FI76782C - Amide containing the d-2- (6-methoxy-2-naphthyl) propionic acid quinconidine salt and process for its preparation - Google Patents

Description

1 76782

Amide-containing cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid and a process for its preparation

Divided separated from patent application 812377 5

The invention relates to the cinchonidine salt of amide-containing d-2- (6-methoxy-2-naphthyl) propionic acid and to a process for the preparation of such a salt.

d-2- (6-methoxy-2-naphthyl) propionic acid is a known substance having anti-inflammatory, analgesic and antipyretic properties and is described in U.S. Patent 3,904,682. Several methods for its preparation are also known, but generally are not stereospecific in that they first prepare a racemic mixture of d- and 1-2- (6-methoxy-15-2-naphthyl) propionic acids, which is then decomposed into two optical antipodes by formation of salts with optically active organic bases, utilizing different solubilities of the salts formed with the bases of the two d- and 1-isomers in a suitable solvent (see, for example, DE-A-1 934 460, 2 005 454, 2 013 641 and 2 159 011, and U.S. Patents 3,658,858 and 3 658 863.

The amide-containing cinonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid of the invention can be used to decompose 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 in satisfactory yield and purity so that it can be used in therapy, has always been difficult, despite the apparent simplicity of the steps.

Several methods have been described in the patent literature for the resolution of mixtures of d- and 1-2- (6-methoxy-2-naphthyl) propionic acids to the corresponding optical antipodes. All of these methods have significant disadvantages due to the use of both volatile and hazardous solvents, 2 76782 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 5 yield.

Thus, for example, according to FR application 2 035 846, the resolution 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 boiling point to achieve complete dissolution, adding molar an organic base, for example cinchonidine dissolved in methanol, by heating the mixture thus obtained and gradually cooling and simultaneously inoculating with a crystal of the quinone salt of d-2- (6-methoxy-15-naphthyl) propionic acid. 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 being treated in a manner known per se to the desired final product, i.e. d-2- To give (6-methoxy-2-naphthyl) propionic acid.

The disadvantages associated with this method are obvious. The process requires the use of large amounts of volatile and flammable solvent, which must be heated to boiling point, and several recrystallizations must be performed to obtain a product of the required degree of purity which degrades the final yield. In fact, neither the yield nor the optical purity values are reported in the said FR application.

Recrystallization is necessary because the quinonidine salt of the dextrorotatory isomer always contains more or less substantial amounts of the corresponding salt of the dextrorotatory isomer.

Two subsequent publications, namely U.S. Pat. No. 3,683,015 and DE-A-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 3,76782 methods essentially follow the method described in FP. Application 2,035,846, with the difference that the separation with an optically active organic base is carried out in the presence of a predetermined basic substance having an SME greater than 8.

a

Usually this substance is triethylamine, according to U.S. Patent 3,683,013 or potassium hydroxide, according to DE-A-2,319,245. The addition of a basic substance is intended to alter the solubility by promoting the precipitation of a salt of d-2- (6-methoxy-2-naphthyl) propionic acid in higher purity while using a small amount of a predetermined optically active organic base which is coincidentally a rather expensive compound.

Also, these improved methods require the use of large amounts of volatile and flammable solvents, such as methanol. In addition, the quinonidine salt of the dextrorotatory isomer must be crystallized several times to obtain it substantially free of the corresponding salt of the dextrorotatory isomer, after which d-2- (6-methoxy-2-naphthyl) propionic acid of the desired purity is recovered in a manner known per se.

The present invention relates to a cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid, which is characterized in that it contains about 9.5 to 14% by weight of an amide which is dimethylformamide or dimethylacetamide. The invention also relates to a process for the preparation of this salt, which process is characterized in that a molar amount of d-2- (6-methoxy-2-naphthyl) propionic acid and a molar equivalent of cinchonidine are dissolved in the amide at a temperature of 55-80 ° C, after which the resulting solution is slowly cooled. to a temperature of about 0-20 ° C.

The salt of the invention can be used as a seed crystal in a process for preparing a solution of a mixture of d- and 1-2- (6-methoxy-2-naphthyl) propionic acids and cinchonidine-35 by dissolving said 4,76782 mixture in an organic solvent at a temperature of about 70-90 ° C. which is formamide, monomethylformamide, dimethylformamide, monoethylformamide, diethylformamide, monomethylacetamide or dimethylacetamide and heating the resulting mixture until complete dissolution. The solution thus obtained is gradually cooled and inoculated at a certain temperature with crystals of the quinone salt of d-2- (6-methoxy-2-naphthyl) propionic acid according to the invention containing about 9.5 to 14% by weight of the amide used above. Cooling is continued until the cinchonidine salt of the dextrorotatory 10 isomer precipitates. The salt of the levorotatory isomer, which is more soluble, as well as the free acid, remain in solution. The resulting salt is treated in a manner known per se, for example with mineral acids in suitable organic solvents to give free d-2- (6-methoxy-2-naphthyl-15) propionic acid.

