FI66342C - FOERENING ANVAENDBAR SAOSOM MELLANPRODUKT VID FRAMSTAELLNING AV THERAPEUTISKT VAERDEFULL 2- (6-METOXI-2-NAFTYL) PROPIONSYRA OCH DESS DERIVAT - Google Patents

Description

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Paten »- och wgifrityral—> ^ A — taw o5> 29.06.84 (32) (33) (31) fyntwqr rnmoUum BhW fhoUtm 27.08.69 USA (US) 853481, 30.09.69 USA (US) 862470, 862469, 862488 , 862489, 862468, 862467, 862477, 862478, 862490, 862491, 862472, 862492, 862461, 862493, 862494, 862462, 862499, 862475, 862500, 862501, 862473, 862502, 862474, 862484, 862487, 862486, 8624 , 862459, 862458, 862457, 862456, 862454, 862452 (71) Syntex Pharmaceutical International Limited, Global House, Church Street, Hamilton 5, Bermuda (BM) (72) John Hans Fried, Palo Alto, Calif., Ian Thomas Harrison, Palo Alto,

Calif., Francisco Sanches Alvarez, Palo Alto, Calif., Peter Harold Nelson, Palo Alto, Calif., Michael Marx, Palo Alto, Calif.,

Karl George Untch, Palo Alto, Calif., USA (74) Oy Kolster Ab (54) Intermediate compound used in the preparation of therapeutically valuable 2- (6-methoxy-2-naphthyl) propionic acid and its derivatives - Förening användbar säsom mellanprodukt vid The present invention relates to a therapeutically valuable formula ίΗ3? The present invention relates to a therapeutically valuable formula ίΗ3? - Framställning av tera-peutiskt värdefull 2- (6-methoxy-2-nafty1) propionyra och dess derivat (62) Separated from application 501/70

jCH - C - OH

A compound used as an intermediate in the preparation of 2- (6-methoxy-2-naphthyl) propionic acid and its derivatives of formula Xu CH30 of formula 2 66342 CH, t 3

CH - X

i 11 Λ ch3o ^ ^ ^ wherein X is halogen or magnesium halide.

The valuable end product is prepared by reacting a novel compound of formula II with carbon dioxide, ethyl orthocarbonate or ethyl chloroformate at a temperature between -65 ° and 100 ° C, preferably between -65 ° and 25 ° C, and treating the reaction product with an acid until a compound of formula I is formed. compound.

For carboxylation with carbon dioxide, the compound of formula II 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 II 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 II 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 the carboxylation is carried out with carbon dioxide, a compound of formula I is formed 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 an excess acid at a temperature between 25 ° C and reflux temperature until a compound of formula I is formed. Usually 1-48 hours is sufficient.

The compound of formula I is then separated from the reaction mixture.

For example, if the organic solvent in the reaction mixture has been removed and 66342 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.

The most preferred compound of formula I is d-2- (6-methoxy-2-naphthyl) propionic acid. To obtain this product, the decomposition of a compound of formula II can be performed using selective biodegradation or diastereoisomeric salts of 2- (6-methoxy-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: CHO CH-I 3 | 3 4. C = 0 _ / CH-X *

I - * I

/ S - .--- / S - - CH30 CH30 '(D) (E) CH- I 3

CH-M

ch3o (It) t 4 66342

In the above schemes, M is magnesium halide and 4 X is iodine, bromine or chlorine.

Compounds of formula (E) 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 slight 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-toluenesulfonyl 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-toluenesulfonate. 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 (E).

Compounds of formula II wherein X is MgCl, MgBr or Mgl (most preferred compounds) are prepared by reacting the corresponding halide of formula (E) in tetrahydrofuran with 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 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, congestion rupture, arthritis, fractures, rheumatoid arthritis, and gout.

Example 1

A solution of 12.5 g of 1-bromo-1- (6-methoxy-2-naphthyl) ethane in 100 ml of tetrahydrofuran is slowly added to a stirred mixture of 10 g of magnesium powder in 100 ml of tetrahydrofuran at 45 ° C. When the addition is complete, the mixture is stirred for 15 minutes and the solution is separated from the excess metal to give 1- (6-methoxy-2-naphthyl) -1-ethylmagnesium bromide.

66342

By repeating the above procedure, but replacing the magnesium powder with lithium or zinc powder, the corresponding 1- (6-methoxy-2-naphthyl) -1-ethyllithium and zinc are formed.

The above solution is mixed (after removal of excess metal) with 7 g of cadmium chloride and the reaction mixture is stirred for 30 minutes to give a solution containing the corresponding 1- (6-methoxy-2-naphthyl) -1-ethyl cadmium. Repeating this procedure, but replacing the cadmium chloride with finely divided sodium or potassium, gives the corresponding 1- (6-methoxy-2-naphthyl) -1-ethyl sodium or potassium.

Example 2

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.

By repeating the above treatment # but substituting 1- (6-methoxy-2-naphthyl) -1-ethylmagnesium bromide for the corresponding 1- (6-methoxy-2-naphthyl) -1-ethylmagnesium iodide, 1- (6-methoxy-2-naphthyl) ) -1-ethylmagnesium chloride, (NMR spectrum: 6.8-7.7 ppm (multiplet) with 1- (6-methoxy-2-naphthyl) -1-ethyllithium, 1- (6-methoxy-2-naphthyl) - 1-ethylzinc, 1- (6-methoxy-2-naphthyl) -1-ethyl cadmium, 1- (6-methoxy-2-naphthyl) -1-ethyl sodium and 1- (6-methoxy-2-naphthyl) - With 1-ethyl potassium, the corresponding 2- (6-methoxy-2-naphthyl) propionic acid is obtained in each case.

