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Preparation method of p-bromomethyl isophenylpropionic acid

A technology of p-bromomethylisophenylpropionic acid and phenylpropionic acid, which is applied in the field of synthesis of pharmaceutical intermediates, and can solve the problem of large-scale industrial production of bromomethylisophenylpropionic acid and the difficulty of obtaining 4-methylstyrene , high cost of 4-methylstyrene, etc., to achieve the effect of easy purchase, low price and low production cost

Pending Publication Date: 2020-07-28
张明
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The weak point of above-mentioned technique is: raw material 4-methylstyrene is not easy to obtain, is difficult to buy by commercially available, and the cost of high-purity 4-methylstyrene is high, is raw material preparation p-bromomethylstyrene with 4-methylstyrene There is no possibility of large-scale industrial production of isoprofen
In addition, the long synthetic route and complex process also limit the market prospect of this process route

Method used

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  • Preparation method of p-bromomethyl isophenylpropionic acid
  • Preparation method of p-bromomethyl isophenylpropionic acid
  • Preparation method of p-bromomethyl isophenylpropionic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0045] Synthesis of A, α-methylbenzyl chloride

[0046] Put 300g of dichloromethane and 100g of styrene into the addition kettle, control the temperature at -5 ~ 5°C, and continuously feed dry hydrogen chloride to react for 10 hours; after the reaction, blow off the residual hydrogen chloride with nitrogen; then distill at atmospheric pressure Remove dichloromethane, high vacuum rectification obtains 133g α-methyl benzyl chloride, after testing, the purity of α-methyl benzyl chloride is 98.3%, and the yield is 98.1%;

[0047] Synthesis of B, 2-phenylpropionic acid

[0048] Dissolve 133g of α-methylbenzyl chloride in 665g of 2-methyltetrahydrofuran, add magnesium powder with a molar ratio (calculated as α-methylbenzyl chloride) of 2 times, and react at 10-20°C for 3 hours to prepare a Grignard solution; Control 5-15°C, pass through dry carbonic acid gas with a molar ratio of 1.5 times, and react for 5 hours to obtain a carboxylated solution. After the reaction was finished, 2...

Embodiment 2

[0052] Synthesis of A, α-methylbenzyl chloride

[0053] Put 200g of dichloromethane and 100g of styrene into the addition kettle, control the temperature at 0-10°C, and continuously feed dry hydrogen chloride to react for 15 hours; after the reaction, blow off the residual hydrogen chloride with nitrogen; Except dichloromethane, high vacuum rectification obtains 128g α-methyl benzyl chloride, after testing, the purity of α-methyl benzyl chloride is 98.0%, and the yield is 94.4%;

[0054] Synthesis of B, 2-phenylpropionic acid

[0055]Dissolve 128g of α-methylbenzyl chloride in 512g of 2-methyltetrahydrofuran, add magnesium powder with a molar ratio of 1.8 times (in terms of α-methylbenzyl chloride), and react at 0-10°C for 10 hours to prepare a Grignard solution; Controlling -15~-5℃, passing through dry carbonic acid gas with a molar ratio of 1.5 times, and reacting for 5 hours to obtain a carboxylated solution. After the reaction was finished, 2-methyltetrahydrofuran was re...

Embodiment 3

[0059] Synthesis of A, α-methylbenzyl chloride

[0060] Put 400g of dichloromethane and 100g of styrene into the addition kettle, control the temperature at 10-20°C, and continuously feed dry hydrogen chloride to react for 5 hours; after the reaction, blow off the residual hydrogen chloride with nitrogen; Except dichloromethane, high vacuum rectification obtains 130g α-methyl benzyl chloride, after testing, the purity of α-methyl benzyl chloride is 98.1%, and the yield is 95.9%;

[0061] Synthesis of B, 2-phenylpropionic acid

[0062] Dissolve 130g of α-methylbenzyl chloride in 780g of 2-methyltetrahydrofuran, add magnesium powder at a molar ratio of 2.2 times (in terms of α-methylbenzyl chloride), and react at 20-30°C for 5 hours to prepare a Grignard solution; Control 20-30°C, pass through dry carbonic acid gas with a molar ratio of 1.5 times, and react for 5 hours to obtain a carboxylated solution. After the reaction was finished, 2-methyltetrahydrofuran was removed by at...

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Abstract

The invention belongs to the field of synthesis of drug intermediates, and particularly relates to a preparation method of p-bromomethyl isophenylpropionic acid, which comprises the following steps: A, synthesis of alpha-methyl benzyl chloride: carrying out addition reaction on styrene serving as a raw material and hydrogen chloride gas in an organic solvent to generate alpha-methyl benzyl chloride, B, synthesis of 2-phenylpropionic acid: preparing alpha-methyl benzyl chloride into a Grignard solution through a Grignard reaction, the Grignard solution and carbon dioxide gas are subjected to acarboxylation reaction to generate a carboxylation solution, and the carboxylation solution is hydrolyzed to obtain 2-phenylpropionic acid, and C, synthesis of p-bromomethyl isophenylpropionic acid: carrying out bromomethylation reaction of 2-phenylpropionic acid, hydrobromic acid and polyformaldehyde so that p-bromomethyl isophenylpropionic acid is generated. The preparation method of p-bromomethyl isophenylpropionic acid provided by the invention has the advantages of cheap and accessible raw materials and simple technique, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of p-bromomethylisoprofen. Background technique [0002] At present, p-bromomethylisoprofen is the key intermediate for the synthesis of loxoprofen sodium, and loxoprofen sodium belongs to the new type of non-steroidal anti-inflammatory drugs of the aryl propionic acid class. The analgesic, anti-inflammatory and anti-rheumatic effects of acid drugs are the best, so they are favored by experts and scholars at home and abroad, as well as respected by the medical profession and patients. This product was developed and launched by Sankyo Pharmaceutical Co., Ltd. in Japan in 1986. It has been launched in Japan, South Korea, Europe, America and many other countries, with a strong growth momentum. [0003] my country has also started production and clinical application in recent years, but the production process of the prior art is complicat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/363C07C57/58C07C51/44
CPCC07C17/08C07C51/15C07C51/363C07C51/44C07C22/04C07C57/30C07C57/58
Inventor 龚华银罗恒强
Owner 张明
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