CS226906B1 - Method of preparing (3a alpha,4 beta,5 alpha,6a alpha)hexahydro-5-hydroxy-4-hydroxymethyl-2h-cyclopenta (b)furan-2 one - Google Patents

Description

The present invention relates to a process for the preparation of (3a ', 4 / 3,5a, 6a') hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta (b) furan-2-one of formula I,

OH (I)

This compound, referred to in the literature as the "Corey lactone", is a key and critical intermediate used in the synthesis of all basic types of prostaglandins and their derivatives modified in both side chains. The compound of formula I has been prepared by a number of procedures, most of which require many relatively difficult synthetic grafts. In many cases, individual intermediates need to be isolated by chromatographic methods [see, for example, J. S. Bindra, A. Grodski, Τ. K. Schaaf, E.J. Corey:

J. Am. Chem. Soc. 95, 7522 (1973); K. Inoxie,

I. Sakař: Tetrahedron Lett. 1977, 4063; E. J.

Corey, N.M. Weinshenker, Τ. K. Schaaf, W. Hubert, J. Am. Chem. Soc. 91, 5675 (1969);

Paul, K.G., F. Johnson, F. Favara, J. Amer, Chem. Soc. 98, 1285 (1976); Fischli A., Klaus M., Mayer H., Schonholzer P., Ruzgg R.: Helv. Chim. Acta 58, 584 (1975); Cs. 211 527 and 226 905, Hungary. U.S. Pat. 173 711], Some simplification of the synthesis of Compound I has resulted in the use of the relatively available (3,3a, 6,6aa) tetrahydro-2H-cyclopentan (b) furan-2-one [P. A. Grieco et al. J. Org. Chem ·. 37, 2363 (1972)]; formula II,

(clay)

In the aforementioned Hungarian patent, the reaction is carried out by treating the lactone of formula II with formaldehyde (Prins reaction) in the presence of trichloro- or trifluoroacetic acid under catalysis with a strong inorganic acid such as sulfuric or phosphoric acid at elevated temperatures in some cases. sealed tube. It is obvious that this embodiment has a number of disadvantages: It uses aggressive and harmful halogenated acids, performs reactions in sealed containers, and last but not least, catalyses with strong inorganic acids. Under these conditions, there is an increased decomposition (carbonization) of the reactants, which makes it difficult to isolate the desired product and hence its yields. Also, the relatively long reaction time reduces the economic advantage of the process.

This process is followed in a positive way by the method according to the invention, which removes these drawbacks. Substance of the Production Method (3aa, 4R, 5a, 6a and 6-hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta (b) furanone)

The OH (I) according to the invention is characterized in that the unsaturated [gamma] -lactone of formula II is added

acts in an anhydrous environment with paraformaldehyde in a solution of an aliphatic carboxylic acid having 1 to 3 carbon atoms under the catalytic action of anhydrous divalent and trivalent metal halides such as iron (III) chloride, aluminum, zinc, iron bromide, antimony fluoride and tin chloride at 40 to 120 ° C . This process produces the diacyl χ-lactone of formula III,

(III) wherein R is hydrogen or alkyl having 1 or 2 carbon atoms. After hydrolysis in an acidic or alkaline medium, or acid catalyzed transesterification with a lower alcohol having 1 to 4 carbon atoms at a temperature of 50 to 130 ° C, the desired lactondlol of the formula I is obtained.

This new method of manufacture uses readily available and inexpensive and hygienically safe substances.

When using the above reaction conditions, the decomposition of the reactants does not take place and the reaction rate is greatly increased. The diacyl β-lactone of formula (III) thus prepared is readily isolated from the reaction mixture in a high yield of 93-97% in pure form so that it can be used without purification for the next reaction step. Hydrolysis carried out under conventional and generally known conditions or, preferably, acid catalyzed transesterification with a lower aliphatic alcohol having 1 to 3 carbon atoms yields the desired "Corey alcohol" of the formula I in a yield of more than 90% from the diacyl χ-lactone of the formula III.

The invention is illustrated by the following examples.

Example 1

To a suspension of 1.3 g paraformaldehyde and 0.5 g aluminum chloride in 20 ml conc. Formic acid (1 g) was added dropwise with vigorous stirring at room temperature. Thereafter, the reaction mixture was heated at 70-80 ° C for 3 hours and then stirred at this temperature for 10 hours (reaction progress was checked by thin layer chromatography). After evaporation of the formic acid on a rotary evaporator, the distillation residue was dissolved in 10 ml of dichloroethane, washed with 2 ml of 2% sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give 1.75 g (95%) of the oily bisphosphate of formula III, the mass spectrum of which is a molecular ion of m / z 228 and further significant fragments of m / z 184 (m ⁺ - CO2 ·], m / z 154, 108, 82 and 43. in infrared spectrum, characteristic bands were found formyl group 1738 cm ^"1 (C = O) in the ester and 1192 cm ^-1 υ (C-O) in the formate Example 2

A mixture of 1.0 g of bisformate III was dissolved in 10 ml of absolute methanol and after addition of 0.2 g of a strongly acidic cation exchange resin based on a sulfonated styrenic polymer (Dowex 50) in an H ^{< + &gt}; The end of the reaction was determined by thin layer chromatography - chloroform-methanol 9: 1. After cooling, the ion exchanger was filtered off, the solvents evaporated in vacuo and the residue 0.7 g (92.3%) was the product of formula I. The identity of the product was demonstrated by mass spectra with a standard preparation with ions m / z 173 (M + 1) + m / z 124 (M-18), m / z 126 (M-18-CO) with a metastable peak of m / z 103.1, corresponding to ion cleavage of (M-18) ⁺ -CO. Example 3

To a suspension of 4 g paraformaldehyde, 0.9 g ferric chloride in 35 ml glacial acetic acid was added with vigorous stirring. 3.2 g of χ-lactone of formula II. After analogous work-up the reaction mixture was obtained

5.58 g of an oil-like bisacetate of formula III (R-CH3), the structure of which was confirmed by mass spectra - a molecular ion of m / z 256 and fragments (M-CH3CO). In the infrared spectrum characteristic bands of 1736 cm ^-1 , corresponding to p (G-O) in the ester and 1242 cm ^-1 , corresponding to (C-O) vacetate, were found.

Claims (2)

SUBJECT Process for the preparation of (3a, 4 / 3,5 ', 6aa) hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta (b) furan-2-one of the formula I OH (f) characterized in that an unsaturated γ-lactone of formula II is added YNALEZ containing from 1 to 3 carbon atoms at the catalysis of divalent and trivalent metal halides, for example ferric chloride, aluminum chloride, zinc, tin (II), ferric bromide, or antimony (III) fluoride, at 40 to 120 ° C to form diacyl χ-lactone; acts in an anhydrous environment with paraforimaldehyde · in a solution of an aliphatic acid, where R is hydrogen or · alkyl containing 1 to 2 carbon atoms, which is hydrolysed in an acidic or alkaline environment or transesterified using an acidic catalyst with a lower alcohol of 1 to 4 carbon atoms to 130 ° C. 2. A process according to claim 1, wherein the transesterification is carried out using an ion exchange resin in an H ^{< + &gt;} cycle as the acid catalyst.