Synthesis method of Velpatasvir intermediate A

A synthetic method, the technology of velpatasvir, applied in the field of medicine, can solve the problems of restricting industrial application, low purity of velpatasvir intermediate A, high synthesis cost of velpatasvir intermediate A, and achieve good application prospects and Market potential, beneficial to industrial production, mild reaction conditions

Inactive Publication Date: 2017-11-03
SHANGHAI TWISUN BIO PHARM
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] There are many disadvantages in the above method: 1) The two-step reaction of compound E and compound G involves noble metal catalyzed cyclization reaction and Suzuki coupling reaction, and the market unit price of vinyl trifluoroborate is high. Therefore, the velpatasvir intermediate A 2) the controllability deviation of the last step TEMPO oxidation reaction, the purity of velpatasvir intermediate A is lower (about 92%), and due to the poor solubility of velpatasvir intermediate A in conventional solvents , it is difficult to carry out further purification, so it is difficult to obtain high-quality products
[0009] Another example is that the patent US2015 / 0361073 also reports a synthetic method using 2-bromo-5-iodobenzyl alcohol (compound I) as a raw material, but in this method, the palladium-catalyzed ring-closing reaction yield of compound N is low, thereby This restricts the industrial application of this method

Method used

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  • Synthesis method of Velpatasvir intermediate A
  • Synthesis method of Velpatasvir intermediate A
  • Synthesis method of Velpatasvir intermediate A

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Under nitrogen protection, 40.0 g of compound 4, 28.0 g of triethylamine and 400.0 mL of dichloromethane were added to a 1 L reaction flask. After cooling down to 0°C, 15.0 g of acetyl chloride was added dropwise. After the dropwise addition, the reaction solution was raised to room temperature, and stirred for 2 hours.

[0074] TLC detected that the reaction was complete, and 200.0 mL of water was added to the reaction bottle, and after stirring for 0.5 hour, liquid separation was carried out to obtain an organic phase. The organic phase was washed once with 200 mL of saturated brine, and concentrated to dryness at 50°C under reduced pressure to obtain 44.0 g of compound 5 as a pale yellow oil with a purity of 95.2% and a yield of 92.9%.

[0075] MS calcd for C 11 h 11 BrO 3 Na(M+Na) + :294.1, found: 294.1.

Embodiment 2

[0077] Under nitrogen protection, 40.0 g of compound 4, 28.0 g of triethylamine and 400.0 mL of dichloromethane were added to a 1 L reaction flask. After cooling down to 0°C, 15.0 g of acetyl chloride was added dropwise. After the dropwise addition was completed, the reaction solution was raised to 40° C. and stirred for 30 minutes.

[0078] TLC detected that the reaction was complete, and 200.0 mL of water was added to the reaction bottle, and after stirring for 0.5 hour, liquid separation was carried out to obtain an organic phase. The organic phase was washed once with 200 mL of saturated brine, and concentrated to dryness at 50°C under reduced pressure to obtain 40.7 g of compound 5 as a pale yellow oil with a purity of 91.4% and a yield of 86.0%.

[0079] MS calcd for C 11 h 11 BrO 3 Na(M+Na) + :294.1, found: 294.1.

[0080] Synthesis of compound I2

Embodiment 3

[0082] Under nitrogen protection, 22.0g of compound 5, 29.0g of biboronic acid pinacol ester, 13.0g of potassium acetate, 3.5g of Pd(dppf)Cl were sequentially added into a 500mL reaction flask 2. CH 2 Cl 2 and 220.0 mL of 1,4-dioxane, replaced with nitrogen three times, and heated to 85°C for 6 hours.

[0083] After the central control reaction is completed, add 300.0mL water and 500.0mL methyl tert-butyl ether to the reaction bottle, stir and extract, then take the organic phase, and then extract the water phase with 200.0mL methyl tert-butyl ether once. Then, the organic phases were combined, washed once with 200.0 mL of saturated brine, and concentrated to dryness under reduced pressure at 55°C. Finally, it was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 5:1), concentrated and dried to obtain 24.1 g of compound I2 as a yellow oil, with a purity of 94.6% and a yield of 93.0%.

[0084] 1H-NMR (400MHz, CDCl 3 )(400MHz,)δ7.96–7.91(m),7....

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Abstract

The embodiment of the invention discloses a synthesis method of a Velpatasvir intermediate A, and further provides three novel compounds for synthesis of the intermediate A: a compound I, a compound I1 and a compound I2. The method for the synthesis of the Velpatasvir intermediate A has the characteristics of low cost, environment friendliness and suitability for industrialized production.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for synthesizing a velpatasvir intermediate. Background technique [0002] Hepatitis C virus (HCV) is a hepatitis virus that is widespread worldwide. It is estimated that about 185 million people in the world are infected with chronic hepatitis C virus. At present, there are about 3.5 million new cases in the world every year, and about 350,000 patients die from hepatitis C every year. The mortality rate related to HCV infection will continue to increase in the next 20 years , has caused great harm to the health and life of patients, and has become a serious social and public health problem. [0003] Fortunately, due to the application of a variety of innovative drugs, breakthroughs have been made in the treatment of hepatitis C in recent years. The most prominent is the successful launch of Sofosbuvir in 2013, which has changed the basic principles of hepatitis C trea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C49/83C07C45/64C07C67/293C07C69/157C07F5/02C07D311/78
CPCC07C45/64C07C49/83C07C67/14C07C67/293C07C69/157C07D311/78C07F5/025
Inventor 叶方国王其安徐佳发
Owner SHANGHAI TWISUN BIO PHARM
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