DE2814048A1 - NEW STEROIDS, METHODS FOR THEIR PRODUCTION AND THEIR USE IN THE SYNTHESIS OF TRITIUM-LABELED STEROIDS - Google Patents

Description

~ ——- - - _ ».— - ίί ...... ι ii. ν. Λ

AFTER «£ REACHES

ROUSSEL-UCLAF, Paris / France

New steroids, processes for their preparation and their "use in synthesis."

of tritiated steroids

description

The present invention relates to new steroids of the general formula I.

R is hydrogen, an alkyl group with 1 to 4 carbon atoms or a tetrahydropyranyl, trityl or trimethylsilyl radical means and

R _{-1 denotes} hydrogen, an acyl radical having 1 to 5 carbon atoms or the tetrahydropyranyl radical.

If R is an alkyl group, it can, for example, be Methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl.

R ₁ is an acyl group, it may be derived from formic, acetic, _Eropion-} butyric acid or valeric acid.

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Among the products of the formula I one can mention in particular:

17a, 21-dimethyl-19-nor-pregna-l, 3,5 (10), 6-tetraene-3,20 £ -diol,

l7a, 21-dimethyl-l9-nor-pregna-l, 3,5 (10), e-tetraen-S-methoxy-20J-ol,

17a, 21-dimethyl-19-nor-pregna-1, 3,5 (10), e-tetraene-S-methoxy-20 ^ -acetoxy and ·

17a, gl-dirnethyl-ig-nor-pregna-l, 3.5 (10), 6-tetraene-3-oil-2O jacetoxy.

The products of the general formula I are used as starting materials for the synthesis of tritiated substituted ones
Steroid derivatives can be used.

The invention also relates to a method of manufacture
of the products of the above general formula I.

This method is characterized in that one

the 17a-methyl-19-nor-pregna-1,3,5 (10) -trien-3-methoxy-20-one methylation in the 21-position with the aid of methyl halide undergoes;

a reducing agent is allowed to act on the obtained l7a, 21-dimethyl-l9-nor-pregna-l, 3,5 (10) -trien-3-methoxy-20-one,
to obtain the 17ä, 21-dimethyl-19-nor-pregna-1,3,5 (10) -trien-3-methoxy-2oi-ol;

subjecting the latter to the action of lithium in ammonia according to the Birch reaction;

the obtained 17a, 21-diraethyl-19-nor-pregn-5 (10) -en-2o | -ol-3-one with the help of a strong acid with formation of 17a, 21-diethyl-19-nor-pregn-4-en-2o | -ol-3-one isomerized;

the latter from the action of an esterifying or etherifying agent undergoes;

to the obtained l7a, 2l-dimethyl-19> -nor-pregn-4-en-2o | -R ₁ 0-3-one, in which Rv has the meanings given above,

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allows a halogenating agent to act and the 2,6-dihalogeno-17a, 21-dimethyl-19-nor-pregn-4-en-20fc-R. ^ O-3-one receives;

of the latter, preferably using one Alkali metal halides in dimethylformamide, hydrogen halide splits off;

the hydroxyl function in the 3-position of the obtained 17a, 21-dimethyl-19-nor-pregna-1,3,5 (10), 6-tetraen-3-ol-20 \ -R «p of the formula I with the aid of a compound selected from the .. Blocked alkylating agents, dihydropyran, trityl chloride and trimethylsilyl chloride;

the product of the general formula I in which R is an alkyl group with 1 to 4 carbon atoms or one of the tetrahydropyranyl, trityl or trimethylsxlyl radicals and R ^ is an acyl radical with 1 to 5 carbon atoms or the tetrahydropyranyl radical, on which product of the formula I the hydroxyl function in the 20 ^ position is optionally released by the action of a base or an acid in order to obtain the product of the general formula I, in which R has the meanings given above and R _{1 is} hydrogen, on which the hydroxyl function in 3 -Position is released by the action of an acid to obtain the product of general formula I, wherein R and R _{1 are} hydrogen.

