methyl (2S)-pyrrolidine-2-carboxylate;hydrochloride

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-1-(2-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-acetyl)-pyrrolidine-2-carboxylic acid methyl ester (114 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (100 mg), L-proline methyl ester hydrochloride (44 mg), HBTU (109 mg), and DIEA (63 uL).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: L-Proline methyl ester hydrochloride (7.2 g, 43.8 mmol) was dissolved in 100 mL of anhydrous DMF at 0° C. To this solution was added triethylamine (4.2 g, 43.8 mmol). After vigorous stirring for 1 hour, the solid triethylamine hydrochloride was removed by filtration. To the filtrate was added 4-benzyloxybenzoic acid (10.0 g, 43.8 mmol) followed by DCC (9.9 g, 48.2 mmol). The reaction mixture was allowed to stir overnight at room temperature. The solid DCU was then removed by filtration, and the filtrated distributed between H2O/ethyl acetate (300 mL ea.). The organic was washed several times with 200 mL portions of H2O to remove DMF. The organic was dried (Na2SO4), and concentrated in vacuo to a solid residue that was chromatographed (SiO2, 15-100% ethyl acetate/hexanes). Isolation provided 5.3 g (35%) of N-(4-benzyloxybenzamido)-L-proline methyl ester as a white solid. MS. the solid triethylamine hydrochloride was removed by filtration to stir overnight at room temperature The solid DCU was then removed by filtration The organic was washed several times with 200 mL portions of H2O to remove DMF The organic was dried (Na2SO4) concentrated in vacuo to a solid residue that was chromatographed (SiO2, 15-100% ethyl acetate/hexanes)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a cooled (0-5° ) solution of N-benzyloxycarbonyl-L-valine (450.0 g) in dry N,N-dimethylformamide (3.0 liter) was added 1-hydroxybenzotriazole hydrate (483.3 g): and the reaction mixture was stirred for 20 min, followed by the addition of a slurry of L-proline methyl ester hydrochloride (296.4 g) and triethylamine (186.6 g) in N,N-dimethylformamide (1.5 liter). After the resulting mixture was cooled to 0°, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (377.6 g, 1.97 mol) in N,N-dimethylformamide (500 ml) was added. The reaction mixture was stirred at 0°-5° for 3 hr and then allowed to warm gradually to room temperature. Stirring was continued for 65 hr, and the mixture was filtered and evaporated. The residue was partitioned between ether and lN HCl, and the precipitate which formed was removed by filtration. The etheral layer was then separated: washed with water, saturated aqueous NaHCO3 and brine; dried (MgSO4); and evaporated. The crude ester was purified by flash chromatography using a gradient elution of methylene chloride, then methanol:methylene chloride (1:99), (2.5:79.5), and, finally, (5:95). The impure material from the first column was rechromatographed using a gradient elution of methylene chloride:hexanes (1:3), methylene chloride, and, finally, methanol:methylene chloride (2:98). The combined chromatographies afforded the ester (596.9 g, 92%) as a colorless oil; TLC, Rf =0.45-0.60, methanol:methylene chloride (5:95); MS, m/e=363(M+1, base), 319, 255, 130, 91. After the resulting mixture was cooled to 0° The reaction mixture was stirred at 0°-5° for 3 hr Stirring was continued for 65 hr the mixture was filtered evaporated The residue was partitioned between ether and lN HCl the precipitate which formed was removed by filtration The etheral layer was then separated washed with water, saturated aqueous NaHCO3 and brine dried (MgSO4) and evaporated The crude ester was purified by flash chromatography a gradient elution of methylene chloride The impure material from the first column was rechromatographed a gradient elution of methylene chloride:hexanes (1:3), methylene chloride

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2 g. (0.006 mole) of 5-bromomethyl-2-nitro-3-phenylbenzofuran, 0.9 g. (0.006 mole) of L-proline methylesterhydrochloride (available from the Aldrich Chemical Company) and 1.2 g. (0.012 mole) of triethylamine in 100 ml. of toluene is heated at reflux for about 100 hours. The mixture is extracted three times with 50 ml. portions of water. The organic layer is then extracted repeatedly with 50 ml. portions of 3N hydrochloric acid to remove all of the yellow product from the toluene layer. The aqueous layer is neutralized with 10 percent sodium carbonate solution. The aqueous layer is then extracted with dichloromethane until the water is colorless. The dichloromethane layer is dried, then evaporated to provide a residue which is diluted with diethyl ether to provide a brownish precipitate. The solid is removed by filtration, and the filtrate is concentrated to provide a residue. The residue is suspended in 50 ml. of concentrated hydrochloric acid diluted 1:1 with water. The mixture is heated at 90° C. for three hours. The mixture is cooled and filtered to provide a yellow precipitate. The precipitate is washed with water to provide N-[(2-nitro-3-phenylbenzofuran-5-yl)methyl]-L-proline hydrochloride hydrate, m.p. 109°-110° C., having the structure ##STR22## A mixture of 2 g at reflux for about 100 hours The mixture is extracted three times with 50 ml The organic layer is then extracted repeatedly with 50 ml portions of 3N hydrochloric acid to remove all of the yellow product from the toluene layer The aqueous layer is then extracted with dichloromethane until the water The dichloromethane layer is dried evaporated to provide a residue which to provide a brownish precipitate The solid is removed by filtration the filtrate is concentrated to provide a residue The mixture is cooled filtered to provide a yellow precipitate The precipitate is washed with water

