NL8204453A - PROCESS FOR PREPARING HEXAHYDRO-5-HYDROXY-4-HYDROXYMETHYL-2H-CYCLOPENTA B - FURAN-2 SUBATIVATES. - Google Patents

Description

* N.0. 31,486

Process for preparing hexahydro-5-hydroxy-4-hydroxy-methyl-2H-cyclopenta [b} -fur an-2-part vessel.

The invention relates to a process for the preparation of hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta [b] -furan-2-derivatives of the general formula 1, 1 in which Z represents the R -CgH 2 CO group and R represent a hydrogen atom, a methyl, phenyl and optionally a nitro group.

The title compound of the general formula 1, commonly referred to in the literature as Corey-lactone, is an important intermediate for the preparation of prostaglanids, compounds with a versatile biological actives derived from the prostanoic acid. A series of methods for preparing compounds of this type have been described heretofore, including an important place in the synthesis starting from norbornadiene.

This synthesis has several predominantly patent-15 and protected variants. A common intermediate of some of these variants is the 7-hydroxymethyl-5-halobicyclo [2,2,1] -heptsan-2-one of the general formula 7 wherein A represents a chlorine, bromine or iodine atom (see the scheme of the formula sheet), which is converted according to known methods into the desired lactone of the general formula 1 such that first the hydroxyl group in the form of an acetal, ether or silyl ether is protected, to form the compound of the general formula 8, wherein A has the foregoing meaning and R represents a tetrahydro-pyranyl, benzyl, methyl, triphenylmethyl or trialkylsilyl group (US Patent 3,943,151, German Offenlegungsschrift 2,704,029 and DDR Patent 122,817). The compounds of the general formula 8 are then converted by oxidation with organic peracids into the--30 lactone of the general formula 9, wherein A and R have the foregoing meaning. By reaction of the c / -lactone of the general formula 9 by the action of alkali metal hydroxide solutions, optionally of inorganic acids, the desired / -lactone of the general formula 10 is obtained and after the protection of the hydroxyl group in the form of the Z-derivative of the general formula II, in which Z and R have the meaning indicated above, 8204453 * - - 2 - after removal of the "protecting group R", the desired--lactone of the general formula 1 is obtained.

A drawback of the aforementioned method is the fact that in most cases the intermediates have an oily or honey-like quality and that it is necessary to use chromatographic methods for their purification. Some reaction steps, in particular the Baeyer-Villiger oxidation and the conversion of the α-lactones to the β-lactones, do not proceed automatically, causing low yields. It is necessary to carry out these reactions in dilute solutions, which involve a considerable consumption of mostly easily flammable solvents, which places considerable demands on technological equipment, hygiene and safety. Furthermore, in some cases the protecting group R, for example the benzyl group, is difficult to remove by catalytic hydrogenation. These facts thus decrease the economic advantage of preparing the compounds of the general formula 1 by the aforementioned known processes.

The method according to the invention positively adheres to these known methods, which overcomes the drawbacks of the hitherto known methods.

The principle of the process according to the invention lies in the fact that a halohydroxyketone of the general formula 2, wherein X represents a chlorine, bromine or iodine atom, in an inert solvent or without solvent, with an acylating agent with the general formula R 2 CO 2, wherein R represents an alkyl radical of 1 to 3 carbon atoms and Y represents a 2 chlorine or bromine atom or the R -C00 group, in the presence of tertiary amines, for example pyridine or triethylamine, to form an acyl derivative with the 2 general formula 3 wherein R and X have the aforementioned meaning acylates.

After washing the reaction mixture with a sodium hydrogen carbonate solution and evaporating the solvent, a crystalline product is generally obtained, which can be oxidized without further purification in the form of a solution 40 in acetic acid or in chlorinated hydrocarbons. -3- by the action of organic peroxyacids in a 3 to 5-fold molar excess of the oxidizing agent at a temperature of 0 to 100 ° C. The excess of the oxidizing agent is decomposed after the reaction 5 has been completed. water and sodium sulfite or by boiling the reaction mixture for several hours. The reaction product is extracted with an organic solvent and after evaporation thereof the crude crystalline / lactone of the general formula O is obtained, wherein R and X have the aforementioned meaning.

