CA1171089A - Process for the optical resolution of mixtures of d- and 1-2(6-methoxy-2-naphthyl)- propionic acids - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Novel cinchonidine salts of d-2-(6-methoxy-2-naphthyl) -propionic acids which are intermediates, the optical resolu-tion of mixtures of d- and 1-2-(6-methoxy-2-naphthyl)-propionic acids, as well as their preparation.

Description

~J7~a~
The present invention relates to a process for the optical resolution of mixtures of d~ and 1~2-(6-methoxy-2-naphthyl)-propionic acids and in particular novel cinochonidine salts of d-2-(6-methoxy-2-naphthyl)-propionic acids which are intermediates in the process.
The present invention is a divisional application of copending appli-cation No. 382,748 filed ~uly 23, 1981.
d-2-~6-methoxy-2-naphthyl)-propionic acid is a known substance having antiphlogistic~ analgesic and antipyretic properties: it is described in U.S. Patent No. 3,904,682.
Several methods for its preparation are also known but in gen-eral, they are not stereospecific in that they first contem-plate the synthesis of a racemic mixtur~ of the d- and 1 2-(6-methoxy-2-naphthyl3-propionic acids, which is subsequently resolved into the two optical antipodes through formation of salts with optically active organic bases, taking advantage from the different solubilities of the salts of the two iso-mers d and l with said bases in a suitable solvent (see, for instance, German Applications Nos. 1,934,4~0; 2,005,454;

2,013,641 and 2,159,011; U.S. Patents Nos. 3,658,858 and

3,658,863.
The present invention as disclosed and claimed in said copending application is directed to a process for the resolution into the optically active antipodes of mixtures of d- and 1-2-~6-methoxy-2-naphthyl)-propionic acids. The separ-ation of the two optically active isomers, namely the dextro-rotatory and the laevorotatory one, and, chiefly, the obtain-ment of the dextrorotatory isomer with satisfactory yields and purity so as to be employed in the therapy, has always represented a very difficult task, notwithstanding the apparent simplicity of th~ operations.
In the patent literature, several methods have been '~ ' described for the resolution of mixtures of d- and 1-2-(6-methoxy-2-naphthyl)-propionic acids into the corresponding optical antipodes. In any case, all of these methods possess remarkable drawbacks, which depend both on the use of volatile and dangerous solvents such as, for instance, methanol or ethanol, and the fact that the desired product i.e., -the dextro-rotatory isomer, is obtained with the necessary purity degree only after several recrystallizations which considerably im-pair the final yields.
Thus, for instance, according to French Applicatio~
No. 2,035,846, the resolution into the optical antipodes took place by pouring a molar amount of a racemic mixture of 2-~6-methoxy-2-naphthyl)-propionic acid in methanol, heating to the boiling point for achieving complete dissolution, adding to this solution a molar amount of an optically active organic base, e.g. the cinchonidine, dissolved in methanol, heating the so obtained mixture and graduall~ cooling and contemporan-eously seeding with previously formed crystal of a salt of d-2-~6-methoxy-2-naphthyl)-propionic acid with cinchonidine.
The salt of d-2-(6-methoxy-2-naphthyl)-propionic acid, being less soluble in methanol than the cor,responding laevorotatory isomer, precipitated and was recrystallized several times before being treated according to usual methods to give the desired final product i.e., d-2-(6-methoxy-2-naphthyl3-propi-onic acidO
The drawbacks inherent to this method are self-evident: it contemplates the use of large amounts of a volatile and inflammable solvent, which must be heated until the boil-ing point, and several recrystallizations, which are necessary for sbtaining a product with the required purity degree but, anyhow, impair the final yields: as a matter of fact, neither yield nor optical purity data are ever reported in this ~171~
application.
The recrystallizations are needed because the cin-chonidine salt of the dextrorotatory isomer always contains more or less relevant portions of the corresponding salt of the laevorotatory isomer.
In two subsequent publications, namely U.S. Patent No. 3,683,015 and German Application No. 2,319,245 two improved procedures for the separation of the d- and 1- isomers of 2-(6-methoxy-2-naphthyl)-propionic acid were described. These procedures followed substantially the method outlined in French ; Application No. 2,035,~46, with the difference that the separ-ation by means of the optically active organic base was carried out in the presence of a predetermined alkali agent having a Pka higher than 8. Usually, this agent was triethylamine, according to U.S. Patent No. 3,683,015 or potassium hydroxide, according to German Application No. 2,319,245. The addition o~
the alkali agent had the purpose of modifying the solubility so as to favor the precipitation of the salt of d-2-(6-methoxy-2-naphthyl)-propionic acid with a higher degree of purity by Z0 contemporaneously utilizing a minor amount of the predetermined optically active organic base which, incidentally, ;s a rather expensive compound. In any case, even following these im-; proved procedures, one must always operate with large amounts ; of volatile and inflammable solvents such as, for instance, methanol. Moreover, the salt of the dextrorotatory isomer with the cinchonidine must be recrystallized several times in order to have it substantially free from the corresponding salt of the laevorotatory isomer and recover, through the usual procedures, d-2-(6-methoxy-2-naphthyl)-propionic acid with the desired purity degree.
The process of the present invention as disclosed and claimed in the copending application can briefly be illustrated by the following steps:

