US3600412A - 6,1'-spirocyclopropyl compounds of the androstane series - Google Patents

6,1'-spirocyclopropyl compounds of the androstane series Download PDF

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US3600412A
US3600412A US442525A US3600412DA US3600412A US 3600412 A US3600412 A US 3600412A US 442525 A US442525 A US 442525A US 3600412D A US3600412D A US 3600412DA US 3600412 A US3600412 A US 3600412A
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cyclopropane
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ene
androst
androstane
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Norman A Nelson
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Pharmacia and Upjohn Co
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Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

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  • This invention relates to novel 6,l-spirocyclopropyl compounds of the androstane series, to processes for the production thereof and to novel intermediates. More particularly, this invention relates to compounds represented by the following structural formulae:
  • novel compounds of this invention represented by the above structural formulae are anabolic, androgenic, estrogenic, hypocholesteremic, antifertility and progestational agents and are useful for all of the medicinal purposes to which these agents are used, for example, as protein builders, in treatment of atherosclerosis because of their lipid (e.g., chloesterol) normalizing effects, for the treatment of gynecologic disorders, controlling libido, birth control, and for the control of unwanted pests, such as rats, mice, pigeons, starlings, and other rodents and birds, by preventing their procreation.
  • lipid e.g., chloesterol
  • novel compounds represented by the above structural formulae are useful in the treatment of animals and birds, and are particularly useful in the treatment of humans and valuable domestic animals. They can be administered in conventional dosage forms, such as pills, tablets, capsules, syrups, or elixirs for oral use, or in liquid forms which are suitable for injectable products. They can also be administered topically in the form of ointments, creams, lotions, and the like, with or without coacting antibiotics, germicides or other materials forming advantageous combinations therewith.
  • 'Got-(T-hYdIOXYGlhYl) group is first introduced into the selected androstane, for example a compound of Formula I-A or I-C, by one of three alternative routes designed hereinafter as routes A, B and C. These routes and the compounds produced are represented by the following reaction schemes.
  • acyl means the acyl radical of an organic carboxylic acid preferably a hydrocarbon carboxylic acid of 1 to 16 carbon atoms, inclusive, for example, saturated and unsaturated aliphatic acids, and aromatic acids such as acetic, propionic, butyric, isobutyric, tert.-butylacetic, valeric, isovaleric, caproic, caprylic, decanoic, dodecanoic, palmitic, acrylic, crotonic, cyclobutanecarboxylic, cyclopentanecarboxylic, cyclopentenecarboxylic, cyclohexanecarboxylic, dimethylcyclohexanecarboxylic, benzoic, toluic, naphthoic, ethylbenzoic
  • lower aliphatic hydrocarbon radical means a saturated or unsaturated aliphatic hydrocarbon radical containing from 1 to 4 carbon atoms, inclusive, such as alkyl, for example methyl, ethyl, propyl, butyl, and isomeric forms thereof, alkenyl, for example, vinyl, propenyl, butenyl and isomeric forms thereof, and alkynyl, for example, ethynyl, propynyl, butynyl, and isomeric forms thereof.
  • alkyl means an alkyl radical of one to eight carbon atoms, inclusive, such as methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, and isomeric forms thereof.
  • cyclic amino radical means a saturated to 9 ring atom cyclic amino radical and is inclusive of pyrrolidino, alkylpyrrolidino such as Z-methylpyrrolidino, 2,2- dimethylpyrrolidino, and the like, piperidino, alkylpiperidino such as Z-methylpiperidino, 3-methylpiperidino, 4,4- dimethylpiperidino and the like, alkylpiperazino such as 4- methylpiperazino and the like, morpholino, alkylmorpholino, such as Z-methylmorpholino, 3methylmorpholino and the like, hexamethyleneimino, homomorpholino, homopiperidino, thiamorpholino, octamethyleneimino, and the like.
  • the 5a,6a-epoxides and 55,6,B-epoxides of Formulae IA and LC employed as starting materials in the process of this invention are for the greater part known or can be prepared from known compounds by known methods such as those set forth below and in the preparations appended hereto.
  • the starting materials of Formulae IA and I-C can be prepared from known compounds of the following formula:
  • heptylene, 1,2-octylene glycol and the like preferably in an organic solvent such as benzene, toluene, xylene, methylene chloride, and the like, and in the presence of an acid catalyst such as p-toluenesulfonic acid, benzenesulfonic acid and the like.
  • the reaction is conducted at a temperature between about 20 C. and about 200 C.
  • time required for the reaction is not critical and may be varied between about 1 and 48 hours, depending on the temperature, the ketalizing agent and catalyst employed.
  • the alkylenedioxy compounds thus obtained are then epoxidized at the 5,6-positions with a peracid such as perbenzoic, peracetic or perphthalic in accordance with methods known in the art [Campbell et al., J. Am. Chem. Soc., 80, 4717 (1958)] to produce the corresponding 50,6aand 55.6,8-expoxides of Formulae IA and'I-C.
  • a peracid such as perbenzoic, peracetic or perphthalic in accordance with methods known in the art [Campbell et al., J. Am. Chem. Soc., 80, 4717 (1958)] to produce the corresponding 50,6aand 55.6,8-expoxides of Formulae IA and'I-C.
  • the reaction is conducted in an inert organic solvent such as tetrahydrofuran, chloroform, methylene chloride, benzene, ether, diglyme, and the like at temperatures from 0 to 100 C
  • a 50,6ot-6POXYE1HC1IOS1I8I1C of Formula IA is reacted with an alkoxyacetylene magnesium halide, preferably an alkoxyacetylene magnesium halide in which the alkyl substituent contains from 1 to 8 carbon atoms, inclusive, and more particularly ethoxyacetylene magnesium bromide in accordance with the procedures disclosed in US. Pat. 3,088,946 to produce the corresponding 6B-ethynyl- 5ot-hydroxy compounds of Formula II-A.
  • the selected 6/3-ethynyl-5a-hydroxy compound of Formula II-A is then subjected to hydrolysis in the presence of an acid such as sulfuric, hydrochloric, hydrobrornic, perchloric, p-toluenesulfonic, oxalic, acetic and the like in the presence of an inert organic solvent, advantageously a solvent miscible with water such as tetrahydrofuran, acetone, a lower-alkanol, 1,2-dimethoxyethane, dioxane, dimethylformamide and the like to remove the alkylenedioxy groups.
