H-脯氨酸-NH2盐酸盐

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

实验步骤: Following the general procedure described previously for t-butyloxycarbonyl-L-phenylalanyl-L-prolinamide, a solution of t-butyloxycarbonyl-L-leucine (32.64 g), in tetrahydrofuran was activated by treatment with N-methylmorpholine (18.22 ml), followed by isobutylchloroformate (16.99 ml) at -5° C. After 15 minutes, L-prolinamide hydrochloride (15.0 g) was added as a solution in dimethylformamide, followed by N-methylmorpholine (18.22 ml) and the mixture stirred overnight at room temperature. The reaction was worked up as described previously to give the desired product, which was used for the next step without further purification.

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

实验步骤: Following the general procedure described previously for t-butyloxycarbonyl-L-phenylalanyl-L-prolinamide, a solution of t-butyloxycarbonyl-L-leucine (32.64 g), in tetrahydrofuran was activated by treatment with N-methylmorpholine (18.22 ml), followed by isobutylchloroformate (16.99 ml) at -5° C. After 15 minutes, L-prolinamide hydrochloride (15.0 g) was added as a solution in dimethylformamide, followed by N-methylmorpholine (18.22 ml) and the mixture stirred overnight at room temperature. The reaction was worked up as described previously to give the desired product, which was used for the next step without further purification.

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

实验步骤: Following the general procedure described previously for t-butyloxycarbonyl-L-phenylalanyl-L-prolinamide, a solution of t-butyloxycarbonyl-L-leucine (32.64 g), in tetrahydrofuran was activated by treatment with N-methylmorpholine (18.22 ml), followed by isobutylchloroformate (16.99 ml) at -5° C. After 15 minutes, L-prolinamide hydrochloride (15.0 g) was added as a solution in dimethylformamide, followed by N-methylmorpholine (18.22 ml) and the mixture stirred overnight at room temperature. The reaction was worked up as described previously to give the desired product, which was used for the next step without further purification.

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

实验步骤: The entitled compound was obtained as a pale yellow solid in the same method as in Example 15 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14, and L-prolinamide hydrochloride. The entitled compound was obtained as a pale yellow solid in the same method as in Example 15 or in accordance with the method

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

实验步骤: The entitled compound was obtained as a pale yellow solid in the same method as in Example 15 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14, and L-prolinamide hydrochloride. The entitled compound was obtained as a pale yellow solid in the same method as in Example 15 or in accordance with the method

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

实验步骤: To a stirred solution of (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl chloride (see Example 5) (50 mg, 0.10 mmol) in anhydrous methylene chloride (1 mL) was added 4-dimethylaminopyridine (DMAP) (37 mg, 0.30 mmol). L-Proline amide hydrochloride (69 mg, 0.30 mmol) was added to the mixture and the reaction was stirred for 18 h at room temperature under nitrogen. The reaction was concentrated and the residue was purified by column chromatography over silica gel (gradient elution with 35-50% EtOAc in hexanes) to provide 141 mg of (S)-1-[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid amide as a white solid. The reaction was concentrated the residue was purified by column chromatography over silica gel (gradient elution with 35-50% EtOAc in hexanes)

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

实验步骤: To a stirred solution of (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl chloride (see Example 5) (50 mg, 0.10 mmol) in anhydrous methylene chloride (1 mL) was added 4-dimethylaminopyridine (DMAP) (37 mg, 0.30 mmol). L-Proline amide hydrochloride (69 mg, 0.30 mmol) was added to the mixture and the reaction was stirred for 18 h at room temperature under nitrogen. The reaction was concentrated and the residue was purified by column chromatography over silica gel (gradient elution with 35-50% EtOAc in hexanes) to provide 141 mg of (S)-1-[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid amide as a white solid. The reaction was concentrated the residue was purified by column chromatography over silica gel (gradient elution with 35-50% EtOAc in hexanes)

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

实验步骤: To the product of Example 116A (21.6 g, 144 mmol), the product of Example 116B (29.1 g, 166 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (27.6 g, 180 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (34.6 g, 180 mmol) and 4-methylmorpholine (63.5 mL, 578 mmol) was dissolved in dichloromethane (960 mL) and stirred at room temperature for 18 hrs. The resultant solution was then concentrated to a residue, water was then added and the solution extracted with a 25% isopropanol in chloroform solution (2×2000 mL) the organic layer washed with brine then the organic extract dried over MgSO4, then concentrated to a yellow oil which was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane to provide 25 g (64%) of the title compound as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 7.28 (m, 2H), 6.81 (s, 1H), 4.24 (dd, J=8.1, 4.4 Hz, 1H), 4.00 (t, J=8.4 Hz, 1H), 3.75 (m, 1H), 3.55 (m, 1H), 3.50 (s, 3H), 2.02 (m, 1H), 1.97 (m, 2H), 1.80 (m, 2H), 0.92 (d, J=6.7 Hz, 3H), 0.86 (d, J=8.6 Hz, 3H). The resultant solution was then concentrated to a residue, water was then added the solution extracted with a 25% isopropanol in chloroform solution (2×2000 mL) the organic layer washed with brine the organic extract dried over MgSO4 concentrated to a yellow oil which was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane

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

实验步骤: To (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (29.8 g, 139 mmol) was added a solution of 4N HCl in dioxane (209 mL, 836 mmol) and the resultant mixture stirred at room temperature for 18 hrs. The mixture was then concentrated and triturated with diethyl ether then vacuum filtered and dried under vacuum to provide 21.6 g (104%) of the title product as a colorless solid. The mixture was then concentrated triturated with diethyl ether vacuum filtered dried under vacuum

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

实验步骤: To (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (29.8 g, 139 mmol) was added a solution of 4N HCl in dioxane (209 mL, 836 mmol) and the resultant mixture stirred at room temperature for 18 hrs. The mixture was then concentrated and triturated with diethyl ether then vacuum filtered and dried under vacuum to provide 21.6 g (104%) of the title product as a colorless solid. The mixture was then concentrated triturated with diethyl ether vacuum filtered dried under vacuum

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

实验步骤: To (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (29.8 g, 139 mmol) was added a solution of 4N HCl in dioxane (209 mL, 836 mmol) and the resultant mixture stirred at room temperature for 18 hrs. The mixture was then concentrated and triturated with diethyl ether then vacuum filtered and dried under vacuum to provide 21.6 g (104%) of the title product as a colorless solid. The mixture was then concentrated triturated with diethyl ether vacuum filtered dried under vacuum

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

实验步骤: Under cold conditions (ice bath) and under an inert atmosphere, 10 ml of triethylamine (69.7 mmol) are added to 5 g (33.2 mmol) of prolinamide hydrochloride suspended in chloroform (50 ml), and 9.7 g (34.9 mmol) of trityl chloride are then added portionwise. The reaction mixture is stirred at room temperature for 2 days. The reaction mixture is dissolved in dichloromethane (200 ml) and washed successively twice with HCl solution (1N) (150 ml), with water (150 ml), with saturated NaHCO3 solution (150 ml) and with saturated NaCl solution (150 ml). The organic phase is dried (Na2SO4), filtered and evaporated under reduced pressure. The residue is recrystallized from 20 ml of hot ethanol, to give 11 g of compound in the form of white crystals. Yield=93%. Melting point: 162° C. washed successively twice with HCl solution (1N) (150 ml), with water (150 ml), with saturated NaHCO3 solution (150 ml) and with saturated NaCl solution (150 ml) The organic phase is dried (Na2SO4) filtered evaporated under reduced pressure The residue is recrystallized from 20 ml of hot ethanol