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Preparation method of drug intermediate (S)-3-hydroxytetrahydrofuran

A hydroxytetrahydrofuran and tetrahydrofuran-based technology is applied in the field of synthesis of a pharmaceutical intermediate-3-hydroxytetrahydrofuran, and can solve problems such as low overall yield, unsuitability for large-scale production, and failure to solve the problem of using intermediates with opposite configurations. , to achieve the effect of high stereoselectivity

Inactive Publication Date: 2017-07-18
杭州述康生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method also belongs to the kinetic resolution catalyzed by lipase, and also fails to solve the problem of the utilization of the opposite configuration intermediate obtained in the preparation process, the overall yield is low, and it is not suitable for large-scale production

Method used

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  • Preparation method of drug intermediate (S)-3-hydroxytetrahydrofuran
  • Preparation method of drug intermediate (S)-3-hydroxytetrahydrofuran

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Add 1.06kg (10mol) of 1,2,4-butanetriol to a 5L reactor, add a catalytic amount of p-toluenesulfonic acid monohydrate 19g (0.1mol) under stirring, and heat to dissolve it completely in 1,2 , 4-Butanetriol. Under reduced pressure (1.6kPa), the temperature was raised to 90°C, and the 80-90°C fraction was collected by a distillation device to obtain 3-hydroxytetrahydrofuran as a colorless liquid. The collected 3-hydroxytetrahydrofuran was dissolved in an appropriate amount of anhydrous dichloromethane, added molecular sieves to dry and filtered, and the dichloromethane was distilled off under reduced pressure to obtain 678 g of anhydrous 3-hydroxytetrahydrofuran with a yield of 77%.

[0042] In a 25L reactor, 678g (7.7mol) of 3-hydroxytetrahydrofuran was dissolved in 8L of anhydrous dichloromethane, and then 1.13L (14mol) of anhydrous pyridine was added. The reaction solution was cooled to 0°C, and a solution of acetyl chloride (600ml, 8.4mol) in dichloromethane (2L) was ...

Embodiment 2

[0046] 10kg of racemic 1,2,4-butanetriol was reacted with 190g of p-toluenesulfonic acid monohydrate, and after vacuum distillation, 6.6kg of racemic 3-hydroxytetrahydrofuran was obtained. Dissolve all the obtained 3-hydroxytetrahydrofuran (racem) in 50L of dichloromethane, add 11L of anhydrous pyridine, and slowly add 6L of acetyl chloride after cooling to 0°C. After the reaction, 8.6kg of tetrahydrofuranyl-3-ethane Ester (racemic). Catalyzed hydrolysis of all tetrahydrofuryl-3-hexanoate (racemic) by 10 g lipase A lyophilized powder aqueous solution, after the reaction, (S)-tetrahydrofuryl-3-hexanoate and (R)-3- Mixtures of hydroxytetrahydrofuran. Dissolve the treated mixture in anhydrous tetrahydrofuran, add 11.7kg triphenylphosphine and 7.5kg p-nitrobenzoic acid, cool to 0-4°C, add 9.5L diisopropyl azodicarboxylate while stirring, and continue Stir until the reaction is complete. Add 10 L of sodium hydroxide solution (1N) to the reaction solution, stir at room temperatur...

Embodiment 3

[0048] Take 5 kg of racemic 1,2,4-butanetriol, add 0.5 L of concentrated hydrochloric acid to react, and obtain 3.3 kg of racemic 3-hydroxytetrahydrofuran after vacuum distillation. All the obtained 3-hydroxytetrahydrofuran (racemic) was dissolved in 20L of dichloromethane, 5.6L of anhydrous pyridine was added, and after cooling to 0°C, 3.8L of acetic anhydride was slowly added. After the reaction, 4.15 kg of tetrahydrofuranyl-3-acetate (racem) was obtained. Catalyzed hydrolysis of all tetrahydrofuranyl-3-acetate (racemic) by 4g lipase A lyophilized powder aqueous solution, after the reaction, (S)-tetrahydrofuryl-3-acetate and (R)-3- Mixtures of hydroxytetrahydrofuran. Dissolve the treated mixture in anhydrous tetrahydrofuran, add 6.5kg triphenylphosphine and 1.5L glacial acetic acid, cool to 0-4°C, add 5L diethyl azodicarboxylate with stirring, and continue stirring until the reaction is complete. Add 5L of sodium hydroxide solution (1N) to the reaction solution, stir at ro...

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Abstract

The invention provides a preparation method of a drug intermediate (S)-3-hydroxytetrahydrofuran. The method comprises the following steps: by taking racemic 1,2,4-butantriol as a raw material, synthesizing racemic 3-hydroxytetrahydrofuran; and carrying out esterification to obtain racemic tetrahydrofuryl-3-fatty acid ester. After the (R)-tetrahydrofuryl-3-fatty acid ester in a racemic mixture is hydrolyzed through lipase, the hydrolyzed (R)-tetrahydrofuryl-3-fatty acid ester is converted into (S)-tetrahydrofuryl-3-carboxylate by utilizing a Mitsunobu reaction under the condition that a hydrolyzed product is not separated; and finally, all tetrahydrofuryl ester is hydrolyzed under an alkaline condition to obtain a final product (S)-3-hydroxytetrahydrofuran.

Description

technical field [0001] The invention relates to a synthesis method of a medicine intermediate (S)-3-hydroxytetrahydrofuran, belonging to the field of medicine synthesis. Background technique [0002] Chiral alcohol (S)-3-hydroxytetrahydrofuran (CAS No.: 86087-23-2) is an important chiral intermediate for the synthesis of afatinib, ibrutinib, fosamprenavir, apagliflozin and other drugs , (S)-(+)-3-hydroxytetrahydrofuran with high optical purity has important uses in the pharmaceutical industry and new drug research and development. [0003] There have been many research results on the synthesis of (S)-3-hydroxytetrahydrofuran and its enantiomer (R)-(-)-3-hydroxytetrahydrofuran. In 1983, Tadon proposed for the first time the synthetic route of optically pure (S)- and (R)-3-hydroxytetrahydrofuran (Synthesis of Enantiomerically Pure (S)-3-Hydroxytetrahydrofuran and Its R Enantiomer from Malic or Tartaric Acid, VishnuK.Tadon et al , J.Org.Chem, 1983, Vol.48, 2767-2769). This r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/20C12P17/04
CPCC07D307/20C07B2200/07C12P17/04
Inventor 林路
Owner 杭州述康生物技术有限公司
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