Synthetic method of Ledipasivir intermediate and product thereof

A synthetic method and intermediate technology, which is applied in the field of synthesis of pharmaceutical intermediates, can solve problems such as no synthetic methods, achieve good application prospects and market potential, be conducive to industrial production, and have mild reaction conditions

Pending Publication Date: 2017-01-04
SHANGHAI TWISUN BIO PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It can be seen that (S)-6-(5-iodo / bromo-1H-imidazol-2-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester is a kind of ledipasvir The key intermediate, so far, there is no report on the synthesis method of this compound

Method used

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  • Synthetic method of Ledipasivir intermediate and product thereof
  • Synthetic method of Ledipasivir intermediate and product thereof
  • Synthetic method of Ledipasivir intermediate and product thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065]

[0066] (1) Synthesis of intermediate product (III)

[0067] Add 48.2 g of compound (II) and 480 mL of tetrahydrofuran into a 1.0 L one-necked bottle, and after cooling down to -4 °C, slowly add 40 mL of borane dimethyl sulfide (10 M ); after the dropwise addition, the temperature was naturally raised to 23°C for 3.5 hours; the sample was sent to LC-MS for detection, and it was found that the starting material was not completely reacted; therefore, the temperature was lowered to 0°C again, and 15 mL of borane dimethyl sulfide was added dropwise (10M), then heated to 24°C and stirred for 1 hour; samples were taken and sent to LC-MS for detection, and the reaction was found to be complete. Cool the reaction solution to -4°C, and slowly add 200 mL of methanol dropwise; after the dropwise addition, stir for 15 minutes, then concentrate to dryness under reduced pressure; then, add 250 mL of dichloromethane and 100 mL of water and stir, the pH of the system = 5~6; then u...

Embodiment 2

[0083]

[0084] (1) Synthesis of intermediate product (III)

[0085] Add 48.2 g of compound (II) and 500 mL of ethyl acetate into a 1.0 L one-necked bottle, and after cooling down to -4 °C, slowly add 40 mL of borane dimethyl sulfide ( 10 M); after the dropwise addition, the temperature was naturally raised to 23°C for 3 hours; the sample was sent to LC-MS for detection, and it was found that the starting material was not completely reacted; therefore, the temperature was lowered to 0°C again, and 15 mL of borane dimethyl was added dropwise thioether (10M), then heated to 25°C and stirred for 1 hour; sampling was sent to LC-MS for detection, and the reaction was found to be complete. Cool the reaction solution to -4°C, and slowly add 200 mL of methanol dropwise; after the dropwise addition, stir for 15 minutes, then concentrate to dryness under reduced pressure; then, add 250 mL of dichloromethane and 100 mL of water and stir. = 5~6; then use saturated sodium bicarbonate s...

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PUM

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Abstract

The invention provides a synthetic method of Ledipasivir intermediate shown in the formula (I) (see the formula in the description), the compound (II) (see the formula in the description) is used as an initial raw material, a carboxyl is reduced into an alcoholic hydroxyl group, the alcoholic hydroxyl group is oxidized into a formyl group, then the modified compound reacts with an alcoholic solution of oxalaldehyde and NH3, a bromination agent or iodination agent is used for halogenating reaction, and the Ledipasivir intermediate is prepared through sodium sulfite reduction. The synthetic method of Ledipasivir intermediate is mild in reaction condition, simple in step, low in cost, environmentally friendly and beneficial for industrial production and has good application prospects and market potential.

Description

technical field [0001] The invention relates to a synthesis method of a pharmaceutical intermediate, in particular to a synthesis method of a ledipasvir intermediate. Background technique [0002] Hepatitis C is a type of viral hepatitis caused by infection with the hepatitis C virus (HCV). According to the statistics of the World Health Organization, the global HCV infection rate is about 3%, with a total of about 180 million people. Currently, as many as 40 million people in China are infected with HCV, and more than 65% of them are infected with genotype 1 hepatitis C. HCV infection mainly includes two types of immune-mediated and HCV direct damage. After infection, the liver will become inflamed and cause liver function decline or even failure. Therefore, the treatment of hepatitis C is a heavy burden for patients and the country. [0003] Harvoni is a compound combination of Gilead's anti-hepatitis C blockbuster product Sofosbuvir and a fixed-dose protease NS5A inhi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04
CPCC07D403/04
Inventor 曾青峰龙双喜叶方国
Owner SHANGHAI TWISUN BIO PHARM
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