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Telaprevir intermediate preparation method

A technology of telaprevir and intermediates, which is applied in the field of preparation of telaprevir intermediates, can solve the problems of toxicity, high requirements on reaction equipment and high production costs, and achieves simple route operation, strong practical value and low production costs. Effect

Inactive Publication Date: 2017-07-07
SHANGHAI DESANO PHARMA INVESTMENT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Although the use of toxic reagents such as carbon disulfide and methyl iodide in the patent EP 0600741 route has been avoided in this route, mercaptan reagents with unpleasant smell and poison are used, and the pollution to the environment is still relatively large; Corrosive boron trifluoride ether has high requirements on reaction equipment and high production costs; at the same time, Raney nickel is used as a desulfurization reagent. Raney nickel is a dangerous reagent, flammable and toxic, and can only be used in small doses; and In this route, two-step reaction yield has only 56%, and yield is still lower, so this synthetic route is still not suitable for industrialized production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Preparation of compound A-2:

[0040]

[0041] Dissolve 4-methyl-5-thiazolyl ethanol A-1 (143.0 g, 1.0 mol) in absolute ethanol (429 mL) solution, then slowly add ethyl bromoacetate (250.5 g, 1.5 mol) dropwise under reflux ), after the dropwise addition, continue to stir and react under reflux conditions for 4 hours, finish the reaction, the reaction solution is concentrated under reduced pressure until no solution is distilled off, and isopropanol (429mL) is added in the residual liquid to carry out recrystallization, suction filtration, filter cake Vacuum drying to constant weight yielded a white to off-white solid product, Compound A-2: 288.5 g, with a molar yield of 93%.

[0042] Tested: MS(ESI,m / z):229.9[M-Br] + ,309.9[M+H] + .

Embodiment 2

[0044] Preparation of Compound A-3:

[0045]

[0046]Compound A-2 (62.0g, 0.20mol) was dissolved in water (62mL), and then at 0-5°C, a DMF solution containing 2-cyclopentenone (24.6g, 0.30mol) was slowly added dropwise, Then triethylamine (26.4g, 0.26mol) was slowly added dropwise. After the dropwise addition, the temperature was raised to room temperature, and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, a little compound A- 3 seed crystals, that is, a large amount of solids precipitated, and then continued to stir at this temperature for 1 hour, and filtered with suction to obtain a light yellow solid (the first part). The filtrate was extracted three times with methyl tert-butyl ether (62mL×3), and the combined Organic phase, the organic phase was washed twice with water (31mL×2), the organic phase was concentrated under reduced pressure until no solution was distilled off, ethyl acetate (43mL) was added to the residue, and...

Embodiment 3

[0050] When the amino protecting group P is tert-butoxycarbonyl, the preparation of compound II is as follows:

[0051]

[0052] Under the protection of argon, compound A-3 (31.1g, 0.10mol) and AIBN (2.46g, 15mmol) were dissolved in toluene (311mL) solution, then the temperature was raised to 70-75°C, and tributyltin hydrogen ( 43.6g, 0.15mol), after the dropwise addition, continue to stir and react at this temperature for 8 hours, end the reaction, add saturated potassium fluoride aqueous solution to quench the reaction, separate liquids, and the toluene organic phase separated is washed three times with 1N hydrochloric acid (31mL×3), combine the acid water phase, add 50wt% sodium hydroxide aqueous solution to the acid water phase to adjust the pH value to 8, then add dichloromethane (93mL), and slowly add Boc 2 O acid anhydride (26.2g, 0.12mol), after the dropwise addition was completed, the temperature was raised to room temperature, and the reaction was stirred at room ...

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Abstract

The invention discloses a telaprevir intermediate preparation method. A telaprevir intermediate is a formula I compound, and a reaction route is as shown in the specification, wherein R is selected from C1-C4 alkyl groups, R1 is selected from hydrogen, C1-C8 alkyl groups, C1-C8 alkoxy groups, C6-C12 aryl groups, alkyl sulfonyl, C6-C12 aryl sulfonyl groups or substituted C6-C12 aryl sulfonyl groups, and P is an amino protection group. The method has advantages of simplicity in operation, safety, freeness of pollution and special requirements on equipment, low production cost, high yield and the like, is suitable for large-scale production and has a high practical value in realization of telaprevir industrialization.

Description

technical field [0001] The invention relates to a preparation method of a telaprevir intermediate, belonging to the technical field of chemical drug synthesis. Background technique [0002] Telaprevir is a chronic hepatitis C treatment drug developed by Vertex Pharmaceutical of the United States. It is an orally effective HCV NS3 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] The telaprevir compound patent WO0218369A2 discloses that the synthesis of telaprevir involves the following three key intermediates [0005] [0006] Among them, for the synthesis of the key intermediate A, the patent EP 0600741 discloses the following route: [0007] [0008]...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52
CPCY02P20/55C07D209/52
Inventor 赵楠华嗣恺
Owner SHANGHAI DESANO PHARMA INVESTMENT
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