Among the preferred operating conditions is that of the invention Process characterized by the following features:

The methylation in the 2! Position is carried out with the help of methyl iodide in the presence of a tertiary base, such as potassium tert-butoxide, carried out, and one works in toluene;

that used to reduce the keto function in the 20-position The reducing agent is an alkali borohydride such as that of sodium;

the Birch reaction takes place in the presence of ethanol;

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during the isomerization of the 5 (10) double bond in the strong acid used is hydrogen chloride acid, and one works in methanol; the esterifying agent for the hydroxyl function in the 2o | position is a functional derivative of acetic acid, like acetic anhydride, in pyridine, and the etherifying agent for the The hydroxyl function in the 2o £ position is a dihydropyrane

the halogenating agent is bromine in acetic acid, and one works in ether;

the alkali metal halide, with the help of which one carries out dehalogenation performs is lithium chloride;

the means by which the hydroxyl function in 3-position blocked, dimethyl sulfate is in the presence of Caustic soda, dihydropyran, trityl chloride or trimethylsilyl chloride;

the base, with the help of which the hydroxyl function in the 20 j position releases is alcoholic potassium hydroxide or caustic soda;

the acid which is used to liberate the hydroxyl function in the 20 i position is aqueous acetic acid;

the acid, with the help of which the hydroxyl function in 3-position liberates is aqueous acetic acid or a hydrochloric acid, such as hydrochloric acid.

The invention also relates to the following compounds as new industrial products:

l7a, 21-dimethyl-l9-nor-pregna-l, 3,5 (10) -trien-3-methoxy-20-one, l7a, 21-dimethyl-l9-nor-pregna-l, 3,5 (10) -triene-3-methoxy-2o £ -ol, 17a, 21-dimethyl-19-nor-pregn-5 (10) -en-2of-ol-3-one, 17oc, 21-dimethyl-19-nor-pregn-4-en-20 £ -ol-3-one, l7a, 21-dimethyl-l9-nor-pregn-4-en-20i-acetoxy-3-one and

2,6-dibromo-17α, 2l-dimethyl-19-nor-pregn-4-en-20 | -acetoxy-3-one.

BO 9 8 41/0 9 1 2

As already indicated, the products of general formula I are the starting materials for the synthesis of tritiated Steroid derivatives.

Their use as such is also the aim of the invention and is characterized in that a product of the general formula I, in which R and R have the meanings given above, is reduced by the action of tritiated hydrogen in the presence of a catalyst and the (6, 7- ³ H) -l7a, 21-dimethyl-l9-nor-pregna-l, 3,5 (10) -triene-3-O-

either when R is the methyl radical and R. is an acyl radical with 1 to 5 carbon atoms, the tetrahydropyranyl radical or hydrogen, directly to the action of lithium in ammonia in the presence of ethanol according to the Birch reaction, to when R is hydrogen or a Acyl radical

3
tet, the (6,7-H) -17a, 21-dimethyl-19-nor-pregna-2,5 (10) -diene-3-methoxy-20E-ol or, when R ₁ denotes the tetrahydropyranyl radical, that (6,7- H) ~ l7a, 21-dimethyl-l9-nor-pregna-2,5 (10) -diene-3-methoxy-20r-tetrahydropyranyloxy,

or , if R is an abovementioned radical which is different from methyl or Xtfassstoff, and R _-1 has meanings other than hydrogen, the action of an acid, such as acetic acid, or a hydrochloric acid, such as

3 hydrochloric acid, subjecting, the (6,7-H) - 17a, 21-dimethyl-19-nor-pregna-l, 3,5 (10) -triene-3-ol-20 ^ -R receives ₁ 0 which If the product is treated with a methylating agent such as dimethyl sulfate, the obtained (6,7-H) -17a, 21-dimethyl-19-nor-pregna-1,3,5 (10) -triene-3-methoxy-20 £ -R 0 subjected to the action of lithium in ammonia according to the Birch reaction in the presence of ethanol, in order, if R. is hydrogen

3 or an acyl radical, including (6,7-H) -17oc, 21-dimethyl-19-nor-pregna-2,5 (10) -diene-3-methoxy-2o £ -ol or "., If R ₁ denotes the tetrahydropyranyl radical to obtain the (6,7-H) -I7a, 21-dimethyl-19-nor-pregna-2,5 (10) -diene-3-methoxy-20 f-tetrahydropyranyloxy.

8U9841 / 0912

The invention also relates to products of the general formula as new industrial products

CH.

wherein R and R. have the meanings given above

zen, and among these in particular (6,7-H) -17oc, 21-dimethyl-19-nor-pregna-1,3,5 (10) -triene-3-methoxy-20E-ol.

