(2S)-pyrrolidine-2-carboxamide

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and (S)-proline amide (0.114 g, 0.57 mmol) gives the title compound.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of compound XIII (1.25 g, 2 mmoles) in dimethylformaide (8 ml) is chilled to -40° C to -50° C in a Dry-ice-acetone bath and 3.66M hydrogen chloride in dioxane (1.37 ml) is added. To this is then added dropwise isoamyl nitrite (0.29 ml, 2.2 mmoles) and the mixture is stirred at -10° C to -20° for 10 minutes. The mixture is again chilled to -40° C to -50° C and an ice-cold solution of XIV (0.30 g, 2 mmoles) and triethylamine (1.1 ml, 7.7 mmoles) in dimethylformamide (10 ml) is introduced. The temperature is allowed to rise to 0° C, at which the mixture is stirred for 3 hours. After the pH have been adjusted to about 8 with an additional quantity of triethylamine (0.27 ml, 2 mmoles) the reaction mixture is kept at 4° C for 2 days. The solvent is removed by evaporation in vacuo at a bath temperature of 40° C. The resulting residue is dissolved in ethyl acetate and the solution is washed with ice-cold M hydrochloric acid and M sodium bicarbonate, dried over magnesium sulfate and evaporated in vacuo. Repeated precipiration of the residue obtained above yields the desired tripeptide XV; yield 1.29 g (91%), mp. 85°-90° C, [α]D22 - 40.5°±0.4° (c 2.0, methanol). The mixture is again chilled to -40° C to -50° C to rise to 0° C, at which is stirred for 3 hours is kept at 4° C for 2 days The solvent is removed by evaporation in vacuo at a bath temperature of 40° C The resulting residue is dissolved in ethyl acetate the solution is washed with ice-cold M hydrochloric acid and M sodium bicarbonate dried over magnesium sulfate evaporated in vacuo obtained

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 74 was prepared according to the procedure described for the synthesis of compound 72 by replacing leucine amide with (S)-pyrrolidine-2-carboxamide. LCMS (+ESI) m/z=521.2 [M+H]+.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 74 was prepared according to the procedure described for the synthesis of compound 72 by replacing leucine amide with (S)-pyrrolidine-2-carboxamide. LCMS (+ESI) m/z=521.2 [M+H]+.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.27 g of Z-Thr(tBu)-OH and 1.56 g of H-Pro-NH2 are dissolved in 60 ml of acetonitrile, the solution is cooled to 0°C and 3.11 g of dicyclohexylcarbodiimide are added. After 1 hour at 0°C and 20 hours at room temperature the dicyclohexylurea is filtered off and the filtrate is evaporated and the residue taken up in ethyl acetate. The ethyl acetate solution is washed with dilute citric acid solution, soda solution and water, and is dried with sodium sulphate and evaporated. On thin layer chromatography on silica gel plates the colourless residue shows Rf45 = 0.76; Rf43c = 0.70; Rf52 = 0.62. 20 hours at room temperature the dicyclohexylurea is filtered off the filtrate is evaporated The ethyl acetate solution is washed with dilute citric acid solution, soda solution and water is dried with sodium sulphate evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.27 g of Z-Thr(tBu)-OH and 1.56 g of H-Pro-NH2 are dissolved in 60 ml of acetonitrile, the solution is cooled to 0°C and 3.11 g of dicyclohexylcarbodiimide are added. After 1 hour at 0°C and 20 hours at room temperature the dicyclohexylurea is filtered off and the filtrate is evaporated and the residue taken up in ethyl acetate. The ethyl acetate solution is washed with dilute citric acid solution, soda solution and water, and is dried with sodium sulphate and evaporated. On thin layer chromatography on silica gel plates the colourless residue shows Rf45 = 0.76; Rf43c = 0.70; Rf52 = 0.62. 20 hours at room temperature the dicyclohexylurea is filtered off the filtrate is evaporated The ethyl acetate solution is washed with dilute citric acid solution, soda solution and water is dried with sodium sulphate evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (WO 2003101442, 38.2 g, 0.125 mol), L-prolinamide (14.3 g, 0.125 mol,) N-methyl morpholine (34.4 mL, 0.313 mol,) and HOBt (18.65 g, 0.138 mol) were dissolved in DMF (400 mL) with stirring. EDC (26.46 g, 0.138 mol) was added portionwise and the solution was stirred at room temperature for 3 hours. The majority of the DMF was removed in vacuo and the residue was diluted with ethyl acetate (1 L.) This solution was washed with cold 0.5M HCl solution (200 mL), twice with water (200 mL), saturated aqueous NaHCO3 solution, brine, and then dried over MgSO4. After filtering and evaporating, the crude material was dissolved in hot ethyl acetate (˜150 mL) with stirring. While keeping the solution hot, hexanes (˜150 mL) was added until the solution was cloudy. Cooling slowly to room temperature while stirring gave a thick slurry. The solid was filtered off and washed with 1:1 ethyl acetate:hexanes, followed by a wash with hexanes. After drying, the product 1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-L-prolinamide was obtained as a white solid (34.4 g, 69% yield). LC/MS m/z 402 (MH+) the solution was stirred at room temperature for 3 hours The majority of the DMF was removed in vacuo the residue was diluted with ethyl acetate (1 L.) This solution was washed with cold 0.5M HCl solution (200 mL), twice with water (200 mL), saturated aqueous NaHCO3 solution, brine dried over MgSO4 After filtering evaporating the crude material was dissolved in hot ethyl acetate (˜150 mL) with stirring hexanes (˜150 mL) was added until the solution while stirring gave a thick slurry The solid was filtered off washed with 1:1 ethyl acetate a wash with hexanes After drying

