DE1291335B - Process for the production of delta 4 steroid spirolactones - Google Patents

Description

The invention relates to a process for the production of, H-steroid spiroIactones of the general Formula I.

wherein R is a 16- or 17-position of the steroid nucleus located

T = O

-Spirolactone group

IO

means.

To build up a steroid lactone with anti-aldosterone activity from the corresponding unsaturated 16- or 17-ketosteroid one had to so far as intermediate compounds produce ethynyl derivatives; then had to be catalytically hydrogenated which had the disadvantage that the other unsaturated groups of the steroid core were attacked could become.

The inventive method avoids this disadvantage by using a ketonide l, 2-dihydroxy-4-halo-butane and allows the later side chain to contain the desired lactone should result to condense without attacking the unsaturated groups of the steroid nucleus will.

In a particular embodiment of the process according to the invention, the ketonide is a 1,2-dihydroxy-4-halo-butane 1,2-isopropylidene-dioxy-4-bromobutane (A) used.

The process according to the invention consists in that 3-oxo-, H-16- or -17-oxo-androstene (II), the 3-keto group of which has been selectively blocked in a known manner by previous enamine or enol ether formation, with the organomagnesium compound of a ketonide of a 1,2-dihydroxy-4-halo-butane condensed by the known Grignard method, in the resulting ketonide of 3-enamino or 3-alkoxy-16 / i- or -17 / i-hydroxy- 16 "- or -17" - (3 ', 4'-dihydroxybutyl) -l ³ - ⁵ -androstadiens (IV) the protected 3-keto group and the alcohol groups of the side chain blocked in the form of the ketonide either simultaneously or successively with an acid released in a manner known per se, the side chain of the 3-oxo-16 / i- or -17 / J-hydroxy-16 "- or -17" - (3 ', 4'-dihydroxybutyl) -H-androstens (V) with an oxidizing agent, e.g. B. periodic acid, with simultaneous cyclization, and that one

a) the obtained 3-oxo-l ', 16 / i- or -l', 17 // - epoxy-16 «- or -17 "- [l'-hydroxypropyl-I-androstene (Vi), which is isolated in the form of epimers A and / or B by known methods can be treated with an oxidizing agent in a known manner and so that Lactone of the w- (3-oxo-16 / i- or -17 / i-hydroxy-. H-androsten-lo «- or -I7a-yl) propionic acid (I) or that one alternatively

b) the obtained 3-oxo-16 // - or - ^ // '- hydroxy-lou- or -17 «- (3', 4 -dihydroxybutyl) -, i ⁴ -androsten (V) with a strong Oxidizing agent, in particular with chromic anhydride or chromosulfuric acid, treated and the desired lactone (I) is thus obtained directly or that c) the 3-oxo-17 // - hydroxy-17 "- (3 ', 4'-dihydroxybutyl) - obtained. l ⁴ -androsten (V b) treated with ammonium periodate in the presence of dimethylformamide, the resulting Γί, ΐί-ether oxide of 3-oxo-l'f, 17 // - epoxy-17 «- (r £ -hydroxypropyl) -l ⁴ -andast by acid hydrolysis in 3-oxo-1 ', 17 // - epoxy- 17a- (l'i-hydroxypropyl) -. l ⁴ -androsten (VI b) transferred and the latter treated further according to procedure a).

The 3-oxol 'obtained in the course of the synthesis, 16 // - or -l ', 17 / i-epoxy-16 "- or -17" - (l'Miydroxypropyl) -H-androsten (VI) itself has antialdosterone activity.

In the alternative variant b) of the process according to the invention, higher yields are obtained and can use technically used reagents.

The method according to the invention is preferably carried out as follows:

To produce the starting steroid, the blocking of the keto group of 3-Oxo-H-16- or -17-oxo-androstene (II) with a secondary amine from the group of the lower Alkylamines or with pyrrolidine, piperidine or morpholine, especially with pyrrolidine in Methanol running;

1,2-isopropylidene-dioxy-4-bromobutane is used as the starting ketonide of a 1,2-dihydroxy-4-halo-butane (A) used;

the condensation of the magnesium derivative of 1,2-isopropylidenedioxy-4-bromobutane with the 3-enamino-16- or -17-oxo l ^{: I5} -androstadiene (III) is carried out in a mixture of ether and benzene;

the release of the 3-keto group blocked in the form of the enamine and that in the form of the Ketonide blocked alcohol groups of the compound IV is made using acetic acid in the presence run from sodium acetate at the same time;

the release of the alcohol groups of compound IV blocked in the form of the ketonide is with hydrochloric acid and the release of the blocked 3-keto group in the form of the enamine the compound obtained is then treated with acetic acid in the presence of sodium acetate executed;

the breakdown of the side chain of the 3-oxo-16 / j- resp. -17 / y-hydroxy-16 "- or -17" - (3 ', 4'-dihydroxybutyl) -H-androstens (V) with simultaneous cyclization is with periodic acid in aqueous tert. Butanol or 50% methanol and in The presence of sodium hydroxide solution or lithium carbonate carried out;

as an oxidizing agent for the oxidation of 3-oxo- Ι ', ίββ- or -l', 17 // - epoxy-16 "- or -17" - (3'i-hydroxypropyl) - H-androstene (VI) Chromosulfuric acid used in aqueous acetone;

the oxidation of 3-0x0-16 // - or -17 /; - hydroxy-16 «- or -17a- (3 ', 4'-dihydroxybutyl) -. H-androstens (V) is made with chromic anhydride carried out in aqueous acetic acid;

when chromosulfuric acid is used as the oxidizing agent of compound V, it is advantageous to work in the presence of acetone.

