DK144947B - ANALOGY PROCEDURE FOR PREPARING D-HOMOPREGNA-4,16-DIEN-3,20-DIONES - Google Patents

Description

(19) DENMARK

- PRESENTATION Fil (1) 4947 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 320/77 (54) | nt.Cl.a C 07 J 63/00 (22) Filing Day 2β. Jan. 1977 (24) Race day 24. strange. 1975 (41) Aim. available Jan 26 1977 (44) Presented 12 Jul. 1982 (86) International application no. - (86) International filing day (85) Continuation day - (62) Master application no. 1230/75 (30) Priority 7 Oct. 1974, 13424/74, CH Dec 2 1974, 15950/74, CH "(71) Applicant F. HOFMANN-1A ROCHE & CO. MTIENGESELLSCHAFT, CH-4002

Basel, CH. .

(72) Inventor Leo Alig, CH: Andor Fuerst, CH: Marcel Mueller, CH: Ulrich Kerb, DE: Rudolf Wiechert, DE.

(74) Plougmann & Vingtoft Patent Bureau.

(54) Analogous procedure for preparing D-homopregna-4,1 6-di = en-3i 20-dione.

The present invention relates to an analogous process for the preparation of novel D-homopregna-4,16-diene-3,20-dione of the general formula I

R21CH2.

Rl m 2 r10 | j! K jl JL li i

cn> · I

* R6

ISLAND

Wherein R and R represent hydrogen or together la, 2a-methylene or a carbon-carbon bond, R6 represents hydrogen, fluorine, chlorine or methyl, R17a represents acyloxy of not more than 15 carbon atoms, R10 represents methyl or, if R 1 and R 2 represents hydrogen, to equal hydrogen, and R21 represents hydrogen, fluorine or chlorine.

2 144947

An acyloxy group is derived from a saturated or unsaturated aliphatic carboxylic acid or from a cycloaliphatic, araliphatic or aromatic carboxylic acid having a maximum of 15 carbon atoms. Examples of such acids are formic acid, acetic acid, pivalic acid, propionic acid, butter. acid, capric acid, enanthic acid, undecylenic acid, oleic acid, cyclopentylpropionic acid, cyclohexylpropionic acid, phenylacetic acid and benzoic acid.

Particularly preferred are alkanoyloxy groups having 1-7 carbon atoms.

A substituent seated in the 6-position may have α or β configuration. The α-isomers are preferred.

The process of the invention for the preparation of D-homopregna-4,16 - diene-3,20-dione of the general formula I is characterized in that:

a) in a D-homosteroid of the general formula II

wherein Rchs represents hydrogen or methyl, and R * 73 - 73 and R₂ ^ have the meaning given above, the 3-hydroxy - /. 4 group oxidizes λ 4 to a 3-keto group. / b grouping, or b) fluorinating or chlorinating a D-homosteroid of the general formula

III

Wherein R / R, R, R and R are as defined above in the 6-position, and if desired, a 6β-isomer is obtained / isomerized to the 6a isomers, or c) methylates a D-homosteroid of the general formula iv r21cH2N2 - ° r1 x. "R17a wherein R, R, R, R and R are as defined above / in the 6-position, or

d) acylating the hydroxy group of a D-homosteroid of the general formula V

R21CH2'0

, 1 / -vJr0H

4, 144947 wherein R1, R2, R6, R10 and R-1 are as defined above, or

e) hydrolyzing a D-homosteroid of general formula VI

R21CH \ - °

I U VI

'A! B in which R 1a and R 2 have the meaning given above, X represents an organic group attached to the ring system with nitrogen, oxygen or sulfur and at least one of the bonds listed in rings A and B with the 4 dotted lines is present; to form a -3 ketone.

The oxidation of a compound of formula II (process variant a) can be carried out after Oppenauer, e.g. by aluminum isopropylate, or with oxidizing agents such as chromium trioxide (e.g.

Jones' reagent) or after Pfitzner-Moffatt by dimethylsulfoxide / dicyclohexylcarbodiimide (the primary ketone then obtained is then isomerized to form a 3-ketone) t or by pyridine / SO- *. Using one of the J 4 oxidants listed above, a 3-keto-A group is obtained.

The halogenation at the 6-position (process variant o) is preferably carried out by converting a D-homosteroid of formula III into a 3-enol ester or 3-enol ether, e.g. 3-enol acetate, and then react with chlorine [cf. J. Am. 82, 1230 (I960)], with an N - halogenimide [cf. J. Am. £ 12, 1230 (1960); TJ_, 3827 (1955)] or perchloryl fluoride [cf. J. Am. 81, 5259 (1959)]; Chem. and Ind. 1959, 1317]. Also, as fluorinating agents, trifluoromethyl hypofluorite can be used.