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Benzoyl chloride (1.40 mL, 12.1 mmol) was added in a dropwise manner to a mixture of L-proline methyl ester hydrochloride (2.00 g, 12.1 mmol) and Et3N (4.20 mL, 30.2 mmol) in CH2Cl2 (40 mL) and the resulting mixture stirred overnight at rt. The mixture was concentrated in vacuo and the residue treated with water and extracted with EtOAc and the combined extracts dried over Na2SO4. Concentration left a residue which was loaded onto a silica gel column and eluted with MeOH/CH2Cl2 which allowed for isolation of 2.76 g (94%) of the title compound as a white solid. MS(ES): (M+1)+ 234.2 m/z. The mixture was concentrated in vacuo the residue treated with water extracted with EtOAc the combined extracts dried over Na2SO4 Concentration left a residue which eluted with MeOH/CH2Cl2 which

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2.15 g (10 mmol) BOC-L-proline and 1.66 g (10 mmol) proline methyl ester HCl salt were coupled according to procedure A. Yield of crude product 2.83 g. The product was purified with a silica column using 5% methanol in ethyl acetate as eluent. Yield 2.40 g (7.4 mmol, 74%) The product was purified with a silica column

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 16 ml (220 mmol) thionyl chloride was added to a solution of 10 g (87 mmol) L-proline in 200 ml methanol at 0° C. The reaction mixture is refluxed for 1 h. The solvent was evaporated. Yield 14 g (86 mmol, 99%). The reaction mixture is refluxed for 1 h The solvent was evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and L-proline methyl ester hydrochloride (Bachem), the title compound was prepared as an oil. The reaction was monitored by tlc (Rf=0.12 in 50% EtOAc/hexanes).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-proline methyl ester hydrochloride (Bachem), the title compound was prepared as a viscous solid. The reaction was monitored by tlc (Rf=0.57 in 10% MeOH/DCM) and the product was purified by acid/base washes. the product was purified by acid/base washes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: L-proline methylester hydrochloride (13.6 g, 82.7 m mole) was suspended in chloroform (200 ml) and to the suspended solution triethylamine (8.3 g, 82.7 m mole) was added while cooling. To the solution, N-t-butyloxycarbonyl glycine (14.5 g, 82.7 m mole) was added and WSC hydrochloride (15.82 g, 82.7 m mole) was gradually added thereto while cooling with ice. The reaction was carried out for 2 hours while cooling with ice, and next overnight at room temperature. The reaction solution was washed with 10% citric acid, aqueous sodium chloride, 5% sodium bicarbonate and aqueous sodium chloride in order, and dried with anhydrous sodium sulfate. The solution was distilled under reduced pressure leaving a syrupy N-t-butyloxycarbonylglycyl-L-proline methylester product (22.5 g, 78.5 m mole, yield: 95%). This product gave a single spot with Rf =0.48 by silica gel thin layer chromatography (developing solvent, benzene:ethyl acetate=1:1, colour forming method: spraying of 25% hydrobromic acid and 0.1% ninhydrin and heating). was added while cooling while cooling with ice The reaction solution was washed with 10% citric acid, aqueous sodium chloride, 5% sodium bicarbonate and aqueous sodium chloride in order dried with anhydrous sodium sulfate The solution was distilled under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: L-proline methylester hydrochloride (13.6 g, 82.7 m mole) was suspended in chloroform (200 ml) and to the suspended solution triethylamine (8.3 g, 82.7 m mole) was added while cooling. To the solution, N-t-butyloxycarbonyl glycine (14.5 g, 82.7 m mole) was added and WSC hydrochloride (15.82 g, 82.7 m mole) was gradually added thereto while cooling with ice. The reaction was carried out for 2 hours while cooling with ice, and next overnight at room temperature. The reaction solution was washed with 10% citric acid, aqueous sodium chloride, 5% sodium bicarbonate and aqueous sodium chloride in order, and dried with anhydrous sodium sulfate. The solution was distilled under reduced pressure leaving a syrupy N-t-butyloxycarbonylglycyl-L-proline methylester product (22.5 g, 78.5 m mole, yield: 95%). This product gave a single spot with Rf =0.48 by silica gel thin layer chromatography (developing solvent, benzene:ethyl acetate=1:1, colour forming method: spraying of 25% hydrobromic acid and 0.1% ninhydrin and heating). was added while cooling while cooling with ice The reaction solution was washed with 10% citric acid, aqueous sodium chloride, 5% sodium bicarbonate and aqueous sodium chloride in order dried with anhydrous sodium sulfate The solution was distilled under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: L-Proline methyl ester hydrochloride (2.68 g, 16.2 mmol) was dissolved in pyridine (20 mL), 3,5-dichlorophenylsulfonyl chloride (3.57 g, 14.6 mmol) was added and the mixture was stirred for 19 hr. Water (5 mL) was added and the mixture was stirred for 45 min before diluting with water (200 mL). The mixture was extracted with Et2O (2×150 mL) and the combined extracts were washed with water (3×100 mL), 1N HCl (150 mL) and saturated aq NaHCO3 (150 mL), then dried (MgSO4), filtered and evaporated in vacuo to give 3,5-dichlorophenyl-sulfonyl-L-proline methyl ester as an oil (4.34 g, 88%). the mixture was stirred for 45 min The mixture was extracted with Et2O (2×150 mL) the combined extracts were washed with water (3×100 mL), 1N HCl (150 mL) and saturated aq NaHCO3 (150 mL) dried (MgSO4) filtered evaporated in vacuo