CN111018870A

CN111018870A - Preparation method of vipatavir intermediate

Info

Publication number: CN111018870A
Application number: CN201911200591.6A
Authority: CN
Inventors: 葛敏; 付明伟; 李亮
Original assignee: Nanjing Zhengji Pharmaceutical Research Co Ltd
Current assignee: Rizhao Zhengji Pharmaceutical Co.,Ltd.
Priority date: 2019-11-29
Filing date: 2019-11-29
Publication date: 2020-04-17
Anticipated expiration: 2039-11-29
Also published as: CN111018870B

Abstract

The invention discloses a preparation method of a wipatavir intermediate, which comprises the steps of dissolving a compound 1 in an organic solvent, adding ammonium acetate and a catalyst, and completing ring closing and oxidation reactions by a one-step method. The method shortens the reaction steps, has simple post-treatment, less three wastes and low production cost, is suitable for industrial production, and has remarkable social and economic benefits.

Description

Preparation method of vipatavir intermediate

Technical Field

The invention relates to the technical field of drug synthesis, and particularly relates to a preparation method of a vipatavir intermediate.

Background

Viral hepatitis c is caused by Hepatitis C Virus (HCV), and hepatitis c virus infection is a serious health problem. The echolucan (Epclusa) is a third-generation oral direct antiviral drug developed by Gilide corporation for treating hepatitis C virus, the cure rate is as high as 99%, and the application range covers the whole genotype. The icolusha is a compound preparation which comprises 400mg of sofosbuvir and 100mg of veapavir tablets, patients receiving treatment so far do not have serious side effects, and the icolusha can be called as a perfect hepatitis C treatment drug.

Patents WO2013173488, WO2013075029, etc. disclose the preparation of vipitavir, all using the following key intermediate 1 in known industrial routes:

after the protecting group of the intermediate 1 is removed, the intermediate is condensed with MOC-D-phenylglycine to obtain the vistasvir. Therefore, the preparation of the intermediate 1 becomes the key for producing the wipatavir. Two main methods are known for the synthesis of intermediate 1, in US20130164260 and US9051340, intermediate 1 is generated by coupling reaction of compound 1 with compound 2 under palladium catalysis.

In the process of preparing the compound 1, the method has long synthesis steps, uses the noble metal palladium as a catalyst for a plurality of times, has complicated post-treatment and high manufacturing cost, and is not suitable for industrial mass production; in US2014309432 and WO2015191437, compound 3 is synthesized by a relatively short procedure, compound 3 is cyclized to give compound 4, and compound 4 is oxidized by an oxidizing agent to give intermediate 1.

Taking a compound 3 as a raw material, carrying out a ring closing reaction at a high temperature by using ammonium acetate, carrying out alkali washing after the reaction is finished, adsorbing tar and other complex post-treatments by using kieselguhr to obtain a compound 4, then oxidizing at a low temperature by using an oxidizing agent to obtain an intermediate 1, similarly carrying out alkali washing after the reaction is finished to remove peroxide impurities, filtering and adsorbing pigments by using the kieselguhr, carrying out complex post-treatment operations such as extraction to obtain a crude product of the intermediate 1, recrystallizing and carrying out to obtain a refined product of the intermediate 1. The method comprises two steps of reaction and two steps of similar post-treatment operation, thereby increasing the working hours and the cost, generating more three wastes and being not suitable for industrial production.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to provide a preparation method of a vitapro intermediate, which solves the problems of multiple process steps, complex post-treatment, multiple three wastes, high cost and unsuitability for industrial production in the prior art.

The technical scheme is as follows: the invention relates to a preparation method of a vipatavir intermediate, which comprises the following synthetic route:

the method comprises the following steps:

dissolving the compound 1 in an organic solvent, adding ammonium acetate and a catalyst, stirring at a reaction temperature, reacting, closing a ring, and oxidizing to generate a target compound intermediate 2.

Further, the molar ratio of the compound 1 to ammonium acetate is 1: 10-1: 20.

Further, the catalyst is palladium carbon, palladium acetate, palladium trifluoroacetate, copper acetate, ferric trichloride or palladium hydroxide.

Further, the mass ratio of the compound 1 to the catalyst is selected from 1: 0.01-1: 0.4.

Further, the organic solvent is one or two of toluene, isopropanol or isobutanol.

Further, the reaction temperature is 80-100 ℃.

Further, the reaction temperature is 90-100 ℃.

The invention has the following beneficial effects:

(1) the method has the advantages of simple operation, shortened reaction steps, reduced post-treatment times and three wastes, reduced production cost, suitability for industrial production and remarkable social and economic benefits;

(2) the innovation is that the two-step reaction is combined into one step by using ammonium acetate and a catalyst and using reaction conditions which are simultaneously suitable for ring closing and oxidation, and an unexpected effect is obtained.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The invention is further described below with reference to examples:

example 1

Adding 50 g (0.0600mol) of compound 1, 500 g of toluene, 50 g of isopropanol, 92.5 g (1.2mol) of ammonium acetate and 20 g of copper acetate into a reaction bottle, heating to 100 ℃, and stirring for reacting for 20 hours; then cooling, adding 200 g of water, 100 g of methanol, 20 g of diatomite and 100.0 g of 20% sodium hydroxide aqueous solution, stirring for 30 minutes, and filtering for layering; the organic layer was washed with water and concentrated to dryness under reduced pressure to obtain crude intermediate 2, and intermediate 2 was recrystallized to obtain 31.4 g of refined product, purity: 96.8%, yield: 66.0 percent.