The following, illustrated by the reaction schemes Examples illustrate the process of the invention. In the reaction schemes means

15th

a di (lower alkyl) amino group, a pyrrolidyl, piperidyl or morpholinyl group and R3 and Ri, which may be the same or different, an alkyl group with 1 to 10 carbon atoms.

In the following, "Epimer A" means an epimer with a low rotational power and "Epimer B" one with a high turning capacity.

The 1,2-isopropylidene-dioxy-4-bromobutane used as the starting component (A) is produced as follows, for which no protection is sought within the scope of the present invention:

1. 1,2-Isopropylidenedioxy-4-hydroxy-butane (C)

250 g of 1,2,4-trihydroxy-butane (B), 3 3 of acetone and 25 ecm of 65% perchloric acid are mixed. These The mixture is left to stand at room temperature under nitrogen and with stirring for about 2 hours, then add 65 g of sodium carbonate, continue stirring for 1 hour, filter, add to the filtrate 1.5 ecm of triethylamine is added, then the acetone is driven off at a slight negative pressure and rectified at 20 mm pressure. 252 g of substance with a boiling point of 107 to 109C (compound C) and boiling point ™ are obtained - 207 C and n £ f - 1,439.

The compound is soluble in alcohol and acetone and insoluble in water and dilute aqueous Alkalis; dilute aqueous acids decompose the compound.

2. Mesylate of 1,2-isopropylidenedioxy-

4-hydroxy-butane (D)

100 g of compound C are dissolved in 125 ecm of pyridine, the solution is cooled to 40 ° C. and 54 ecm of mesyl chloride are slowly added; then the acetone phase is left with ether, the ethereal extract is dried and concentrated under nitrogen. The residue of the ethereal extract is then combined with the organic phase and the solution is left to stand over potassium carbonate in the presence of triethylamine. It is then filtered, rectified in vacuo and 55 g of compound A with a boiling point of 19 = 89 to 90 ³ C and n ¥ = 1.462 are obtained.

The compound is soluble in acetone and chloroform and insoluble in water and diluted aqueous alkalis; diluted aqueous acids decompose them.

Analysis: C ₇ Hi ₃ O ₂ Br; Molecular Weight = - 209.09.

Calculated ... C 40.20, H 6.26, Br 38.22%;
found ... C 40.3, H 6.1, Br 37.9, ¹ vol.

example 1

Lactone of ro- (3-oxo-16p'-hydroxy
H-androsten-16f / -yl) propionic acid

I, R = <

in 16 position

Temperature to -10 to

rise and stir

2 hours. Then the temperature is allowed to rise to room temperature, water is added, extracted with ether, the extract washes successively with sodium bicarbonate solution and normal Sodium hydroxide solution and stir overnight with sodium bicarbonate solution in the presence of triethylamine. Then it is washed with salt water, dried over magnesium sulfate, concentrated under nitrogen and receives 140 g of liquid, which consists of the crude compound D.

The compound is soluble in chloroform and insoluble in water and dilute aqueous Alkalis; diluted aqueous acids decompose them.

3. 1,2-Isopropylidenedioxy-4-bromo-bi! Tane (A)

280 g of lithium bromide are added to 1400 can of acetone and then 140 g of mesylate of 2-isopropylidenedioxy-4-hydroxy-butane (D) and 7.5 ecm of triethylamine are added. Heating the Reaktioasmischung with stirring for about 5 hours under reflux and then in 1500 cc of water were added, the organic phase is separated off, the aqueous to extract Preparation of serving as starting steroid 3-PyriOlidyl-16-oxo - l ^3-5 -androstadiens

'■ Rix
IHa,> N = N

7.07 g of 3,16-dioxo-.l ⁴ -androstene (Ha, prepared according to the process described in Chem. Listy, Vol. 47, p. 1207 [1953]) are dissolved in 140 ecm of methanol and then added Stir and add 3.5 ecm of pyrrolidine under nitrogen. The reaction mixture is stirred under nitrogen for about 15 to 20 minutes at room temperature and the precipitate formed is then filtered off with suction, washed with methanol and dried. 6.76 g of compound III a are obtained as a crude product. A second yield of 685 mg of substance is obtained by crystallization from the mother liquors. The compound is purified by dissolving it in benzene and then precipitating it with methanoi. The compound has the F. - 193 to 194 C.

The compound is soluble in benzene and chloroform, slightly soluble in alcohol and ether and insoluble in water and dilute aqueous alkalis; diluted aqueous acids salt them out.

Analysis: C23H33ON; Molecular weight - 339.50. Calculated ... C 81.36, H 9.80, N 4.12%.
Found ... C 81.2, H 9.6, N 4.4%.

The compound has not yet been described in the literature.

