DE1280248B - Process for the preparation of mixtures from 17ª ‡ -Chloraethinylsteroiden - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

German class:

Number:
File number:
Registration date:
Display day:

C 07 c

12 ο -25/04 25/07

P 12 80 248.1-42 (M 61674)

April 17 , 1961

17th October 1968

The invention relates to a process for the preparation of mixtures of ha-chloroethinyl steroids of the general kind formula

OR '

- C = CCl.

in which R 'denotes a tetrahydropyranyl radical and R "denotes an alkylene radical with up to 7 carbon atoms, which is characterized in that 17α-ethynyl-19-nor-4-androsten-17β-ol-3-one in a manner known per se with an alkylene glycol containing no more than 7 carbon atoms or converted into the 3-ethylenedioxy derivative by exchange dioxolanization, the resulting mixture of corresponding Δ ⁵ - and / t ^{5 (10)} -3-alkylenedioxy-l 7a-äthinyl-19-nor- androstene-17 / i-ols with dihydropyran in the presence of an acidic reagent, in particular p-toluenesulfonyl chloride, etherified in a manner known per se and the resulting mixture of corresponding and zl ^{5 (10)} - 3 - alkylenedioxa - 19 - nor - androstene-17 / i-ol-tetrahydropyranyl ether is chlorinated by reaction with tertiary butyl hypochlorite in the presence of a tertiary alcohol.

ι- C ξ CH Process for the preparation of mixtures from 17a-chloroethinyl steroids

Applicant:

Merck & Co., Incorporated,

Rahway, N. J. (V. St. A.)

Representative:

Dr.-Ing. W. Abitz and Dr. D. Morf, patent attorneys,

8000 Munich 27, Pienzenauer Str. 28

Named as inventor:

Arthur Eugene Oberster, North Canton, Ohio; Roger Eldon Beyler, Carbondale, JIL; Lewis Hastings Sarett,

Princeton, N.J. (V. St. A.)

Claimed priority:

V. St. v. America April 20 , 1960 (23394)

The new compounds are valuable as intermediates for the production of 21-chloro-norethisterone, which has high progestational activity.

The method according to the invention can be represented by the following equation:

HO

Stage la

C = CH

'Level Ib

II-A

809 627/1415

Stage Ib.

CH

Level 2

II-B

III

vaporizes and deliver a mixture of the in 5-position and the 17a-ethynyl-3-ethylenedioxy-19-nor-androsten-17 / S-ol unsaturated in the 5 (10) position.

To a solution of all of the raw material obtained from the above reaction in 10 ml of dihydropyran (distilled over metallic sodium) are added with stirring 120 mg of p-toluenesulfonyl chloride and continue stirring at room temperature

The compound I is the 17a-ethynyl-19-nor-4-an- i ₅ dried and evaporated in vacuo. The so drosten-17 /? - ol-3-on. The compounds II-A / II-B and the residue obtained is chromium-coated on aluminum oxide

III consist of mixtures of A ⁵ - and zl ^{S (10)} -anomatographed, whereby the mixture of the ent-

drostenen. This is given by the dashed lines speaking 21-chloro steroid compounds, between the carbon atoms C ₅ and C ₁₀ or C ₆

indicated. ₂₀ example

According to a preferred embodiment of the invention, the 3-keto group of the starting material is added to a solution of 1 g of 17a-ethynyl-19-nor-4-and drosten-17 / J-ol-3-one in 75 ml of benzene by reaction with excess ethylene glycol one 7.5 ml in benzene, toluene or ethylene dichloride as a solution ethylene glycol together with 50 g of p-toluenesulfonic agent in the presence of an acidic catalyst such as 25 acid. The reaction mixture is heated under reflux for 20 hours to p-toluenesulphonic acid or sulfuric acid, in the 3-ethy boilers, a water / iendioxide group being converted, this being used as a secondary separator. The water formed in the reaction mixture is continuously removed. is cooled, 10 ml of bicarbonate solution are added. The 3-keto group can also be extracted by exchange and three times with 100 ml of ether each time. The dioxolanation in the 3-ethylenedioxy derivative overgrown extracts are washed with water, are carried over, the ethylene glycol portion of a sodium sulfate is dried and 2,2-dialkyldioxolanes simple to dryness, such as 2,2-dimethyl-1,3- dioxolane (acetone ethyl ketal) or preferably 2-methyl-2-ethyl-1,3-dioxolane (butanone ethyl ketal)
the implementation with the ketones either in a 35
inert solvents, such as benzene, or simply in
an excess of the reagent in the presence of
acid catalyst is transferred.

