SU403170A1 - - Google Patents

Description

METHOD OF OBTAINING 9a-METHYL-11-KETO-17-ETHYLENETETALS OF STEROIDS

The invention relates to a process for the preparation of new 9a-methyl-11-keto-17-ethylene ketals of steroids, which are valuable intermediates for the synthesis of substances with high physiological activity. 5 A method for the preparation of 9a-methyl derivative of cortisone is known, which consists in An 11-ketone with a protected keto group is reacted with methylmagnesium iodide, as a result of which the bromine atom is replaced by a methyl group. The proposed method differs from the well-known one in that CHsZ is used as the methylating agent, where Z is the residue of a mineral or organic sulfonic acid, with the exception of hydrofluoric acid residue, which makes it impossible not to protect the steroid group. The proposed method produces steroid derivatives, which are intermediate products for the synthesis of substances with high physiological activity. A method is proposed for the preparation of 9a-methyl 11-keto-17-ethylene ketals of steroids of general formula I25 e RI denotes hydrogen or alkyl upra with 1 or 2 carbon atoms, R2 denotes an alkyl group with 1-4 carbon atoms, which consists of

where Ri and RZ have the specified value, subjected to the exchange reaction with the compound of the formula III

CHsZ

where Z is the acidic residue of a mineral or organic sulfonic acid, with the exception of a hydrofluoric acid residue, in the presence of a strong base, and the resulting desired product is isolated by known techniques.

As compounds of structure III, methyl chloride, methyl bromide, methyl iodide, methyl arylsulfonates, for example methyl p-toluenesulfonate, and methylalkylsulfonates, for example methyl methanesulfonate, can be used for this exchange reaction.

Compounds of structure IV may be used as strong bases.

MA

where M denotes an alkali metal, for example sodium or potassium, and A represents hydrogen, an alkoxy group with 1-6 carbon atoms or NH2 or -CHa-Z3-CH3-group.

The reaction of the exchange of compounds of structure I with compounds of structure III is carried out in an atmosphere of inert gas, for example nitrogen, and in an inert organic solvent, for example treg-butanol or methyl sulfoxide. Instead of the solvent, a 10 to 200-fold excess of compounds of structure III can be consumed if the compounds of structure III are liquid. Methyl iodide is the preferred compound of structure III, and tertiary potassium butyllate is used as the base of structure III.

The reaction can be carried out at a temperature of from -10 to. The reaction mixture is cooled with ice and then allowed to temperature to rise to room temperature.

Example. 17-Ethylenedioxy-3-methoxy-9-methylestra-1; 3.5 (10) -trien-11-one.

A. 17-Ethylenedioxy-1 lp-hydroxy-3-methoxy-estra-1, 3.5 (10) -triene.

A mixture consisting of 15 g of 17-ethylenedioxyestra-1, 3.5 (10) -triene-3,11p-diol, 30 g of anhydrous potassium carbonate, 75 ml of methanol and 60 ml of methyl iodide is boiled for 3 hours while stirring reflux condenser. Then the mixture is cooled and diluted with 200 ml of water. Methanol and methyl iodide are removed under vacuum and the aqueous residue is extracted twice with methylene chloride. The combined organic extracts are washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After removal of the solvent, a residue is obtained which is recrystallized from diethyl ether. 17-ethylenedioxy-1 lp-oxy-3-metoxycaster-l, 3.5 (10) -triene is obtained, which melts between 125 and 126 ° C.

B. 17 - Ethylenedioxy - 3 - methoxyestra1, 3,5 (10) -trien-11-one.

To a solution of 5.13 g of 17-ethylenedioxy-11p-oxy3-metxyestra-1, 3.5 (10) -triene in a mixture of 25 ml of sulfur dioxide methyl and 25 ml of benzene were added 3 ml of pyridine and 9.3 g of M, S -dicyclohexylcarbodiimide. This mixture is then cooled and 1.5 ml of dichloroacetic acid is added to it. Stir the mixture for an hour and a half at room temperature. The mixture is then diluted by adding 50 ml dropwise.

diethyl ether and a solution of 4 g of oxalic acid in 10 ml of methanol. Stir the resulting suspension for 40 minutes at room temperature and then filter. The filtrate is evaporated to dryness and the residue is distributed between methylene chloride and 10% aqueous sodium bicarbonate solution. The organic phase is separated, washed with water and dissolved over sodium sulfate and evaporated to dryness under reduced pressure.

The residue is chromatographed using a silica gel column, and chloroform is used as eluant, to which several parts of methanol are added. The combined fractions obtained by elution with chloroform containing 5% methanol were evaporated to dryness. The resulting residue is recrystallized from a mixture of hexane and diethyl ether (1; 1). The resulting 17-ethylenedioxy-3-methoxyestra-1, 3.5 (10) -triene - 11on melts between 122 and 123 ° C.

B. 17-Ethylenedioxy-3-methoxy-9a-methyl estra-ra-1,3,5 (10) -trien-11-one.

To a stirred and ice-cooled solution of 10.5 g of 17-ethylenedioxy-Zmetoxyestra-1, 3.5 (10) -trien-11-one in 300 ml of methyl iodide was added under nitrogen atmosphere over 10 minutes 120 ml 1.1 AV solution of tertiary potassium butylate in tertiary butyl alcohol. The temperature is then allowed to rise to room temperature and the mixture is stirred for 18 hours, then the mixture is poured into 500 ml of water and extracted twice with methyl chloride. Wash the combined organic extracts with water and dry them over sulfate.

on three . After removal of the solvent, an oil is obtained which is recrystallized from diethyl ether. The resulting 17-ethylenedioxy-3-methoxy-9a-methylestra-1,3,5 (10) -triene-U-QH melts at 142 and 145 ° C.

„

Subject invention

The method of obtaining 9a-methyl-11-keto-17-ethylene ketals steroids of General formula I

CH.

where RI denotes hydrogen or an alkyl 65 group with 1 or 2 carbon atoms.

R2 denotes an alkyl group with 1-4 carbon atoms,

characterized in that the compounds of formula II

where RI and RT have the above value, subjected to the exchange reaction with the compound of the formula III

CHsZ,

where Z is the acidic residue of a mineral or organic sulfonic acid, with the exception of a hydrofluoric acid residue, in the presence of a strong base, and the resulting desired product is isolated by known techniques.