  • the hydrolysis can be carried out within a relatively wide temperature range such as from 0 to 50 C.
  • the hydrolysis is advantageously conducted at room temperature, i.e., of the order of 25 C. or at moderately elevated temperatures.
  • room temperature i.e., of the order of 25 C. or at moderately elevated temperatures.
  • the time required for completion of the reaction varies with the temperature employed, a period of from about 3 to 8 hours is generally sufiicient at the preferred temperature range.
  • Suitable reducing agents are lithium aluminum hydride, potassium borohydride, diborane, diisobutyl aluminum hydride, and the like.
  • the preferred reducing agent is lithium aluminum hydride in tetrahydrofuran, etherbenzene, ether, combinations thereof and the like.
  • the reaction is preferably conducted at reflux temperature and a period of 1 to 4 hours is generally suflicient for completion of the reaction.
  • the reaction can be carried out in the presence of an inert solvent, such as ether, methylene chloride, benzene, toluene and the like, or the acid can act as the solvent for the steroid.
  • an inert solvent such as ether, methylene chloride, benzene, toluene and the like
  • the reaction is carried out at temperatures from O to 80 C., with a temperature of about 25 C. being preferred.
  • the time required for completion of the reaction is from about 1 to 48 hours, depending on the acid and temperature employed.
  • the product is separated from the reaction medium by conventional methods, for example by diluting the reaction mixture with an excess of cold aqueous base, such as sodium or potassium hydroxide, and extracting the product with a water-immiscible organic solvent such as ethyl acetate, methylene chloride, toluene, benzene, Skellysolve B isomeric hexanes and the like.
  • a water-immiscible organic solvent such as ethyl acetate, methylene chloride, toluene, benzene, Skellysolve B isomeric hexanes and the like.
  • the extract thus obtained is then washed and dried and the solvent removed by evaporation or distillation.
  • the compounds of Formula I II-B are then subjected to acid hydrolysis in accordance with known methods, for example, under midly acidic conditions at moderate temperatures to remove the alkylenedioxy group or groups giving the corresponding free-x0 compounds of Formula IV-B.
  • the compounds of Formula IV-B are then subjected to dehydration with a base to produce the corresponding 6on- (2'hydroxyethyl)-androst-4-ene of Formula VA.
  • Bases which can be used include sodium or potassium hydroxide, alkali metal alkoxides, e.g., sodium methoxide or ethoxide, alkali earth hydroxides such as barium hydroxide or calcium hydroxide, and the like, in the presence or an inert organic solvent such as methanol, ethanol, dioxane, or other suitable solvents.
  • the alkaline reaction mixture can be allowed to react slowly at room temperature or the mixture can be brought to reflux temperature and refluxed until the reaction is complete, 1 to 30 minutes is usually sufiicient.
  • W is can likewise be used as starting materials in both Routes A and B, above, however, the 17-acylate group is hydrolyzed in each route to the free l7-alcohol during the reduction step if not during the conversion of LA and II-A.
  • ROUTE C In carrying out the process of Route C of this invention a 55,6,8-epoxyandrostane of Formula LC is dissolved in an inert organic solvent such as benzene, toluene, ethyl ether and the like and treated with boron trifluoride-ethyl ether under anhydrous conditions.
  • the reaction is advantageously carried out at room temperature, i.e., about 25 C.
  • a reaction time of from 1 to 8 hours is usually sufficient for completion of the reaction.
  • the product thus obtained is then separated from the reaction mixture by conventional methods, e.g., the reaction mixture is poured into water and the organic layer separated, washed, dried and concentrated.
  • the product is then treated With a base, in the same manner as disclosed in Route B, above, for the dehydration of the compounds of Formula IV-B to the compounds of Formula V-A to give the corresponding 6- 0x0 compounds of Formula II-C.
  • 6-oxo compounds of Formula II-C can be prepared by treating a 55,6fl-epoxide of Formula II-C or the corresponding, 5u,6ot-epoxide or a mixture of isomeric 5u,6u.-and 55,6-[i-epoxides with formic acid followed by treatment With a base in accordance with the procedure disclosed by Fried et al., J. Am. Chem. Soc., 81, 1235 (1959).
  • the compounds of Formula II-C wherein W is are acylated at the l7-position in accordance with methods well known in the art for acylating the l7-hydroxy groups of androstanes, for example, by reaction with the selected acid anhydride or acid halide and by reaction with an acid in the presence of an esterification catalyst.
  • Acylating agents which can be employed are organic carboxylic acids, particularly hydrocarbon carboxylic acids containing from 1 to 16 carbon atoms, inclusive, or acid anhydrides or acid halides thereof, such as those hereinbefore listed.
  • Acylates containing from 2 to 6 atoms are preferred as protecting groups.
  • the selected compound is treated with an alkyl haloacetate such as methyl bromoacetate, or other u-haloester, wherein the alkyl substituent contains from 1 to 8 carbon atoms, inclusive, and the halo substituent is bromine, chlorine, or iodine, in the presence of zinc or magnesium, and in a suitable solvent such as ethyl ether, propyl ether, butyl ether, and the like, or mixtures of these solvents with benzene, toluene, Xylene, and the like, to obtain the corresponding 6-carbalkoxymethyl-G-hydroxy compounds of Formula III-C.
  • an alkyl haloacetate such as methyl bromoacetate, or other u-haloester
  • the compounds of Formula IIIC are then subjected to dehydration with a dehydrating agent, such as thionyl chloride, N-bromoacetamide in pyridine followed by treatment with sulfur dioxide, phosphorous oxychloride, and the like, to produce the corresponding compounds of Formula IV-C, which comprises a mixture of three isomeric forms, namely, the corresponding androst--ene-6-acetic acid alkyl ester, the 5a-androst-6-ene-6-acetic acid alkyl ester and the Su-androStane-A -acetic acid alkyl ester.
  • the isomeric mixture thus obtained can be used in the next step without separation into its various components or if desired the isomers, especially the A -isomer can be separated and purified by conventional methods such as chromatography and crystallization.
  • the A and A -compounds of 'Formula IV-C are then treated with a reducing agent to obtain the corresponding 6-(2-hydroxyethyl) compounds of Formula VC, in the same manner as disclosed in Route A, above, for the conversion of the compounds for Formula IV-A to the compounds of Formula V-A.
