FI64348C - FOERFARANDE FOER UPPDELNING AV EN BLANDNING AV D- OCH 1-2- (6-METOXY-2-NAPHTHYL) -PROPIONSYROR I OPTICAL ACTIVE ISOMER - Google Patents

Description

64348

Process for the resolution of mixtures of d- and 1-2 (6-methoxy-2-naphthyl) -propionic acids into optically active isomers d-2- (6-methoxy-2-naphthyl) -propionic acid is a known anti-inflammatory, analgesic and antipyretic properties; it is described in U.S. Pat. U.S. Pat. No. 3,904,682. Several methods for its preparation are also known, but are generally not stereospecific in that they first consider the synthesis of a racemic mixture of d- and 1-2- (6-methoxy-2-naphth-10-style) -propionic acids, which the mixture is then decomposed into two optical antipodes by formation of salts, with optically active organic bases, taking advantage of the different solubilities of the d- and 1-salts of the two isomers with these bases in a suitable solvent (see, for example, German Patent Applications 1,934,460; 2,005,454; 2 013,641 and 2,159,011, U.S. Patents 3,658,858 and 3,658,863.

The present invention relates to a new process for the resolution of mixtures of d- and 1-2- (6-methoxy-2-naphthyl) -propionic acids into optically active antipodes. Separation of these two optically active isomers, namely the dextrorotatory and levorotatory isomers, and obtaining a predominantly dextrorotatory isomer with satisfactory yield and purity so that it can be used for therapy, has always represented a very difficult task, despite the apparent simplicity of the work steps.

Several methods for resolving mixtures of d- and 1-2- (6-methoxy-2-naphthyl) -propionic acids into the corresponding optical antipodes have been described in the patent literature.

30 In all cases, all these methods have significant disadvantages due to the use of both volatile and hazardous solvents, such as methanol or ethanol, and the fact that the desired product, i.e. the dextrorotatory isomer, is obtained with the required purity only after several recrystallizations which significantly degrade the final catches.

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Thus, for example, according to French patent application 2,035,846, decomposition into optical antipodes took place by pouring a molar amount of a racemic mixture of 2- (6-methoxy-2-naphthyl) -propionic acid into methanol, heating to the boiling point of the hop to achieve complete dissolution, adding to this solution an organic base, for example cinchonidine dissolved in methanol, by heating the mixture thus obtained and gradually cooling and simultaneously inoculating the salt of d-2- (6-methoxy-2-10 naphthyl) -propionic acid with the crystal previously formed. The salt of d-2- (6-methoxy-2-naphthyl) -propionic acid, which is less soluble in methanol than the corresponding levorotatory isomer, precipitated and recrystallized several times before treatment according to conventional methods to give the desired final product, i.e. d-2 To obtain - (6-methoxy-2-naphthyl) -propionic acid.

The disadvantages of this method are self-evident: it requires the use of large amounts of volatile and flammable solvent, which must be heated to boiling point, and several recrystallizations necessary to obtain a product of the required degree of purity, but which nevertheless degrade the final yields: in fact and no optical purity values are given in this application.

Recrystallization is necessary because the cinchonidine salt of the right-hand circulating isomer always contains more or less substantial amounts of the corresponding salt of the left-hand circulating isomer.

Two subsequent publications, namely U.S. Patent No. 3,683,015 and German Application No. 2,319,245, describe two improved methods for the separation of the d- and 1-isomers of 2- (6-methoxy-2-naphthyl) -propionic acid. These methods essentially followed the method described in French application 2,035,846, with the difference that the separation by means of an optically active organic base was carried out in the presence of a predetermined basic substance having a pka greater than 8.

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Usually this substance was triethylamine, U.S. Pat. according to patent 3,683,013, or potassium hydroxide, according to German application 2,319,245. The addition of a basic substance was intended to change the solubility so as to promote the precipitation of the salt of d-2- (6-methoxy-2-naphthyl) -propionic acid in a higher purity while using a small amount of a predetermined optically active organic base which, by chance, is quite expensive. compound. In all cases, including following these improved methods, large amounts of volatile and highly flammable solvents, such as methanyl, must always be used. In addition, the salt of the dextrorotatory isomer with cinchonidine must be crystallized several times to obtain it substantially free of the corresponding salt of the dextrorotatory isomer and recover d-2- (6-methoxy-2-naphthyl) -propionic acid of the desired purity by conventional methods.

