CS248946B1 - Method of (+)-4-hydroxymethyl-5-(1,1-biphenyl-4-carbonyl oxy(-hexahydro-2h-cyclopenta(b)furane-2-on's hydrogenalkanes cleavage - Google Patents

Abstract

Method of hydrogenalkanoate fission / - / - -4-Hydroxymethyl-5- (1,1'-biphenyl-9-carbonyloxy) -hexahydro-2H-cyclopenta [b] furan-2-one wherein R is 4-C8H8C8H4CO, A is ethylene, trimethylene, which is based in racemic general acid of Formula I act optically active organic bases in an amount not greater than equimolar in an organic solvent environment 4 * O and at a temperature of 30-10 ° C, then to the solution the resulting salt is added to 0.1 to 5% by weight appropriate crystalline diastereoisomeric salts of the compound of formula I, solution The mixture was cooled to 0-20 ° C and then stirred of the compound of formula (I) enriched in one diastereoisomer after trans purification isolates pure diastereoisomeric salt from which the action of mineral acid releases the optically active isomer of hydrogen alkanoate of formula I. Optically active substances are significant intermediates in prostaglandin synthesis.

Description

The present invention relates to a process for the cleavage of (4-hydroxymethyl) -5- (1,1'-biphenyl-4-carbonyloxy) -hexahydro-2H-cyclopenta (b) furan-2-one hydrogenalkanoates of the general formula I, wherein R is 4 -CgHjCgH2CO, A denotes ethylene, trimethylene, to the individual (- / or / +) optically pure active isomers of formula I. Said optically active compounds of formula I represent an important intermediate in the synthesis of optically active Corey lactone used in the production of prostaglandins and their derivatives and analogs / Prostaglandins and Thromboxanes / Eds. Roberts S.M., R.F. Newton / Butterworths, London, 1982; Chemistry and Biotechnology of Biology Active Natural Products / Ed. Cs. Szántay /, Akad. Kiadó, Budapest, 1984; Prostaglandin Synthesis Academic Press, Inc., New York, 1977 /.

To date, the resolution of racemic Corey alcohol and its derivatives into the individual optically active isomers has not been described (see above). Optically active Corey alcohol is prepared by a number of complex syntheses that are very demanding on the chemicals and workflows involved. ,

The present invention provides a process for resolving an readily available racemic mixture of a compound of formula I by optically active bases with which it forms diastereoisomeric salts with different solubilities. Said diastereoisomeric salts of optically active bases with compounds of formula I are novel and form part of the invention.

The process of the invention may be adapted to either separate the optically pure diastereoisomeric salt which serves to produce the optically active (-) - isomer of the Corey lactone of formula (II) or the (+) - isomer thereof, wherein R is as defined above. Since the / - / - isomer of formula (II) is used for the production of natural prostaglandins and their analogs, it has been of greater commercial importance for the time being, and therefore, processes with respect to separation of the diastereoisomeric salt resulting in this optical isomer are preferred. The conditions of the process according to the invention described below can be applied analogously to the necessary necessary changes for the preferential separation of the optically pure diastereoisomeric salt resulting in the optically pure (+) isomer of the lactone of formula II.

According to the invention, the racemic acid of the formula I is treated with an optically active organic base in an amount not greater than equimolar in an organic solvent medium at a temperature of 30-30 ° C. 0,5 preferably 0.5 to 1 mol of an optically active base such as L - [-] - ephedrine, L - [-] - α-methylbenzylamine, D - (+) - and -methylbenzylamine are used per mole of the acid of the formula I, L - (+) - threo-1- (p-nitrophenyl) -2-dichloroacetamino-1,3-propanediol (chloramphenicol L-base), chloramphenicol D-base, quinine and others.

When using less than equimolar amounts of optically active base, it is preferable to add to the reaction mixture a corresponding amount of optically inactive organic base such as triethylamine, diisopropylethylamine and the like. The organic solvents used are C 3 -C 6 alkyl alkanoates, preferably ethyl acetate, isopropyl acetate; alcohols having 1 to 3 carbon atoms, ethers having 4 to 8 carbon atoms such as diisopropyl ether, aromatic hydrocarbons having 6 to 8 carbon atoms such as benzene, toluene and xylenes, or mixtures thereof.

