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Synthesis method of oseltamivir intermediate

A technology of oseltamivir and a synthesis method, which is applied in the field of synthesis of oseltamivir intermediates, can solve the problems of long route, unsuitability for scale-up production, low yield and the like, shorten the reaction route, improve drug safety, The effect of high safety

Pending Publication Date: 2022-07-01
中润药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The current industrial production route of compound 2 is generally obtained by protecting compound 1 shown in the following structural formula 1 through methanesulfonyl protection, ring opening, basic ring closure, tert-butyl ring opening, sulfonyl chloride ring closure, and diallylamine ring opening. , the production route needs to go through six steps of reaction, the route is long, the yield is low (the overall yield is less than 20%), and sulfuryl chloride is used for cyclization, and impurities with genotoxicity warning structures are introduced
There is a related technology to prepare compound 2 by nucleophilic substitution of azide compound, but azide compound is a first-class explosive hazard compound and is not suitable for scale-up production

Method used

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  • Synthesis method of oseltamivir intermediate
  • Synthesis method of oseltamivir intermediate
  • Synthesis method of oseltamivir intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0053] A kind of synthetic method of oseltamivir intermediate, its synthetic route is:

[0054]

[0055] The specific synthetic method comprises the following steps:

[0056](1) in 100L reactor, add 10kg compound 1 and 30L methylene chloride, drum nitrogen protection, about -10 ℃ of refrigerant temperature control, add 12kg trifluoromethanesulfonic anhydride under stirring, keep low temperature and slowly drip triethylamine 6kg, Incubate and stir for about 2 hours, wash with water after the reaction, and concentrate at room temperature until no liquid flows out to obtain a viscous liquid reaction mixture. To the reaction mixture was added 5 kg of diallylamine, 30 L of toluene with stirring, and the temperature was raised to 80°C. Start timing when the temperature reaches 80°C and stir for about 8 hours. After the reaction was completed, the temperature was cooled to below 20° C., 20 L of toluene was added and stirred for 30 minutes, 30 L of 5% citric acid aqueous solution...

Embodiment 2

[0066] A kind of synthetic method of oseltamivir intermediate, comprises the steps:

[0067] (1) Inject 10kg of compound 1 and 40L of methylene chloride into a 100L reaction kettle, drum nitrogen protection, and control the temperature of the refrigerant at about -20°C. 12kg of trifluoromethanesulfonic anhydride was added under stirring, and 8kg of diisopropylethylamine was slowly added dropwise at a low temperature, and the mixture was kept stirring for about 4 hours. After the reaction, wash with water, and concentrate at room temperature until no liquid flows out to obtain a viscous liquid reaction mixture. To the reaction mixture was added 5 kg of diallylamine, 30 L of toluene with stirring, and the temperature was raised to 90°C. When the temperature reached 90° C., the timer was started, and the mixture was stirred for about 20 hours. After the reaction was completed, the temperature was cooled to below 20° C., 20 L of toluene was added and stirred for 30 minutes, 30 L...

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Abstract

The invention discloses a synthesis method of an oseltamivir intermediate, which comprises the following steps of: carrying out addition on a compound 1 and diallylamine under the protection of acid, and then carrying out ring opening and tert-butyl nucleophilic addition to obtain the oseltamivir intermediate, and carrying out three-step reaction to obtain the oseltamivir intermediate. Compared with an existing industrial six-step reaction route, the reaction route is remarkably shortened, the yield is high, the overall yield exceeds 70%, and the production efficiency is improved. Meanwhile, according to the synthesis method, methylsulfonyl chloride cyclization is not needed, introduction of impurities with a genetic toxicity warning structure is avoided, and the medicine safety is improved. Moreover, the synthesis method does not use any azide, is high in safety, and is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical production, in particular to a method for synthesizing an oseltamivir intermediate. Background technique [0002] Ethyl(3aR,7S,7aS)-7-(diallylamino)-2,2-diethyl-3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxo -5-Carboxylate with ethyl (3R,4S,5S)-5-(diamino)-4-hydroxy-3-(pent-3-oxy)cyclohex-1-ene-1-carboxylate (Compound 2 shown in the following structural formula 2) is an important intermediate for the synthesis of oseltamivir. The current industrial production route of compound 2 is generally obtained from compound 1 shown in the following structural formula 1 through methanesulfonyl protection, ring opening, basic cyclization, tert-butyl ring opening, sulfonyl chloride cyclization, and diallylamine ring opening. , the production route needs to go through six-step reactions, the route is long, the yield is low (the overall yield is lower than 20%), and sulfonyl chloride is used for cyclization to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/16C07C229/48C07D317/48
CPCC07C227/16C07D317/48C07C2601/16C07C229/48Y02P20/55
Inventor 魏林华朱少璇覃东庆邓成斌王凤群
Owner 中润药业有限公司
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