The novel process which is the subject of the present invention can be briefly described by the following steps: a) A solution of a mixture of d- and 1-2- (6-methoxy-2-naphthyl) -propionic acid and an optically active organic base is prepared by dissolving, at a temperature between n. 70 to about 90 ° C, the above mixture into an organic solvent selected from formamide, monomethylformamide, dimethylformamide, menoethylformamide, diethylformamide, monomethylacetamide and dimethylacetamide, and heated mixture. until complete dissolution; b) the solution thus obtained is gradually cooled and seeded, at a predetermined temperature, with crystals of d-2- (6-methoxy-2-naphthyl) -propionic acid and the preformed salt of the optically active organic base used in step a) containing the salt in step a) the amount of organic solvent used, which preferably ranges from about 9.5% to about 14%. Cooling is continued until the salt of the dextrorotatory isomer with the optically active organic base, due to its lower solubility in a predetermined organic solvent, precipitates, the salt still containing the same 4,64348 organic solvent by weight, preferably ranging from the above percentages; the salt of the levorotatory isomer, which is more soluble, as well as the free acid, remain in solution; C) The salt obtained in b) is treated according to known methods, for example with mineral acids in suitable organic solvents to give free d-2- (6-methoxy-2-naphthyl) propionic acid.

In the actual practice of step a), a molar amount of a substantially racemic mixture of d- and 1-2- (6-methoxy-2-naphthyl) propionic acid and about 0.5 molar equivalents of an optically active organic base, which is preferably cinchonidine, to a suitable organic solvent, preferably an amide selected from formamide, monomethylformamide, dimethylformamide, monoethylformamide, diethylformamide, monoethylacetamide and dimethylacetamide, most preferably dimethylformamide (hereinafter dimethylformamide) then short-20 dMA is used), at temperatures between about 70-n. 90 ° C, preferably about 75-80 ° C. The resulting solution is maintained at this temperature for about 10 minutes to about 30 minutes, then slowly and gradually cooled (step b). When the temperature drops to about 70-50 ° C and preferably to about 66-60 ° C, the solution of ym-25 is terminated with d-2- (6-methoxy-2-naphthyl) propionic acid and an optically active organic base. crystals of the salt formed, wherein the base is preferably cinconidine and the salt contains a predetermined amide used as a solvent, for example DMF or DMA in an amount by weight which preferably varies between about 9.5% and about 14%. It has been found that this amount of weight can range from about 9.5-12% when DMF is used, and from about 10.5 to about 14% when DMA is used.

The salt used for inoculation is prepared by dissolving a molar amount of d-2- (6-methoxy-2-naphthyl) -propionic acid-35 poa and a molar amount of an optically active organic base in one of the aimides listed above at a temperature between about 55 ° C and about 80 ° C. and slowly cooling the resulting solution to about 0 ° C.

teaspoon 5 64348 The temperature at which inoculation takes place can vary within sufficiently wide limits. However, the indicated range of 70-50 ° C proved to be the most suitable for obtaining the salt of the dextrorotatory isomer, which is essentially free of the salt of the dextrorotatory isomer.

Cooling is continued according to step b) until a temperature between about room temperature and about 0 ° C is reached, whereby, due to its low solubility, the salt of d-2- (6-methoxy-2-naphthyl) propionic acid is predetermined. Precipitates with the optically active organic base, the salt still containing the amide selected as solvent in an amount ranging from n, 9.5% to 14%.

The product thus obtained is recovered by filtration and, if desired, can be further recrystallized using the same amide used in steps a) and b) as the solvent to remove a small amount of the dextrorotatory isomer salt which may co-precipitate with the desired dextrorotatory isomer salt. with. However, it has been found that this delivery is not absolutely necessary because the subsequent treatment of the non-refilled salt obtained according to step b) according to step c) gives the final compound, d-2- (6-methoxy-2-naphthyl) propionic acid. , with a fairly good catch and an excellent degree of purity.

This step is carried out at room temperature in the presence of a mineral acid such as hydrochloric acid and an organic solvent such as ethyl acetate.

