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Synthetic method of (S)-(+)-3-hydroxytetrahydrofuran

A technology of hydroxytetrahydrofuran and synthesis method, applied in directions such as organic chemistry, can solve problems such as difficulty in meeting purity requirements, difficulty in industrialized production, etc., and achieve the effects of short synthetic route steps, easy removal, and high total yield

Inactive Publication Date: 2015-04-01
SUZHOU JONATHAN NEW MATERIALS TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The product that above-mentioned method obtains either is difficult to reach purity requirement, or is not easy to industrialized production, so it is necessary to adopt new synthetic method to obtain the qualified (S)-(+)-3-hydroxytetrahydrofuran of purity

Method used

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  • Synthetic method of (S)-(+)-3-hydroxytetrahydrofuran

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] (1) Add 100g of L-malic acid and 650ml of methanol into a three-neck flask, add 1ml of concentrated sulfuric acid under stirring, heat up to 60-70°C and reflux for 10h. Cool, add saturated aqueous sodium bicarbonate dropwise until the pH value reaches 7-8, concentrate, add water, extract with ethyl acetate, wash the organic phase with water, dry, and concentrate to obtain 103.0 g of a colorless liquid with a yield of 85.2% and a purity of 98.9%; HNMR (CDCl 3 , 300MHz) δ: 4.47(d,1H), 3.76(s,3H), 3.67(s,3H), 3.19(br,1H), 2.71~2.88(m,2H).

[0019] (2) Add 500ml of ethanol and 103g of sodium borohydride to the three-necked flask, and control the temperature at 0 to 10°C under stirring. Add 103.0g of the ethanol (250ml) solution of the product in step 1 dropwise, and drop it within 90min. React at 25°C for 12h, then heat up to 70-80°C and reflux for 8h. Cool, concentrate until there is no solvent, add 2h methanol to the residue, add 10% methanolic hydrochloric acid solutio...

Embodiment 2

[0022] (1) Add 100g of L-malic acid and 300ml of methanol into the three-necked flask, cool to -10°C ~ 0°C, add 120ml of thionyl chloride dropwise under stirring, drop for 2h, stir at room temperature for 4h, then heat up to 60°C React at ~70°C for 1 h, cool, concentrate, add saturated aqueous sodium bicarbonate solution dropwise to the residue until the pH value reaches 7-8, concentrate, add water, extract with ethyl acetate, wash the organic phase with water, dry, and concentrate to obtain a colorless liquid 106.9g, yield 88.4%, purity 97.9%; HNMR (CDCl 3 , 300MHz) δ: 4.47(d,1H), 3.76(s,3H), 3.67(s,3H), 3.19(br,1H), 2.71~2.88(m,2H).

[0023] (2) Add ethanol 500ml ethanol, 103g sodium borohydride to the three-necked flask, control the temperature at 0-10°C under stirring, add dropwise 106.9g of the ethanol (250ml) solution of the product of step 1, drop it within 90min, and finish it in 20-10℃ React at 25°C for 12h, then heat up to 70-80°C and reflux for 8h. Cool, concentra...

Embodiment 3

[0026] (1) Add 100g of L-malic acid and 700ml of isopropanol into a three-necked flask, add 1ml of concentrated sulfuric acid while stirring, heat up to 60-70°C and reflux for 10h. Cool, add saturated aqueous sodium bicarbonate dropwise until the pH value reaches 7-8, concentrate, add water, extract with ethyl acetate, wash the organic phase with water, dry, and concentrate to obtain 133.2 g of a colorless liquid with a yield of 81.9% and a purity of 98.7%; HNMR (CDCl 3 , 300MHz) δ: 4.47(d,1H), 3.57(m,1H), 3.19(br,1H), 2.71~2.88(m,2H), 1.16(d,6H).

[0027] (2) Add 500ml of ethanol and 103g of sodium borohydride to the there-necked flask, and control the temperature at 0 to 10°C under stirring, add dropwise 133.2g of the ethanol (250ml) solution of the product in step 1, drop it within 90min, and finish it in 20~10℃. React at 25°C for 12h, then heat up to 70-80°C and reflux for 8h. Cool, concentrate until there is no solvent, add 2h methanol to the residue, add dropwise 10% m...

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Abstract

The invention provides a synthetic method of (S)-(+)-3-hydroxytetrahydrofuran. The synthetic method comprises the following steps: (1) with L-malic acid as a raw material, carrying out esterification on two carboxyls of the L-malic acid to obtain a product with a formula shown in the specification; (2) reducing a product in the first step by virtue of sodium borohydride to obtain a product with a formula shown in the specification; and (3) carrying out cyclization on a product obtained in the second step to obtain the (S)-(+)-3-hydroxytetrahydrofuran. According to the synthetic method provided by the invention, the synthetic route is short in step, the used raw materials are cheap and easy to acquire, no racemization phenomenon occurs in the reaction process, a by-product in the third step is easy to remove, the total yield is high, and the (S)-(+)-3-hydroxytetrahydrofuran is suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of (S)-(+)-3-hydroxytetrahydrofuran, belonging to the field of synthesis of pharmaceutical intermediates. Background technique [0002] Amprenavir, systematically named (3S)-3-tetrahydrofuryloxy N-[(1S,2R)-3-(N-isobutyl N-4-aminobenzenesulfonyl)-1- Phenyl-2-hydroxypropyl] carbamate is the fifth-generation antiretroviral protease inhibitor developed by Glaxo-Smith Company in the United Kingdom, and it was launched in the United States and Japan in May 1999. It has strong antiviral activity and good drug resistance, so it has good clinical application value. The synthetic route of existing industrialization prospect is to be raw material with (2R, 3S)-2-epoxy-4-phenyl-3-butylcarbamate tert-butyl ester derived from L-phenylalanine, and isobutylamine Carry out amine alkylation reaction to obtain intermediate (I), then carry out sulfonylation reaction with 4-nitrobenzenesulfonyl chloride, deprotection, and (S)-(...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/20
CPCC07D307/20
Inventor 李卓才李苏杨
Owner SUZHOU JONATHAN NEW MATERIALS TECH
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