KR830000127B1 - Process for preparing cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid - Google Patents

Abstract

No content.

Description

Process for preparing cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid

The present invention relates to a process for preparing cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid of the following general formula (I).

The compounds have anti-inflammatory, analgesic and antipyretic effects and are therefore useful for the treatment of diseases exhibiting pain, fever or inflammation. In the treatment of such diseases, the cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid of the present invention is 0.1-50 mg / kg body weight per day The dosage range (preferably in the range of about 1-15 mg / kg body weight per day) can be administered locally, orally, rectally or parenterally.

Although 5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid may be present in both cis and trans isomers, the benzylidene group is under the phenyl ring of the indene nucleus. Those skilled in the art will appreciate that the aligned cis isomers are the most preferred isomeric forms.

In addition, the sulfur atoms in cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid form an asymmetric center, and this polymer is incorporated in the art. It will be appreciated by those skilled in the art that the separation into (+) and (-) forms by well known methods is possible.

In addition, the compounds are polymorphic and have more than one crystal structure, so that they can be separated into solid states having different melting points.

It is an object of the present invention to provide a novel process for preparing cis-5-fluoro-2-methyl-1- [p- (methyl-sulfinyl) benzylidene] indene-3-acetic acid.

Another object of the present invention is to provide a method for preparing a compound of the present invention in which a p-methylsulfinyl phenyl substituent is formed as a final step of the present method.

One feature of the present invention is that diazotized p-fluoroaniline and then reacted with ethyl-4-methyl-3-oxo (OXO) -4-hexenoate to yield ethyl-5- (p-fluoro as the first intermediate. Phenyl) -4-methyl-3-oxo-4-hexenoate compound is prepared. The diazotization reaction is carried out by acidifying p-fluoroaniline at 0-10 ° C. and then treating with aqueous sodium nitrite solution. The resulting solution of the diazonium salt of p-fluoroaniline was warmed up to 20-25 ° C and then added to a mixture of ethyl-4-methyl-3-oxo-4-hexenoate, sodium acetate trihydrate and cupric chloride dihydrate. Was added and stirred at 20-30 ° C. for 1-3 hours to prepare ethyl-5- (p-fluorophenyl) -4-methyl-3-oxo-4-hexenoate.

The obtained product is cyclized by treating with sulfuric acid to produce substituted indene. In this step, ethyl-5- (p-fluorophenyl) -4-methyl-3-oxo-4-hexenoate is heated with concentrated sulfuric acid at 100-150 ° C. for 1-4 hours to give 5-fluoro- 2-Methyl-1-methylidene-3-indeneacetic acid is prepared.

In the final step of the process, the diazotized p-methylsulfinylaniline is coupled with the intermediate 5-fluoro-2-methyl-1-methylidene-indene-3-acetic acid to yield the desired product cis-5- Fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid is prepared. To explain this step more specifically, p-methylsulfinylaniline is dissolved in an acid at 0-10 ° C. and treated with an aqueous sodium nitrite solution to prepare a diazonium salt, and the diazonium salt obtained is warmed to 20-30 ° C. Next, to a mixture of 5-fluoro-2-methyl-1-methylidene-indene-3-acetic acid, sodium acetate trihydrate and cupric chloride dihydrate, the desired product, cis-5-fluoro-2-methyl- Prepare 1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid.

Briefly describing the reactor of the present application is as follows.

Cis-isomers and small but indeterminate trans-isomers.

The presence of cis and trans isomers for the compounds of the present invention was confirmed by spectroscopy, and the UV absorption data of the solution at a concentration of 1 g in 100 ml of solution (0.1NHCl / methanol) are shown in Table 1.

TABLE 1

The present invention is described in detail based on the following examples.

Example 1

Ethyl 5- (p-fluorophenyl) -4-methyl-3-oxo-4-hexenoate

p-fluoroaniline (27.8 g, 0.25 mol) was dissolved in 300 ml of 5N hydrochloric acid, cooled to 5-10 ° C. and then treated with 70 ml of 30% aqueous sodium nitrite solution to convert to the corresponding diazonium chloride. The solution was added to a mixture of 42.3 g (0.25 mol) of ethyl 4-methyl-3-oxo-4-hexenoate, 30 g of sodium acetate trihydrate and 5 g of cupric chloride dihydrate in 200 ml of acetone. Dropwise at 25 ° C. After 2 hours at 25-30 ° C., nitrogen gas evolution ceased. The precipitate was filtered off and washed with 200 ml of water to afford ethyl 5- (p-fluorophenyl) -4-methyl-3-oxo-4-hexenoate.

Example 2

5-Fluoro-2-methyl-1-methylidene-indene-3-acetic acid

A mixture of ethyl 5- (p-fluorophenyl) -4-methyl-3-oxo-4-hexenoate and 250 ml of concentrated sulfuric acid (132 g, 0.5 mole) was stirred at 125 ° C. for 3 hours. The reaction was cooled to 25 ° C. and then quenched in 750 ml of water. The precipitate was filtered off, washed with water and dried with air to afford 5-fluoro-2-methyl-1-methylidene-indene-3-acetic acid.

Example 3

Cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] -indene-3-acetic acid

p-methylsulfinanianiline (77.6 g, 0.5 mole) was dissolved in 600 ml of 5N hydrochloric acid and then cooled to 5-10 ° C. and then treated with 140 ml of 30% aqueous sodium nitrite solution to convert to the corresponding diazonium chloride. This solution was prepared from 13213 g (0.5 mole) of 5-fluoro-2-methyl-1-methylidene-indene-3-acetic acid, 60 g of sodium acetate trihydrate and 10 g of cupric chloride dihydrate in 400 ml of acetone. To the mixture was added dropwise at 20-25 ° C. After 2 hours at 25-30 ° C., nitrogen gas evolution ceased. The precipitate was filtered off, washed with water and dried with air to afford cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid.

Claims (1)

Diazolation of p-fluoroaniline to produce the corresponding diazonium salt, followed by reaction of the obtained diazonium salt with ethyl 4-methyl-3-oxohexanoate to give ethyl-5- (p-fluorophenyl)- 4-Methyl-3-oxo-4-hexenoate is prepared and cyclized to sulfuric acid to give 5-fluoro-2-methyl-1-methylidene-indene-3-acetic acid followed by indene-3-acetic acid Cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene- of general formula (I), characterized by reacting with diazotized p-methylsulfinylaniline Process for preparing 3-acetic acid.