Velpatasvir intermediate and preparation method thereof

A technology for intermediates and compounds, applied in the field of Velpatasvir (GS-5816) intermediates, can solve the problems of inability to process preparation, long reaction routes, and expensive raw materials

Inactive Publication Date: 2016-02-03
CONSCI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In order to solve the existing problems of expensive raw materials, long reaction routes, and the inability to technically prepare Velpatasvir (GS-5816), the inventors of the present invention realized it through the following technical scheme: (as shown in route 2) using compound 13 through halogen Compound 12 was prepared on behalf of Compound 12. Compound 11 was prepared by metal-catalyzed coupling reaction between Compound 12 and Compound 14. Compound 11 was prepared by reduction with reducing agent to obtain Compound 10. Compound 9 was prepared by reaction, compound 7 was prepared by electrophilic substitution of compound 8 and halogenated reagent, compound 6 was prepared by esterification of compound 7 and compound 15 under alkaline conditions, and compound 6 was prepared by ring closure in the presence of ammonium acetate Compound 5 is obtained, compound 5 is prepared by oxidative dehydrogenation in the presence of an oxidant to obtain compound 4, compound 4 is prepared by hydrogenation debenzylation in the presence of a metal catalyst to obtain compound 3, compound 3 and compound 9 undergo a nucleophilic substitution reaction to obtain compound 2, compound 2 In the presence of a palladium catalyst, a coupling reaction occurs to prepare compound 1

Method used

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  • Velpatasvir intermediate and preparation method thereof
  • Velpatasvir intermediate and preparation method thereof
  • Velpatasvir intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0012]

[0013] Add 402g of 2-bromobenzoic acid, 500g of nidosuccinimide, 1L of tetrahydrofuran, and 450g of concentrated sulfuric acid into a 3L reaction flask. Control, iodine color development, raw material points disappear, after concentrating tetrahydrofuran, add methanol 1L, sulfuric acid 250g reflux reaction, TLC (hexane: ethyl acetate 1:2) control, after the intermediate reaction is complete, cool down to 0-5 °C , dropwise added 40% sodium hydroxide to neutralize to neutrality, concentrated the solvent methanol, added ethyl acetate to extract the product, dried over anhydrous magnesium sulfate, concentrated to obtain 610 g of 12a product, 89.5%.

example 2

[0015]

[0016] In a 5L reaction flask, under argon protection, add 610g of methyl 2-bromo-5-iodobenzoate (12a), add 3L of toluene, 380g of potassium acetate, 490g of pinacol borate, 2-dicyclohexylphosphorus-2 35g of '-methylbiphenyl, 20g of palladium acetate, heat up and reflux for 1 hour, TLC (hexane: ethyl acetate 1:2) spot on the central control plate, iodine color develops, the raw material point disappears, cool to room temperature, add potassium phosphate 1200g and 715g iodoimidazole 14a, under the protection of argon, heat up to reflux reaction for 2 hours in the control, TLC (hexane: ethyl acetate 1:2) spot plate in the control, iodine color, the raw material point disappears, cool to At room temperature, separate liquids, add 1L of ethyl acetate to the organic phase to dilute, wash twice with 2L of saturated sodium chloride solution, filter the organic phase with diatomaceous earth, add 100g of N-acetyl-L-cysteine, and stir at room temperature for 12 After 2 hours...

example 3

[0018]

[0019] In a 5L reaction flask, under the protection of nitrogen, add 700g of 11a and 3.5L of anhydrous tetrahydrofuran, cool down to 0 to 5°C, slowly add 70g of lithium aluminum hydride in batches, after the addition is completed, naturally warm up to room temperature and react for 6 hours, add decahydrate sulfuric acid for sampling Sodium quenching, TLC (hexane: ethyl acetate 1:4) spot plate central control, iodine color development, raw material point disappears, add 1200g sodium sulfate decahydrate to quench the reaction, pay attention to temperature control, filter, filter cake with 1L tetrahydrofuran After washing, the filtrates were combined and concentrated to obtain 600 g of product 10a with a yield of 93%, which was directly used in the next reaction.

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PUM

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Abstract

The invention relates to a preparation method of a Velpatasvir (GS-5816) intermediate compound which serves as a hepatitis C resisting compound and is as shown in a formula 1, as well as preparation methods of a compound as shown in a formula 3 and a compound as shown in a formula 9. The compound as shown in the formula 3 and the compound as shown in the formula 9 are used for preparing a compound as shown in a formula 2 by nucleophilic substitution under the alkaline conditions; the compound as shown in the formula 2 is used for preparing the compound as shown in the formula 1 by a coupling reaction in the presence of a metal catalyst.

Description

technical field [0001] The invention relates to a Velpatasvir (GS-5816) intermediate and a preparation method thereof. Background technique [0002] Velpatasvir (GS-5816) is a new generation of antiviral drug developed by Gilead Farmoxet Co., Ltd. Its structural formula is as follows. [0003] [0004] Compound 2 is an important intermediate in the synthesis of Velpatasvir (GS-5816), and its synthesis method is currently reported in CN201280004097 (such as route 1): [0005] [0006] Route 1. Velpatasvir (GS-5816) synthetic route [0007] There are the following problems in this method: first, the starting material is expensive, and the route is long resulting in higher cost of the whole route. Second, in the reaction, a two-step palladium-catalyzed coupling reaction is involved, and there are many impurities in dehalogenation. At the same time, two imidazole rings are closed at one time, the temperature is high, there are many side reactions in the reaction, and pur...

Claims

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Application Information

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IPC IPC(8): C07D491/052C07D403/04
CPCC07D491/052C07D403/04
Inventor 牟祥刘念
Owner CONSCI PHARMA
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