CS261797B1 - A method for cleaving a racemic mixture of lactones - Google Patents

Abstract

The present invention relates to the cleavage of a racemic mixture of lactones, wherein the racemic mixture of the Corey lactone isomers of Formula Ia and Ib is subjected to quantitative enantioselective esterification of the (+) - isomer of Formula Ib under the influence of glyceryltributate in the presence of a catalytic amount of lipase forming the corresponding ester of formula IIIb. From the reaction mixture containing (-) - isomer Ia and (+) - isomer IIIb, the individual pure components are easily separated by chromatographic methods. From the ester of formula IIIb, the desired (+) - isomer of formula Ib is obtained by transesterification with a C 1 -C 3 alcohol.

Description

Said racemic mixture of Corey lactones is readily available and its preparation has been the subject of numerous publications (e.g., Prostaglandins and Thromboxanes / Eds. SM Roberts, EF Newton / Butterworths, London 1982; Chemistry and Bioteohnology of Biological Active Natural Products Ed. Cs. Academie Kiadó, Budapest 1984; Prostaglandins Synthesis / Ed. J.S.Bindra,

R. Bindra, Academic Pres, Inc., New York 1977).

The optically active isomers of Corey lactone, in particular the (-) - isomer of Formula Ia, represent an important intermediate in the synthesis of natural prostaglandins and their synthetic analogs. Prostaglandins are a naturally occurring group of polyhydroxy derivatives of unsaturated fatty acids with a broad spectrum of biological effects. They are used as very effective drugs in veterinary and human medicine, especially in obstetrics and gynecology, in the treatment of circulatory diseases, in the treatment of gastrointestinal tract disorders and in many other applications. Among the known methods for the preparation of the optically active isomers of formulas Ia and Ib, the cleavage of (-) - 3-oxotricyclo [2.2.1.0 '] heptane-7-carboxylic acid by L - (-) - alpha-methylbenzylamine (US U.S. Patent Nos. 3,992,438, 3,943,151, J. Amer. Chem. Soc., 95, 7222 (1973), J. Med. Chem., 23, 1072 (1980), Kexue Tongbao 27, 39 (1982); Tetrahedron Lett.

34, 3527 (1983); AO 240 862 (1985)) followed by the transformation of optically active acids into compounds of formula Ia, respectively. [0057] Ib. An analogous method was used in the resolution of (±) - (5-benzyloxymethyl-4-hydroxycyclopent-2-en-1-yl) acetic acid (U.S. Pat. No. 3,873,605 (1975)). from (-) - (3α-alpha, 6α-alpha) -tetrahydro-2H-cyclopenta (b) furan-2-one by the Prins reaction (Tetrahedron Lett. 27, 4,639 (1976)) Another approach to obtaining both optically active isomers of formula Ia and Ib, respectively, represent microbial reductions of substituted bicyclo [2.2.1] heptan-2-one (e.g., AO 225 987 (1984), AO 236 386 (1985)). by means of active bases (eg ephedrine, quinine, L - (-) - alpha-methylbenzylamine) enables to obtain both enantiomeric lactones of formula Ia and Ib AO 248 945, 249 098, 248 946, respectively. lactone (Youji Hauxue 5, 371 (1984)).

Chem. Abstr. 102, 113, 106 (1985)).

The above methods of producing optically active forms of Corey lactone have a number of disadvantages.

In all cases, they are based on laborious multi-stage syntheses, often demanding on technological equipment. Another disadvantage is the use of relatively expensive optically active bases, many of which are highly toxic and costly to recover. Moreover, both optical isomers cannot be simultaneously obtained in the desired purity using a single cleavage agent.

These disadvantages are eliminated by substantially method for resolving a racemic mixture of Corey lactone according to the invention whose principle consists in that a racemic mixture of isomers Corey lactone of Formula Ia and Ib is mediated glyceroltributyrátu (tributyrin) II nC ₃ H ₇ nC ₃ COOCH _{2 H?} COOCH ₂ (II) nc ₃ h ₇ cooch ₂

In the presence of a catalytic amount of a lipase enzyme isolated from yeast Candida cylindarea (EC 3.1.1.3) to quantitatively enantioselectively esterify the (+) - isomer of formula Ib to give the corresponding ester of formula IIIb

(Illb)

