FI71299B - FOERENING ANVAENDBAR SAOSOM MELLANPRODUKT VID FRAMSTAELLNING AV THERAPEUTISKT VAERDEFULL 2- (6-METOXI-2-NAFTYL) -PROPIONSYRA - Google Patents

Description

1 71299

The present invention relates to a therapeutically valuable 2- (6-methoxy-2-naphthyl) propionic acid having the formula

10 CH-j O

I »

CH - C - OH

J J

15 / \ ch3o intermediate used in the preparation.

Said therapeutically valuable end product, i.e. 2- (6-methoxy-2-naphthyl) propionic acid, can be prepared by treating 2- (6-methoxy-2-naphthyl) -2-propanol or 6-methoxy-2- (2- propenyl) naphthalene with sulfur and an anhydrous amine at a temperature of at least 100 ° C until a thioamide is formed, after which this thioamide is hydrolyzed to form 2- (6-methoxy-2-naphthyl) propionic acid and 2- (6-methoxy) 2-Naphthyl) propionic acid is separated from the reaction mixture. The hydrolysis is preferably carried out by treating the thioamide with an aqueous solution containing a strong acid.

SE-A-428/68 (Patent No. 352069) discloses a process for the preparation of a compound of formula II and its salts and esters.

By using the intermediate according to the invention, the following advantages are obtained: 2 71299 (A) The conversion of the intermediate into the final product of formula II can be carried out in one step (the thioamide intermediate does not need to be isolated).

(B) The method does not require the use of very high or low temperatures, which simplifies the method and reduces production and equipment costs.

(C) The process does not require solvents in the preparation of the thioamide intermediate; the thioamide intermediate formed can be converted to the final product in aqueous solution. Thus, the solvent cost is low.

The first step of the process comprises a compound of formula _ R29 15

P.M

ch3o "20 29 wherein R is 2-hydroxy-2-propyl or 2-propenyl, by treatment with sulfur and anhydrous amine at elevated temperature, preferably at least 100 ° C, until thioamide is formed. The reaction mixture should contain at least 2c 2 and preferably at least 3 molar equivalents of sulfur in finely divided form At least 2 molar equivalents of amine must be used.

The amine used in this reaction may be any primary or secondary, aliphatic or ali-30 cyclic amine, such as a primary or secondary hydrocarbon amine having 12 carbon atoms, e.g., methylamine, dimethylamine, ethylamine, diethylamine, n-butylamine, n -hexylamine, n-octylamine, etc., and a cyclic amine which may be substituted with alkyl groups and which may have an oxygen in the ring structure such as p.peridine, morpholine, etc. A preferred such amine is morpholine because it allows the reaction to be carried out at atmospheric pressure. .

3,71299

No solvent is required in the reaction mixture. However, if desired, pyridine or an excess of an amine such as dimethylformamide may be used.

The time required for this reaction depends on the reaction temperature. Usually 4-48 hours is sufficient.

The thioamide is then hydrolyzed to form a compound of formula II. The hydrolysis is preferably carried out using an aqueous solution of a strong acid, which may preferably contain a water-miscible, acid-stable solvent such as a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol or tert-butanol, or a lower carboxylic acid such as acetic acid and the like. acids include trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc. The hydrolysis is preferably carried out at an elevated temperature such as 60 ° C to reflux until the compound is refluxed. The time required depends on the reaction temperature. Usually 1/2 to 24 hours is sufficient.

The compound of formula II is isolated from the reaction mixture in a conventional manner. For example, the reaction mixture can be diluted with water and extracted with ether. The etherase can be evaporated to dryness and the residue recrystallized from acetone-hexane to give the compound of formula II.

Alternatively, other conventional methods may be used, such as chromatographic treatment to separate the compound of formula II from the reaction mixture.