The method of the invention described herein has considerable advantages when compared to methods hitherto known and described in the literature. For example, volatile and flammable organic solvents such as methanol are never used, solvent amounts are generally lower and reaction times are also considerably shortened. More importantly, the disadvantageous step of comprising a salt of 35 d-2- (6-methoxy-2-naphthyl) -propionic acid with an optically active organic base from subsequent re-additions of the corresponding salt of the levorotatory isomer to obtain a substantially free product can be practically avoided. , so that the desired final compound is obtained in fairly good yields (usually more than 80%, based on the molar amount of the d-isomer contained in the 5 racemic mixtures and with a specific rotation which is in good agreement with the standards given in 1978 Addendum to the British Pharmacopeia of 1973 page 40, according to which the specific rotation 10 of d-2- (6-methoxy-2-naphthyl) -propionic acid must be between +63 and + 68 ° (4dm tube; c = 1% in CClCl).

salts of d-2- {6-methoxy-2-naphthyl; -propionic acid with optically active organic bases containing certain amounts of the amides described above used as solvents in steps a) and ab) are novel; thus, they are to be considered as a further object of the present invention.

Gas chromatographic analysis was performed on a Perkin-Elmer F 33 instrument. I.R. (infrared) books were recorded on a Perkin-Elmer 297 spectrometer. The specific rotation was determined with a Perkin-Elmer 241 polarimeter.

Example 1, Preparation of seed crystal 45.05 g (0.2 moles) of d-2- (6-methoxy-2-naphthyl) propionic acid and 58.87 g (0.2 moles) of cinchonidine were suspended in 400 ml of DMF. At a temperature of 60 ° C. The temperature was raised to 80 ° C until complete dissolution and then the resulting solution was slowly cooled to 20 ° C over about 3 hours. A precipitate was obtained which was collected by filtration, washed with 50 ml of cold DMF and dried in vacuo at 60 ° C. 110 g of the cinchonidine salt of d-2- (6-methoxy-2-naphthyl) -propionic acid containing 10.6% by weight of DMF 30 (gas chromatographic assay) were obtained. Infrared: The compound gave an absorption band at 1660 cm -1, which is characteristic of DMF in this compound.

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Example 2, Preparation of seed crystal

By operating in essentially the same manner as in Example 1 and using DMA instead, a cinchonidine salt of d-2- (6-methoxy-2-naphthyl) -propionic acid was obtained, which contained 11.2% by weight of DMA (gas chromatographic assay).

Infrared spectrum: the compound gave an absorption band at 1630 cm -1, which is characteristic of DMA in this compound.

Example 3 A) 230.26 g (1.0 mol) of d 1-2- (6-methoxy-naphthyl) propionic acid and 147.19 g (0.5 mol) of cinchonidine were suspended in 1000 ml: DMF at 75 ° C, the mixture was kept at this temperature for about 15 minutes and then the resulting solution was slowly cooled. At 64 ° C, the solution was inoculated

With 2.0 g of the compound prepared as in Example 1, cooling was continued for a further 3 hours to 0 ° C. A precipitate was obtained which was collected and washed with 200 ml of cold DMF

2Q and dried in vacuo at 60 ° C. Yield: 247.0 g of the cinchonidine salt of d-2- (6-methoxy-2-naphthyl) -propionic acid containing 10.6% by weight of DMF (gas chromatographic assay).

Infrared spectrum: the compound gave an absorption band at 1660 cm, which is characteristic of DMF in this context.

B) The product obtained in A) was treated with stirring at room temperature with 1500 ml of ethyl acetate a and 1.12 5 ml of 1.1N hydrochloric acid. After about 2 hours, the organic layer was separated, washed with water until neutral and evaporated to dryness. Yield: 93.9 g (80.7% of theory) of d-2- (6-methoxy-2Q-2-naphthyl) -propionic acid. Sp. ; 155 ° C. t ot) δ = 66.3 ° (c = 1% in CHCl 3).

Example 4 A) 46 g (0.2 moles) of dl-2- (6-methoxy-2-naphthyl) propionic acid and 32.38 g (0.11 moles) of cinchonidine were suspended in 35,200 ml of DMA at 70 ° C. . The temperature was raised to 90 ° C and held for about 15 minutes until a clear solution was obtained, then the resulting solution was gradually cooled.