  • Lithium aluminum hydride is the preferred reducing agent.
  • the product V-C thus obtained, comprises a mixture of two isomeric forms of the corresponding 6-(2'-hydroxyethyl) compounds, namely, the corresponding 6-(2 -hydroxyethyl)-androst-5-ene and the corresponding 6-( 2'-hydroxyethyl)-5ut-androst-6-ene.
  • a 17-acylate group is present in the compounds of Formula IV-C, it is hydrolyzed to the free l7-alcohol during the reduction.
  • the compound (V-C) is then subjected to hydrolysis to remove the alkylenedioxy group or groups present in accordance with known methods, such as disclosed in Route B, above, for the hydrolysis of the compounds of Formula III-B to the compounds of Formula IV-B.
  • hydrolysis to remove the alkylenedioxy group or groups present in accordance with known methods, such as disclosed in Route B, above, for the hydrolysis of the compounds of Formula III-B to the compounds of Formula IV-B.
  • the desired compounds of Formula V-A are recovered from the reaction mixture by conventional methods such as chromatography and/or crystallization.
  • the selected 6a-(2'-hydroxyethyl) compounds of Formula V-A are treated with one equivalent of an organic sulfonic acid halide, preferably a hydrocarbon sulfonic acid halide, containing from 1 to 12 carbon atoms, inclusive, generally in the presence of pyridine with or without co-sol'vents, such as methylene chloride, tetrahydrofuran, benzene, toluene, and the like, in accordance with the procedure disclosed in US. Pat. 3,105,083, to produce the corresponding 6a-(2-organic sulfonyloxyethyl) derivative.
  • an organic sulfonic acid halide preferably a hydrocarbon sulfonic acid halide, containing from 1 to 12 carbon atoms, inclusive
  • organic sulfonic acid halides which can be employed are the acid halides of saturated aliphatic sulfonic acids, such as methanesulfonic, ethanesulfonic, propanesulfonic, butanesulfonic, pentanesulfonic, hexanesulfonic, nonanesulfonic, dodecanesulfonic, Z-propanesulfonic, 2 butanesulfonic, Z-pentanesulfonic, 2-octanesulfonic, tertiarybutanesulfonic; satuarted cycloaliphatic sulfonic acids, such as cyclopentanesulfonic and cyclohexanesulfonic; aralkyl sulfonic acids such as phenylmethanesulfonic, and phenylethanesulfonic; and aryl sulfonic acids such as benzenesulfonic, o-
  • the 6a-(2-sulfonyloxyethyl) compounds are then subjected to a displacement reaction under basic conditions to effect ring closure at the 6-position.
  • Ring closure is effected under a wide range of conditions and with a wide variety of bases.
  • bases which can be used are alkali metal alkoxides such as potassium tert.-butoxide, sodium methoxide, lithium ethoxide, and the like, sodium or potassium hydroxide in alcohols or aqueous alcohols, secondary amines in alcohols such as pyrrolidine in methanol, alkali earth hydroxides such as barium or calcium hydroxide, and the like.
  • the reaction is advantageously conducted in an organic solvent such as alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, tert.-butanol, and the like; tetrahydrofuran, dioxane or other suitable solvent.
  • an alkali metal alkoxide is used the reaction is preferably conducted using the corresponding alcohol. There is thereb obtained the corresponding androst-4-ene-6,l-cyclopropane-3-one of Formula I.
  • Substituents other than sulfonyloxy such as chlorine, bromine, iodine, quaternary ammonium ions and the like can be used effectively in the displacement reaction. These substituents can be introduced into the 6-(2'-hydroxyethyl) side chain in accordance with known methods.
  • the compounds of Formula I, wherein W is no n can be acylated to give the corresponding l7-acylates of Formula II in the same manner as hereinbefore disclosed for acylating the compounds of Formula IIC.
  • Acylating agents which can be employed in the preparation of the above acylates are organic carboxylic acids, particularly hydrocarbon carboxylic acids containing from 1 to 16 carbon atoms, inclusive, such as those acids hereinbefore listed or acid anhydrides or acid halides thereof.
  • the 17,8- hydroxy compounds of Formula I can also be esterified at the l7-position in accordance with methods known in the art to produce the corresponding 17B-phosphate and 17psulfate esters thereof. See for example Hirschmann et al., Chem. and Ind., 682 (1958) and Butenandt et al., Z. PhysioL, 259, 222 (1939).
  • the 50,6zx-6POXld88 of Formula I-AA are reacted in accordance with the procedure of Route A, above to introduce a 6a-(2-hydroxyethyl) group.
  • the selected a,6oc-pOXld6 is reacted with an alkoxyacetylene magnesium halide to produce the corresponding 6 6-ethynyl- 5a-hydroxy compound of Formula II-AA, which is then subjected to hydrolysis in the presence of an acid to produce the corresponding 3-oxo-6/3-acetic acid alkyl ester (III-AA).
  • the latter compound is then reacted with a secondary cyclic amine to give the corresponding 3- enamine (IV-AA).
  • the enamine thus obtained is then treated with a reducing agent to produce the corresponding 6-(2'-hydroxyethyl) 3 enamine (when an ll-oxo group is present it is concomitantly reduced to an 115- hydroxy group) which gives on hydrolysis the corresponding 6a-(2 hydroxyethyl)-androst 4 ene of Formula V-AA.
  • the compounds of Formula III can be reduced to the saturated A-ring compounds of Formula IV in accordance with known methods, for example using hydrogen with a catalyst such as palladium on charcoal or using lithium or sodium in liquid ammonia with or without co-solvents such as ether, tetrahydrofuran, benzene and the like. See Djerassi, Steroid Reactions, Holden-Day, Inc., San Francisco, p. 304 (1963).
  • the compounds of Formulae III and IV can be reduced in accordance with known methods to obtain the corresponding 3,8-hydroxy compounds of Formula VI, for example using sodium borohydride in the presence of pyridine. See Steroid Reactions, supra, page 139.
  • the compounds of Formula III can also be selectively reduced to the corresponding 3B-hydroxy-A compounds of Formula V in accordance with known methods, for example, using lithium aluminum tri-t-butoxyhydride in tetrahydrofuran or with sodium borohydride in an alkanol 12 such as ethanol, isopropanol and the like. See Steroid Reactions, supra, page 138.
