CS240862B1 - Process for the preparation of (+) - 3-oxaticyclo [2.2.1.0 < 2,6 >] heptane-7-carboxylic acid - Google Patents

Abstract

The method of producing /+/-3-oxoticyclo/2,2,1,02,6/heptane-7-carboxylic acid by cleavage of salts of /±/-ketoacid with L-/-/-/ methylbenzylamine by fractional crystallization and subsequent release of the /+/-ketoacid consists in adding a solution of L-/-/~ £ -methylbenzylamine in the same solvent at a temperature of 15 to 50 °C in a molar ratio of components of 1:0.4 to 0.8 to a solution of the mixture of /±/-ketoacids in an organic solvent and after cooling to 5 to 15 C, the precipitated salt enriched in the /±/-isomer of the ketoacid of formula I is filtered off with suction and recrystallized from the same solvent, the obtained optically pure salt of the /±/-ketoacid of formula I is dissolved in an aqueous alcoholic solution, made alkaline with an alkali metal hydroxide to pH 10 to 13, The liberated amine is extracted into an organic solvent, after which the pH of the solution is adjusted to pH 2 to 4 with dilute mineral acid, and the optically pure /+/ -keto acid of formula I is obtained from the extraction reaction. This acid is a significant intermediate in the production of natural prostaglandins A, B, C, E, F 2 sd-fa including their optically active analogues and prostacyclins.

Description

(54) p

Process for the preparation of (+) - 3-oxaticyclo [2.2.1-1.0] heptane-7-carboxylic acid

Process for the preparation of (+) - 3-oxoticyclo [2,2,1,02,6] heptane-7-carboxylic acid by cleavage of the salts of (±) -keto acid L - (-) - by methylbenzylamine by fractional crystallization followed by release of (+) - keto-acid is characterized in that to a solution of the (. + -.) - keto acid mixture in an organic solvent is added a solution of L - (-. beta.-methylbenzylamine) in the same solvent at a temperature of 15 DEG to 50 DEG C. 4 to 0.8 and after cooling to 5 to 15 DEG C., the precipitated salt enriched in the (. + -.) - isomer of the keto acid of formula (I) is filtered off with suction and recrystallized from the same solvent. It is basified with an alkali metal hydroxide to pH 10-13, the liberated amine is extracted into an organic solvent, the pH of the solution is adjusted to pH 2-4 with dilute mineral acid, and the optically pure (+) - keto acid of formula I is recovered from the extract by extraction. This acid is a prominent intermediate in the production of natural prostaglandins A, B, C, E, F ₂ sd-fa including their optically active analogs and prostacyclins.

240 862

- 1 240 862

The present invention relates to a process for the preparation of N, N-oxotricyclo [2.1.0] heptane-7-carboxylic acid of formula I. This acid is a prominent intermediate in the production of natural prostaglandins.

1 * 2 _and if _and including their optically active analogs and prostacyclin. Prostaglandins and prostacyclins are tissue hormones that affect biologically important processes in a living organism. They are currently used mainly in human medicine in obstetrics and gynecology, pediatric cardiosurgery, nephrology, in the treatment of hypertension, ulcer of the stomach and duodenum and in other areas.

Until acid /+/-3-oxotricyklo/2,2,l,.0 ² »^ / heptane-7-carboxylic acid obtained by resolution of the racemic mixture of the acid of formula I with L _ / _ / _ {/ -methylbenzylamine / see e.g. £ JS Patents No. 3,992,438;

943 151, J.Amer.Chem.Soc. 95, 7522 (1973); J.Med.Chem. 23, 1072 (1980); Kexue Tongbao 27, 39 (1982); Tetrahedron Lett. 34, 3527 (1983). The cleavage process described in the above references involves the preparation of salts of the (I) acid mixture of formula (I) with L - (-) - methyl benzylamine, which then undergoes fractional crystallization, separating the less soluble salt from the other more soluble enantiomeric salt. . In these processes, a 1: 1 molar ratio of acid / amine is used. The salt yields of the desired (+) isomer after about 2 to 3 recrystallizations are about 75%, and the experimental conditions such as solvent used, crystallization method, including the procedure for releasing the (+) - keto acid of formula I are not sufficiently described.