These products lead in particular to (6,7-H) -l7a, 21-dimethyl-19-nor-pregna-2,5 (10) -dien-3-methoxy-2o | -ol, which is described in DE patent application P 27 55 818.5.

This product is an important intermediate in the synthesis of (6,7-H) -17oc, 21-dimethyl-19-nor-pregna-4,9-diene-3,20-dione.

According to the synthesis described in the patent application cited above, the (6,7-H) -I7a, 21-dimethyl-19-nor-pregna-2,5 (10) -dien-3-methoxy-20f-ol is allowed to react weak aqueous acid, such as acetic acid to act, the obtained (6,7 ³ H) -l7a, 21-dimethyl-19-nor-rpregn-5 (10) -en-20 ^ -ol-3-one, subjecting this latter to the action of pyridinium perbromide and leaves to the obtained (6,7- ³ H) -l7a, 21-dimethyl-l9-nor-pregna-4,9-dien-20f-ol-3-one, an aqueous chromic sulfuric acid solution to act to form the desired (6,7-H) -I7a, 21-dimethyl-19-nor-pregna-4,9-diene-3,20-dione.

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¹² "28HCK8

The (6, 7-H) - 17α, 21-Dimethy1-19-nor-pregna-4,9-diene-3,20-dione allows easy determination of the specific progesterone receptor in the uterine cytosol or in the cytoplasm of tumor cells (Blood cancer) and tumors caused by DMBA (9,10-dimethyl-1,2-benzanthracene) in the rat.

With regard to progesterone, this product has the advantage of not being fixed to the transcortin and an affinity for the above-mentioned progesterone receptor, which is 6 to 8 times higher than the affinity of the latter.

The use of (6,7-H) -17oc, 21-dimethyl-19-nor-pregna-4,9-diene-3,20-dione for the characterization of the progestogenic receptor has been described in numerous publications, such as: J.P. Raynaud and D. Philibert, Steroids, July 1973, pages 89-97.

The starting product for the process of manufacturing the products of the general formula I was described in FR-PS 1,480,247.

The following examples illustrate the invention without restricting it.

example 1

l7a, 21-dimethyl-l9-nor-preqna-l, 3.5 (10), 6-tetraene-3-methoxv-20Ιοί

Stage A: 17a, 21-dimethyl-19-nor-pregna-l, 3,5 (10) -trien-3-methoxy-20-one

126 g of potassium tert-butoxide are introduced into 1840 ml of toluene, stirs for 15 minutes at room temperature under an inert atmosphere, then brings within 15 minutes 306 g of I7a-methyl-19-nor-pregna-1,3,5 (10) -trien-20-one in 900 ml of toluene, rinsed with 300 ml of toluene, leaves the reaction mixture for 1 hour with stirring at room temperature and then cools to 0 ° C. 600 ml of methyl iodide are introduced and the reaction mixture is left 20 hours with stirring at a temperature of about

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0 ° C. 6000 ml of water are then added, the aqueous phase is separated off and extracted in several steps with chloroform. The combined extracts are washed with water, then dried over sodium sulfate and evaporated to dryness under reduced pressure. 312 g of 17oc, 21-dimethyl-19-nor-pregna-1,3,5 (10) -trien-S-methoxy- ^ O-one are obtained. This product can be purified by chromatography on silica gel eluting with a cyclohexane / benzene / ethyl acetate mixture (5 / 3.5 / 1.5), F ? 97 ° C.

The product was used as such in the following synthesis step.

Level B; l7g, 21-dimethyl-l9-nor-preqna-l, 3,5 (10) -triene-3-meth-

With stirring at room temperature, 60 g of the obtained in the previous step are added to 300 ml of ethanol and 90 ml of water Product and 17.5 g sodium borohydride. The reaction mixture is brought to reflux with stirring for about 5 hours, then cools to about 50 ° C and pours it into 900 ml of water while stirring. The crystallized product is suctioned off, washed with water and dried.

59.6 g of 17a, 21-dimethyl-19-nor-pregna-l, 3,5 (10) -triene-3-methoxy-20r-ol are obtained, which is obtained by chromatography on silica gel while eluting with a Cyclohexane / ethyl acetate mixture (7/3) cleans, P - 70 ° C. The product is used as such in the following synthesis step.