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (WO 2003101442, 38.2 g, 0.125 mol), L-prolinamide (14.3 g, 0.125 mol,) N-methyl morpholine (34.4 mL, 0.313 mol,) and HOBt (18.65 g, 0.138 mol) were dissolved in DMF (400 mL) with stirring. EDC (26.46 g, 0.138 mol) was added portionwise and the solution was stirred at room temperature for 3 hours. The majority of the DMF was removed in vacuo and the residue was diluted with ethyl acetate (1 L.) This solution was washed with cold 0.5M HCl solution (200 mL), twice with water (200 mL), saturated aqueous NaHCO3 solution, brine, and then dried over MgSO4. After filtering and evaporating, the crude material was dissolved in hot ethyl acetate (˜150 mL) with stirring. While keeping the solution hot, hexanes (˜150 mL) was added until the solution was cloudy. Cooling slowly to room temperature while stirring gave a thick slurry. The solid was filtered off and washed with 1:1 ethyl acetate:hexanes, followed by a wash with hexanes. After drying, the product 1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-L-prolinamide was obtained as a white solid (34.4 g, 69% yield). LC/MS m/z 402 (MH+) the solution was stirred at room temperature for 3 hours The majority of the DMF was removed in vacuo the residue was diluted with ethyl acetate (1 L.) This solution was washed with cold 0.5M HCl solution (200 mL), twice with water (200 mL), saturated aqueous NaHCO3 solution, brine dried over MgSO4 After filtering evaporating the crude material was dissolved in hot ethyl acetate (˜150 mL) with stirring hexanes (˜150 mL) was added until the solution while stirring gave a thick slurry The solid was filtered off washed with 1:1 ethyl acetate a wash with hexanes After drying

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.28 g of H-Pro-NH2 and 7.57 g of Z-Ala-ONP are dissolved in 20 ml of dimethylformamide and the yellow solution is left standing at room temperature for 18 hours. It is then evaporated to dryness in a high vacuum, the residue is mixed with ether and the resulting powder is thoroughly triturated. After filtering off and drying, 5.5 g of Z-Ala-Pro-NH2 of melting point 167.5°-168.5° C. are obtained. [α]D20 = -74° (c = 1 in methanol). the yellow solution is left It is then evaporated to dryness in a high vacuum the residue is mixed with ether the resulting powder is thoroughly triturated After filtering off drying

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.28 g of H-Pro-NH2 and 7.57 g of Z-Ala-ONP are dissolved in 20 ml of dimethylformamide and the yellow solution is left standing at room temperature for 18 hours. It is then evaporated to dryness in a high vacuum, the residue is mixed with ether and the resulting powder is thoroughly triturated. After filtering off and drying, 5.5 g of Z-Ala-Pro-NH2 of melting point 167.5°-168.5° C. are obtained. [α]D20 = -74° (c = 1 in methanol). the yellow solution is left It is then evaporated to dryness in a high vacuum the residue is mixed with ether the resulting powder is thoroughly triturated After filtering off drying

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.28 g of H-Pro-NH2 and 7.57 g of Z-Ala-ONP are dissolved in 20 ml of dimethylformamide and the yellow solution is allowed to stand for 18 hours at room temperature. It is then evaporated to dryness in a high vacuum, the residue is mixed with ethyl acetate and the resulting powder is thoroughly triturated. After filtering off and drying, 5.5 g of Z-Ala-Pro-NH2 of melting point 164°-165° C. are obtained. It is then evaporated to dryness in a high vacuum the residue is mixed with ethyl acetate the resulting powder is thoroughly triturated After filtering off drying

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of (2S,3S)-2-azido-3-(4-fluorophenyl)butanoic acid Example 1, Step D, 91.8 mg, 0.309 mmol) in anhydrous N,N-dimethylformamide (DMF, 1.5 mL) was added [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HATU, 141 mg, 0.371 mmol), 1-hydroxy-7-azabenzotriazole (HOAT, 50.5 mg, 0.371 mmol), L-prolinamide (38.8 mg, 0.340 mmol) and N,N′-diisopropylethylamine (0.135 mL, 0.773 mmol). After stirring at room temperature for 16 h, the reaction was diluted with ethyl acetate. The organic phase was washed sequentially with water, saturated aqueous sodium bicarbonate solution and brine, dried (magnesium sulfate), and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (silica, ethyl acetate eluant) to afford the title compound. The organic phase was washed sequentially with water, saturated aqueous sodium bicarbonate solution and brine dried (magnesium sulfate) concentrated under reduced pressure The residue was purified by preparative thin layer chromatography (silica, ethyl acetate eluant)