HU191845B - Process for the production of /d/-2-/6-methoxy-2-naphthyl/-propionic acid and of its therapeutically acceptabel salts - Google Patents

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Description

The present invention relates to a process for the preparation of (d) -2- (6-methoxy-2-naphthyl) -propionic acid and its pharmaceutically acceptable salts. (D) -2- (6-Methoxy-2-naphthyl) -propionic acid is known as an anti-inflammatory, analgesic, antipyretic, naproxen.

Naproxen and its salts are optically active compounds which are generally prepared from a mixture of the (d) and (1) enantiomers.

No. 79,102,502.6. and 80 103 828.2. In the process of European Patent Application, naproxen and its salts are prepared by using N-R-D-glucamine or a salt thereof as a resolving agent, wherein R is a C 1-36 alkyl group or

C3-C8 cycloalkyl. In the resolution process, a mixture of the two enantiomers forms a salt with N-R-D-glucamine, the salts are subjected to fractional crystallization, and the less soluble naproxen salt is crystallized from the other, more soluble, enantiomeric salt.

No. 1,274,271. The preparation of d, l-2- (5-halo-6-methoxy-2-naphthyl) -propionic acids is known from the British patent, and these acids can be resolved with alkaloids such as zinconidine.

It has now been found that N-R-D-glucamines or salts thereof, wherein R is C 1 -C 14, preferably C 2 -C 14 alkyl, or

C 4 -C 8 cycloalkyl groups, especially C 5 -C 8 cycloalkyl groups, can be used as resolving agents for the preparation of naproxen precursors which can be easily converted to naproxen. Therefore, according to the invention, N-R-D-glucamines or their salts are used as resolving agents for the preparation of naproxen precursors. These resolving agents form the diastereomeric (dl) -naproxen precursor salts from which the salt of the naproxen precursor can be isolated. The separation is preferably carried out by fractional crystallization of diastereomeric salts.

Thus, in accordance with the present invention, these resolving agents are used for the resolution of naproxen prodrugs containing a portion of naproxen propionic acid, but with substituents present on the molecule away from the asymmetric center. These substituents can be readily converted to provide the naproxen molecule.

In a preferred embodiment of the process of the invention, the distance between the point of attachment of these convertable substituents to the naphthalene ring and the asymmetric center, i.e. the carbon atom to which the methyl group is attached, is from about 5.8 to about 6.6 A. substituents include halogen at the 5-position of the naphthyl and hydroxy at the 6-position of the naphthyl. Both groups can be easily converted to the substituents present in naproxen (i.e., the 5-position hydrogen atom and the 6-position methoxy group) while maintaining the stereo configuration of the molecule.

In particular, the naproxen precursors are represented by formula (I) wherein R ¹ is hydrogen or methyl, X is halo, preferably chloro or bromo and n is 1; or R ¹ is hydrogen and. n is 0. The daily-oxen precursors also include salts of the compounds of formula (I).

Racemic mixtures of compounds of formula I are known. For example, (d, l) -2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid is

No. 934,460 German Patent Publication No. 4,198,198. [This is a compound of formula (I) wherein R ¹ is methyl, X is bromo, n is

1.] to give the compound of formula (I), wherein R ¹ is methyl, X is chlorine, n is 1, in the form of racemic mixture 752 627. Belgian patent. No. 1,793,825. German Patent Publication No. 25778-A / 76; Italian patent application discloses compounds of formula I in the form of racemic mixtures wherein R ¹ is hydrogen, X is halogen and n is 0 or 1. However, salts of the compounds of formula I and their salts have not been described so far. Some of the enantiomers of the compounds of formula (I).

The present invention thus provides a novel process for the preparation of d-2- (6-methoxy-2-naphthyl) -propionic acid (naproxen) and pharmaceutically acceptable salts thereof, wherein the 2- (6-methoxy-2-naphthyl) -propionic acid is a A racemic prodrug of formula (I) - in this formula

R ¹ is hydrogen or methyl; X is halogen, preferably bromine or chlorine and n = 1; obsession

R ¹ is hydrogen and n = 0;

or by reacting a salt of such a compound in a reaction-inert organic solvent with an NRD-glucamine, wherein R is a C 1 -C 14 alkyl group or a C 4 -C 8 cycloalkyl group, and separating the resulting diastereomeric salts; Converting d-precursor of formula I to d-2- (6-methoxy-2-naphthyl) -propionic acid;

and optionally converting the resulting d-2- (6-methoxy-2-naphthyl) -propionic acid into a pharmaceutically acceptable salt thereof; and optionally racemizing the 1-form precursor obtained in the resolution step and resolving the resulting racemic precursor as described above.

Preferred starting materials for the process of the invention are of formula (I)

-2191845 are racemic mixtures formed by known chemical syntheses.

Alkyl as used herein means a straight or branched hydrocarbon group having 1 to 14 carbon atoms. Typical alkyl groups include methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, η-hexyl, n-octyl, n-dodecyl and the like.

Cycloalkyl as used herein refers to a C4-C8 cycloaliphatic hydrocarbon group. Typical cycloalkyl moieties include cyclobutyl, cyclopentyl, eiclohexyl, methylcyclohexyl, cycloheptyl, and cyclooctyl.

Preferred cycloalkyl groups are eiclohexyl and cycloheptyl.

Preferred resolving agents are N-alkylglucamines wherein R is a C 2 -C 14 alkyl group.

Particularly preferred are resolving agents wherein R is C 6-14 alkyl.

Preferred resolving agents include: N-ethyl-D-glucamine, N- (n-propyl) -D-glucamine, N- (η-butyl) -D-glucamine, N- (n-octyl) -D- glucamine, N- (n-decyl) -D-glucamine and N- (n-hexadecyl) -D-glucanamine.

Particularly preferred resolving agent is N-methyl-D-glucamine of naproxen precursor of formula (I) The resolution of where R ^l is hydrogen and X is chlorine or bromine and n is 1 or ^R1 is hydrogen and n is 0.