A. 3-Oxo 16 / J-hydroxy-16, i- (3 ', 4' "dihydroxybutyl) -H-andro-tane (Va)

2.04 g of magnesium are added to 30 ecm of ether and then slowly put under dry »nitrogen and while stirring with a few milliliters of a solution of 16.72 g of 1,2-isopropyiidenedio \ y-4-bromobutane (A) in 80 ecm ether. When the reflux temperature is reached, in about an hour the whole of the above-mentioned solution and the solution of 7.22 g of the starting

compound III a in 80 ecm benzene added. The reaction mixture is kept under stirring at room temperature for about 21 hours. Then, while stirring, 100 ecm of saturated ammonium chloride solution are slowly added, the organic phase is separated off, washed with water, dried over magnesium sulphate and concentrated under nitrogen; the residue crystallizes. The last traces of benzene are washed out with methanol and a methanolic suspension is obtained, which is cooled to 0 _° C.; the crystals formed are filtered off with suction, washed with methanol and dried. 3.56 g of acetonide of 3-pyrrolidyl-16 are obtained / i-hydroxy-16a- (3 ', 4-dihydroxybutyl) l ³ - ⁵ -androstadiene (IVa) as a crude product

n =

R :, and Ri = CH ₃

as a crude product, which one tert by recrystallization from aqueous. Butanol can clean. The compound has a temperature of 150 "C (not very hot and [a] f = + 57 ± 2 ° (c = 0.5" /,) in dioxane).

The compound is soluble in alcohols and chloroform and insoluble in water and diluted) aqueous acids and alkalis.

Analysis: Ca ₂ HSaOs; Molecular Weight = 344.48. Calculated ... C 76.70, H 9.36%;
found ... C 76.9, H 9.4%.

This compound has not yet been described in the literature. It is in the form of a mixture of epimers A and B.

C. Lactone of w- (3-oxo-16 / i-hydroxy-. L ⁴ -androsten 16'-yl) propionic acid

A second crop of 0.48 g of substance is obtained from the mother liquors. The whole will the end . Isopropyl ether recrystallized. A compound is obtained from F. about 204 C, which is as it is, used for the following process step.

The compound has not yet been described in the literature.

The reagent A used was prepared in the manner described above.

1.5 g of compound IVa are dissolved in 15 ecm of acetic acid containing 50 "/ h of water, then added with 3 g of sodium acetate and heated the reaction mixture with stirring and under nitrogen in an oil bath for about 1 hour at 100 ° C. It is then cooled in an ice bath and neutralized with Sodium hydroxide solution, mixed with 15 ecm of methanol and then makes it alkaline up to pH 10, neutralized the solution by adding hydrochloric acid and pouring into salt water. The resulting extract is then extracted Precipitate with ethyl acetate, wash the extract with salt water, concentrate, take the residue with a mixture of benzene and ethyl acetate and allows the solution to crystallize. Man receives 691 mg 3-oxo-16 / i-hydroxy-16u- (3 ', 4'-dihydroxybutyl) -l'-androstene (Va) as a crude product; the compound is dissolved in boiling benzene; man the solution cools, allows to crystallize, sucks off and dries. The connection has the F. 140 to 142 C.

The compound is soluble in alcohol, chloroform and ethyl acetate, slightly soluble in benzene and insoluble in water.

20th -Ο

ι = Ο

40

Analysis: CaaHsnOi; Molecular weight 376.52.

Calculated ... C 73.36. H 9.64%:
found ... C 73.0. H 9.6%.

The compound has not yet been described in the literature.

B. 3-Oxo-1 ', 16 // - epoxy-16u- (1' £ -hydroxypropyl) -l'-androstene (VI a)

150 mg of compound Va are dissolved in 10 ecm tert. Butanol and then mixed with a solution of 300 mg periodic acid, 10 ecm water and 75 mg lithium carbonate. The mixture is stirred for about 3 hours Room temperature, then adds water, sucks off the crystals that have formed and washes them with water and dries. 118 mg of compound VI a 1, R = are obtained

in 16 position

140 mg of compound VI a ii are suspended in 10.5 ecm acetone and 3.5 ecm water, and the mixture is cooled

0 C and then stirs 0.15 ecm of a mixture from 135 g of chromic acid, 115 ecm of sulfuric acid and water, made up to 500 ecm. One lets you < Rise the temperature to room temperature by stirring for a further hour; then you move mi

1 ecm of methanol to remove the excess oxidation medium to destroy, pour in water, extract the precipitate with methylene chloride, wash the Extract with water, dry it and concentrate. May takes up the residue with ether, lets crystallize sieren and receives 75 mg of compound I.

/O-

R =

in 16 position

as a crude product, which is recrystallized from a mixture of benzene and isopropyl ether. The compound has a melting point of 168 C and [u] J ^r · 39 (e 0.5% in dioxane).

The compound is soluble in alcohols, acetone, benzene, and chloroform, and sparingly soluble in ether and insoluble in water and dilute aqueous acids and alkalis.

Analysis: C22H30O3; Molecular weight
Calculated ... C 77.15, H 8.83%;
found ... C 76.9, H 8.8%.

342.46.

60 IR spectrum:

The IR spectrum shows a / -lactone bandc at 1766 cm '.

The compound has not yet been described in the literature.

