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Preparation method of anti-new crown drug Paxlovid intermediate

A technology for intermediates and drugs, applied in the field of preparation of intermediates of anti-new crown drug Paxlovid, can solve the problems of cumbersome synthesis steps, high comprehensive cost, large amount of three wastes, etc., and achieves high operability, low cost, and reduced amount of three wastes. Effect

Active Publication Date: 2022-03-04
ZHEJIANG LEPU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In summary, the current synthesis steps of compound I are cumbersome, with a large amount of three wastes and high overall cost

Method used

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  • Preparation method of anti-new crown drug Paxlovid intermediate
  • Preparation method of anti-new crown drug Paxlovid intermediate
  • Preparation method of anti-new crown drug Paxlovid intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Preparation of Compound IV

[0039] Add 981g of compound II, 450g of triethylamine and 3L of dichloromethane into a 5L round bottom flask, add 801g of p-toluenesulfonyl chloride under ice cooling, stir until compound II disappears, add water to quench, extract and separate the liquids, and the water phase is again washed with 2L dichloromethane Chloromethane extraction once. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure.

[0040] The obtained p-toluenesulfonate intermediate was dissolved in 4L of dioxane solution, 672g of potassium tert-butoxide was added under ice-cooling, and the temperature was raised to reflux until the intermediate disappeared. 1 L of 10% ammonium chloride aqueous solution was added to quench, dioxane was removed under reduced pressure, and the aqueous phase was extracted twice with 2 L of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sul...

Embodiment 2

[0045] Preparation of Compound IV

[0046] Add 981g of compound II, 450g of triethylamine and 3L of dichloromethane into a 5L round-bottomed flask, add 930g of p-nitrobenzenesulfonyl chloride under ice cooling, stir until compound II disappears, add water to quench, extract and separate, and use the water phase again 2L dichloromethane extracted once. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure.

[0047]The obtained p-nitrobenzenesulfonate intermediate was dissolved in 4L of dioxane solution, 576g of sodium tert-butoxide was added under ice-cooling, and the temperature was raised to reflux until the intermediate disappeared. 1 L of 10% ammonium chloride aqueous solution was added to quench, dioxane was removed under reduced pressure, and the aqueous phase was extracted twice with 2 L of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, and concentrated to dryn...

Embodiment 3

[0049] Preparation of Compound IV

[0050] Add 981g of compound II, 450g of triethylamine and 3L of dichloromethane into a 5L round-bottomed flask, add 481g of methanesulfonyl chloride under ice bath, stir until compound II disappears, add water to quench, extract and separate the liquids, and use 2L of dichloromethane again for the water phase methane extraction once. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure.

[0051] The obtained mesylate intermediate was dissolved in 4L of toluene solution, 1220g 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added under ice cooling, and the temperature was raised to reflux to the intermediate disappear. Add 1 L of 10% hydrochloric acid aqueous solution to quench, separate liquid extraction, and extract the aqueous phase with 2 L of toluene once. The combined organic phases were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced...

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Abstract

The invention discloses a preparation method of an intermediate of an anti-new crown drug Paxlovid. According to the preparation method, cheap and easily available N-Boc-trans-4-hydroxy-L-proline methyl ester (compound II) is taken as an initial raw material, the Paxlovid intermediate can be obtained through a plurality of steps of reactions, and the structural formula of the anti-new crown drug Paxlovid intermediate is as shown in the formula I. The method has the advantages of simple process, low production cost, easiness in industrial production and the like.

Description

technical field [0001] The invention relates to a preparation method of an anti-new crown drug Paxlovid intermediate, in particular to a (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3,1,0]hexyl-2 - Process for the preparation of methyl carboxylate hydrochloride (CAS: 565456-77-1). The invention belongs to the field of pharmaceutical synthesis chemistry. Background technique [0002] Paxlovid is an anti-new crown drug developed by Pfizer. Its active ingredients are composed of small molecule compounds PF07321332 and ritonavir. On November 5, 2021, Pfizer announced the results of the Phase II / III clinical study of Paxlovid, showing that within three days of symptom onset, Paxlovid can reduce the risk of COVID-19-related hospitalization or death from any cause by 89%. The FDA is expected to approve the Emergency Use Authorization (EUA) for Paxlovid by the end of 2021. [0003] The chemical structure of PF07321332 is shown below: [0004] [0005] Among them, (1R,2S,5S)-6,6-dimet...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52
CPCC07D209/52Y02P20/55
Inventor 陈洪斌林义
Owner ZHEJIANG LEPU PHARMA CO LTD
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