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United States Patent Office Patented May 5, 1970 3,510,477 United States Patent Office Patented May 5, 1970. 1. 2 3,510,477 a carboxylic acyl group having from one to about twelve 22-ETHYLENE-3-OXO-STEROIDS carbon atoms. AND INTERMEDIATES When the 4'-hydroxyspirosteroid-2,4'-m-dioxan-3-one Andrew John Manson, Beaconsfield, Quebec, Canada, as or ester thereof is subjected to mild alkaline conditions signor to Sterling Drug Inc., New York, N.Y., a cor the dioxane ring is cleaved to produce a 2-methylene-3- poration of Delaware oxo-steroid (III). The mild alkaline conditions are pro No Drawing. Continuation-in-part of application Ser. No. duced by contacting the steroid with a weak inorganic 502,394, Oct. 22, 1965. This application Oct. 4, 1967, Ser. No. 672,713 base, for example, an alkali metal carbonate or aluminum Claims priority, application Great Britain, Oct. 17, 1966, oxide. 46,383/66 0 The 2-methylene-3-oxo-steroid reacts with diazometh Int. C. C07c 173/10, 169/22, 169/12 ane to give a spirosteroid-2,3'(2'o)-1-pyrazolin-3-one U.S. C. 260-239.5 39 Claims (IV-A). The latter may in part rearrange to the isomeric spirosteroid-2,3’ (2'oz) - 5 - pyrazolin - 3 - one (IV-B) under the reaction conditions and work-up procedures ABSTRACT OF THE DISCLOSURE 5 used. The pyrazolines (IV-A and IV-B) in acid medium, or by simple pyrolysis, lose nitrogen and are converted to 2,2-ethylene-3-oxo-steroids are prepared starting from a 2,2-ethylene-3-oxo-steroid (V). The nature of the acid 3-oxo-2-hydroxymethylene-steroids and proceeding suc in the acid medium is not critical and can be any conven cessively through the intermediate 4'-hydroxyspiroste tional inorganic or organic acid as well as an acid of the roid-2,4'-m-dioxan-3-ones, 2-methylene - 3-oxo-steroids, 20 Lewis type such as boron trifluoride. and spirosteroid-2,3'(2'o)-1-pyrazolin - 3 - ones, which All of the above reactions in the sequence I-V take readily lose nitrogen to form the 2,2-ethylene-3-oxo-ste place in an inert solvent at room temperature. Reactive roids. The latter and the novel precursors possess hor oxo groups in the steroid molecule can be protected by monal properties, especially progestational activity. ketalization and the free oxo compounds regenerated by treating the ketals with acid. The starting materials, the 2-hydroxymethylene-3-oxo This application is a continuation-in-part of Manson steroids (I) are a known class of compounds readily pre application Ser. No. 502,394, filed Oct. 22, 1965 now pared by reacting the appropriate 3-oxo-steroid with ethyl abandoned. formate in the presence of a strong base such as sodium This invention relates to steroids and processes for 30 methoxide or sodium hydride under anhydrous conditions. their preparation. In particular, the invention relates to The exact nature of the remainder of steroid moiety is a multi-step process for preparing 2,2-ethylene-3-oxo not critical, and it can be derived from any steroid of the steroids, as well as to the individual steps of said process general type known to have hormonal or other phar and to products of the individual process steps. macological or endocrinological properties. Such steroid The over-all process aspect of the invention can be rep 35 moieties have from seventeen to about twenty-three car resented as follows: bon atoms, not counting carbon content which may be provided by esterified hydroxy groups. Esterified hydroxy steroids are included within the scope of the invention, but the carbon content contributed by the acid moiety of the O 40 ester is not considered part of the essential carbon content 1, NH, of the steroid. HOCH-12-/ HoHo OS conditionsAlkaline The steroid moiety can be any member of the estrane, -ms of --> 18-norestrane, androstane, etiocholane (56-androstane), ... 3 pregnane or allopregnane series. The foregoing can con O=& HO1 O 45 tain varying degrees of unsaturation and a variety of sub I II stituents in the form of hydrocarbon radicals or functional groups conventionally employed in the steroid art. Repre 2C-CH2 "-p sentative of the steroid moieties which make up the com pounds of the invention are those having at position 17 a CH2 CH2N2 . I/ N. acid 50 hydroxy, acyloxy, oxo, or both a hydroxy and a lower --> -- -> alkyl radical, characteristic of the androgenic and anabolic O- O= Os. or heat steroids; or a lower-alkenyl, lower-alkynyl, acetyl, hy III IW-A. IW-B droxyacetyl, 1,2-dihydroxyethyl, 1-hydroxyethyl, and the like radicals, characteristic of the progestational and adrenal cortical steroids. The steroid moiety can also have one or more substituents at other positions of the nu cleus, for example, hydroxy, acyloxy, or oxo radicals at positions 6, 7, 11, 12 or 16; halogen atoms, preferably