Method for producing zaltoprofen and derivative thereof

Abstract

The invention pertains to a method for producing zaltoprofen or a zaltoprofen derivative by an intramolecular cyclization reaction of the Friedel-Crafts reaction type, wherein zaltoprofen or a zaltoprofen derivative is produced at an industrially usable yield, simply, economically, and on an industrial scale at adequate purity for use as a pharmaceutical active ingredient without generating detectable amounts of dimer or other such impurities, using polyphosphoric acid in a quantity of 6.5 times or less the uncyclized raw material compound as a condensing agent. Specifically, the invention pertains to a method for producing zaltoprofen or a zaltoprofen derivative by cyclization of an uncyclized raw material compound in the presence of one or more organic solvents selected from the group consisting of 1,1,2-trichloroethene, methyl cyclohexane, cyclohexane, n-heptane, and the like.

Description

technical field [0001] The invention relates to a novel production method of zaltoprofen and its derivatives. Background technique [0002] Known compound shown in following formula (A) (in the formula, R 1 represents a lower alkyl group) as a non-steroidal analgesic and anti-inflammatory agent has excellent anti-inflammatory and analgesic effects (Japanese Patent Publication No. 61-7199, Japanese Patent Application Laid-Open No. 2005-289949). [0003] [0004] The compound of above-mentioned formula (A) can be by using the compound shown in following formula (B) (wherein R 1 and R 2 Each independently represents a lower alkyl group) as a starting material, which can be obtained by a Friedel-Crafts reaction-type intramolecular cyclization reaction (JP-A-1-29793, JP-A-2005-289949). [0005] [0006] Among the compounds of the above formula (A), especially R 1 for CH 3 2-(10,11-dihydro-10-oxodibenzo[b,f]thiazin-2-yl)propionic acid represented by the following formul...

AI Technical Summary

Problems solved by technology

[0015] However, when Zaltobuprofen is produced by the method described in Japanese Patent Publication No. 01-29793 (Example 3) or Japanese Patent Application Laid-Open No. 57-171991 (Table 1), there is a problem that it is difficult to remove because it is presumed to be produced. The trace impurity of the dimer, so when improving as a medicine, it is necessary to further repeat column chromatography or recrystallization to improve the purity (Japanese Patent Application No. 2006-273731, Japanese Patent Application No. 2005-289949)

[0017] However, the method of Japanese Patent Laid-Open No. 2006-273731 has the following problems: the organic solvent used in the ring-closing reaction is dichloromethane, and dichloromethane is worried about environmental burden and human toxicity, and its utilization and disposal are "specified". Substances regulated by the Act on the Grasp of the Discharge of Chemical Substances into the Environment, etc. and the Promotion of Management Improvement

And, the purity of gained zaltoprofen has only 98.01% (embodiment 5)~99.01% (embodiment 12), although compare as the purity 95.13% of zaltoprofen obtained when not adding inorganic base or inorganic salts % (Comparative Example 1) to 96.14% (Comparative Example 2) is high purity, but it cannot be said to be sufficiently pure as a drug

Especially for the method of Japanese Patent Laid-Open No. 2006-273731, it contains 0.02% (Example 12) to 0.15% (Example 3) of dimers that are extremely difficult to remove, which is a big problem in industrial production.

In addition, the method of Japanese Patent Laid-Open No. 2006-273731 also has the following problem. That is, when inorganic bases or inorganic salts form salts with zaltoprofen, they must be converted into free forms or hydrochlorides, so the number of steps increases.

[0018] In addition, the method of Japanese Patent Publication No. 6-51697 has the following problems: three recrystallizations are required, and after recrystallization, the crystalline salt with the organic amine must be converted into a free body or a hydrochloride

In addition, in the embodiment of the method of Japanese Patent Publication No. 6-51697, only the spot of impurities was not confirmed in the purified product obtained by recrystallization by thin-layer chromatography belonging to a simple measurement method, and it cannot be said that there are no impurities.

[0019] The method of Japanese Patent Application Laid-Open No. 2006-290753 has the following problems: 10 g of the crude product needs to be dissolved in 100 ml of ketone-based solvent and then distilled off to 20 ml, and seed crystals are added at room temperature, and stirred for 12 hours while cooling to 5° C., and then Complicated operations such as stirring for 1 hour while cooling to -30°C require large equipment capable of cooling to -30°C

In addition, the method of Japanese Patent Laid-Open No. 2006-290753 still has the problem that 0.01% to 0.12% of dimers are not removed.

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