HU193525B - Process for preparing hexahydro-5-hydroxy-4-hydroxymethyl-2h-cyclopenta/b/-furan-2-one derivatives - Google Patents

Abstract

The present invention relates to a hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta [b] uran-2-one derivative of formula (I) wherein Z is an R'-C6H4CO group and wherein R1 is hydrogen. , which represents a methyl, phenyl or nitro group, for the preparation of a halo-hydroxy ketone of formula (II) wherein X is chlorine, bromine or iodine with an acylating agent of formula R2-COY wherein R2 is C1-C3 alkyl; Y is chloro or bromo or R2-COO is reacted in the presence of a tertiary amine to oxidize the resulting acyl derivative of formula (III) with a peroxyacid to the corresponding lactone and with an alkali metal hydroxide of the corresponding formula (V). converting to lactone to protect the hydroxyl group of this lactone with the Z group as defined above, and to selective transesterification from the diester thus obtained n by liberating Corey-lactone of formula (1). This synthesis can produce an important intermediate in the production of prostaglandins. (V) -1-

Description

The present invention relates to hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta [b] furan-2-one derivatives of formula (I):

Z is a R 1 -C ₆ H ₄ -CO- group wherein R ^{1 is} methyl or phenyl, hydrogen or nitro.

The compounds of formula (I), commonly referred to in the literature as Corey-lactone, are important intermediates in the synthesis of prostaglandins with versatile biological activity derived from prostanoic acid. Several processes for the preparation of this type of compound have been described so far, including synthesis from norbornadiene. There are several patented versions of this known synthesis, most of them patented. In many such embodiments, the 7-hydroxymethyl-5-halo-bicyclo [2,2,1] heptanone compounds of formula (a), wherein A represents chloro, bromo or iodo, form a common intermediate which can be formed in known manner. to the desired corresponding lactone of formula (I), this is first protected on the hydroxy group in the form of acetal, ether or silyl ether, whereby the corresponding compound of formula (b) - wherein A is the same as R and R is tetrahydropyranyl, benzyl, , represents a 1-methyl or trialkylsilyl group of triphenic acid (cf. U.S. Patent No. 3,943,151, German Patent Publication No. 2,704,029, U.S. Patent No. 122,817). ). The compound of formula (b) thus obtained is then converted, by oxidation with organic peracid, to the corresponding oil of formula (c), wherein A and R are as defined above. The latter compound is then converted to the corresponding γ-lactone of formula (d) by treatment with an alkali metal hydroxide solution or optionally with a mineral acid, converting its hydroxyl function to a Z derivative where Z and R are obtains and finally removes the desired γ-lactone of formula (I) as depicted in Scheme 1, wherein A, R and Z are as defined above. .

A disadvantage of the process outlined above is that the resulting intermediates are generally of oil or honey-like consistency and therefore need to be purified by chromatography. In addition, some of the reaction steps, in particular Baeyer-Villiger oxidation and the conversion of δ-lactone to γ-lactone, are unclear, which results in the desired reaction products being obtained in low yields. These reactions have to be carried out in dilute solutions, which results in a significant loss of often flammable solvents and imposes significant demands on technological equipment and health and safety regulations. In some cases, it is also difficult to remove the protecting groups, for example by catalytic hydrogenation of the benzyl group at the R-position. All these disadvantages greatly diminish the economics of the preparation of the compounds of formula (I) by the processes outlined above.

It is desirable to improve the processes outlined above in the positive sense of the present invention by eliminating the drawbacks of the known methods.

The principle of the process of the present invention is that a halogen hydroxy ketone of formula II wherein X represents chlorine, bromine or iodine, in an inert solvent or without the use of an acylating agent of formula R ² -COY, wherein R ² C 1 -C 3 alkyl and Y represents a chlorine or bromine atom or a R ² -COO group (where R ^{2 is} as defined above) is reacted in the presence of a tertiary amine such as pyridine or triethylamine to give the corresponding general formula (III). wherein R ² and X are as defined above.