The resolving step of the process of the invention is carried out in an inert organic solvent having a significant difference in solubility of the naproxen prodrug salt of formula I with the resolving agent and the solubility of the other enantiomer. Resolution is generally carried out at a temperature between room temperature or ambient temperature and generally higher than the boiling point of the solvent. The naproxen precursor may be combined with a resolving agent (e.g., N-methyl-D-glucamine, N- (n-propyl) -D-glucamine, N- (n-butyl) -D-glucamine or N- (n-octyl) -D-). glucamine) should be substantially less soluble in the solvent of choice than the salt of the other enantiomer with the resolving agent and, accordingly, when the warm solution is cooled, usually to ambient or room temperature, the salt of the naproxen precursor with the resolving agent will precipitate.

Suitable solvents for the resolution are: water, C 1-10 monovalent alcohols, especially C 1-10 alkanols such as methanol, ethanol, n-propanol, isopropanol, butanol, pentanol, hexanol, cyclohexanol, 2-ethylhexanol, benzyl alcohol, furfuryl alcohol, etc., C2-C6 divalent alcohols, e.g., ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, etc., C3-C4 trivalent alcohols, e.g., glycerol, C3-C11 ketones, e.g. acetone, acetylacetone , ethyl methyl ketone, diethyl ketone, di-n-propyl ketone, diisopropyl ketone, diisopropyl ketone and the like. Other solvents such as ethylene glycol and diethylene glycol mono- and di-lower alkyl ethers, dimethylsulfoxide, sulfolanes, formamide, dimethylformamide, N-methylpyrrolidone, pyridine, dioxane, dimethylacetamide and the like can be used.

Preferred solvents are C1-C3 alcohols such as methanol and isopropanol. A particularly preferred solvent is methanol. If necessary, enough water may be added to the solvent used to solubilize any substance present. Mixtures of polar solvents with aromatic hydrocarbons such as toluene or benzene can also be used as the solvent medium. Such is the mixture of methanol and toluene where methanol is the main component.

The starting material (i.e., a mixture of the naproxen precursor and the other enantiomer or their soluble salts) is generally heated to a temperature of from 60 to 100 ° C or to the boiling point of the solvent in the presence of a resolving agent to dissolve all of the solvent. If desired, the solvent may be kept at a higher temperature until all materials are dissolved. After keeping the solution at a higher temperature for the desired time, allow it to cool slowly to ambient temperature. During cooling, the solution is suitably inoculated with the salt of the naproxen precursor and the resolving agent. The crystalline precipitate formed primarily contains a salt of the naproxen precursor with a resolving agent. For practical reasons, the final temperature at which the solution is cooled is selected, but generally cooling is sufficient to maintain a high temperature difference in crystals. The mixture is kept at low temperature until the crystallization is complete or nearly complete. This usually requires 30 minutes to several hours. The crystalline precipitate formed is filtered off and washed.

The crystalline material obtained at this stage of the process of the invention, which contains a significant amount of the salt of the naproxen precursor with a resolving agent, may be heated with water, if desired, after filtration to isolate and wash with water to redissolve the crystalline material. In the case of N-R-D-glucamines which are soluble in water, the resulting solution is acidified, for example, with a mineral acid such as sulfuric or hydrochloric acid or an organic acid such as acetic acid, and the resulting crystalline precipitate is filtered, washed and dried. The crystalline product obtained is significant

-3191845 is enriched in the naproxen precursor.

In the case of N-R-D-glucamines which are insoluble in water, it is also possible to treat the salt of the naproxen precursor with a resolving agent with a strong base such as potassium hydroxide or another strong base having a pKa greater than 10. After the salt has been decomposed in this way, the resolving agent is filtered and the filtrate is acidified with, for example, a mineral acid such as hydrochloric or sulfuric acid or an organic acid such as acetic acid. Filtration, washing and drying gave a crystalline material which was significantly enriched in the naproxen precursor.

Before decomposing the material enriched in the salt of the naproxen precursor with the resolving agent to obtain the optically pure naproxen precursor, it is generally desirable to redissolve the salt-enriched material in an additional solvent, warm to the desired temperature, generally higher, salt of the naproxen precursor with a resolving agent and cooling the solution. In this way, one or more recrystallizations may be carried out. Each recrystallization increases the proportion of naproxen precursor salt with resolving agent in the o-crystallized material.

Especially preferred resolving agents for the process of the invention are N-methyl-D-glucamine, N-ethyl-D-glucamine, N- (n-propyl) -D-glucamine, N- (n-butyl) -D-glucamine, N- (n-hexyl) -D-glucamine and N- (n-octyl) -D-glucamine, since in their use only one recrystallization is sufficient before the resulting crystalline salt is redissolved and acidified. This gives a naproxen precursor having a purity of 97-99%.

N-methyl-D-glucamine, N-ethyl-D-glucamine and N- (n-octyl) -D-glucamine are preferred resolvents since their salts with the naproxen precursor can be readily separated by filtration and use with an optically pure naproxen precursor can be obtained without the need for one or more recrystallization steps, and the resolving agent used can be directly recovered by filtration in good yield (about 97-98%). In addition, the decomposition of the salt can be carried out in either an alkaline or acidic medium.

N- (n-octyl) -D-glucamine is substantially insoluble in water and can therefore be recovered in good yield from an aqueous medium. This also applies to other resolving agents of the invention where R is at least C 6 alkyl, i.e., N-R-D-glucamines where R is C 6-18 alkyl.

The other enantiomer may be recovered from the material enriched in another enantiomer of the compound of formula (I) or in its salt with N-R-D-glucamine, where R is as defined above, and then racemized in a manner known per se. See, e.g., U.S. Patent No. 3,686,183. See U.S. Pat.

In the process according to the invention, the resolving agent is used in an amount of 50-100%, based on the moles of d, l-carboxylic acid of the formula I to be resolved. However, since about 50% of the amount of resolving agent is required to make the insoluble salt of the naproxen precursor, the remaining amount of the resolving agent, usually up to 40-50 mol%, may be replaced, if desired, by a cheaper base, e.g. such as an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an organic base having a pKa of at least 8, such as an organic tertiary amine such as triethylamine, triethanolamine, tributylamine and the like.

