HU188393B - Process for producing lactandiol derivatives - Google Patents

Abstract

Racemic or optically active lactone-diol derivs. of general formula I are prepd. from cpds. of general formula II by reacting the cpds. of general formula II in an aprotic solvent that is water miscible with aq. solns. of strong mineral acids to eliminate the tri-phenyl-methyl gp. - In the formulae R1 is benzoyl, a p-phenyl-benzoyl or a p-phenyl-carbamoyl gp., R2 is tri-phenyl-methyl. In the three-phase reaction the pure cpd. of general formula I appears as crystalline solid free of byprods. It is isolated and dried.

Description

The invention selective detritylation procedure without side reactions to racemic or optically active Formula (I) laktondiol bicyclic derivatives, in which R ^l is selected from .beta.-benzoyl, benzoyl, or .beta.-carbamoyl.

The compounds of formula I are important intermediates in the synthesis of natural prostaglandins and prostanoids. (J. Am. Chem. Soc. 1969 91, 5675, Tetrahedron Letters 1972, 2063).

Hungarian Patent No. 174,555 discloses a process for the preparation of compounds of formula (I) by selectively protecting the hydroxy group of a primary bicyclic lactondiol having a 5-hydroxy group, for example by tritylation, then acylating the secondary alcohol with the desired protecting group. the compounds of formula (II) wherein R ¹ is as defined above; R ² is triphenylmethyl - detritylated in a homogeneous reaction mixture of water and acetic acid.

Conventional acid detritylation processes (boiling or heating in 80% acetic acid in chloroform saturated with hydrogen chloride gas or chloroform saturated with hydrogen bromide gas) for the preparation of compounds of formula I from compounds of formula II are disclosed in U.S. Patent No. 174,555. are not applicable since in these cases the migration of the acyl group can be detected in the range of 5-10% after detritylation. (After one hour reaction time, both secondary - ♦ primary and primary -> secondary migration were detected). Thus, carrying out the detritilization step in this form did not result in a uniform final product.

According to Example 10 of U.S. Patent No. 174,555, the acyl group was not migrated by detritilization (in 80% aqueous acetic acid for 30 minutes at 60 ° C), but in this case another by-product was isolated. 20%.

It was found that the product mixture obtained could not be separated by simple methods such as crystallization because the melting point values and solubilities of the products formed were very close to each other. However, the use of chromatographic methods in industrial prostaglandin synthesis is certainly disadvantageous.

In order to overcome these difficulties, it has been unexpectedly found that the trityl derivatives of formula II can be converted to the corresponding (I) hydrolysis reaction with excellent yields, without formation of a by-product, in a heterogeneous three-phase reaction with products of the general formula.

According to the present invention, the bicyclic trityl acyl or tritylcarbamoyl lactones of formula II are dissolved in a water-immiscible aprotic lubricant and then, while stirring, an aqueous solution of a strong mineral acid is added. The two immiscible solvent mixtures form a single crystalline detrilylated product of formula (I). The new solid phase formation serves as a reaction ^hajtó2: constituted ^by the power, since thus the reaction equilibrium is completely shifted towards products formation. Following the above-described detritilation reaction, the product is recovered from the mixture by filtration and dried. The product of formula (I) thus obtained was found to be more than 99% pure by TLC. In the choice of reaction media, aromatic solvents such as toluene, benzene, chlorinated hydrocarbons such as methylene chloride, dichloroethane and carbon tetrachloride may also be used.

Preferably the hydrochloric acid, sulfuric acid or hydrobromic acid is used as the strong mineral acid, and the aromatic hydrocarbons, preferably toluene, are used as the aprotic, water-immiscible organic solvent. It is also possible to use chlorinated hydrocarbons, preferably methylene chloride, dichloroethane or carbon tetrachloride as an aprotic, water immiscible organic solvent.

The invention is further illustrated by the following examples, which are not intended to limit the invention.

EXAMPLES Example 1 (-) - 3,3aP, 4,5,6,6aP-Hexahydro-4β-hydroxymethyl-5α- (p-phenylbenzoyloxy) -2H-cyclopentano [b] furan-2-one.

g (33.6 mmol) of (-) - 3,3ap, 4,5,6,6aβ-hexahydro-4β- (triphenylmethyloxymethyl) -5α- (p-phenylbenzoyloxy) -2H-cyclopentane [b Furan-2H-one is dissolved in 80 mL of toluene and 10 mL of 10M hydrochloric acid is added over 10 minutes with stirring at 50-55 ° C. The reaction mixture was further stirred at 50 ° C and the progress of the reaction was monitored by TLC. (Benzene: ethyl acetate = 7: 1 _Rf value silica plate after the starting material is 0.7 and the product R _f = 0.1 / 1 hour of mixing the suspension of crystals is cooled to 20-25 ° C and then 30 ml of water The suspension is then cooled to 0 ° C and filtered after stirring for 1 hour.

