DE2106753C3 - Sterically directed process for the production of estatrial compounds with a natural configuration - Google Patents

Description

where R - O; OH; OCOCH ₃ ; Ri = CH ₃ ; C ₂ H 1 -C ₃ H ₇ ; R ₂ = H, CH ₃ , COCH ₃ ; π = I or 2, characterized in that 1,3,5 (10), 8 (9) -estratetraene compounds of the general formula:

(CH ₂ ),

where R = O; OH; OCOCH ₃ ; R, = 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:

(CH ₂ ) ,,

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

The proposed method is used in the synthesis of the female sex hormone d- and d, l-östra-3,17 /? - 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 the Synthesis of 19-nor-steroids. contraceptive preparations and anabolic steroids, which are used as growth substances in farm animals.

A process for the sterically directed reduction of the styrene-i ⁸ · ⁹ ) double bond in estran compounds with a natural configuration is currently known. This procedure is applicable for the

where R = OH; R, = CH ₃ ; C ₂ H ₅ ; nC ₃ H ₇ ; R ₂ = CH ₃ ; η = 1 or 2
The method consists in that the cleaned and dried ammonia with stirring at a temperature of -60 to - the output l, 3,5 (10), 8 (9) -östratetraenverbindungen in a mixture of tetrahydrofuran with ether adding 70 ⁰ C , then add potassium in portions, the reaction mixture is kept at a temperature of -60 to -70 ° C. for 1.5-2 hours, after which ammonium chloride is added in portions. 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 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 C ^ contain. 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.

(CH ₂ L

ORj-

where R = O; OH: OCOCH ₃ ; Ri = CH i; C ₂ H; n-CjH ₇ :

R ₂ = H; CHi; COCH ₃ ; π =; ^: 1 or 2 are, according to the invention, 13.5 (10) £ (9) -estratetraene compounds of the general formula:

OR

(CH ₂ ) ,,

where R = O; OH; OCOCH ₃ ; Ri = CHj; CiH _s: nC ₃ H ₇ ; Ft _? = H; CH ₃ ; COCH ₃ ; π = 1 or 2, the reduction unit is subjected to a mixture of trifluoroacetic acid with trietbylsilane 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 133 (10), 8 (9) -ostratetraene compounds, tri- (luoroacetic acid and triethylsilane from 1:20 to 50:20.

For the preparation of estriene compounds of the general formula

(CH ₂ ),

where R = O; OCOCHj; R, = C ₂ H ₅ ; nC ₃ H /; 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 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

where R ^ = H; CHj; 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 successively with benzene and chloroform. Washing of the extract obtained with 5 - 10 ° / cent sodium bicarbonate solution, evaporation of the solvent and saponification with sodium borohydride in methanol or 5% methanolic alkali solution at 40 ⁰ C and treatment of the reaction mixture with 2% acetic acid, with separation of the crystallized end product for the production of oestradiol - 3.170-3-methyl ethers one reduces the 4 * ⁹ > -Dehydroestrone-3-methyl ether with a mixture of

Trifluoroacetic acid and triethylsilane, which are in a molecular ratio of 1; 50:20 to be taken under boiling. _;

The process according to the invention is carried out as follows: Triethylsilane and trifluoroacetic acid, preferably at a molecular ratio of 1:20-30: 20, are added to a solution of starting 1,3,5 (10) 3 (9j-estratetraene compound in methylene chloride or benzene is maintained without stirring at a temperature of 20 ⁰ C during 3 to 48 hours, depending on the structure of the output 13 ^ (10) £ (9) -Östratetraenverbindung. the separation of the final product depending on the structure of the output 13 , 5 (10) 3 (9) -östratetraenverbindea If one of the reduction 17-keto or 17- or 17a-O-acyl-13 ^ (10), 8 {9) -Östratetraenverbindungen subjects, the reaction mixture is poured into Ice water, extracted successively with benzene and chloroform, washes the extract with aqueous sodium bicarbonate solution and, after evaporation of the solvent, receives the end product. If the reduction is subjected to 17- or ^ a-hydroxy-estratriene compounds, 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 , the solvent evaporates. saponified to Rücksund with sodium borohydride in methanol or with 5% methanol solution of alkali at a temperature of 40 ⁰ C, the reaction mixture was treated with 2% acetic acid and separated from the crystallized product.