The term "mixture of d - and (1) - enantiomer of formula (I)" also encompasses salts which are soluble in the solvent used in the resolution process of the present invention. Such salts include, for example, the corresponding sodium salts, potassium salts, lithium salts, and the like. These salts may be prepared by adding a base such as an alkali metal hydroxide such as sodium or potassium hydroxide to a solution of a mixture of the (d) and (1) enantiomers of the carboxylic acid (I). For example, the resulting mixture of the salts of d-2- (6-methoxy-2-naphthyl) -propionic acid and 1-2-(6-methoxy-2-naphthyl) -propionic acid is resolved according to the invention with the salt of the resolving agent. The salt of d-2- (6-methoxy-2-naphthyl) -propionic acid is then formed with N-R-D-glucamine. Suitable glucamine salts for this purpose are salts with inorganic or organic acids such as hydrochloride or acetate. Other salts may also be used, such as propionate, butyrate, isobutyrate, sulfate, nitrate, maleate, and the like.

Accordingly, the term N-R-D-glucamine, where R is as defined above, also encompasses salts that provide resolution of the corresponding salts of the mixture of des 1- (6-methoxy-2-naphthyl) -propionic acid.

The carboxylic acids of formula (I) are prepared by methods known per se. See, e.g., U.S. Patent No. 1,934,460. German Patent Publication No. 752 627; Belgian Patent No. 1,668,654; German Patent Publication No. 1,793,825; The German Federal Republic of the Federal Republic of the Federal Republic of the United States of America, Italian patent application.

After the naproxen prodrug of formula (I) is prepared in optically pure or crude form, it can be converted to naproxen or its pharmaceutically acceptable salts. so

-4191845 case of compound (I) wherein ^R1 is hydrogen or methyl and X is halogen, n is dehalogénezzük (I) to compounds of formula 1, the conversion to naproxen. The halogen atom is replaced by a hydrogen atom.

In the case where in formula (I), ^R1 is hydrogen, X is halogen and n is 1, it is preferred that the compounds are first methylated as described in the following manner and removing halogens present in the 5-position.

The prodrug of naproxen 2- (5-halo-6-methoxy-2-naphthyl) -propionic acid can be subjected to dehalogenation reactions that do not affect the rest of the molecule during the formation of naproxen. A suitable method is to react the resolved 5-halogen compounds of formula I with an alkaline earth metal alcoholate such as magnesium methylate and a tertiary amine such as tri-lower alkylamine such as triethylamine in the presence of an inert solvent. An example of an inert solvent is the alkanol from which the alkaline earth metal alcohol used is derived. The reaction is carried out at a temperature between 30 ° C and the boiling point of the solvent.

For example, we can do the following. A mixture of magnesium powder, methanol and excess triethylamine is used under an inert atmosphere such as nitrogen. Resolved 2- (5-halo-6-methoxy-2-naphthyl) -propionic acid in anhydrous methanolic solution is added. When the reaction was complete, i.e. after the reaction mixture was refluxed for 1 hour, hydrochloric acid was added to dissolve all unreacted magnesium. The naproxen may be isolated from the mixture by methods known per se. For example, the reaction mixture containing naproxen can be poured into water and extracted with a suitable solvent such as dichloromethane. The organic phase is then separated off, washed with water and crystallized on pure naproxen.

Alternatively, the naproxen precursor of formula (I) is reacted with at least 2 molar equivalents, preferably 2 to 50 molar equivalents of nickel aluminum or cobalt aluminum, based on the amount of aluminum, at least 2 molar equivalents, preferably 2 to 50 molar equivalents. in the presence of an amount of alkali metal hydroxide in an inert solvent. The reaction is carried out until the 5-halo group is removed. Preferred nickel-aluminum or cobalt-aluminum alloys have a particle size of less than 1 millimeter and an aluminum concentration of at least 10% by weight (based on the amount of alloy).

Suitable alkali metal hydroxides are sodium hydroxide, potassium hydroxide or lithium hydroxide. The reaction is carried out in an inert solvent which is preferably methanol, ethanol, propanol, i-propanol, tert-butanol, tetrahydrofuran or dioxane. The reaction temperature is between 0 ° C and the boiling point of the solvent, preferably at least 40 ° C. The reaction time may range from 15 minutes to 12 hours.

The resolved 5-halogen compounds of formula (I) may also be directly reacted with a mixture of magnesium (preferably a particle size of less than 1 mm), a lower alkanol and optionally a molar excess of an aliphatic amine. The reaction is carried out at a temperature between 0 ° C and the boiling point of the reaction mixture, preferably at least 20 ° C, and under an inert atmosphere such as nitrogen. The time required for the reduction of the 5-position halogen atom depends on the reaction temperature. The reaction time is usually from 10 minutes to 12 hours. The reaction is usually carried out at the boiling point of the reaction mixture within 1 hour.

Alternatively, the 5-halogen compound of formula (I) may be treated with Raney nickel in an inert organic solvent, optionally under hydrogen. The inert organic solvent is, for example, a lower alkanol, an ester having up to 6 carbon atoms, such as ethyl acetate, or a lower alkanoic acid, such as acetic acid, propionic acid, and the like. may. The reaction is carried out at a temperature of at least 0 ° C, preferably above 20 ° C, for 10 minutes to 24 hours. The reaction is preferably carried out at the boiling point of the reaction mixture.

A further possibility for the preparation of naproxen is to treat the 5 halogen compound (Ϊ) with hydrogen in the presence of palladium on carbon, platinum or platinum oxide in an inert organic solvent as described above for Raney nickel treatment. The reaction is carried out at a temperature between 0 ° C and the reflux temperature of the solvent, preferably at room temperature for 10 minutes to 12 hours.

The naproxen precursor of formula (I) wherein R ¹ is hydrogen, n is 0 can also be converted crude to naproxen. Alternatively, the material may be purified by crystallization to the desired optical rotation and then converted to naproxen. The latter is done by treating the naproxen precursor with a suitable methylating agent.

During the methylation, the naproxen precursor of formula (I), i.e. the 6-hydroxy compound, is reacted with dimethyl sulfate, dimethyl carbonate or methyl halide in an alkaline medium. As the solvent, for example, water or lower aliphatic alcohols can be used. The alkaline medium may be provided with sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. The reaction is brought to a specific rotation of + 63.5 ° (in chloroform) at a temperature between 40 ° C and the boiling point of the reaction mixture.

gauze. The optimum reaction temperature is 40-70 ° C. The reaction time depends on the reaction temperature, however, the reaction usually takes from 1 to 10 hours. The resulting naproxen is isolated by adding a solution of a strong organic or inorganic acid to the reaction mixture after cooling and filtering the product from the acid mixture. The resulting precipitate is washed and dried at a temperature that does not damage naproxen.

