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Method for synthetizing (S)3-hydroxy-gamma-butyrolactone by L-malate dioester catalytic hydrogenation

A malic acid diester, catalytic hydrogenation technology, applied in the direction of organic chemistry, etc., can solve the problems of difficult product purification, waste generation, and separation of butyrolactone

Inactive Publication Date: 2007-09-05
富乐马鸿凯(大连)医药有限公司
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  • Summary
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  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chinese patent (CN1425658A, 2003) generates acid anhydride by L-malic acid under the action of acid chloride compounds, and the acid anhydride is reduced to (S)-3-hydroxyl-γ-butyrate by metal borohydride under the catalysis of Lewis acid Lactone, because the process uses expensive borane or metal borohydride, and the product is difficult to purify, a large amount of waste is generated, which is extremely unfavorable to environmental protection, so it is not suitable for large-scale industrial production
These methods all have a shortcoming, because the composition of reaction mixture is quite complicated and carries out in water, it is quite difficult to separate desired product butyrolactone therefrom

Method used

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  • Method for synthetizing (S)3-hydroxy-gamma-butyrolactone by L-malate dioester catalytic hydrogenation

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Embodiment 1, the synthesis of catalyst:

[0018] 2.0 g of RhCl[Ph 2 PCH 2 CH 2 Si(OC 2 h 5 ) 3 ] 3 (Rh-P) complex, 50 mL of toluene and 10 g of SiO 2 Supported palladium catalyst (Pd-SiO 2 , Pd content is 10wt%) placed in the reaction flask, reflux reaction under nitrogen protection for 5 hours, filtered, the filter cake was washed three times with toluene, and dried to obtain the homogeneous-heterogeneous composite catalyst Rh-P / Pd-SiO 2 . By a similar method, respectively, with SiO 2 Supported nickel, platinum and ruthenium catalysts (Ni-SiO 2 , Pt-SiO 2 , Ru-SiO 2 ) instead of supported palladium catalyst Pd-SiO 2 , the composite catalyst Rh-P / Ni-SiO can be prepared 2 , Rh-P / Pt-SiO 2 and Rh-P / Ru-SiO 2 .

Embodiment 2～5

[0019] Embodiments 2 to 5, hydrogenation catalytic reaction: 0.5 gram of the composite catalyst obtained in Example 1, 10 gram of L-dimethyl malate and 50 milliliters of tetrahydrofuran were added in a pressure reactor, and after the reactor was replaced by hydrogen, the The mixture was stirred and reacted under 120 atmospheres of hydrogen at 100° C. for 24 hours. The catalyst was separated from the reaction mixture by filtration, and the filtrate was analyzed by chromatography. The results are shown in Table 1.

[0020] catalyst

Embodiment 6

[0025] Embodiment 6, the synthesis of catalyst:

[0026] 1.5 g of RhCl[Ph 2 PCH 2 CH 2 Si(OC 2 h 5 ) 3 ] 3 (Rh-P) complex, 50 mL of toluene and 10 g of SiO 2 Supported palladium catalyst (Pd-SiO 2 , Pd content is 5wt%) is placed in the reaction flask, reflux reaction under nitrogen protection for 5 hours, filtered, the filter cake is washed three times with toluene, and dried to obtain the homogeneous-heterogeneous composite catalyst Rh-P / Pd-SiO 2 . By a similar method, respectively, with SiO 2 Supported nickel, platinum and ruthenium catalysts (Ni-SiO 2 , Pt-SiO 2 , Ru-SiO 2 ) instead of supported palladium catalyst Pd-SiO 2 , the composite catalyst Rh-P / Ni-SiO can be prepared 2 , Rh-P / Pt-SiO 2 and Rh-P / Ru-SiO 2 .

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Abstract

A process for preparing (S)-3-hydroxy-gamma-butyrolactone by catalytic hydrogenation of L-diester malate features that its composite catalyst is prepared by anchoring RhLn on the metal carried SiO2, the reaction pressure and temp is respectively 5-150 atm and 50-100 deg.C, and the solvent is chosen from tetrahydrofuran, methanol, ethanol and isopropanol.

Description

Technical field: [0001] The invention provides a method for synthesizing (S)-3-hydroxyl-γ-butyrolactone by catalytic hydrogenation of L-malic acid diester. Background technique: [0002] (S)-3-Hydroxy-γ-butyrolactone is a very important intermediate and chiral source in organic synthesis. It is mainly used to synthesize the key intermediate (R)-4-cyano-3-hydroxybutyrate ethyl ester of the hypolipidemic drug Lipitor, and it is also the synthetic neuromodulator (R)-γ-amino-β-hydroxybutyrate The key intermediate of acid. And the brain metabolism accelerator (N-carbamoylmethyl-(S)-3-hydroxyl-γ-butyrolactam is also synthesized by it. In addition, from (S)-3-hydroxyl-γ-butyrolactone can also Prepare (S)-3-hydroxytetrahydrofuran, which is an indispensable intermediate for many AIDS drugs. [0003] The present synthetic method of (S)-3-hydroxyl-γ-butyrolactone mainly contains: 1) take L-malic acid as raw material, through esterification, reduction, acid hydrolysis ring synthesis,...

Claims

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Application Information

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IPC IPC(8): C07D307/33
Inventor 高汉荣林英虎赵世强
Owner 富乐马鸿凯(大连)医药有限公司
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