The reaction mixture thus obtained is washed with sodium bicarbonate solution and the solvent is evaporated to give a usually crystalline product which can be oxidized without further purification in the form of a solution of acetic acid or a chlorinated hydrocarbon, even 3 to 5 times organic peroxyacid. using a molar excess of the molar as an oxidizing agent at a temperature of 0 ° C to 100 ° C. After completion of the reaction, excess oxidant is removed by addition of water and sodium sulfite or by refluxing the reaction mixture for several hours. The resulting reaction product is extracted from the reaction mixture with an organic solvent and the organic solvent is evaporated to give the δ-lactone of formula IV, where R ² and X are as defined above, in the form of a crystalline crude product.

The resulting compound of formula (IV) may be recrystallized from a mixture of cyclohexane and dichloroethane prior to the next reaction step, or it may be used directly in the form of the crude crystalline product thus obtained for the next step.

The conversion of the δ-lactone (IV) into the γ-lactone (V), where R ² is as defined above, is accomplished by the addition of an equimolecular amount of an aqueous solution of alkali metal hydroxide which is added at 30 ± 30 ° C. a δ-lactone of the general formula represented by a solution of a water miscible organic solvent such as tetrahydrofuran and hydrogen peroxide in a ratio of 0: 0.5 to 2 by volume. After completion of the reaction, the reaction mixture was diluted with water, acidified to pH 5-6 with acetic acid, and the excess peroxide present was removed by reduction with solid sodium sulfite. The reaction mixture is separated from the reaction mixture by repeated extraction with an organic solvent, the organic solvent extract is dried over anhydrous magnesium sulfate and the solvent is evaporated off under vacuum. The crude compound (V) thus obtained can be reacted without further purification, optionally in the presence of triethylamine or pyridine diluted with an inert solvent, to give an acyl chloride of the formula R'-C ₆ H ₄ -COC ¹ where R ¹ is as defined above. With a molar excess of 1 to 1.5 times; the reaction mixture was allowed to stand at 40 ± 20 ° C until the reaction was complete, the excess acylating agent was quenched by the addition of a little water, the excess base was removed by evaporation in vacuo or the reaction mixture washed with dilute hydrochloric acid and the residue dissolved in , the solution was repeatedly washed with aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and the residual aromatic acids removed by filtration over an alumina column. The solvent is evaporated in vacuo, the crude product obtained is recrystallized from aqueous ethanol or used directly as a crude product for further processing.

The compound of formula (VI) thus obtained, wherein R ² and Z are as defined above, provides the desired compound of formula (I) by selective transesterification of the aliphatic ester function. This transesterification reaction is carried out at 50 ± 30 ° C using a C 1 -C 3 alcohol such as methanol or ethanol in the presence of an acidic catalyst such as a mineral acid, a sulfonic acid or a strongly acidic H ⁺ ring ion exchanger; the resulting compound of formula (I) is purified by recrystallization.

A particular advantage of the process of the present invention is that the intermediates are predominantly in the form of solid compounds which are easily purified by crystallization; the reactions are carried out with relatively concentrated solutions of readily available and in most cases chlorinated, non-flammable solvents; these advantages result in high selectivity and excellent production rates in each step of the synthesis.

Practical embodiments of the process of the invention as well as the effectiveness of each reaction step are illustrated by the following examples; It should be noted, however, that these examples are provided for purposes of illustration only, and the scope of the invention is in no way limited to these specific examples.

Example 1

To a hydroxy ketone (II) containing 2.62 g of X is chlorine, 1.84 g of freshly distilled acetic anhydride and 1.43 g of anhydrous pyridine are added. As the starting material dissolves, the mixture becomes self-heating and becomes a homogeneous solution, which is allowed to stand at room temperature overnight. The reaction mixture was then diluted with dichloroethane (20 mL), washed with dilute hydrochloric acid (1: 5, 10 mL), saturated aqueous sodium bicarbonate (10 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo; 3.23 g (99% of theory) of a colorless oil are obtained which crystallize in a short time. Cyclohexane, dichloroethane, after recrystallization from a pure state is obtained in which X is chlorine, the acetyl of formula R ² = methyl (III), mp 70-72 ° C.

