Synthesizing method for baloxavir marboxil key parent nuclear intermediate

By simplifying the synthesis method of the key core intermediate of baloxavir disipil, using condensation and deprotection reactions, combined with one-step cyclization, high-cost raw materials and highly toxic substances are avoided, and the problems of complex synthetic routes and high costs in the existing technology are solved. problem and achieve efficient and low-cost industrial production.

CN109912624AActive Publication Date: 2019-06-21HANGZHOU CHEMINSPIRE TECH CO LTD
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Patent Information

Application Number
CN201910291543.6
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Filing Date
2019-04-11
Publication Date
2019-06-21
Estimated Expiration
2039-04-11

AI Technical Summary

Technical Problem

The existing synthesis route of the key core intermediate of baloxavir distil has long steps and uses highly toxic substances and high-cost raw materials, resulting in low overall yield and high process cost, making it difficult to be suitable for industrial production.

Method used

Using a simplified synthesis method, through condensation reaction and deprotection reaction to avoid unnecessary substituent protection and replacement, combined with a one-step cyclization reaction, using cheap (S)-tetrahydrofuran-2-carboxylic acid as a splitting prosthetic group, we can directly obtain The target product is obtained, and the intermediate with the correct configuration is obtained by recrystallization, and finally forms a salt with p-toluenesulfonic acid to form a key intermediate.

Benefits of technology

It greatly reduces the steps and costs of the reaction route, improves the overall yield and product purity, and is suitable for industrial production. It has fewer steps and is simple to operate. The obtained product has high purity and low cost.

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Abstract

The invention provides a synthesizing method for a baloxavir marboxil key parent nuclear intermediate which is shown in formula 6. The synthesizing method comprises the following steps: taking the compound which is shown in the formula 1 as a starting material; performing condensation reaction on the compound which is shown in the formula 1 and the compound which is shown in the formula 2 to obtain an intermediate compound which is shown in formula 3; performing one-step cyclization on the intermediate compound which is shown in the formula 3 and hydrazine hydrate directly to obtain a racemiccompound which is shown in formula 4; then, performing condensation reaction on the racemic compound which is shown in the formula 4 and (S)-tetrahydrofuran-2-methanoic acid, crystallizing and splitting to obtain an intermediate compound which is shown in formula 5; finally, removing a chiral auxiliary group to obtain a target product which is shown in the formula 6. According to the route, unnecessary substituent group protection and replacement are avoided; steps of a reaction route are greatly reduced in combination with the one-step cyclization; the efficiency and the yield of the route are improved; the cost is greatly reduced. The route is shown in the specification.
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