The chlorination can also be carried out by means of chromyl chloride in methylene chloride or ethers. .

If the halogenations described above form isomer mixtures, i.e. mixtures of 6α and 6β-halo steroids, these can be cleaved into the pure isomers by known methods, e.g. chroma chromatography.

The isomerization of a 6B halogen-D homosteroid obtained, in particular a β-fluorine or chlorine compound * can be carried out by treatment with an acid, especially a mineral acid such as hydrochloric acid, or hydrochloric acid in a solvent, e.g. dioxane or glacial acetic acid.

The methylation according to process variant c) can e.g. is carried out by converting the starting compound of formula IV into a 3-enol ether (for example, by treatment with an ortho-acid ester, eg orthomyric acid ethyl ester, in the presence of an acid, e.g. p-toluenesulfonic acid, optionally with or by treating the starting compound IV with a dialkoxypropane, e.g.

2,2-dimethoxypropane in methanol-dimethylformamide in the presence of p-τ -toluenesulfonic acid) and reaction of the enol ether with a tetrahalogen-methane, e.g. CBr ^, CC ^ Brj or CCl ^ Br to form the trihalo gene methyl A? ~ 3 ketone. The trihalomethyl / β-ketone can be dehydrohalogenated with bases such as collidine to form dihalo-4-methylene / β-3-ketone, which, in turn, by catalytic hydrogenation under mild conditions, e.g. with a palladium / strontium carbonate catalyst, can be converted to the 6α-methyl - [4 ~ 3 ketone.

For compounds of formula IV, wherein R 2 = R 2 = hydrogen, an advantageous methylation method consists in converting such a compound of formula IV in the manner described above into a 3-enol ether, and in a manner known per se. is reacted to form a corresponding 6-formyl derivative, the formyl group is reduced by sodium borohydride to a hydroxymethyl group, and the reaction product is then dehydrated during cleavage of the enol ether to give a 6 U4947

D-homosteroid with the general formula VII

R21 ™, ^ 0 Τ '* 173 * iorf \

In JJ VII

Where R 2, R 2 and R 2 a have the meaning given above.

6-Methylene intermediates may also be prepared by converting compounds of formula IV into a 3-enamine, e.g. 3-pyrrolidinium enamine, hydroxymethylation with formaldehyde and water decomposition by acids such as p-toluenesulfonic acid.

The 6-methylene intermediates may be hydrogenated in the usual manner by known hydrogenation catalysts to form the corresponding 6-methyl compounds.

The acylation of the 17α-hydroxy group in a D-homosteroid of formula V (process variant d) can be carried out in a manner known per se by treatment with a reactive acid derivative, e.g. an acyl halide or anhydride in the presence of p-N, N-dimethylamino-pyridine.

The hydrolysis of the substituent at the 3-position of a D-homosteroid of formula VI by process variant e) can be carried out in a manner known per se by means of acids, e.g. mineral acids such as hydrochloric acid, or with carboxylic acids such as oxalic acid. Particularly alcoholic or aqueous-alcoholic solutions, e.g. methanol or methanol / water, as optional additional solvents, e.g. chloroform.

Examples of D-homosteroids of formula VI are those in which X together with the double bond system in ring. A and / or B form a 3-alkoxy- (e.g., methoxy-) - [2] 2; 3-alkylthio- (eg 3-methylthio-) - / 2f **. 3-sec.amino - (e.g., pyrrolidino-) ~ / 2 '; 3-alkylenedioxy- (e.g., ethylenedioxy -) - / -, - or / / Or a 3-alkylenedithio (e.g. ethylene dithio), β, β or β group.

A particularly preferred embodiment of the process of the invention is that compounds of formula I are prepared in which R 1 and R 2 are hydrogen, R 2 is hydrogen or methyl, R 7a is al-canoyloxy of 1-7 carbon atoms, and R is hydrogen, thereby providing compounds which are particularly preferred because of their particularly potent action.

The D-homosteroids used in the process according to the invention as starting materials, if their preparation is not described herein, can be prepared by analogy to the methods set forth in the examples.

The compounds of formula I have hormonal action, especially on the endocrine system, and are peculiar to selectivity in action. They can therefore be used as hormonally active agents, e.g. as progestatives and may be administered orally or parenterally. 0.005 mg / kg - 0.15 mg / kg per dosage guideline day.

