阿哌沙班杂质85

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: The title compound (0.0042 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.15 g) using methyl 5-chlorovalerate (0.90 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-1-(4-methoxycarbonyl-butyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C19H24ClN3O2, 361.16; found, m/z 362.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.54-7.51 (m, 2H), 7.31-7.29 (m, 2H), 3.95 (t, J=7.0 Hz, 2H), 3.60 (s, 3H), 3.03-3.01 (m, 2H), 2.93-2.91 (m, 4H), 2.56-2.53 (m, 2H), 2.16 (t, J=7.4 Hz, 2H), 1.67-1.62 (m, 2H), 1.41-1.38 (m, 2H).

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

实验步骤: The title compound (0.0042 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.15 g) using methyl 5-chlorovalerate (0.90 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-1-(4-methoxycarbonyl-butyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C19H24ClN3O2, 361.16; found, m/z 362.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.54-7.51 (m, 2H), 7.31-7.29 (m, 2H), 3.95 (t, J=7.0 Hz, 2H), 3.60 (s, 3H), 3.03-3.01 (m, 2H), 2.93-2.91 (m, 4H), 2.56-2.53 (m, 2H), 2.16 (t, J=7.4 Hz, 2H), 1.67-1.62 (m, 2H), 1.41-1.38 (m, 2H).

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

实验步骤: The title compound (0.0042 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.15 g) using methyl 5-chlorovalerate (0.90 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-1-(4-methoxycarbonyl-butyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C19H24ClN3O2, 361.16. found, m/z 362.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.54-7.51 (m, 2H), 7.31-7.29 (m, 2H), 3.95 (t, J=7.0 Hz, 2H), 3.60 (s, 3H), 3.03-3.01 (m, 2H), 2.93-2.91 (m, 4H), 2.56-2.53 (m, 2H), 2.16 (t, J=7.4 Hz, 2H), 1.67-1.62 (m, 2H), 1.41-1.38 (m, 2H).

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

实验步骤: The title compound (0.0042 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.15 g) using methyl 5-chlorovalerate (0.90 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-1-(4-methoxycarbonyl-butyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C19H24ClN3O2, 361.16. found, m/z 362.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.54-7.51 (m, 2H), 7.31-7.29 (m, 2H), 3.95 (t, J=7.0 Hz, 2H), 3.60 (s, 3H), 3.03-3.01 (m, 2H), 2.93-2.91 (m, 4H), 2.56-2.53 (m, 2H), 2.16 (t, J=7.4 Hz, 2H), 1.67-1.62 (m, 2H), 1.41-1.38 (m, 2H).

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

实验步骤: To a solution of dimethyl methylphosphonate (2.16 mL, 20 mmol) in anhydrous THF (30 mL), cooled at −78° C. was added n-BuLi (1.6 M in hexane, 13.75 mL, 22 mmol). The mixture was stirred for 30 minutes at this temperature under nitrogen. Methyl 5-chloropentanoate (1.50 g, 10 mmol) was added dropwise for 10 minutes. The mixture was stirred for 2 hours at −78° C., gradually was warm to room temperature. The mixture was quenched with addition of 1N HCl to pH 4-5. The organic layer was separated, washed with brine and dried over MgSO4. The residue was purified through flash chromatography on silica gel (MeOH:CH2Cl2=2:98) to give the product (1.60 g) with colorless oil in 17% yield. 1HNMR (CDCl3, ppm) δ 1.76 (m, 6H), 2.67 (t, J=6.6 Hz, 2H), 3.01 (d, J=21.7 Hz, 2H), 3.35 (t, J=6.2 Hz, 2H), 3.76 (s, 3H), 3.79 (s, 3H). The mixture was stirred for 2 hours at −78° C. The mixture was quenched with addition of 1N HCl to pH 4-5 The organic layer was separated washed with brine dried over MgSO4 The residue was purified through flash chromatography on silica gel (MeOH:CH2Cl2=2:98)

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: To a solution of dimethyl methylphosphonate (2.16 mL, 20 mmol) in anhydrous THF (30 mL), cooled at −78° C. was added n-BuLi (1.6 M in hexane, 13.75 mL, 22 mmol). The mixture was stirred for 30 minutes at this temperature under nitrogen. Methyl 5-chloropentanoate (1.50 g, 10 mmol) was added dropwise for 10 minutes. The mixture was stirred for 2 hours at −78° C., gradually was warm to room temperature. The mixture was quenched with addition of 1N HCl to pH 4-5. The organic layer was separated, washed with brine and dried over MgSO4. The residue was purified through flash chromatography on silica gel (MeOH:CH2Cl2=2:98) to give the product (1.60 g) with colorless oil in 17% yield. 1HNMR (CDCl3, ppm) δ 1.76 (m, 6H), 2.67 (t, J=6.6 Hz, 2H), 3.01 (d, J=21.7 Hz, 2H), 3.35 (t, J=6.2 Hz, 2H), 3.76 (s, 3H), 3.79 (s, 3H). The mixture was stirred for 2 hours at −78° C. The mixture was quenched with addition of 1N HCl to pH 4-5 The organic layer was separated washed with brine dried over MgSO4 The residue was purified through flash chromatography on silica gel (MeOH:CH2Cl2=2:98)

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

实验步骤: A mixture of 0.167 mole of methyl δ-chlorovalerate and 0.25 mole of sodium iodide in 120 ml. of acetone is stirred and heated at reflux for 16 hours. After cooling the mixture, a solid is removed by suction filtration, and the acetone is distilled off using a rotary evaporator. The residue is dissolved in 300 ml. of diethyl ether, and additional solid is removed by filtration. The ethereal solution is washed twice with a 10% sodium thiosulfate solution, one with water and dried over sodium sulfate. The ether is evaporated and the residue distilled at b.p. 107°-110° C. (15 mm.) to give 30.0 g. (74%) of methyl δ-iodovalerate as a light yellow liquid. 30.0 g. (0.124 mole) of methyl δ-iodovalerate and 42.5 g. (0.50 mole) of piperidine are dissolved in 250 ml. of benzene and heated at 60° C. for 3 hours with stirring. A colorless solid begins to appear shortly after the materials are combined. The solid is removed by suction filtration, and the benzene evaporated to give methyl δ-piperidinovalerate which distills as 23.5 g. (95%) of colorless liquid, b.p., 122°-24° C. (12.5 mm.). heated at reflux for 16 hours After cooling the mixture a solid is removed by suction filtration the acetone is distilled off a rotary evaporator The residue is dissolved in 300 ml of diethyl ether, and additional solid is removed by filtration The ethereal solution is washed twice with a 10% sodium thiosulfate solution, one with water dried over sodium sulfate The ether is evaporated the residue distilled at b.p. 107°-110° C. (15 mm.) to give 30.0 g The solid is removed by suction filtration the benzene evaporated