Intermediate of telaprevir and preparation method thereof

A compound and solvent technology, applied in the preparation of telaprevir intermediates and the field of intermediates, can solve the problems of high cost, low efficiency, difficult industrialized production and the like, and achieve the effect of high yield

Active Publication Date: 2018-02-09
LIANHE CHEM TECH +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is to provide a method for preparing telaprevir intermediates in order to overcome defects such as low efficiency and high cost in the process of synthesizing telaprevir in the prior art, and it is difficult to truly realize industrialized production. Intermediate

Method used

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  • Intermediate of telaprevir and preparation method thereof
  • Intermediate of telaprevir and preparation method thereof
  • Intermediate of telaprevir and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] In a 500mL three-necked flask, add 118g (1mol) hexanediol, 1200mL dichloromethane and 900mL water, cool the reaction to 0-5°C in an ice-water bath, add 5.9g (50mmol) KBr, 0.16g (1mmol) TEMPO, 35.8g successively (100mmol) Na2HPO4.12H2O, 15.6mg (100mmol) NaH2PO4.2H2O, control the reaction temperature 0-5 ℃, slowly dropwise add 1360mL (2mol) 7.5% NaClO solution, while keeping the reaction temperature below 5 ℃. After 2 hours of reaction, the starting material basically disappeared. The reaction was stopped, the organic phase was directly separated, the aqueous layer was extracted with 400 mL of DCM, the organic phases were combined, washed once with 600 mL of saturated sodium bicarbonate solution, once with 600 mL of water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 105 g of a brown transparent liquid, namely compound 1, with a yield of 92%.

Embodiment 2

[0133]Add 118g (1mol) hexanediol, 1200mL dichloromethane and 900mL water to a 500mL three-neck flask, cool the reaction to 0-5°C in an ice-water bath, add 5.9g (50mmol) KBr, 0.16g (1mmol) TEMPO, 35.8g (100mmol) Na2HPO4.12H2O, 15.6mg (100mmol) NaH2PO4.2H2O, control reaction temperature 0-5 ℃, slowly drop 1360mL (2mol) 7.5% NaClO solution, keep reaction temperature below 5 ℃ simultaneously. After 2 hours of reaction, the starting material basically disappeared. Stop the reaction, separate the organic phase directly, extract the aqueous layer with 400 mL of 2-dichloroethane, combine the organic phases, wash once with 600 mL of saturated sodium bicarbonate solution, once with 600 mL of water, and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 100 g of a brown transparent liquid, namely compound 1, with a yield of 88%.

Embodiment 3

[0135] Add 118g (1mol) hexanediol, 1200mL dichloromethane and 900mL water to a 500mL three-necked flask, cool the reaction to 0-5°C in an ice-water bath, add 5.9g (50mmol) KBr, 0.16g (1mmol) TEMPO, 41g carbonic acid Sodium hydrogen (2.85mol) was used to control the reaction temperature at 0-5°C, and 1360mL (2mol) of 7.5% NaClO solution was slowly added dropwise while keeping the reaction temperature below 5°C. After 2 hours of reaction, the starting material basically disappeared. Stop the reaction, separate the organic phase directly, extract the aqueous layer with 400mL DCM, combine the organic phases, wash once with 600mL saturated sodium bicarbonate solution, once with 600mL water, and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 62 g of a brown transparent liquid, namely compound 1, with a yield of 54%.

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Abstract

The invention discloses an intermediate of telaprevir and a preparation method thereof. The invention specifically discloses a method for preparing a compound shown in the formula 6. The method comprises that a compound shown in the formula 7 or 5 undergoes a reaction under the action of an acid aqueous solution at a temperature of 50-100 DEG C. The preparation method is easy to operate, realizesa low cost, has a high yield, produces a product with high purity and is easy to industrialize.

Description

technical field [0001] The invention relates to a preparation method of a telaprevir intermediate and the intermediate. Background technique [0002] Telaprevir (Telaprevir, VX-950) is a drug that has been used clinically for the treatment of chronic hepatitis C, and its structural formula is as follows. It was on May 23, 2011 that the U.S. Food and Drug Administration (FDA) approved Incivek (the active ingredient telaprevir) in combination with pegylated interferon alfa and ribavirin for the treatment of untreated Patients treated with interferon-based anti-infective drugs, or patients who do not respond well to such treatments. The data showed that Telaprevir, when combined with existing drugs, reduced the virus to below detectable levels in 79% of patients for 24 weeks compared with 48 weeks for existing drugs. [0003] [0004] The preparation of this compound has been reported in the literature. In patent WO2009 / 055467, US2007 / 0087973, (3aR, 6aS)-octahydrocyclopen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52C07C205/44C07C201/12C07C47/21C07C45/29C07C205/29
CPCC07C45/29C07C45/61C07C201/12C07C205/29C07D209/52C07C205/44C07C47/21C07C47/40
Inventor 谢四维邹本立武芳莉李永锋
Owner LIANHE CHEM TECH
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