The compounds of formula I are closely related, for their progestogenic effect, known compounds are superior in the Clauberg test to rabbits, as shown by the McPhail values given below: 8 144947

Gestagenic effect in Clauberg test.

Compound Dose (mg) McPhail Comparative Index Compound 17aa-Acetoxy-D-Homo 0.1 Subcutaneously 3.3 3.0 19-nor-acetoxy-19-nor-4,16-pregna-0.03 subcutaneous 3.2 2,5-progesterone diene-3,20-dione 0.01 subcutaneous 2.7 1.3 17 aa-acetoxy-D-homo 0.1 subcutaneous 3.3 2.4 acetoxyprogeste-pregna-4 , 16-diene 0.03 subcutaneous 2.2 1.1 ron -3.20-dione 0.01 subcutaneously 1.4 1 17aa-acetoxy-6a-0.1 0.1 oral 2.5 1.1 "Provera Thy1-D-homopregna- 0.03 peroral 1.2 1.0 -4.16-diene-3,20-dione ab aj 17aa-hexanoyloxy-D-3 subcutaneously 3.7 ^ 2.4 ^ progesterone -homopregna-4,16-diene-1 subcutaneous 2,9 * Ir 4 ** capronate -3,20-clion 3 subcutaneously 2.2 * 1.2 * 1 subcutaneously 1.6 * 1.2 * * 8 days after injection fcfc 12 days after injection

The compounds of formula I should be used as drugs, e.g. in the form of pharmaceutical compositions containing them in admixture with an organic or inorganic inert carrier suitable for enteral, percutaneous or parenteral application.

The process according to the invention is further illustrated by the following examples:

Example 1.

To 440 mg of 17aa-acetoxy-3 (i-hydroxy-D-homopregna-5,16-diene-20-one in 30 ml of acetone is added 0.55 ml of Jones' reagent, which is stirred for 5 minutes, poured into water and The methylene chloride solutions are washed with water, dried and evaporated. 17aa-acetoxy-D-homopregna-4,16-diene-3,20-dione melted at 222 - 223 ° C (acetone-hexane).

Preparation of the starting material: 33,17aa-dihydroxy-D-homopregna-5,16-dien-20-one is reacted in acetic anhydride and triethylamine in the presence of pN, N-dimethylaminopyridine to form 33,17aa-diacetoxy-D-homopregna -5,16-diene-20-one (m.p. 179-180 ° C, [α] D = -273 °, c = 0.1% in dioxane) and this is then partially hydrolyzed with potash in methanol to give 17a a-acetoxy-30-hydroxy-D-homopregna-5,16-dien-20-one.

Example 2.

4.65 g of 17α-α-hydroxy-D-homopregna-4,16-diene-3,20-dione and 1.55 g of pN, N- dimethylaminopyridine are stirred under argon atmosphere in 23.5 ml of triethylamine and 14.5 ml acetic anhydride for 16 hours at room temperature. The mixture is poured into ice-cold dilute hydrochloric acid and extracted with methylene chloride. The methylene chloride solutions are washed neutral with dilute sodium bicarbonate solution and dilute brine, dried and evaporated. Chromatography of the crude product on silica gel and two-fold crystallization of acetone-hexane gives 17aa-acetoxy-D-homopregna-4,16-diene-3,20-dione, mp 223 - 224 ° C; UV Spectrum: ^ 240 ~ 16800i [a) D = " 134 ° (c = 0.1% in dioxane).

The starting material can be prepared by oxidation of 3 (3-hydroxy-D - homopregna-5,17-diene-20-one in dimethylformamide and tetrahydrofuran in the presence of potassium tert.butylate and trimethylphosphite with oxygen to give 33.17aa-dihydroxy -D-homopregna-5,16-diene-20-one Melting point 241 - 243 ° C; [ο] β = -187 ° (c = 0.1% in dioxane). By Pfitzner-Moffatt oxidation, 17aa is obtained -hydroxy-D-homopregna - 4,16-diene-3,20-dione, m.p. 177 - 178 ° C; UV Spectrum: e24Q = 16800; [a) D = + 18 ° (c = 0.1% in dioxane).

