methyl (2S)-pyrrolidine-2-carboxylate

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

実験手順: 2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol prepared in Example 5 and (S)-pyrrolidin-2-yl-carboxylic acid methyl ester were reacted according to the same procedure as Example 156 to give the title compound.

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

実験手順: A colorless oil of 1-[1-(2-indenylacetyl)-L-prolyl]-L-proline methyl ester was prepared in the same manner as in Example 1, except that 1-(2-indenylacetyl)-L-proline and L-proline methyl ester were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 75%).

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

実験手順: A colorless oil of 1-[1-(2-indenylacetyl)-L-prolyl]-L-proline methyl ester was prepared in the same manner as in Example 1, except that 1-(2-indenylacetyl)-L-proline and L-proline methyl ester were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 75%).

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

実験手順: A colorless oil of 1-[(R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-L-proline methyl ester was prepared in the same manner as in Reference Example 1, except that (R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and L-proline methyl ester were used instead of 2-indanyl acetic acid and L-thioproline ethyl ester, respectively (yield: 86%).

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

実験手順: A colorless oil of 1-[(R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-L-proline methyl ester was prepared in the same manner as in Reference Example 1, except that (R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and L-proline methyl ester were used instead of 2-indanyl acetic acid and L-thioproline ethyl ester, respectively (yield: 86%).

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

実験手順: Colorless crystals of 1-[(S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-L-proline methyl ester were prepared in the same manner as in Reference Example 1, except that (S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and L-proline methyl ester were used instead of 2-indanyl acetic acid and L-thioproline ethyl ester, respectively yield: 72%).

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

実験手順: 1-(6-methoxy-1,2,3,4 tetrahydronaphthalen-2-ylacetyl)-L-proline methyl ester was prepared as an oily substance in the same manner as Reference Example 1, except that 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and L-proline methyl ester were used instead of 2-indanylacetic acid and L-thioproline ethyl este respectively (yield: 79%).

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

実験手順: 1-(6-methoxy-1,2,3,4 tetrahydronaphthalen-2-ylacetyl)-L-proline methyl ester was prepared as an oily substance in the same manner as Reference Example 1, except that 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and L-proline methyl ester were used instead of 2-indanylacetic acid and L-thioproline ethyl este respectively (yield: 79%).

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

実験手順: To a solution of N-CBZ-D-phenylalanine (47.3 g, 0.158 mmol) in DMF (300 mL) at 0° C., was added L-proline-methylester.HCl (25.0 g, 0.151 mmol), 1-hydroxybenzotriazole hydrate (20.28 g, 0.166 mmol), ethyl-3-(3-dimethylamino)-propyl carbodiimide.HCl (31.8 g, 0.166 mmol) and 4-methylmorpholine (16.0 g, 0.159 mmol). The reaction mixture was stirred for 8 h while allowing the reaction to warm to room temperature. The reaction mixture was poured in water (1.2 L) and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed as follows: KHSO4 (0.25M, 2×200 ml), water (1×200 mL), saturated aqueous NaHCO3 (2×200 ml) and saturated NaCl (1×200 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo to give title compound, 60.9 g (98%), as an oil. the reaction extracted with ethyl acetate (3×300 mL) The combined organic extracts were washed The organic layer was dried over MgSO4 filtered the solvent removed in vacuo

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

実験手順: To a solution of N-CBZ-D-alanine (28.1 g, 0.149 mol) in DMF (250 mL) at 0° C., was added L-proline-methylester.HCl (24.6 g, 0.149 mmol), 1-hydroxybenzotriazole hydrate (22.2 g, 0.164 mmol), ethyl-3-(3-dimethylamino)-propyl carbodiimide.HCl (31.4 g, 0.164 mmol) and 4-methylmorpholine (22.6 g, 0.224 mmol). The reaction mixture was stirred for 12 h while allowing the reaction to warm to room temperature. The reaction mixture was poured in water (750 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed as follows: KHSO4 (0.25M, 2×50 mL), water (1×50 mL), saturated aqueous NaHCO3 (2×50 mL) and saturated NaCl (1×50 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound, 41.16 g (92%), as an oil. MS (M+H)+ =301+. the reaction extracted with ethyl acetate (2×150 mL) The combined organic extracts were washed The organic layer was dried over MgSO4 filtered the solvent removed in vacuo

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

実験手順: To a solution of N-CBZ-D-alanine (28.1 g, 0.149 mol) in DMF (250 mL) at 0° C., was added L-proline-methylester.HCl (24.6 g, 0.149 mmol), 1-hydroxybenzotriazole hydrate (22.2 g, 0.164 mmol), ethyl-3-(3-dimethylamino)-propyl carbodiimide.HCl (31.4 g, 0.164 mmol) and 4-methylmorpholine (22.6 g, 0.224 mmol). The reaction mixture was stirred for 12 h while allowing the reaction to warm to room temperature. The reaction mixture was poured in water (750 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed as follows: KHSO4 (0.25M, 2×50 mL), water (1×50 mL), saturated aqueous NaHCO3 (2×50 mL) and saturated NaCl (1×50 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound, 41.16 g (92%), as an oil. MS (M+H)+ =301+. the reaction extracted with ethyl acetate (2×150 mL) The combined organic extracts were washed The organic layer was dried over MgSO4 filtered the solvent removed in vacuo

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

実験手順: 2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol prepared in Example 5 and (S)-pyrrolidin-2-yl-carboxylic acid methyl ester were reacted according to the same procedure as Example 156 to give the title compound.