Example 2

Lactone of the c> - (3-Oxo-17 / i-hydroxy-H-androsten-17u-yl ) propionic acid

= 0

I b, R = <

in 17 position

For the production of the "3-pyrrolidyl-17 / S-hydroxy-17a- (3 ', 4'-dihydroxybutyl) -3-pyrrolidyl-17-oxo -.- J ³ - ⁵ - androstadiene J ³ - ⁵ - andro stages

Ri \ r

III b,> N = N

IVb,

R ₂ '

10 g of 3,17-DJoxo-J ⁴ -androEten (II b, prepared according to the method described by Ruzicka and Wettstein in HeIv. CMm. Acta, Ed. 18, p. 986 [1935], described) are added to 200 under nitrogen ecm of methanol and stir in 5 ecm of pyrrolidine. The resulting solution is stirred under nitrogen at room temperature for 15 to 20 minutes, then the resulting precipitate is filtered off with suction, triturated with methanol and dried. 11.6 g of compound IIIb are obtained as a crude product, which is used as it is as the starting compound for the process according to the invention. The compound has the F. = 224 ° C. The compound is soluble in benzene and insoluble in water and alcohol.

A. 3-Oxo-17 /} - hydroxy-17a- (3 ', 4'-dihydroxybutyl) -

. l ⁴ -andst (Vb)

25th

5.5 g of magnesium are added to 40 ecm of ether and then slowly stirred under dry nitrogen a few milliliters of a solution of 47 g of 1,2-isopropylidenedioxy-4-bromobutane (A) in 200 ecm ether. When the solution refluxes, add one at the same time in about 50 minutes with all of the above-mentioned solution and the Solution of 11.7 g of the starting compound IHb in 200 ecm benzene.

The reaction mixture is kept in a closed container with stirring for 65 hours at room temperature. The mixture is then cooled to 0 to -1 10 ° C., 50 ecm of saturated ammonium chloride solution is added, the mixture is stirred for about 30 minutes, then water is added and the mixture is decanted. The organic solution is separated off, washed with water, dried over magnesium sulfate, treated with 50 mg of hydroquinone and concentrated under nitrogen. This gives 30 g of acetonide S-pyrrolidyl-n / i-hydroxy-17 "- (3 ', 4'-dihydroxybutyl) -l ^3-5 -androstadien

i \

and Rj = - CH ₃

as a crude product, which is used as it is for the following stage.

The compound has not yet been described in the literature.

The crude compound IVb is added to 200 ecm η-hydrochloric acid and the mixture is stirred under nitrogen for 1 hour. The undissolved part is separated off, washed several times with chloroform which contains methanol, and the combined washing liquids are extracted with 50 ecm η-hydrochloric acid. The aqueous phases are combined, made alkaline by adding sodium hydroxide solution under nitrogen and with stirring, the precipitate formed is separated off, extracted with chloroform, the chloroform solution is washed with water until the wash water is neutral, dried over magnesium sulfate and concentrated under nitrogen. This gives 12 g of a crude product which was, as it is, used for the following step ate.

The compound "has not yet been described in the literature.

The compound IVb is taken as a crude product with a mixture of 36 ecm acetic acid, 36 ecm Water and 12 g of sodium acetate, stir the resulting solution for 30 minutes at room temperature, then gives 70 ecm of caustic soda and 500 ecm Add methanol to dissolve the resulting precipitate and neutralize by adding • about 20 ecm of concentrated hydrochloric acid. Then it is concentrated under nitrogen until the precipitate becomes visible, extracted with methylene chloride, washed the extract with water, dried it over Magnesium sulfate and constricts. 8.4 g of compound V b are obtained as a crude product.

The compound is purified by chromatography by adsorbing it on magnesium silicate and eluted with methylene chloride containing 8% methanol; the compound is crystallized and then recrystallizes from ether. 2.6 g of compound V b are obtained.

Further purification is carried out by recrystallization from isopropanol. You get 980 mg of compound Vb, mp = 194 ° C. A second crop of 840 mg of substance is made get the mother liquors.

The compound is soluble in alcohol, sparingly soluble in benzene and chloroform, and insoluble in water, ether and dilute aqueous acids and alkalis.

Analysis: C23H36O4; Molecular Weight = 376.52.

Calculated ... C 73.36, H 9.64%;
found ... C 73.1, H 9.5%.

The compound has not yet been described in the literature.

B. 3-Oxo-1 ', 17 / i-epoxy-17a- (1'Mrydroxypropyl) -l ⁴ -androsten (VI b)

700 mg of compound Vb are dissolved in 70 ecm tert. Butanol and 1.5 ecm of water and then stirs a solution of 1.4 g of periodic acid, 70 ecm Water and 6 ecm η-sodium hydroxide solution. The reaction mixture is stirred for about 2 hours in one closed vessel, then mixed with water and extracted the resulting precipitate with Chloroform. The organic solution is washed with salt water, dried over magnesium sulfate, filtered and concentrated. The residue is taken up in ether, crystallized and filtered off with suction.

The crystals obtained are then dissolved in benzene, the solution is filtered, concentrated and then treated with isopropyl ether; then allowed to crystallize out.

Then it is suctioned off and the crystals formed are dried. 430 mg of compound VI b are obtained as Crude product that is purified by chromatography by being adsorbed on magnesium silicate and eluted with methylene chloride containing 5% ether;

909513/1978

then it is recrystallized from ether. The compound has the mp = 160 and 192 ⁰ C and [ _a ] f = + 29.6 ° (c = 1% in dioxane). The compound forms a mixture of epimers in which form A predominates.

The compound is soluble in alcohol, benzene and chloroform, slightly soluble in ether and isopropyl ether and insoluble in water and dilute aqueous acids and alkalis.

