FI57927B - FOERFARANDE FOER RESOLVERING AV 2- (6-METOXY-2-NAPHTHYL) -PROPIONSYRA TILL OPTICAL ANTIPODER - Google Patents

Description

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Patent- and RegicterttyrelMn '' AmMcm utkfd och utUkriftM publkurarf 31.07.80 (32) (33) (31) Utuelleuii * —BugM prlorHut 21.04.72 11.04.73 USA (US) 246461, 350193 (71) Syntex Corporation, Apartado Postal 7386 , Panama, Panama (PA) (72) Pasquale Gallegra, Freeport, Grand Bahama Island, Bahamas-Bahamas (BS) (74) 0y Kolster Ab (54) Method for the resolution of 2- (6-methoxy-2-naphthyl) propionic acid into optical isomers - For the preparation of 2- (6-methoxy-2-naphthyl) -propionyl is an optical antipode

The invention relates to a process for the resolution of a mixture of d- and 1-2- (6-methoxy-2-naphthyl) propionic acids into their optical isomers to give mixtures in which most of the d-isomer is obtained.

Prior to the present invention, 2- (6-methoxy-2-naphthyl) propionic acid has been resolved into its isomers by cinchonidine by a process that requires numerous crystallizations from a low molecular weight alcohol such as methanol. Instead of this time-consuming and expensive method, there has been a desire to find better methods in terms of both quality and quantity. The present invention relates to a process for the separation of a mixture of d- and 1-2- (6-methoxy-2-naphthyl) propionic acids into its isomers to give mixtures with a higher proportion of the d-isomer, which process improves the quality in one crystallization step (enrichment). and even better performance of the entire method.

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The present invention relates to a process for the resolution of 2- (6-methoxy-2-naphthyl) propionic acid into optical antipodes by forming the cinchonidine salts of d- and 1-2- (6-methoxy-2-naphthyl) propionic acids in the presence of an auxiliary base in an inert organic solvent to which the 1-acid cinchonidine salt more soluble than the cinchonidine salt of d-acid and in which the salts of said acids with the auxiliary base are more soluble than their cinchonidine salts, the total molar number of the bases being approximately the same as the molar number of 2- (6-methoxy-2-naphthyl) propionic acid and the molar ratio of quinonidine to the auxiliary base : 3-3: 2, by selectively crystallizing the cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid from the resulting mixture and releasing the d-acid from the resulting cinconidine salt, which is characterized in that an alkali metal hydroxide is used as said auxiliary base.

To improve the purity of the d-isomer, one or more recrystallizations may be performed prior to the release of the d-acid.

2- (6-methoxy-2-naphthyl) propionic acid and methods for its preparation are described, for example, in U.S. Patent Application 176,700, filed August 31, 1971; and U.S. Patent Nos. 3,651,106; 3,652,683; 3,658,858; 3,658,863; 3,663,58 and 3,686,238. One such method involves a reaction in which 1-halo-2-methoxynaphthalene reacts with acetyl chloride in nitrobenzene in the presence of three molar equivalents of aluminum chloride to give the corresponding 2-acetyl-5-halo-6-methoxynaphthalene derivative. The obtained derivative is heated with morpholine in the presence of sulfur at 150 ° C, and the obtained product is heated under reflux with concentrated hydrochloric acid to give the corresponding 2-naphthylacetic acid derivative. The latter compound is then esterified, for example, by reacting it with an alkanol in the presence of boron trifluoride, and the ester is treated with an alkali metal hydride in ether followed by an alkyl halide, for example methyl iodide, to give the corresponding 2- (6-methoxy-2-naphthyl) propionate. The latter is hydrolyzed, for example in basic aqueous solution, to give a mixture of the d- and 1-isomers of 2- (6-methoxy-2-naphthyl) propionic acid.

