DE2106753B2 - STERICALLY DIRECTED PROCESS FOR PRODUCING OESTRATRIAL CONNECTIONS WITH NATURAL CONFIGURATION - Google Patents

Description

(CH ₂ ) _n

where R = O; OH; OCOCH ₃ ; Ri = CH ₃ ; C ₂ H ₅ ; nC ₃ H ₇ ; R ₂ = H; CH ₃ ; COCH ₃ ; π = 1 or 2 are subjected to reduction with a mixture of trifluoroacetic acid with triethylsilane in the medium of an inert organic solvent and then the end product is separated off.

The present invention relates to a sterically directed process for the preparation of Estratriene compounds with natural configuration of the following general formula:

where R = O; OH; OCOCH ₃ ; R, = CH ₃ ; C ₂ H ₅ ; nC, H ₇ ; R ₂ = H; CH ₃ ; COCH ₃ ; n = 1 or 2.

The proposed method is used in the synthesis of the female sex hormone d- and d, l-oestra-3,17 / 9-diol and its analogues, which are described in the Medicine for the treatment of diseases of the genital sphere, atherosclerosis and tumor diseases be used. In addition, the method according to the invention is used in Synthesis of 19-nor-steroids, contraceptive preparations and anabolic steroids, which act as growth substances farm animals are used.

It is currently a process for the sterically directed reduction of the styrene-zJW double bond known in estran compounds with natural configuration. This procedure is applicable for the

where R = O; OH; OCOCH ₃ ; Ri = ₃ J ₂₅ J R ₂ = H; CH ₃ ; COCH ₃ ; π = ί or 2, characterized in that 1,3,5 (10), 8 (9) -östratetraenverbindungen of the general formula:

where R = OH; Ri = CH ₃ ; C ₂ H ₅ ; nC ₃ H ₇ ; R ₂ = CH ₃ ; η = 1 or 2.

The process consists in adding the starting 1,3,5 (10), 8 (9) -Östratetraenyerbindungen in a mixture of tetrahydrofuran with ether to the purified and dried ammonia with stirring at a temperature of -60 to -70 ° C , then portionwise added potassium, the reaction mixture at a temperature from -60 to -70 ⁰ C during 1.5-2 hours stops, after which portions Ammoniumchiürid is added. After the ammonia has evaporated, the residue is treated with water, extracted with ether, the extract is neutralized with carbonic acid, washed with water, dried and evaporated. After the solvent has been distilled off, the product obtained is crystallized or subjected to purification by adsorption chromatography (Belgian patent specification No. 6 32 345; copyrights

of the USSR No. 1 30 368, No. 1 57 056).

However, the known method has a number of disadvantages. It is not applicable in the case of the compounds which contain a hydroxyl group (R _{2 = H) at C 3} , as well as in the case of the compounds

which contain a keto or ester group (R = O; OCOCH ₃ ) on Q ₇ or Q _7a. The process requires a large amount of ammonia of high purity and highly flammable solvents (ether, tetrahydrofuran). The process requires a high degree of purity for all reagents, an underestimation of this fact leading to irreproducible results or to a reduction in the yield of the end product. A disadvantage of the method is the complicated apparatus design ^{required to maintain a temperature of -60 to -7O 0} C, as well as the complicated technology, which in some cases includes chromatographic purification on aluminum oxide using larger amounts of highly flammable solvents.

The aim of the present invention is to eliminate the disadvantages mentioned.

In accordance with the aim, the task was set by changing the technological operations to simplify the technology of the process and its equipment design.

This object has been achieved in that one in the sterically directed process for the preparation of estatriene compounds of the natural configuration of the general formula:

R.

where R = O; OH; OCOCH ₃ ; R, = CH ₃ ; C ₂ H ₅ ; HC ₃ H ₇ ;

R ₂ = H; CH ₃ ; COCH ₃ ; η = 1 or 2, 1,3,5 (10), 8 (9) -Östratetraenverbindungen according to the invention of the general formula:

(CH ₂ ).

whereR = 0; OH; OCOCH ₃ ; R ₁ = CH ₃ ; C ₂ H ₅ ; nC ₃ H ₇ ; R ₂ = H; CH ₃ -, COCH ₃ ; π = 1 or 2 are subjected to reduction with a mixture of trifluoroacetic acid with triethylsilane in the medium of an inert organic solvent and then the end product is separated off.