10 144947

Example 3

396 mg of 17aa-acetoxy-6-methylene-D-homopregna-4,16-diene-3,20-dione and 396 mg of palladium / calcium carbonate are hydrogenated in 39.6 ml of toluene until an equivalent amount of hydrogen is taken up. The catalyst is filtered off, the filtrate is evaporated and the residue is stirred in 10 ml of dioxane and 1 ml of 2N hydrochloric acid for 1 hour at room temperature. The solution is evaporated and the residue is purified on a small amount of silica gel. 17aa-acetoxy-6a-methyl-D-homopregna-4,16-diene-3,20-dione is obtained, mp 216 - 218 ° C, Ca] D = -136 ° (c = 0.1 in dioxane), UV Spectrum: ^ 241 ~ 14600.

The starting material can be prepared as follows: 17α-Acetoxy-D-homopregna-4/16-diene-3,20-dione is reacted in methanol in the heat with pyrrolidine. 17aa-acetoxy-3-pyrrolidino-D-homopreg-na-3,5,16-triene-20-one is obtained, which is reacted with aqueous formaldehyde solution in alcohol and benzene to give 17aa-acetoxy-6-hydroxymethyl-D -homopregna-4,16-diene-3,20-dione, m.p. 224 - 226 ° C (acetone-hexane),

Upon treatment thereof with hydrochloric acid in dioxane, 17aa-acetoxy-6-methylene-D-homopregna-4,16-diene-3,20-dione is obtained, mp 211 - 213 ° C (acetone - hexane); UV spectrum: 251 = 10800, [α] D = -13 ° (c = 0.1% in dioxane).

Example 4

A solution of 3.2 g of 17aa-acetoxy-6-dibromo-methylene-D-homopregna- 4,16-diene-3,20-dione in 60 ml of dioxane and 2.5 ml of triethylamine is hydrogenated with 5 g of 2 % palladium / strontium carbonate catalyst until three equivalents of hydrogen are taken up. The catalyst is filtered off and the filtrate is acidified to pH 1 by the addition of 2N hydrochloric acid, whereby the 17aa-acetoxy-6β-methyl-D-homopregna-4,16-diene-3,20-dione isomerized to give the corresponding 6a - methyl compound. The mixture is allowed to stand for 2 hours at room temperature, water is added and extracted with methylene chloride. The organic extracts are washed neutral with sodium bicarbonate solution and water, dried with sodium sulfate and evaporated in vacuo. The residue 11 is chromatographed on silica gel and the chromatographically pure fractions are recrystallized from acetone-hexane. Pure 17aa-acetoxy-6a-methyl-D-homopregna-4,16-diene-3,20-dione is obtained, m.p. 216 - 218 ° C / UV spectrum: e2H ~ 14600, [a] D = -136 ° (e = 0.1% in dioxane).

The starting material can be prepared as follows: 17aa-Acetoxy-D-homopregna-4,16-diene-3,20-dione is reacted in dioxane with orthoformic acid methyl ester in the presence of p-toluenesulfonic acid and some methanol to give 17aa-acetoxy-3-methoxy -D-homopregna-3,5,16 - triene-20-one, m.p. 185 - 187 ° C.

This enol ether is reacted in colldine with tetrabromomethane for 80 hours to give 17aa-acetoxy-6-tribromomethyl-D-homopregna-4,16-diene-3,20-dione. This is converted by heating in pyridine to 17aa-acet-oxy-6-dibromomethylene-D-homopregna-4,16-diene-3,20-dione.

Example 5

17aa-Acetoxy-D-homopregna-4,16-diene-3,20-dione is converted into ether by acetic anhydride and perchloric acid to 3,17aa-diacetoxy-D- ^ -homopregna-3,5,16-triene-20 -one, which is then reacted in aqueous acetic acid with chlorine in the presence of potassium acetate to give 17aa-acetoxy-6-chloro-D-homopregna-4,16-diene-3,20-dione. Melting point 199 - 200 ° C (ether).

Example 6

To a solution of 4 g of 17act-hydroxy-D-homo-19-norpregna-4,16-diene - 3,20-dione in 40 ml of acetic anhydride and 40 ml of triethylamine is added 0.5 g of 4-dimethylaminopyridine and stirred. After 25 hours, the mixture is poured onto ice cold 1N hydrochloric acid solution and extracted with ether. After twice washing with water, drying over sodium sulfate and evaporation on a rotary evaporator, 7 g of crude product is obtained, which is adsorbed on 200 g of silica gel. with dichloromethane is obtained · 2.5 g of 17aa-acetoxy-D-homo-19-norpregna-4,16-diene-3,20-dionej melting point 210 - 212 ° C (dichloromethane-ether-hexane); 196 ° (c 11 0.100 in dioxane).