The basicity, pKa, of the inorganic auxiliary base used in the process of this invention is greater than 8. The solubility of the auxiliary base and the salts of d- and 1-2- (6-methoxy-2-naphthyl) propionic acids in an inert organic solvent must be greater than that of d- and 1- Solubility of cinchonidine salts of 2- (6-methoxy-2-naphthyl) propionic acids. Suitable auxiliary bases include alkali metal hydroxides such as potassium, sodium and lithium hydroxides. The choice of auxiliary base depends on each inert organic solvent system used in the crystallization.

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The best inorganic auxiliary base for use in the process can be determined using the above criterion. The most preferred inorganic auxiliary base for use in methanol solvents is potassium hydroxide.

As the inert organic solvent system of the present invention, any inert organic solvent can be used in which a cinonidine salt of 1-2- (6-methoxy-2-naphthyl) propionic acid and a mixture of 2- (6-methoxy-2-naphthyl) propionic acid and an inorganic base can be used. the salts dissolve. Examples of such solvents are acetone, acetylacetone, adiponitrile, benzonitrile, benzyl alcohol, benzyl mercaptan, butyl alcohol, caprylic alcohol, diacetone alcohol, propylene glycol and diethylene glycol mono- and di (small) alkyl, ethylene, ethylene 1,2-propylene glycol, 1,3-propylene glycol, 2-ethylhexanol, dimethyl sulfoxide, sulfolanes, dimethylformamide, N-methylpyrrolidinone, formamide, furfuryl alcohol, glycerol, isoamyl alcohol, pyrimethylene glycol, isoamyl sulfoxide, isobutyl mercaptan, isobutyl mercaptan dime-ethylacetamide, and the corresponding solvents. Preferred solvents are polar and not acidic or strongly basic.

The mixture should contain essentially the same molar amounts of 2- (6-methoxy-2-naphthyl) propionic acid and bases, including both cinchonidine and an inorganic auxiliary base. The molar ratio of cinchonidine to inorganic base is not critical for partitioning. Useful molar ratios of cinchonidine to auxiliary base are, for example, 2: 3 to 3: 2. In pursuit of the best quality and the best yields of d-2- (6-methoxy-2-naphthyl) propionic acid, the molar ratio of cinchonidine to auxiliary base should be about 1: 1. With a lower molar ratio of cinchonidine to auxiliary base, the quality of the product is not affected, but the amount or yield decreases rapidly. With higher molar ratios of cinchonidine and auxiliary base, the amount or yield is satisfactory, but the quality is poorer.

Crystallization is generally carried out by mixing together d- and 1-2- (6-methoxy-2-naphthyl) propionic acids, cinchonidine, an inorganic auxiliary base and a sufficient amount of solvent to dissolve the components to give a suspension containing mainly d-2- (6-methoxy). -2-naphthyl) propionic acid cinchonidine salt in a nearly saturated solution of the other components, cooling the mixture, and separating the crystallized salts. As cooling continues, more dissolved salts crystallize continuously. It is preferred that a small amount of the cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid-57927 li is seeded in the solution during cooling, because then the distribution takes place well and the yield of the desired d-acid salt is good. The initial and final temperatures of the solvent are chosen as required by practice, provided that the temperature does not have a significant degrading effect on other components. The initial temperature of the mixture may be, for example, between 50-100 ° C and the mixture may be cooled to a lower final temperature below the initial temperature, e.g. below 100 ° C, mainly to about 35 ° C, with a temperature difference sufficient for good crystal formation. The crystalline mixture is maintained at lower temperatures until crystallization is complete or nearly complete, usually more than 15 minutes and most preferably more than 0.5 hours. The crystals are isolated from the resulting mixture, for example, by filtration.

The quality or percentage of the d-isomer contained in the product can be improved, if desired, by recrystallization of the above-mentioned crystals using the same solvents used in the initial crystallization or, if desired, by using different solvents, the recrystallization generally being carried out as described above.

The mother liquors obtained from all the crystallization steps can be reused in combination in the process. Depending on the purity requirements of the product, one or more recrystallizations may be performed.

