CS255172B1 - Process for the production of prostaglandins - Google Patents

Abstract

A process for producing prostaglandins wherein X is a hydroxyl group and Y is hydrogen or X together with Y is oxygen, Z is n-butyl, 3-chlorophenoxy or 3- (trifluoromethyl) phenoxy, R is tetrahydropyran-2-yl. The compound of formula (II) is treated with a 1- to 4-membered mass excess of a macrorethicone sulfonated polystyrene resin having an ion exchange capacity of 4.6 meq / g in the H + cycle in an aliphatic alcohol containing 1-3 carbon atoms, optionally diluted with water at 20 to 50 ° C for 1 to 6 hours. The ion exchanger is then filtered off, washed with the above solvent, and the combined filtrates are evaporated, either directly or after prior alkaline hydrolysis of the ester present and acidification of the reaction mixture, under vacuum. The residue is extracted with an organic solvent, the extract is dried and, after evaporation of the solvents in vacuo, the product of formula (I) is isolated from the residue by chromatography.

Description

The present invention relates to a process for the production of prostaglandins of the E ₂ and F ₂ series of the general formula (I)

X Y

OH 'CQOH

A is OH where X is hydroxyl, Y is hydrogen or X together with Y is oxygen and Z is n-butyl, 3-chlorophenoxy or 3- (trifluoromethyl) phenoxy.

Prostaglandins are a group of naturally occurring hydroxylated unsaturated fatty acids that are characterized by extensive biological activity. They are considered to be tissue hormones acting as modulators of cellular functions and in this way affect the regulation of, e.g., the endocrine, reproductive or cardiovascular system. Because of these properties, prostaglandins, together with their synthetic analogues, have found use as medicaments in human and veterinary medicine.

In addition to methods of their isolation from natural materials, a number of technologically more or less demanding methods of their total synthesis have been developed for the production of prostaglandins. The main advantage of these synthesis processes lies, in spite of the limited availability of natural raw materials for obtaining prostaglandins by their isolation, in their versatility and the possibility of modifications that allow not only the production of basic types of prostaglandins (eg A, B, E, f, I etc.). ), but also their various analogues (see, e.g., MBLCaton, TW Hart: Synthesis of Classical Prostaglandins, Adv. Prost. Thromb. Leuk. Res. 14, 73 (1985)).

Regardless of the overall strategy, the last phase of the synthesis is the removal of the so-called protecting groups blocking the undesired reactivity of the functional groups of the prostaglandin system during each reaction step. An example of such a procedure is the removal of protecting groups from hydroxyl functions at positions 11 and 15 (prostaglandin numbering) outlined in the PGF ₂ prostaglandin preparation scheme (see, e.g., JSBindra, R.Bindra: Prostaglandin Synthesis, Academic Press, Ltd., New York) 1977)

OH

COOH

OH

OH where R = protecting group.

Of the many useful protecting groups, the tetrahydropyranyl group occupies an important position. Its introduction into the system is technologically undemanding, the reagents used are relatively inexpensive and the yields of the reaction are high. However, removal of this protecting group by catalyzed hydrolysis or transesterification may present a problem for substances which are highly sensitive to acidity, in particular prostaglandins of type E, which are easily subjected to undesired elimination and isomerization reactions. Hitherto known methods using aqueous acetic acid to remove tetrahydropyranyl (THP) groups (e.g., TKSchaaf, EJCorey: J. Org. Chem. 37, 2921 (1972)), a mixture thereof with tetrahydrofuran (P.Grieco et al. J. Amer. Chem. Soc., 99, 4111 (1977), aqueous methanolic hydrochloric acid solution (EJCorey, R.Noyori, TKSchaaf: J. Amer. Chem. Soc. 92, 2586 (1970), acidic ion exchangers based sulfonated polyester with an ion exchange capacity of 4.8 meq / g of DOWEX type in aqueous solutions of ketones and cyclic esters (M. lever et al., AO 230 236) and the like are characterized by a relatively low yield of the final product due to incomplete removal of THP protecting on the other hand, by desirable tetrahydropyranylation of the product during its isolation from the reaction mixture.

The above-mentioned drawbacks are overcome by the process for producing prostaglandins according to the invention. SUMMARY OF THE INVENTION The invention is based on the degradation of THP protecting groups from the intermediate of formula (II)

OTHP

COOH

OTHP (II) wherein X, Y and Z are as previously defined by the action of a macroreticular resin based on sulfonated polystyrene having an ion exchange capacity of 4.6 meq / g (Amberlyst 15) in an alcoholic or aqueous alcoholic medium.

For the preparation of prostaglandins of the type II, wherein X together with Y forms an oxo group and Z is as defined above, is dissolved in a lower alcohol (preferably methanol) to 5 to 10% by weight. solution, which is diluted with water in a ratio of 3: 1 to 1: 1, the above-specified Amberlyst 15 resin (1 to 4 times the weight of the starting compound) is added, and the mixture is stirred or shaken at 20 to 50 ° C. The progress of the reaction was monitored by TLC analysis until virtually complete removal of the starting material (usually within 2 to 6 hours). The ion exchanger is filtered off and re-extracted with aqueous alcohol until the retained product is removed. The combined extracts are evaporated on a rotary evaporator, the solution is dissolved in ethyl acetate and the organic phase is dried over magnesium sulphate. After removal of the solvent in vacuo, the desired product is isolated from the residual oil by column chromatography.