Stage C; 17g, 21-dimethyl-19-nor-preqn-5 (10) -en-2of-ol-3-one

A solution of 85 g of the product obtained in stage B is brought into 1400 ml of ammonia at -40 ° C. for 40 minutes 850 ml of tetrahydrofuran, add 42 ml of ethanol with stirring at -40 ° C. under an inert atmosphere and then for about 40 minutes 8.940 g of lithium are added and the reaction mixture is left at about -40 ° C. for 15 minutes, with stirring.

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This process of adding ethanol and lithium is repeated two more times. One then adds 127.5 ml of ethanol and the ammonia is distilled off under an inert atmosphere until the temperature reaches 15 ° C. 850 ml of water are then added and the mixture is left then rest for approx. 20 hours under an inert atmosphere at 20 C. The precipitate is filtered off with suction, rinsed with ether, and recovered the organic phases are distilled under vacuum, the residue is taken up in 85 ml of tetrahydrofuran and added to the obtained Solution 255 ml of acetic acid and leaves it with stirring for one hour at 20 C under an inert atmosphere.

The solution is poured into a water-ice-ammonia mixture, the precipitate formed is filtered off with suction, washed with water and taken it up with 850 ml of ether, dried over sodium sulfate and then evaporates to dryness under vacuum.

The residue is made into a paste with 170 ml of petroleum ether (boiling point 64-75 ° C.) while stirring, then filtered off with suction and dried. You get 70.7 g l7a, 21-dimethyl-l9-nor-pregn-5 (10) -en-2o | -ol-3-one, P * 129 ° C.

This product is used as such in the following synthesis step.

Step D: 17,21-dimethyl-19-nor-preqn-4-en-20 ^ -ol-3-one

7.85 g of the product prepared in stage C are introduced into 78.5 ml of methanol, and 7.9 ml are added to the resulting solution ln-hydrochloric acid and brings the reaction mixture approx. 1 hour to reflux.

It is cooled, the precipitate is filtered off with suction, washed with methanol and with petroleum ether (boiling point 40-70 ° C.) and dried in vacuo and receives 6.68 g of 17a, 21-dimethyl-19-nor-pregn-4-en-2o £ -ol-3-one.

The product can be chromatographed on silica gel while eluting with a methylene chloride / ethyl acetate mixture

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(9 / l) can be cleaned, F = 221 ° C.

Level E: 17g, 21-Dimethvl-19-nor-prean-4-en-205-3r.gtnyv -. ^ -

6.68 g of the product prepared in step D are introduced into 33.5 ml of pyridine and 16.5 ml of acetic anhydride and the mixture is stirred Reaction mixture for about 24 hours at 70 ° C., then poured into a mixture of 200 ml of 1N hydrochloric acid and Ice, extracted in several steps with methylene chloride, washes the extracts with 1N hydrochloric acid and with water and with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, treated with activated carbon + aluminum oxide, filtered and concentrated to dryness in vacuo.

The residue is taken up in isopropyl ether, filtered off with suction and dried in vacuo and 6.3 g of l7a, 21-dimethyl-l9-norpregn-4-en-20 <^ - acetoxy-3-one are obtained, which is obtained by chromatography on silica gel, eluting with a methylene chloride / ethyl acetate mixture (95/5) and purified by recrystallization from a methylene chloride / isopropyl ether mixture, F = 222 ° C.

Analysis; C ₃₄ H ₃₈ O ₃

Calculated: C 77.37 H 9.74%
Found: 76.9 9.7%

Step F: 2,6-dibromo-17a, 21-dimethyl-19-nor-preqn-4-en-2ofacetoxy-3-one

4.88 g of the product prepared in step E are suspended in 50 ml of ether and then slowly brought to 27 ml at about 15 ° C Bromine in 15.6% solution in acetic acid. One stirs that Reaction mixture for 15 minutes at about 15 ° C. 100 ml of methylene chloride are then added, the mixture is poured into water and washed with an aqueous sodium bicarbonate solution, then with water, dry over sodium sulfate, filter and obtain a solution of 2,6-dibromo-l7cc, 21-dimethyl-19-nor ~ pregn-4-en-20J-acetoxy-3-one, which are used as such for the following synthesis step without isolating the desired product.