12 1 / U947 17aa-Acetoxy-D-homo-19-norpregna-4,16-diene-3,20-dione can also be prepared from 17aa-acetoxy-3,3- (ethylenedioxy) -D-homo-19 norpregna - 5 (10), 16-diene-20-one by analogy with the hydrolysis of 3,3- (ethylenedioxy) -17aa-hydroxy-D-homo-19-norpregna-5 (10), 16- -diene-20-one to form 17aa-hydroxy-D-homo-19-norpregna-4,16 - diene-3,20-dione.

Preparation of the starting material: In a solution of 27.7 ml of N-cyclohexylisopropylamine in 100 ml of tetrahydrofuran, stir at -78 ° C under an argon atmosphere 76.5 ml of a ca. 20-25% solution of n-butyllithium in hexane. 150 ml of this solution is stirred for 2 hours under an argon atmosphere in a solution cooled to -78 ° C of 20 g of D-homoestrone methyl ether in 100 ml of dichloromethane. After a further 2 hours of stirring at -78 ° C, a solution of 10 g of ammonium chloride in 50 ml of water is added, the aqueous phase is adjusted to acidic reaction by addition of 1N hydrochloric acid solution and extracted with dichloromethane. After washing with saturated hydrogen carbonate solution and The crude product is dissolved in 100 ml of toluene and heated for 4 hours under reflux and the evaporation residue is adsorbed on 600 g of silica gel 0.06 - 0.2 mm; 9: 1 hexane-ethyl acetate gives 20.8 g (90% of theory) of 17aa-chloro-3-methoxy-D-homoestra-1,3,5 (10) - triene-17ap-carboxaldehyde, m.p. 116 - 117 ° C (dichloromethane - hexane); 539 = 5 ° (c = 0.101 in dioxane).

To a solution of 20.8 g of 17aa-chloro-3-methoxy-D-homoestra-1,3,5 (10) -triene-17a3-carboxaldehyde in 25 ml of hexamethylphosphoric triamide is added 2.5 g of lithium chloride and stirred. 12 hours at 50 ° C with portion addition of 5 g of sodium bicarbonate gradually. After standing overnight at 25 ° C, ether is added, washed three times with water and once with saturated hydrogen carbonate solution, dried over sodium sulfate and evaporated on a rotary evaporator. The residue is adsorbed on 1 kg of silica gel, 0.06 - 0.2 mm; eluting with dichloromethane gives 10.1 g (50% of theory) of 3-methoxy-D-homoestra-1,3,5 (10) -17 "tetraene-17a-carboxaldehyde; mp 126 - 127 ° C (acetone ether); Ca] 589 ° + 207 ° (c = 0.100 in dioxane).

13 144947

To a solution of 18 g of 3-methoxy-D-homoestra-1,3,5 (10), 17-tetra-ene-17a-carboxaldehyde in 250 ml of absolute tetrahydrofuran is added dropwise with stirring at 0 ° C and under 45 ml of argon atmosphere. and approx. 2M solution of methyl lithium in ether. After 2 hours, aqueous ammonium chloride solution is added and extracted four times with ether.

The organic phases are washed twice with soda, dried over sodium sulfate and evaporated on a rotary evaporator. The crude product is dissolved in 400 ml of tert-butanol and 400 ml of tetrahydrofuran and dripped to 1.2 liters of anhydrous ammonia. To the boiling solution is added portionwise 6.1 g of sodium. After 2 1/2 hours, the ammonia is distilled off and the reaction mixture is evaporated on a rotary evaporator and partitioned between ether and water. After drying over sodium sulfate, evaporate on rotary evaporator. The evaporation residue is dissolved in 50 ml of dichloromethane, 100 ml of ethylene glycol and 25 ml of glacial acetic acid are added and stirred for 18 hours at 25 ° C. The mixture is poured onto ice-cold 3N sodium hydroxide solution, extracted with ether and evaporated on a rotary evaporator after washing with water and drying over sodium sulfate. The crude product is dissolved in 100 ml of pyridine and 200 ml of an approx. 1M solution of chromium trioxide in 10: 1 pyridine-water. After stirring at 25 ° C for 4 hours, 5 ml of ethanol is added and evaporated on rotary evaporator. To the residue are added 500 ml of ether and 300 ml of water and isolated by suction filtration over "Speedex". The organic phase of the filtrate is washed with water, dried over sodium sulfate and evaporated on a rotary evaporator, then adsorbed on 500 g of silica gel, 0.06 - 0.2 µmw and with dichloromethane + 0.5 - 1% methanol eluted 10.5 g 3,3- (ethylenedioxy) -D-homo-19-norpregna-5 (10), 17-diene - 20-one; mp 147 - 148 ° C (ether-hexane); C5Q9 = + 238 ° (c = 0.101 in dioxane).

