Process for the preparation of (3r,4r,5s)-4,5-epoxy-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester

A technology of ethyl propoxy and ethyl formate, applied in the -4 field, can solve the problems of ring opening of epoxy products, benzene ring impurities, etc., and achieve the effect of reducing the cost of raw materials

Inactive Publication Date: 2011-12-07
SHANGHAI ACEBRIGHT PHARMA GRP +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The base used in the elimination reaction of the last step in the above-mentioned route is all to use sodium bicarbonate at present at home and abroad, and the inventor finds that this step is eliminated with similar bases such as sodium bicarbonate and potassium bicarbonate During the reaction, it is easy to cause the ring opening of some epoxy products to generate a benzene ring impurity (structural formula is as follows), and the amount of this impurity in HPLC analysis is as high as 15%.

Method used

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  • Process for the preparation of (3r,4r,5s)-4,5-epoxy-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester
  • Process for the preparation of (3r,4r,5s)-4,5-epoxy-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester
  • Process for the preparation of (3r,4r,5s)-4,5-epoxy-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Preparation of (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid ethyl ester

[0028] At room temperature, shikimic acid (HPLC purity: 95%) (100.0 g, 0.55 mol) was suspended in 400.0 ml of absolute ethanol, and thionyl chloride (19.5 ml, 0.27 mol) was added dropwise with stirring. After the dropwise addition, the mixture was heated to 78°C and refluxed for 3 hours. After the reaction was completed, it was cooled to 40°C and concentrated under reduced pressure to obtain a brown oil.

Embodiment 2

[0030] Preparation of (3R,4S,5R)-3,4-O-isopentylidene-5-hydroxy-1-cyclohexene-1-carboxylic acid ethyl ester

[0031] Under nitrogen protection, triethyl orthoformate (96.5ml, 0.57mol), 3-pentanone (61.5ml, 0.57mol), absolute ethanol (34.0ml, 0.57mol), benzenesulfonic acid (0.2g, 1.26mmol), stirred for 1 hour, and naturally heated to 45°C. In another reaction bottle, add 100ml of absolute ethanol to the brown oil obtained in Example 1, and stir well. The solution obtained above was added dropwise to the ethanol solution of ethyl (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate, and the stirring was continued for 2 hours. After completion of the reaction, it was concentrated to dryness under reduced pressure to obtain a dark brown oil. Add 500ml of isopropyl acetate to dissolve the oily matter and proceed to the next reaction.

Embodiment 3

[0033] Preparation of (3R, 4S, 5R)-3,4-O-isopentylidene-5-O-(methylsulfonic acid)-1-cyclohexene-1-carboxylic acid ethyl ester

[0034] Cool the isopropyl acetate solution of (3R, 4S, 5R)-3,4-O-isopentylidene-5-hydroxyl-1-cyclohexene-1-carboxylic acid ethyl ester obtained in Example 2 to 0°C , add methanesulfonyl chloride (56.8ml, 0.73mol), and then add triethylamine (160.0ml, 1.15mol) dropwise, and control the temperature not to exceed 10°C. After the dropwise addition, the temperature was naturally raised to room temperature, and stirring was continued for 30 minutes. Filter and wash the filter cake with 100ml of isopropyl acetate. The combined filtrates were washed with 300 ml of water. The separated isopropyl acetate layer was concentrated to dryness under reduced pressure to obtain a yellow oil.

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Abstract

The invention discloses a method for preparing ethyl (3R,4R,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-1-cyclohexene-1-formate. The preparation method disclosed by the invention comprises the following steps: (a) dissolving ethyl (3R,4R,5R)-3-(1-ethyl-propoxy)-4-hydroxy-5-O-methyl-sulfonyl-1-cyclohexene-1-formate in an alcohol solvent, and carrying out elimination reaction under the effect of ammonia water; and (b) collecting ethyl (3R,4R,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-1-cyclohexene-1-formate from the reaction solution. By using the method disclosed by the invention, the product yield reaches more than 90%, the product purity measured by HPLC (high-performance liquid chromatography) reaches more than 99.5%, and the individual impurity content in the product is less than 0.1%; and the method is suitable for industrial mass production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to (3R, 4R, 5S)-4,5-epoxy-3-(1-ethylpropoxy)-1-cyclohexene-1-ethyl carboxylate Preparation. Background technique [0002] (3R,4R,5S)-4,5-Epoxy-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester is a key intermediate in the synthesis of oseltamivir phosphate body. Oseltamivir phosphate is a specific inhibitor acting on neuraminidase, which inhibits the action of neuraminidase and can inhibit the mature influenza virus from leaving the host cell, thereby inhibiting the spread of influenza virus in the human body to play a role to the treatment of influenza. The structural formula of oseltamivir phosphate is as follows: [0003] [0004] Oseltamivir Phosphate came out in 1996. It was clinically developed by Gillid Company and jointly developed and operated by Roche Pharmaceuticals (trade name: Tamiflu). In 1999, oseltamivir was first launched in Sweden f...

Claims

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Application Information

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IPC IPC(8): C07D303/40C07D301/02
Inventor 李金亮赵楠
Owner SHANGHAI ACEBRIGHT PHARMA GRP
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