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Level G: 17α, 2! -Dimethyl-19-nor-preqna-1,3, 5 (10), 6-tetraen-3-ol-20 ^ -acetoxy

Bring 4.88 g of lithium chloride in 50 ml of dimethylformamide a, heated to 120 C with the help of an oil bath, then adds a solution over a period of about 35 minutes with constant distillation of the dibromo product obtained in step F. As soon as the methylene chloride has been removed, the reaction mixture is left as it is approx. 15 minutes at 100 ° C., then allowed to cool to room temperature, add methylene chloride, pour into water, wash with a saturated aqueous sodium carbonate solution and with water, extracted with methylene chloride, dried the combined organic phases over sodium sulfate and concentrated in vacuo. The residue is taken up with methanol and passed through Purified chromatography on silica gel eluting with a methylene chloride / isopropyl ether mixture (95/5). Man this gives 2.65 g of 17a, 21-dimethyl-19-nor-pregna-l, 3,5 (10), 6-tetraen-3-ol-2o £ -acetoxy, F = 246 ° C.

Level H: 17a, 21-dimethyl-19-nor-preqna-1,3,5 (10), 6-tetraene-3-methoxy-20 Jc-acetoxy

1.92 g of the product prepared in stage F is introduced into 29 ml of methylene chloride and 19 ml of water, then 13 ml of sodium hydroxide solution is added at 20 ° C.
Tetrabutylammonium iodide too.

20 ° C 13 ml sodium hydroxide solution, 1.45 ml methyl sulfate and 190 mg

The reaction mixture is stirred for 3 hours at 20 ° C., then poured into 100 ml of 0.1N sodium hydroxide solution, extracted in several operations with methylene chloride, the organic phases are separated off, washed with hydrochloric acid and with water, dries over sodium sulfate, concentrates, adds isopropyl ether, concentrated, then cooled, filtered off with suction, washed with isopropyl ether, dried under vacuum and obtained 1.87 g of 17a, 21-dimethyl-19-nor-pregna-l, 3,5 (10), 6-tetraene-3-methoxy -20 ^ -acetoxy, F = 162 C. The product can be purified by chromatography on silica gel while eluting with a cyclohexane / ethyl acetate mixture (85 / l5) can be cleaned.

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Stage I: 17g, 21-dimethyl-19-nor-preqna-1, 3, 5 (10), 6-tetraene-3-methoxy-20% -ol

1.87 g of the product prepared in stage H and 7.5 ml of 3N ethanolic potassium hydroxide solution are added with stirring for 6 hours to reflux, then poured into 30 ml of water, extracted in several steps with methylene chloride, washes the combined extracts with hydrochloric acid and thereafter with water, dried over sodium sulfate, treated with aluminum oxide, concentrated to dryness in vacuo, the residue was taken up in isopropyl ether, cooled, and the crystallized material was filtered off with suction Product off, wash it with isopropyl ether and dry it under vacuum. 1.13 g of 17a, 21-dimethyl-19-nor-pregna-1,3,5 (10), 6-tetraen-3-methoxy-20 | -ol are obtained in crude form obtained by chromatography on silica gel with elution Purify with a cyclohexane / ethyl acetate mixture (9o / 10) can.

The purified product has a melting point of 141 ° C.

Example 2

Step A: (6,7 ³ H) -l7a, 21-dimethyl-l9-nor-preqna-l, 3,5 (IQ) -triene-3-methoxy-20-ol £

The reaction mixture is cooled with liquid nitrogen from 65 mg of 17a, 21-dimethyl-19-nor-pregna-l, 3,5 (10), 6-tetraen-3-methoxy-20fc-ol, 20 mg palladium black and 2.5 ml Ethyl acetate, then brings in under vacuum 7.95 ml of tritium with an activity of 20 Ci, then leaves the reaction mixture return to room temperature, stir for 3 hours, cool again with liquid nitrogen and recover excess Tritium, then allows the reaction mixture to return to room temperature, the catalyst is filtered off and washed with it Ethyl acetate, the filtrate is evaporated in vacuo and 65 mg of crude product are obtained in the form of a resin.

The crude product is purified by thin layer chromatography on silica gel while eluting with a methylene chloride / acetone mixture (l / l) cleaned. The eluate is then filtered off,

B "0 9 8 4 1/0 9 1 2

" ¹⁸ " 28HCH8

evaporates to dryness, the residue is taken up with a benzene / ethyl acetate mixture (lo / l) and obtained after evaporation of the Solvent 55 mg of product, Rf = 0.38, its specific Activity is 56.5 Ci / mmol.

