condition B): 453.4 (M+1); retention time=1.44 min. The reaction was quenched by brine was extracted with EtOAc The combined organic layer was washed with brine dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The obtained residue was purified by flash chromatography (silica gel, 30 to 50% EtOAc/HEP)

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

实验步骤: A solution of (S)-3-(biphenyl-4-yl)-2-(1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxamido)propanoic acid (201.7 mg, 0.476 mmol), (S)-benzyl pyrrolidine-2-carboxylate hydrochloride (138 mg, 0.572 mmol), WSC.HCl (137 mg, 0.714 mmol), DIPEA (0.125 ml, 0.714 mmol) and 1-hydroxy-7-azabenzotriazole (97 mg, 0.714 mmol) in DMF (2 ml) was allowed to stir at room temperature under nitrogen for 14 hours. The reaction was quenched with H2O. The products were extracted with EtOAc. The organic layer was washed with NH4Claq, 0.1 M HCl (twice) and then brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (heptane/EtOAc=100:0 to 0:100) to give (S)-benzyl 1-((S)-3-(biphenyl-4-yl)-2-(1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxamido)propanoyl)pyrrolidine-2-carboxylate (243 mg); Retention time=1.74 minutes (condition B); MS (m+1)=611.2; 1H NMR (400 MHz, CD3CN, mixture of rotamers) δ ppm 0.91-1.06 (m, 3H) 1.33-1.42 (m, 6H) 1.55-2.09 (m, 6H) 2.25-2.42 (m, 2H) 2.57-2.93 (m, 2H) 3.06-3.59 (m, 2H) 3.75-3.91 (m, 2H) 4.14-4.61 (m, 2H) 4.68-5.09 (m, 3H) 6.40-6.52 (m, 1H) 7.00-7.45 (m, 14H). The reaction was quenched with H2O The products were extracted with EtOAc The organic layer was washed with NH4Claq, 0.1 M HCl (twice) and then brine dried over MgSO4 filtered concentrated under reduced pressure The obtained residue was purified by flash column chromatography on silica gel (heptane/EtOAc=100:0 to 0:100)

反应条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N-t-butyloxycarbonyl-L-alanine (3.8 g, 20 m mole), L-proline benzyl ester hydrochloride (5 g, 20.6 m mole) and 1-hydroxy benzotriazole, which is hereinafter referred to as HOBt (2.7 g, 20 m mole) were suspended in tetrahydrofuran, which is hereinafter referred to as THF (50 ml). N,N'-dimethylaminopropylethylcarbodiimide, which is hereinafter referred to as WSC (3.8 ml) in THF (10 ml) solution was added dropwisely to the above suspended solution while cooling with coolant of -15° C. and stirring. The reaction was carried for 3 hours at a temperature of less than 0° C. and thereafter at room temperature overnight. The solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid, water, 5% aqueous sodium bicarbonate and water in order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized in ether-n-hexan to give N-t-butyloxycarbonyl-L-alanyl-L-proline benzyl ester (6.7 g, yield: 89%) having melting point of 71° to 72° C. This product gave one spot by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method; spraying with 0.1% ninhydrin and heating). was added dropwisely to the above suspended solution at room temperature overnight The solvent was removed by distillation under reduced pressure The residue was dissolved in ethyl acetate washed with 1N hydrochloric acid, water, 5% aqueous sodium bicarbonate and water in order dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure The residue was recrystallized in ether-n-hexan

反应条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N-t-butyloxycarbonyl-L-alanine (3.8 g, 20 m mole), L-proline benzyl ester hydrochloride (5 g, 20.6 m mole) and 1-hydroxy benzotriazole, which is hereinafter referred to as HOBt (2.7 g, 20 m mole) were suspended in tetrahydrofuran, which is hereinafter referred to as THF (50 ml). N,N'-dimethylaminopropylethylcarbodiimide, which is hereinafter referred to as WSC (3.8 ml) in THF (10 ml) solution was added dropwisely to the above suspended solution while cooling with coolant of -15° C. and stirring. The reaction was carried for 3 hours at a temperature of less than 0° C. and thereafter at room temperature overnight. The solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid, water, 5% aqueous sodium bicarbonate and water in order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized in ether-n-hexan to give N-t-butyloxycarbonyl-L-alanyl-L-proline benzyl ester (6.7 g, yield: 89%) having melting point of 71° to 72° C. This product gave one spot by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method; spraying with 0.1% ninhydrin and heating). was added dropwisely to the above suspended solution at room temperature overnight The solvent was removed by distillation under reduced pressure The residue was dissolved in ethyl acetate washed with 1N hydrochloric acid, water, 5% aqueous sodium bicarbonate and water in order dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure The residue was recrystallized in ether-n-hexan

反应条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: All the obtained oily t-butyloxycarbonyl-ε-carbobenzoxy-L-lysine and L-proline benzylester hydrochloride (4.3 g, 17.8 m mole) were dissolved in methylene dichloride and WSC (3.3 ml, 17.8 m mole) was added thereto while cooling to -15° C. The mixture was stirred overnight and the methylene dichloride solution was distilled under reduced pressure leaving a residue. The residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order, and dried with anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure to obtain an oily t-butyloxycarbonyl-ε-carbobenzoxy-L-lysyl-L-proline benzylester. the methylene dichloride solution was distilled under reduced pressure leaving a residue The ethyl acetate solution was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order dried with anhydrous sodium sulfate The ethyl acetate was distilled off under reduced pressure

反应条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: All the obtained oily t-butyloxycarbonyl-ε-carbobenzoxy-L-lysine and L-proline benzylester hydrochloride (4.3 g, 17.8 m mole) were dissolved in methylene dichloride and WSC (3.3 ml, 17.8 m mole) was added thereto while cooling to -15° C. The mixture was stirred overnight and the methylene dichloride solution was distilled under reduced pressure leaving a residue. The residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order, and dried with anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure to obtain an oily t-butyloxycarbonyl-ε-carbobenzoxy-L-lysyl-L-proline benzylester. the methylene dichloride solution was distilled under reduced pressure leaving a residue The ethyl acetate solution was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order dried with anhydrous sodium sulfate The ethyl acetate was distilled off under reduced pressure