  • the llfi-hydroxy compounds of Formulae III and IV can be oxidized at the ll-position by known methods for oxidizing llfl-hydroxy groups of steroids, for example with chromic acid, an N-haloamide or N-haloimide, e.g. N-bromoacetamide in pyridine, and the like to give the corresponding ll-oxo compounds.
  • the compounds of Formulae V and VI can also be oxidized at the ll-position. These compounds are first acylated at the 3-position to protect the 3/3-hydroxy group, using mild acylation conditions, for example using an anhydride of an organic carboxylic acid, particularly an anhydride of a hydrocarbon carboxylic acid containing from 1 to 16 carbon atoms, inclusive, such as those acids hereinbefore listed, in the presence of pyridine. The 3fiacylates of V or VI thus obtained are then oxidized at the ll-position in the manner disclosed above to produce the corresponding Sfl-acyloxy-ll-oxo compounds. These Zip-acylates can, if desired, be hydrolyzed under mildly basic conditions to obtain the corresponding 3,8-hydroxyll-oxo compounds by known methods, for example using aqueous sodium bicarbonate.
  • the compounds of Formulae III, IV, V and VI, the corresponding l-oxo compounds and the 3B-acylates of the 3,8-hydroxy compounds can be acylated to give the corresponding 17,8-acylates in accordance With know meth ods for acylating the 17,8-hydroxy group of 17ot-alkylated steroids.
  • Acylating agents which can be employed in the preparation of the above acylates are organic carboxylic acids, particularly hydrocarbon carboxylic acids containing from 1 to 16 carbon atoms, inclusive, such as those acids hereinbefore listed or acid anhydrides or acid halides thereof, in the presence of an acylation catalyst such as pyridine or with the selected anhydride in the presence of an alkali earth carbonate, such as calcium carbonate.
  • an acylation catalyst such as pyridine
  • an alkali earth carbonate such as calcium carbonate.
  • 35-acylate group When a 35-acylate group is already present prior to the l7-acylation reaction, mixed esters are obtained in which the acyl radical at the 3-position can be different from that at the l7-position.
  • the 35,17,6- diacylates can be selectively hydrolyzed using a mild base such as sodium bicarbonate to give the corresponding 35- hydroxy-17fi-acylates.
  • the conversion of the compounds of Formula VII to the compounds of Formula VIII is carried out by selective reduction in accordance with known methods, for example, using sodium borohydride in an alkanol or lithium aluminum tri-t-butoxide hydride in tetrahydrofuran, ether, diglyme, and the like as hereinbefore disclosed for the conversion of the compounds of Formulae III to V.
  • the compounds of Formula VII are reduced to the saturated A-ring compounds of Formula XV in accordance with known methods; for example using hydrogen with a catalyst such as palladium on charcoal or using lithium or sodium in liquid ammonia with or without co-solvents such as ether, tetrahydrofuran, benzene and the like. See Djerassi, Steroid Reactions, Holden-Day, Inc., San Francisco, page 304 (1963).
  • the conversion of the compounds of Formula VH or XV to the compounds of Formula XVI is carried out using a reducing agent, for example, sodium borohydride or potassium borohydride in pyridine, and the like.
  • a reducing agent for example, sodium borohydride or potassium borohydride in pyridine, and the like.
  • the conversion of the compounds of Formulae VIII and XVI, wherein R is acyl to the compounds of Formulae IX and XVII respectively is carried out by reacting the starting steroid of this step with dihydropyran in the presence of a Lewis acid, such as boron trifluoride etherate, p-toluenesulfonic acid, sulfuric acid, Zinc chloride, and the like.
  • a Lewis acid such as boron trifluoride etherate, p-toluenesulfonic acid, sulfuric acid, Zinc chloride, and the like.
  • the reaction is carried out in the presence of an organic solvent, such as ether, benzene, and the like.
  • the reaction. is carried out at temperatures of from 0 to C., with a temperature of about 25 C. being preferred.
  • the hydrolysis of the compounds of Formulae IX and XVII to the compounds of Formulae X and XVIII, respectively, is carried out in accordance with known methods, for example, in an alkaline aqueous medium using relatively water soluble alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydroxides, alkaline earth hydroxides, e.g., sodium or potassium carbonate, calcium carbonate, sodium or potassium hydroxide, calcium hydroxide, and the like, at a temperature of from about 10 to and for about 1 to 20 hours.
  • the reaction is carried out in an inert watermiscible organic solvent, such as methanol, ethanol, isopropanol, and the like.
  • the oxidation of the compounds of Formulae X and XVIII to the compounds of Formulae XI and XIX, respectively, is carried out by reacting the starting steroid of this step with an oxidizing agent in the presence of an organic solvent.
  • Suitable oxidizing agents are chromic anhydride-pyridine complex, chromic anhydride/sulfuric acid, sodium dichromate, and the like.
  • Suitable solvents are pyridine, acetone, acetone-Water, and the like.
  • Chromic anhydride-pyridine complex is the preferred oxidizing 15 agent.
  • the reaction is carried out at temperatures of about to 50 C. for about 2 to 20 hours.
  • the removal of the tetrahydropyranyl ether group is carried out by treating the compounds of Formulae XI and XIX with an acid in the presence of an organic solvent to obtain the compounds of Formulae XII and XX, respectively.
  • the acid is a mineral acid, such as hydrochloric, hydrobromic, sulfuric acids, and the like.
  • Suitable solvents are acetone-Water, methanol-water, di methylsulfoxide-water, dimethylformamide-Water, and the like.
  • the reaction is conveniently carried out at a temperature of 10 to 50 C. for from about 5 to 50 hours.
  • the 17-oxo compounds of Formulae XII and XX are then treated with an appropriate alkylating agent such as the appropriate Grignard reagent, alkyl or alkenyl lithium compound or alkali metal alkyne derivative to obtain the compounds of Formulae XIII and XXI, respectively.