Analysis: C22H32O3; Molecular Weight = 344.48. Calculated ... C 76.69, H 9.36%; found ... C 76.6, H 9.4%.

The compound has not yet been described in the literature.

By slow recrystallization of the above epimer mixture of benzene can be the epimeric form A isolate [a] f = + 18 ° (c = 1% in dioxane), mp = 210 ⁰ C and.

The 3-oxo-l ', 17 /? - epoxy-17a- (l'Miydroxypropyl) - £ l ⁴ -androsten (VI b) can be characterized in the form of ethers or esters, as described under Bi, Bo and B3 will.

IO

15th

Bi

3-Oxo-1 ', 17 /? - epoxy-1 Ja- (V f-methoxypropyl) - / J ⁴ -androsten (VII b)

1.00 g of 3-oxo-l ', 17 e-epoxy-17a (l'Miydroxypropyl) - /. L ⁴ -androsten (VI b) is dissolved in 25 ecm of methanol, is 0.5 ecm of n-sulfuric acid solution added, the whole thing is refluxed for 1 hour and then water is slowly added until crystallization begins. The crystals formed are then filtered off with suction and washed with water, dried, and 957 mg of 3-oxo-l ', 17 /? -Epoxy- (I' | -methoxypropyl) - / l ⁴ -andrene (VII b) are obtained as the crude product from F. = 130 to 132 ° C.

The compound VII b can be purified by recrystallization from cyclohexane. It has a temperature of 134 to 135 ° C and [a] f = + 132.8 ° (c = 0.6% in dioxane).

The compound forms a mixture of epimers in which form B predominates.

The compound is soluble in ether, benzene and chloroform, slightly soluble in cyclohexane and insoluble in water and dilute aqueous acids and alkalis.

Analysis: C23H34O3; Molecular weight = 358.50. Calculated ... C 77.05, H 9.56%; found ... C 77.2, H 9.6%.

The compound has not yet been described in the literature.

1900 mg of the above crude product of compound VII b are washed several times with methanol and the compound is then dissolved in hot methanol; then the resulting solution is allowed to cool and crystallize; the crystals obtained are filtered off with suction, washed with a small amount of methanol and dried. The resulting crude product is recrystallized from methanol by dissolving in the heat and cooling, the resulting crystals are suctioned off, dried and 322 mg of 3-oxo-Y, YIβ- epoxy-17 "- (rf-methoxypropyl) - / 'l are obtained ⁴ -androsten (VII b, Epimer B) of m.p. = 143 ° C and [a] f = + 140 ± 1.5 ° (c - 0.7% in dioxane).

50

55

60

65 The compound is soluble in ether and chlorine form, sparingly soluble in cyclohexane and methanol, very sparingly soluble in alcohol and insoluble in water and dilute aqueous acids and alkalis.

Analysis: C23H34O3; Molecular weight = 358.50.
Calculated ... C 77.05, H 9.56%;
found ... C 76.8, H 9.5%.

The methanolic liquids that are formed when washing 1900 mg of crude 3-oxo-l ', 17 /? - epoxy-17a- (r £ -methoxypropyl) - / l ⁴ -aridrosten are combined and evaporated. The crystalline residue is taken up in hot methanol, the resulting solution is then cooled and allowed to crystallize.

The crystals obtained are then filtered off with suction, dried, recrystallized from methanol by dissolving in the heat and cooling, suctioned off, dried and 516 mg of 3-oxo-l ', 17 / i-epoxy-17ö- (rf-methoxypropyl ) -. J ⁴ -androsten (VII b) as a mixture of the epimers A and B to 50% each of the F. = 123 to 124 ° C and [a] f = 52.5 ± 1 ° (c = 1 ° / ₍ The compound is soluble in ether, benzene and chloroform, sparingly soluble in cyclohexane and methanol, very sparingly soluble in alcohols, and insoluble in water and dilute aqueous acids and alkalis.

Analysis: C23H34O3.

Calculated ... C 77.5, H 9.56, O 13.39%;
found ... C 77.0, H 9.5, O 13.8%.

From mixtures of epimers rich in form B, only 50% of epimer B and the mixture of epimers A and B are isolated by fractional crystallization. On the other hand, chromatography by adsorption on silica gel offers the possibility of separating epimers A and B, starting from a mixture of 50% each of the epimers mentioned. 900 mg of the mixture of 50% each of the epimers A and B are chromatographed in this way by adsorbing on silica gel and eluting with benzene which contains 2.5% acetone. The first eluates showing negative rotatory power are collected, re-adsorbed on silica gel and eluted with benzene containing 2% acetone; the product obtained is recrystallized from pentane; 53 mg of substance with a temperature of 125 ° C. and [a] l ° = -25 ± 2 ° (c = 0.65% in dioxane) are obtained. The compound is the epimer A of 3 - Oxol ', 17 / i-epoxy-17a- (r £ -methoxypropyl) -. l ⁴ -andast (VII b).

