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Process for producing 2-substituted propionic acid

a technology of propionic acid and substituted propionic acid, which is applied in the direction of carbon monoxide carboxylic preparation, organic chemistry, biocide, etc., can solve the problems of inconvenient industrial practice, and inability to achieve the effect of reducing the number of solvents

Inactive Publication Date: 2001-11-15
NIPPON PETROCHEMICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although above 2-(p-halomethylphenyl)propionic acid ester is relatively inexpensive, 2-cyclopentanone carboxylic acid ester is an expensive reagent.
However, the necessity for large quantity of solvent relative to the substrate substance of p-chloromethylstyrene is not advantageous in industrial practice.
This method cannot always be regarded as reasonable in industrial scale process in view of the fact that the high reactivity of vinyl group is not taken into consideration sufficiently.
Moreover, the method disclosed in the above International Publication cannot be said as inexpensive because expensive cyclopentanone carboxylic acid alkyl ester is used as a starting material.
In addition, the yield is not always satisfactory either.
Therefore, when halomethylstyrene is directly subjected to carbonylation, it is necessary to dilute the reaction system with a large amount of solvent as mentioned above, which is industrially costly.
However, a compound I, which is obtained by coupling halomethylstyrene with cyclopentanone carboxylic acid ester, is difficult to polymerize by itself.
These Lewis acids in themselves are difficult to handle.

Method used

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  • Process for producing 2-substituted propionic acid
  • Process for producing 2-substituted propionic acid
  • Process for producing 2-substituted propionic acid

Examples

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example 1

[0145] [Step (1-1)]

[0146] Into a reaction vessel of 15 liters were put 7.2 liters of toluene, 243 g (4.27 mol) of sodium methoxide (purity 95%) and 900 g (5.11 mol) of dimethyl adipate (purity 99%), and the mixture was heated with stirring. After the temperature in the vessel reached 60.degree. C., removal of the solvent of toluene was started under reduced pressure (9.3 kPa (70 mmHg) or less). At the same time, a by-product of methanol was also distilled off. The reaction was carried out for 40 minutes. As the result of measurement after the reaction, the total volume of mixed solvents of toluene and methanol was 6 liters. After that, 5.5 liters of acetone was added to the mixture. Further, 612 g (3.81 mol) of chloromethylstyrene (purity 95%; containing 500 ppm of nitrocresol, nitrophenol and 4-tert-butylcatechol in total; para-isomer:meta-isomer ratio=96:4) was added at room temperature, then the mixture was heated with refluxing for 8 hours.

[0147] At the temperature of 60.degree....

example 2

[0161] [Step (2-1)]

[0162] Into a reaction vessel of 300 ml were put 65 ml of toluene, 2.2 g (0.039 mol) of sodium methoxide (purity 95%) and 8.0 g (0.046 mol) of dimethyl adipate (purity 95%), and the mixture was heated with stirring, then the solvent was removed under reduced pressure. After that, 50 ml of acetone was added, then 30 ml of a toluene solution of methyl 2-(bromomethylphenyl)propionate (purity 92.7%; prepared from 9.09 g of 2-(bromomethylphenyl)propionic acid (purity 99.25%) was added at room temperature, and the mixture was heated with refluxing for 4 hours.

[0163] Acetone was distilled off under reduced pressure, then 50 ml of toluene, 30 ml of water and 1 ml of concentrated hydrochloric acid were added, and extraction was conducted by separation of liquids. After the organic phase was washed twice with 30 ml of water, filtration was carried out. With the removal of toluene under reduced pressure, 12.9 g of compound II (R'=R"=Me) in pale yellow was obtained as a raw p...

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Abstract

Adipic acid diester is caused to react with alkoxide M(OR)n, wherein R is an alkyl group and M is an alkali metal or alkaline earth metal, the reaction product is successively subjected either to coupling with halomethylstyrene followed by carbonylation, or to coupling with 2-(halomethylphenyl)propionic acid or its ester followed by decarboxylation and hydrolysis. With this process, it is possible to produce more efficiently a specific 2-substituted propionic acid, loxoprofen.

Description

[0001] (1) Field of the Invention[0002] The present invention relates to a process for producing 2-substituted propionic acid having effects as anti-inflammatory agent, analgesic, antipyretic and so forth.[0003] (2) Prior Art[0004] As disclosed in Japanese Patent Publication No. S58-004699, compounds of 2-substituted propionic acid have effects as anti-inflammatory agent, analgesic and antipyretic. Especially, 2-[4-(2-oxocyclopentan-1-yl methyl)phenyl]propionic acid, "loxoprofen", is commercially available as an excellent analgesic drug.[0005] In addition to the above disclosure, as disclosed in Japanese Laid-Open Patent Publication No. S62-161740, the conventional preparation process includes the steps of (1) coupling reaction of 2-(p-halomethylphenyl)propionic acid ester with 2-cyclopentanone carboxylic acid ester in the presence of a base, and (2) decarboxylation and hydrolysis of ester with an acid.[0006] In the above first coupling step, the hydrogen atom at .alpha.-position of...

Claims

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Application Information

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IPC IPC(8): C07C51/14C07C67/343C07C69/74C07C67/38
CPCC07C51/14C07C67/343C07C67/38C07C2101/08C07C59/86C07C69/757C07C2601/08C07C69/74
Inventor WATANABE, SAISUKESUYAMA, KAZUHARU
Owner NIPPON PETROCHEMICAL CO LTD
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