Example 3 10 g of ethyl orthocarbonate are added to a solution of 0.5 equivalents of 1- (6-methoxy-2-naphthyl) -1-ethylmagnesium bromide in 250 ml of tetrahydrofuran, and the reaction mixture is stirred for 4 hours. Excess 4-hydrochloric acid is then slowly added to the reaction mixture and heated at reflux for 24 hours. The reaction mixture is extracted with diethyl ether, the ether phase is evaporated to dryness and the residue is recrystallized from acetone-hexane to give 2- (6-methoxy-2-naphthyl) propionic acid.

By repeating this treatment but replacing 1- (6-methoxy-2-naphthyl) -1-ethylmagnesium bromide with the corresponding 1- (6-methoxy-2-naphth-66342 style) -1-ethylmagnesium iodide, 1- (6-methoxy-2- naphthyl) -1-ethylmagnesium chloride, 1- (6-methoxy-2-naphthyl) -1-ethyllithium, 1- (6-methoxy-2-naphthyl) -1-ethylzinc, 1- (6-methoxy-2- naphthyl) -1-ethyl cadmium, 1- (6-methoxy-2-naphthyl) -1-ethyl sodium and 1- (6-methoxy-2-naphthyl) ethyl potassium, the corresponding 2- (6-methoxy-2-naphthyl) propionic acids.

Example 4

A solution of 1- (6-methoxy-2-naphthyl) -1-ethylmagnesium bromide (0.5 equivalents) in 100 ml of tetrahydrofuran is slowly added to a solution of 6 g of ethyl chloroformate in 100 ml of tetrahydrofuran. The mixture is then acidified with 75 ml of concentrated hydrochloric acid and the mixture is heated under reflux for 24 hours. The reaction mixture is then diluted with water and extracted with diethyl ether. The ether phase is evaporated to dryness and the residue is recrystallized from acetone-hexane to give 2- (6-methoxy-2-naphthyl) propionic acid.

By repeating the above procedure but replacing 1- (6-methoxy-2-naphthyl) -1-ethylmagnesium bromide with the corresponding 1- (6-methoxy-2-naphthyl) -1-ethylmagnesium chloride, 1- (6-methoxy-2-naphthyl) ethyl) lithium, 1- (6-methoxy-2-naphthyl) -1-ethylzinc, 1- (6-methoxy-2-naphthyl) -1-ethylcadmium, 1- (6-methoxy-2-naphthyl) li) -1-ethyl sodium and 1- (6-methoxy-2-naphthyl) -1-ethyl potassium, the corresponding 2- (6-methoxy-2-naphthyl) propionic acid is obtained.

Example 5

A solution of 12.5 g of 2- (1-bromoethyl) -6-methoxynaphthalene (melting point 86.5-88 ° C) in 200 ml of tert-butanol containing 11.5 g of potassium t-butoxide, treated with 50 g of nickel carbonyl and the reaction mixture is heated at 50 ° C for 24 hours. The mixture is then evaporated to dryness. Addition of 200 ml of 6-hydrochloric acid, followed by heating under reflux for 12 hours, gives 2- (6-methoxy-2-naphthyl) propionic acid, which is extracted with ether. The ether phase is evaporated to dryness and the residue is recrystallized from acetone-hexane.

Example 6 A. 111.6 kg of acetaldehyde and 4019 l of toluene are mixed and added to a mixture of 602.4 kg of 6-methoxynaphthyl-2-magnesium bromide in 2630.8 l of tetrahydrofuran and 2649.7 l of toluene. The reaction mixture is stirred after the addition, after which it is poured into a mixture of 1306.3 kg of ice and 235.9 kg of hydrochloric acid (22 degrees Baum). The aqueous phase is separated, extracted with 4019 l of toluene and the extracted toluene is combined with the organic phase. The organic phase is washed first with sodium bisulfite / water solution and then with sodium carbonate / water solution. The solvent is removed and 34.1 l of methanol are added. The resulting slurry containing 1- (6'-methoxy-naphthyl-2 ') - 1-ethanol is cooled and used in the next step.

To the slurry obtained above is added 136 kg of anhydrous hydrochloric acid, the mixture is stirred, the aqueous phase is separated, extracted with about 1359 l of toluene, neutralized and discarded. 4.5 kg of DARCO G-60 bleach and 4.5 kg of SOLKA FLOG bleach are added to the combined organic phase, the organic phase is stripped at low temperature to remove (acid) water and most of the toluene. 2- (1-chloroethyl) -6-methoxynaphthalene is obtained, m.p. 84-84.5 ° C.

B. Using anhydrous hydrobromic acid instead of anhydrous hydrochloric acid in the process described in A above gives 2- (1-bromoethyl) -6-methoxynaphthalene, m.p. 86.5-88 ° C.

J

Claims (1)

8,66342 Claims 1. A compound used as an intermediate in the preparation of 2- (6-methoxy-2-naphthyl) propionic acid of the formula CH_ O f 3 II ^ CH - C - OH "ΎΎ CH.O and its derivatives, characterized in that it has the formula? H3 CH - X CH.CT wherein X is halogen or magnesium halide 2. 1- (6-methoxy-2-naphthyl) -1-ethylmagnesium halide wherein the halide is bromide, chloride or iodide 3. 2- (1-haloethyl) -6 -methoxynaphthalene in which the halogen is bromine, iodine or chlorine 4. 2- (1-bromoethyl) -6-methoxynaphthalene.