Benzene or methylene chloride is expediently used as the inert organic solvent. Man expediently carries out the process at a molecular ratio of 1,3,5 (10), 8 (9) -Östratetraenverbindungen, trifluoroacetic acid and triethylsilane from 1:20 to 50:20.

For the production of estratriene compounds of the general formula

(CH ₂ ) "

where R = O; OCOCH ₃ ; R, = C ₂ H ₅ ; nC ₃ H ₇ ; η = 1 or? the process of separating off the end product is carried out by treating the reaction mixture with ice water, extracting the end product successively with benzene and chloroform, washing the extract with 5-10% aqueous sodium bicarbonate solution and evaporating the solvent.

For the production of estatriene compounds of the general formula

OH

45

(CH,

where R ₂ = H; CH ₃ ; η = 1 or 2, the process of separating off the end product is carried out by treating the reaction mixture with ice water, extracting the 17- or 17a-trifluoroacetate of the end product in succession with benzene and chloroform, washing the extract obtained with 5-10% sodium bicarbonate solution, evaporation of the solvent and saponification with sodium borohydride in methanol or 5 ° / cent methanolic alkali solution at 4O ⁰ C and treatment of the reaction mixture with 2% acetic acid with removal of the crystallize out (15 overbased final product for preparing the estradiol 3.170-3-methyl ether reduced to the deW dehydroestrone-3-methyl ether with a mixture of trifluoroacetic acid and triethylsilane, which are taken in a molecular ratio of 1:50:20, with boiling.

The process according to the invention is carried out as follows. Triethylsilane and trifluoroacetic acid are added to a solution of starting 1,3.5 (10), 8 (9) -estratetraene compound in methylene chloride or benzene, preferably at a molecular ratio of 1:20-50:20. The reaction mixture is kept without stirring at a temperature of 20 ^° C. for 3 to 48 hours, depending on the structure of the starting 1,3,5 (10), 8 (9) -estratetraene compound. The separation of the end product differs depending on the structure of the starting 1,3,5 (10), 8 (9) -estratetraenic compound. If 17-keto- or 17- or 17a-O-acyl-1,3,5 (10), 8 (9) -estratetraene compounds are subjected to the reduction, the reaction mixture is poured into ice water, extracted successively with benzene and chloroform, washed the extract with aqueous sodium bicarbonate solution and the end product is obtained after evaporation of the solvent. If 17- or 17a-hydroxy-estatriene compounds are subjected to the reduction, the reaction mixture is treated with ice water, then the 17- or 17a-trifluoroacetate of the end product is extracted successively with benzene and chloroform, the extract is washed with 5-10% aqueous sodium bicarbonate solution, if the solvent evaporates, the residue is saponified with sodium borohydride in methanol or with 5% strength methanol solution of alkali at a temperature of 40 ^° C., the reaction mixture is treated with 2% strength acetic acid and the crystallized product is separated off.

The process according to the invention also allows a simultaneous sterically directed reduction of the J ^ '- styrene double bond and the 17-keto group in the starting 1,3,5 (1O), 8 (9) -estratetraene compound. So you can z. B. from the jdW-Dehydroostron-j-methyl ether Estratriene 3.17 /? - diol-3-methyl ether by reduction with a mixture of triethylsilane and trifluoroacetic acid in an inert solvent (Benzene, methylene chloride) with boiling and subsequent treatment of the reaction mixture with ice water and extracting the final product.

By the inventive method, it is possible to simplify the technology of the process because the process can be carried out at a temperature of 2O ⁰ C and the necessity of wegfallt Adsorptionschromaiographie.

The process according to the invention is simple in terms of apparatus design compared with the known process, because it does not require any cooling apparatus, any highly flammable alkali metals and solvents. The method can be used for 1,3,5 (10), 8 (9) -östratetraenverbindungen, which on Cu or C _{) 7a} a keto or ester group R = O; OCOCH3) included. The method according to the invention has a high stereospecificity.

The invention also relates to the new compounds according to the invention.

In order that the present invention may be better understood, the following examples of its operation are shown below of the sterically directed process for the production of estatrial compounds with natural Configuration listed.

example 1

1.2 g of 18-nor-13-ethyl-1,3,5 (10), 8 (9) -östratetraen-3-ol-17-one with melting point 252-254 ° C., is dissolved in 120 ml

absolute benzene which contains 12 ml of triethylsilane. 5.8 ml of trifluoroacetic acid are added to the mixture and the mixture is left to ^{stand at a temperature of 20 °} C. for 48 hours. The mixture is poured into ice water and extracted successively with benzene and chloroform. The extract is washed with 5-10% aqueous sodium bicarbonate solution and evaporated. The residue is washed with ether and 900 mg (75% by weight of theory) of 18-nor-13-ethyl-oestrone with a melting point of 228-231 ° C., which does not reduce the melting point with the sample obtained by the known method, are obtained supplies. From the mother liquor is separated additional 150 mg of less pure product with mp. 215-225 ° C and 70 mg of mp. 195-220 ⁰ C..