The resulting salt is liberated with any organic or inorganic acid that does not damage the product to give the d-isomer-rich 2- (6-methoxy-2-naphthyl) propionic acid. Alternatively, according to the presently preferred method, the desired acid can be liberated from the cinchonidine salt product by treating the salt product with a strong base such as potassium hydroxide or another strong base having a pKa greater than 10, then acidifying the mixture to give U-2. - (6-methoxy-2-naphthyl) propionic acid. When this release is carried out, for example, in a water / methanol mixture (3: 1 by weight) at room temperature, foaming of the reaction mixture, which occurs by heating the alkaline suspension of cinchonidine at 83-86 ° C, can be prevented and the product can be easily filtered.

The present invention is considered to be an improvement over the method of distribution described in U.S. Patent No. 3,683,015. The process of the present invention, using potassium hydroxide, makes it possible to significantly increase the concentration of the mixture of d- and 1-2- (6-methoxy-2-naphthyl) propionic acids to be placed in the reaction vessel (for example, this allows the amount of dl in methanol to be 78 g to disclosed in the above-mentioned patent - may be added to 320-370 g of dl mixture per liter of methanol, as shown in the examples below).

5,57927 As a result of this higher feed rate, more product is passed through a reaction vessel of a certain size, which means lower production costs per volume of product obtained. In addition, the use of potassium hydroxide requires the preparation of a methanolic slurry of only one mixture of d- and 1-2- (6-methoxy-2-naphthyl) propionic acids to give a cinchonidine salt product suitably enriched in d-2- (6-methoxy-2- naphthyl) propionic acid cinchonidine salt and has a satisfactory optical rotation (liberated acid). In general, this applies to the product (as the free acid) having an optical rotation of about 58 °, in which case only one additional crystallization from methanol is required to obtain a substantially pure salt with an optical rotation of about 66 ° (liberated acid). This essential feature of the present invention also implies a reduction in production costs per unit amount of product obtained. All these benefits are achieved in addition to a better distribution with slightly better yields. The present invention therefore represents an improvement over the method described in U.S. Pat. No. 3,683,015 as a whole.

The following examples are provided to facilitate the understanding and practice of this invention by those skilled in the art.

Example 1

Prepare the mixture by adding 70 g (0.305 moles) of dl-2- (6-methoxy-2-naphthyl) propionic acid, g (0.150 moles) of cinchonidine, 8.6? g (0.155 mol) of potassium hydroxide and 220 ml of methanol. These substances are mixed together and the mixture is refluxed for k hours. The mixture is then gradually cooled to 25 ° C over five hours and maintained at this temperature for a further 12 hours. The resulting suspension is then filtered and the solids are washed with 100 ml of methanol and dried at 50-55 ° C. The yield of the cinchonidine salt of d-2- (6-methoxy-2-naphthyl) -propionic acid is about 90% by weight. [· *] ’= 57-58 ° (liberated acid).

Example 2

By repeating the procedure of Example 1, but replacing 8.67 g of potassium hydroxide with 7.6 g (0.136 moles) of potassium hydroxide, the cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid is also obtained in better yields than that obtained with 100% cinchonidine.

Example 3 65 g of the cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid ([.alpha.] D @ 20 = 58.8 DEG; free acid) are stirred in 195 ml of methanol and the mixture is stirred and refluxed for 1+ hours. The solution is cooled to 25 ° C over 5 hours at 6,57927 and filtered. The filtrate is washed with 30 ml of methanol at 25 ° C and dried at * + 5-50 ° C, the yield of the cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid is about 95.2% by weight. - #. = 66.1 ° (liberated acid).

Example * +

The product of Example 3 (61.8 g) is mixed with * + 50 ml of ethyl acetate and 300 ml of dilute hydrochloric acid (volume ratio water / acid = 5: 1). · The ethyl acetate layer is then filtered and the ethyl acetate is replaced by isopropanol by distillation and with increasing addition of isopropanol. The product is mixed with water, cooled to 20 ° C, filtered and the residue is washed with water to give d-2- (6-methoxy-2-naphthyl) propionic acid, = 66.1 °.