The naproxen precursor of formula (I) wherein R ¹ is hydrogen, X is halogen and n is 1 can also be methylated and dehalogenated by the procedure described above.

Naproxen, obtained either by dehalogenation of the 5-halo compound of the formula I or by methylation of the 6-hydroxy compound of the formula I, can be recrystallized to give a material of very high optical rotation, i.e., [α] D = 62-67 ° (chloroform). .

The naproxen of the present invention may be converted into pharmaceutically acceptable salts by reacting the naproxen with at least an equivalent amount of an organic or inorganic base, preferably sodium hydroxide. The salt formation is carried out in an inert solvent at a temperature between 0 ° C and the boiling point of the solvent. The naproxen is crystallized from the solvent, optionally after removal of some or all of the solvent. The purity of the crystalline salt can be further enhanced by recrystallization.

The invention is illustrated by the following examples.

Example 1 g of d, l-2- (6-hydroxy-2-naphthyl) -propionic acid was dissolved in 215 ml of methanol and 13.8 ml of toluene with heating. To the solution was added 67.8 g of N- (n-octyl) -D-glucamine, cooled to 40 ° C, and seeded with d-2- (6-hydroxy-2-naphthyl) -propionic acid N- (n-octyl). Crystals of its salt with D-glucamine. The mixture was stirred overnight at room temperature to give the N-(n-octyl) -D-glucamine salt of d-2- (6-hydroxy-2-naphthyl) propionic acid. Cleavage gave 11.5 g of d-2- (6-hydroxy-2-naphthyl) propionic acid with a specific rotation of + 91.3 ° (in chloroform). Yield: 23.0%.

A solution of 10.5 g of the resulting 6-hydroxy precursor is dissolved in 60 ml of acetone and 100 ml of 1.5 N aqueous potassium hydroxide solution, and 44 g of methyl iodide are added. The reaction mixture was maintained at 0 to 20 ° C for 14 hours. The resulting naproxen methyl ester is hydrolyzed in situ to naproxen under basic reaction conditions.

The 6-hydroxy-naproxen precursor was converted to naproxen in 90.3% yield. example

17.0 g of d, l-2- (6-hydroxy-2-naphthyl) propionic acid and 15.34 g of N-methyl-D-glucamine are dissolved in 150 ml of boiling methanol containing 10 ml of water (10% by weight). The solution was filtered and carefully cooled to 45 ° C with slow stirring. This gives the salt of the 6-hydroxy-naproxen precursor with N-methyl-D-glucamine. The salt was suspended three times in the same solvent system to give 3.1 g of d-2- (6-hydroxy-2-naphthyl) -propionic acid after decomposition with a specific rotation of + 91.7 ° (in chloroform). Yield: 18.3%.

The resulting d-2- (6-hydroxy-2-naphthyl) -propionic acid was converted to d-2- (6-methoxy-2-naphthyl) -propionic acid as described in Example 1 with a specific rotation of + 63.8 °. chloroform).

Example 3 gd, 1- 2- (5-Bromo-6-methoxy-2-naphthyl) -propionic acid, 23.7 g of N- (n-octyl) -D-glucamine and 60 ml of 10% toluene in methanol The mixture is heated to reflux to dissolve the crystalline material and refluxed for 20 minutes and then allowed to cool slowly. At 30 ° C, the solution is inoculated with a small amount of the N-(n-octyl) -D-glucamine salt of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid. The mixture was allowed to stand overnight at room temperature. The precipitate was filtered off with suction and washed with cold methanol (30 mL). 16.7 g are obtained, which is enriched in the N-n-octyl-D-glucamine salt of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid.

A 1.0 g sample of this salt is suspended in 50 ml of water, heated to 80 ° C and acidified with concentrated hydrochloric acid. The precipitate, which was concentrated in Cl-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid, was filtered at 50 ° C, washed with water and dried in a vacuum oven. [α] D + 28.2 ° (c = 0.5%, chloroform).

The residue (15.7 g) was dissolved in a mixture of toluene (2 mL) and methanol (18 mL). The solution was cooled to 25 ° C, seeded with N- (n-octyl) -D-glucamine salt of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid and left overnight. . The precipitate was filtered and washed with cold methanol (20 mL). The separated material was suspended in 100 ml of water, heated to 80 ° C and acidified with hydrochloric acid. The precipitate was collected to give 5.5 g of practically pure d-2- (6-bromo-6-methoxy-2-naphthyl) -propionic acid, [α] D + 42.5 ° (c = 0.5%, chloroform). .

-613

The 5-bromo-naproxen precursor compound obtained above is converted to the desired naproxen by removal of the bromine atom, as follows:

To a solution of 1.5 g of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid in 20 ml of 10% aqueous sodium hydroxide solution at 90 ° C, a total of 3 g of nickel aluminum we add an alloy. The mixture was stirred for 2 hours, then filtered, diluted with excess dilute hydrochloric acid and extracted with dichloromethane. The separated organic solvent phase was evaporated to dryness and the resulting crude product was recrystallized from dichloromethane / hexane. This gives d-2- (6-methoxy-2-naphthyl) -propionic acid with a specific rotation [α] D = + 64 ° (in chloroform).

Example 4 gd, 1- 2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid, 2.42 g of triethylamine, 7.03 g of N- (n-octyl) -D-glucamine and A mixture of 10 ml of methanol in 10% toluene was heated to reflux, refluxed for 20 minutes and then allowed to cool slowly. The 30 ° C solution was inoculated with a small amount of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid salt of N- (n-octyl) -D-glucamine and allowed to stand overnight at room temperature. The precipitate was filtered off with suction and washed with cold methanol (20 mL). This gives 4.47 g of material which is enriched in the N-n-octyl-D-glucamine salt of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid.