The compound of the general formula IV can be recrystallized from the mixture of cyclohexane and dichloroethane for the further reaction step or used directly in the crude state. The conversion of the /-lactone of the general formula 4 into the /-lactone of the general formula 2, wherein R has the aforementioned meaning, is effected by the action of an equimolar amount of an aqueous solution of an alkali metal hydroxide which is added to the solution of the la-lactone of general formula 4 in a mixture of a water-miscible organic solvent and hydrogen peroxide in a volume ratio of 0; 0.5-2, for example tetrahydrofuran hydrogen peroxide, at a temperature of 30 ° + 30 ° C. After completion of the reaction, the mixture is diluted with water, acidified with acetic acid to a pH of 5 to 6, and the peroxide present is removed by reduction with solid sodium sulfite.

The reaction product is isolated by repeated extraction with an organic solvent, drying the extract with magnesium sulfate and evaporating the solvent under vacuum. It is possible to use the crude product of the general formula 5 without further purification in the presence of optionally diluted triSylamine or pyridine diluted with an inert solvent, with a 1.1 to 1.5-fold molar excess of an acyl chloride of the general formula R1-C6H4-COCl, in which r4 has the aforementioned meaning, the reaction mixture is allowed to stand at a temperature of 40 + 20 ° C until completion of the reaction, the excess of the acylating agent is decomposed by adding 40 little water, the excess base is removed either by evaporation under vacuum 8204453 · 4 - or by washing the reaction mixture with dilute hydrochloric acid The residue is dissolved in methylene chloride or dichloroethane, washed repeatedly with a sodium hydrogen carbonate solution and after drying with magnesium sulfate, the residues of the aromatic acids are removed by filtration through an alumina column, after evaporation of the solvent in vacuo The crude product is made from aqueous ethanol or used directly for further processing. From the compound of the general formula 6, prepared in this way, in which R and Z have the aforementioned meaning, the aliphatic ester function is carried out selectively by transesterification at a temperature of 50 + 30 ° C by the action of alcohols with 1 to 3 carbon atoms, for example, methanol or ethanol, in the presence of acidic catalysts, for example inorganic acids, sulfonic acids or strongly acidic ion exchangers in the H + cycle, the desired product of the general formula 1, which is purified by recrystallization .

A particular advantage of the preparation process according to the invention is that the intermediates are predominantly present as solids, which can be easily purified by crystallization, the reactions being in easily accessible, in the majority of cases chlorinated, non-flammable solvents with comparatively concentrated solutions of such agents are assured, which ensure high selectivity and excellent yields at all reaction steps of the synthesis.

The invention and its effects are illustrated in the following examples, which are illustrative only and in no way limit the subject and scope of the invention.

Example I

1.84 g of newly distilled acetic anhydride and 1.43 g of anhydrous pyridine were added to 2.62 g of hydroxyketone of the general formula 2 (X = 35 chlorine). The mixture warmed spontaneously while simultaneously dissolving the starting material to a homogeneous solution, which was stored overnight at room temperature. The reaction mixture was diluted 40 with 20 ml of dichloroethane, washed with 10 ml of dilute hydrochloric acid 8204453% - 5 - (1: 5) and 10 ml of a saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. After evaporation of the solvent under vacuum, 3.23 g (99% of theory) of a colorless oil were obtained, which crystallized rapidly. Crystallization from a mixture of cyclohexane and dichloroethane gave the pure acetyl derivative of the general formula 3 (X-chloro, ft = CH2), mp 70 to 72 ° C.

Example II

Analogously to Example I, the propionyl derivative with the general p was obtained from the hydroxyketone of the general formula 2 (X = bromine) by the action of propionyl chloride and pyridine. Formula 2 (X bromo, R = CH 2 Cl 2) was prepared with a yield of 92% of theory.

