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Synthesis method of telaprevir

A synthetic method, the technology of telaprevir, applied in the field of drug synthesis, can solve the problems of high reagent cost and post-processing cost, cumbersome post-processing steps, and high cost, and achieve the goal of reducing yield and purity, reducing yield and purity Effect of loss, short reaction time

Inactive Publication Date: 2013-10-09
SUZHOU UUGENE BIOPHARMA
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  • Abstract
  • Description
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Problems solved by technology

[0012] The method uses 1-hydroxy-7-azobenzotriazole / N,N'-dicyclohexylcarbodiimide (HOAt / DCC) and 1-hydroxybenzotriazole in the first and third steps The azole / carbodiimide (HOBt / EDCI) condensation system has high cost, and the by-product dicyclohexyl urea (DCU) produced in the first step reaction is difficult to completely remove from the reaction system. After water washing, pickling, alkali washing, brine washing, and then column chromatography separation, the pure product can be obtained, the yield is low, the cost is high, the post-processing steps are loaded down with trivial details and produce a large amount of three wastes; and, the tetramethylpiperene used in the fourth step Pyridine / sodium hypochloride (TEMPO / NaClO) reagent cost and post-treatment cost are high

Method used

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  • Synthesis method of telaprevir
  • Synthesis method of telaprevir
  • Synthesis method of telaprevir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] At -10°C, 25g (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valine, 10g (1S,3aR,6aS)- Add tert-butyl octahydrocyclopenta[c]pyrrole-1-carboxylate, 13g N,N'-diisopropylcarbodiimide into a reaction flask of 40mL dichloromethane, keep stirring at -10°C for 10 minutes , the mixture was slowly warmed to room temperature and stirred overnight at room temperature. After the reaction was detected by TLC and HPLC, the temperature of the reaction solution was lowered to 3° C., stirred for 10 minutes, and then suction-filtered to obtain a white filter cake and a yellow-green filtrate. The filter cake was washed twice with 20 mL of dichloromethane. Drained, combined filtrate, washed three times with 100mL of water, 100mL of 1N hydrochloric acid once, 100mL of saturated sodium bicarbonate aqueous solution once, then washed once with 100mL of saturated brine, dried with 10g of anhydrous sodium sulfate and concentrated to obtain the intermediate product (1 ).

[0043] A...

Embodiment 2

[0046] At -15°C, 50g (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valine, 20g (1S,3aR,6aS)- Add tert-butyl octahydrocyclopenta[c]pyrrole-1-carboxylate, 32g N,N-dicarbonylimidazole into a reaction flask of 80mL N,N-dimethylformamide, keep stirring at -15°C for 15 minutes , the mixture was slowly warmed to room temperature and stirred overnight at room temperature. After the reaction was detected by TLC and HPLC, the temperature of the reaction solution was lowered to 5° C., stirred for 15 minutes, and then suction-filtered to obtain a white filter cake and a yellow-green filtrate. The filter cake was washed twice with 40 mL of dichloromethane. Drained, combined filtrate, washed three times with 200mL water, 200mL1N hydrochloric acid washed once, 200mL saturated sodium bicarbonate aqueous solution washed once, then washed once with 200mL saturated brine, 20g of anhydrous sodium sulfate dried and concentrated to obtain the intermediate product (1 ).

[0047] Afte...

Embodiment 3

[0050]At -5°C, 12.5g (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-valine, 5g (1S, 3aR, 6aS) - tert-butyl octahydrocyclopenta[c]pyrrole-1-carboxylate, 8.0 g of 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine added to 20 mL In a reaction flask of dimethyl sulfoxide, the mixture was stirred at -5°C for 5 minutes, and then the mixture was slowly warmed to room temperature and stirred overnight at room temperature. After the reaction was detected by TLC and HPLC, the temperature of the reaction solution was lowered to -2°C, stirred for 6 minutes, and suction filtered to obtain a white filter cake and a yellow-green filtrate. The filter cake was washed twice with 10 mL of dichloromethane. Drained, combined filtrate, washed three times with 50mL of water, washed once with 50mL of 1N hydrochloric acid, washed once with saturated aqueous sodium bicarbonate solution of 50mL, washed once with saturated brine of 50mL, dried with 5g of anhydrous sodium sulfate and concentra...

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Abstract

The invention relates to a synthesis method of telaprevir. The synthesis method comprises the following steps: dissolving (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valine and (1S,3aR,6aS)-octahydrocyclopentane[c]pyrryl-1-tert-butylcarboxylate in a solvent, and condensing under the action of a condensing agent to obtain a compound disclosed as Formula (III); dissolving the compound disclosed as Formula (III) in a solvent, and carrying out acidolysis reaction on the compound disclosed as Formula (III) under the action of acid to obtain a compound disclosed as Formula (IV); and finally, dissolving the compound disclosed as Formula (IV) and (S)-3-amino-N-cyclopropyl-2-oxohexanamide salt in a solvent, carrying out condensation reaction under the action of a condensing agent and an acid-binding agent, and pulping to obtain the final product telaprevir. The invention has the advantages of mild reaction conditions, short time and high yield, does not need to use any expensive oxidizer, reduces the loss of yield and purity of the product in after-treatment, and lowers the cost.

Description

technical field [0001] The invention relates to a synthetic method of telaprevir, which belongs to the technical field of drug synthesis. Background technique [0002] Hepatitis C is a kind of viral hepatitis caused by hepatitis C virus (Hepatitis C virus, HCV) infection, mainly through blood transfusion, acupuncture, drug abuse, etc., according to the statistics of the World Health Organization, the global HCV infection rate is about 3%, an estimated 180 million people are infected with HCV, and about 35,000 new cases of hepatitis C occur each year. Hepatitis C is a global epidemic, which can lead to chronic inflammation, necrosis and fibrosis of the liver, and some patients can develop liver cirrhosis and even hepatocellular carcinoma (HCC). Some data show that the mortality rate (liver failure and hepatocellular carcinoma) related to HCV infection will continue to increase in the next 20 years, which is extremely harmful to the health and life of patients and has become ...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/02
Inventor 胡凡王伸勇邵长坤王晓俊胡隽恺
Owner SUZHOU UUGENE BIOPHARMA
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