CS272019B1 - Method of (2-acetoxymethyl-5-halogen-3-hydroxycyclopent-1-yl)acetic acid's delta-lactone production - Google Patents

Abstract

Process for preparing O-lactones of (2-acetoxymethyl-5-halo-3-hydroxycyclopent-1-yl) acetic acid of formula I wherein X is chloro or bromine, Baeyer-Villiger and oxidation of the general ketone of formula II, wherein X "is as defined above, by the action of organic peroxyacids in the medium acetic acid or chlorinated aliphatic hydrocarbons having 1 or 2 carbon atoms and 2 or 3 chlorine atoms at 0 to 30 ° C it is that the oxidation is carried out in the presence alkaline reactants are preferred an alkali metal acetate, optionally generated in situ from the corresponding bicarbonate or carbonate, or a basic ion exchanger, optionally in the presence of an inorganic desiccant, whereupon the excess is removed after dilution of the mixture of the oxidizing agent with sodium sulfite and extraction with an organic solvent having the following by concentrating the combined organic portions optionally recrystallizing the product of formula (I). As the organic peroxyacid, it is using peracetic acid or m-chloroperbenzoic acid. As an alkaline reactive additive preferably, sodium acetate or basic polystyrene anion exchange containing quaternary ammonium group in an amount of 0.05 to 0.90 equivalent used acids. As an inorganic desiccant sodium sulphate, magnesium sulphate is used or molecular sieves based on aluminosilicates in amounts up to the starting weight ketone of formula II. Compounds of formula I are intermediates for the production of prostaglandins, prostacyclins and their analogs.

Description

The invention relates to a process for the preparation of (2-acetoxymethyl-5-halo-3-hydroxycyclopent-1-yl) acetic acid (I-lactones) of the general formula I, in which X is chlorine or bromine.

The compounds of formula I are important intermediates in the synthesis of natural prostaglandins, prostacyclins and their analogues. These substances can be characterized as modulators of cellular functions, have the nature of tissue hormones and are generally characterized by broad biological activity. It is used mainly in the regulation of the endocrine, nervous, reproductive, digestive, respiratory, cardiovascular and renal systems. For these properties, some prostaglandins and their derivatives have found use in human and veterinary medicine, where they form the active ingredient of a number of pharmaceutical preparations (see, for example, Kontckte Merck Darmstadt 50, 1984; Chern. Eng. News 16, 30 (1982)).

Many methods for preparing prostaglandins and their analogs are currently known. In addition to isolation and biotechnological processes, which have limited applications, they are now the main source of these total synthesis materials (see, for example, Js Bindra, R. Bindra: Prostaglandin Synthesis, Academic Press, Inc., 1977; SM Roberts, RFNewton (Editors): Prostaglandins and Thromboxanes, Butterworth Scientific, London, 1982). Due to its flexibility, the so-called norbornadiene pathway is particularly popular, which has been developed in several variants (J. Americi Chem. Soc. 95, 7522 (1973); J. Chem. Soc. Chem. Commun. 1974, 151; J. Org. Chem. 42, 786 (1977), U.S. Pat. No. 3,992,438, U.S. Pat. No. 3,943,151, CS 223,402, CS 214,514). The preparation of lactones of formula I is also described in MS. author's certificate No. 226 905, according to which these substances are obtained by oxidation of ketones of general formula II by the action of 40% peracetic acid (Persteril) at room temperature and the product is extracted with an organic solvent. In this embodiment, the crystalline product is obtained in a maximum yield of 75% of theory. Methods for preparing lactones from the corresponding ketones by Baeyer-Villiger oxidation are described in the technical literature. either change the regioselectivity or substantially increase the yields (see Methoden der Organischen Chemie (Houben-Weyl) 6 / la, Vol. 2, pp. 880-896; G. Thieme Verlag, Stuttgart, New York 1980 and citations therein). It is clear from the above citation that this embodiment is predominantly used for bicyclic ketones containing alkyl or alkoxyalkyl groups as substituents. In the case of cyclic keto acid esters, only examples in an acidic medium, i.e. in a mixture of acetic acid and peracetic acid, are given.