Example III

To a solution of 3.04 g of acetyl derivative of the general formula 3 (X = chlorine, R = CH2) in 30 ml of acetic acid, 15 ml of 40% peracetic acid were added for 10 minutes. The mixture was stirred at room temperature for 8 hours and then left overnight. After dilution with 100 ml of ice water, the peroxides were decomposed by addition of solid sodium sulfite, the organic components were extracted with dichloroethane (8x with 25 ml each), the extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried with magnesium sulfate. . After evaporation of the solution under vacuum, 2.41 g (75% of theory) of crystalline Alacton of the general formula 4 (X = chlorine, R = CH2) with a melting point of 102 to 104 ° C, obtained.

Example IV

To a solution of 4.6 g of β-lactone of general formula (4) (X = chlorine, R = CH2) in a mixture of 100 ml of tetrahydrofuran and 50 ml of 30% hydrogen peroxide was stirred at room temperature 10 ml of a 2 N lithium hydroxide solution was added quickly, after 2 hours the reaction mixture was acidified with 10 ml of acetic acid and left overnight. After diluting the mixture with 100 ml of water, the excess hydrogen peroxide was decomposed by addition of 40 solid sodium sulfite under stirring and external cooling such that 8204453 bT - β - so that the temperature did not exceed 30 ° C. After evaporation of the tetrahydrofuran under vacuum, the aqueous solution was extracted with ethyl acetate (5x each with 50 ml), the extract was washed with saturated aqueous sodium hydrogen carbonate solution and dried with magnesium sulfate. After evaporating the solvent, 3.85 g of honey-like lactone of the general formula p 5 (R = CH 2) were obtained, which was used for further processing without purification.

10 Example V

5.50 g of p-phenylbenzoyl chloride and 4 ml of anhydrous triethylamine were added to a solution of 3.80 g / -lactone of the general p formula 5 (R = CH 2) in 50 ml of dichloroethane. The reaction mixture, which spontaneously warmed, was left overnight at room temperature and the excess of the acylating agent was decomposed by adding 1 ml of water. After 1 hour, the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (2x 50 ml each), dried with magnesium sulfate and filtered over a column of 100 g alumina, which was washed with 250 ml dichloroethane. After evaporation of the solvent under vacuum, 6.90 g of crude ester of the general formula 6 (R = CH 2, Z = p-CgH 2 -CgH 2 -CO) were obtained, which, after recrystallization from aqueous ethanol, produced a product with a mp 90 to 92 ° C.

Example VI

To a solution of 3.94 g of ester of the general formula 6 (R2 = CH3, Z = p-CgH ^ -CgH ^ -CO) in 100 ml of methanol, 4.0 g of an ion exchange resin (Amberlite IR-30 120 ) in the H + cycle and the mixture was heated to boiling for 10 hours with stirring. Methanol was then distilled off, the residue was stirred with 50 ml of dichloroethane, the ion exchanger was filtered off, washed with 20 ml of dichloroethane and the combined filtrates were evaporated in vacuo. A product with a melting point of 150 to 151 [deg.] C. was obtained from recrystallization from a mixture of dichloromethane and cyclohexane from 3.7 g of crude lactone of the general formula 1 (Z = p-CgH 2 -CgH 2 -CO).

Example VII

8204453 - 7 -

To a solution of 1.72 g of ester of the general formula 6 (R ^ = CH ^ CHg »Z = CgH ^ -CO) in 50 ml of ethanol was added 0.1 g of p-toluenesulfonic acid and the solution was boiled for 4 hours heated. The ethanol was then evaporated under vacuum, the residue was dissolved in 20 ml of dichloroethane, the solution was washed with 10 ml of a saturated solution of sodium hydrogen carbonate and dried with magnesium sulfate. After evaporation of the solvent, 1.34 g of the practically chromatographically homogeneous product of the general formula 1 (Z = C 8 H 2 CO) were obtained. Example VIII

4.9 g of p-toluyl chloride and 4 ml of anhydrous triethylamine were added to a solution of 3,80 g / lactone of the general formula (R = CH-j) in 50 ml of dichloromethane.