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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 comprised between about 70 and about 90C, the above mixture in an oryanic solvent selected from formamide, monomethylformamide, di-methylformamide, monoethylformamide, diethylfor~amide, monomethylacetamide and dimethylacetamide, and heating -the resulting mixture unti.l complete dissolution;
b) the so obtained hot solution is gradually cooled and, at a predetermined temperature, is seeded with crystals of a previously formed salt of d-2-(6-methoxy-2-naphthyl)-propionic acid and the optically active organic base em-ployed in step a) r which salt contains an amount by weight of the organic solvent employed in step a) preferably varying between about 9.5% and about 14%. Cooling is con- ' tinued until the salt o~ the dextrorotatory isomer with the optically active organic base, owing to its minor solubility in the predetermined organic solvent precipi-tates, which salt still contains an amount by weight of the same organic solvent preferably varying between th~ above seen per cent limits; the salt of the laevorotatory isomer, :
which is more soluble, as well as the free acid remains in the solution;
c) the salt obtained as under b) is treated according to known procedures, as an example with mineral acids in : suitable organic solvents, to obtain the free d-2-(6-methoxy-2 naphthyl)-propionic acid.
~n the actual practice according to step a) a molar amount of a substantially racemic mi.xture of d- and 1-2-(6-methoxy-2-naphthyl)-propi.onic acids and about 0.5 molar equiva-lents of an optically active organic base whîch, preferably, - is the cinchonidine, are suspended in a suitable organic ~ ~7 1 Q~g solvent, which preferably is an amide selected from formamide, monomethylformamide, dimethylformamide, monoethylformamide, diethylformamide, monomethylacetamide and dimethylacetamide, being dimethylformamide (hereinafter referred to as DMF) and dimethylacetamide (hereinafter referred to as 3MA) the most preferred ones, at a temperature comprised between about 70 and about 90C, preferably at about 75-~0Co The resulting solu-tion is kept within this temperature interval for a period of time varying from about 10 to about 30 minutes, then it is slowly and gradually cooled (step b). When the temperature reaches the value of about 70-50C and, preferably about 66-60C, the solution is seeded with crystals of a previously pre-pared salt of the d-2-(6-methoxy-2-naphthyl)-propionic acid with the optically active organic base which, preferably, is the cinchonidine r which salt contains an amount by weight of the predetermined amide used as the solvent such as, for instance, DMF or DM~, preferably varying between about 9.5% and about 14%. It has been found that the amount by weight may vary ; between about g.5% and 12% when DMF is used and between about 20 10.5% and about 14% when DMA is employed.
According to the present invention therefore there is provided the cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing about 9.5% to about 14% by weight of an amide selected from formamide, monomethylformamide, dimethyl-formamide, monoethylformamide, diethylformamide, monomethyl-acetamide and dimethylacetamide.
The present invention also provides a process for preparing the cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing from about 95 to 14~ by weiyht of an amide selected from formamide, monomethylformamide, di-methylformamide, monoethylformamide, diethylformamide, mono~

