Method for preparing telaprevir intermediate

Abstract

The invention discloses a method for preparing a telaprevir intermediate. The method comprises the following steps: carrying out a ring-closure reaction between 2-cyclopentenone and a compound of a formula II in a mixed solvent system formed by an amide solvent and water according to a volume ratio of 1:1-3:1. According to the method, a solvent system in which the ring-closure reaction is carried out is changed, the mixed solvent system formed by the amide solvent and water according to a certain volume ratio is creatively adopted, the ring-closure product is separated out of the reaction system in a solid form, after the reaction is ended, only are the solids needed to be filtered and collected, and a target product with the high performance liquid chromatography (HPLC) purity of 97 percent can be obtained. The operations are greatly simplified, the yield is obviously increased, and the mole yield is increased from 20-30 percent in the prior art to be over 67 percent; the method is suitable for large-scale production, meets the large-scale industrial production requirement of telaprevir and has a high industrial application value.

Description

technical field

[0001] The present invention relates to a telaprevir intermediate: (4bS,7aS,8S)-5H-cyclopenta[3,4]-pyrrolo[2,1-b]-furo[2,3-d]- The preparation method of thiazole-decahydro-9a-methyl-5-oxo-8-carboxylic acid ethyl ester belongs to the technical field of chemical drug synthesis. Background technique

[0002] Telaprevir is an HCV direct protease inhibitor for the treatment of genotype 1 chronic hepatitis C. Compared with other HCV protease inhibitors, telaprevir combined with PEGylated interferon α or ribavirin can significantly improve the cure rate of hepatitis C patients and shorten the course of treatment. The specific chemical structural formula of telaprevir is as follows:

[0003]

[0004] Important intermediates of telaprevir in the prior art (EP0600741): (4bS,7aS,8S)-5H-cyclopenta[3,4]-pyrrolo[2,1-b]-furo[2,3 The synthetic route of -d]-thiazole-decahydro-9a-methyl-5-oxo-8-carboxylic acid ethyl ester is shown below:

[0005] That is: under the pr...

Examples

Embodiment 1

[0025] Add 300mL DMF, 27.0g (0.6mol) LiCO 3 , 2.1g (0.04mol) LiBr, 0.1g (0.0015mol) hydroquinone, after the addition, the temperature was raised to 100°C, and 100g (0.61mol) of 2-bromocyclopentanone was added dropwise. Hours, the reaction was completed, and vacuum distillation was performed to obtain 200 g of a DMF solution containing 2-cyclopentenone (compound of formula I) (the molar yield was 80%, and the mass concentration was 20%) for use.

[0026] Dissolve 50.0g (0.16mol) of the compound of formula II in 50mL of water to prepare an aqueous solution; control the temperature of the reaction system at -10 to 10°C, add 84mL of the above-mentioned DMF solution containing 2-cyclopentenone (0.24mol) dropwise to the formula In the aqueous solution of compound II; after dropping, keep warm and stir at -10-10°C for 5-10 minutes; slowly add 21.1g (0.21mol) Et 3 N; After dropping, continue to keep warm and react at -10-10°C for 2-3 hours; naturally rise to room temperature and reac...

Embodiment 2

[0028] Add 300mL N-methylacetamide, 101g (1.0mol) triethylamine, 2.1g (0.05mol) LiCl, 0.1g (0.0015mol) hydroquinone into a 500mL three-necked flask, raise the temperature to 160°C after the addition, and add dropwise 100g (0.84mol) 2-chlorocyclopentanone, dropwise, heat preservation reaction for 3 to 4 hours, after the reaction is completed, vacuum distillation to obtain N-methyl ethyl alcohol containing 2-cyclopentenone (compound of formula I). Amide solution 374g (molar yield is 70%, mass concentration is 13%), stand-by;

[0029] 50.0g (0.16mol) of the compound of formula II was dissolved in 50mL of water to prepare an aqueous solution; the temperature of the reaction system was controlled at -10 to 10°C, and 159mL of the above-mentioned N-methylacetamide containing 2-cyclopentenone (0.24mol) Add the solution dropwise to the aqueous solution of the compound of formula II; after dropping, keep warm and stir at -10~10°C for 5~10 minutes; slowly add 21.1g (0.21mol) Et 3 N; Aft...

Embodiment 3

[0031] Weigh 17g (0.21mol) of 2-cyclopentenone and dissolve it in 94g of DMF to prepare 117mL of 2-cyclopentenone-containing DMF solution with a mass concentration of 18%.