At 64 ° C, the solution was inoculated with 200 mg of the compound prepared as in Example 2.

Cooling was continued slowly to 54 ° C whereupon a large precipitate began to separate. The mixture was kept at this temperature for about 30 minutes and then cooled to 20 ° C in about 90 minutes. The resulting precipitate was collected by filtration, washed with 50 ml of cold DMA and dried in vacuo at 60 ° C. Yield: 51.42 g of the cinchonidine salt of d-2- (6-methoxy-2-naphthyl) -propionic acid containing 10.9% DMA (gas chromatographic determination).

Infrared spectrum: the compound gave an absorption band at 1630 cm -1, which is characteristic of DMA in this compound.

B) By proceeding essentially as described in B) of the previous example, 19.1 g (83% of theory) of d-2- (6-methoxy-2-naphthyl) -propionic acid were obtained.

M.p .: 154-55 ° C. [α] D 20 = 64.2 ° (c = 1% C in HCl).

Example 5 230.26 g (1.0 mol) of dl-2- (6-methoxy-2-naphthyl) -pro-2Q pionic acid and 161.9 g (0.55 mol) of cinchonidine were suspended in 1000 ml of DMF At 80 ° C and the mixture was kept at this temperature until a clear solution was obtained. The solution was then gradually cooled and, at 64 ° C, seeded with 2 g of the compound of Example 1 and slowly cooled to 0 ° C over a further 3.5 hours. A dense suspension was obtained, filtered and the recovered precipitate was washed with 200 ml of cold DMF.

It was resuspended with stirring in 700 ml of DMF at a temperature of about 80 ° C until a clear solution was obtained, gradually cooled and inoculated again at 64 ° C with 2 g of the compound of Example 2Q. Cooling was continued slowly to 0 ° C, the resulting precipitate was collected by filtration, washed with 150 ml of cold DMF and finally dried in vacuo at 60 ° C. The product thus obtained was finally treated according to Example 3 (B). Yield: 96.7 g (84.0% of theory) of d-2- (6-methoxy-2-naphthyl) -N-propionic acid. Sp. : 155-56 ° C. [α] D 20 -68.50 (c - 1% C in HCl).

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The following example shows that without inoculation with a salt of d-2- (6-methoxy-2-naphthyl) -propionic acid and an optically active organic base containing certain amounts of amides used as reaction solvents, no degradation to optical antipodes occurs.

Example 6

A mixture of 115.17 g (0.5 moles) of dl-2- (6-methoxy-2-naphthyl) propionic acid and 80.96 g (0.275 moles) of cinchonidine in 500 ml of DMF was heated to 75 ° C. at 15 minutes until complete dissolution was observed, then it was gradually cooled to 0 ° C in about 3 hours. The solid precipitate formed was collected by pouring, washed with 100 ml of cold DMF and dried in vacuo at 60 ° C. 109 g of the quinoneidine salt of del-2- (6-methoxy-2-naphthyl) -propionic acid, which was essentially free of DMF, were obtained.

No infrared absorption band in 1660 emes, typical of DMF in this compound, was observed.

Claims (2)

6 4 3 4 8 Claim: υι A process for the resolution of a substantially racemic mixture of d- and 1-2- (6-methoxy-2-naphthyl) -propionic acids into optically active isomers, characterized in that a) a solution containing said racemic mixture of molar equivalents is prepared and about 0.5 molar equivalents of quinonidine, in dimethylformamide or dimethylacetamide at a temperature of about 75-80 ° C; b) the resulting solution is gradually cooled and inoculated at a temperature of about 66-60 ° C with a cinchonidine salt of d-2- (6-methoxy-2-naphthyl) -oropionic acid containing about 9.5-14% by weight of cimethylformamide or dimethylacetamide. crystals and cooling is continued to a temperature between room temperature and C ° C, wherein the cinchonidine salt of d-2- (6-methoxy-2-naphthyl) -propionic acid containing about 9.5% to 14% by weight di-15 methylformamide or dimethylacetamide, precipitates; and c) treating the resulting product with hydrogen chloride in the presence of ethyl acetate to give free d-2- (6-methoxy-2-naphthyl) -propionic acid.