CZ293892B6 - Refining process of F series prostaglandins - Google Patents

Abstract

In the present invention, there is disclosed a refining process of F series prostaglandins of the general formula I, in which R represents an alkyl group containing 1 to 8 carbon atoms or a phenoxyl group being optionally substituted with a halogen or a haloalkyl, wherein the process is characterized in that 1.1 to 1.5 equivalents of 0.2 to 2.0 molar aqueous solution of alkali metal hydroxide are added at a temperature ranging from 0 to 85 degC to a solution of a raw acid of the general formula I in an alcohol having 1 to 4 carbon atoms or an ether that is miscible with water, the obtained mixture is agitated for a period of 0.5 to 48 hours, the reaction mixture is then acidified with an inorganic acid to give pH 3.0 to 4.5, the released acid of the general formula I is extracted into a water immiscible organic solvent, the obtained extract is then washed with a saturated salt brine, dried with inorganic desiccant and after filtering off the extract, the required product is isolated by vacuum evaporation of solvents. Due to the action of alkalis, a nearly complete removal of contaminant of the type of acid alkyl esters of the general formula I, being present in the starting material, takes place. In the same time, a partial or complete removal of some minor unidentified compounds takes place or they can be transformed to contaminants that can be easily separated by chromatography.

Description

Process for refining prostaglandins of the F series

Technical field

The invention relates to a process for refining prostaglandins of the F-series of formula I

OH

COOH (I), wherein R represents an alkyl of 1 to 8 carbon atoms optionally branched, or a phenoxy group optionally substituted by halogen or haloalkyl, in particular a 3-chlorophenoxy or 3-trifluoromethylphenoxy group.

These prostaglandins are an active ingredient of some drugs.

BACKGROUND OF THE INVENTION

For pharmaceutical purposes, prostaglandins and their analogs are obtained almost exclusively by complex organic syntheses. The final phase is more or less difficult to purify the desired product from its isomers and reagent residues. For this purpose, several procedures have been developed for the F-series prostaglandins, which often have a syrupy, or crystalline, but difficult to obtain form. Some rely on crystallization refining of salts (see, for example, British Pat. No. 190,545), precipitation of prostaglandins with lithium salt additions (German Pat. U.S. Pat. No. AO 242 281). The method of combined extraction and induced crystallization for purification of prostaglandins F _2a (German Pat. No. 31 28 637) is also known. Column chromatography is often used (see, for example, U.S. Pat. No. AO 244 710), which is, however, technically and therefore economically very demanding, especially in the case of impurities which are difficult to separate.

These known processes are followed in a positive manner by the refining process according to the invention, which replaces or supplements these processes and by combining them increases their efficiency. The new method is easy to use, safe and environmentally friendly.

SUMMARY OF THE INVENTION

The essence of the refining according to the invention is based on the action of aqueous solutions of alkali hydroxides on solutions of the prostaglandins of the F-series of formula I in organic solvents which are unrestricted or partially miscible with water and are not subject to basic hydrolysis or other undesirable reactions. C 1 -C 4 alcohols, in particular methanol, ethanol, isopropyl alcohol and the like, and certain ethers such as tetrahydrofuran, dioxane, dimethoxyethane and the like meet the requirements. up to 2.0 molar solution at temperatures of 0 to 85 ° C within 0.5 to 48 hours, virtually complete removal of impurities of the alkyl esters of the acids of the formula I, which are present in the starting material in the amount of tenths to 1% and related to its previous treatment (eg use of alcohols in chromatographic systems, evaporation or storage of alcoholic solutions). At the same time, some minor or minor non-identical minorities are removed

Or for their transformation into chromatographically more separable contaminants. Upon completion of the hydrolysis, the reaction mixture is acidified to pH 3.0 to 4.5 with a mineral acid such as hydrochloric acid or sodium hydrogen sulphate, the original organic solvent is removed by evaporation in vacuo, and the product is extracted into a suitable solvent such as ethyl acetate, tert- butyl methyl ether or chlorinated solvents (dichloromethane, chloroform, 1,2-dichloroethane, etc.), the organic mixture is washed with brine, dried with an inorganic desiccant such as magnesium or sodium sulfate, and after filtering off the desiccant, the extraction solvent is evaporated. If necessary, the process is supplemented by chromatographic purification of the partially refined product.

The effects of the invention are set forth in the following examples, which are illustrative only and in no way limit the scope and scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a solution of 10.8 g of cloprostenol of formula I (R represents a 3-chlorophenoxy group) containing 0.5% methyl ester and 1.1% cloprostenol ethyl ester, 15 ml of methanol was added in 15 ml of methanol and stirred at room temperature under stirring. 28 ml of sodium hydroxide solution were added successively to a pH of 12.3. The homogeneous reaction mixture was allowed to stand at room temperature for 24 hours. The solution was acidified by adding 15 mL of a 3.73 M sodium hydrogen sulfate solution to pH = 3.3. The solution was concentrated on a rotary evaporator, after removal of methanol, the precipitated product was extracted with 70 ml of ethyl acetate, the separated organic phase was washed with 15 ml of saturated brine and dried over magnesium sulfate. After filtering off the desiccant, the filtrate was evaporated under vacuum to constant weight. 10.2 g of cloprostenol containing below 0.1% of the corresponding methyl and ethyl ester were obtained.