methylacetamide and dimethylacetamide which comprises dissolving ~17~89 a molar amount of d-2-(6-methoxy-2-naphthyl)-propionic acid and a molar equivalent of cinchonidine in an amide selected from formamide, monomethylformamide, dimethylformamide, mono-ethylformamide, diethylformamide, monomethylacetamide and di-methylacetamide at a temperature comprised between about 55C
and about 65C and 510wly cooling the resulting solution to about 20C.
he salt used for seeding is prepared by dissolving a molar amount of d-2-(6-methoxy-2-naphthyl)-propionic acid and a molar amount of the optically active organic base in one o~ the above listed amides, at a temperature comprised between about 55 and about 80C and slowly cooling the resulting solu-tion to about 0C.
The temperature at which seeding occurs may vary with-in sufficiently wide limits. Anyhow, the indicated interval of 70-50C proved to be the most suitable one for obtaining a salt of the dextîorotatory isomer substantially free from the salt of the laevorotatory isomer.
Cooling is continued according to step b) until a temperature comprised between about room temperature and about - 0C is reached, whereby, owing to its minor solubilityr the salt of d-2-(6-methoxy-2-naphthyl)-propionic acid wi~h the predetermined optically active organic base precipitates, which salt still contains an amount by weight of the amide selected as the solvent varying between about 9.5% and 14%.
;; The so obtained product is recovered by filtration and, if desired, it may undergo a further recrystallization by using as the solvent the same amide employed in step a) and b) in order to remove the small amount o~ the salt of the laevoro-tatory isomer which may co-precipitate together with the salt of the desired dextrorotatory isomer. Anyhow, it has been found that this operation is not strictly necessary, as the ~L I 7 1 U B~

subsequent treatment according to step c) of the non-recry-stallized salt o~tained according to step b) affords the final compound, d-2-(6-methoxy-2-naphthyl)-propionic acid with a very good yield and an excellent purity degree.
This step is carried out at room temperature, in the presence of a mineral acid such as, for instance, hydrochloric acid, and an organic solvent such as, for instance, ethyl acetate.
The process of the lnvention as herein described possesses remarkable advantages, if compared with the methods so far known and described in the literature. As an example, volatile and inflammable organic solvents like methanol are never usedt the amounts of solvent are generally lower and also the reaction times are considerably reduced. What is more important is that the disadvantageous step regarding the subsequent recrystallizations of the salt of d-2-(6-mekhoxy-2-naphthyl)-propionic aeid with the optically active organic base for obtaining a produet substantially free of the corres-ponding salt of the laevorotatory isomer is practically avold-ed, so that the desired final compound is obtained wlth verygood yields (generally hlgher than 80~, calculated over the molar amount of the d-isomer contained in the racemlc mlxture) and a speeiflc rotation well in agreement with the standards as provided for on page 40 of the 1978 Addendum to the Britlsh Pharmacopoeia of 1973~ accordlng to whlch the specific rotation of d-2-(6-methoxy-2-naphthyl)-propionlc acld must be comprlsed between -~63 and ~68 (tube of 4 dm; c = 1~ in CHC13).
The salts of d-2-(6-methoxy-2-naphthyl)-propionle acid with the optically active organic bases conkaining eer-tain amounts of the above illustrated amides used as the sol-~ents ln skep a) and b) are new: therefore, they must be con-sldered as a further object of the present lnvention.

