CS268616B1 - Process for the preparation of hexahydro-4-acyloxymethyl-5-hydroxy-2H-cyclopenta [b] furan-2-one - Google Patents

Abstract

The method for producing hexahydro-4-acyloxymethyl-5-hydroxy-2H-cyclopenta/b/-furan-2-one of the general formula I, where R denotes an alkyl with 1 to 3 carbon atoms from the δ - -lactone of the general formula II, where R has the above-mentioned meaning and X denotes a chlorine or bromine atom, by the action of an aqueous solution of an alkali metal hydroxide in a tetrahydrofuran-hydrogen peroxide environment consists in that hydrogen peroxide is used to prepare the tetrahydrofuran-hydrogen peroxide or dioxane- -hydrogen peroxide solvent system, the pH of which has been adjusted to a value of 6.5 to 6.7 using barium hydroxide, after which, after dissolving the δ -lactone of the general formula II in the said mixture, its pH is adjusted to a value of 7.5 to 8.0 by adding lithium carbonate and at a temperature of -2 to +5 °C, an aqueous solution of 1.8 to 2.2 M lithium hydroxide is added within 2 to 5 hours to maintain the pH values of the mixture within the range specified above, after which, after the reaction is complete, the mixture is diluted with water and the excess hydrogen peroxide is removed with solid alkali metal sulfite at a temperature of 20 to 50 °C and then the product is extracted at the above temperature with ethyl, isopropyl or butyl acetate and finally, after evaporation of the solvents, it is purified by crystallization from an aliphatic hydrocarbon containing 5 to 10 carbon atoms.

Description

The invention relates to a process for the preparation of hexahydro-4-acyloxymethyl-5-hydroxy-2H-cyclopenta (b) -

furan-2-ones of formula I, wherein R is alkyl of 1 to 3 carbon atoms. Municipal compounds;

formula I, tev. Corey lactone is one of the important intermediates in the production of natural

prostaglandins and their synthetic analogues. , j

Several synthetic methods are currently known (Bindra J. S., Bindra R., i;

in Prostaglandin Synthesis, Academia Press, N. Y. 1977, Roberts S. M., Newton R. F. &

in Prostaglandin and Thromboxanes, Butterworths Scientific, London 1982, Noyori R., Suzuki M .: Angew. Chem. Int. Ed. Engl. 23, 847 (1984); Caton Μ. P. L. Hart T. W .: Advan-jes in Prostaglandin, Thromboxane and Leukotriene Research (4, 73 (1985)), by which it is possible to prepare not only all basic natural prostaglandins, but also their variously modified analogues. One of the most commonly used procedures is the so-called norbornadiene pathway, which- <

It provides various variants of the synthesis of the Corey lactone, mostly quite complex, see previously cited references, and U.S. Patent Nos. 3,992,438 (1976), 3,943,151 (1976). In the individual stages of these syntheses, it is for the most part necessary to isolate the individual oils;

intermediates by chromatographic methods. According to the process protected by the author's certificate No. 226 905, the conversion of (2-acetyloxymethyl-5-halo-3-hydroxy-1'-cyclopenten-1-yl) acetic acid δ-lactone of general formula II into δ-lactone of general formula I is carried out in a solution of tetrahydrofuran and hydrogen peroxide by the action of 2 N lithium hydroxide at room temperature, without controlling the pH of the reaction mixture. In this embodiment, the δ-lactone of the general formula I is obtained with a honey-like consistency and contains less than 85% of the desired substance. These facts are at a significant disadvantage:

the above method of production both from a technological point of view, increased laboriousness in the isolation of subsequent intermediates, as well as from an economic point of view.

The process for the preparation of hexahydro-4-acyloxymethyl-5-hydroxy-2H- / eliminates these disadvantages.

-cyclopenta (b) furan-2-ones of the general formula I, in which R denotes alkyl having 1 to 3 carbon atoms according to the invention, the essence of which consists in the fact that the δ-lactone of the general formula II in which R has $ > X is chlorine or bromine, treated with an aqueous solution of lithium hydroxide in a solvent system containing tetrahydrofuran-hydrogen peroxide or dioxane-hydrogen peroxide, using hydrogen peroxide, the pH of which is adjusted to barium hydroxide, to prepare the solvent system. 6.5 to 6.7. After dissolving the δ-lactone of formula II in the solvent mixture, its pH is adjusted to 7.5 to 8.0 with lithium carbonate, and at -2 to + 5 ° C, an aqueous solution of 1.8 to 8.0 ° C is added over 2 to 5 hours. ? '

2.2 M lithium hydroxide so that the pH of the mixture is kept within the above values. Prů- <

the progress of the reaction is monitored by thin layer chromatography. After the rearrangement is complete, the reaction mixture is diluted with water and the excess hydrogen peroxide is removed by adding solid sodium sulfite at a temperature of 20 to 50 ° C, preferably 30 to 35 ° C. The presence of peroxide is demonstrated by>

by means of an iodostarch reaction. After complete removal of hydrogen peroxide, the reaction mixture is heated to about 40 DEG C. and the product is extracted with ethyl or isopropyl or butyl acetate, the combined portions being washed with brine and, after drying with an inorganic desiccant, the solvents are evaporated off. Crystallization of the distillation residue from an aliphatic hydrocarbon having 5 to 10 carbon atoms, preferably cyclohexane, gives the crystalline product in high purity (above 95% as determined by high pressure liquid chromatography) and a yield above 80%.