  • an appropriate alkylating agent such as the appropriate Grignard reagent, alkyl or alkenyl lithium compound or alkali metal alkyne derivative
  • the l7-oxo compounds (XII or XX) can be reacted with the appropriate alkyl, alkenyl, or alkynyl magnesium halide in the presence of a solvent such as diethyl ether, tet-rahydrofuran, benzene and the like, to produce the corresponding compounds of Formulae XIII and XXI, wherein R is alkyl, alkenyl or alkynyl as hereinbefore defined.
  • the Grignard reagent is employed in 'an excess of the order of about 5 to 10 moles per mole of steroid.
  • the alkylating agent employed to convert XII and XX to the corresponding 17-alkylated compounds XIII and XXI, respectively, in the case where R is alkyl or alkenyl can be the appropriate alkyl or alkenyl lithium compound.
  • the reaction is conducted advantageously in the presence of an inert solvent such as ether, benzene, toluene, and the like.
  • the lithium compounds are employed advantageously in excess of the stoichiometric proportion and are employed preferably in an amount of at least 2.5 moles per mole of steroid.
  • the reaction is ordinarily conducted at room temperature but may also be conducted at elevated temperatures up to the boiling point of the solvent employed.
  • the compounds having the Formulae XIII and XXI, wherein R represents a 2 to 4 carbon atom alkynyl group can also be prepared by reacting compounds XII or XX with an alkali metal derivative, for example, the sodium or potassium derivative of the corresponding alkyne.
  • the reaction is carried out preferably in the presence of an inert solvent such as dimethylformamide or dimethylsulfoxide.
  • the compounds of Formulae XIII and XXI can be oxidized to the compounds of Formulae XIV and XXII,
  • an oxidizing agent in accordance with known methods, for example, using manganese dioxide in chloroform, chromium trioxide in pyridine, chromic acid in acetone and the like. See for example Djerassi, Steroid Reactions, Holden-Day, Inc., San Francisco (1963), pages 104-ll8.
  • the compounds of Formulae XII and XX can likewise be oxidized in the manner disclosed above, to give the corresponding 3-oxo compounds.
  • the compounds of Formulae VIII, XVI, XII, XX, XIII and XXI can be acylated at the 3-position using mild acylation conditions known in the art for acylating secondary hydroxy groups in steroids as hereinbefore disclosed.
  • the compounds of Formulae XIII, XXI, XIV and XXII and the B-acylates of XIII and XXI can be acylated at the 17-position in accordance with methods known in the art for acylating tertiary hydroxy groups of steroids as hereinbefore disclosed.
  • the compounds of Formulae XIII and XXI will be concomitantly acylated at the 3- position to give the corresponding 3,17-diacylates.
  • the 3-oxo-A compounds of this invention represented collectively by Formulae XXIII and XXIV, below, exclusive of the l9-nor compounds, can be dehydrogenated at the 1,2-position by fermentation or chemical dehydrogenation to give the corresponding A compounds of Formulae XXV and XXVI, respectively.
  • R R R X, Y and W have the same meanings as hereinbefore given.
  • novel compounds of Formulae XXV and XXVI are anabolic, androgenic, hypocholesteremic, antifertility and progestational agents, which can be used and administered as hereinbefore disclosed for other compounds of this invention having similar activities.
  • Fermentative dehydrogenation comprises the use of microorganisms such as Septomyxa, Corynebacterium, Fusariurn, and the like, under fermentation conditions well known in the art (e.g., US. 2,602,769; 2,902,410 and 2,902,411). Where Septomyxa is used to effect the dehydrogenation it is found to be adavntageous to use with the substrate and medium a steroid promoter.
  • the free alcohols are usually employed as starting material for the fermentative dehydrogenation process. However, the corresponding 17-acylates can be used. In these cases the 17- ester group is generally hydrolyzed during the fermentation process giving the corresponding free alcohols (XXV) and XXVI.
  • the free alcohols can be acylated in the same manner as previously disclosed for acylating the corresponding A -compounds.
  • Chemical dehydrogenation can be carried out with selenium dioxide according to known procedures, see for example Meystre et al., Helv. Chim. Acta, 39, 734 (1956) or with 2,3-dichloro-5,6-dicayno- 1,4-benzoquinone in a suitable organic solvent such as dioxane or benzene, see for example Djerassi, Steroid Reactions, Holden-Day, Inc., San Francisco (1963), p. 232.
  • the l7-acylates are generally preferred as starting materials in the selenium dioxide dehydrogenation reaction giving the corresponding A -compounds of Formulae XXV and XXVI.
  • the 17-acylates thus obtained can be saponified, if desired, by methods known in the art to give the corresponding 17-free alcohols.
  • R is hydrogen, acyl, alkyl, cycloalkyl, aralkyl, aryl, heterocyclic nucleus, or substituted derivatives thereof, and the dotted line appearing between carbon atoms 4 and represents a single bond linkage or a double bond linkage in which when a single bond linkage is present the configuration of the hydrogen attached at the 5-position is u(alpha).
  • acyl and alkyl used above have the same meanings as previously given.
  • cycloalkyl means a cycloalkyl radical of 3 to 8 carbon atoms, inclusive, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • aralkyl means an aralkyl radical of 7 to 13 carbon atoms, inclusive such as benzyl, phenethyl, phenylpropyl, benzhydryl, and the like.
  • aryl means an aryl radical of 6 to 12 carbon atoms, inclusive, such as phenyl, tolyl, xylyl, naphthyl, diphenyl, halophenyl, such as p-fluorophenyl, nitrophenyl, and the like.
  • heterocyclic nucleus means a ring system of from 4 to 9 carbon atoms, inclusive, containing at least one substituent selected from the group consisting of nitrogen, sulfur and oxygen, such as 2 pyridyl, S-pyridyl, 3-pyrimidyl, 3-pyrimidyl, 3-quinolyl, 4-quinolyl, 2morpholinyl, 2-thiomorpholinyl, 2-pyranyl, 3-thiophenyl, 2-furyl, Z-indolyl and the like.
  • the pyrazoles of Formulae XXIX and XXXIII are [3,2-c1-pyrazoles whereas those of Formulae XXX and XXXIV are [2,3-d]-pyrazoles.
  • R is hydrogen
  • novel pyrazoles of Formulae XXIX, XXX, XXXIII and XXXIV, and the novel intermediates XXVIII and XXXII are anabolic, androgenic, hypocholesteremic, antifertility and progestational agents which can be used and administered as hereinbefore disclosed for the other compounds of this invention having similar activities.