These known processes are followed in a positive sense by the process according to the invention, which promotes the formation of the desired -lactones of the general formula II and substantially reduces the formation of undesired products. The process according to the invention is based on the fact that the Baeyer-Villiger oxidation of the ketone of the formula II is carried out in a buffered medium using peracetic or m-chloroperbenzoic acid. Acetic acid or chlorinated aliphatic hydrocarbons containing 1 or 2 carbon atoms and 2 or 3 chlorine atoms are preferably used as solvents. The reaction mixture is buffered with an alkali metal acetate, preferably sodium acetate, which can optionally be generated in situ by the addition of the corresponding bicarbonates or carbonates or base-reacting polystyrene-type anions containing a quaternary ammonium group. The addition of inorganic drying agents, such as anhydrous magnesium sulfate, sodium sulfate or molecular sieves based on aluminosilicates, to the reaction mixture during the oxidation also has a favorable effect on the course and yield of the above reaction. The oxidation is carried out at a temperature in the range of 0 to 30 ° C for 10 to 48 hours. The oxidation is monitored by thin-layer chromatography (TLC) (silica gel, benzene-dioxane-ethyl acetate 90: 7: 3). After completion of the reaction, the mixture was diluted with water, the excess oxidizing agent was quenched by the gradual addition of solid sodium sulfite (until negative to iodine-starch paper) and the product was extracted with the above chlorinated hydrocarbon or aliphatic

CS 272019 B1 ester containing 3 to 6 carbon atoms, preferably ethyl acetate. After washing the organic phase with sodium bicarbonate solution, the solvent is evaporated off under reduced pressure and the residue gives, after cooling, a crystalline product in a yield of 78-90% of theory in purity usually suitable for further synthetic use, which may be purified by recrystallization, preferably from cyclohexane or chromatography .

The process for the preparation of the .beta.-lactone of the general formula II according to the invention in comparison with the known state of the art (Czechoslovak author's certificate No. 226,905) achieves an average increase of yields by about 10. it is operationally safe and practically environmentally friendly.

The invention and its effects are further illustrated by the following examples, which are illustrative only and do not limit the scope of the invention in any way.

Example 1 - '^;'

5 g of sodium acetate, 15 g of the ketone of formula II (X denotes chlorine) were dissolved in 70 ml of acetic acid, and 12.5 ml of 35% perootic acid (Persteril) was added to the solution under cooling so that the temperature did not exceed 28 ° C. The mixture was then stirred at room temperature for 24 hours when it was free of starting material by TLC analysis. 30 g of ice was added to the reaction mixture, and the excess peracid was quenched by the gradual addition of solid anhydrous sodium sulfite in a total amount of 20 g with vigorous stirring. The completion of the decomposition was verified by an iodostarch paper test, the mixture was diluted with 100 ml of water and the product was extracted with 250 ml of 1,2-dichloroethane. The organic phase was washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. After evaporation of the solvent in vacuo on a rotary evaporator, 13.2 g (82% of theory) of the lactone of the formula I are obtained (X is chlorine), m.p. = 102 to 104 ° C, containing by gas chromatographic analysis (internal standard method, crosslinked methylsilicone capillary column, 25 m, helium carrier gas, 180 ° C, split 200: 1) less than 2% of the isomeric lactone of formula Ia (X denotes chlorine ), The identity of the product was also confirmed by comparing the retention times, NMR and MS spectra with the spectra of the standard.

Example 2.