The salt (4.47 g) was dissolved in toluene (1 mL) and methanol (9 mL) at reflux. The solution was cooled to 30 ° C, seeded with N- (n-octyl) -D-glucamine salt of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid and allowed to stand overnight. The precipitate was filtered and washed with cold methanol (10 mL). The material was suspended in water (75 mL), heated to 80 ° C, acidified with hydrochloric acid, and the precipitate was filtered. 1.2 g of product are obtained which is significantly enriched in d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid, [α] D = + 42 ° (c = 0.5%, chloroform). ).

The resulting 5-bromo-naproxen precursor was converted to naproxen as described previously.

Example 5

A mixture of 5.30 gd, l-2- (5-chloro-6-methoxy-2-naphthyl) propionic acid, 1.01 g (0.5 eq.) Of triethylamine and 35 ml of isopropanol is dissolved in the solvent to form the carboxylic acid. is heated to about the boiling point. 2.09 (0.5 equivalents) of N-ethyl-D-glucamine was added and the solution was cooled to room temperature (i.e., 20-30 ° C). In this way, 4 g of material is obtained which is enriched in the salt of the less soluble naproxen precursor N-ethyl-D-glucamine.

A sample of the latter is taken, dissolved in about 25 ml of water while heating to 80 ° C, and hydrochloric acid is added until acidic. At this time, the acid enriched in the naproxen precursor precipitated out of solution and was recovered by filtration.

A 1.00 g portion of the salt enriched in N-ethyl-D-glucamine was dissolved in 19.5 mL of isopropanol and 1.5 mL of water near the boiling point of the solvent. The resulting solution was cooled to room temperature to give 0.50 g of recrystallized salt. This material was treated with hydrochloric acid as described above to give a material which was further enriched in the naproxen precursor.

To a solution of d-2- (5-chloro-6-methoxy-2-naphthyl) -propionic acid (g) in 90 ml of 10% aqueous sodium hydroxide solution was added 3 g of nickel-aluminum alloy in small portions. The reaction mixture was stirred for 2 hours, filtered, the filtrate diluted with excess dilute hydrochloric acid and extracted with dichloromethane. The organic phase is evaporated to dryness and the residue is recrystallized from dichloromethane / hexane. Optical rotation of the resulting 2- (6-methoxy-2-naphthyl) -propionic acid 60 '(in chloroform).

If the above procedure is repeated with the corresponding 5-bromo compound, after recrystallization, naproxen is obtained with an optical rotation of 61 ° (in chloroform).

Example 6

A mixture of 6.2 gd, 1- 2- (5-bromo-6-methoxy-2-naphthyl) propionic acid, 1.01 g triethylamine (0.5 equivalent), 30 ml isopropanol and 1.5 ml water maintained at about the boiling point of the solvent to dissolve the starting material. N-ethyl-D-glucamine (2.09 g) was added and the solution was cooled to room temperature. In this way, 4.32 g of material is obtained which is enriched in the salt formed with N-ethyl-D-glucamine. Take a sample, dissolve in about 25 ml of water heated to about 80 ° C and acidify with hydrochloric acid. At this time, the naproxen precursor precipitated in carboxylic acid and was filtered off.

1.00 g of the N-ethyl-D-glucamine salt-enriched material is dissolved in 20 ml of 5% aqueous isopropanol and 1.0 ml of water at about the boiling point of the solvent. The solution was cooled to room temperature to give 0.6 g of a single recrystallization material. A sample of this is treated with hydrochloric acid as described above,

-715 to obtain a material which is further enriched in the carboxylic acid naproxen precursor.

0.50 g of a single recrystallization material is dissolved in 10 ml of 5% aqueous isopropanol and 0.5 ml of water at about the boiling point of the solvent. Cooling the solution to room temperature gave 0.43 g of twice recrystallized salt. A sample thereof is treated with hydrochloric acid as described above to obtain an even higher optical purity. A sample thereof is treated with hydrochloric acid as described above to obtain an even higher optical purity.

0.33 g of the twice-recrystallized salt were dissolved in 12 ml of 5% aqueous isopropanol and 1.0 ml of water at about the boiling point of the solvent. Cooling the solution to room temperature gave 0.27 g of a three-recrystallized salt. The latter is treated with hydrochloric acid as described above to give a substantially pure 5-bromo-naproxen precursor.

Into a 250 ml flask equipped with a reflux condenser and a nitrogen bubbler were weighed 60 g of magnesium powder, 50 ml of anhydrous methanol and 10 g of triethylamine. The flask was purged with nitrogen and a nitrogen atmosphere was maintained throughout the reaction.

To the contents of the flask was slowly added a 0.1 molar solution of the 5-bromo-naproxen precursor in 15 g of methanol and the reaction mixture was refluxed for an additional 1 hour after the addition of the 5-bromo-naproxen precursor was completed. To the cooled mixture was added 6N hydrochloric acid until magnesium was no longer present. The mixture was poured into water and extracted with dichloromethane. The organic layer was separated, washed with water and crystallized by concentration of the solution and addition of hexane. Optical rotation of the resulting naproxen after recrystallization 64 ° (in chloroform).

If the above procedure is repeated starting from the corresponding 5-chloro-naproxen precursor, the resulting naproxen has an optical rotation of 62 ° (in chloroform).

Example 7 A mixture of gd, 1- 2- (5-chloro-6-methoxy-2-naphthyl) propionic acid, 0.50 g (0.5 equivalent) of triethylamine, 15 ml of isopropanol and 0.5 ml of water heating to the boiling point of the solvent to dissolve the propionic acid derivatives. To the warm solution was added 1.32 g of N-cyclohexyl-D-glucamine (0.5 equivalent) and a precipitate was formed immediately. After addition of additional 15 ml of isopropanol and 1.5 ml of water, the mixture was heated to near the boiling point of the solvent to dissolve the precipitate and cooled to room temperature to give 2 g of N-cyclohexyl-D-naphthene precursor carboxylic acid. glucamine salt. A sample of the latter is taken, dissolved in about 25 ml of water at a temperature in the region of 80 ° C, acidified with hydrochloric acid and the precipitate enriched in the naproxen precursor carboxylic acid is filtered off.

1.00 g of the material enriched in the N-cyclohexyl-D-glucamine salt of the naproxen prodrug carboxylic acid is dissolved in 20 ml of 5% aqueous isopropanol at about the boiling point of the solvent. Cooling the solution to room temperature gave 0.79 g of a single recrystallization material. A sample was taken and treated with hydrochloric acid as described above. The material thus obtained is further enriched in the 5-chloro-naproxen precursor.