A solution of 5.5 g of 3,3- (ethylenedioxy) -D-homo-19-norpregna-5 (10), 17-dien-20-one in 25 ml of tetrahydrofuran is added dropwise to a mixture of 15 ml of tert.butanol , 25 ml of dimethylformamide and 2.5 ml of trimethylphosphite. The solution is cooled to -25 ° C, 1.3 g of potassium tert-butylate is added and stirred vigorously in an oxygen atmosphere. In 25 minutes, 360 ml of oxygen is consumed. The mixture is poured onto ice water and extracted with ether. After washing with water, drying over sodium sulfate and evaporation on a rotary evaporator, the crude product is combined with 2.3 g of an identical crude product and adsorbed on 250 g of silica gel, 0.06 - 0.2 mm; by elution with hexane-ethyl acetate in a 4: 1 ratio, 4.18 g of amorphous 3,3- (ethylenedioxy) -17aa-hydroxy-19-norpregna-5 (10), 16-diene-20-one is obtained.

Claims (3)

To a solution of 4.9 g of 3,3- (ethylenedioxy) -17aa-hydroxy-D-homo-19-norpregna-5 (10), 16-diene-20-one in 100 ml of methanol is added 1, 5 ml of concentrated hydrochloric acid in 10 ml. water and stir for 18 hours at 25 ° C. The mixture is neutralized by addition of aqueous bicarbonate solution, freed from methanol on rotary evaporator and partitioned between dichloromethane and water. After washing with water, drying over sodium sulfate and evaporation on a rotary evaporator, 5 g of crude product is obtained, of which 3.4 g of 17aa-hydroxy-D-homo-19-norpregna-4 are obtained after crystallization of dichloromethane ether in two crystallisates. 16-diene-3,20-dione melting point 219 - 220 ° C; [α] g | g = 41 ° (c = 0.099 in dioxane). Example 7. To a solution of 2.5 g of 17aa-hydroxy-D-homo-19-norpregna-4,16-diene - 3,20-dione in 30 ml of capric anhydride and 30 ml of triethylamine is added 0.5 g of dimethylaminopyridine and stirred at 25 ° C. After 21 hours, the mixture is poured onto ice cold 1N hydrochloric acid solution and extracted with ether. After three times washing with water, drying over sodium sulfate, evaporation on a rotary evaporator and heating in vacuo (0.1 mm Hg), 3.3 g of crude product are adsorbed on 100 g of silica gel, 0. 06 - 0.2 mm. Elution with dichloromethane gives 1.7 g of 17act-caproyl-oxy-D-homo-19-norpregna-4,16-diene-3,20-dione; UV spectrum (ethanol): 238/9 nm (ε = 17000), m.p. 148-149 ° C. An analogous process for the preparation of D-homopregna-4,16-diene - 3,20-dione of the general formula I wherein R and R are hydrogen or together represent 1a, 2a-methylene or a carbon-carbon bond, R4 represents hydrogen, fluorine, chlorine or methyl, R'L4a represents acyloxy of not more than 15 carbon atoms, R10 is 2, methyl or, if R and R are hydrogen , as well as hydrogen, and R represents hydrogen, fluorine or chlorine, characterized in that a) in a D-homosteroid of the general formula II R 21 c H 2 and R 2 73 and R 2 have the meaning set forth above, oxidizing the 3-hydroxy-β group to a 3-keto-β, 4 group, or b) fluorinating or chlorinating a D-homosteroid of the general formula III R21cH2 \ ^ ° VjXjCU wherein R, R, R ^ °, R ^ 7a and R ^ have the above meaning, in the 6-position, and, if desired, a won 6 | 3 isomer isomerizes to a 6a isomer or c) methylates a D-ho asteroid of the general formula IV κ · * ΌΗ-v r2 \ A | aJj IV wherein R1, R2, R10, R17a and R21 have the ° Friendship meaning, at the 6-position, or d) acylate the hydroxy group in a D-hO01osteroia with the general forinel V Κ2ΐ ° Η2γ * 0 rI -oh VtOi V i6 1. C \ I Λ wherein R, R, R, R and R have the meaning given above, or e) hydrolyzes a D-homosteroid of the general formula VI R21CH2 Ri7a / C VI I I in