The advantage of the process according to the invention is, in addition to a simple embodiment, a high yield and purity of the product. The particularly high purity makes it possible to substantially intensify the process in the further reaction steps, which represents a considerable economic benefit.

The invention and its effects are explained in more detail in the following examples, which-3;

do not limit the scope of the invention.

Example 1.

To 10.8 g of the δ-lactone of formula II, wherein R is CH 2 and X is chlorine, dissolved in 117 ml of tetrahydrofuran, was added over 1 hour after cooling to 0 to + 3 ° C;

59 ml of 30% hydrogen peroxide, the pH of which has been previously adjusted with 0.1 N solution, are added dropwise.

flow of barium hydroxide Ba (OH)? to 6.6. After the addition of hydrogen peroxide, the pH of the reaction mixture was adjusted to 7.5 with aqueous lithium carbonate solution and at a temperature of -1%. ^; íj

CS 268 616 B1 to +1 ° C was added with vigorous stirring over 5 hours 238 ml of 2N lithium hydroxide solution so fast that the pH of the reaction mixture was between 7.5 and 8. After a further 2.5 hours of stirring (in case of decrease The pH is adjusted to 7.5 below the addition of lithium hydroxide solution to the above range) and the reaction is complete. The control is performed by thin layer chromatography. 125 ml of water were then added and 70 g of solid sodium sulphite were added portionwise to decompose the excess hydrogen peroxide, the temperature of the mixture rising to 30-35 ° C. After complete decomposition of the peroxide (control by iodostarch reaction) in about 15 to 20 minutes, the mixture was heated to about 40 ° C, the organic layer was separated and the aqueous phase was extracted with 5 x 24 ml of ethyl acetate. The combined organics were washed with brine, dried over anhydrous magnesium sulphate (5 g) and the solvents distilled off under reduced pressure (2.6 to 5 kPa) on a rotary evaporator. After crystallization from cyclohexane, 8.35 c (84%) of crystalline substance are obtained from the distillation residue, mp 65-70 ° C, which according to high-performance liquid chromatography has the same elution time as the standard and contains 96.5% of the product of formula I, where R denotes a CH- group. The infrared spectrum (chloroform) contains a p ‘- 1 - 1 sy: 1 770 cm corresponds to the valence vibration of the CO group in the δ-lactone and 1 740 cm corresponds to the valence vibration of the CO group in the acetate residue.

Example 2

To a solution of 12.87 g of δ-lactone of formula II, where R is CH- and X is bromine, in 110 ml of tetrahydrofuran, after cooling to 0 DEG C., 60 ml of 30% hydrogen peroxide at pH 6 were added dropwise over 45 minutes. , 55, after which the pH of the reaction mixture was adjusted to 7.6 by adding lithium carbonate. Proceed as in Example 1 to obtain 8.43 g (85%) of crystals, m.p. 63-71 DEG C., which, according to high-performance liquid chromatography, contain 96.2% of the product of the formula I in which R is CH2. The elution time and the infrared spectrum are identical with the data obtained with the standard substance.

Example 3. .

To a mixture of 1.29 g of δ-lactone of formula II, wherein R is CH- and X is bromine O and 11.4 ml of dioxane was ^{added dropwise at -1 to X} 1 C with stirring over 30 minutes. % of hydrogen peroxide, the pH of which has been previously adjusted to 6.6 with bamate hydroxide. After adjusting the pH of the reaction mixture to 7.65 by adding lithium carbonate, a 2 M lithium hydroxide solution was added dropwise. After working up analogously to the reaction mixture as in Example 1, 854 mg (86.5 g of crystalline product, mp 65-70 DEG C., are obtained, the spectral characteristics of which are identical to those of the standard substance.

Claims (2)

1. Process for the preparation of hexahydro-4-acyloxymethyl-5-hydroxy-2H-cyclopenta (b) furan-2-ones of general formula I, wherein R represents alkyl of 1 to 3 carbon atoms from a δ-lactone of general formula II, wherein R has the above-mentioned meaning and X denotes a chlorine or bromine atom by the action of an aqueous solution of an alkali metal hydroxide in a tetrahydrofuran-hydrogen peroxide medium, characterized in that hydrogen peroxide at a pH of adjusted to a value of 6.5 to 6.7 with barium hydroxide, after which, after dissolving the δ-lactone of formula II in said mixture, its pH is adjusted to 7.5 to 8.0 by adding lithium carbonate and at a temperature of -2 to +5. An aqueous solution of 1.8 to 2.2 M lithium hydroxide is added over 2 to 5 hours to keep the pH of the mixture within the above range, after which the mixture is diluted with water and excess hydrogen peroxide is removed with solid alkali metal sulfite at 20 to 50 ° C, then the product e.g. at the above temperature, it is extracted with ethyl, isopropyl or butyl acetate and finally, after evaporation of the solvents, it is purified by crystallization from an aliphatic hydrocarbon containing 5 to 10 carbon atoms. 2. Process according to claim 1, characterized in that hexane or cyclohexane is used as the aliphatic hydrocarbon.