Step B: (6,7 ³ H) -l7g, 21-dimethyl-l9-nor-preqna-2,5 (10) -diene-3-methoxy-20-ol £

To 25 ml of liquid ammonia (cooled to a temperature between -35 and -40 ° C) 55 mg (6.7-H) -17a, 21-dimethyl-19-nor-pregna-l, 3.5 (10 ) -triene-3-methoxy-20 ^ -ol in solution in 5 ml of tetrahydrofuran and 0.5 ml of ethanol and then brings 200 mg of lithium in small portions. The reaction mixture is stirred for 1 hour at about -35 ° C. and 10 ml of ethanol are then slowly added. The ammonia is then removed by allowing the reaction mixture to return to room temperature again, 50 ml of water are added and the mixture is extracted in several steps with benzene, the organic phase is dried over sodium sulfate, evaporated to dryness in vacuo and 55 mg (6.7 - ³ H) -l7a, 21-dimethyl-19-nor-pregna-2,5 (10) -dien-3-methoxy-2o £ -ol in the form of a resin, which is used as such for the following step for the synthesis of (6,7-H) -17oc, 21-dimethyl-19-nor-pregna-4,9 (10) -diene-3,20-dione was used.

The product obtained can be chromatographed on silica while eluting with a benzene / ethyl acetate mixture (10 / l) to be cleaned. Rf = 0.38.

This product is identical to that in the DE patent application P 27 55 818.5 described identically.

8Ö9841 / 0912

Claims (1)

