Preparation method of substituted phenylacetic acid derivative

A low-substitution, compound technology, applied in the field of drug synthesis, can solve problems that are not suitable for industrial production

Active Publication Date: 2018-12-18
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Considering the good medicinal prospect of loxoprofen sodium, but the above-mentioned route is not suitable for in

Method used

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  • Preparation method of substituted phenylacetic acid derivative
  • Preparation method of substituted phenylacetic acid derivative
  • Preparation method of substituted phenylacetic acid derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0079] In a 3L reactor, add 1.1kg (7w) of dichloromethane, 333.4g (2.5mol) of anhydrous aluminum trichloride, heat up to reflux, drop adipic anhydride (140.8g dissolved in 470g of dichloromethane, Adipic anhydride is prepared by dehydration of adipic acid), and keep warm for 2-3 hours after the dropwise addition is completed. 157g (1mol) of bromobenzene was added dropwise under reflux, and 3-5 hours after the addition was completed, a sample was taken by HPLC to detect that the raw material was <0.5%, and 160g (5mol) of methanol was added dropwise, kept for 3-4 hours, and the reaction was complete by HPLC detection. Cool to room temperature, add the reaction solution to 1.78kg (10w) of crushed ice, stir well, separate the organic phase, extract the aqueous phase twice with 356g (2w) dichloromethane, combine the organic phases, and use 356g (2w) The 5% sodium bicarbonate solution was washed once, and the organic phase was separated and concentrated to obtain a yellow solid A-5,...

Embodiment 2

[0081] In a 3L reactor, add 1.1kg (7w) of dichloromethane, 333.4g (2.5mol) of anhydrous aluminum trichloride, heat up and reflux, drop 140.8g of adipic anhydride dissolved in 470g of dichloromethane, drop After the addition is complete, keep warm for 2-3 hours. 178g (1mol) of ethyl 2-phenylpropionate was added dropwise under reflux, and 3-5 hours after the addition, HPLC was taken to detect that the raw material was <0.5%, and 160g (5mol) of methanol was added dropwise, kept for 3-4 hours, and detected by HPLC. The response is complete. Cool to room temperature, add the reaction solution to 1.78kg (10w) of crushed ice, stir well, separate the organic phase, extract the aqueous phase twice with 356g (2w) dichloromethane, combine the organic phases, and use 356g (2w) The 5% sodium bicarbonate solution was washed once, and the organic phase was separated and concentrated to obtain a yellow solid A-5, which was beaten with 356g (2w) of n-heptane, filtered with suction, and dried ...

Embodiment 3

[0083] In a 30L dry reaction kettle, add 16.00kg of monomethyl adipate, add 11.30kg (0.95eq) of thionyl chloride dropwise at a temperature of 10-25°C, and finish the dropwise addition in about 5 hours. After the dropwise completion, stir at room temperature After 2 hours, control in ethanol derivatization. After the reaction is completed, concentrate in a rotary evaporator water bath at 25-30°C to obtain an oily substance, which is dried with 5kg of dichloromethane to obtain 16.02kg of compound A-4. Yield 90.0%, GC 92.8%.

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Abstract

The invention belongs to the field of drug synthesis and relates to a preparation method of a substituted phenylacetic acid derivative, especially to a preparation method for preparing 2-[4-(2-oxyamylmethyl)phenylpropionic acid]. The preparation method includes a Friedel-Crafts reaction, ring-closure reaction and a coupled reaction which are sequentially exchangeable, and a reduction reaction. Thepreparation method hasn't been enlightened by the prior art and also cannot obtain technical enlightenment from the prior art. The preparation method is suitable for production on a commercial scaleand provides another technical scheme for the industrial production of loxoprofen sodium.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a preparation method of substituted phenylacetic acid derivatives, in particular to a preparation method of 2-[4-(2-oxopentylmethyl)phenylpropionic acid]. Background technique [0002] Substituted phenylacetic acid derivatives are disclosed in US patents, such as US4161538, and the structural formula is as follows: [0003] [0004] They are also reported to have very good anti-inflammatory, analgesic and antipyretic activities in US4161538. [0005] When A is oxygen in the above general structure, the value of n is 1, and R 1 When it is a methyl group, a very representative substituted phenylacetic acid derivative is loxoprofen, and the specific structural formula is as follows: [0006] [0007] Loxoprofen is a class of non-steroidal anti-inflammatory propionic acid derivatives that also includes ibuprofen and naproxen. Loxoprofen is listed in Brazil, Mexico and Japan respe...

Claims

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Application Information

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IPC IPC(8): C07C67/00C07C67/14C07C69/738C07C67/307C07C69/44C07C45/65C07C49/813C07C67/313C07C67/317C07C249/02C07C251/20
CPCC07C45/65C07C49/813C07C67/00C07C67/14C07C67/307C07C67/313C07C67/317C07C69/44C07C69/738C07C249/02C07C251/20C07C51/347C07C51/41C07C59/86C07C67/30C07C49/807
Inventor 高照波郑辉刘声民李洁平王长发郑俊成郭必豹宋亮刘阿情胡凯梅义将
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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