These known processes are followed in a positive way by the process according to the invention, which brings about a simplification and an increase in the yield of the (+) - ketoacid of the formula I.

240 802

The process according to the invention is characterized in that the H-keto acid of the formula I prepared according to the prior art (see, for example, U.S. Pat. No. 2,202,478) is treated with methylbenzylamine in an organic solvent solution, such as esters of organic acids containing 2 to 2. 6 carbon atoms, or cyclic ethers such as phioxioxane, tetrahydrofuran or aromatic hydrocarbons such as benzene, toluene. The amount of L - (-) - methylbenzylamine used is 0.4 to 0.8 mol, preferably 0.5 to 0.6 mol, based on 1 mol (4) of the keto acid of the formula I. The remaining amount of L - (-) - q N-methylbenzylamine to 1 mole can be replaced by a cheaper base (such as triethylamine, tributylamine, triethanolamine). According to the invention the procedure is such that the solution / 4 / acid of formula I in the above solvent while stirring at 15 to 50 ° C _/ s preferably 20 to 50 ° C was slowly added a solution of L - / - / - £ xf-methylbenzylamine and upon completion of addition and cooling to 5 ° C, the precipitated salt crystals enriched in the N / isomer of the acid of formula I are aspirated. After 1 to 2 subsequent crystallizations from the same solvent, the optically pure salt of the (+) - keto acid of formula I with L - (-) - N -methylbenzylamine is obtained in a yield of 85-90%, m.p. 155-155 ° C and (Vf) p ^ + 57 _and z = 590 / c of 1.0 M in methanol /.

From this optically pure salt, the (+) - acid of formula I is liberated by basifying its aqueous-alcoholic solution containing 10 to 40% by volume of methanol, ethanol or propanol with a strong base, preferably sodium or potassium hydroxide, to a pH of 10 to 15 and the liberated L - (-) - N - (methylbenzylanine) is extracted with an organic solvent, preferably ether, benzene, 1,2-dichloroethane. the aqueous-alcoholic solution of the N-keto acid alkali salt of formula I is acidified with a dilute mineral acid such as hydrochloric or sulfuric acid to pH 2-4, followed by extraction of the product with an organic solvent / e.g. The organic extracts are dried and, after evaporation of the solvents, crystallization gave 85-90% of the (+) - keto acid of formula I, mp 155-158 ° C, [α] D + 72-74 ° (c = 1.0M methanol).

- 3 240 862

An advantage of said process according to the invention is the lower consumption of expensive L - [-] -. Along with the simple design, its economic advantage is also evident.

The process according to the invention is illustrated by several examples, which are illustrative only and do not limit the scope of the invention in any way.

Example 1

To a solution of 100 g (0.66 mol) of the (k) -acetoacid of formula I dissolved in 2.5 of ethyl acetate was added dropwise 38.8 g (0.32 mol) of (L - / -) - b < -methylbenzylanine dissolved in 90 ml of the same solvent at 20-25 ° C. After addition of the amine, the reaction mixture was cooled to 10 ° C and the precipitated crystals enriched in the salt of the (+) - isomer were aspirated and dried. 78 g (86.8%) of the product with a value of (C?)? + 10.2 ° (c = 0.9 M methanol).

After these two crystallizations from the same solvent yielded 55.8 g of optically pure salt / + / - isomer ketoacid of formula I, mp 153-155 ° C / P </ £ ⁵ = + 57 ° / c = 0, 9 M methanol /. Literature /J.Amer.Chem.Soc. 95, 7522 (1973) reports mp 154-155 ° C and + 59 ° (c-1.0 M methanol).