The most preferred product is d-2- (6-methoxy-2-naphthyl) -propionic acid. To obtain this product, the resolution of a racemate of formula II into optical isomers can be performed using selective biodegradation or by preparing diastereoisomeric salts of 2- (6-methoxy-2-naphthyl) propionic acid with a resolved optically active amine base such as cinchonidine. , and then separating the diastereoisomeric salts thus formed by fractional crystallization. The separated diastereoisomeric salts are then cleaved with an acid to give the corresponding d-2- (6-methoxy-2-naphthyl) -propionic acid.

The starting 2- (6-methoxy-2-naphthyl) -2-5 propanol can be prepared from the known 6-methoxy-2-acetylnaphthalene by reaction with methylmagnesium bromide in tetrahydrofuran for 10 minutes at room temperature. The reaction mixture is diluted with water and extracted with chloroform, and the chloroform extract is dried and evaporated to dryness to give 2- (6-methoxy-2-naphthyl) -2-propanol.

6-Methoxy-2- (2-propenyl) -naphthalene can be prepared by reacting 6-methoxy-2-acetyl-naphthalene with methylmagnesium bromide in tetrahydrofuran at reflux temperature in the presence of an acid such as hydrochloric acid for two hours. The reaction mixture is then diluted with water, extracted with chloroform and the chloroform phase is dried and evaporated to dryness to give 6-methoxy-2- (2-propenyl) -naphthalene.

The compound of formula II has anti-inflammatory, artalgesic and antipyretic activity and is thus used to treat inflammation, pain and pyrox in mammals. In this case, inflammatory conditions of, for example, the musculature, joints and other tissues can be treated. Thus, this compound is useful in the treatment of conditions characterized by inflammation, such as rheumatism, concussion, rupture, arthritis, fractures, post-rheumatic conditions, and gout.

Example 1 2- (6-Methoxy-2-naphthyl) -propionic acid

A mixture of 7 g of 2- (6-methoxy-2-naphthyl) -2-propanol (melting point 79 ° C), 1.7 g of sulfur and 4.6 g of morpholine is heated under reflux for 18 hours. Excess morphol.ini is removed in vacuo and the residue is heated to reflux with 35 ml of concentrated hydrochloric acid and 35 ml of acetic acid for 4 hours. The mixture is then poured into water and extracted with ether. The ether phase is dried and evaporated to dryness and the residue is recrystallized from acetone-hexane to give 2- (6-methoxy-2-naphthyl) -propionic acid.

Repeating the above procedure but substituting 2- (6-methoxy-2-naphthyl) -2-propanol for 6-methoxy-2- (2-propenyl) naphthalene gives the corresponding 2- (6-methoxy-2-naphthyl) ) propionic acid.

Example 2 2- (6-methoxy-2-naphthyl) -2-propanol

Dissolve 20.0 g of 6-methoxy-2-acetylnaphthalene in 200 ml of tetrahydrofuran. The solution is cooled to 0 ° C and 100 ml of 0.1 M methylmagnesium bromide (tetrahydrofuran solution) are added slowly (30 min). After stirring for 30 minutes, 300 ml of water, 200 ml of 1.0 M hydrochloric acid and 300 ml of chloroform are added. The chloroform solution is separated, dried over magnesium sulphate and evaporated to dryness to give 2- (6-methoxy-2-naphthyl) -2-propanol; mp. 79 ° C. Example 3 6-Methoxy-2- (2-propenyl) naphthalene

Dissolve 5.0 g of 6-methoxy-2-acetylnaphthalene 200 in any tetrahydrofuran, and add 100 ml of 1.0 M methylmagnesium bromide (dissolved in tetrahydrofuran). The solution is boiled briefly, 300 ml of 5.0 M hydrochloric acid are added and the mixture is refluxed for a further 2 hours. Water is added to the reaction mixture, and extracted with chloroform. The chloroform phase is separated and dried over magnesium sulphate and evaporated to dryness to give 6-methoxy-2- (2-propenyl) naphthalene; mp. 104-105 ° C.