After work-up of the reaction mixture analogous to example V.

2, 5 µg of crude ester of the general formula 6 (R = CH3, Z * p-CH3-C6H4-CO) were obtained.

Example IX

A solution of 2.10 g of ester of the general formula 20 6 (R ^ a CH ^, Z .b ο-Ν02-0 ^ Η4-00) and 0.1 g of p-toluenesulfonic acid in 50 ml of methanol was added for 8 hours heated for a long time to boil.

The solution was neutralized in the heat by addition of triethylamine and after evaporation of the methanol to a total volume of the solution of 10 ml, after cooling, 1.26 g of crystalline chromatographically pure product of the general formula 1 (Z = o- NO2-C8H4-CO2).

8204453

Claims (4)

A process for the preparation of hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta [b] -furan-2-derivatives of the 1 1 general formula 1, wherein Z is the R -C 8 H 2 -CO- group and R is a a hydrogen atom, a methyl, phenyl and optionally a nitro group, characterized in that on a halohydroxyketone of the general formula 2, wherein X represents a chlorine, bromine or iodine atom, a 2 2 acylating agent with the general formula R COY, wherein R represents an alkyl radical having 1 to 3 carbon atoms and Y represents a chlorine or bromine atom or the R 1 -C00 group in the presence of tertiary amines, for example pyridine or triethylamine, whereby the acylation is optionally carried out in the presence of an inert solvent, such as dichloromethane or dichloroethane, to form an acyl derivative of the general formula 3, in which R and X have the aforementioned meaning that one is acetic acid, dictiloromethane or dichloroethane , at a temperature v 0 to 100 ° C with organic peroxyacids, for example with 40% peracetic acid, to the corresponding </ - - lactone 20 of the general formula 4, in which R and X have the aforementioned significance, oxidizing the excess of the oxidizing agent with sodium sulfite or by boiling, and the compound of the general formula (4) by action of alkali metal hydroxides in a system of a water-miscible organic solvent - hydrogen peroxide in a volume ratio of 1: 0.5 - 2.0, at a temperature of 30 + 30 ° C in the corresponding J-lactone of the -2 general formula 5, in which R has the aforementioned meaning, in which lactone the hydroxyl group in the 5-position with the group Z, which has the aforementioned meaning, to form a diester of the general formula 6, wherein R and Z have the aforementioned meaning, from which one can by selective transesterification with an aliphatic alcohol of 1 to 3 carbon atoms, in the presence of acidic catalysts, the aliphatic ester function is removed, liberating the lactone of the above general formula 1. 2. Process according to claim 1, characterized in that the σ-lactone in the corresponding la-lactone is characterized by the action of a 0.5 to 2 molar lithium or sodium hydroxide solution in the presence of 30 to 40 percent hydrogen peroxide, which is removed after completion of the reaction by reduction with sodium sulfite and the reaction product is isolated by repeated extraction with an organic solvent, for example ethyl acetate. 3. Process according to claim 1, characterized in that the hydroxyl group in the 5-position of the compound of the general formula 5 is reacted by the action of a 1.1- to 1.5-fold molar excess of an acyl-11. chloride of the general formula R -C 8 H 2 -COCl, wherein R has the aforementioned meaning, in a pyridine solution or in the presence of a 1.5- to 1.8-fold molar excess of triethylamine in an inert solvent, such as di- chloromethane or dichloroethane, at a temperature of 40 + 20 ° C. 4. Process according to claim 1, characterized in that the transesterification at temperatures of 20 to 80 ° C with methanol or ethanol in the presence of inorganic acids, such as sulfuric acid, aromatic sulfonic acids, such as p-toluenesulfonic acid or strongly acidic ion exchange conducting resin resins in the H + cycle. 8204453