Example 2 g of the (+) - ketoacid salt of formula I of Example 1 was dissolved in 450 ml of 20% aqueous ethanol and then basified with ca 10% sodium hydroxide solution to pH 11. Extraction of the solution with ether gave L- N-p-methylbenzylamine. The aqueous alcoholic solution was then acidified with dilute hydrochloric acid (1: 1) to pH 2 and the desired product extracted with ether. After drying the ether extract and evaporation of the solvents, 15 g (89.8%) of the product were obtained, which, after recrystallization from ethyl acetate, gave the optically pure (+) - isomer of the keto acid of formula I with m.p. 136 DEG-138 DEG C. and [.alpha.] D @ 20 = + 72.8 DEG (c = 0.95 M methanol). The literature states m.p. 137 DEG-138 DEG C. and [.alpha.] D @ 25 +79 DEG (c = 1.0 M methanol).

- 4 Example 3 240 8β2

10 g of the (+) - ketoacid of formula I from Example 1 were dissolved in 150 ml of 20% aqueous propanol and then basified with ca 10% aqueous sodium hydroxide solution to pH 11. The obtained solution was extracted 3x with 50 ml of benzene, the combined fractions were evaporated and collected back L - / - / - methylbenzylamine. The aqueous solution was acidified with ca. 10% sulfuric acid to pH 1.5-2 and extracted with 4x 50 mL of chloroform. The combined chloroform solutions were dried over anhydrous magnesium sulfate, and after distilling off the solvents, 5.8 g of crude product was obtained, which after working up as in Example 2 gave the product m.p. 136 DEG-138 DEG C., [.alpha.] D @ + + 72.5 DEG (c = 0.77 M methanol).

Example 4 »g of the salt of the (+) - keto acid of formula I of Example 1 was dissolved in 300 ml of about 20% ethanol was basified with about 10% sodium hydroxide solution to pH 10.5-11 and the liberated amine was extracted 3 x 150 ml 1.2 -dichloroethane. 8.4 g of L - N - methylbenzylamine were recovered from the combined extracts after evaporation of the solvents. Aqueous alcoholic solution after analogous work-up as in Example 2 gave 10.5 g of product m.p. Mp 135-138 ° C.

Claims (5)

SCOPE OF THE INVENTION 240 862 Process for the preparation of (+) - 3-oxotricyclo [2.2.1.0.0] heptane-7'-carboxylic acid of formula I by cleavage of the salts of the (1) -keto acid of formula I with L - (-) - # - methylbenzylamine by fractional crystallization and subsequent release of the (+) - keto acid of formula I _, characterized in that to a solution of the mixture of (*) - keto acid of formula I in an organic solvent is added a solution of L - (-) - methylbenzylamine in the same solvent at 15 to 50 ° C in a molar ratio of components of 1: 0.4 to 0.8 and, after cooling to 5 to 15 ° C, the precipitated salt enriched in the (+) - keto acid isomer of formula I is aspirated and recrystallized from the same solvent to obtain optically pure The (+) - keto-acid salt of formula I is dissolved in an aqueous alcoholic solution containing 10 to 40% alcohol by volume and has a carbon number of 1 to alkaline with alkali metal hydroxide to pH 10-13, the amine liberated is extracted into an organic solvent. adjusted to pH 2 with mineral acid. to 4 and the optically pure (+) - keto acid of formula I is obtained from the solution by extraction. 2 carbon atoms and 2 to 4 chlorine atoms. 2. A process according to claim 1, wherein the organic solvent used in the preparation of the salts is an ester of an organic acid having 2 to 6 carbon atoms. 3. A process as claimed in claim 1, wherein 0.5 to 0.6 moles of L - (-) - N -methylphenylamine are used per mole of the (±) ketoacid mixture of formula (I). 4. Process according to any one of claims 1 to 3 _, characterized in that ethers containing 4 to 8 carbon atoms, benzene, toluene or chlorinated alkanes containing 1 to 8 carbon atoms are used as solvent in the extraction of the amine. 5. A process as claimed in any one of claims 1 to 4, wherein, in the extraction of the (+) - keto acid of formula (I), ethers having 4 to 6 carbon atoms, benzene, toluene and chlorinated hydrocarbons are used as solvent.