N-BOC-R-环丙基丙氨酸

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 from N-[5-fluoro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide and N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alanine (Example 31, Step C) followed by deprotection with HCl-EtOAc essentially according to the procedures described in Example 31, Steps D and E. HPLC RT=0.93 min (Method B); LCMS (M+H): 402; 1H NMR (400 MHz, DMSO-d6): δ 9.86 (s, 1H), 8.66 (t, J=6 Hz, 1H), 8.22–8.35 (m, 2H), 7.64–7.67 (m, 1H), 7.38–7.39 (m, 2H), 4.18–4.30 (m, 1H), 4.00–4.22 (m, 3H), 3.73–3.82 (m, 1H), 3.52–3.58 (m, 1H), 2.0–2.13 (m, 1H), 1.77–1.94 (m, 3H), 1.65–1.74 (m, 1H), 1.52–1.61 (m, 1H), 0.77–0.85 (m, 1H), 0.44–0.48 (m, 2H), 0.05–0.17 (m, 2H).

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 N-[5-fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl]-L-prolinamide (86 mg, 0.25 mmol), N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alanine (Example 31, Step C, 57 mg, 0.25 mmol) and HOBt hydrate (33 mg, 0.25 mmol) in DMF (2 mL) was added EDC (48 mg, 0.25 mmol). Diisopropylethylamine was then added in portions (0.1 mL total) to bring the pH of the solution to 6–7 as measured on wetted E. Merck pH indicator strips. The mixture was stirred at ambient temperature for 4 hours. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the oily residue was purified by preparative reverse phase HPLC eluting with 95/5 to 5/95 1%TFA H2O/CH3CN in 30 min at a flow rate of 15 mL/min. The product fractions were combined and lyophilized to give 35 mg of the title compound. 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 8.12 (s, 1H), 7.63 (m, 1H), 7.23–7.29 (m, 1H), 7.02–7.06 (m, 1H), 5.17 (d, J=5.5 Hz, 1H 4.62 (d, J=5.6 Hz, 1H), 4.22–4.41 (m, 4H), 3.94 (br, s, 1H), 3.60 (m, 1H), 2.34 (s, 1H), 1.98 (s, 2H), 1.44 (m, 1H), 1.30 (s, 9H), 0.71–0.73 (m, 1H), 0.47–0.51 (m, 2H), 0.12 (br s, 2H). The DMF was removed under reduced pressure the residue was partitioned between EtOAc and saturated aqueous NaHCO3 The EtOAc layer was separated dried over anhydrous MgSO4 filtered The filtrate solvent was removed under reduced pressure the oily residue was purified by preparative reverse phase HPLC eluting with 95/5 to 5/95 1%TFA H2O/CH3CN in 30 min at a flow rate of 15 mL/min

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 N-[5-fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl]-L-prolinamide (86 mg, 0.25 mmol), N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alanine (Example 31, Step C, 57 mg, 0.25 mmol) and HOBt hydrate (33 mg, 0.25 mmol) in DMF (2 mL) was added EDC (48 mg, 0.25 mmol). Diisopropylethylamine was then added in portions (0.1 mL total) to bring the pH of the solution to 6–7 as measured on wetted E. Merck pH indicator strips. The mixture was stirred at ambient temperature for 4 hours. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the oily residue was purified by preparative reverse phase HPLC eluting with 95/5 to 5/95 1%TFA H2O/CH3CN in 30 min at a flow rate of 15 mL/min. The product fractions were combined and lyophilized to give 35 mg of the title compound. 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 8.12 (s, 1H), 7.63 (m, 1H), 7.23–7.29 (m, 1H), 7.02–7.06 (m, 1H), 5.17 (d, J=5.5 Hz, 1H 4.62 (d, J=5.6 Hz, 1H), 4.22–4.41 (m, 4H), 3.94 (br, s, 1H), 3.60 (m, 1H), 2.34 (s, 1H), 1.98 (s, 2H), 1.44 (m, 1H), 1.30 (s, 9H), 0.71–0.73 (m, 1H), 0.47–0.51 (m, 2H), 0.12 (br s, 2H). The DMF was removed under reduced pressure the residue was partitioned between EtOAc and saturated aqueous NaHCO3 The EtOAc layer was separated dried over anhydrous MgSO4 filtered The filtrate solvent was removed under reduced pressure the oily residue was purified by preparative reverse phase HPLC eluting with 95/5 to 5/95 1%TFA H2O/CH3CN in 30 min at a flow rate of 15 mL/min

