FI66344B - PROCEDURE FOR FRAMSTATION OF AV D-2- (6-METOXY-2-NAPHTHYL) PROPIONYRA - Google Patents

Description

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Church Street, Hamilton 5, Bermuda (BM) (72) John Hans Fried, Palo Alto, California, lan Thomas Harrison, Palo Aito, California, Francisco Sanches Alvarez, Palo Alto, California, Peter Harold Nelson, Palo Alto, California, Michael Marx, Palo Alto, California, Karl George Untch, Palo Alto, California, USA (74) Oy Koister Ab (54) Process for the preparation of d-2- (6-methoxy-2-naphthyl) prop ionic acid -Förfarande f $ r framställning av d-2- (6-methoxy-2-nafty1) propionyl (62) Divided by application 501/70 - Avdelad frän ansökan 501/70

The present invention relates to a process for the preparation of d-2- (6-methoxy-2-naphthyl) propionic acid.

According to the process of the invention, 2- (1-haloethyl) -6-methoxynaphthalene of the formula CH3

. I ^ II

cH3cr ^^ where Hal represents a halogen atom is reacted with magnesium to give 1- (6-methoxy-2-naphthyl) ethylmagnesium halide of formula 2,66344 CH3 CH-MgHal

XXJ

cn3 <r v wherein Hal is as defined above, and the resulting magnesium halide is reacted with carbon dioxide to give d-2- (6-methoxy-N, N-naphthyl) propionic acid.

For carboxylation with carbon dioxide, the compound of formula III is preferably contacted with solid carbon dioxide and the mixture is allowed to warm to room temperature. For the reaction with ethyl orthocarbonate and ethyl chloroformate, the compound of formula III is preferably mixed with the reagent at about room temperature.

Suitable solvents for this reaction are all solvents which are inert to the compound of formula III and the reagent. Suitable solvents include ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, tetrahydropyran and the like.

The reaction mixture is then acidified with an organic or inorganic acid, preferably a strong acid such as trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, hydroiodic acid, hydrobromic acid, and the like.

When carboxylation is performed with carbon dioxide, the formula is formed

CH. O

I * 3 I »

CH - C - OH

immediately after acidification of the intermediate.

When the carboxylation is performed using ethyl orthocarbonate or ethyl chloroformate, the reaction mixture containing the intermediate is treated with excess acid at a temperature of 25 ° C.

3 66344 and the reflux temperature until the compound of formula I is formed, Usually 1-48 hours is sufficient.

The compound of formula I is then separated from the reaction mixture. If, for example, the organic solvent in the reaction mixture is removed and replaced with water, the acidification immediately precipitates the compound of formula I. The precipitate can be separated by filtration and recrystallized from acetone-hexane. If the reaction mixture contains an organic solvent, it can be extracted with ether and the organic phase can be evaporated to give a compound of formula II which is recrystallized from acetone-hexane. Other conventional separation methods may also be used, including chromatographic treatment.

To obtain d-2- (6-methoxy-2-naphthyl) propionic acid of formula I, the resolution of a compound of formula I can be performed using selective biodegradation or by preparing diastereoisomeric salts of 2- (6-methoxy-2-naphthyl) propionic acid with a resolved optically active 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 compounds of formula II are prepared by a method which can be represented as follows: CH, CH,

I -3 | J

^ c = 0 - CH-Hal ΓTj - * rfx (D) (II)

In the above formulas, Hai means iodine, bromine or chlorine,

Compounds of formula II are prepared by the following method: Compounds of formula (D) are reduced to the corresponding alcohol by treatment with sodium borohydride in ethanol at room temperature for 30 minutes, followed by mild acidification of the reaction mixture with dilute hydrochloric acid and extraction of the reaction mixture with diethyl ether. The ether phase is evaporated to dryness to give the alcohol. The residue is reacted with p-toluenesulphonyl chloride in pyridine at room temperature for about 15 hours, followed by washing with dilute hydrochloric acid, extraction with ether and evaporation of the ether phase to give the corresponding p-toluenesulphonate. The residue of this reaction is then reacted with excess lithium halide (lithium bromide, chloride or iodide) in acetone for 24 hours at room temperature and the reaction mixture is diluted with water and extracted with ether. The ether phase is then evaporated to dryness to give the corresponding halides of formula II.

Compounds of formula III are prepared by reacting the corresponding halide of formula II in tetrahydrofuran using an excess of powdered magnesium at a temperature of about 45 ° C. The reaction product is then separated from the excess metal.

The compound of formula I has anti-inflammatory analgesic and antipyretic activity and is thus used to treat inflammation, pain and pyroxia in mammals. In this case, inflammatory conditions of, for example, musculoskeletal, joint and other tissues can be treated. Thus, this compound is useful in the treatment of conditions characterized by inflammation, such as rheumatism, conccussion, tears, arthritis, fractures, post-rheumatic conditions and gout.

The reaction according to the invention is special because the yield is good, above about 80%. For example, J. Am. Chem, Soc. 62 (1940) 2295-2300, poor yield is expected when grignardating a compound having a methyl group on the carboxylating carbon due to a steric hindrance.

The invention is further illustrated by the following example.

Example

A solution of 1- (6-methoxy-2-naphthyl) -1-ethylmagnesium bromide in 200 ml of tetrahydrofuran is poured into 500 g of solid carbon dioxide. After allowing the mixture to warm to room temperature, the solvent is removed in vacuo and the residue is treated with excess dilute hydrochloric acid. Upon acidification, 2- (6-methoxy-2-naphthyl) propionic acid precipitates, which is separated from the reaction mixture by filtration and recrystallized from acetone-hexane; yield 82%, m.p. 153-154 ° C, 5,66344

By repeating the above treatment but replacing 1- (6-methoxy-2-naphthyl) -1-ethylmagnesium bromide with 1- (6-methoxy-2-naphthyl) -1-ethylmagnesium iodide, 1- (6-methoxy-2-naphthyl ) -1-ethylmagnesium chloride, 1 '- (6-methoxy-2-naphthyl) -1-ethyllithium, 1- (6-methoxy-2-naphthyl) -1H-ethylzinc, 1- (6-methoxy-2- naphthyl) -1-ethyl cadmium, 1- (6-methoxy-2-naphthyl) -1-ethyl sodium and 1- (6-methoxy-2-naphthyl) -1-ethyl potassium, 2- (6 * - methoxy (2-naphthyl) propionic acid in good yield,

Claims (1)

66344 A process for the preparation of d-2- (6-methoxy (2-naphthyl) propionic acid having the formula CH-. O-M / CH - C - OH ^ Ύ ^ I characterized in that 2- (1-haloethyl) -6-methoxy-naphthalene of the formula CH3 ^ ^ ^ ^ ^ CH-Hal II ch3o ^ / " wherein Hal represents a halogen atom, is reacted with magnesium to give 1- (6-methoxy-2-naphthyl) ethylmagnesium halide of formula ch3 CH-MgHal Jk Λ III ch3o ^ wherein Hal represents the same as above, and obtained magnesium halide is reacted with carbon dioxide to give d-2- (6-methoxy-2-naphthyl) propionic acid,