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Industrial preparation method of acetyl tetrahydrofuran with high optical purity

A technology of acetyltetrahydrofuran and optical purity, which is applied in the industrialized preparation field of acetyltetrahydrofuran with high optical purity, can solve the problems of difficult product purification, complicated operation and high cost, and achieves the effects of stable quality, low preparation cost and low raw material cost

Active Publication Date: 2016-05-11
CHENGDU LIKAI CHIRAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The purpose of the present invention is to provide an industrialized preparation method of acetyl tetrahydrofuran with high optical purity, so as to solve the problems of complicated operation, high cost, difficult product purification and low yield in the existing process

Method used

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  • Industrial preparation method of acetyl tetrahydrofuran with high optical purity
  • Industrial preparation method of acetyl tetrahydrofuran with high optical purity
  • Industrial preparation method of acetyl tetrahydrofuran with high optical purity

Examples

Experimental program
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Effect test

Embodiment 1

[0035] A kind of industrial preparation method of high optical purity S-acetyl tetrahydrofuran, comprises the following steps:

[0036] (1) S-tetrahydrofuroyl chloride ( Ⅲ ) preparation

[0037] Add 100Kg of S-tetrahydrofurancarboxylic acid, 100Kg of dichloromethane, and 5Kg of DMF into the dry reaction kettle, slowly pump in 160Kg of thionyl chloride, keep stirring at 20-30°C for 3 hours, and absorb the tail gas with liquid caustic soda (that is, liquid sodium hydroxide) , then heated up to 50°C, concentrated under reduced pressure, when the vacuum no longer increased, pumped in 50Kg of dichloromethane respectively, and continued to concentrate three times; after concentrating, added 270Kg of dichloromethane, lowered to room temperature, and put it in a barrel for future use. One-step reaction, optical purity: 99.3%;

[0038] (2) Preparation of Condensate (II)

[0039] Add 270Kg of dichloromethane and 132Kg of isopropylidene malonate to the reaction kettle, stir and cool d...

Embodiment 2

[0043] A kind of industrial preparation method of high optical purity S-acetyl tetrahydrofuran, comprises the following steps:

[0044] (1) Preparation of S-tetrahydrofuroyl chloride (Ⅲ)

[0045] Add 100Kg of S-tetrahydrofurancarboxylic acid, 120Kg of toluene, and 4Kg of pyridine into the dry reaction kettle, slowly pump in 200Kg of phosphorus oxychloride, keep stirring at 20-40°C for 4 hours, and absorb the tail gas with liquid caustic soda (that is, liquid sodium hydroxide) , then heated up to 50°C, concentrated under reduced pressure, when the vacuum no longer increased, sucked in 50Kg toluene respectively, and continued to concentrate three times; Purity: 99.3%;

[0046] (2) Preparation of Condensate (II)

[0047] Add 270Kg of toluene and 132Kg of isopropylidene malonate to the reaction kettle, stir and cool down to 5-10°C, add 255Kg of triethylamine, after the addition is complete, add the prepared S-tetrahydrofuran dropwise at -5-0°C The toluene solution of formyl chl...

Embodiment 3

[0051] A kind of industrial preparation method of high optical purity R-acetyl tetrahydrofuran, comprises the following steps:

[0052] (1) Preparation of R-tetrahydrofuroyl chloride (Ⅲ)

[0053] Add 100Kg of R-tetrahydrofurancarboxylic acid, 100Kg of tetrahydrofuran, and 5Kg of DMF into the dry reaction kettle, slowly suck in 160Kg of thionyl chloride, keep stirring at 20-30°C for 3 hours, absorb the tail gas with liquid caustic soda (that is, liquid sodium hydroxide), and then Raise the temperature to 50°C, concentrate under reduced pressure, and when the vacuum no longer increases, suck in 50Kg of dichloromethane, and continue to concentrate three times. After concentrating, add 270Kg tetrahydrofuran, cool down to room temperature, put it in barrels for the next reaction, optical purity: 99.4%;

[0054] (2) Preparation of Condensate (II)

[0055] Add 270Kg of tetrahydrofuran and 132Kg of isopropylidene malonate to the reaction kettle, stir and cool down to 5-10°C, add 273...

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Abstract

The invention discloses an industrial preparation method of acetyl tetrahydrofuran with a high optical purity, and belongs to the field of chemical synthesis. According to the preparation method, tetrahydrofuroic acid is taken as the raw material and then is chlorinated to obtain tetrahydrofuran carbonyl chloride, tetrahydrofuran carbonyl chloride and Meldrum's acid carry out condensation reactions, and reaction product is hydrolyzed to obtain the target compound namely acetyl tetrahydrofuran. The preparation method has the advantages that the raw material cost is low, the preparation method does not need any Grignard reagent, the product property is stable, the purity can reach 98% or more, the optical purity can reach 99% or more, and the yield can reach 70% or more. The method has applied to industrial production. The product quality is stable. The reaction conditions are mild. The operation is safe and reliable. Dichloromethane can be recycled. The technology has the advantages of good repeatability and low preparation cost, and is a reliable industrial production method of acetyl tetrahydrofuran with a high optical purity.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to an industrial preparation method of high optical purity acetyl tetrahydrofuran. Background technique [0002] Acetyl tetrahydrofuran (chemical name: 1-[(2S)-tetrahydro-2-furyl]ethanone, CAS#: 131328-27-3) is a synthetic antibacterial drug Cefovecin and a new carbapenem The key intermediate, the structure is as formula compound (Ia). [0003] [0004] At present, there are mainly the following two commonly used preparation methods reported at home and abroad. [0005] Method 1: U.S. Patent US2003-114693A, using S-2-tetrahydrofurancarbonitrile as the starting material, reacted with methylmagnesium chloride to prepare S-acetyltetrahydrofuran with a yield of 60%. [0006] [0007] The method has simple steps, but the reagent S-2-tetrahydrofurancarbonitrile used is expensive and its source is limited, so it is not suitable for large-scale industrialization, and the meth...

Claims

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Application Information

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IPC IPC(8): C07D307/12
CPCC07D307/12
Inventor 袁伟成邢志奎徐小英牟行彦李宗林欧仁树葛真真赵建强陈诚雷继中
Owner CHENGDU LIKAI CHIRAL TECH
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