Example 2

In a similar manner to that described in Example 1, the propionyl derivative of formula (III) is prepared from the hydroxy ketone (II) wherein X is bromo and the propionyl chloride is X and R ² is ethyl; Yield: 92% of theory.

Example 3

3.04 g X is chlorine, acetyl derivative of formula R ² = methyl (III) dissolved in 30 ml of 40% acetic acid, 15 ml of peracetic acid was added over 10 minutes. The mixture was stirred at room temperature for 8 hours and then allowed to stand overnight. The reaction mixture was then diluted with 100 mL of ice water, the peroxide was decomposed by addition of solid sodium sulfite, the organic material was extracted with dichloroethane (25x25 mL), the combined extracts washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. . The solvent was evaporated in vacuo; The residue is crystalline δ-lactone (75% of theory), wherein X is chlorine atom, X is chlorine atom, R ² is methyl group (75% of theory), m.p. 102-104 ° C.

Example 4

To a solution of 4.6 g of X-lactone (IV) wherein X is chlorine and R ² is methyl in a mixture of 100 ml of tetrahydrofuran and 50 ml of 30% hydrogen peroxide is added 10 ml of 2 N lithium hydroxide under stirring at room temperature. The reaction mixture was allowed to stand for 2 hours, then acidified with 10 ml of acetic acid and allowed to stand overnight. The resulting mixture was diluted with water (100 mL) and the excess hydrogen peroxide was stirred under solid sodium sulfite and then cooled.

-3193525, so that the temperature of the reaction mixture does not rise above 30 ° C. The tetrahydrofuran was evaporated in vacuo, the aqueous solution was extracted with ethyl acetate (5 x 50 mL), the extracts were combined, washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. After evaporation of the solvent, 3.85 g of a γ-lactone of formula V wherein R ² is methyl are obtained in honey-like form; this product is used in the next step without further purification.

example

To a solution of γ-lactone (V) (3.80 g of R ² in methyl) in 50 ml of dichloroethane is added 5.50 g of p-phenylbenzoyl chloride and 4 ml of anhydrous triethylamine. The self-warming reaction mixture was allowed to stand overnight at room temperature and the excess acylating agent was quenched by addition of 1 mL of water. After 1 hour, the mixture was washed twice with 50 ml of saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and filtered through a 100 g alumina column, followed by 250 ml of dichloroethane. The combined filtrate was evaporated in vacuo; 6.90 g of an ester of formula VI are obtained wherein R ² is methyl and Z is pC ₆ H ₅ -C ₆ H ₄ -CO-; this crude product is recrystallized from aqueous ethanol. The product thus obtained melts at 90-92 ° C.

Example 6

To a solution of 3.94 g of an ester of formula VI wherein R ² is methyl and Z is pC ₆ H ₅ -C ₆ H ₄ -CO- in 100 ml of methanol is 4.0 g of H ⁺ ring in Amberlite IR-120 ion exchange resin was added and the mixture was heated under reflux for 10 hours with stirring. The methanol is then distilled off, the residue is stirred with 50 ml of dichloroethane, the ion exchanger is filtered off, washed with 20 ml of dichloroethane and the filtrate combined with the washings are evaporated in vacuo. The residue obtained is 3.7 g of crude lactone of general formula (I) wherein Z is pC ₆ H ₅ -C ₆ H ₄ -CO-; this was recrystallized from a mixture of dichloromethane and cyclohexane. The product thus obtained melts at 150-151 ° C.