Dr. F. Zumstein Sr. - Dr. E. Ass-manr. - Dr. R. Koenigsberger Dipl.-Phys. R. Holzhauer - Dipl.-InQ. F KlipQse'sen - Lc * F. Zumstein jun. PATENT LAWYERS 800O Munich 2 · Bräuhausstrasse 4 · Telephone collective no. 22 5341 · Telegrams Zumpat ■ Telex 529979 14/9 θ / Ν Cas 1790 D 28U0AB Claims 1. Steroids of the general formula I CH. (I) wherein R is hydrogen, an alkyl group with 1 to 4 carbon atoms or a tetrahydropyranyl, trityl or trimethylsilyl radical and R ^ hydrogen, an acyl radical with 1 to 5 carbon atoms or denotes the tetrahydropyranyl radical. 2. Any of the compounds of Formula I with the following designations: 17a, 21-dimethyl-19-nor-pregna-l, 3,5 (10), 6-tetraene-3, diol 17a, 21-dimethyl-19-nor-pregna-1,3,5 (10), 6-tetraen-3-methoxy-20i-ol 809841/0912 INSPECTED -2- 2 Ö 1 4 G 4 H 17α, 21-dimethyl-19-nor-pregna-1,3,5 (10), 6-tetraene-3-methoxy-20E-acetoxy and 17α, 21-dimethyl-19-nor-pregna-1,3,5 (10), 6-tetraen-3-ol-20t-acetoxy. 3. Process for the preparation of products according to claim 1 or 2, characterized in that one 17cc-methyl-19-nor-pregna-l, 3, 5 (10) -trien-3-methoxy-20-one methylation in the 21-position with the aid of a methyl halide undergoes, on the obtained 17a, 21-dimethyl-19-nor-pregna-1,3,5 (10) -trien-3-methoxy-20-one allows a reducing agent to act to reduce the 17a, 21-dimethyl-19-nor-pregna-l, 3,5 (10) -trien-3-methoxy-2o | -ol to obtain, subjecting the latter to the action of lithium in ammonia , the obtained 17a, 21-dimethyl-19-nor-pregn-5 (10) -en-20J ^: -ol-3-one with the help of a strong acid to form 17α, 21-dimethyl-19-nor-pregn-4 -en-20J-ol-3-one isomerized, subjecting the latter to the action of an esterifying agent or an etherifying agent, on the obtained 17a, 21-dimethyl-19 ~ nor-pregn-4-en-20 £ - R 0-3-one, in which R _{1 has} the meanings given above, allows a halogenating agent to act and the 2,6-dihalogeno- receives l7α, 21-dimethyl-l9-nor-pregn-4-en-20j-R ₁ 0-3-one, splitting off hydrogen halide from the latter with the aid of an alkali metal halide in dimethylformamide, the hydroxyl function in position 3 of the obtained 17a, 21-dimethyl-19-nor-pregna-1,3,5 (10), 6-tetraene-3-ol-20 ^ -R ₁ 0 of the formula I with a compound selected from the group 8,098 41/091 2 ORIGINAL IMSf ³ ECTED 28 H 04 8 consisting of the alkylating agents, dihydropyran, trityl chloride and trimethylsilyl chloride, blocked, the product of the general formula I in which R is an alkyl group with 1 to 4 carbon atoms or one of the tetrahydropyranyl, trityl or trimethylsilyl radicals and R _{1 is} an acyl radical with 1 to 5 carbon atoms or the tetrahydropyranyl radical, on which product of the formula I if necessary, the hydroxyl function in the 20 ^ position is released by reaction with a base or an acid in order to obtain the product of the general formula I, wherein R has the meanings given above and R ^ is hydrogen, on which the hydroxyl function is optionally in 3-position is set free by reaction with an acid in order to obtain the product of the general formula I, in which R and R are hydrogen. 4. The method according to claim 3, characterized in that one works under the following preferred conditions: methylation in the 21-position is carried out with the aid of methyl iodide in the presence of a tertiary base, such as potassium terfc.-butyiate, carried out, and one works in toluene; the halogenating agent is bromine, in acetic acid, and man works in ether; the alkali metal halide, with the help of which one carries out dehalogenation performs is lithium chloride. 5. As new industrial products: 17a, 21-dimethyl-19-nor-pregna-1,3,5 (10) -trien-3-methoxy-20-one , 17a, 21-dimethyl-l9-nor-pregna-l, 3,5 (10) -triene-3-methoxy-20 ^ - oi, - '. . HU984170912 - 4 - ^L -1 28H048 l7a, 21-dimethyl-l9-nor-pregn-5 (10) -en-2o £ -ol-3-one, 17a, 2! -Dimethyl-19-nor-pregn-4-en-20 i-acetoxy-3-one and 2,6-dibromo-17a, 21-dimethyl-19-nor-pregn-4-en-20 ^ -acetoxy-3-one. 6. Use of the products according to claim 1 or 2 for the synthesis of tritiated compounds, characterized that a compound of the general formula I in which R and R. are specified in claim 1 Have meanings, reduced by the action of tritiated hydrogen in the presence of a catalyst, and the obtained (6,7-H) -17oc,21-dirne thyl-19-nor-pregna-1,3,5 (10) -triene-3-RO-2Oj -R ₁ O either when R denotes the methyl radical and R ^ denotes an acyl radical with 1 to 5 carbon atoms, the tetrahydropyranyl radical or hydrogen, is directly subjected to the action of lithium in ammonia in the presence of ethanol, in order, when R ₁ denotes hydrogen or an acyl radical, that ( 6,7- ³ H) -l7a, 21-dimethyl-l9-nor-pregna-2,5 (10) -diene-3-methoxy-20f-ol or when R represents the tetrahydropyranyl radical, the (6,7 - H) -l7a, 21-dimethyl-l9-nor-pregna-2,5 (10) -diene-3-methoxy-20i-tetrahydropyranyloxy, or , when R is one of the aforementioned radicals which is different from methyl or hydrogen, and R ^ has meanings different from hydrogen, the action of an organic acid or a hydrochloric acid subjects the (6,7-H) -l7a, 21 -dimethyl-l9-nor-pregnal, 3,5 (10) -triene-3-ol-20 ^ -R ₁ 0 is obtained, which product is treated with a methylating agent, the resulting (6,7- ³ H) -l7a , 21-Dimethyl-19-nor-pregna-l, 3,5 (10) -trien-3-methoxy-20i-R-0 subjected to the action of lithium in ammonia in the presence of ethanol, in order to, when R- water- 3 substance or an acyl radical, also the (6,7- H) - 809841/0912 17α, 21-dimethyl-l9-nor-pregna-2,5 (10) -diene-3-methoxy-20i-ol or when R ₁ is the tetrahydropyranyl it means t, the (6,7- ³ H) -l7a To obtain 21-dimethyl-19-nor-pregna-2,5 (10) -diene-3-methoxy-20 ^ -tetrahydropyranyloxy. 7. As new industrial products, the general connections formula wherein R and R. are as defined in claim 1. 8. As a new industrial product, (6,7-H) -17a, 21-dimethyl-19-nor-pregna-1,3 , 5 (10) -triene-3-methoxy-20 £ -ol. 8Ü9841 / 09 12