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Method for preparing (S)-3-hydroxy group-gamma-butyrolactone

A technology of butyrolactone and hydroxyl, applied in the field of chiral drug intermediates, can solve the problems of energy consumption, time-consuming, many by-products, difficult industrialization, etc., and achieves the effects of easy operation, mild conditions and high optical purity

Inactive Publication Date: 2005-10-26
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method has low raw material cost and moderate yield (about 60%), in actual operation, due to the low concentration of reaction raw materials, many by-products, and the need to remove a large amount of water, it is extremely energy-consuming and time-consuming, so Industrialization of this method is still difficult

Method used

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  • Method for preparing (S)-3-hydroxy group-gamma-butyrolactone
  • Method for preparing (S)-3-hydroxy group-gamma-butyrolactone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] First prepare (2R, 3R)-2-sulfonyloxy-3-hydroxyl-γ-butyrolactone (2), and (2R, 3R)-2,3-dihydroxyl-γ-butyrolactone (1) Dissolve in dichloromethane to make a 0.1 mol / liter solution, cool to 0°C with an ice-water bath, add dropwise triethylamine equivalent to 1.3 times the molar amount of (1) under stirring; then add equivalent to (1) 1.1 times the molar amount of thionyl chloride, the mixture was stirred until the conversion of the raw materials was complete, the solid was removed by filtration, and the solvent was evaporated to obtain (2R, 3R)-2,3-dihydroxy-γ-butyrolactone (2R, 3R) - The crude product of 2-sulfonyloxy-3-hydroxyl-γ-butyrolactone (2) was directly used in the next reaction.

[0022] Dissolve the above (2R, 3R)-2-sulfonyloxy-3-hydroxyl-γ-butyrolactone (2) in methanol to make a 1.4 mol / liter solution, and then add the equivalent of (2R, 3R) -2-sulfonyloxy-3-hydroxyl-γ-butyrolactone (2) 1.1 times the molar amount of lithium chloride, the reaction mixture was s...

Embodiment 2

[0025] Similar to Example 1, the difference is that (2S, 3R)-2-sulfonyloxy-3-hydroxyl-γ-butyrolactone (2) is prepared first, and (2R, 3R)-2,3-dihydroxy - γ-butyrolactone (1) was dissolved in dichloromethane to make a 0.25 mol / liter solution, cooled to 0°C in an ice-water bath, and then added dropwise with diisocyanate equivalent to 1.2 times the molar amount of (1) under stirring. Propylethylamine; then add methanesulfonyl chloride equivalent to 1.2 times the molar amount of (1), stir the mixture until the raw material is completely converted, remove the solid by filtration, and evaporate the solvent to obtain (2S, 3R)-2-methanesulfonyloxy The crude product of base-3-hydroxy-γ-butyrolactone (2) was directly used in the next reaction.

[0026] Dissolve the above (2R, 3R)-2-sulfonyloxy-3-hydroxy-γ-butyrolactone (2) in formic acid to make a 1.5 mol / liter solution, and then add the equivalent of (2R, 3R) -2-sulfonyloxy-3-hydroxyl-γ-butyrolactone (2) 1.0 times the molar amount of ...

Embodiment 3

[0029] Similar to Example 1, the difference is that (2R, 3R)-2-sulfonyloxy-3-hydroxyl-γ-butyrolactone (2) is prepared first, and (2R, 3R)-2,3-dihydroxy - Gamma-butyrolactone (1) was dissolved in dichloromethane to make a 0.3 mol / liter solution, cooled to 0°C in an ice-water bath, and then added dropwise with pyridine equivalent to 1.4 times the molar amount of (1) under stirring; Then add trifluorosulfonic anhydride equivalent to 1.4 times the molar amount of (1), stir the mixture until the conversion of raw materials is complete, remove the solid by filtration, and evaporate the solvent to obtain (2S, 3R)-2-trifluoromethanesulfonyloxy-3 -The crude product of hydroxy-γ-butyrolactone (2) was directly used in the next reaction.

[0030] Dissolve the above (2R, 3R)-2-sulfonyloxy-3-hydroxyl-γ-butyrolactone (2) in acetic acid to make a 1.3 mol / liter solution, and then add the equivalent of (2R, 3R) -2-sulfonyloxy-3-hydroxyl-γ-butyrolactone (2) 1.3 times the molar amount of lithium i...

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Abstract

The present invention relates to a method for preparing (S)-3-hydroxy-gamma-butyrolactone. Said method incldues the following steps: dissolving (2R, 3R)-2,3-dihydroxy-gamma-butyrolactone in dichloromethane, cooling to zero deg.C, drop-adding organic alkali acid-binding agent, adding sulfonylation reagent, filtering to remove solid, distillation to remove solvent to obtain (2R, 3R)-2-sulfonyloxy-3-hydroxy-gamma-butyrolactone; dissolving the above-mentioned product in organic solvent, adding alkali metal halide, evaporating to remove solvent, adding ethyl acetaet to make extraction, reduced pressure distillation to remove solvent to obtain (2S, 3R)-2-halogene-3-hydroxy-gamma butyrolactone, then dissolving said product in organic solvent, adding dehalogenation catalyst, filtering to remove solid, reduced pressure distillation to remove solvent, purifying to obtain the invented product.

Description

technical field [0001] The invention relates to a chiral drug intermediate, in particular to a preparation method of a multipurpose chiral drug intermediate (S)-3-hydroxyl-γ-butyrolactone. Background technique [0002] (S)-3-Hydroxy-γ-butyrolactone (4) is a versatile chiral drug intermediate widely used in the asymmetric synthesis and synthesis of several statin lipid-lowering drugs. The synthetic method of existing (S)-3-hydroxyl-γ-butyrolactone mainly contains: [0003] 1) Using L-malic acid as raw material, through the method of esterification, selective reduction and cyclization. Although the method is short and the yield is high, the complex of borane and dimethyl sulfide is used as a reducing agent in the reaction, which requires anhydrous and oxygen-free conditions; meanwhile, the borane dimethyl sulfide complex is not only very Expensive and highly toxic, so this route is dangerous and difficult to prepare (S)-3-hydroxy-γ-butyrolactone on an industrial scale. Alth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/58
Inventor 陈安齐茅永琳
Owner XIAMEN UNIV