Method for producing zaltoprofen and derivative thereof

A manufacturing method and technology of derivatives, applied in the direction of drug combinations, active ingredients of heterocyclic compounds, antipyretics, etc., can solve problems such as dimers not being removed, purity that cannot be said to be sufficient, toxicity, etc.

Active Publication Date: 2014-12-03
NIPPON CHEMIPHAR CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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

Method used

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  • Method for producing zaltoprofen and derivative thereof
  • Method for producing zaltoprofen and derivative thereof
  • Method for producing zaltoprofen and derivative thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0146] Production of zaltoprofen by ring closure in the presence of methylcyclohexane

[0147] In the 5-(1-carboxyethyl)-2-phenylthiophenylacetic acid shown in the following formula (IV) of 50g (0.158mol), add the polyphosphoric acid of 250g degree of condensation 105% and the methyl Cyclohexane was stirred at an internal temperature of 90 to 95°C for 3.5 hours while slowly heating. Thereafter, heating was stopped, and when the internal temperature reached 45° C., 250 mL of water and 250 mL of ethyl acetate were simultaneously added dropwise, and the organic solvent layer was fractionated. The aqueous layer was extracted with 150 mL of ethyl acetate, the separated ethyl acetate and the organic solvent layer were combined, 200 mL of water and 200 mL of brine were added, and the organic solvent layer was separated and washed. After adding 50 g of anhydrous sodium sulfate to the fractionated organic layer for dehydration, the organic solvent was distilled off under reduced pre...

Embodiment 2

[0151] Production of zaltoprofen by ring closure in the presence of n-heptane

[0152] In the 5-(1-carboxyethyl)-2-phenylthiophenylacetic acid shown in the following formula (IV) of 100g (0.316mol), add the polyphosphoric acid of 500g degree of condensation 105% and the n-heptyl of 120mL alkane, and stirred at an internal temperature of 98° C. for 4.5 hours while heating slowly. Thereafter, heating was stopped, and when the internal temperature reached 45° C., 500 mL of water and 500 mL of ethyl acetate were simultaneously added dropwise with an internal temperature of 60° C. as the upper limit, and the organic solvent layer was separated. The aqueous layer was extracted with 300 mL of ethyl acetate, combined with the above organic solvent layer, and after adding 500 mL of water and 500 mL of saline, the organic solvent layer was separated and washed. After adding 50 g of anhydrous sodium sulfate to the fractionated organic layer for dehydration, the organic solvent was dis...

Embodiment 3

[0156] Production of zaltoprofen by ring closure in the presence of 1,1,2-trichloroethylene

[0157] In 5-(1-carboxyethyl)-2-phenylthiophenylacetic acid shown in the following formula (IV) of 5.20g (16.4mmol), add polyphosphoric acid and 8.0mL polyphosphoric acid of 33.5g degree of condensation 105% 1,1,2-trichloroethylene was stirred at an internal temperature of 89° C. for 3 hours while slowly heating. Thereafter, heating was stopped, and when the internal temperature reached 40° C., 25 mL of water and 25 mL of ethyl acetate were simultaneously added dropwise with an internal temperature of 60° C. as the upper limit, and the organic solvent layer was separated. The aqueous layer was extracted with 15 mL of ethyl acetate, and the separated ethyl acetate was combined with the above organic solvent layer to obtain the zaltoprofen fraction. After adding 30 mL of water and 30 mL of saline to the zaltoprofen portion, the organic solvent layer was separated and washed. After ad...

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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...

Claims

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Application Information

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IPC IPC(8): C07D337/14A61K31/38A61P29/00
CPCC07D337/14A61P29/00
Inventor 天童温
Owner NIPPON CHEMIPHAR CO LTD
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