From the reaction mixture containing the (-) - isomer of Ia and the (+) - isomer of formula IIIb, the individual pure components are readily separated by chromatographic methods. From the ester of formula XXXb, transesterification with a C1-C3 alcohol yields the desired (+) - isomer of formula Ib. The isomers Ia and Ib obtained are purified by crystallization. The process of the invention comprises adding to a 0.02-0.2 M solution of a racemic mixture of Corey lactone isomers in a non-polar aprotic solvent, preferably chloroalkane, glycerol tributyrate in a weight ratio of 1: 2 to 6, further adding lipase in a weight ratio of 1: 0.05 to 0.2 and the heterogeneous mixture is stirred or shaken at 20 to 40 ° C. The progress of the reaction is monitored by chromatographic methods, preferably by thin layer chromatography or high pressure liquid chromatography. After 8 to 48 hours, i.e. the conversion of the (+) - isomer of formula (Ib), the catalyst is separated by filtration or centrifugation and the solution obtained is directly subjected to a column chromatography technique using silica gel. The elution is carried out with the solvents used in the reaction, optionally in a mixture containing 2 to 5% by volume of methanol or ethanol. The first of the eluted components, the ester of formula (IIIb), after evaporation of the solvents under reduced pressure, respectively. after optional purification by crystallization, it converts by transesterification with methanol or ethanol in the presence of a catalytic amount, preferably 1 to 2 mol%, of acidic reagents such as sulfuric acid or ion exchangers in an H ^{+ +} cycle to an optically pure (+) - isomer of formula Ib. The optically pure (-) - isomer of formula Ia, representing the more polar component of the separated mixture, is obtained directly by evaporating the solvent from the appropriate chromatographic fraction. Both isomers of formula Ia and Ib are refined by crystallization, e.g. from ethanol. In the reaction itself, dichloromethane, chloroform or 1,2-dichloroethane are used as the haloalkanes, it being preferable to equilibrate the solvent and glycerol tributyrate for several hours with a 0.1 M phosphate buffer solution before use. For ease of separation of the catalyst, it is preferable to anchor the lipase on an inert support such as polymers and styrene copolymers. The catalyst thus treated can be readily recovered and reused in the subsequent esterification without significantly losing its catalytic activity.

The process according to the invention is particularly advantageous in that it uses readily available and inexpensive reagents and solvents which are largely easy to regenerate. Technically, there are no special demands on the equipment, all operations are safe and no toxic waste products are created that are harmful to the environment.

The effects of the invention are illustrated by several specific exemplary embodiments, which in no way limit the scope of the invention.

He did

A solution of 2 g of racemic Corey lactone in 40 ml of 1,2-dichloroethane was added to a 100 ml flask, 400 mg of lipase (EC 3.1.1.3, manufactured by Sigma, catalog number L 1 754) was mixed well with 2 g of Sorsilen. , 8 ml glycerol tributyrate (equilibrated by shaking β 2 ml of 0.1 M phosphate buffer solution) and the mixture was shaken at 35 ° C for hours containing 50 8 of the starting substrate. The suspension was centrifuged, the supernatant was discarded and the residue after stirring with 20 ml of 1,2-dichloroethane was centrifuged again. The supernatant was added to the original aliquot and the recovered enzyme was used in the next cycle. By column chromatography of the supernatant (25 mm diameter, 50 cm length, filled with 25 g of TLC silica), a 150 ml fraction of EDC (ethylene dichloride) containing an ester of formula IIIb was eluted, then using a EDC +58 vol. The isomer of formula (Ia) Evaporation of the ester fraction under vacuum and recrystallization of the oily crystals (1.3 g, from a mixture of n-hexane (4 ml) and ether (4 ml) afforded 0.95 g of practically pure ester II, m.p. to 72 ° C / / ² * «57.8 ° / c 1, CHCl, /. the ester II (0.8g, was rozpuitěn in 20 ml of methanol was then added 1 g of cation exchanger

Amberlite IR 120 in an H " cycle and the mixture was refluxed with stirring for hours. After cooling the mixture, the ion exchanger was filtered off and the filtrate was evaporated in vacuo.

Recrystallization of the residue from 3 ml of ethanol yielded 0.51 g of pure (+, - Corey lactone of formula Ib, [.alpha.] D @ ² = 83.1 DEG (c -1, CHCl3), m.p. 130 DEG-132 DEG C. Evaporation of alcohol chromatographic fractions in vacuo and recrystallization of the residue (1.05 g) from 4 ml of ethanol yielded 0.75 g of (-) - Corey lactone of formula (Ia), ([beta] -83.7, (c1, CHCl3)), mp 131-132 ° C.

Example 2

In a 100 ml flask 2 g of racemic Corey lactone were dissolved in 50 ml of dichloromethane, 200 mg of lipase anchored on 2 g of Chromosorb 101, 8 ml of equilibrated glycerol tributirate were added and the mixture was stirred at 22 ° C for 48 hours. After this time, according to high pressure liquid chromatography analysis (column packed with silica gel 5 m, 150 mm x 3.2 mm, eluent n-hexane and ethanol in a ratio of 9: 1, 1 ml / min, 254 nm) contained 52 8 substrate. Following the procedure of Example 1, 0.9 g of the ester of formula IIIb and 0.72 g of the (-) - Corey lactone of formula Ia were obtained. Transesterification of 0.8 g of ester IIIb in 20 ml of ethanol containing 0.2 ml of concentrated sulfuric acid was completed after refluxing for 8 hours. The acid was then neutralized with 0.5 ml of triethylenamine and the solution was evaporated in vacuo. The residue was extracted with 10 ml of chloroform and the extract was again evaporated in vacuo. Recrystallization of the residue from 3 mL of ethanol gave 0.5 g of the (+, -) isomer of Corey lactone of formula Ib.

Example 3

40 ml of 1,2-dichloroethane, 2 g of racemic Corey lactone, ml of equilibrated glycerol tributyrate and the regenerated catalyst of Example 1 were mixed in a 100 ml flask. The mixture was shaken at 25 ° C. After 41 hours, 53.78 conversions were achieved (monitored by high pressure liquid chromatography analysis). Further processing of the mixture was carried out as in Example 1.

Claims (6)

SUBJECT OF THE INVENTION 1. A method for resolution of a racemic mixture of lactones "OH" -xCgHgCgHjCOO -C * H _{e e} C ₅ H ₄ COO · OH '(Ia) (Ib) wherein IE racemic mixture of Corey lactone of Formula Ia and Ib are treated glyceroltributyrátem II nC, H, COOCH 3 7 * 2 nC ₃ H ₇ COOCH ₂ (II) nc ₃ h ₇ cooch ₂ in the presence of a catalytic amount of yeast lipase enzyme Candids cylindarea (EC 3.1.1.3) in an aprotic solvent medium at a temperature of 20 to 40 ° C for 5 to 48 hours, whereby the (+) - isomer of formula Ib is converted to the corresponding ester of formula IIIb ⁴ -C ₆ ^H 5 ^C 6 ^H 4 ^CO °, and after separation of the catalyst by filtration or centrifugation, optically pure (-) is isolated from the reaction mixture by column chromatography. - the isomer of formula Ia and the ester (+) - of the formula IIIb from which the optically active (+) - isomer of formula Ib is liberated by transesterification with a C 1 -C 3 alcohol in the presence of acidic catalysts and the isomers of formula Ia and Ib obtained are refined by crystallization . 2. A process according to claim 1, characterized in that 0.02-0.2 M solutions of racemic Corey lactone in methylene chloride, chloroform or 1,2-dichloroethane are used, wherein the weight ratio of the racemic Corey lactone: glycerol tributyrate: enzyme- Yippee 1: 3 to 5: 0.05 to 0.2. 3. Process according to claim 1 or 2, characterized in that the enzyme lipase is anchored on a suitable inert carrier such as polymers and styrene copolymers. 4. Process according to claim 1 and / or 2 and / or 3, characterized in that the acid catalyst used in the transesterification is a mineral acid, preferably sulfuric acid, or an ion exchange in an H * ⁺ * cycle such as polystyrenesulfonic acid. 5. Process according to claim 1 and / or 2 and / or 3 and / or 4, characterized in that the refining of the optical isomers of the Corey lactone is carried out by crystallization from an alcohol having 1 to 3 carbon atoms. 6. The process according to claim 1 and / or 2 and / or 3 and / or 4 and / or 5, characterized in that the solvent used for the reaction is glycerol tributyrate equilibrated with a 0.1 M phosphate buffer solution for several hours before use.