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Preparation method of ledipasvir and derivative thereof, and intermediate compound for preparing the ledipasvir

A technology of compound and coupling reaction, which is applied in the preparation of the compound of formula 1, the preparation of intermediate compounds of ledipasvir, the preparation of ledipasvir and its derivatives, and can solve the problem of low yield and increased discharge of three wastes, etc. question

Active Publication Date: 2015-08-12
SHANGHAI FOREFRONT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] This method is more efficient than the method in US20100310512, but it still needs to prepare Boc-protected compound 24 and compound 27, and remove the protecting group Boc by hydrolysis, the yield is still not high, and it will also increase the discharge of three wastes

Method used

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  • Preparation method of ledipasvir and derivative thereof, and intermediate compound for preparing the ledipasvir
  • Preparation method of ledipasvir and derivative thereof, and intermediate compound for preparing the ledipasvir
  • Preparation method of ledipasvir and derivative thereof, and intermediate compound for preparing the ledipasvir

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preparation example Construction

[0160] The present invention provides various preparation methods of ledipasvir, and the preparation methods include one or more of the following features:

[0161] 1) The reaction temperature is 0-100°C, preferably 20-90°C;

[0162] 2) The reaction time is 0.1-48h, preferably 2-20h;

[0163] 3) The reaction is carried out in an inert solvent.

[0164] The preferred preparation method of the present invention is shown in Scheme 1-3.

[0165] Route 1

[0166]

[0167] In this method, the Moc-val group is firstly introduced into compound 11 without Boc protection, which can significantly improve the synthesis efficiency and reduce the emission of three wastes.

[0168] route 2

[0169]

[0170] In this method, compound 11 and compound 3-Moc are first introduced into Moc-Val, which eliminates the protection and deprotection reactions, greatly reduces the synthesis steps, improves the synthesis efficiency, significantly reduces the production cycle, significantly reduces...

Embodiment 1

[0178] Embodiment 1: the synthesis of compound 12-Br-Cbz

[0179]

[0180] Add compound 10-Br-Cl (2.03g, 5.675mmol), compound 21 (1.72g, 6.243mmol), DIPEA (0.81g, 6.243mmol) and acetonitrile (40mL) in the there-necked flask, heat to 70°C, stir for 5 hour, then cooled to room temperature, distilled off the solvent, then added ethyl acetate (100mL), washed once with dilute hydrochloric acid (0.01M / L, 200mL), dried the organic phase with anhydrous sodium sulfate, and distilled off the solvent to obtain the product ( 3.384 g, yield 100%).

Embodiment 2

[0181]Embodiment 2: the synthesis of compound 2-Br-Cbz

[0182]

[0183] Add compound 12-Br-Cbz (3.384g, 5.675mmol), ammonium acetate (2.187g, 28.375mmol), ethylene glycol monomethyl ether (4mL) and toluene (70mL) in a three-necked flask, heat to 90°C, stir 5 hours, then cooled to room temperature, then added ethyl acetate (100mL), washed twice with brine (200mL), the organic phase was dried over anhydrous sodium sulfate, and the product (3.2g, yield 98% ).

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Abstract

The invention relates to a preparation method of ledipasvir and a derivative thereof, and an intermediate compound for preparing the ledipasvir, and in particular, the invention discloses a preparation method of a compound represented as the formula I, and a series of new preparation methods of the ledipasvir. The methods are simple and high-effective and are excellent in application prospect.

Description

technical field [0001] The invention belongs to the field of medicine synthesis. Specifically, the present invention relates to a preparation method of ledipasvir and its derivatives and an intermediate compound used for the preparation of ledipasvir; more specifically, it relates to a preparation method of the compound of formula 1. Background technique [0002] Ledipasvir (LDV, whose structure is shown in Formula 1-LDV) is a hepatitis C drug developed by Gilead. The FDA has granted the LDV / SOF (Sofosbuvir) fixed-dose combination drug breakthrough therapy designation. This combination therapy is expected to be available in a short period of time. Patients with genotype 1 HCV were cured within 8 weeks without injection of interferon or combination with ribavirin. [0003] [0004] US20100310512 reports that the synthetic route of ledipasvir is as follows: [0005] [0006] The two side chains of compound 1-LDV are both Moc-Val, but Cbz- is first introduced into compo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14
CPCC07D403/14A61P31/14
Inventor 黄成军富刚傅绍军魏哲文李巍张锡璇
Owner SHANGHAI FOREFRONT PHARMA CO LTD
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