fluorine, chlorine or bromine, for example, at the 4-, 6-, 7-, 9-, 12-, 16-, 17- or 21-positions; and lower-alkyl groups, for example, at the 4-, 5-, 6-, 7-, 11- or 16-posi tions. The steroid moiety can also have one or more dou The above structures are partial formulas representing ble bonds, for example, at the 4,5-, 6,7-, 9,11-, 15, 16-, a portion of Ring A of the steroid molecule including the 16,17- or 17,20-positions. The steroid moiety usually pos 2- and 3-positions. sesses angular methyl groups at C10 and C13, although A 2-hydroxymethylene-3-oxo-steroid (I) reacts with 18- and 19-norsteroids and 18, 19-bisnorsteroids, lacking formaldehyde to form a 4'-hydroxyspirosteroid-2,4'-m- one or both of the angular methyl groups at C18 and Co, dioxan-3-one (II). The reaction takes place readily with respectively, are also representative steroids. out heating, preferably in the presence of pyridine. The The 18, 19-bisnorsteroid, 18, 19-norsteroid and normal 4'-hydroxy group can readily be esterified by conventional 70 steroid moieties in the compounds of the invention con esterification procedures to produce a 4-acyloxyspiro tain, respectively, seventeen, eighteen and nineteen car steroid-2,4'-m-dioxan-3-one wherein the acyl group is bon atoms plus any carbon content which may be pro 3,510,477 3 4. vided by one or more nuclearly substituted carbon con A further product aspect of the invention resides in taining radicals, up to and including a total of about 2-methylene steroids of the formula twenty-three carbon atoms, exclusive of ester radicals. CH When acyloxy radicals are present in the steroid moie C3 ty, the acyl radicals are preferably derived from car &=o boxylic acids having from one to about twelve carbon atoms, conventionally employed in the steroid art, and CH krz having a molecular weight less than about 250. Repre sentative of the acyl radicals which can be present are lower-alkanoyl radicals, e.g., formyl acetyl, propionyl, butyryl, isobutyryl, caproyl, heptanoyl, octanoyl, tri O CH2= / methylacetyl, and the like; carboxy-lower-alkanoyl radi cals, e.g., succinyl (6-carboxypropionyl); cycloalkyl-lower Oc alkanoyl radicals, e.g., B-cyclopentylpropionyl, B-cyclo III-A. hexylpropionyl, and the like; benzoyl; phenyl-lower-al 5 wherein Z is hydrogen or hydroxy. The 20-oxo group kanoylor-alkenoyl radicals, such as phenylacetyl, g-phen can be protected in the form of a ketal which is readily ylpropionyl, cinnamoyl, and the like; and phenoxy-lower cleaved to the free 20-oxo compound with dilute acid. The alkanoyl radicals, such as phenoxyacetyl, and the like. In ketals are within the purview of the invention and the 20 the acyl radicals containing phenyl, the benzene ring of oxo compounds and the ketals thereof are considered Sub the phenyl can, if desired, bear any number and kind of 20 stantial equivalents. substituents as will be obvious to the chemist skilled in A further product aspect of the invention resides in this art, and including, but not limited to, lower-alkyl the spirosteroid-2.3 (20)-1-pyrazolin-3-one of Form (e.g., methyl), lower-alkoxy (e.g., ethoxy), lower-alkylthio ula IV-A and the spirosteroid-2,3'(2'o)-5'-pyrazolinl-3- (e.g., ethylthio), halogen (including fluorine, chlorine, ones of Formula IV-B. An especially preferred group bromine and iodine), nitro, and trifluoromethyl. 25 A product aspect of the invention resides in the 4'-hy of compounds, derived from readily available starting ma droxyspirosteroid-2,5'-m-dioxan-3-ones of Formula II. terials, comprises those having the formula An especially preferred group of compounds, derived from R readily available starting materials, comprises those hav Y'l-z ing the formula 30 Xc H.-E. Y N N." Yitz N O Xe 35 O= 61, ych, Y i. () W-C N O Ho?o 40 Y t 2. i x-/N I-A Hg C wherein R is hydrogen, lower-alkyl, lower-alkenyl, lower 45 N NH alkynyl, acetyl, hydroxyacetyl, 1,2-dihydroxyethyl or 1 O hydroxyethyl; R is hydrogen or methyl; X is H2, (H)(OH) or O; Y and Y are hydrogen or methyl; and Z i. is hydrogen or hydroxy, Zbeing restricted to hydroxy when 50 IW-D R is hydrogen, lower-alkyl, lower-alkenyl or lower-alkynyl. wherein R is hydrogen, lower-alkyl, lower-alkenyl, lower Also included are compounds of the above Formula II-A alkynyl, acetyl, hydroxyacetyl, 1,2-dihydroxyethyl or 1 having a double bond in the 45-position, or two double hydroxyethyl; R is hydrogen or methyl; X is H2 (H)(OH) bonds in the 4,5- and 6,7-positions, and carboxylic acid or O; Y and Y are hydrogen or methyl; and Z is hydrogen esters, including 3-enol esters, of the foregoing in which 55 or hydroxy, Z being restricted to hydroxy when R is hy the acyl group has from one to twelve carbon atoms of drogen, lower-alkyl, lower-alkenyl or lower-alkynyl.
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