In practice, the process is carried out by suspending a molar amount of a predominantly racemic mixture of d- and 1-2- (6-methoxy-2-naphthyl) propionic acids and about 0.5 molar equivalents of cinconidine in an amide which is hereinafter abbreviated as dimethylformamide. DMF) or dimethylacetamide (hereinafter abbreviated as DMA), at a temperature of about 70-90 ° C, preferably about 75-80 ° C. The resulting solution is maintained at this temperature for about 10-30 minutes, after which it is slowly cooled and gradually cooled. When the temperature drops to about 70-50 ° C, preferably about 66-60 ° C, the solution is seeded with crystals of the cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid of the invention containing about 9.5 to 14% by weight. -% amide, for example DMF or DMA.

It has been found that the weight of amide can range from about 9.5 to 12% when DMF is used and from about 10.5 to about 14% when DMA is used.

The temperature at which inoculation takes place can vary within sufficiently wide limits. However, a temperature range of 70-50 ° C indicated 35 to be the most suitable for obtaining the salt of the dextrorotatory 5,76782 isomer, which is substantially free of the salt of the levorotatory isomer.

Cooling is continued until a temperature between about room temperature and 0 ° C is reached, in which case, due to its low solubility, the cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid precipitates, the salt still containing about 9.5 to 14% by weight of amide.

The product thus obtained is recovered by filtration and, if desired, can be further recrystallized using the same amide as the solvent used in the previous steps to remove a small amount of the levorotatory isomer salt which may co-precipitate with the desired levorotatory isomer salt. However, it has been found that this operation is not absolutely necessary, since treatment of the obtained non-recrystallized salt with e.g. mineral acid gives the final compound, d-2- (6-methoxy-2-naphthyl) propionic acid, in quite good yield and in very pure form.

The treatment with a mineral acid such as hydrochloric acid is carried out at room temperature in the presence of an organic solvent such as ethyl acetate.

The method described above using the salt of the invention has considerable advantages over the methods known to date and described in the literature. For example, volatile and flammable organic solvents such as methanol are not used. The amounts of solvent are generally lower and the reaction times are also considerably shortened. More importantly, it is possible to avoid recrystallization of the cinchonidine-30 salt of d-2- (6-methoxy-2-naphthyl) propionic acid to give a product which is essentially free of the corresponding salt of the levorotatory isomer and that the desired final compound is obtained in fairly good yield (usually over 80 % calculated from the molar amount of the d-isomer contained in the racemic mixture) and a specific rotation well in accordance with the standards set out in the 1978 Addendum to the British Pharmacopoeia of 1973, p. 40, according to which 6 76782 d-2- (6 -methoxy-2-naphthyl) propionic acid must have a specific rotation between + 63 and + 68 ° (4 dm tube; c = 1% in CHCl 3).

The following examples illustrate the invention.

5 Gas chromatographic analysis was performed on a

With the Elmer F 33. I.R. (infrared) spectra were obtained on a Perkin-Elmer 297 spectrometer. The specific rotation was determined with a Perkin Elmer 241 polarimeter.

Example 1 45.05 g (0.2 mol) of d-2- (6-methoxy-2-naphthyl) propionic acid and 58.87 g (0.2 mol) of cinchonidine were suspended in 400 ml of DMF at 60 ° C. at. The temperature was raised to 80 ° C until complete dissolution and then the resulting solution was slowly cooled to 20 ° C over about three 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 (gas chromatographic assay) were obtained. Infrared spectrum: 20 compounds gave an absorption band at 1660 cm, which is characteristic of DMF in this compound.

Example 2

By operating essentially in the same manner as in Example 1 and using DMA instead of DMF, a cinchonidine salt of d-2-25 (6-methoxy-2-naphthyl) propionic acid containing 11.2% by weight of DMA (gas chromatographic assay) was obtained.