Example 2 Example 4

500 mg of zl ^ J-dehydrol-D-bomoestradioI are dissolved in 80 ml of absolute benzene which contains 0.95 ml of triethylsilane. The solution is poured into one 1 ml of trifluoroacetic acid and leaves at a temperature of 2O ⁰ C door for 24 hours. In the following, the process is carried out analogously to Example 3. 260 mg of crystalline product with a melting point of 199-204 ° C. are obtained, from which, according to the

ίο Crystallization from methanol separates 170 mg of D-homoestradiol with melting point 207-212 ° C, which does not result in a depression of the melting point with the sample obtained by the known method, but according to the UV spectrum {y _m , _K 278.355 ΐημ, ε 2550; 64) to judge, contains 2% by weight D-homoequilenol, which cannot be separated off by crystallization.

1.7 g of 18-nor-13-propyl-1,3,5 (10), 8 (9) -ostratetraen-3-ol-17-one with melting point 231-237 ° C. are dissolved in 85 ml of absolute Benzene, which contains 15 ml of triethylsilane. 6 ml of trifluoroacetic acid are added to the mixture and the mixture is left to ^{stand at a temperature of 20 °} C. for 48 hours. The process is then carried out analogously to Example 1. 1.2 g (70% by weight of theory) of le-nor-on-propylestrone, mp.

220 -226 ⁰ C. From the mother liquor separated is additionally 50 mg of final product, mp. 195-210 ⁰ C, from.

Example 3

200 mg of zl ^ l-dehydro-D-homoestradiol diacetate are dissolved in 10 ml of absolute benzene which contains 2 ml of triethylsilane. 2.5 ml of trifluoroacetic acid are poured into the solution and the mixture is left to ^{stand at a temperature of 20 °} C. for 48 hours. The mixture is poured into ice water, extracted with benzene and chloroform. The extract is washed with 5-10% aqueous sodium bicarbonate solution and evaporated. The residue is dissolved in 16 ml of methanol, 1 g of sodium borohydride in 24 ml of methanol is added and the mixture is stirred at a temperature of 40 ^° C. for 4 hours. The mixture is poured into 2% acetic acid, the precipitated crystals were filtered off to give 120 mg (60 wt .-% of theory) of D-Homoöstradiol, mp. 203-207 ⁰ C, which no depression of the melting point with the known in the Method provides sample obtained.

Example 1 5

500 mg of zl ^ -dehydroestradiol ^ methyl ether is dissolved in 25 ml of benzene which contains 5 ml of triethylsilane. 2.4 ml of trifluoroacetic acid are added to the solution and the mixture is left to stand ^{at a temperature of 20 ° C. for 3 levels.} The process is then carried out analogously to Example 4. 300 mg (60 wt .-% of theory) of estra-3,170-diol-3-methyl ether with mp. 129-131 ⁰ C, which provides no depression of the melting point with that obtained by the known process sample.

Example 6

1 g of ^ 'l-Dehydroöstron ^ -methylälher is dissolved in a mixture of 10 ml of dry benzene and 10.7 ml of triethylsilane. 13.1 ml of trifluoroacetic acid are added to the solution and the mixture is boiled for 2.5 hours. The reaction mixture is poured into an aqueous sodium bicarbonate solution with ice, and the product obtained is extracted with benzene and then with chloroform. The extract is washed with water and evaporated. The residue is dissolved in 20 ml of 5% strength caustic potash solution in methanol and boiled for 0.5 hours. The mixture is poured into cold water and the product extracted with benzene. The extract is washed with dilute hydrochloric acid, then with water and evaporated. The crystalline residue is washed with methanol, and 610 mg (60 wt .-% of theory) Östratrien-3,17jS-diol-3-methyl ether with mp. 123- 127 ^C C. the no depression of the melting point with the known in the Method provides sample obtained.

Claims (1)

Claim: Sterically directed process for the preparation of estatriene compounds of the natural configuration of the general formula: Manufacture of estatrial compounds of general Formula: