DE1793687C3 - Process for making steroid compounds. Eliminated from: 1493108 - Google Patents

Description

»5

of the general formula III

oxidized or acyüert

Process according to Claim 1, characterized in that R ² in the starting substances is preferably ethyl or ethyl.

in which R ^{1 is} a methyl or ethyl group, R ^{2 is} an alkyl, alkenyl or alkynyl group with up to 6 carbon atoms, which is in the trans position to the group R ¹ , and Y is an oxo, hydroxy or acyloxy group, the Ring A contains an ethylene bond at the 4- or 5 (10) -position, as indicated by the dashed lines, and each of the hydrogen atoms H is in the trans position to the group R ¹ , characterized in that in a manner known per se ( A) a compound of the general formula II

35

- OH

(H)

50

in which X is a protected oxo group which, together with the unsaturated bonds in rings A and B, indicated by the dashed lines, are hydrolyzed by an acid to a 4 (5) - or 5 (10) -ethylene-3-octone can, hydrolyzed and optionally reduced the 3-oxo group in the product formed first to a 3-hydroxy group and this in turn optionally acylated to a 3-acyloxy group, (B) a compound of the general formula I with an ethylene bond on the 5 (10) - Position to a compound with an ethylene bond at the 4 (5) position isomerized, (C) a compound of the general formula I in which R ^{2 is} a substituted or unsubstituted alkenyl or alkynyl group, partially or completely selectively in the R group ² hydrogenated. (D) a connection

The invention relates to a process for the production of steroid compounds which are weakly estrogenic, have progestational or pituitary gonadotropin-inhibiting or other steroid hormone properties, in particular, a method of manufacture of steroid compounds of the general formula 1

R ¹

in which R ^{1 is} a methyl or ethyl group. R ^{2 is} an alkyl, alkenyl or alkynyl group with up to 6 carbon atoms, which is in the trans position to the group R ¹ , and Y is an oxo, Hj jroxy or acyloxy group, the ring A is an ethylene bond on the 4- or 5 (1O) position, as indicated by the dashed lines, and each of the hydrogen atoms H is in the trans position to the group R ¹ , in which a compound of the formula II can be obtained in a manner known per se (A)

i 793

ι ,, the X is a foamy OxQgruppe, which to -dioxygruppe (e.g. an Äthyjendioxygruppu). one «Hamen with the unsaturated bonds in the alkylene diethio or alkylene thioxy group. Rings A and B, indicated by the dashed unsaturation in rings A and B. Lines, through an acid to a 4 (5) - or is present and connected to the group X to «LO) -Ethylen-3-ketone can be hydrolyzed, 5 to form such an atomic arrangement that a hydrolyzed and optionally the 3-oxo group in acid hydrolysis containing this arrangement the first formed product to a 3-hydroxy compound in a 4,5- or 5 (10) -ethylene-3-ketone group reduced and this in turn can implement if necessary, can from a single Äthylenbin-5n, acylated a 3-acyloxy group, (B) a compound exist which ends at the 5-position, so Formation of the formula I with an ethylene bond on the io that they are in the 4,5-, 5,6- or 5,10-position 5 (! 0) control to a connection with an ethylene can. The unsaturation can also be in the form of "on

. . j-, λι * \ c »» n """:": -: -, ^. . _{there are two} ethylene bonds, one of which is on

the 3-position, so that they are in the 2,3- or 3,4-position can be and the other ends at the 5-position;

bond at the 4 (5) position isomerized, (C) a compound of the formula I in which R ^{2 is} a substituted or unsubstituted alkenyl or alkynyl group

I: is partially or fully selective in the group R ² 15 such ethylene linkers can be conjugated or

hydrogenated, (D) a compound of formula III

R ¹

- OH

(IH)

oxidized or acylated.

The group R ² can preferably be a methyl. Ethyl, vinyl, ethynyl, chloroethinyl, n-propyl, isopropyl, allyl, l-propynyl, n-butyl or 1-2-methallyl groups.

Compounds in which R 'is a methyl or ethyl group and R ^{2 is} an ethynyl group. are particularly preferred. Compounds of particular importance are 17a - ethynyl - 17 /; - hydroxy-13 // - methyl - 8 - isogen - 5 (10) - en - 3 - one, 13 / i - ethy 1-I7 (i - ethinyl - 17 / * - hydroxy - 8 - isogen - 5 (10) - en - 3 - one and 17d-ethinyl- 17,) '- hydroxy-1 Sji-methyl-S-isogen-5 (10) -en-3- ol-3-acetate.

X can be a substituted or unsubstituted ali-

to be conjugated with nichi. The compounds with an ethylene bond are derivatives of a 3-ketone which, for. B. 3-ketals, 3-mercaptols and 3-hemithioketals can be. The connections with two ethy-

Linkings are derivatives of the enol frm a

3-ketones and are z. B. of 3-enol ethers. 3-enolthioethers and 3-tert-amino compounds are formed.

Typical arrangements of the unsaturations and

the groups X are in mixtures of 3-alkoxy-3,5-

and -3,5 (10) -dienes (enol ethers from 4,5-ethylene-3-ketones). 3-alkoxy-2.5 (10) -dienes (enol ethers of 5.10-ethylene-3-ketones). 3-acyloxy-3,5-dienes (enol ester of 4,5-ethylene-3-ketones). Mixtures of 3,3-alkylenedioxy-5- and -5 (10) -enes (alkylene ketals from

4,5-ethylene-3-ketones). 3.3-alkylenedioxy-5 (10) -enes (alkylene ketals from 5.10-ethylene-3-ketones) and 3-tert-alkylamino-3.5 (6) -dienes (the tertiary enamines from 4.5-ethylene-3-ketones). Hydrolysis processes in which as

Starting materials 3-alkoxy-2.5 (10) -dienes (e.g. the 3-methoxy compounds). 3.3-alkylenedioxy-5- and -5 (10) -enes (e.g. the ~ 3.3-ethylenedioxy compounds) and 3-alkoxy-3.5 (6) - or 3.5 (10) -dienes (e.g. the 3-ethoxy compounds) can be used.

Suitable starting materials can be prepared from 13-methyl- or ethyl-8-isogona-1.3,5 (10) -trien-17-ones by known processes or 17-ols (see British Patent 991 593). So results the Birch reduction of a 13-methyl- or ethyl-3-alkoxy-8-isoeona-1.3.5 (10) -trien-17-ol the corresponding 13-methyl or ethyl-3-alkoxy-8-isogona-2.5 (10) -dien-17-ol; this can under the conditions the Oppenauer reaction oxidized to the corresponding 17-ketone and this ketone in turn with a

phatic hydrocarbon or acyl groups. ._ .. _ ..,

the one with ring A over oxygen. Nitrogen or 50 organometallic compound to introduce the sulfur is connected. together with two ethylene bonds, one of which is at the 3-position and the
other ends at the 5 position. X can also be two

substituted or unsubstituted aliphatic carbon

desired group R ² can be alkylated at the 17-position to form a 13-methyl- or ethyl-17-R ² -3-alkoxy-X-isogona-2,5 (10) -diene-17-o! to deliver.

. Alternatively, the 13-methyl- or ethyl-3-alk-

Hydrogen groups (which are linked together 55 oxy-8-isogona-2.5 (l ()) - dien-17-ol with acid to form a may be) represent those with the ring A via 3-oxogon-4,5 or 5, (10) -one or a mixture Oxygen or sulfur are linked, are hydrolyzed together by these, their 3-oxo group with a single ethylene bond, which at the 5-place through realization, thio- or hemithioketalisielung ends. tion. Enol acylation and ether formation, tertiary end

Preferably, the organic radical of X is an amine formation or the like. Protected around the group X is an unsubstituted aliphatic hydrocarbon radical. and unsaturation in rings A and B. as in X can form an alkoxy group (e.g. methoxy or structure II shown. The protected 3-oxo-ethoxy group) or a substituted alkoxy group 17-hydroxy intermediate can then be mixed with Chromium (e.g. a methoxymethoxy or dihydroxypropyl acid and pyridine are oxidized at the 3-position, oxy group), an alkylthio group (e.g. an ethyl 65 to provide a 17-oxo group which alkylates thio- or benzylthio group), an acyloxy group to introduce the desired group R ² (e.g. an acetoxy group), a disubstituted amino and a starting material for the application flow group (e.g. an N-pyrrolidyl group), an alkylene process to deliver.

A 13-methyl- or ethyl-3-alkoxy-8-isogona-1,3,5 (10Ηπβη-Π-οη is alkylated at the 17-position in order to introduce a group R ^{3 of} the type which, under Birch reduction conditions is stable (in general groups R *. which are saturated in the vicinity of the linking bond, such as, for example, alkyl groups). The 13-methyl- or ethyl-17-RM-alkoxy-8-isogon-1,3 , 5 (10) -trien-17-ol is then subjected to the Birch reduction to form a 13-methyl- or ethyl-17-R ² -3-alkoxy-8-isogona-2,5 (10) -diene -l7-ol as a starting material for the process according to the invention.

The protected 3-oxo-17-R ^a -8-iso-gonen- or gonadien-l7-oI-Zwiscbenprodukte and their preparation are known from the literature.

The hydrolysis can be effected by bringing the starting material into contact with an acid and water at a suitable temperature. If the starting material contains an ethylene bond in the 5,10-position, the α, / ί-unsaturated ketones of the invention can under the conditions of a mild hydrolysis, e.g. B. with aqueous alcoholic oxalic acid at 30 ° C and below; under more acidic conditions, such as with aqueous hydrochloric acid at 30 ° C., a certain amount of isomerization occurs to give unsaturated (4,5-alkylene) ketones and the product obtained is generally a mixture of 4,5- and 5 (10) ethylene-3-ketones. In some cases, e.g. When X is an acyloxy group, hydrolysis can be carried out using a base, e.g. B. sodium hydroxide in aqueous methanol can be carried out. Hydrolysis with water is often not necessary and only a medium containing hydroxyl groups, e.g. B. an alcohol or a carboxylic acid, necessary.

The steroidal ketones with a Äthylenbindung in the 4,5-position can also by isomerization of the corresponding compounds are obtained with a Äthylenbindung at the 5,10-position, but in ^Genera: NEN mixtures are obtained with the starting material. This isomerization can take place under basic conditions, e.g. B. with aqueous alcoholic sodium or potassium hydroxide at room temperature or with sodium alkoxide in alcohol at 6O ⁰ C are carried out. Strongly acidic conditions such as heating in methanol with concentrated hydrochloric acid can also be used. Such merization processes are the direct hydrolysis equivalents for these mixtures.

The steroid ketones, especially those with a 4,5-ethylene bond, can also be obtained through the selective reduction of other steroid ketones. whose group R ^{2 has} a greater degree of unsaturation can be obtained. For example, a compound with an ethynyl or an allyl group at the 17-position can be catalytically hydrogenated to the corresponding compound in which R ^{2 is} a vinyl, ethyl or n-propyl group. The hydrogenation of such compounds can be carried out by dissolving the compound in a suitable solvent and shaking the solution with hydrogen in the presence of a palladium or Raney nickel catalyst until the appropriate amount of hydrogen has been absorbed ^{for the selective conversion of the group R 2.}

In another method of the invention, a steroid ketone of the invention is oxidized a corresponding steroid diol of the structure St.

R ¹ R ²

HO

which contains an ethylene bond attached to the 5-position as indicated by the dashed lines indicated ends. Such an oxidation can be carried out using an Oppenauer reagent, z. B. aluminum isopropoxide and a ketone, e.g. B. Cyclohexanons or using Chromic acid can be carried out in pyridine.

Starting materials for a similar oxidation process can be used by alkylation of the corresponding 17-ketones with suitable organometallic compounds can be obtained. So can an 8-isogon-4,: 5-en-3-ol 17-one with an organomagnesium halide or an organolithium compound (e.g. lithium acetylide. Lithium chloracetylide or lithium ethyl'i reacted and the 17-alkylated compound obtained then oxidized to a 17-alkylated-8-isogon-4,5-en-17-ol-3-one to obtain. The 8-Iscigon-4.5-en-3-ol-17-ones can be obtained from 17-Oxo-13-alkyl-3-alkoxy-8-iso-gona-1,3.5 (10) -trienes by ketalization at the 17-position, Birch reduction to the corresponding Gona-2.5 (! 0) -serves. selective mild hydrolysis with acid, e.g. B. oxalic acid, to form the corresponding gon-5 (I0) -en-3-ones and. if 4,5-enes are required, isomerization with an alkali, followed by editing with a hydride transfer agent such as B. borohydride or aluminum hydride with subsequent decentralization at the 17-position under acidic conditions.

In the structural formulas 1 to III above, the \ 3 [t and 13fi compounds (defined according to the Horeau-Reichstein convention: cf. Fieser & Fieser, Steroide. Reinhold. P. 336) are not differentiated separately and have structures in these a solid line connecting an atom or group to the steroid nucleus has no chemical structure meaning, but sol! only show the point in the nucleus to which the atom or group is connected. The product of a total synthesis. which did not include a suitable level of resolution. contains the 13 / i- and 13. (- forms in an equimolecular mixture or in racemate form. If the 8-hydrogen a <om is referred to as 8-iso (8n-), this is done with reference to compounds which have the "natural" chemical structure with a 13 / (- methyl or ethyl group and optionally, for example, 17o-alkyl and -17 / i-hydroxy groups, but it includes the "unnatural" Fn anriomercn with an 8/1 hydrogen atom and a 13th «-Methyl or ethyl group and optionally, for example, 17 / <- alkyl and 17 (i-hydroxy groups. Preferably, the starting material in a process of the invention is a dissolved 13 / i-enantiomer. The invention particularly includes the Enantiomers with the 13 / f-methyl

or ethyl group in the presence or absence their 13 "-Methyl- or Äthylenantiomercn. so that the dissolved 13, '<- methyl or ethyl compounds and the 13 / f-Fortncn in admixture with the corresponding 13 ”shapes. in particular racemic mixtures.

In the following examples, the compounds obtained were racemates and are referred to as 13 '>' forms, the (±) or dl prefix of the Horeau-Reichstein convention having been omitted. The 13-methyl- or ethyl-17-R ² -8-isogonic-17-ols of the formula according to the invention can be processed together with a pharmacologically acceptable carrier to form liquid or solid pharmacological preparations.

The Gonen derivatives obtained by the process according to the invention show different properties of steroid hormones. The following compounds showed the following in conventional test procedures Efficacies: *>

17 «- ethynyl-17 / i - hydroxy - \ 2ß - methyl - 8 - isogona - 5 (10) - en - 3 - one shows progestational. pituitary gonadotropin-inhibiting and weakly estrogenic activity. Mixtures of these compounds with the e-isogon- ^ en-isomer show similar effects.

17a - ethynyl -17 / i - hydroxy -13 / ί - ethyl - 8 - isogon-5 (10) -en-3-one shows progestational, pituitary gonadotropin-inhibiting and weakly estrogenic effects.

3-acetoxy-17a-ethinyl-13 /? - methyl-8-isogon-5 (10) -en-17 /? - ol shows a progestational and pituitary gonadotropin-inhibiting effect.

35

For the quantitative determination of the effectiveness in comparison to the known compound ethinylöslradiol adult female rats were ovarian-extirpated on one side and daily for 14 days treated with the test compound. At an autopsy on the 15th day, the remaining ovary was removed and weighed. Half-castration partially frees the hypothalamic-pituitary system from ovarian control and leads to an increase in gonadotropin secretion. which at a compensatory Hypertrophy of the remaining ovary becomes apparent. Prevent effective connections this hypertrophy, presumably causing the gonadotropin secretion To block.

The following results were obtained with the compounds obtained according to the invention:

55

A. (±) - 1 Tn - ethynyl - 13.4 - methyl- |
8-isogor.-5 (IO) -en-3-on (conn- j
manure according to example 1 a. 1 b. 3) ...

B. Mixture of A with the corresponding 4-Fn-3-one (compound
according to example la)

C. (±) - 13; - Ethynyl - 17, - * - ethinyl-17, -ihydroxy -8-isogon-5 (10) - en-3-one (compound according to Example 2
and 7)

160

236

290

D. (ι) - 3 - acetoxy - 17- / - äthinyl-13, i - methyl - 8 - i'sogon - 5 (10) - en-Π, ί-ηΐ (compound according to example 5)

Ethinyl estriol
(Comparison connection)

800 1000

1
(subcutaneous)

10
(orally)

The compounds obtained according to the invention also have other activities as steroid hormones. Compound A thus shows 5% of the progestational effectiveness of progesterone in the Clauberg test according to Elton and Edgren. Endrocrinology. 1958. 63. 464-472. The compound is also a weak estrogenic agent, showing activity in the test described by Edgren and C a 1 h o u η (Amer. J. Physic, 1958, 189, 355-357); it still has 1% of the effectiveness of oestrone in the experiment described by Edgren (Proc. r, oc. Exp. Biol. and Med. 1956, 92, 569-571). In this latter experiment, the mixture containing the I ⁴ -En compound (Compound B) showed approximately 0.3% oestrone potency and Compound C showed approximately 1% oestrone potency. Compound C is also effective in the Clauberg test.

The 3-hydroxy compounds not contained in the table above are valuable intermediates for the production of the end products obtained according to the invention,

example 1

8-isogon-4- and -5 (10) -en-3-ones

a) 3-Methoxy-13 /} - methyl-8-isogona-2.5 (10) -dien-17 / i-ol (20 g) was refluxed for 3 hours under nitrogen in toluene (1.3 1) and cyclohexanone ( 283 cc) to which aluminum isopropoxide (16.7 g) had been added. treated. The product was recrystallized from aqueous methanol and Ciqab 3 - methoxy - 13 / i - methyl - 8 - tsogona - 2.5 (10) - dien-17-one. Melting point 106 to UFC (npoh softening, at 94 to 96 "C) r" _ax 1724, 1695 and 1667 cm- '.

The above-mentioned ketone (10 g) was stirred for 2 hours at room temperature with a lithium acetylide-ethylcndiamine complex (13.9 g) in dimethylacetamide (1 1. previously saturated with acetylene), through which acetylene was slowly bubbled. The mixture was poured onto an ice / ammonium chloride mixture and extracted with ether. The product was recrystallized from methanol. and nn-ethynyl-S-methoxy-B ^ -inethyl-S-isogona-2,5 (10) -dien-17 / <- ol (8e) was obtained. Melting point 174 to 182-C. v _max 3401, 3205, 1695 and 1667cm " ^1. This alcohol (8 g) was stirred for 2 hours in methanol (500 cc) and water (90 cc) which contained oxalic acid ₍ from the dihydrate. 10.3 g) The product was recrystallized from ethyl acetate and there was obtained 17a-ethynyl-17,? -Hydroxy-13, -methyl-8-isogon-5 (10) -en-3-one (5.045 g), melting point 185 bis

409 638/95

ίο

19I ⁰ Cw 3367, 3215.1088 and 1701 cm "', homogeneous according to thin-layer chromatography.

Analysis door C ₂₀ H ₂₆ O ₂ :
Calculated ... C 80.5, H 8.8%; found .... C 80.0, H 8.6%.

IO

The ob'igi ketone (0.3 g) was stirred in methanol (36 cc), concentrated hydrochloric acid (2.4 cc) and water (1.6 cc) under nitrogen for 3 hours. The entire crystalline crude product had infrared absorption bands of comparable intensities at 1704 and 1653 cm ¹ , which indicates approximately equal amounts of the 5 (10) and 4,5-ethylene-3-ketones, and after recrystallization from ethyl acetate gave crystals (0.15 g), melting point 180 to 192 ° C, _Vmwc 243 πΐμ (f 2,700,. · "," 3367, 3215, 2083, 1701 and 1650 cm " ¹ ), the penultimate band being almost twice as intense as the last band ( found C 80.4, H 8.8%).

b) 3-methoxy-13p-methy! -8-isogona-2,5 (10) -dien-17 /? - ol (3.6 g) was refluxed for 20 hours in benzene (100 cc), which ethylene glycol (7.2 cc) and Toluene-p-sulfonic acid (0.36 g), treated, wherein the water was removed by means of a water separator. The product was obtained by extraction isolated with ether, washed, dried and the solvent evaporated; one obtained 17 /? - hydroxy-13 /) - muhyl - 8 - isogona - 5 (10) - en 3 - one, ethylene ketal (3.6 g), melting point 118 to 123 ° C. Infrared maxima at 3.05, 9.1 and 9.45 µ.

This ketal (0.69 g) was under nitrogen in pyridine (10 cc) with chromium trioxide (0.6 g) for 20 hours left to stand for a long time at room temperature. Ethyl acetate (10 cc) was added and the mixture filtered through neutral aluminum hydroxide (10 g). Evaporation of the ethyl acetate eluate and crystallization from ethanol gave crystals (0.56 g), melting to 148 ° C, of 13ö-Methvl-8 '

Dimethylacetamide (150 ecm, previously saturated with acetylene), which contained a lithium acetylide-ethylenediamine complex (2.54 g), was stirred. The product was recrystallized from methanol; one received 13 /? - Ethyl - 17a - äthinyl - 3 - methoxy - 8 - isogona-2,5 (10) -dien-17 /? - ol, melting point 1146 to 149 ° C. Hydrolysis of this alcohol with methanol or aqueous oxalic acid at room temperature for 45 minutes, followed by ether extraction and chromatography on neutral aluminum oxide and elution with benzene-petroleum ether gave a product which was recrystallized from petroleum ether-benzene; B / J-ethyl-lTa-äthinyl-np-hydroxy-S-isogon * 5 (10) -en-3-one (0.75 g), melting point 145 to 152 ° C, _1Wt 3322, 3185 and 1706 cmr '.

Analysis for C ₂ | H ₂₈ O ₂ :

Calculated ... C 80.7, H 9.0%; found .... C 80.2, H 9.0%.

Example 3

17a-ethynyl-17 /? - hydroxy-13 / J-methy 1-8-isogon-5 (10) and 4,5-en-3-ones

3,3 - Ethylenedioxy -1 Iß - methyl - 8 - isogon -5 (10) - en-17-one (0.56 g) in toluene (20 cc) was added to a stirred solution of potassium (0.56 g) in tert-amyl alcohol (20 cc) added under a nitrogen atmosphere. A purified stream of acetylene was bubbled through the mixture for 20 hours. The product was eluted on aluminum hydroxide (50 g) chromatographies, with petroleum ether-benzene and benzene, and with benzene-ether (6: 4). After recrystallization from petroleum ether, S ^ -ethylene-dioxy-Wn-athinyl-13 /) - methyl-8-isogon-5 (10) -cn-17 /? - ol, melting point 168 to 170 ° C.

Dots 139 to 148 ° C, from up-ivitiuji-u- · ^^ .. «. -, -. · .. * ..,. »... ,,. ^" J. ,, »" ^ .... j. ..- ,. ...— j- -

Sf im en-3 17-diene-3-ethylene-keta ;. Infrared maxima 40 gon-5 (10) -en-17 /? - ol (0.25 g) in tert.rA.myl alcohol (5 cc)

at 5 75 and 9.0 μ. ^{un <1} toluene (5 cc) was mixed with 30% hydrogen chloride

This ketone (3.1 g) was reacted in an acid (10 cc) overnight, the mixture for 10 minutes

previously boiled suspension saturated with acetylene and the organic solvents

Lithium aluminum hydride (16 g) in tetrahydrofuran removed by vacuum distillation. The product

(300 cc) left to stand. The mixture was recrystallized on ice from ethyl acetate-petroleum ether

Eauessen acidified with 2N sulfuric acid and with and proved to be a mixed uni according to IR analysis

Ether extracted. The product was at neutral (0.138 g), melting point 175 to 190 ° C, from 17a-ethi

Aluminum hydroxide chromatography; one obtained nyI-17 /) - hydroxy-13p "-methyl-8-isogon-5 (10) -en-3-or

Htf- hydroxy-Πα- äthinyl-13 /? -methyl -8 -isogon- (about 75%) and 17a-ethynyl-17 /? - hydroxy-13 /? - methyI

5 (10> en-3-one-ethyl-ketalene (2.2 g), melting point 160 50 8-isogon-4,5-en-3-one (about 25%).
up to 164 ° C (from ether — petroleum ether).

This alcohol (1 g) was refluxed in t-amyl alcohol (10 cc), toluene (10 cc), Sn-hydrochloric acid (40 cc) for 10 minutes. The organic solvents were evaporated, water added and the mixture extracted with ether-ethyl acetate. The product was chromatographed on neutral aluminum hydroxide; one obtained 17a - ethynyl - 17 /? - hydroxy -13 /? - methyl - 8 - isogon-5 (10) -en-3-om. Mp 185-190 ° C (0.39 g); no depression by the sample prepared as in a). »■""3378, 3215, 2083, 1704 and 1642 cm" ¹ (black ..). Example 2

13 /? - ethyl-17tt-äthinyl-17 /? - hydroxy-8-isogon-5 (10) -en-3-one

13 /? - Ethyl - 3 - methoxy - 8 - isogona - 2.5 (10) - dien- Yi-one (4 g) were for 4 hours under acetylene in Example 4 55 17a-ethynyl-l 3 /? - methyl-8- isogon-5 (10) -en-3.17 / i-dioi

17a - ethynyl -1 Iß - hydroxy -13 /? - methyl - 8 - isogon 5 (10) -en-3-one (0.85 g) was reduced with sodium borohydri (0.3 g) in methanol (50 cc). After extraction on the ether, washing and drying, and recrystallization of the product from ether, 17n-ethyny 13 /? - methyl - 8 - isogonic - 5 (10) - en - 3.17 /? - diol (0.5 g melting point 193 to 203 ° C.

⁶⁵ Analysis for C ₂₀ H ₂₈ O ₂ :

Calculated ... C 79.95, H 9.33%; found .... C 79.05, H 9.33%.

Example 5

3-acetoxy-17n-ethinyl-13 / J-methyl-8-isogon-5 ( 10) -en-17 / f-ol

The above alcohol (Example 4, 0.5 g) was stirred in a mixture of pyridine (5 ml) and acetic anhydride (5 ml) at room temperature for 20 hours. After extraction with ether, washing, drying and evaporation of the solvent, the rubber obtained was recrystallized from ether-hexane; one obtained 3-acetoxy-17 "-äthinyl- 13 /? - methyl - 8 - isogonic - 5 (10) - en -17/9 - oil (110 mg), melting point 165 to 174 ° C.

Analysis for C ₂₂ H ₃₀ O ₃ :

Calculated ... C 77.15, H 8.3%;
found .... C 77.1, H 8.62%.

17 <z-Ethy I-17 / Miydroxy-13 /) - methy 1-8-isogon-5 ( 10) -en-3-one

'5

The UV spectrum showed no selective absorption; Infrared maxima (potassium bromide) at 2.90, 3.11, 5.80, 7.93, 9.03 and 9.23 µ; Infrared maxima (carbon disulfide) at 2.81, 3.06, 3.75, 7.85, 8.04 and 9.57 µ. Evaporation of the ether-hexane mother liquors gave a fraction of the title compound, m.p. 117 to 127 ° C (no lowering of the melting point of the larger fraction; infrared maxima (potassium bromide) at 3.06, 3.11, 3.80, 7.93, 8.05, 9.04 and 9.75 µ; Infrared maxima (carbon disulfide) at 2.81, 3.06, 5.76, 7.85, 8.05 and 9.85 µ.

30th

Example 6

35

A solution of 17'-ethyl-13 ^ -methyl-3-methoxy-8-isogona-2,5 (10) -dien-17-ol (0.24 g) in methanol (10 cc) was treated with concentrated hydrochloric acid ( 0.6 cc) and water (0.5 cc) and the mixture left to stand at room temperature for 2 hours. Water was added, most of the methanol was removed under reduced pressure and the residue was extracted with ether. The ethereal solution was washed, dried and evaporated. The solid residue (0.18 g) was chromatographed on neutral aluminum hydroxide and eluted with benzene-ether (19: 1) and benzene-ether (7: 3). The solid fractions were combined and crystallized from methanol to provide the title compound which contained approximately 25% nn -ethyl-17-hydroxy-13 / J-methyl-8-isogon-4-en-3-one. Melting point 139 to 164 ⁰ C; Infrared maxima at 2.9, 6.05 and 5.9 µ.

Example 7

13f; -Ethyl-17a-ethinyl-17 / i-hydroxy-8-isogon-5 ( 10) -en-3-one

13 / f- Ethyl- 3-methoxy-8-isogona- 2,5 (10) -17 // -öl (1 g) is refluxed with p-toluenesulfonic acid (0.1g) in benzene (50 cc) and ethylene glycol Treated (2 cc) for 18 hours with continual removal of water. Extraction with ether, washing, drying and evaporation of the solvent gives 13 / J - ethyl -1 7 β - hydroxy - 8 - isogone - 5 (10) - en - 3 - one, ethylene ketal. This ketal (1 g) is dissolved in pyridine (15 cc) and chromium trioxide (1 g) is added while cooling. The mixture is left to stand at 25 ° C. overnight. Extraction with ethyl acetate, filtering through a short aluminum hydroxide column and evaporation gives 13/9 ethyl-8-isogon-5 (10) -en-3, l7-dione, 3-ethylene ketal, infrared maxima 5.75 μ.

This ketal (1.5 g) is dissolved in dimethyl acetamide (50 cc) and the solution is saturated with acetylene. Lithium acetylide-ethylenediamine (0.8 g) is added and the mixture under acetylene for 4 hours touched. After pouring onto ice, extraction with benzene, washing, drying and evaporation of the Solvent gives 17'-ethynyl-13 /? - ethyl-17-hydroxy-8-isogon-5 (10) -en-3-one, cyclic ethylene ketal; Infrared absorption at 3.0 and 3.14 µ.

This alcohol (0.5 g) is dissolved in tert-amyl alcohol (10 cc), toluene (10 cc) and 5N hydrochloric acid (40 ecm) dissolved and refluxed for 10 minutes. Separation of the organic layer, evaporation to dryness and chromatography on neutral Aluminum hydroxide gives 13 / <- ethyl-17a-äthinyl-17 /? - hydroxy-8-isogon-5 (10) -en-3-one, Melting point 145 to 150 ° C.

Example 8

1 3ß- 17n-diethyl-17 /? - hydroxy-8-isogon-4,5-
and 5 (10) -en-3-one

1 3β- 17n-Diethyl-3-methoxy-8-isogona-2,5 (10) -dien-17 / f-ol (0.7 g) is dissolved in methanol (20 cm) and 6N hydrochloric acid (10 cc) 30 Stirred for minutes. Ether extraction, washing. Drying, evaporation of the solvent and recrystallization from ethyl acetate-hexane gives a mixture of the title compounds.

Claims (1)

Claim ": 1, Method of Making Steroid Compounds of the general formula I. R ¹ R ² OH (I) IO