The 17,8-hydroxy group is created by reaction

with dihydropyran in the presence of an acidic reagent, 4 ° for another 64 hours,

such as p-toluenesulfonyl chloride, in the corresponding After adding 10 ml to the reaction mixture

Tetrahydropyranylether transferred. This unsaturated sodium bicarbonate solution is extracted

settlement takes place e.g. B. when adding p-toluenesulfonyl three times with 50 ml of ether each time. The extracts are

chloride to a solution of the steroid in excess, washed with water and over sodium sulfate

sigem dihydropyran instead. The reaction mixture 45 dried. By evaporation in vacuo to

is stirred at room temperature for 16 to 64 hours. When dry, 3.5 g of a crude oil are obtained, which in

The product can be dissolved by neutralizing the reagent petroleum ether and activated on 100 g with acetone

tion mixture with a dilute base and fourth alkaline aluminum oxide chromatography

final extraction with ether can be obtained. is phiert. The chromatogram is

The ether extracts are washed with water, mixed 50 eluted from ether and petroleum ether. Man

dried and evaporated. The crude product is obtained 1.043 g of a mixture of the 5-position

dissolved in a 'solvent such as petroleum ether and the 17a-ethynyl which is unsaturated in the 5 (10) position

chromatographed on aluminum oxide. This gives 3-ethylenedioxy-19-nor-andΓOSten-17 / S-ol-tetrahydro-

one the corresponding tetrahydropyranyl derivative. pyranyl ether. The infrared spectrum shows bands at

In stage 2 of the method according to the invention 55 2.9 and 9.0 μ.

the above obtained, in the 3- and 17-position to a solution of 2.130 g of the mixture from

Protected steroid compound with tertiary butyl- the one in the 5-position and the one in the 5 (I0) -position un-

treated hypochlorite / After a preferred saturated na-ethynyl-S-ethylenedioxy - ^ - nor-an-

Implementation of the invention is the steroid drosten-17 / J-ol-tetrahydropyranyl ether in 50 ml dry

Binding dissolved in tertiary butyl alcohol, with potassium 60 kenem tertiary butanol is added with stirring

Treated tert-butoxide and then with the ChIo- 5.5 ml 1 molar potassium tert-butoxide solution. The Re-

ration funds implemented. The choice of the tertiary action mixture will take 90 minutes to 'boil'

Alcohol is based on practical facial reflux and then heated to room temperature

score points, such as accessibility, solubility and the like. After adding 0.95 ml of tertiary butyl-21-chloro steroid compounds If it is more appropriate to hypochlorite, the reaction mixture becomes more

wise by adding water to the reaction stirred for 16 hours at room temperature. Man

mixed and extracted with ether. The sets with 100 ml of water and extracted the aqueous

Ether extracts are then washed with water, solution with three portions of 200 ml ether each. the

Extracts are combined, washed with water, dried over sodium sulfate, filtered and under evaporated to dryness under reduced pressure. 2.2 g of crude product are obtained, which is alkaline in 100 g Aluminum oxide is chromatographed. A solution of the material in petroleum ether to which a Add a small amount of benzene, is chromatographed on aluminum oxide and with ether-petroleum ether mixtures eluted. 1.9 g of a semicrystalline product are obtained, which is a mixture of the in 5-position and the 5 (10) -saturated chloroethinyl-3-ethylenedioxy-19-nor-aridrosten-17j3-ol-tetrahydropyranyl ether represents. The infrared absorption spectrum shows bands at 4.45 μ and a strong absorption in the 9 to ΙΟ μ range.

Claims (1)

Claim: Process for the preparation of mixtures from 17a-chloroethinyl steroids of the general formulas OR ' --- C = CCl and in which R 'denotes a tetrahydropyranyl radical and R "denotes an alkylene radical with up to 7 carbon atoms, characterized in that na-ethynyl-W-nor- ^ androsten-n ^ -ol-3-one in a manner known per se with an alkylene glycol which contains no more than 7 carbon atoms, or converts it ^{into the 3-ethylenedioxy derivative by exchanging 1} · dioxolanation, the resulting mixture of corresponding OR ' - C = CCl Λ ⁵ - and yyy androstene-17j3-ols etherified with dihydropyran in the presence of an acidic reagent, in particular p-toluenesulfonyl chloride, in a manner known per se, and the resulting mixture of corresponding zl ⁵ - and J ^{5 (10)} -3-alkylenedioxy-19-nor-androstene-170 -ol-tetrahydropyranyl ether is chlorinated by reaction with tertiary butyl hypochlorite in the presence of a tertiary alcohol. M9 627/141 $ 10.6t O Bundddruckerel Berlin