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 N-[5-chloro-2-(1H1,2,4-triazol-1-yl)benzyl]-L-prolinamide (Example 27, Step B, 0.046 g, 0.121 mmol), N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alanine (30 mg, 0.121 mmol), and HOBt hydrate (20 mg, 0.145 mmol) in DMF (3 mL) was added EDC (0.028 g, 0.145 mmol). Diisopropylethylamine (0.083 mL, 0.484 mmol) was added and the mixture was stirred at ambient temperature for 18 hours, at which time HPLC analysis indicated complete consumption of the proline starting material. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and 10% aqueous Na2CO3. The EtOAc layer was separated, washed with water and brine, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure to give N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alanyl-N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-L-prolinamide as a gum (0.058 g). HPLC RT=2.18 min, Method B; LCMS (M+H): 517, 519. consumption of the proline starting material The DMF was removed under reduced pressure the residue was partitioned between EtOAc (50 mL) and 10% aqueous Na2CO3 The EtOAc layer was separated washed with water and brine dried over anhydrous MgSO4 filtered The filtrate solvent was removed under reduced pressure

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 N-[5-chloro-2-(1H1,2,4-triazol-1-yl)benzyl]-L-prolinamide (Example 27, Step B, 0.046 g, 0.121 mmol), N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alanine (30 mg, 0.121 mmol), and HOBt hydrate (20 mg, 0.145 mmol) in DMF (3 mL) was added EDC (0.028 g, 0.145 mmol). Diisopropylethylamine (0.083 mL, 0.484 mmol) was added and the mixture was stirred at ambient temperature for 18 hours, at which time HPLC analysis indicated complete consumption of the proline starting material. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and 10% aqueous Na2CO3. The EtOAc layer was separated, washed with water and brine, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure to give N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alanyl-N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-L-prolinamide as a gum (0.058 g). HPLC RT=2.18 min, Method B; LCMS (M+H): 517, 519. consumption of the proline starting material The DMF was removed under reduced pressure the residue was partitioned between EtOAc (50 mL) and 10% aqueous Na2CO3 The EtOAc layer was separated washed with water and brine dried over anhydrous MgSO4 filtered The filtrate solvent was removed under reduced pressure

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 methyl N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alaninate (1.0 g, 4.1 mmol) in MeOH (25 mL) at 0° C. was added 1M NaOH (5.0 mL, 5.0 mmol) dropwise. After 1 h, the cold bath was removed, and the reaction followed by HPLC. After 5.5 h, the methanol was removed at reduced pressure, and the residue diluted with 15 mL water and washed with ether. The aqueous layer was acidified with cold 2M HCl and extracted with three portions of EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated at reduced pressure to give the title compound as a colorless oil (929 mg): 1H NMR (300 MHz, CDCl3): δ 5.10–5.22 (br d, J=6.1 Hz, 1H), 4.35–4.46 (m, 1H), 1.72 (t, J=6.2 Hz, 2H), 1.39 (s, 9H), 0.70–0.85 (m, 1H), 0.42–0.60 (m, 2H), 0.03–0.21 (m, 2H). the cold bath was removed After 5.5 h the methanol was removed at reduced pressure the residue diluted with 15 mL water washed with ether extracted with three portions of EtOAc The combined organic layers were washed with water, brine dried over Na2SO4 concentrated at reduced pressure