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

Example I

A) 230.26 g (1.0 mol) of dl-2- (6-methoxy-2-naphthyl) -propionic acid and 147.19 g (0.5 mol) of cinchonidine were suspended in 1000 ml of DMF at 75 ° C: n, the mixture 35 was kept at this temperature for about 15 minutes and then the resulting solution was slowly cooled. At 64 ° C, the solution was seeded with 2.0 g of the compound prepared as in Example 7,767,782, and cooling was continued for an additional three hours at 0 ° C. A precipitate was obtained which was collected, washed with 200 ml of cold DMF and dried in vacuo at 60 ° C. Yield: 247.0 g of the Kinko-5 nidine 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 of -1 at 1660 cm, which is characteristic of DMF in this context.

B) The product obtained in A) was treated with 1,500 ml of ethyl acetate and 1125 ml of 2N hydrochloric acid with stirring at room temperature. After about two 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-2-naphthyl) propionic acid. M.p .: 155 ° C. 15 / C <7p0 = 66.3 ° (c = 1% in CHCl3).

Example II

A) 46 g (0.2 mol) of dl-2- (6-methoxy-2-naphthyl) propionic acid and 32.38 g (0.11 mol) of cinchonidine were suspended in 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 60 ° C, the solution was inoculated with 200 mg of the compound prepared as in Example 2.

Cooling was continued slowly to 54 ° C, at which point a copious 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-30) propionic acid containing 10.9% DMA (gas chromatographic assay).

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

B) By the method essentially as described in B) of the previous 35 examples, 19.1 g (83 S

theoretical) d-2- (6-methoxy-2-naphthyl) propionic acid. M.p .: 154-155 ° C. = 64.2 ° (c = 1% in CHCl 3).

8 76782

Example III

230.26 g (1.0 mol) of dl-2- (6-methoxy-2-naphthyl) propionic 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 further cooled to 0 ° C over 3.5 hours. A dense suspension was obtained, filtered and the recovered precipitate was washed with 10,200 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 again inoculated at 64 ° C with 2 g of the compound of Example 1. 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 I, point B). Yield: 96.7 g (84.0% of theory) of d-2- (6-methoxy-2-naphthyl) propionic acid. M.p .: 155-56 ° C. = 68.5 ° (c = 20 in 1% CHCl 3).

The following example shows that without inoculation with the cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid containing certain amounts of amides used as reaction solvents, decomposition to optical antipodes does not occur.

Comparative Example

A mixture of 115.17 g (0.5 mol) of dl-2- (6-methoxy-2-naphthyl) propionic acid and 80.96 g (0.275 mol) of cinchonidine in 500 ml of DMF was heated to 75 ° C: for 15 minutes to 30 minutes until complete dissolution was observed, then it was gradually cooled to 0 ° C over about three hours. The solid precipitate formed was collected by filtration, washed with 100 ml of cold DMF and dried in vacuo at 60 ° C. 109 g of the cinchonidine salt of dl-2- (6-methoxy-2-naphthyl) propio-35-nic acid, which was essentially free of DMF, were obtained.

Infrared spectrum: no absorption band at 1660 cm -1, typical of DMF in this compound, was observed.

Claims (6)

9,76782 1. A cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid, characterized in that it contains about 59.5 to 14% by weight of an amide which is dimethylformamide or dimethylacetamide. The cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid according to claim 1, characterized in that it contains about 9.5 to 12% by weight of dimethylformamide. The cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid according to claim 1, characterized in that it contains about 10.5 to 14% by weight of dimethylacetamide. A process for the preparation of a cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid containing about 9.5 to 14% by weight of amide, wherein the amide is dimethylformamide or dimethylacetamide, characterized in that the molar amount of d-2- (6-methoxy-2-naphthyl) -methoxy-2-naphthyl) propionic acid and 20 molar equivalents of cinchonidine are dissolved in the amide at 55-80 ° C, after which the resulting solution is slowly cooled to about 0-20 ° C. A process according to claim 4 for the preparation of a cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid containing about 9.5 to 12% by weight of dimethylformamide, characterized in that a molar amount of d-2- (6-methoxy- 2-Naphthyl) propionic acid and a molar equivalent of cinchonidine are dissolved in dimethylformamide at a temperature of about 55-65 ° C, after which the resulting solution is slowly cooled to about 20 ° C. A process for the preparation of a cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid containing about 10.5 to 14% by weight of dimethylacetamide according to claim 4, characterized in that a molar amount of 35 d-2- (6-methoxy- 2-Naphthyl) propionic acid and the molar equivalent of cinconidine are dissolved in dimethylacetamide at a temperature of about 55-65 ° C, after which the resulting solution is slowly cooled to about 20 ° C.