To a solution of 2.17 g of the ketone of formula II (X is chlorine) in 20 ml of dichloromethane was added 4.4 g of peyium sodium bicarbonate. The suspension was stirred at 27 ° C and 2.5 mL of 35% Persteril was added gradually over 6 hours. After stirring for 16 hours, a further 0.5 ml of Persteril was added and the mixture was stirred for a further 2 hours, when it no longer contained the starting product. The solid was filtered off, washed with dichloromethane and 5 ml of water were added to the filtrate. Excess peracid was removed by the addition of 0.2 g of solid sodium sulfite with vigorous stirring. The aqueous phase was separated, the organic layer was washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. After filtering off the drying agent and evaporating the solvent in vacuo, 1.80 g (78% of theory) of the lactone of the formula I (X is chlorine) are obtained with a purity of 97.7% (according to gas chromatographic analysis, internal standard method), containing 0.9% an isomeric lactone of formula Ia. ~

Example 3

To a solution of 2.60 g of a ketone of formula II (X denotes bromine) in 20 ml of dichloroethane was added 0.8 g of a basic ion exchanger based on the polystyrene type containing a quaternary ammonium group in the OH cycle (Amberlite IRA-400), 1 g of ground Potassit 3A molecular sieve and 3.45 g of m-chloroperbenzoic acid were added portionwise over 2 hours with stirring at room temperature. The mixture was stirred for 24 hours, the solid phase was filtered off and washed with 1,2-dichloroethane. To the filtrate was added 5 ml i

CS 272019 B1 water and 0.5 g solid sodium sulphite with vigorous stirring. After decomposing the excess oxidizing agent, the organic phase was separated, washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. Evaporation of the solvent in vacuo gave 2.50 g (90% of theory) of the lactone of formula I (X is bromine), identical to the standard NMR and MS spectra.

Example 4.

To a solution of 108 g of a ketone of formula II (X represents chlorine) in 750 ml of 1,2-dichloroethane were added 100 g of sodium bicarbonate and 100 g of anhydrous magnesium sulfate. At room temperature, 125 ml of 35% Persteril were added over 1 hour. The temperature of the reaction mixture rose to 29 ° C and was further maintained at 25 ° C for 16 hours. The suspension was then diluted with 750 ml of water and the excess oxidizing agent was quenched by careful gradual addition of 50 g of solid sodium sulfite with stirring and external cooling so that the temperature of the mixture did not exceed 35 ° C. were washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. Evaporation of the solvent in vacuo gave 108 g (93% of theory) of crystalline product, m.p. = 85-105 ° C, which according to GLC analysis contained 0.8% of the starting ketone II and 10% of the isomeric lactone Ia (X denotes chlorine). Recrystallization of the crude product from cyclohexane gave 95 g (82% of theory) of the lactone of formula I, m.p. = 100 to 104 ° C containing, by gas chromatographic analysis (internal standard method), 1,5% of the isomeric lactone of formula Ia.

Claims (4)

OBJECT OF THE INVENTION A process for the preparation of δ -lactone of (2-acetoxymethyl-5-halo-3-hydroxycyclopent-1-yl) acetic acid of general formula I, wherein X represents chlorine or bromine, by Bayer-villiger oxidation of a ketone of general formula II, wherein X has as defined above, by treatment with organic peroxyacids in acetic acid or chlorinated aliphatic hydrocarbons containing 1 or 2 carbon atoms and 2 or 3 chlorine atoms at a temperature of 0 to 30 ° C, characterized in that the oxidation is carried out in the presence of alkali-reactive additives, preferably alkali metal acetate, optionally generated in situ from the corresponding bicarbonate or carbonate, or basic ion exchanger, optionally in the presence of an inorganic desiccant, then after completion of the reaction the mixture is diluted with water, decomposed excess oxidant with alkali sulfite and extracted with organic solvent a crystalline product of formula I, which is optionally purified by crystallization. 2. A process according to claim 1, characterized in that peracetic acid or m-chloroperbenzoic acid is used as the organic peroxyacid. 3. The production method according to item 1, characterized in that sodium acetate or a basic anion of the polystyrene type containing a quaternary ammonium group in an amount of 0.05 to 0.90 equivalents of the acid used is used as a buffering additive. CS 272019 El 4. A process as claimed in claim 1, wherein anhydrous sodium sulfate, magnesium sulfate or aluminosilicate molecular sieves are used as the inorganic desiccant in an amount up to the weight of the starting ketone of the formula II.