B ₂

3-Oxo-l ', 17 / i-epoxy-17 "- (l'f-benzyloxypropyl) - / i ⁴ -android

A suspension of mg 3-oxo-r, 17 ^ -epoxy-17rz- (l'f-hydroxypropyl) -l ⁴ -androsten (VIb) in 7 ecm benzene with 0.2 ecm n-sulfuric acid solution and 1 ecm benzyl alcohol and the reaction mixture is stirred under reflux for about 2 hours. The mixture is then allowed to cool, an excess of potassium carbonate is added, the mixture is stirred, filtered off with suction, about 1 ml of triethylamine is added and the mixture is concentrated; the remaining benzyl alcohol is then removed with steam and allowed to crystallize for about hours; one sucks the

1,291,535

crystals stand off and wash them with Isopropylätfaer.

The compound obtained is dissolved in hot cyclohexane, then crystallized out by cooling, and 214 mg of 3 - oxo - Γ, 17/5 -epoxy-17a - (Vξ- benzyloxypropyl) -J ⁴ -androstene are obtained. Repeated crystallization results in a compound of F. = 158 ⁰ C and [a] l ° = -35 ± 1.5 ° (c = 0.7 ⁽⁾ / o in dioxane).

The compound is soluble in benzene and chloroform, slightly soluble in alcohols, ether and cyclohexane and insoluble in water and hexane.

Analysis: C29H38Q3; Molecular Weight = 434.5 ?.
Calculated ... C 80.14, H 8.81 ^o / o;
found ... C 80.0, H 8.8%.

The compound has not yet been described in the literature.

The connection is the epiremal A (with little turning ability) of the above connection. That on The epimer mixture rich in epimer B (with high rotating power) can be obtained from the mother liquors and Uinkrystallization liquids are isolated, the one combined and then by adsorption on magnesium silicate and elution with benzene, the Contains 0.75% acetone, chromatographed. The epimer B was not crystallized.

The 3-oxo- Γ, 17 / ί-epoxy- 17α - (Vξ- benzyloxypropyl-, l ⁴ -androstene can also be obtained by adding benzyl bromide to 3-Oxoi ', 17 / i- at room temperature and in the presence of silver oxide epoxy-17a- (l '| -hydroxypropyl) -l ⁴ -androsten (VI b) can act.

To this end, 2.064 g of compound (VI b) are dissolved in 40 ecm acetone, and 7.44 ecm benzyl bromide is added added and suspended 13.86 g of silver oxide, stirred under nitrogen at room temperature for 24 hours, filtered and concentrated in vacuo. Purify with steam and chromatograph the obtained 5.35 g of crude product by adsorbing on magnesium silicate and eluting with benzene containing 1% Contains acetone.

One-time recrystallization from cyclohexane gives 404.5 mg of 3-oxo-l ', 17 // - epoxy-17a- (l'f-benzyloxypropyl) -. l ⁴ -andst of the temperature = 158 ⁰ C and MS ¹ = -29 ± 1.5 ° (c = 0.8% in dioxane); the compound corresponds to the epimer A obtained above.

B ₃

3-Oxo-1 ', 17 / i-epoxy-17a- (1' i-acetoxypropyl) -J ⁴ -androsten

689 mg of 3-oxo-1 ', 17 / i-epoxy-1 Ia- (V f-hydroxypropyl) -J ⁴ -androsten (VIb) are added to 1 ecm of pyridine, the mixture is stirred and mixed with 1 ecm of acetic anhydride. The reaction mixture is stirred at room temperature for about 65 hours and a mixture of water and ice and 1 ecm of pyridine is then added. Then it is extracted with a mixture of methylene chloride and ethanol, the extract is washed with water, dried and concentrated. The traces of pyridine are removed by washing with toluene and 782 mg of 3-oxo-l ', 17 / J-epoxy-17a- (l'E-acetoxypropyl) - are obtained. l ⁴ -androsten as a crude product, which is purified by being recrystallized successively from mixtures of isopropyl ether and benzene.

This gives a first crop of 273 mg of material, mp = 132-133 ⁰ C and [ "If = +81 ± 1.5 ° (c = 0.7% in dioxane) [rich in epimer B]. In addition, a second yield of 327 mg of substance with a temperature of 135 to 136 ° C. and [a] l ° = + 55 ° (c = 0.7% in dioxane) is obtained. The compound is a mixture of 50% of the epimers A and B.

Analysis of the product of the first crop: C2.iH3.jO4;

Molecular weight = 386.51.
Calculated ... C 74.57, H 8.86%;
found ... C 74.6, H 8.8%.

The compound of the second crop (Epinsere A and B) is soluble in ether, benzene and chloroform, Slightly soluble in cyclohexane and insoluble in water and isopropyl ether.

The connection has not yet been described in the literature.

To isolate the epimers B is crystallized the first crop (m.p. = 132 ⁰ C and [ "] £" = i-8 i °) twice in succession from cyclohexane and .isopropyläther order. This gives 81 mg of substance from

F. = 136 ° C and [α] ί ° = -t-108 ± 1.5 ° (c = 0.7% in dioxane). The substance contains about 94% epimer B and 6% epimer A.

In order to isolate the epimer A with a low rotational power, 3-oxol ', 17 /? -Epoxy-17a- (l' | -acetoxypropyl) -J ⁴ -androsten is prepared as described above, but the proportions of the compounds used are varied . From 1035 mg of 3-oxo-l ', 17 />' - epoxy-17a- (l '| -hydroxypropyl) -J ⁴ -androsten 943 mg of a first yield of mp = ss 126 ° C and [α] ί ° = + 41.5 ± 1.5 ° (c = 0.7% in dioxane). The first crop is a mixture of 40% epimer B and 60% epimer A.
This first yield of substance is then recrystallized twice in succession from isopropyl ether containing benzene.