To a solution of the 5-chloro-naproxen precursor (g) in anhydrous methanol (10 mL) was added 1 g of Raney nickel and the reaction mixture was refluxed for 12 hours. The mixture was filtered, the filtrate was diluted with water, and the precipitate was dried and recrystallized from a mixture of acetone and hexane. In this way, naproxen is obtained.

If the above procedure is repeated with the appropriate 5-bromo compound, naproxen is obtained having an optical rotation of 60 ° (in chloroform).

If the above procedure is repeated, except that N-methyl-D-glucamine and N- (n-octyl) -D-glucamine are used as resolving agents, naproxen is obtained which has an optical rotation of 60-65 ° (in chloroform). .

Example 8

A mixture of 6.2 d, 1- 2- (5-bromo-6-methoxy-2-naphthyl) propionic acid, triethylamine (1.01 g, 0.5 equiv.), Isopropanol (30 mL) and water (1.5 mL) heating at about the boiling point of the solvent to dissolve the racemic carboxylic acid. To the solution was added 2.93 g (0.5 equivalents) of N- (n-octyl) -D-glucamine and the solution was cooled to room temperature. 4.5 g of material are obtained, which is enriched in the salt of the naproxen precursor with N- (n-octyl) -D-glucamine. A sample was taken, dissolved in about 25 ml of water at about 80 ° C, acidified with hydrochloric acid, and filtered to precipitate the precipitate which was concentrated in the naproxen precursor carboxylic acid.

A solution of 1.00 g of the substance enriched in the salt of naproxen prodrug propionic acid with N- (n-octyl) -D-glucamine in 9.5 ml of isopropanol and 0.5 ml of water at about the reflux temperature of the solvent. The solution was cooled to room temperature to give 0.85 g of recrystallized salt. This stuff

-817 was treated with hydrochloric acid as described above to give a substantially pure product.

Weigh 60 g of magnesium powder into 50 ml of anhydrous flask with a reflux condenser and a nitrogen inlet flask. methanol and 10 g of triethylamine. A nitrogen atmosphere is maintained in the flask throughout the reaction. To the contents of the flask was added dropwise 0.1 mol of 5-bromo-naproxen precursor dissolved in 15 g of methanol. After the addition was complete, the reaction mixture was heated under reflux for an additional hour, cooled to room temperature, and enough 6N hydrochloric acid was added until no more magnesium remained. The mixture was diluted with water, dichloromethane was added, the organic layer was separated, washed with water, concentrated and the naproxen was crystallized by addition of hexane. Recrystallization gave naproxen, m.p. 155 ° C, optical rotation 65 °.

Repeat the above reaction using d, l-2- (5-chloro-6-methoxy-2-naphthyl) propionic acid to give naproxen, m.p. 154 ° C, optical rotation 62 ° (in chloroform).

Example 9

A mixture of 2.16 gd, 1- 2- (6-hydroxy-2-naphthyl) propionic acid, 0.50 g (0.5 equivalent) of triethylamine and 30 ml of ethylene glycol was heated to 90 ° C. To dissolve 2- (6-hydroxy-2-naphthyl) -propionic acid. 1.47 g of N- (n-octyl) -D-glucamine are added, the solution is cooled to 40 ° C and seeded with d-2- (6-hydroxy-2-naphthyl) -propionic acid N- (n). -octyl) -D-glucamine. The reaction mixture was stirred overnight at room temperature to give 1.47 g of material which was enriched in the N-n-octyl-D-glucamine salt of d-2- (6-hydroxy-2-naphthyl) propionic acid.

A sample of the latter was taken, dissolved in about 25 ml of water with heating to 80 ° C, acidified with hydrochloric acid and filtered to precipitate which was concentrated in d-2- (6-hydroxy-2-naphthyl) -propionic acid.

Dissolve 6 g of the 6-hydroxy precursor in 30 ml of 1N aqueous sodium hydroxide solution and add 3.8 g of dimethyl sulfate. The solution was heated at 60 ° C for 2 hours and then cooled to room temperature and the reaction mixture was acidified by the addition of a dilute hydrochloric acid solution. The precipitate was filtered off and washed with water until neutral. This gives 1.5 g of naproxen, which after recrystallization has an optical rotation of 62 °.

When d, l-2- (6-hydroxy-5-bromo-2-naphthyl) propionic acid is resolved and methylated as described above and then dehalogenated as described in Example 4, naproxen is obtained with an optical rotation of 60 °.

Example 10

A mixture of 3.1 gd, l-2- (5-bromo-6-methoxy-2-naphthyl) propionic acid, 0.50 g (0.5 equivalent) of triethylamine, 15 ml of isopropanol and 0.75 ml of water warming to about the boiling point of the solvent to dissolve d, l-2- (5-bromo-6-methoxy-2-naphthyl) propionic acid. To the solution was added 1.75 g of N- (n-dodecyl) -D-glucamine (0.5 eq) and then cooled to room temperature. In this way, 2.50 g are obtained which is enriched in the N-n-dodecyl-D-glucamine salt of the naproxen precursor. A sample of the latter is taken and suspended in 25 ml of water at room temperature in the presence of 300 mg of potassium hydroxide and kept at this temperature for 60 minutes. The precipitate was filtered and the filtrate was acidified with hydrochloric acid. At this time, the material enriched in the 5-bromo-naproxen precursor precipitated and was filtered.

1.00 g of the material enriched in the salt of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid with N- (n-dodecyl) -D-glucamine is dissolved in 20 ml of 5% aqueous isopropanol. at about the boiling point of the solvent. The solution was then cooled to room temperature to give 0.88 g of a single recrystallization material. A sample is taken and treated first with potassium hydroxide and then with hydrochloric acid as described above. This gives you even more enriched material.

0.62 g of a single recrystallized material (i.e., the material enriched in the N-n-dodecyl) -D-glucamine salt of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid in 15 ml, Dissolve in isopropanol containing water at about the boiling point of the solvent. The solution was cooled to room temperature to give 0.5 g of twice recrystallized material.