~ ~7~9 The following Examples are given only with the pur-pose to allow the art skilled technician to better understand and perform the present in~ention but in no way they must be construed as a limitation of the invention itself.
The gas-chromatographic analysis was carried out with a Parkin-Elmer F 33 apparatus. The I.R. (infra-red) spectra were recorded in nujol with a Perkin-Elmer 297 spectro-meter. The specific rotation was determined with a Perkin-Elmer 241 polarimeter.
Example 1 45.05 grams (0.2 mole) of d-2-(6-methoxy-2-naphthyl)-propionic acid and 58.87 g (0.2 mole) of cinchonidine were suspended in 400 ml of DMF at a temperature of 60C. The temp-erature was brought to 80C until complete dissolution then the resulting solution was slowly cooled in about 3 hours to 20C. A precipitate was obtained, which was recovered by fil- ~ -tration, washed with 50 ml of cold DMF and dried under vacuum ~at a temperature of 60C. 110 grams of the cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing 10.6%
by weight of DMF (gas-chromatographic determination) were obtained. Infra-red spectrum: the compound showed an absorp-tion band at 1660 m 1, which is characteristic of DMF in that compound.
Example 2 By operating substantially as described in Example 1 and employing DMA instead of DMF, it was obtained the cin-chonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing 11.2~ by weight of DMA (gas-chromatographic deter-mination). Infra-red spectrum: the compound showed an absorp-tion band at 1630 cm , which is characteristic of DMA inthat compound.

1 1 7 ~ 9 Example 3 A) 230.26 grams (1.0 mole) of dl-2-(6-methoxy-2-naphthyl~-propionic acid and 147.19 (0.5 mole) of cinchonidine were suspended in 1000 ml of DMF at a temperature of 75C, the mixture was kept at this temperature for about 15 minutes, then the obtained solution was slowly cooled. At the tempera-ture of 64C, the solution was seeded with 2.0 g of the com-pound prepared as in Example 1, then cooling was continued for further 3 hours to 0C. A precipitate was obtained, which was recovered, washed with 200 ml of cold DMF and dried under vacuum at 60C. 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 determination). Infra-red spectrum: the compound showed an absorption band at 1660 cm 1, whieh is characteristic of DMF in that compound.
B) The product obtained as under A) was treated under stirring at room temperature with 1500 ml of ethyl ace-tate and 1125 ml of 2N hydrochloric acid. After about two -' hours, the organic layer was separated, washed with water to 20 neutrality and concentrated to dryness. Yield: 93.0 g (80.7%
of theoretical) of d-2-(6-methoxy 2-naphthyl)-propionic acid.
M.P.: 155C. Ia]D - 66.3~ (c = 1% in CHC13).
Example 4 ~ .
A) 46 grams (0.2 mole) of dl-2-(6-methoxy-2-naphthyl) -propionic acid and 32.38 g ~0.11 mole) of cinchonidlne were ; suspended in 200 ml of DMA at 70C. The temperature was brought to 90C and kept at this va],ue for about 15 minutes until a elear solution was obtained, then the resulting solu-tion was gradually cooled. At the temperature of 60~C, the solution was seeded with 200 mg of the compound prepared as in Example 2. The cooling was slowly continued to 54C, whereby an abundant precipitate began to separate. The mixture was _ g -~ ~ 7 ~

kept at this temperature for about 30 minutes, then it was further cooled to 20C in about 90 minutes. The obtained precipitate was recovered by filtration, washed with 50 ml of cold DMA and dried under vacuum at 60C. Yield: 51.42 g of the cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing 10.9% of DMA (gas-chromatographic determina-tion). Infra-red spectrum: the compound showed an absorption band at ]630 cm 1, which is characteristic of DMA in that compound.

B) By operating substantially as described in point B) of the foregoing Example, 19.1 g (83% of theoretical) of d-2-(6-methoxy-2-naphthyl)-propionic acid were obtained. M.p.:
154-55C. [~]DO = 64.2C (c = 1% in CHC13).
Example 5 230.26 grams (1.0 mole) of dl-2-(6-methoxy-2-naphthyl) -propionic acid and 161.9 g (0~ 55 mole) of cinchonidine were suspended in ~000 ml of DMF at 80~C and the mixture was kept at this temperature until a clear solution was obtained. Then the solution was gradually cooled and, at the temperature of 64C, it was seeded with 2 g of the compound of Example 1 and further slowly cooled at 0C in 3 hours and a half. A
dense suspension was obtained, filtered and the recovered solid was washed with 200 ml of cool DMF. It was re-suspended ; under stirring in 700 ml of DMF at a temperature of about 80C, until a clear solution was obtained, then it was gradually cooled and again seeded at 64C with 2 g of the compound of Example 1. Cooling was slowly continued to 0C, the obtained precipitate was recovered by filtration, washed with 150 ml of cold DMF and finally dried under vacuum at 60C. The so obtained product was finally treated according to point B) of Example 3. ~ield: 96.7 g (84.0% of theoretical) of d-2-(6-methoxy-2-naphthyl)-propionic acid. M.p.: 155-56C.