This gives 294 mg of a first yield of substance with a temperature of 142 ° C. and [α] ί ° = + 17 ° and 140 mg of a yield of M. = 134 ° C and WS = + 59 °.

Then the substance, melting is crystallized successively = 142 ° C from cyclohexane and then from isopropyl ether, thus obtaining 107 mg of material, mp = 150 ⁰ C and [a] f = -7.5 ± 1.5 ° (c = 0.7% in dioxane). The compound is the epimer A of 3-Oxo-r, 17 />'- epoxy-17a- (r £ -acetoxypropyl ⁴ -android.

Analysis: Co-iH ^ Oj; Molecular weight = 386.51.
Calculated ... C 74.57, H 8.8%;
found ... C 74.4, H 8.8%.

The compound is soluble in ether, benzene and chloroform, slightly soluble in cyclohexane and isopropyl ether and insoluble in water.

C. Lactone of <u- (3-oxo-17β-hydroxy-J ⁴ -androsten-17a-yl) propionic acid

/ Ο

ι = Ο

Ib, R =

in 17 position

100 mg of the epimer mixture of compound VI b are dissolved in a mixture of 4 ecm Acetone and 1.5 ecm of water and then slowly stirs 0.1 ecm of a solution of 135 g of chromic acid, 115 ecm sulfuric acid made up to 500 ecm with water.

After 30 minutes, 1 ecm of methanol is added to remove excess oxidizing agent destroy, and then add 500 mg sodium carbonate for neutralization. Then you pour the reaction mixture in water, then extracted with ether, washing the extract until neutral the wash water with water, dries it, evaporates to dryness and leaves the resulting residue Crystallize with the help of a little petroleum ether.

The compound is taken up in methylene chloride, the solution is centrifuged, concentrated and mixed with a little petroleum ether, allowed to crystallize and then sucked off the crystals obtained. You get 70 mg of compound I b

Example 4

Lactone of m- (3-Oxo-17,? - hydroxy-J ⁴ -androsten-17 «-yl) -propionic acid

/ Ο

ι = Ο

Ib, R =

in 17 position

, 0

R =

in 17 position

as a crude product, which is recrystallized by recrystallization from isopropyl ether with a little methylene chloride. The connection then has the F. = - 165 C.

The compound is soluble in chloroform, slightly soluble in isopropyl ether and insoluble in water.

The IR spectrum shows a / lactone band at 1765 cm '.

Example 3
Lactone of (.j- (3-Oxo-16 / J-hydroxy- H-androsten-

16fi-yl) propionic acid

O-

F = O

LR =

in 16-position

40

45

30 mg of 3-oxo-16 / i-hydroxy-16 «- (3 ', 4'-dihydroxybutyl) are dissolved -H- androsten (V a, obtained according to Example 1) in 0.5 ecm acetic acid and then stirred 0.4 ecm of a solution of 4 g of chromic anhydride, 5 ecm of water and acetic acid, made up to 50 ecm, a. The mixture is stirred for about 5 hours at room temperature. Then add one after the other with Methanol, water and ammonia to neutralize most of the acetic acid. One extracts with methylene chloride, wash the extracts with sodium bicarbonate solution and with water, dry it and concentrated to dryness in a vacuum.

The residue is taken up with acetone containing a drop of sulfuric acid. To the Solution is added to water.

The precipitate is isolated, dried and crystallized from isopropyl ether. The crystals are suctioned off and dried; 15 mg of lactone of ω - (3-oxo-16 // - hydroxy- I ⁴ -androsten-16 «-yl) -propionic acid (I) with a temperature of 168 C and [«]: - '• 39 (c 0.5 ", () in dioxane), which is identical to the compound described in Example 1.

750 mg of 3-oxo-17 / i-hydroxy-17a- (3 ', 4'-d hydroxybutyl) -I ⁴ -androsten (V b, obtained according to Example 2) are dissolved in 12 ecm acetic acid, the en is cooled The resulting solution drops to −H15 ° C. and 10 ecm of a solution of 4 g of chromic anhydride is added with 5 ecm of water and acetic acid, made up to 50 cc. The reaction mixture is stirred for about 1 Nacr at room temperature and then 1.5 cc of methanol and water are added , extracted with methyl chloride, washes the extracts with aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to dryness in a vacuum

The residue is dissolved with 10 ecm of acetone! taken, which contains a drop of concentrated sulfuric acid; the resulting solution is left to stand still for about 40 minutes at room temperature, then water is added, the resulting precipitate is filtered off with suction, washed with aqueous acetone and dried. This gives 441 mg lactone oj- de (3-Oxo-17 / - hydroxy-l ⁴ -androsten-17-yl) -propioii acid (Ib), mp = 165 ⁰ C, which described with in the case of game 2 Connection is identical.