  • pyrazoles of this invention are prepared in accordance with procedures well known in the art. See for example U.S. Pats. 3,116,287 and 3,067,194 and Clinton et al., J. Am Chem. Soc., 1478-1491 (1961).
  • the compounds of Formulae XXVII and XXXI are treated with an alkyl formate and sodium hydride in an inert atmosphere to produce the corresponding 2-hydroxymethylene compounds of Formulae XXVIII and XXXII, respectively.
  • the Z-hydroxymethylene compounds thus produced are then treated with a lower-alkanol in the presence of an acidic reagent such as p-toluenesulfonic acid to give the corresponding 2-alkoxymethylene derivatives.
  • the 2-hydr0xymethyl compounds, or the 2-alkoxy methylene derivatives thereof, are then reacted with hydrazine or a monosubstituted hydrazine to give the corresponding pyrazoles of Formulae XXIX and XXX, and XXXIII and XXXIV, respectively, which can be separated by conventional methods such as chromatography and/ or crystallization.
  • Representative monosubstituted hydrazines which can be used to prepare the pyrazoles of this invention are: alkylhydrazines, such as methylhydrazine, ethylhydrazine, propylhydrazines, butylhydrazines, ,B-hydroxyethylhydrazine, cycloalkylhydrazines; arylhydrazines including phenylhydrazine and the substituted phenylhydrazines, such as o-, m-, and p-halophenylhydrazines, o-, m-, and p-tolylhydrazines, 0-, rm, and p-alkoxyphenylhydrazines, 0-, m-, and pnitrophenylhydrazines, l-hydrazinonaphthalene, 2- hydrazinopyridine, 3-hydrazinopyridine, 4-hydrazinopyridine, thydrazinopyr
  • the compounds of Formulae XXVIII, XXIX, XXX, XXXII, XXXIII and XXXIV can be acylated at the 17- position in accordance with known 17- acylation methods as hereinbefore disclosed to give the corresponding 17,8- acylates.
  • R is hydrogen the N-acyl-17f3-acylates will be concomitantly produced giving compounds wherein the acyl groups orient at R and the 17-position are the same.
  • Acyl groups present at R and/or the 17-position can be removed by known methods, for example, by treating the compound with sodium hydroxide in methanol, aqueous alcoholic potassium bicarbonate and the like.
  • N-acyl groups present at R can be selectively removed by treatment with an aqueous organic acid such as formic acid or acetic acid.
  • the N-unsubstituted 17fi-acylates thus obtained can then be reacylated in the same manner as previously disclosed to give compounds wherein the acyl group at R and the l7-position. are different.
  • the pyrazoles of Formulae XXIX and XXX, wherein R is hydrogen, can be oxidized to the corresponding l7-oxo compounds in accordance with methods knoWn in the art, for example, using chromic acid in pyridine or using the Oppenauer oxidation [Djerassi, Steroid Reaction, Holden-Day, Inc., San Francisco, page 98 (1963)].
  • novel 3-desoxy compounds of Formulae XXXVI, XXXVIII, XL, XLII, XLIII, XLIV, XLV and XLVI, and the 17,6-acylates of XLIV and XLVI are anabolic, androgenic, hypocholesteremic, antifertility and progestational agents which can be used and administered as hereinbefore disclosed for the other compounds of this invention having similar activities.
  • the compounds of Formulae XXXVI and XL can be converted to the compounds of Formulae XXXVIII and XLII, respectively, by reduction of the A -bond using methods known in the art, for example, catalytic hydrogenation using palladium on charcoal.
  • the compounds of Formulae XL and XLII are converted to the corresponding 17-oxo compounds of Formulae XLIII and XLV in accordance with methods hereinbefore disclosed, for example, the chromic acid oxidation of the compounds of Formulae X and XVII to the compounds of Formulae XI and XVIII, respectively.
  • the 17-oxo compounds of Formulae XLIII and XLV are then converted to the corresponding 17,8-hydroxy-17e-lower-aliphatic hydrocarbon compounds of Formulae XLIV and XLVI, respectively, using the methods hereinbefore disclosed for the conversion of the compounds of Formulae XII and XX to the compounds of Formulae XIII and XXI, respectively.
  • Additional ptuification of the products can be accomplished by conventional methods, for example, by elution chromatography from an adsorbent column with a suitable solvent such as acetone, methanol, ethanol, ether, methylene chloride and Skellysolve B (hexanes), mixtures and combinations of these solvents; also by gradient elution chromatography from an adsorbent column with a suitable mixture of solvents, such as methylene chloride- Skellysolve B, acetone-Skellysolve B, and the like.
  • a suitable solvent such as acetone, methanol, ethanol, ether, methylene chloride and Skellysolve B (hexanes), mixtures and combinations of these solvents
  • a suitable solvent such as acetone, methanol, ethanol, ether, methylene chloride and Skellysolve B (hexanes)
  • the enarnine (3.7 g.) in about 50 ml. of benzene was added with stirring to a slurry of 1.7 g. of lithium aluminum hydride in ml. of ether under a nitrogen atmosphere.
  • the mixture was refluxed for 60 minutes, cooled, and 14 ml. of ethyl acetate was added cautiously followed by 12 ml. of water.
  • the mixture was concentrated to a paste in vacuo.
  • a solution of 120 ml. of methanol and 20 ml. of acetic acid was added to the residue thus obtained and the mixture was stirred at 50 C. for a period of about 15 minutes, cooled and a solution of 25 g. of sodium hydroxide in 150 m1.
  • EXAMPLE 2 17 -hydroxy-6a- 2'-hydroxyethyl) -androst-4-en- 3-one (V-A)
  • the mixture is poured into 500 m1. of ice and water containing 25 g. of sodium hydroxide and extracted with warm ethyl acetate.
  • Zinc turnings were purified by dipping them briefly in dilute hydrochloric acid, water, acetone and then drying them in a vacuum oven. A mixture was prepared consisting of 5 g. of these purified zinc turnings, a trace of iodine, 100 ml. of dry benzene and 100 ml. of anhydrous ether under an atmosphere of nitrogen. To this stirred mixture was added 5 g. of the 3-ethylenedioxy-17B-acetoxyandrostan-6-one and 2 ml. of methyl bromoacetate. For the next three 45-minute intervals, 2.5 g. of zinc was added and at the 90-minute interval 2 ml. of methyl bromoacetate was added.