0.1 g of 5-bromo-naproxen prodrug in methanol are slowly added to a 250 ml reflux flask containing 60 g of magnesium, 50 ml of anhydrous methanol and 10 g of triethylamine. Throughout the reaction, the flask was purged with nitrogen. After the addition was complete, the contents of the flask were refluxed for an additional hour and the mixture was cooled and 6N hydrochloric acid was added until all magnesium was dissolved. The mixture was poured into water, extracted with dichloromethane, the organic phase separated, washed with water, concentrated and crystallized by addition of hexane. After recrystallization, naproxen is obtained with an optical rotation of 62 °.

-919

The above procedure was repeated using the appropriate 5-chloro-naproxen precursor to obtain a naproxen having an optical rotation of 60 °.

Example 11

A mixture of 135 mg of d, l-2- (5-bromo-6-methoxy-2-naphthyl) propionic acid, 100 mg of N- (n-butyl) -D-glucamine hydrochloride and 2 ml of 5% aqueous isopropanol was added. heating to about the boiling point of the solvent. The reaction mixture was slowly cooled, seeded with a small amount of the N-n-butyl-D-glucamine salt of the 5-bromo-naproxen precursor, and then cooled to room temperature. After filtration and washing, 1.10 g of material is obtained, which is enriched in the salt of the 5-bromo-naproxen precursor with N- (n-butyl) -D-glucamine. Take a sample, dissolve in water, acidify with hydrochloric acid and filter the precipitate which is enriched in d-2- (6-methoxy-2-naphthyl) -propionic acid.

To a solution of the 5-bromo-naproxen precursor (g) in anhydrous methanol (10 ml) was added 1 g of Raney nickel and the mixture was heated under reflux for 14 hours. The reaction mixture was filtered, the filtrate was diluted with water and the precipitate was recrystallized from acetone-hexane after drying. The resulting naproxen has an optical rotation of 65 °.

Example 12

A mixture of 2.1 gd, 1- 2- (6-hydroxy-2-naphthyl) propionic acid, 1.46 g of N- (n-hexyl) -D-glucamine (0.55 eq.) And 15 ml of water at 80 ° C was added. Heat to about C. Potassium hydroxide (0.17 g, 0.45 eq.) Was added and the pH of the solution was adjusted to 8 by addition of potassium carbonate. The solution was inoculated with a small amount of the N-(n-hexyl) -D-glucamine salt of d-2- (6-hydroxy-2-naphthyl) propionic acid and cooled. In this way, 1.25 g of material is obtained which is enriched in the salt of d-2- (6-hydroxy-2-naphthyl) propionic acid with N- (n-hexyl) -D-glucamine.

The N-(n-hexyl) -D-glucamine salt of d-2- (6-hydroxy-2-naphthyl) -propionic acid is dissolved in 15 ml of dioxane, 15 ml of 20% aqueous sodium hydroxide solution are added, and and saturated with methyl bromide. The reaction mixture was cooled to room temperature while methyl bromide was continuously introduced. After cooling, it is acidified with 1N aqueous hydrochloric acid, extracted with diethyl ether, the extracts are separated, washed with water, dried over anhydrous sodium sulfate, filtered and then concentrated. The resulting naproxen had an optical rotation of 58 °.

Example 13

4.60 g of d, l-2- (6-hydroxy-2-naphthyl) -propionic acid are suspended in 25 ml of water and 0.60 g (0.45 equivalents) of potassium hydroxide at 70 ° C for 10 minutes. 3.22 g (0.55 equivalent) of N- (n-octyl) -D-glucamine are added and the solution is slowly cooled to 50 ° C. A small amount of the N-(n-octyl) -D-glucamine salt of d-2- (6-hydroxy-2-naphthyl) propionic acid is added and the solution is cooled to room temperature overnight with stirring. Filtration gave 4.0 g of the material which was enriched in the salt of d-2- (6-hydroxy-2-naphthyl) -propionic acid with N- (n-octyl) -D-glucamine.

A sample of the latter material is taken, suspended in 25 ml of water at room temperature in the presence of 300 mg of potassium hydroxide and kept at this temperature for about 60 minutes. The precipitate is filtered off, the filtrate is acidified with hydrochloric acid and the precipitate which is concentrated to d-2- (6-hydroxy-2-naphthyl) -propionic acid is filtered off.

Dissolve 6 g of the 6-hydroxy-naproxen precursor in 1 ml of aqueous sodium hydroxide solution and add 4 g of dimethyl sulfate and keep at 65 ° C for 2.5 hours. The mixture was cooled to room temperature, acidified with dilute hydrochloric acid and the resulting precipitate was washed neutral with water. 1.6 g of naproxen are obtained with an optical rotation of 64 ° (in chloroform).

Example 14

433 g of racemic 2- (6-hydroxy-2-naphthyl) -propionic acid (2 mol) and 390.5 g (2 mol) of N-methyl-D-glucamine are dissolved in 4 L of boiling methanol. The solution was filtered and cooled to 45 ° C with slow stirring. Add 1 g of N-methyl-D-glucamine salt of 6-hydroxy-naproxen precursor (prepared in a preliminary experiment by rubbing the vessel wall with cooling with a glass rod, then filtering off the precipitated crystals under vacuum and washing with a little methanol). . Immediately after inoculation, vigorous crystallization begins. Meanwhile, the temperature was maintained at 45 ° C and then slowly lowered to 15 ° C.

The precipitated crystals are filtered off and washed with a little methanol. 300 g of N-methyl-D-glucamine salt of d-6-hydroxy-naproxen precursor are thus obtained.

The residue from the precipitation is dissolved in water and the salt solution is acidified by the addition of dilute hydrochloric acid. The d-6-hydroxy-naproxen precursor precipitates.

200 g of d-2- (6-hydroxy-2-naphthyl) propionic acid in 350 ml of 1N aqueous sodium hydroxide solution11

The solution was concentrated and the product crystallized by addition of hexane. Optical rotation of the isolated naproxen after recrystallization, 64 ° (in chloroform).

The above procedure was repeated with the appropriate 5-chloro-naproxen precursor after optical rotation of the resulting naproxen, after recrystallization, at 62 °.