1 ~7~9 [~]D = 68.5 (c = 1% in CHC13).
The followlng Example is provided only with the pur-pose of further better illustrating the inventions. It shows that without seeding with the salts of d-2-(6-methoxy-2-naphthyl)-propionic acicl with the optically active organic base containing certain amounts of the amides used as the reac-tion solvents, the resolution into the optical antipodes does not occurr.
Example 6 A mixture of 115.17 g (0.5 mole) of dl-2~(6-methoxy-2-naphthyl)-propionic acid and 80.96 g (0.275 mole) of cin chonidine in 500 ml of DMF was heated at 75C for 15 minutes until complete dissolution was observed, then it was gradually cooled to O~C in about 3 hours. The solid precipitate which formed was recovered by filtration, washed with 100 ml of cold DMF and dried under vacuum at 60C. 109 grams of the cinchoni-dine salt of dl-2-(6-methoxy-2-naphthyl)-propionic acid prac-tically free from DMF were obtained. Infra-red spectrum: the ; absorption band at 1660 cm 1, typical of DMF in that compound, was not observed.
The resolution into optical antipodes of the mixtures of d- and 1-2-(6~methoxy-2-naphthyl)-propionic acids can also be carried out by advantageously using as the resolving agent an optically active organic base selected from 1-2-amino-1-propanol, 1 2-aminobutanol, d-2~amino-butanolt d-treo-(2-arNno-l-p-nitrophenyl)-1,3-propandiol, d-anphetamine, d-menthyl-amine, cholestiramine, dehydro-abietylamine, 1-2-benzylamino-l-propanol, d-deoxyephredin, l-ephredin, d-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol, 1-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol, glucosamine, solanidine, N-methyl-d glucamine and analogs.

Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLU-SIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing the cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing from about 9.5 to 14% by weight of an amide selected from forma-mide, monomethylformamide, dimethylformamide, monoethylforma-mide, diethylformamide, monomethylacetamide and dimethylaceta-mide, which comprises dissolving a molar amount of d-2-(6-methoxy-2-naphthyl)-propionic acid and a molar equivalent of cinchonidine in an amide selected from formamide, monomethyl-formamide, dimethylformamide, monoethylformamide, diethylforma-mide, monomethylacetamide and dimethylacetamide at a tempera-ture comprised between about 55°C and about 65°C and slowly cooling the resulting solution to about 20°C.

2. A process for preparing the cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing from about 9.5% to about 12% by weight of dimethylformamide, which comprises dissolving a molar amount of d-2-(6-methoxy-2-naphthyl)-propionic acid and a molar equivalent of cinchonidine in dimethylformamide at a temperature comprised between about 55°C and about 65°c and slowly cooling the resulting solution to about 20°C.

3. A process for preparing the cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing from about 10.5 to about 14% by weight of dimethylacetamide, which comprises dissolving a molar amount of d-2-(6-methoxy-2-naphthyl)-propionic acid and a molar equivalent of cinchonidine in dimethylacetamide at a temperature comprised between about 55°C and 65°C and slowly cooling the resulting solution to about 20°C.

4. The cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing about 9.5% to about 14%

by weight of an amide selected from formamide, monomethylforma-mide, dimethylformamide, monoethylformamide, diethylformamide, monomethylacetamide and dimethylacetamide whenever prepared or produced by the process as claimed in claim 1 or an obvious chemical equivalent thereof.

5. The cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing from about 9.5% and about 12% by weight of dimethylformamide whenever prepared or produced by the process as claimed in claim 2 or an obvious chemical equivalent thereof.

6. The cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing from about 10.5% and 14%
by weight of dimethylacetamide whenever prepared or produced by the process as claimed in claim 3 or an obvious chemical equivalent thereof.