  • Example 3 substituting as starting material in Example 3 other 55,6fi-epoxides of Formula l-C in place of 5[3,613-ep0xy-3-ethylenedioxyandrostan-175-01, for example:
  • EXAMPLE 4 l7fi-hydroxyspiro [androst4-ene-6,1-cyclopropane1-3-one (I) A homogeneous mixture of 1.90 g. of dried 17B-hydroxy 6a (2-hydroxyethyl)-androst-4-en-3-one (V-A), 50 ml. of methylene chloride, 3 ml. of dry pyridine, and 1.10 g. of p-toluenesulfonyl chloride was allowed to stand at room temperature for about 18 hours. The mixture was diluted with methylene chloride and washed with water, dilute hydrochloric acid, dilute sodium bicarbonate solution, water and dried. A trace of pyridine was added to the organic layer before concentrating it in vacuo to give a residue comprising l7p-hydroxy-6a-(2'-tosyloxyethyl)-androst-4-en-3-one.
  • the crude tosylate residue thus obtained was dissolved in about 50 ml. of anhydrous t-butyl alcohol and 0.80 g. of potassium t-butoxide was added with stirring under a nitrogen atmosphere.
  • the mixture was warmed to 35- 40 C. for about 1.5 hours, cooled and neutralized with acetic acid.
  • the mixture was concentrated in vacuo and the residue was dissolved in methylene chloride and the organic solution was washed with dilute hydrochloric acid, dilute sodium bicarbonate solution, water, dried and concentrated in vacuo.
  • the residue was chromatographed on Florisil.
  • EXAMPLE 6 11 8,17fl-dihydroxy-17rx-methyl 6a (2'-hydroxyethyl)- androst-4-en-3-one and 11p,17p-dihydroxy-9a-fluoro- 17a-methyl 6a (2'-hydroxyethyl)-androst-4-en-3-one
  • 5a,6a-epoxy-3-ethylenedioxy-17u-methylandrostane-1lfi,17B-diol (I-AA) as the starting steroid in place of 5a,6a-epoxy-3-ethylenedioxyandrostan-17fi-ol is productive of 11 ,8,l7(3-dihydroxy-17otmethyl 6a-(2'hydroxyethyl)-androst 4 en 3 one (V-AA).
  • the ll-oxo compounds of Formula I-AA can likewise be used as starting materials in Example 6. However, during the lithium aluminum hydride reaction the ll-oxogroup is reduced to llB-hydroxy.
  • EXAMPLE 7 11,8,17/3-dihydroxy 17a. methylspiro[androst 4 ene- 6,1-cyclopropane]-3-one (III) and 11,8,175-dihydroxy- 9u-fluoro a methylspiro[androst-4-ene-6,1'-cyclopropane]-3-one ('III) Substituting in Example 4, llB,l7ot-dihydroxy-l7amethyl-6w(2-hydroxyethyl)-androst-4-ene-3-one or 115, l7u-dihydroxy-9ot-fluoro 17oz methyl-6a(2'-hydroxyethyl)-androst-4-en-3-one as the starting steroid in place of 17B-hydroxy 6a (2'-hydroxyethyl)-androst-4-ene-3-one, is productive of 115,17/3-dihydroxy 17a methylspirolandrost-4-ene-6,1-cyc
  • EXAMPLE 9 17 a-methylspiro [5 a-androstane-6, 1-cyclopropane] 3,5, 1 113,17fi-triol (VI) To a solution of 2.5 g. of 115,175 dihydroxy 170L- methylspiroIandrost 4 ene 6,1 cyclopropaue1-3-one (III) in pyridine is added 1.0 g. of sodium borohydride. After stirring for about 5 hours, acetic acid is added to the reaction mixture until the excess 'borohydride is destroyed. The crude product is then extracted with methylene chloride.
  • Example 9 is productive of:
  • EXAMPLE 10 17a-methylspiro[androst-4-ene-6,1'-cyc1opropane] 35,115,17/3-tri0l (V) To 5 g. of 11B,17B-dihydroxy-17a-methy1spiro[androst- 4-en-6,1-cyclopropane]-3-one (III) in 125 ml. of purified tetrahydrofuran, cooled to between 5 C. to -15 C., there is added in small portions with stirring g. of lithium aluminum tri-t-butoxy hydride. The reaction mixture is allowed to gradually come to room temperature and the excess lithium aluminum tri-t-butoxy hydride is destroyed by the addition of dilute acid.
  • the extract is washed with dilute acid, dilute base, Water, dried and concetntrated in vacuo.
  • the residue is chromatographed on g. of silica gel wet packed in m1. of chloroform and 20 ml. of methanol.
  • the column is eluted with chloroform containing increasing proportions of absolute ethanol and those fractions which by thin-layer chromatographic analysis show the presence of the desired product are taken to dryness and recrystallized from ether to give 3,8-acetoxy-l7a-methylspiro[androst-4-ene- 6,1-cyclopropane]11B,17,8diol.
  • 3fl-acy1ates of the above starting steroids such as the Zip-acetate, 3,8-butyrate, 3,8- valerate, 3,8 hexanoate, 3/3 trimethylacetate, 3,8 isobutyrate, 3,8 isovalerate, 3B cyclohexanecarboxylate, 35 cyclopentylpropionate, 35 *benzoate, 3B hemisuccinate, 3B phenylacetate, 3B undecylenate, 3fl-maleate, 3B-citraconate and the like, can be prepared by substituting in place of acetic anhydride, the appropriate acid anhydrides or acid halides of organic carboxylic acids,
  • hydrocarbon carboxylic acids of from 1 to 16 carbon atoms, inclusive, previously listed.
  • EXAMPLE 12 175-hydroxy-17a-methylspiro [androst-4-ene- 6,1-cyclopropane]-3,1l-dione
  • a suspension of chromium trioxide pyridine complex prepared from 300 mg. of chromium trioxide and 5 ml. of pyridine.
  • the reaction mixture is allowed to stand at room temperature until the reaction is complete, a period of about 18 to 24 hours is usually sufficient. Water and methylene chloride (1:1) is then added and the mixture is stirred thoroughly.