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

实验步骤: Prepared by the same method as described in example 1 except that (i) steps A, B and C were omitted; (ii) 1-(2-fluoro-4-iodo-phenyl)-propan-1-one (prepared as described below) was used in place of 1-(2-fluoro-4-iodo-phenyl)-ethanone in step 13-D; (iii) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step 13-F was omitted, and (iv) in step 13-G commercially available (R)-2-tert-butoxycarbonylamino-3-cyclopropyl-propionic acid was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid. Prepared by the same method

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

实验步骤: Prepared by the same method as described in example 1 except that (i) steps A, B and C were omitted; (ii) 1-(2-fluoro-4-iodo-phenyl)-propan-1-one (prepared as described below) was used in place of 1-(2-fluoro-4-iodo-phenyl)-ethanone in step 13-D; (iii) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step 13-F was omitted, and (iv) in step 13-G commercially available (R)-2-tert-butoxycarbonylamino-3-cyclopropyl-propionic acid was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid. Prepared by the same method

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

实验步骤: To a solution of above mentioned (R)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (1.0 g, 4.36 mmol) in DMF (10 ml) was added EDC (1.0 g, 5.24 mmol) and HOBt.H2O (367 mg, 2.4 mmol) at room temperature, 20 min later, it was added ammonia in MeOH (7N, 0.6 mL, 4 mmol) at room temperature. After stirring for 30 min, it was diluted with water and EtOAc, organic layer was separated and washed with Sat. NaHCO3, brine, dried and concentrated to give (R)-tert-butyl-1-amino-3-cyclopropyl-1-oxopropan-2-ylcarbamate (750 mg) as crude oil, which was treated with 4N HCl in Dioxane (5 mL). 30 min later, it was concentrated to give (R)-2-amino-2-cyclopropylacetamide hydrochloride salt. was separated washed with Sat. NaHCO3, brine dried concentrated

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

实验步骤: To a solution of (R)-2-amino-3-cyclopropylpropanoic acid (1.0 g, 7.7.4 mmol) in Ethanol (15 mL) and water (8 mL) was added 1N NaOH (10 mL) and Di-tert-butyl carbonate (1.86 g, 8.52 mmol) in THF (8 mL). After stirring at room temperature for 15 h, the solution was diluted with water, extracted with ether, the aqueous layer was separated and was acidified to pH 2 with conc. HCl, the aqueous layer was extracted with EtOAc, organic layer was separated, washed with brine, dried and concentrated to give (R)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (1.0 g). extracted with ether the aqueous layer was separated the aqueous layer was extracted with EtOAc, organic layer was separated washed with brine dried concentrated

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

实验步骤: To a solution of above mentioned (R)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (1.0 g, 4.36 mmol) in DMF (10 ml) was added EDC (1.0 g, 5.24 mmol) and HOBt.H2O (367 mg, 2.4 mmol) at room temperature, 20 min later, it was added ammonia in (7N, 0.6 mL, 4 mmol) at room temperature. After stirring for 30 min, it was diluted with water and EtOAc, organic layer was separated and washed with Sat. NaHCO3, brine, dried and concentrated to give (R)-tert-butyl-1-amino-3-cyclopropyl-1-oxopropan-2-ylcarbamate (750 mg) as crude oil, which was treated with 4N HCl in Dioxane (5 mL). 30 min later, it was concentrated to give (R)-2-amino-2-cyclopropylacetamide hydrochloride salt. was separated washed with Sat. NaHCO3, brine dried concentrated

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

实验步骤: To a solution of (R)-2-amino-3-cyclopropylpropanoic acid (1.0 g, 7.7.4 mmol) in Ethanol (15 mL) and water (8 mL) was added 1N NaOH (10 mL) and Di-tert-butyl carbonate (1.86 g, 8.52 mmol) in THF (8 mL). After stirring at room temperature for 15 h, the solution was diluted with water, extracted with ether, the aqueous layer was separated and was acidified to pH 2 with conc. HCl, the aqueous layer was extracted with EtOAc, organic layer was separated, washed with brine, dried and concentrated to give (R)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (1.0 g). extracted with ether the aqueous layer was separated the aqueous layer was extracted with EtOAc, organic layer was separated washed with brine dried concentrated