Example 7

To a solution of the ester (VI) (1.72 g of R ² in ethyl, Z in benzyl) in ethanol (50 ml) was added p-toluenesulfonic acid (0.1 g) and the solution was refluxed for 4 hours. The ethanol is then distilled off in vacuo, the residue is dissolved in 20 ml of dichloroethane, the solution is washed with 10 ml of saturated aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated; 1.34 g of the compound of formula (1) containing benzoyl are obtained in the form of a substantially homogeneous chromatographic product.

Yield: 98%.

Mp: 58-63 ° C.

IR Spectrum: 1715 cm ^-1 (CO group benzoate);

1780 cm ^-1 (lactone group).

Example 8

To a solution of γ-lactone (V) (3.80 g) in which R ² is methyl in 50 ml of dichloromethane are added 4.9 g of p-toluyl chloride and 4 ml of anhydrous triethylamine. The reaction mixture was then worked up in a similar manner to that described in Example 5 to give 5.2 g of the crude ester having R ^{2 as} methyl and Z as p-CH ₃ -C ₆ H ₄ -CO-.

Claims (4)

1. A compound of formula álatlános hexahydro-5-hydroxy-4-hydroxymethyl-cyclopent the ti 1-2H [b] furan-2-ones (I) - moiety, wherein Z is a R ¹ -C ₆ H ₄ -CO- wherein R 'represents a methyl or phenyl group, a hydrogen atom or a nitro group, characterized in that a halogen hydroxy ketone of the formula (II) in which X represents a chlorine, bromine or iodine atom With an acylating agent of the formula R ² -COY, wherein R ^{2 represents a C} 1 -C 3 alkyl group, Ύ represents a chlorine or bromine atom, or a R ² -COO- group in which R ² represents the same as the above, in the presence of triethylamine, wherein the acylation reaction is optionally carried out in a reaction-inert solvent, preferably dichloromethane or dichloroethane, and then the acyl derivative (III) - in which R ² and X are as defined above - oxidized in acetic acid, dichloromethane or dichloroethane at a temperature of 0 ° C to 100 ° C with an organic peroxyacid, preferably 40% peracetic acid, to give the corresponding o-lactone of formula IV - wherein R ² and X are as above - and excess oxidant by means of sodium sulfite or by boiling decompose and react the resulting compound of general formula (IV) with an alkali metal hydroxide in a water-miscible organic solvent / hydrogen peroxide (1: 0.5-2.0 v / v) at 30 ± 30 ° C. γ-lactone of the formula - protecting the 5-hydroxy group as defined above Z groups and the thus obtained (VI) di-4193525 ester of formula - - wherein R ² is as defined above and wherein R ² and Z are as above the same - by selective transesterification with a C 1-3 aliphatic alcohol in the presence of an acidic catalyst, the aliphatic ester function is removed, thereby releasing the lactone of formula (I) as defined above. Process according to claim 1, characterized in that the conversion of the γ-lactone of the formula IV, wherein R ² and X are as defined in claim 1, into the corresponding γ-lactone of the formula V 0.5 molar solution of lithium or sodium hydroxide in the presence of 30-40% hydrogen peroxide, after completion of the reaction, the hydrogen peroxide is removed by trituration with sodium sulfite and the reaction product is treated with an organic solvent, preferably ethyl by repeated extraction with acetate. 3. A process according to claim 1, wherein the 5-hydroxyl group of the γ-lactone of formula V is An acyl chloride of the formula R'-C ₆ H ₄ -COC ¹ , wherein R ¹ is as defined in claim 1, in an excess of 1.1 to 1.5 times in a pyridine solution or in a molar excess of J, 5 to 1.8 times. in the presence of triethylamine by reaction in an inert solvent, preferably dichloromethane or dichloroethane, at 40 ± 20 ° C. Process according to claim 1, characterized in that the ester of formula (VI), wherein R ² and Z are as defined in claim 1, is transesterified with methanol or ethanol at a temperature between 20 ° C and 80 ° C. , in the presence of a mineral acid such as sulfuric acid, an aromatic sulfonic acid such as p-toluenesulfonic acid or a strongly ferric ion exchanger in the H ⁺ ring. 1 sheet with formulas