  • 35-acylates can be substituted as the starting steroid in Example 12, in place of the 35-a'cetates named above, to obtain the corresponding 35-acy1oxy-11-oxo compounds.
  • EXAMPLE 13 175-propionyloxy-l15-hydroxy-17oc-methylspiro- [androst-4-ene-6,1-cyclopropane]-3-one
  • a solution of 2.5 g. of 115,175-dihydroxy-17a-methylspiro[androst-4-ene-6,1'-cyclopropane] 3 one (III), 5 ml. of pyridine and 2.5 ml. of propionic anhydride is heated until the acylation is complete as deter-mined by thin-layer chromatography. Water is then slowly added to the reaction mixture and the product extracted with methylene chloride, washed with dilute sodium hydroxide, saturated sodium chloride solution, dried and the solvent removed.
  • 175-acylates of 115,175 dihydroxy- 17a-methylspiro[androst 4 ene 6,1 cyclopropane] 3-one such as the 175-acetate, 175-butyrate, 175-valerate, 175-hexanonate, 175 isobutyrate, 175 isovalerate, 175- cyclohexanecarboxylate, 175-cyclopentylpropionate, 175- benzoate, 175-hemisuccinate, 175-phenylacet'ate, 175-undecylenate, 175-maleate, 175-citraconate, and the like, can be prepared by reacting the 17-free hydroxy compound with the appropriate acid anhydride or halide of an organic carboxylic acid, among which are the hydrocarbon carboxylic acids of 1 to 16 carbon atoms, inclusive, previously listed.
  • EXAMPLE 14 175-propionyloxy-17a-methylspiro[androst-4-ene- 6,1-cyclopropane] -3 5,115-diol
  • a mixture comprising 2.0 g. of 35,175-dipropionyloxy- 17a-methylspiro[androst 4 ene 6,1'-cyclopropane]- 115-01, ml. of 5% potassium carbonate in methanolwater (4:1) solution is allowed to stand at room temperature until the selective hydrolysis is complete; the progress of the reaction can be followed by thin-layer chromatography, about 18 to 20 hours is usually sufficient.
  • 17fl-triol can likewise be selectively hydrolyzed to remove the Sfl-acyiate group, to give the corresponding 17fi-acyloxy-17u methylspiroIandrost 4 ene 6,1- cyclopropane]-313,1lfl-diol.
  • reaction mixture is washed with dilute hydrochloric acid, dried and chromatographed over a Florisil column packed wet with commercial hexanes.
  • the column is eluted with Skellysolve B containing increasing amounts of acetone and those fractions which by thin-layer chromatography and infrared absorption show the presence of the desired product are taken to dryness and recrystallized from mixtures of acetone-water and acetone-Skellysolve B to yield 17fl-acetoxyspiro[androst-4 ene 6,1 cyclopropane]- 3 3-o1 (VIII).
  • the ether solution is stirred for about 16 hours, extracted successively with sodium bicarbonate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to yield 17fi-acetoxyspiro[androst-4-ene-6,1-cyclopro pane]-3,8-ol 3-tetrahydropyranyl ether (IX). This residue is employed in the following example without further purification.
  • EXAMPLE 21 3 ⁇ 3-hydroxyspiro[androst 4-ene 6,1-cyclopropane1-l7- one B-tetrahydropyranyl ether (XI)
  • the residue comprising spiro[androst-4-ene-6,l-cyclopr0pane]-3fl,l7,B-diol 3-hydropyrany1 ether (X) (obtained in Example 20) is taken up in 10 ml. of pyridine and added to pyridine-chromic acid complex prepared from 2 g. of chromic anhydride in 20 ml. of pyridine.
  • reaction mixture is stirred for about 5 hours at room temperature, diluted with a 1:1 mixture of ether and benzene and filtered on a Celite (diatomaceous earth) pad.
  • the filtrate is washed successively with dilute acid, Water, saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to yield a residue comprising BB-hydroxyspiro [androst-4-ene-6,1-cyclopropane]-17-one 3 tetrahydropyranyl ether (XI) which was used Without further purification in the following example.
  • the corresponding 17fi-hydroxy- 3-ones such as 17B-hydroxyspiro[androst-4-ene-6,1-cyc1opropane]-3-one and the like, can be substituted as startmg material in place of the 3B-hydroxy-17-ones in Example 23, to obtain corresponding 3,17-diones, such as spiro[androst-4-ene-6,1-cyclopropane] 3,17-dione and the others named in the immediately preceding paragraph.
  • EXAMPLE 24 A solution of 2.75 g. of 3fihydroxyspiro[androst-4- ene-6,1'-cyclopropane]-17-one (XII) in 70 ml. of tetrahydrofuran is added over a short period with stirring under an atmosphere of nitrogen to 25 ml. of a 3 M solution of methylmagnesium bromide in diethyl ether. The resulting mixture is heated under reflux for approximately 4 hours. To the mixture so obtained is added carefully with stirring an iced ammonium chloride solution followed by 130 ml. of methanol and 25 ml. of aqueous sodium hydroxide. The mixture is stirred at 40 C.
  • Example 24 Using the procedure of Example 24 but replacing methyl-magnesium bromide by ethyl magnesium bromide, propylmagnesium bromide, isopropylmagnesium bromide, butylmagnesium bromide, allylmagnesium bromide, vinyl magnesium bromide, propenyl magnesium bromide, isopropenyl magnesium bromide, and 2-butynyl bromide, and the like, there are obtained the corresponding 17a-ethyl, 17a-propyl, 17a-isopropyl, 17a-butyl, 17a-allyl, 17a-vinyl, 17a-propenyl, l7a-isopropenyl and 17a-methallyl, compounds of Formulae XIII and XXI, and the like.
  • EXAMPLE 25 17a-ethynylspiro [androst-4-ene-6,1-cyclopropane] 318,17/3-di0l (XIII)
  • a volume of 2 ml. of a 20 percent by weight suspension of sodium acetylide in xylene is centrifuged and the solid which separated is taken up in ml. of redistilled dimethylformamide.
  • To the resulting mixture is added 0.5 g. of 3B hydroxyspiro[androst 4 ene-6,l'-cyclopropane]- 17-one.
  • the mixture so obtained is maintained under an atmosphere of nitrogen for about five hours at the end of which time the excess sodium acetylide is destroyed by dropwise addition of water.

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