Example 5

Lactone of the ο> - (3-Ο \ ο-Π ß-hydroxy-. H-androsten-

17 «-yl) -propionic acid (I b)

about the Ι'ί, Ι'ί-ether oxide of 3-oxo-l '£, 17 / i-epoxy-17a- (l'i-hydroxypropyl) -H-andrbsten

Dissolve 376 mg of 3-oxo-17 / i-hydroxy-17a- (3 ', 4'-dihydroxybutyl) - H-- androsten (V b, obtained according to Example 2, A) in 4 ecm of dimethylformamide, then give up 564 mg ammonium periodate are added and the whole thing is stirred at room temperature for about 3 hours. Then 50 ecm water is added, the precipitate formed is suctioned off, washed with water, dried and taken up with hot benzene. It is filtered, concentrated, mixed with methanol, cooled to OC, the crystals which have formed are filtered off with suction, washed with methane and dried. 150 mg of Ί'ί, Γί-Äthei oxide of 3-oxo-l'i, 17 / i-epoxy-17a- (ri-hydroxy propyl) -H-androsten are obtained as a crude product, which is recrystallized from benzene with addition purifies from methanol. The compound has the F. -315 (and [a] f = - 36Jl (C = - 1% in dioxane).

The compound is soluble in benzene and chlorine form, sparingly soluble in alcohols and insoluble ii Water, methanol and dilute aqueous acids and alkalis.

Analysis: CnHo ₂ O.- ,; Molecular Weight = -670.94. Calculated ... C 78.75, H 9.31%; found ... C 78.6, H 9.3%.

The compound has not yet been described in the literature. . _; .

The compound easily hydrolyzes in acidic Environment for 3-oxo-r, 17 / i-epoxy-17 <i- (i '; 7hydroxy propyl) - H-androstene (VI b), which is converted into the lactone (Ib) according to Example 2, C. \\

Claims (8)

Patent claims: 1. Process for the production of. 1 ⁴ -steroid spirolactones of the general formula I where R is a 16 or 17 position , 0- F = O -Spirolactone group means, characterized in that 3-oxo-l ⁴ -16 or-17-oxo-androstene (II), the 3-keto group is selectively blocked by prior enamine or Enolätherbildung in a known manner ·, with the compound magnesiumorganisehen a ketonide of a 1,2-dihydroxy-4-halo-butane condensed by the known Grignard method, in the resulting ketonide of 3-enamino or 3-alkoxy-16 / i- or -H / S-hydroxy- lou- or -17h- (3 ', 4' - dihydroxybutyl) -, l ³ · ⁵ - androstadiens (IV) the protected 3-keto group and the alcohol groups of the side chain blocked in the form of the ketonide either simultaneously or successively with an acid in in a manner known per se, the side chain of the 3-0x0-16 / 3- or -H / i-hydroxy-loa or -17H- (3 ', 4'-dihydroxybutyl) -l ⁴ -androstene (V ) degrades with an oxidizing agent with simultaneous cyclization, and that one. a) the 3-oxo-l ', 160- or -l', 17 / i-epoxy-16n- or -17a- [l'f-hydroxypropyl] - obtained. l ⁴ -androsten (VI), "which can be isolated in the form of the epimers A and / or B by known methods, treated with an oxidizing agent in a manner known per se, and so the lactone of ω- (3-Οχο-16/3 - or -17 / Hydroxy-.l ⁴ -androsten-16a or -17hyl) -propionic acid (I) is obtained or alternatively b) the obtained 3-oxo-16 / i- or -17 / f-hydroxy-16h- or -17 «- (3 ', 4'-dihydroxybutyl) -. l ⁴ -androsten (V) with a strong Treated oxidizing agent and so directly receives the desired lactone (I) or that one c) the 3 - oxo -17/9 - hydroxy - 17α- (3 ', 4'-dihydroxybutyl) -I ⁴ -androsten (V b) obtained is treated with ammonium periodate in the presence of dimethylformamide, the l' £, l thus obtained £ -ether oxide of 3-oxo-l'i, 17 ^ -epoxy-17n- (l '£ -hydroxypropyl) -J ⁴ -androsten by acid hydrolysis in 3-oxo-l', 17/3-epoxy-17a- (1 '£ -hydroxypropyl) - J ⁴ -androstene (VI b) transferred and the latter treated further according to procedure a). 2. The method according to claim 1, characterized in that the ketonide is a 1,2-dihydroxy - 4 - halogen - butane 1,2 - isopropylidenedioxy-4-bromobutane (A) is used. 3. The method according to claim 1 and 2, characterized in that the condensation of the magnesium derivative of 1,2-isopropylidenedioxy-4-bromobutane with the 3-enamino-16- or -17-oxo-J ³⁵ -androstadiene ( III) in an ether-benzene mixture. 4. The method according to claim 1 to 3, characterized in that the release of the in 3-keto group blocked in the form of the enamine and the alcohol groups blocked in the ketonide form of compound IV using acetic acid in the presence of sodium acetate simultaneously. 5. The method according to claim 1 to 4, characterized in that in the form of the ketonide blocked alcohol groups of the compound IV with hydrochloric acid and then in the form of the enamine blocked 3-keto group of the compound obtained with acetic acid in the presence of sodium acetate released. 6. The method according to claim 1 to 5, characterized in that the side chain of the obtained compound V with simultaneous cyclization with periodic acid in aqueous tert. Butanol or 50% methanol and in the presence of sodium hydroxide solution or lithium carbonate degrades. 7. The method according to claim 1 to 6, characterized in that one is used as the oxidizing agent used to oxidize the compound VI obtained, chromosulfuric acid in aqueous acetone. 8. The method according to claim 1, characterized in that the compound V obtained oxidized with chromic anhydride in aqueous acetic acid. For this purpose 2 sheets of drawings 909 513Ί 978