For the preparation of prostaglandins of the type F6 from the starting compounds of formula II, wherein X represents a hydroxyl group, Y represents hydrogen and Z is as defined above, the procedure can be used in a completely analogous manner or modifications involving the replacement of the aqueous medium with anhydrous alcohol,

In this case, the reaction proceeds faster under otherwise identical conditions, but after completion of the reaction after 1 to 3 hours, a small amount of the corresponding ester formed in parallel to the free acid is required. To this end, the filtrate and the extracts are basified with 1M sodium hydroxide solution to pH = 9-10 after separation of the ion exchange solution, and the solution is heated to 40-50 ° C for 30 minutes to 1 hour, when the ester is completely hydrolyzed. After acidification (preferably with sodium hydrogen sulphate) to pH = 3-4, the solution is evaporated and further processed analogously to the previous case.

The advantage of this procedure is that the chemicals used are readily available, individual operations are simple and safe, and the results achieved are excellent.

The invention is illustrated by the following examples, which are not to be construed as limiting the invention in any way.

He did

0.96 g of the bis-tetrahydropyranyl derivative of the formula II, where X together with Y represents oxygen atoms and z is n-butyl, was dissolved in 15 ml of ethanol, diluted with 7 ml of water, then 3 g of Amberlyst 15 was added and stirred at 40 ° C. Progress of the reaction was monitored by TLC analysis on silica gel plates in chloroform-methanol-acetic acid (90: 10: 1) system. After 4 hours, the ion exchanger was filtered off and washed twice with 3 ml of 70% aqueous ethanol. The combined filtrates were evaporated in a rotary evaporator, the residual oil was dissolved in 20 ml of chloroform, washed with 3 ml of saturated sodium chloride solution and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the residue was purified by column chromatography on silica gel in chloroform-acetone-acetic acid (85: 15: 0.05), to which 0.5 to 5% by volume of methanol was gradually added. Pooling of the fractions containing the desired product and evaporation of the solvent under vacuum gave 0.48 g (74%) of the PGE ₂ prostaglandins of formula I wherein X, Y, Z are as defined above. This obtained PGE 2 is identical to liquid high pressure chromatographic analysis (HPLC) with an authentic sample.

Example2

0.86 g of the bis-tetrahydropyranyl derivative of formula II wherein X is OH, Y is hydrogen, z is n-butyl, dissolved in 15 ml of methanol, then 0.86 g of Amberlyst 15 is added and the mixture is stirred at 40 ° C. ° C for 2 hours. The ion exchanger was filtered off, washed twice with 3 ml of methanol and 4 ml of 1M sodium hydroxide solution were added to the combined filtrates. The mixture was heated at 50 ° C for 30 minutes, when no longer found to be the corresponding ester according to TLC analysis analogously to Example 1. Methanol was evaporated from the reaction mixture in vacuo, the aqueous residue was acidified with 1 ml of 4M sodium hydrogen sulfate solution to pH = 3 and the liberated oil was extracted into 10 ml of ethyl acetate. The extract was washed with 3 ml of saturated sodium chloride solution and dried over magnesium sulfate. After filtering off the desiccant and evaporating the solvent under vacuum, the residual oil was subjected to silica gel column chromatography using chloroform-methanol-acetic acid (95: 3 to 6: 0.05). 291 mg of prostaglandin PGF 40, Formula I, wherein X, Y, Z are as defined above, are thus obtained. This obtained PGF? Is identical according to HPLC analysis to the authentic preparation.

Example 3

1.12 g of the bis-tetrahydropyranyl derivative of the formula II, where X together with Y represents oxygen atoms and Z represents a 3-chlorophenoxy group, was dissolved in 20 ml of methanol and the solution was diluted with 12 ml of water. Then 4 g of Amberlyst 15 was added and the mixture was stirred at 22 ° C for 6 hours. By analogous treatment of the reaction mixture as in Example 1, 0.57 g of a prostaglandin analogue of formula I wherein X, Y, Z are as defined above is obtained. The identity of this prostaglandin obtained was verified by HPLC analysis compared to an authentic sample.

Claims (4)

OBJECT OF THE INVENTION A process for the production of prostaglandins of the general formula (I) OH OH wherein X represents a hydroxyl group and Y represents hydrogen or X together with Y a n-butyl, 3-chlorophenoxy- or 3- (trifulomethyl) phenoxy group of the ran-2-yl derivatives of the general formula (II) represents oxygen atoms, Z represents z their bis-tetrahydropy- COOH (II) wherein R is a tetrahydropyran-2-yl group and X, Y, Z is as defined above, characterized in that a compound of formula (II) is treated with a 1-4 fold excess weight of sulfonated polystyrene-based macroreticular resin of ion exchange capacity 4.6 meq / g in an H ⁺ cycle in an aliphatic alcohol containing 1 to 3 carbon atoms optionally diluted with water at 20 ° C to 50 ° C for 1 to 6 hours, then the ion exchanger is filtered off, washed with the above solvent, combined the filtrates are evaporated under vacuum or after previous alkaline hydrolysis of the ester present and acidification of the reaction mixture, the residue is extracted with an organic solvent, the extract is dried and, after evaporation of the solvents under vacuum, the product of formula I is isolated from the residue. 2. A process according to claim 1, wherein the alcohol is methanol, ethanol or aqueous solutions thereof, diluted in a ratio of 3 to 1: 1 in amounts of 5 to 10% by weight. a solution of a compound of formula II in the solvent used. 3. A process according to claim 1 wherein the alkaline ester hydrolysis is carried out at 40-50 [deg.] C. by addition of 1M sodium hydroxide solution at pH = 9-10 for 0.5 to 1 hour, after which the reaction is quenched by acidifying the solution with sodium hydrogen sulfate. to pH = 3-4. 4. The process according to claim 1, wherein an alkylalkanoate having 3 to 6 carbon atoms such as ethyl acetate or a chlorinated hydrocarbon such as chloroform or 1,2-dichloroethane is used to extract the crude product.