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Preparation method of mupiravir

A technology of temperature control and compounding, which is applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve the problems of lack of purity, high cost, low yield, etc., and achieve simple operation and low cost , the effect of high yield

Active Publication Date: 2022-01-21
SHANDONG CHENGCHUANG BLUE OCEAN PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Among them, the multi-step intermediates of route one are all oily substances, which require column chromatography purification, resulting in difficulty in purification, and low yield and high cost. Conducive to industrial production;
[0010] The advantage of route two compared to route one is that the column chromatography purification step is removed, but in the preparation of intermediate 3, aqueous hydroxylamine solution is used, which is A kind of explosive dangerous compound, there is great danger in industrial production; The impurity content of the product produced by the process of route 2 is high, single impurity exceeds 0.1%, product purity is relatively poor, yield is low, cost is high, cannot obtain Products whose purity meets the requirements of raw materials; route 2 requires the use of organic solvents during refining, which is more polluting to the environment. In summary, route 2 is also not conducive to industrial production

Method used

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  • Preparation method of mupiravir
  • Preparation method of mupiravir
  • Preparation method of mupiravir

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] The present embodiment provides a kind of preparation method of mopiravir, comprising the following steps:

[0056] (1) Add the compound of formula (I) (200g, 0.47mol) in ethanol (600g), stir and dissolve, add purified water (400g), then add anhydrous sodium acetate (38.5g, 0.47mol) and hydroxylamine hydrochloride ( 65.3g, 0.94mol), heat up to 70-80°C, react for 17h, cool down to 40-45°C, add purified water (1000g), distill ethanol out under reduced pressure, cool down to 20-30°C, crystallize for 2h, filter, The filter cake was washed with a small amount of water and dried at a temperature of 50-60°C to obtain the compound of formula (II) (165g) with a purity of 99.32% and a molar yield of 94.6%;

[0057](2) The compound of formula (II) (165g, 0.45mol) was added in chloroform (825g), cooled to -5~0°C, and concentrated hydrochloric acid (67.6g, 0.67mol) was added dropwise. React for 2 hours at a temperature of 0-5°C. After the reaction is complete, add sodium carbonate ...

Embodiment 2

[0059] The present embodiment provides a kind of preparation method of mopiravir, comprising the following steps:

[0060] (1) Add the compound of formula (I) (2000g, 4.7mol) into isopropanol (6kg), stir to dissolve, add purified water (4kg), then add anhydrous sodium acetate (385g, 4.7mol) and hydroxylamine sulfate (1929g, 11.75mol), heat up to 70-80°C, react for 20h, cool down to 40-45°C, add purified water (10kg), distill isopropanol under reduced pressure, cool down to 20-30°C, crystallize for 2h, Filter, wash the filter cake with a small amount of water, and dry at a temperature of 50-60°C to obtain the compound of formula (II) (1600g), with a purity of 99.09% and a molar yield of 91.72%;

[0061] (2) The compound of formula (II) (1600g, 4.3mol) was added in dichloromethane (8kg), cooled to -5~0°C, and concentrated hydrochloric acid (438g, 4.3mol) was added dropwise. Reaction under the condition of 0~5℃ for 2h, after the reaction is completed, add ammonia water dropwise,...

Embodiment 3

[0063] The present embodiment provides a kind of preparation method of mopiravir, comprising the following steps:

[0064] (1) Add the compound of formula (I) (100kg, 235mol) in isopropanol (300kg), stir and dissolve, add purified water (200kg), then add anhydrous sodium acetate (19.3g, 235mol) and hydroxylamine sulfate ( 77.2kg, 470mol), heat up to 70-80°C, react for 20h, cool down to 40-45°C, add purified water (500kg), distill isopropanol under reduced pressure, cool down to 20-30°C, crystallize for 2h, filter , the filter cake was washed with a small amount of water, and dried at a temperature of 50-60°C to obtain a compound of formula (II) (83.5kg), with a purity greater than 99.20% and a molar yield of 95.73%;

[0065] (2) The compound of formula (II) (80kg, 216mol) is added in dichloromethane (400kg), cooled to -5~0°C, and concentrated hydrochloric acid (32.8kg, 324mol) is added dropwise. React at 0-5°C for 3 hours. After the reaction is complete, add ammonia water dro...

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Abstract

The invention discloses a preparation method of mupiravir, and belongs to the technical field of medicine preparation. The preparation method comprises the following steps: (1) adding a compound shown as a formula (I) into an alcohol solvent, adding water, sodium acetate and hydroxylamine sulfate, or adding water, sodium acetate and hydroxylamine hydrochloride, reacting, and performing post-treatment to obtain a compound shown as a formula (II); and (2) adding the compound of the formula (II) obtained in the step (1) into dichloromethane or trichloromethane, adding hydrochloric acid, reacting, and carrying out post-treatment and refining to obtain mupiravir. The preparation method is easy to operate, safe, environmentally friendly, low in cost and beneficial to large-scale production of products; the prepared product has high yield, and the purity reaches 99.8% or above; and the obtained product is suitable for production of bulk drugs.

Description

technical field [0001] The application relates to a preparation method of mopiravir, which belongs to the technical field of medicine preparation. Background technique [0002] Mopiravir (Molnupiravir), chemical name: 4-oxime-5′-(2-methylpropionyl)uridine (EIDD-2801, MK-4482), is an oral bioactive ribonucleoside analog β-d The prodrug of -N4-hydroxycytidine has broad-spectrum antiviral activity, and because it is an oral drug, it is convenient to use, and can be used as a preventive drug, as well as for outpatients and inpatients. Mopiravir has been shown to be effective against the pathogens of SARS-CoV-2, MERS-CoV, SARS-CoV and COVID-19 on multiple occasions. Its structural formula is: [0003] [0004] At present, there are two main synthetic routes for the preparation of mopiravir, namely the synthetic route 1 of the compound reported in the patent publication No. WO2019113463 and WO2019173602, and the synthetic route 2 reported in the patent publication No. CN11255...

Claims

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Application Information

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IPC IPC(8): C07H19/067C07H1/00C07H1/06
CPCC07H19/067C07H1/00C07H1/06Y02A50/30
Inventor 刘彬彬吕志波樊浩王丽曹燕朱敬轩杨川
Owner SHANDONG CHENGCHUANG BLUE OCEAN PHARM TECH CO LTD
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