The filtered crystals were washed with cold toluene (10 mL) and water (20 mL). The product thus isolated was dried under infrared light to constant weight to give 11.1 g (93.7%) of the title compound. The analytical characteristics of the product are as follows:

R _f (ethyl acetate run) 0.3 (a) “= -89 '(c = 1.0 CHCl 3)

NMR / CDCl ₃ δ: 3.72 / d, 2H, CH ₂ OH

5.05 / m, 1H, 6a-H, CHO 5.42 (q, 1H, 5-H)

Example 2 (-) - 3,3a3,4,5,6,6a,? -Hexahydro-4? -Hydroxyethyl-5? -Benzoyloxy-2H-cyclopentano [b] furan-2-one.

The procedure of Example 1 is followed by a

188,393, except that 17.4 g (33.6 mmol) of (-) - 3, 3ap, 4, 5, 6, 6a, 3-hexahydro-4β-triphenylmethyloxymethyl-5α-benzoyloxy is obtained as starting material; 2H-Cyclopentano [b] furan-2-one was weighed. 8.74 g (94.1%) of the title compound are obtained. Analytical characteristics of the product: mp 118-119 ° C, IR max (KBrpastilla), 3450, 2920, 1770, 1710, 1600, 1580, 1540,

1270, 1200, 1165, 1110, 1070, 1030 cm ^-1

Example 3 (-) - 3,3aP, 4,5,6,6aP-Hexahydro ^: 4β-hydroxymethyl-5α- (p-phenylphenylcarbamoyloxy) -2H-cyclopentano [b] furan-2-one.

The procedure described in Example 1 was followed except that 20.5 g (33.6 mmol) of (-) - 3,3aP, 4,5,6,6a, 3-hexahydro-4p (triphenylmethyloxy) -methyl) -5a- (p-phenylphenylcarbamoyloxy) -2H-cyclopentano [b] furan-2-one.

11.24 g (91.1%) of the title compound are obtained. Analytical characteristics of the product:

R _f = 0.15 (Benzene: Ethyl acetate = 3: 1)

NMR / CDCl, ε: 3.75 / d, 2H, CH ₂ OH

5.0-5.5 / n, 2H, 6a-H and 5-H

Example 4 (-) - 3,3ap, 4,6,5,6,6a-Hexahydro-4β-hydroxymethyl-5α- (p-phenylbenzoyloxy) -2H-cyclopentano [b] furan-2-one

The procedure described in Example 1 was followed except that (-) - 3,3aP, 4,5,6,6aP-hexahydro-4β- (triphenylmethyloxymethyl) -5α- (p) was dissolved in dichloroethane instead of toluene. -phenylbenzoyloxy) 2H-cyclopentano [b] furan-2-one, to give 10.17 g (85.8%) of the title compound.

Analytical characteristics: R _f = 0.3 (ethyl acetate)

NMR / CDCG, δ: 3.7 / m, 2H, CH ₂ OH 5.02 / m, IH, 6a-H 5.4 / m, IH, 5-H)

7.25-8.3 / m, 9H, aromatic protons

Example 5 (-) - 3,3ap, 4,5,6,6ap-hexahydro-4β-hydroxymethyl-5α- (p-phenylbenzoyloxy) -2H-cyclopentano [b] furan-2-one.

The same procedure as in Example 1 was followed, except that 10 ml of 5 molar sulfuric acid solution was used instead of 10 ml of 10 M hydrochloric acid for detritilization. 9.54 g (80.5%) of the title compound are obtained.

Physico-chemical constants: see Example 1

Example 6 (-) - 3,3aP, 4,5,6,6aP-Hexahydro-4p-hydroxymethyl-5c- (p-phenylbenzoyloxy) -2H-cyclopentano [b] furan-2-one.

The procedure described in Example 1 was followed, except that 10 ml of 10 molar hydrobromic acid was used instead of 10 ml of 10M hydrochloric acid solution for detritilization. 9.36 g (79.0%) of the title compound are obtained.

Physico-chemical constants: see Example 1.

Claims (4)

Patent claims A process for the preparation of a racemic or optically active lactondiol derivative of formula I wherein R ^{1 is} 25 is benzoyl, phenyl-ρ-benzoyl, or p-fenilfenilkarbamoil group - from the compounds of formula (II) - wherein ^R? has the meaning given above; R ² represents a trityl group - characterized ^three θ ve detritilezésével with compounds with a strong mineral acid to solute dissolved in an aprotic, water-immiscible organic solvent (II) - wherein the substituents are as defined above - tritilcsoportjának compounds cleavage of strong mineral acids is carried out in an aqueous solution of a three-phase reaction - with ³⁵ of water and a water-immiscible aprotic organic solvent forms the two fluids, while free of the precipitated product from the product, the solid phase - and the pure, crystalline product is isolated by filtration and dried. ⁴⁰ 2. A process according to claim 1 wherein the strong mineral acid is hydrochloric acid, sulfuric acid or hydrobromic acid. 3. Process according to claim 1, characterized in that the aprotic, water-immiscible organic solvent is aromatic hydrocarbons, preferably toluene. 4. The process of claim 1, wherein the process is aprotic with water Chlorinated hydrocarbons, preferably methylene chloride, dichloroethane or carbon tetrachloride, are used as 50 immiscible organic solvents.