Example 5

To a suitably sized vessel containing potassium hydroxide (61.8 kg) dissolved in methanol (1,557 liters) is added dl-2- (6-methoxy-2-naphthyl) propionic acid (500 kg) with constant stirring. Add cinconidine (315 kg) and reflux for about four hours. After cooling at 8 ° C per hour to 25-30 ° C and storing the batch for five hours, the mixture is filtered and the filter cake is washed with methanol (1 * + 18 liters). The moist filter cake is added in methanol (1 * + * + * + liters) to another suitably sized vessel and the mixture is refluxed for four hours. After cooling at 8 ° C per hour to 25-30 ° C, the batch is filtered and the filter cake (d-cinchonidine salt) is washed with methanol (* + 50 ml). The yield of the cinchonidine salt of d-2- (6-methoxy-2-naphthyl) propionic acid is about 86-92% by weight.

Example 6

To a suitably sized container of potassium hydroxide (5 * + kg) dissolved in methanol (730 liters) is added the wet d-cinchonidine salt cake (* + 55 kg) obtained as described in Example 5. After stirring for 20 minutes at 20-25 ° C under nitrogen, water (2,080 liters) is added and stirring is continued for a further 2 hours. The precipitated cinchonidine is filtered off and the filter cake is washed with water. The combined filtrate and washings are extracted with chloroform (3 x * + ΐβ liters). Hydrochloric acid (125 kg) dissolved in water (79 * + liters) is then added to the aqueous layer, and the mixture is heated at 35 ~ * + 0 ° C to remove chloroform. The batch is cooled to 25 ° C, stored for one hour and the d-2- (6-methoxy-2-naphthyl) propionic acid is filtered off and washed with water.

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Example 7

Acetone (2,000 liters), the moist d-2- (6-methoxy-2-naphthyl) propionic acid cake obtained in Example 6 and activated carbon (e.g. Darco G-60) obtained in Example 6 are placed in a suitably sized vessel and the mixture is stirred for 5 minutes. The batch is filtered and the filter cake is washed with acetone. The combined filtrate and washings are distilled in vacuo to a volume of 1,000 liters and cooled to 25-30 ° C. Water (3,000 liters) is added and the batch is kept for 30 minutes at 5 ~ 0 ° C, and the precipitated d-2- (6-methoxy-2-naphthyl) propionic acid is filtered off, washed with water and dried at about 1-50 ° C C. The yield of d-2- (6-methoxy-2-naphthyl) propionic acid is 3-38% by weight.

Claims (3)

57927 8 A process for resolving 2- (6-methoxy-2-naphthyl) propionic acid into optical antipodes by forming quinonidine salts of d- and 1-2- (6-methoxy-2-naphthyl) propionic acids in the presence of an auxiliary base in an inert organic solvent to which the cinchonidine salt of 1-acid is more soluble. than the cinchonidine salt of d-acid and in which the salts of said acids with the auxiliary base are more soluble than their cinchonidine salts, the total molar number of the bases being approximately the same as the molar number of 2- (6-methoxy-2-naphthyl) propionic acid and the molar ratio of cinconidine to auxiliary base : 2, by selectively crystallizing the cinchonidine salt of d-2- (6-methoxy-2-naphthyl] propionic acid from the resulting mixture and liberating the d-acid from the resulting cinconidine salt, characterized in that an alkali metal hydroxide is used as said auxiliary base. Process according to Claim 1, characterized in that the quinonidine salt obtained is decomposed by treating it with a strong base at approximately room temperature in a water-methanol mixture having a weight ratio of about 3: 1, after which the reaction mixture is acidified. Process according to Claim 1 or 2, characterized in that potassium hydroxide is used as the alkali metal hydroxide and methanol is used as the inert organic solvent.