The process according to the invention also allows a simultaneous sterically directed reduction of the JW-styrene double bond and the 17-keto group in the starting 1,3,5 (10), 8 (9) -estratetraene compound. So you can z. B. from the ^ * ⁹ > -Dehydroöstron-3-methyläther östratrien-3,17 /? - diol-3-methylether by reduction with a mixture of triethylsilane and trifluoroacetic acid in an inert solvent (benzene, Methylencnlorid) with boiling and subsequent treatment the reaction mixture obtained with I- ^ water and extraction of the end product.

The method according to the invention makes it possible to simplify the technology of the process. because the process can be carried out at a temperature of 20 ^° C. and the need for adsorption chromatography is eliminated.

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 is applicable to 13,5 (10), 8 (9) -estratetraene compounds, which amCu or Cw · a keto or ester group R = O; OCOCH ₃ ) 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-l, 3.5 (10), 8 (9) -ostratetraen-3-ol-17-one with melting point 252-254 ° C. are dissolved in 120 ml

absolute benzene to which 12 ml triethylsilane contains the mixture is one 5.8 ml TriftuoressigsS.ure to and leaves at a temperature of 20 ⁰ C for 48 hours standing. The mixture is poured into water and extracted successively with benzene and chloroform. The extract is washed with 5-10% strength aqueous sodium bicarbonate solution and evaporated. The residue was washed>] nan with ether and received 900 mg (75 wt .-% of theory) of 18-nor-13-ethyl-oestrone with melting point 228-23 ° C that no depression of the melting point with that obtained by the known process provides sample is separated from the mother liquor an additional 150 mg of less pure product with mp. 215-225 ° C and 70 mg of mp. 195-220 C. ^c.

Example 2

1.7 g of 18-Nor-13-propyl-U, 5 (10), 8 (9} -östratetraen-3-ol-17-one with mp. 231-237 ⁰ C. is dissolved in 85 ml of absolute benzene to which 15 ml of triethylsilane are added to the mixture, 6 ml of trifluoroacetic acid are added and the mixture is left to stand for 48 hours at a temperature of 20 ° C. The process is then carried out analogously to Example 1. 1.2 g (70% by weight) are obtained. % of theory) 18-nor-13-n-propylestrone, m.p.

220-226 ° C. An additional 50 mg of end product are separated from the mother liquor. 195-210 ^: C, ab.

Example 3 Example 4

500 mg / d ^ 'i-dehydrol-D-homoiistradiol is dissolved in 80 ml of absolute benzene which contains 0.95 ml of triethylsilane. The solution is poured in t ml of trifluoroacetic acid and allowed to stand at 20 ° C. for 24 hours . Furthermore, the process is analogous to Example 3 performed is obtained 260 mg of crystalline product with mp. 199-204 ⁰ C of which, after the

■ ο 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 " 278355 mu, ε 2550; 64) judging.

Contains 2% by weight of D-homoequilenol, which is characterized by Can not separate crystallization

Example 5

500 mg ^ W-dehydroestradiol-S-methyl ether dissolves one in 25 ml of benzene containing 5 ml of triethylsilane.

2.4 ml of trifluoroacetic acid are added to the solution and

leaves at a temperature of 20 ° C for 3 hours stand. In the following, the process is carried out analogously to Example 4. 300 mg (60% by weight

:> the theory) östra-3,17 /? - diol-3-methyl ether with m.p.

129-131 ° C, with no depression of the melting point with the sample obtained by the known method.

200 mg of d ^ 't-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 are filtered off and 120 mg (60% by weight of theory) of D-homoestradiol are obtained. Mp 203-207 ° C. which does not result in a depression of the melting point with the sample obtained by the known method.

Example 6

1 g of <d8C) dehydroostrone-3-methyl ether 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% caustic potash solution irr methanol au ^f 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% by weight of theory) of estatriene-3,170-diol-3-methyl ether with a melting point of 123-127 ° C. are obtained. which does not result in a depression of the melting point with the sample obtained by the known method.

Claims (1)

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