In particular, the process according to the invention is carried out by adding to the suspension or solution of the compound of formula I in the above-mentioned solvent an appropriate amount of an optically active organic base under stirring at 30-30 ° C, or optionally to equimolarity with an optically inactive otganic base. After reaction (formation of a homogeneous mixture), the solution is seeded with a small amount (0.1 to 5% by weight) of the crystals of the optically pure diastereoisomeric salt, whereupon the mixture is cooled slowly to + 0 - 20 ° C with occasional stirring.

As soon as the crystalline salt begins to precipitate, the optical rotation monitoring of the mother liquors is started. After reaching a certain value of this turn point (for individual salts it is determined empirically, for example for the salt of L-ephedrine with a racemic mixture of the hydrogen succinate of the formula I corresponds to the optimum value (a) ( ² + 25 to + 32 °). the solvent used and determine its optical rotation. From the enriched crystalline salt with one diasteroisomer, an optically pure diasteroisomeric salt is obtained by subsequent extraction or digestion or crystallization, preferably with combinations thereof.

From the diasteroisomeric salt of the corresponding onium carboxylate (e.g., L-ephedrine hydrogen succinate), the optically active hydrogen succinate of formula I is released in an aqueous medium by treatment with a mineral acid such as hydrochloric, sulfuric, phosphoric at a temperature of 10 to 80 ° C. The released product is then extracted from the aqueous phase with an organic solvent, preferably a halogenated hydrocarbon such as chloroform, dichloroethane, trichlorethylene or benzene, and toluene ethyl acetate.

Then the solution is dried, the solvents are evaporated and the product obtained is optionally recrystallized from a suitable solvent. The optically active base used can be recovered from the aqueous acidic phase by simple methods known to those skilled in the art. In addition, the process according to the invention makes it possible, after purification of the onium carboxylate, to recover from the mother liquor a second isomer-enriched compound of the formula I, which serves as an optional raw material for the preparation of the opposite optically active diastereoisomeric salt.

In some cases, it is preferable to reverse the process to obtain optically pure diasteroisomeric onium carboxylates, i.e. first to remove the corresponding optically active base from the racemic mixture, and then isolate the desired optically active compound from the mother liquors as described above. The choice of these procedures depends on a number of factors: the availability of the optically active amines, their cost, the solubility of the individual diastereoisomeric compounds, their ease of purification, and so on.

The process according to the invention brings many advantages, is technologically easy to handle even in large batches, uses relatively available industrially produced optically active bases, inexpensive reagents and the resulting product is obtained in high optical purity and yields.

This also implies the economical advantage of the process according to the invention.

The process according to the invention is demonstrated in several exemplary embodiments, which are illustrative only and do not limit the scope and subject matter of the invention in any way.

Example 1

To a mixture of 2100 ml of ethyl acetate and 452.4 grams of a compound of formula I wherein A represents CH ₂ CH ₂ group and R is p-CgHgCgH CO, with stirring at 25-30 ° C was added 165 g of L-ephedrine dissolved in 795 ml of the same solvent. After stirring for 2 hours, the reaction mixture was cooled to 0 ° C and 0.2 g of crystalline optically active diastereoisomeric salt of L-ephedrine succinate was added. After 2-3 days crystals began to precipitate, a sample of 0.7 ml of mother liquor was taken, evaporated to dryness at 50 ° C in a vacuum oven, dissolved in a 10 ml volumetric flask in chloroform and measured for optical rotation.

Upon reaching the rotation of the mother liquors (a) of ²² + 28 °, the crystals were aspirated, washed with ethyl acetate. After drying to afford 330 g / and / ²² - 43,5 ° / c = l, CHCl /. The ephedrine salt obtained was slurried in 3000 ml of ethyl acetate, heated to boiling for 5-10 minutes, and after cooling, the precipitated crystals were aspirated and recrystallized from 9: 1 ethyl acetate-ethanol (9 ml of solvent per g of salt). After repeated crystallisation from the same mixture yielded 265 g efedriniumhydrogensukcinát / «/ ²² - 76,5 ° / c» 1, CHC1 ₃ /, mp 136-141 ° C.

Example 2

To a mixture of 45.2 g of a compound of formula I wherein A is a CH ₂ CH ₂ group and R is a C 8 H 8 C 9 H 4 CO group and 220 ml of ethyl acetate was added 11.5 g of L - / - ephedrine dissolved in 60 ml of the same solvent. 3 g of triethylamine and 6 ml of the same solvent and the reaction mixture was heated to boiling and slowly cooled to 10 ° C, then 0.03 g of pure diastereoisomeric salt was added. After work-up as in Example 1 yielded 25.4 g efedriniumhydrogensukcinát / ar / ²² - 78,1 ° / c = l, CHCl₃ /.

Example 3 of a solution of 100 g of L-ephedrinium hydrogen succinate of Example 1, wherein A represents a CH 3 CH 3 group and R represents a C 8 H, C ₈ H ₄ CO group, in 2,200 ml of water at 60 ° C was added 70 ml of dilute hydrochloric acid After cooling, the aqueous phase was extracted successively with 3 x 1000 ml of chloroform, the chloroform solutions were combined, washed with 500 ml of 0.5% hydrochloric acid, 300 ml of water and dried over magnesium sulfate.

After evaporation of the solvents, an oily product was obtained which crystallized in a crystalline state after complete drying in a vacuum of 1 mm Hg to 30 mm Hg. Crystallization from ethyl acetate gave hydrogen succinate of formula ^I 22 'wherein R and A are as defined above, mp 52-56 ° C / OA / ^22-83 ° / c = 1, CHCl? /. It was shown to contain 99.7% of the correct isomer by HPLC.

Example 4

To a solution of 45.2 g of compound of formula I wherein A represents CHjCHj group and R is ^C 6 ^H 5 ^< '6 ^H 4 ^{CO with} P4 ^nu ^ ^u> in 250 ml of ethanol was added a solution of 32.5 g quinine in 50 ml ethanol at room temperature. After standing at this temperature for 48 hours, the precipitated crystals were aspirated and dried. 46 g of crystalline salt were obtained, from which, after recrystallization twice from ethanol, 30 g of quininium hydrogen succinate ([.alpha.] D @ ²⁰ - 19.9 DEG (c; 1, CHCl3)) were obtained;

Mp 166-170 ° C.

Example 5

To a solution of 36 g of quininium hydrogen succinate of Example 4 in 500 ml of water at 70 ° C was added 30 ml of dilute hydrochloric acid (1: 1). After cooling, the precipitated hydrogen succinate was extracted with 3x100 ml of chloroform, the chloroform extracts were dried over magnesium sulfate, the chloroform was evaporated and crystallization of the residue from 150 ml of ethyl acetate yielded 18.1 g of an optically pure crystalline product of formula I, mp 130-132 ° C. denotes CH, CH ₂ and R denotes C 1 -C 8 H 2 O (α) ( ²⁰ + 83 °) (c = 1, CHCl 3).

Claims (6)

CLAIMS 1. A process for the cleavage of (4) -hydroxyalkanoates of 5- (1,1'-biphenyl-4-carbonyloxy) -hexahydro-2H-cyclopenta (b) furan-2-one of the general formula I, wherein R is 4-CgHgCgH2CO, A denotes ethylene, trimethylene, characterized in that the racemic acid of the formula I is treated with an optically active organic base in an amount not greater than equimolar in an organic solvent medium at a temperature of 30-10 ° C and then to the solution the resulting salts are added to 0.1 to 100 5% by weight of the respective crystalline diastereoisomeric salt of the compound of formula (I), the solution is cooled to 0-20 ° C, and the purified diastereoisomeric salt is isolated from the precipitated salt of the compound of formula (I) enriched in a single diastereoisomer. isomer of hydrogen alkanoates of formula I. 2. The process of claim 1, wherein the organic solvents are C 3 -C 6 alkyl alkanoates, such as ethyl acetate, isopropyl acetate, ethylbuanoate; alcohols containing 1 to 3 carbon atoms, ethers containing 4 to 8 carbon atoms such as diisopropyl ether, aromatic hydrocarbons benzene, toluene, or mixtures thereof. 3. Process according to claim 1, characterized in that 1 to 1 mol of the racemic compound of the formula I is treated with 0.5 to 1 mol of an optically active base such as L - / - / - ephedrine, quinine, L - / - / - and methylbenzylamine. , D - (+) - and -methylbenzylamine. 4. Process according to claim 1, characterized in that the precipitated salt of the compound of the formula I enriched in one diastereoisomer is purified by digestion or crystallization, or a combination thereof, of said organic solvents. 5. A process according to claim 1, wherein dilute sulfuric, hydrochloric or phosphoric acid is used to liberate the optically active isomer of the compound of formula (X) from the diastereoisomeric salt. 6. The process of claim 1 wherein, using less than an equimolar amount of an optically active base, an optically inactive base such as triethylamine, diisopropylethylamine and the like is added to the stoichiometric ratio.