Example 2

Adding 50 g (0.0600mol) of compound 1, 500 g of toluene, 50 g of isopropanol, 92.5 g (1.2mol) of ammonium acetate and 1 g of palladium acetate into a reaction bottle, heating to 90 ℃, and stirring for reacting for 20 hours; then cooling, adding 200 g of water, 100 g of methanol, 20 g of diatomite and 100.0 g of 20% sodium hydroxide aqueous solution, stirring for 30 minutes, and filtering for layering; washing the organic layer, concentrating under reduced pressure to dryness to obtain a crude intermediate 2, recrystallizing the intermediate 2 to obtain 38.1 g of a refined product with purity: 98.5%, yield: 80.0 percent.

Example 3

Adding 50 g (0.0600mol) of compound 1, 500 g of toluene, 50 g of isopropanol, 92.5 g (1.2mol) of ammonium acetate and 1 g of palladium trifluoroacetate into a reaction bottle, heating to 93 ℃, and stirring for reacting for 20 hours; then cooling, adding 200 g of water, 100 g of methanol, 20 g of diatomite and 100.0 g of 20% sodium hydroxide aqueous solution, stirring for 30 minutes, and filtering for layering; the organic layer was washed with water and concentrated to dryness under reduced pressure to obtain crude intermediate 2, and intermediate 2 was recrystallized to obtain 37.3 g of refined product, purity: 97.6%, yield: 78.4 percent.

Example 4

Adding 50 g (0.0600mol) of compound 1, 500 g of toluene, 50 g of isopropanol, 46.3 g (0.6mol) of ammonium acetate and 1 g of palladium acetate into a reaction bottle, heating to 95 ℃, and stirring for reacting for 20 hours; then cooling, adding 200 g of water, 100 g of methanol, 20 g of diatomite and 100.0 g of 20% sodium hydroxide aqueous solution, stirring for 30 minutes, and filtering for layering; washing the organic layer, concentrating under reduced pressure to dryness to obtain a crude intermediate 2, recrystallizing the intermediate 2 to obtain 34.1 g of a refined product with purity: 97.1%, yield: 71.6 percent.

Example 5

Adding 50 g (0.0600mol) of compound 1, 500 g of toluene, 50 g of isopropanol, 69.5 g (0.9mol) of ammonium acetate and 0.5 g of palladium acetate into a reaction bottle, heating to 80 ℃, and stirring for reacting for 20 hours; then cooling, adding 200 g of water, 100 g of methanol, 20 g of diatomite and 100.0 g of 20% sodium hydroxide aqueous solution, stirring for 30 minutes, and filtering for layering; the organic layer was washed with water and concentrated to dryness under reduced pressure to obtain crude intermediate 2, and intermediate 2 was recrystallized to obtain 29.8 g of refined product, purity: 93.3%, yield: and (4) 64.6%.

Example 6

Adding 50 g (0.0600mol) of compound 1, 500 g of toluene, 50 g of isopropanol, 92.5 g (1.2mol) of ammonium acetate and 10 g of palladium acetate into a reaction bottle, heating to 87 ℃, and stirring for reacting for 20 hours; then cooling, adding 200 g of water, 100 g of methanol, 20 g of diatomite and 100.0 g of 20% sodium hydroxide aqueous solution, stirring for 30 minutes, and filtering for layering; the organic layer was washed with water and concentrated to dryness under reduced pressure to give crude intermediate 2, and intermediate 2 was recrystallized to give 34.5 g of a refined product. Purity: 97.2%, yield: 74.3 percent.

Claims

1. The preparation method of the intermediate of the vipatavir is characterized in that the synthetic route is as follows:

the method comprises the following steps:

2. The preparation method of the vipatavir intermediate as claimed in claim 1, wherein: the molar ratio of the compound 1 to the ammonium acetate is 1: 10-1: 20.

3. The preparation method of the vipatavir intermediate as claimed in claim 1, wherein: the catalyst is palladium carbon, palladium acetate, palladium trifluoroacetate, copper acetate, ferric trichloride or palladium hydroxide.

4. The preparation method of the vipatavir intermediate as claimed in claim 1, wherein: the mass ratio of the compound 1 to the catalyst is 1: 0.01-1: 0.4.

5. The preparation method of the vipatavir intermediate as claimed in claim 1, wherein: the organic solvent is one or two of toluene, isopropanol or isobutanol.

6. The preparation method of the vipatavir intermediate as claimed in claim 1, wherein: the reaction temperature is 80-100 ℃.

7. The preparation method of the vipatavir intermediate as claimed in claim 6, wherein: the reaction temperature is 90-100 ℃.