40 g of dimethyl sulfate were added and the reaction mixture was heated at 60 ° C for 2 hours. The mixture was cooled to room temperature, acidified with dilute hydrochloric acid, the precipitate formed was filtered and washed with water until neutral. This gives 175 g of naproxen, which is 62 ° after optical rotation after recrystallization.

Example 15

A mixture of 6.2 gd, 1- 2- (5-bromo-6-methoxy-2-naphthyl) propionic acid, 1.01 g (0.5 eq.) Of triethylamine and 20 ml of methanol is dissolved to give 1-carboxylic acid. heating to the boiling point of the solvent. N-methyl-D-glucamine (1.95 g, 0.5 eq.) Was added and the solution was cooled to room temperature, i.e. 20-23 ° C. 3.52 g are obtained which is enriched in the salt of the 5-bromo-naproxen precursor with N-methyl-D-glucamine. The salt was dissolved in water (about 25 ml), acidified with hydrochloric acid and filtered to isolate the precipitated material which was concentrated in the 5-bromo-naproxen precursor.

1.00 g of the material enriched in the N-methyl-D-glucamine salt of the 5-bromo-naproxen precursor is recrystallized from 10 ml of methanol and 20 ml of ethanol, concentrated by evaporation of 5 ml of solvent and cooled. 0.85 g of recrystallized salt is obtained, which is treated with hydrochloric acid as described above. This gives a substantially pure 5-bromo-naproxen precursor.

To a solution of the 5-bromo-naproxen precursor (g) in dry methanol (10 mL) was added palladium on carbon (100 mg) and the mixture was stirred at room temperature under hydrogen for 12 hours. The mixture was filtered, diluted with water and extracted with dichloromethane. The organic phase is evaporated to dryness and the residue is recrystallized from dichloromethane / hexane. The resulting naproxen has an optical rotation of 58 °.

Alternatively, in a 250 ml flask equipped with a reflux condenser and a nitrogen bubbler, 60 g of magnesium powder, 50 ml of anhydrous methanol and 10 g of triethylamine are weighed. The flask was saturated and purged with nitrogen and a nitrogen atmosphere was maintained throughout the reaction.

A solution of 0.1 mol of 5-bromo-naproxen precursor compound prepared in the first part of Example 11 in methanol (15 g) was added slowly to the flask and the reaction mixture was refluxed for an additional hour. To the cooled mixture was added 6N hydrochloric acid until all of the magnesium was dissolved. The mixture was poured into water, extracted with dichloromethane, the organic phase separated, washed with water and

Example 16 d-2- (6-Methoxy-2-naphthyl) -propionic acid, prepared as described in Example 1, was mixed with 4 g of sodium hydroxide in 500 ml of aqueous methanol and stirred for 3 hours at room temperature. . Concentration gave 2- (6-methoxy-2-naphthyl) -propionic acid sodium salt. The product is dissolved in toluene, the solution is centrifuged, and the isolated product is washed with hexane and dried. The sodium salt of 2- (6-methoxy-2-naphthyl) -propionic acid thus obtained melted at about 255 ° C (with decomposition). The product has infrared maxima at 1260, 1600, 1625, and 1725 cm * ¹ . Yield: 95% relative to d-2- (6-methoxy-2-naphthyl) -propionic acid.

Example 17

To a solution of 8.5 g of triethylamine in 100 ml of toluene is added 13 g of 1- 2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid. The mixture was heated to 110 ° C for 20 hours and then poured into 0.5 N sodium hydroxide solution. The aqueous layer was separated and adjusted to pH 1-2 with 12N hydrochloric acid. The resulting precipitate was collected by filtration and dried. This gives dl-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid.

Claims (7)

PATENT CLAIMS A process for the preparation of d-2- (6-methoxy-2-naphthyl) -propionic acid and its pharmaceutically acceptable salts, characterized in that the 2- (6-methoxy-2-naphthyl, yl) -propionic acid is a compound of general formula (I). a racemic prodrug of formula (II) - in this formula R ¹ is hydrogen or methyl; X is halogen, preferably bromine or chlorine and n = 1; obsession R ¹ is hydrogen and n = 0; or a salt of such a compound in a reaction inert organic solvent with an N-R-D-glucamine, wherein R is C 1 -C 14 alkyl or C 4 -C 8 cycloalkyl, or a salt thereof; By resolution of the diastereomeric salt formed to convert the resulting d-precursor (I) to d-2- (6-methoxy-2-naphthyl) -propionic acid; and optionally converting the resulting d-2- (6-methoxy-2-naphthyl) propionic acid into a pharmaceutically acceptable salt thereof, and optionally racemizing the resulting 1-form precursor and resolving the resulting racemic precursor as described above. 2. A process according to claim 1 wherein the prodrug of 2- (6-methoxy-2-naphthyl) -propionic acid is a compound of formula (I) wherein R ¹ is methyl, X is bromo or chloro. = 1 - or a salt thereof is resolved in an inert organic solvent or solvent mixture other than a mixture of methanol and toluene, with NRD-glucamine containing a methyl group of R or a salt thereof. 3. A method according to claim 1, characterized in that the 2- (6-methoxy-2-naphthyl) propionic acid precursor of ^R1 is hydrogen and optionally X is bromine compound containing chlorine (I) - where n = 0 or 1 - or a salt thereof is resolved with NRD-glucamine or a salt thereof containing R; The method of claim 1, wherein Characterized in that N-R-D-glucamine or a salt thereof is used as a resolving agent in the group R in which R is a C 2 -C 14 alkyl group or a C 4 -C 8 cycloalkyl group. The process according to claim 4, wherein the resolving agent is N-R-D-glucamine or a salt thereof containing R 6 -C 6 alkyl or C 4 -C 8 cycloalkyl. Process according to claim 1, 3, 4 or 5, characterized in that the d-2- (6-hydroxy-2-naphthyl) propionic acid or a salt thereof obtained in the resolution step is methylated, preferably with θ methyl halide. or by reaction with dimethyl sulfate to form d-2- (6-methoxy-2-naphthyl) -propionic acid. Process according to claim 1, 2, 4 or 5, characterized in that the resolution The d-2- (5-halo-6-methoxy-2-naphthyl, yl) -propionic acid obtained in Step 5 is converted to d-2- (6-methoxy-2-naphthyl) -propionic acid by dehalogenation.