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The preparation method of psi-7977 intermediate compound

A compound, the technology of tin tetrachloride, applied in the field of medicine, can solve the problems such as the proportion of patients' antiviral response to be increased, unfavorable large-scale production, inability to cure hepatitis C, etc., and achieve the effects of easy post-processing, stable properties and short reaction period

Active Publication Date: 2017-05-10
QILU PHARMA HAINAN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the combination of α-interferon and ribavirin has a certain effect on the treatment of hepatitis C and saved the lives of many patients with hepatitis C virus, the proportion of patients with sustained antiviral response needs to be improved, which cannot meet the clinical needs
[0003] In May 2011, the U.S. Food and Drug Administration (FDA) successively approved Telaprevir (Telaprevir) and Boceprevir (Boceprevir) as drugs for the treatment of hepatitis C. The proportion of viral response has increased from 40% to 50% of α-interferon / ribavirin to 60% to 70%, but still cannot cure hepatitis C
[0009] Currently widely used is route 2 (WO2006 / 031725, WO2008 / 045419 and J.Med.Chem.2010, 53, 7202–7218), which is relatively short, but the reaction time is long, the reaction temperature is high, and the conditions are relatively harsh , the process is cumbersome, not conducive to large-scale production

Method used

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  • The preparation method of psi-7977 intermediate compound
  • The preparation method of psi-7977 intermediate compound
  • The preparation method of psi-7977 intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1, Preparation of 2,4-bis(trimethylsiloxy)pyrimidine

[0042] Under the protection of nitrogen, add 3.0g uracil (SM1) to 30ml hexamethyldisilazide (HMDS), then add 70mg ammonium sulfate, heat to reflux until the solution is dissolved (about 1 hour), and then keep warm and react for 1 hour. Then, it was cooled to 70°C, and unreacted hexamethyldisilamine was evaporated under reduced pressure to obtain 6.7 g of the title compound, which was directly used in the next step without purification.

Embodiment 2

[0043] Example 2. Preparation of 2,4-bis(trimethylsiloxy)pyrimidine

[0044] Under the protection of nitrogen, add 30g of uracil (SM1) to 250ml of hexamethyldisilazide (HMDS), then add 0.9g of ammonium sulfate, and heat to reflux until the solution is dissolved (about 1 hour). After the solution is clear, the reaction is kept for 1 hour. Then, it was cooled to 70°C, and the unreacted hexamethyldisilamine was evaporated under reduced pressure to obtain 67.8 g of the title compound, which was directly used in the next step without purification.

Embodiment 3

[0045] Example 3. Preparation of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine-3',5'-dibenzoate (Compound II)

[0046]

[0047] Under the protection of nitrogen, 1g compound III-1 was dissolved in 10ml chlorobenzene, cooled to 0℃, 0.6ml tin tetrachloride was added, and then 1g compound IV in chlorobenzene (10ml) was added dropwise. After the addition, The reaction was heated to 70°C for 20 hours. TLC showed that the reaction of compound III-1 was complete. After cooling to room temperature, 50ml of dichloromethane was added, and sodium bicarbonate (10g) and diatomaceous earth (5g) in dichloromethane were added to the solution. (20ml) suspension. Slowly add 20 ml of water to quench the reaction, then stir at room temperature for 30 min, filter, and wash the filter cake with dichloromethane and dry to obtain 0.77 g of off-white solid with a yield of 87.7%.

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Abstract

The invention belongs to the technical field of a medicine, and in particular relates to a preparation method for synthesizing a PSI-7977 intermediate compound. The method disclosed by the invention has the advantages of being simple to operate, mild in reaction condition, easy in post-treatment, short in reaction cycle, high in yield, and safe and controllable, and the prepared intermediate compound I has the advantages of high optical purity and stable nature; and the preparation method is more suitable for industrial scaled production.

Description

Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a preparation method for synthesizing an intermediate compound of the anti-hepatitis C drug sofosbuvir (PSI-7977). Background technique [0002] Hepatitis C virus (HCV) infection is a serious global health problem. According to estimates by the World Health Organization, there are approximately 170 million people (about 3% of the global population) who are chronically infected and are at risk of developing liver cirrhosis or hepatocellular carcinoma. From the discovery of hepatitis C virus in 1989 to May 2011, there was no therapeutic drug for hepatitis C in the world. Clinically, only alpha-interferon and ribavirin with broad-spectrum antiviral effects can be used to treat C Hepatitis. Although the combination of alpha-interferon and ribavirin has a certain curative effect on the treatment of hepatitis C, saving the lives of many patients with hepatitis C virus, the pro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/073C07H1/00
CPCY02P20/55
Inventor 李燕张占涛刘禄娟刘永康林栋范传文
Owner QILU PHARMA HAINAN