Example 2

To a solution of 16.0 g of an acid of formula I (R represents a 3-trifluoromethylphenoxy group) containing 1.2% methyl ester and 7.6% ethyl ester of this acid together with 0.1% unknown impurity X (RRT = 1.33 when analyzed by HPLC for reverse phase) in 80 mL of tetrahydrofuran was added 80 mL of water followed by 23 mL of 1.8 M sodium hydroxide solution until the pH reached 12.3. The mixture was stirred at room temperature for 24 hours, then the mixture was acidified with 21 ml of 2M hydrochloric acid to pH = 3.1, the solution was concentrated on a vacuum evaporator to two-thirds the volume, the oily product extracted with 90 ml of tert-butyl methyl ether and organic phase. was washed with 15 mL saturated brine. The extract was dried over magnesium sulfate, the desiccant was filtered off and the filtrate was evaporated on a rotary evaporator at 50 ° C. 15.8 g of purified acid of formula I (R as defined above) containing below 0.1% methyl ester and ethyl ester I and impurity Y (RRT = 1.45) in an amount of 0.3% were thus obtained.

Example 3

To 50 g of the dextrorotatory isomer of the acid of formula I (R represents a 3-chlorophenoxy group) contaminated with 7,4% of methyl ester and 1,2% of ethyl ester of this acid together with unknown impurity X (RRT = 0,646, 0,7%) and impurity Y ( RRT = 1.274, 0.9%), 250 mL of methanol was added and after dissolution at 40 ° C the mixture was diluted with 250 mL of water. To the solution was added successively 70 mL of sodium hydroxide at a pH of 12.4. The reaction mixture was stirred at 25-30 ° C for 48 hours. The cloudy solution was filtered and the filtrate was acidified by the addition of 37 ml of a 3.55 M sodium hydrogen sulfate solution to pH = 3.1. The solution was evaporated in vacuo to half volume

The precipitated product was extracted with 150 ml of ethyl acetate. The organic phase was separated, washed with 50 ml of saturated brine solution and dried over magnesium sulfate. Evaporation of the solvent in vacuo gave 49.6 g of a product which contained below 0.1% methyl and ethyl ester of formula I, 0.5% impurity X and 0.3% impurity Y. Chromatographic purification of the product (500 g silica gel Meter 60) eluent dichloromethane-methanol (2-10%)) and evaporation of the eluent on a rotary evaporator at 50 ° C to a constant weight of the residue gave 41.3 g of an acid of formula I (R as defined above) containing 0.2% of its methyl ester .

Example 4

10.5 g of the dextrorotatory isomer of the acid of formula I (R is a 3-chlorophenoxy group) contaminated with 1.4% isopropyl ester of this acid was dissolved in 20 ml of ethanol, diluted with 20 ml of water and 15 ml of 2M potassium hydroxide solution was added. The contents were heated at 80 ° C for 1 hour. The solution was concentrated under reduced pressure to half volume, the solution was acidified by the addition of 7.5 ml of sulfuric acid, and the liberated acid of formula I was extracted with 50 ml of ethyl acetate. After drying the extract with calcined magnesium sulfate, the desiccant was filtered off and the solvent was evaporated in vacuo. The residual oil (10.1 g) containing less than 0.05% isopropyl ester of the acid of formula I according to HPLC analysis was further processed by crystallization from a mixture of ethyl acetate and diethyl ether.

Claims (5)

A process for refining prostaglandins of the F-series of formula I OH COOH (I), wherein R represents an alkyl of 1 to 8 carbon atoms optionally branched or phenoxy optionally substituted by halogen or haloalkyl, in particular 3-chlorophenoxy or 3-trifluoromethylphenoxy, characterized in that a solution of the crude acid of formula I in an alcohol having 1 to 8 4 water-miscible carbon atoms or ether add 1.1-1.5 equivalents of 0.2-2.0 molar aqueous alkaline hydroxide solution at 0-85 [deg.] C., stirring for 0.5-48 hours, the reaction mixture is acidified with a mineral acid to pH 3.0 to 4.5, the liberated acid of formula I is extracted into a water-immiscible organic solvent, the extract is washed with saturated brine, dried with an inorganic desiccant and filtered to collect the desired product by evaporating the solvents under vacuum . Process according to claim 1, characterized in that lithium, sodium or potassium hydroxide is used as the alkali hydroxide and methanol, ethanol, propanol, isomeric butanols or a mixture of said alcohols as water-miscible as the alcohol having 1 to 4 carbon atoms. ethers using tetrahydrofuran, dioxane or dimethoxyethane or a mixture thereof. Method according to claim 1, characterized in that the mineral acid used is hydrochloric, sulfuric acid or preferably sodium or potassium hydrogen sulphate. -3GB 293892 B6 A process according to claim 1 wherein the acid of formula I is in racemic or any optical form. 5. The process of claim 1 wherein the hydrolysis procedure is combined with a chromatographic or crystallization purification of the product.