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Preparation method of (s)-3-hydroxytetrahydrofuran

A technology of hydroxytetrahydrofuran and hydroxyl, which is applied in the field of preparation of -3-hydroxytetrahydrofuran, can solve the problems of unsatisfactory large-scale production, expensive biological enzymes, long reaction cycle, etc., and achieve low production cost, short reaction route and environmental pollution small effect

Active Publication Date: 2019-11-01
SHANGHAI SHINE HIGH INT TRADE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The biological enzymes used in these methods are expensive, the reaction cycle is long, and the yield is low, which cannot meet the needs of large-scale production.

Method used

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  • Preparation method of (s)-3-hydroxytetrahydrofuran
  • Preparation method of (s)-3-hydroxytetrahydrofuran
  • Preparation method of (s)-3-hydroxytetrahydrofuran

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Step 1, preparation of (s)-4-chloro-3 hydroxy-1-butanol:

[0034] Step 1-1, under nitrogen protection, [Ir(COD)Cl] 2 1. The chiral phosphine-pyridine ligand was dissolved in ethanol and stirred at room temperature for 10 minutes to prepare the first catalyst.

[0035]Step 1-2, according to the amount of substance of the first catalyst theoretically prepared in step 1-1, according to the ratio of the amount of substance of the first catalyst and the amount of substance of ethyl 4-chloroacetoacetate to 1:3000, The substrate 4-chloroacetoacetate was dissolved in ethanol. Wherein, the volume ratio of the total volume of the ethanol used in step 1-1 and the ethanol used in step 1-2 to the substrate ethyl 4-chloroacetoacetate is 3:1. Then, the above ethanol solution of ethyl 4-chloroacetoacetate was added to the first catalyst prepared in step 1-1.

[0036] Step 1-3, according to the molar ratio of potassium tert-butoxide and ethyl 4-chloroacetoacetate is 1:15, the molar r...

Embodiment 2

[0040] Step 1, preparation of (s)-4-chloro-3 hydroxy-1-butanol:

[0041] Step 1-1, under nitrogen protection, [Ir(COD)Cl] 2 1. The chiral phosphine-pyridine ligand was dissolved in methanol and stirred at room temperature for 10 minutes to prepare the first catalyst.

[0042] Step 1-2, according to the amount of substance of the first catalyst theoretically prepared in step 1-1, according to the ratio of 1:2000 of the amount of substance of the first catalyst and the amount of substance of ethyl 4-chloroacetoacetate, The substrate 4-chloroacetoacetate was dissolved in methanol. Wherein, the volume ratio of the total volume of the methanol used in step 1-1 and the methanol used in step 1-2 to the substrate ethyl 4-chloroacetoacetate is 5:1. Then, the above methanol solution of ethyl 4-chloroacetoacetate was added to the first catalyst prepared in step 1-1.

[0043] Step 1-3, according to the molar ratio of sodium methylate and ethyl 4-chloroacetoacetate is 1:20, the molar ra...

Embodiment 3

[0047] Step 1, preparation of (s)-4-chloro-3 hydroxy-1-butanol:

[0048] Step 1-1, under nitrogen protection, [Ir(COD)Cl] 2 1. The chiral phosphine-pyridine ligand was dissolved in anhydrous dichloromethane and stirred at room temperature for 10 minutes to prepare the first catalyst.

[0049] Step 1-2, according to the amount of substance of the first catalyst theoretically prepared in step 1-1, according to the ratio of the amount of substance of the first catalyst and the amount of substance of ethyl 4-chloroacetoacetate to 1:5000, The substrate, ethyl 4-chloroacetoacetate, was dissolved in anhydrous dichloromethane. Wherein, the volume ratio of the total volume of the anhydrous dichloromethane used in step 1-1 and the anhydrous dichloromethane used in step 1-2 to the substrate ethyl 4-chloroacetoacetate is 2:1. Then, the above-mentioned ethyl 4-chloroacetoacetate solution in anhydrous dichloromethane was added to the first catalyst prepared in step 1-1.

[0050] Step 1-3...

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Abstract

The invention provides a preparation method of (s)-3-hydroxytetrahydrofuran. According to the preparation method, ethyl 4-chloroacetoacetate is taken as an initial raw material, (s)-4-chloro-3 hydroxyl-1-butanol is prepared, wherein a substrate is dissolved in a first solvent, an alkali is added, under the catalytic effect of a first catalyst and a second catalyst, asymmetric hydrogenation reaction with hydrogen gas is carried out to produce (s)-4-chloro-3 hydroxyl-1-butanol; chiral 3-hydroxytetrahydrofuran is prepared, wherein prepared chiral 4-chloro-3 hydroxyl-1-butanol is dissolved in a second solvent, an acid is added as a catalyst, and reaction is carried out to obtain (s)-3-hydroxytetrahydrofuran; wherein the first catalyst is a complex generated through reaction of [Ir(COD)Cl]2 with phosphine-pyridine ligand, and the second catalyst is Ru-MACHO complex. The reaction route is short; technology is simple; raw materials are cheap and easily available; production cost is low; reaction process environment pollution is low; product optical purity is high; and the preparation method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of (s)-3-hydroxytetrahydrofuran. Background technique [0002] Optically pure (S)-3-hydroxytetrahydrofuran is an important pharmaceutical intermediate, which can be used in diabetes drug Empagliflozin, breast cancer drug Afatinib, anti-AIDS drug Amprenavir ( Amprenavir) and Fusamprenavir (Fosamprenavir) etc. have a large market demand and have good application prospects. [0003] [0004] Synthetic methods for chiral 3-hydroxytetrahydrofuran have been widely reported. In 1983, Tadon first proposed the synthesis route of chiral 3-hydroxytetrahydrofuran (J.Org.Chem, 1983, 48, 2767-2769). This route uses chiral malic acid as a starting material, requires the use of a large amount of lithium aluminum hydride, and is not suitable for large-scale production. Many disclosed synthetic methods improve the synthetic route of Tadon, such as p...

Claims

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Application Information

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IPC IPC(8): C07D307/20
CPCC07D307/20
Inventor 胡信虎呼延旺
Owner SHANGHAI SHINE HIGH INT TRADE CO LTD
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