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Telaprevir and preparation method of telaprevir intermediate

A compound and selected technology, applied in the preparation of organic compounds, carboxylic acid amide preparation, cyanide reaction preparation, etc., can solve problems such as unsuitable for industrial production and long route

Active Publication Date: 2014-02-12
SHANGHAI DESANO PHARMA INVESTMENT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] This method route is long, and total recovery is only 7.5%, is not suitable for industrialized production

Method used

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  • Telaprevir and preparation method of telaprevir intermediate
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preparation example Construction

[0115] The preparation method of the formula IV compound of the present invention or its acid salt, comprises the steps:

[0116] (a) trans-2-hexenoic acid is oxidized to obtain the compound of formula V;

[0117] (b) the compound of formula V is aminated to obtain the compound of formula VI;

[0118] (c) In the presence of a base, the amino group of the compound of formula VI is protected to obtain the compound of formula VII;

[0119] (d) the compound of formula VII and cyclopropylamine are condensed to obtain the compound of formula VIII under the action of a condensing agent;

[0120]

[0121] (e) the compound of formula VIII is oxidized to obtain the compound of formula IX;

[0122] (f) the compound of formula IX removes R2, and obtains the compound of formula IV or its acid salt through resolution;

[0123] Wherein, R2 is selected from amino protecting group, and described amino protecting group is selected from tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), m...

Embodiment 1

[0199] The preparation of embodiment 1 formula IV-1 compound

[0200] 1) Preparation of formula V compound

[0201]

[0202] Add trans-2-hexenoic acid (102.7g, 0.90mol) and 800ml water into the reaction flask, stir to dissolve, add NaHCO 3 (294.0 g, 3.50 mol). 30% hydrogen peroxide aqueous solution (419.3 g, 3.70 mol) was added dropwise at room temperature, and the dropwise addition was completed in about 2-3 hours. The reaction was continued for 24-30 hours. TLC detected that the reaction of the raw materials was basically complete, and 1 L of ethyl acetate was added and stirred for 10 minutes. The layers were separated, the organic phase was washed twice with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 100.6 g of the compound of formula V with a yield of 85.9%. MS (ESI) m / z: (M+H) = 131.1.

[0203] 2) Preparation of formula VI compound

[0204]

[0205] Add the compound of formula V (100.6g, 0.77mmol) and 30% am...

Embodiment 2

[0219] The preparation of embodiment 2 formula III-2 compound

[0220]

[0221]The compound of formula II-2 (56.6g, 0.20mol) was suspended in 600ml of ethanol, and a 20wt% aqueous solution made of 12.0g of sodium hydroxide was added dropwise, and the mixture was stirred at room temperature for 2 hours. TLC detected that the reaction of raw materials was complete, and neutralized to neutrality with 3N hydrochloric acid. Concentrate to remove part of the solvent, add 500ml ethyl acetate to the residue, and stir well. The layers were separated, and the organic layer was washed once with 200 ml of saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain 48.5 g of the compound of formula III-2, with a yield of 95.0%. MS (ESI) m / z: (M+H) = 256.3.

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Abstract

The invention discloses telaprevir and a preparation method of a telaprevir intermediate. The intermediate disclosed by the invention is a compound of formula I or an acid salt thereof and is prepared from a compound of formula III and a compound of formula IV in condensation; the intermediate is further reacted with a compound of formula A to prepare telaprevir. In the formula I, R1 is defined as specification. According to the method disclosed by the invention, the raw material is simple and easy to obtain, the reaction condition is mild, the final step of oxidation reaction in the prior art is avoided, the total yield is greatly improved, and the method is suitable for industrial application.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of telaprevir and an intermediate thereof. Background technique [0002] Telaprevir (Telaprevir, VX-950), developed by Vertex Pharmaceutical Company of the United States, is a reversible protease inhibitor. The chemical name is: (1S,3aR,6aS)-2-((S)-2((S)-2-cyclohexyl-2-(pyrazinamide-2-hydroxyamide)acetamido)-3,3 -Dimethylbutyryl)-N-((S)-1-(cyclopropylamino)-1,2-dicarbonyl-3-propyl)octahydrocyclopenta[c]pyrrole-1-carboxamide, The structural formula is as follows: [0003] [0004] Telaprevir combined with pegylated α-interferon and ribavirin can effectively inhibit the replication of HVC virus for the treatment of chronic hepatitis C. [0005] There are many methods for preparing telaprevir disclosed at present, mainly including the following synthetic routes: [0006] Route 1: WO0218369A2 of Eli Lilly Company of the United States dis...

Claims

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Application Information

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IPC IPC(8): C07D209/52C07K7/06C07C237/04C07C231/12
CPCY02P20/55C07D209/52C07C227/08C07C231/12C07C269/04C07C269/06C07C2601/02C07D303/48C07K7/02C07C237/04C07C271/22C07C229/22
Inventor 李金亮赵楠葛瑞娟
Owner SHANGHAI DESANO PHARMA INVESTMENT
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