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Preparation method of Molnupiravir

A compound and reaction technology, applied in the field of medicine, can solve the problems of the product monabiravir, which is difficult to improve the quality, unfavorable for product separation and purification, and the acetonide protecting group is easy to fall off. friendly effect

Pending Publication Date: 2022-01-04
厦门蔚嘉制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still some problems in this process. First, the sulfate intermediate is unstable, and the acetonylidene protecting group is easy to fall off; secondly, the organic base DBU used is expensive, and the efficiency of monoacylation is not high.
Finally, the last step of the route uses formic acid deprotection, which is not conducive to the separation and purification of the product, and the quality of the product monabigravir is difficult to improve

Method used

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  • Preparation method of Molnupiravir
  • Preparation method of Molnupiravir
  • Preparation method of Molnupiravir

Examples

Experimental program
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Effect test

Embodiment 1

[0056] 1.1 Preparation of compound 4:

[0057] Reaction A: Add compound 1 (cytidine) (5g, 20mmol), acetone (80mL) and 2,2-dimethoxypropane (10mL) in a reaction flask, add concentrated sulfuric acid (1mL, 20mmol) dropwise at 0°C ), rose to room temperature and reacted for about 10 hours until compound 1 was completely reacted. 20% aqueous sodium hydroxide solution was added dropwise at 0°C to adjust the pH of the system to 8-10. Acetone was distilled under reduced pressure to no distillate. Acetonitrile (50 mL) was added to the residue, heated to above 60° C., stirred for 30 minutes, and filtered. Acetonitrile (20 mL) was added to the filter cake, heated to 60° C. and stirred for 30 minutes, and filtered to obtain a filtrate. The filtrates were combined, dried over anhydrous sodium sulfate, and filtered to obtain an acetonitrile solution of compound 2, which was directly used in the next reaction.

[0058] Reaction B: Triethylamine (6.1 g, 60 mmol) was added to the acetonit...

Embodiment 2

[0063] 2.1 Preparation of Compound 4:

[0064] Reaction A: At room temperature, add cytidine (150kg, 1.0eq), 2,2-dimethoxypropane (256kg, 4.0eq) and acetone (1950kg) into the reactor, and stir evenly. Cool down to below 0°C, and add concentrated sulfuric acid dropwise. Raise the temperature to room temperature and react for 10 hours until the cytidine reaction is complete, then cool down to 0°C, and add triethylamine (about 130kg) dropwise until the system pH=8-10. Concentrate under reduced pressure until there is no distillate, add acetonitrile (1500kg) and stir evenly to obtain an acetonitrile solution of compound 2, which is directly used in the next reaction.

[0065] Reaction B: At room temperature, add triethylamine (187kg, 3.0eq) and 4-dimethylaminopyridine (7.5kg, 0.1eq) to the acetonitrile solution of compound 2 in the previous step, and stir well. The temperature was lowered to 0°C, and isobutyryl chloride (164kg, 2.5eq) was added dropwise. Keep warm at 5°C for ab...

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Abstract

The invention discloses a preparation method of Molnupiravir, and relates to the technical field of medicines. The preparation method comprises the following steps of: taking cytidine (1) as a starting material, and carrying out hydroxyl protection to obtain a compound 2; carrying out acylation on a compound 2 through isobutyryl chloride to obtain a diacylation intermediate 3; carrying out regioselective deacylation and hydroxyamination cascade reaction on the compound 3 to obtain a compound 4; and carrying out deprotection and refining on the compound 4 to obtain the finished product Molnupiravir (5). The process route is as follows.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of an antiviral drug Molnupiravir. Background technique [0002] Monabiravir (Molnupiravir) (code name MK-4482 or EIDD-2801) is an oral medication of a small molecule cytidine antiviral drug developed by Merck & Co. of the United States. The drug is a SARS-CoV2 polymerase inhibitor. Studies have confirmed that in animal experiments, monabigravir used to treat ferrets infected with SARS-CoV-2 can effectively inhibit the virus, and within 24 hours Stop the growth of the new coronavirus, thereby inhibiting the spread of the virus. Therefore, the research team believes that if monabigravir can achieve similar effects in human trials, then patients with new crowns treated with this oral drug can become non-infectious within a day. At present, Merck has started clinical trials to treat patients with the new coronavirus. Once successful, the drug will have huge m...

Claims

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Application Information

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IPC IPC(8): C07H19/067C07H1/00
CPCC07H19/067C07H1/00Y02P20/55
Inventor 侯鹏翼涂福荣
Owner 厦门蔚嘉制药有限公司
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