[0032] 50.0g (0.16mol) of the compound of formula II was dissolved in 50mL of water to prepare an aqueous solution; the temperature of the reaction system was controlled at -10 to 10°C, and 117mL of the above-mentioned DMF solution containing 2-cyclopentenone (0.21mol) was added dropwise to the formula In the aqueous solution of compound II; after dropping, keep warm and stir at -10-10°C for 5-10 minutes; slowly add 21.1g (0.21mol) Et 3N; After dropping, continue to keep warm and react at -10-10°C for 2-3 hours; naturally rise to room temperature and react for 13-15 hours, then cool down in an ice bath to -10-10°C and solids will precipitate, stir for 0.5 hours After that, the solid was collected by suction filtration and dried to obtain 40 g of the compound of formula III (molar yield: 80.0%, HPLC purity:...

technical field

[0001] The present invention relates to a telaprevir intermediate: (4bS,7aS,8S)-5H-cyclopenta[3,4]-pyrrolo[2,1-b]-furo[2,3-d]- The preparation method of thiazole-decahydro-9a-methyl-5-oxo-8-carboxylic acid ethyl ester belongs to the technical field of chemical drug synthesis. Background technique

[0002] Telaprevir is an HCV direct protease inhibitor for the treatment of genotype 1 chronic hepatitis C. Compared with other HCV protease inhibitors, telaprevir combined with PEGylated interferon α or ribavirin can significantly improve the cure rate of hepatitis C patients and shorten the course of treatment. The specific chemical structural formula of telaprevir is as follows:

[0003]

[0004] Important intermediates of telaprevir in the prior art (EP0600741): (4bS,7aS,8S)-5H-cyclopenta[3,4]-pyrrolo[2,1-b]-furo[2,3 The synthetic route of -d]-thiazole-decahydro-9a-methyl-5-oxo-8-carboxylic acid ethyl ester is shown below:

[0005] That is: under the pr...

Examples

Embodiment 1

[0025] Add 300mL DMF, 27.0g (0.6mol) LiCO 3 , 2.1g (0.04mol) LiBr, 0.1g (0.0015mol) hydroquinone, after the addition, the temperature was raised to 100°C, and 100g (0.61mol) of 2-bromocyclopentanone was added dropwise. Hours, the reaction was completed, and vacuum distillation was performed to obtain 200 g of a DMF solution containing 2-cyclopentenone (compound of formula I) (the molar yield was 80%, and the mass concentration was 20%) for use.

[0026] Dissolve 50.0g (0.16mol) of the compound of formula II in 50mL of water to prepare an aqueous solution; control the temperature of the reaction system at -10 to 10°C, add 84mL of the above-mentioned DMF solution containing 2-cyclopentenone (0.24mol) dropwise to the formula In the aqueous solution of compound II; after dropping, keep warm and stir at -10-10°C for 5-10 minutes; slowly add 21.1g (0.21mol) Et 3 N; After dropping, continue to keep warm and react at -10-10°C for 2-3 hours; naturally rise to room temperature and reac...

Embodiment 2

[0028] Add 300mL N-methylacetamide, 101g (1.0mol) triethylamine, 2.1g (0.05mol) LiCl, 0.1g (0.0015mol) hydroquinone into a 500mL three-necked flask, raise the temperature to 160°C after the addition, and add dropwise 100g (0.84mol) 2-chlorocyclopentanone, dropwise, heat preservation reaction for 3 to 4 hours, after the reaction is completed, vacuum distillation to obtain N-methyl ethyl alcohol containing 2-cyclopentenone (compound of formula I). Amide solution 374g (molar yield is 70%, mass concentration is 13%), stand-by;

[0029] 50.0g (0.16mol) of the compound of formula II was dissolved in 50mL of water to prepare an aqueous solution; the temperature of the reaction system was controlled at -10 to 10°C, and 159mL of the above-mentioned N-methylacetamide containing 2-cyclopentenone (0.24mol) Add the solution dropwise to the aqueous solution of the compound of formula II; after dropping, keep warm and stir at -10~10°C for 5~10 minutes; slowly add 21.1g (0.21mol) Et 3 N; Aft...

Embodiment 3

[0031] Weigh 17g (0.21mol) of 2-cyclopentenone and dissolve it in 94g of DMF to prepare 117mL of 2-cyclopentenone-containing DMF solution with a mass concentration of 18%.

[0032] 50.0g (0.16mol) of the compound of formula II was dissolved in 50mL of water to prepare an aqueous solution; the temperature of the reaction system was controlled at -10 to 10°C, and 117mL of the above-mentioned DMF solution containing 2-cyclopentenone (0.21mol) was added dropwise to the formula In the aqueous solution of compound II; after dropping, keep warm and stir at -10-10°C for 5-10 minutes; slowly add 21.1g (0.21mol) Et 3N; After dropping, continue to keep warm and react at -10-10°C for 2-3 hours; naturally rise to room temperature and react for 13-15 hours, then cool down in an ice bath to -10-10°C and solids will precipitate, stir for 0.5 hours After that, the solid was collected by suction filtration and dried to obtain 40 g of the compound of formula III (molar yield: 80.0%, HPLC purity:...

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