2,891,967 United States Patent Office Patented June 23, 1959 2 compound can be shown by the partial formulas as 2,891,967 follows: SULFONIC ACIDESTERS OF 1-(2-HYDROXY GH, Chs ETHYL)-2-METHALLYL DODECAHYDRO C-C=C. CH, -CH, PHENANTHRENE COMPOUNDS AND PROCs 5 C s-le ESSES OF PREPARING THE SAME -CH COOR -CECHOH Lewis H. Sarett, Princeton, N.J., and William F. Johns, 'Morton Grove, E., assignors to Merck & Co., Inc. Rahway, N.J., a corporation of New Jersey (I) / (II) 10 4. No Drawing. Application January 8, 1957 CH Serial No. 632,974 -CH-C=CH, CH-CO-CH 6 Claims. (C. 260-340.9) Hild M -CHCH-O-SO2R1 CHCH-O-SOR This invention relates to cyclopentanopolyhydrophenan 5. threne compounds and processes of obtaining the same. (III) (IV) More particularly, it is concerned with a novel process for converting polyhydrophenanthrene compounds to CH cyclopentanopolyhydrophenanthrene compounds. Spe O cifically, it is concerned with the preparation of dl-11 20 keto progesterone and d1-11-hydroxy progesterone, and novel polyhydrophenanthrene compounds useful in pre D paring the same. This application is a continuation-in-part of our co pending application Serial No. 310,134, filed September 25 (V) 17, 1952, now Patent 2,786,064. i wherein R represents hydrogen, an alkyl radical, an aryl The preparation of steroid substances by total syn radical, or an aralkyl radical, and R represents an alkyl thesis involving the formation of the four ring system, radical, an aryl radical or an aralkyl radical. the introduction of angular methyl groups at pesitions In accordance with the foregoing flow sheet, the start 10 and 13, and the placing of desired functional Sub 30 ing polyhydrophenanthrene compound having a methally stituents in the ring system presents a formidable chal substituent at C-2 and a carboxymethyl or esterified lenge. In addition to these difficulties, the problem is, carboxymethyl substituent at C-1 (I) is reacted with an further complicated by the stereochemistry of steroidal alkali or an alkaline earth metal or an alkali or alkaline substances. Thus, saturated steroids, with a minimum of earth metal aluminum hydride to form the correspond six asymetric centers, are capable of existing in at least 35 ing primary alcohol (II). This latter compound is then sixty four stereochemical modifications. However, in treated with an organic sulfonyl halide in the presence view of the therapeutic value and importance of steroids of a tertiary amine to form the sulfonic acid ester (III). such as cortisone and the like, and the scarcity of raw In the next step of our process, the sulfonic acid ester materials suitable for use as starting materials in the is oxidized to convert the 2-methallyl substituent into an preparation of cortisone and related compounds, efforts 40 acetonyl substituent and form Compound IV. Upon in have been made to prepare these compounds by total timately contacting Compound IV with an alkali, ring synthesis. closure is effected to form the 20-keto-steroid Com It is an object of the present invention to provide a pound V. new method for converting polyhydrophenanthrene ?com Alternatively, as will be apparent to those skilled in pounds to 12-cyclopentanopolyhydrophenanthrene com 45 the art, the order of carrying out these reactions can be pounds; thereby making possible the preparation of ster varied. Thus, the oxidation of the methallyl substituent oids by total synthesis. to form the acetonyl compound can be effected prior to Another object is to provide a novel process for the - the formation of the sulfonate derivative if desired. How preparation of dl-11-keto progesterone and d1-11-hydroxy ever, we have found that the sequence of the reactions progesterone from functionally substituted dodecahydro 50 shown previously is most satisfactory. phenanthrene compounds. - * '...The processes described above can be used to convert An additional object is to provide novel dodecahydro- saturatedsat pre or unsaturated polyhydrophenanthrene com phenanthrene compounds which are useful as intermedi 'pounds having in ring C the substituents depicted above ates in the synthesis of d1-11-keto progesterone and d1-11 to the corresponding steroid compounds. In addition, hydroxy progesterone. 55 the starting polyhydrophenanthrene compounds can also Other objects will be apparent from the detailed de have other functional substituents such as keto groups or scription of our invention hereinafter provided. protected hydroxyl groups in rings A, B or C of the start In accordance with our invention, we have found that ling polyhydrophenanthrene compound. When this polyhydrophenanthrene compounds having in ring C a method is utilized in the preparation of a steroid hav methallyl substituent at position 2 and a carboxymethyl 60 ing angular methyl groups at positions 10 and 13, poly or esterified carboxymethyl substituent at position 1 can hydrophenanthrenes having methyl substituents at posi be treated to effect ring closure, thereby forming ring D tions 2 and 4b are employed as starting materials. of the steroid skeleton and providing a functional sub Thus, pursuant to a further embodiment of our in stituent at position, 17. ...Our process for effecting this 65 vention, the above-described procedures may be utilized ring closure and the formation of a 20-keto pregnane in the preparation of d1-11-keto progesterone from 2,4b 2,891,96? 3 4. dimethyl - 1 - carboxymethyl - 2 - methallyl - 7 - ethyl- esterified carboxymethyl substituent in place of the car enedioxy - 1,2,3,4,4a,4b,5,6,7,8,10,10a - dodecahydrophe- boxymethyl group. These reactions may be shown as nanthrene-4-ol, or the corresponding compound having an follows: CH (H, EO -CH-C-CH, O -CH-C=CH -CHCOOR -CHCHOH rCO O (W) (VII) GH, (H, O -CH-C=CH O -CH-C=CH, -CH-CHOSOR -CHCOSOR COo^ O (XII) (VIII) O -CaCOOH O -CECOCE --CaCOSOR -CHCOSOR o' W NY. (XIII) (IX) CE C do do O EO COo^ O. CXIVA) (XA) CH (H, do CO O L. (XIWB) (XB) s fCOCH, - oCOCH 2,891,967 5 6 wherein R represents hydrogen, and alkyl radical, an aryl periodic acid, lead tetraacetate, and the like yields the radical, or an aralkyl radical, and R1 represents an alkyl, acetonyl compound. Alternatively, the preparation of aryl, or aralkyl radical. the acetonyl substituted dodecahydrophenanthrene com Thus, in accordance with the foregoing reaction scheme, pound is effected by intimately contacting Compounds the starting compound, 2,4b-dimethyl-1-(carboxymethyl)- VIII and XII with ozone, and decomposing the resulting 2-methallyl-7-ethylenedioxy - 1,2,3,4,4a,4b,5,6,7,8,10,10a ozonide derivative with a suitable reducing agent to form dodecahydrophenanthrene-4-ol, or the corresponding com Compounds IX and XIII, respectively. y pound having an esterified carboxymethyl substituent Alternatively, as indicated above, Compound VII an (VI), is first reduced to form the corresponding primary the corresponding 4-keto compound can be oxidized to carbinol (VII). This reduction is readily effected by in O form the corresponding acetonyl compounds which can timately contacting compound VI with an alkali or an then be reacted with the sulfonyl halide to obtain Com alkali metal aluminum hydride or the free metal in a suit pounds IX and XIII, respectively. able inert reaction medium (inter alia dioxane, tetrahy The ring closure of Compounds IX and XIII to form dropyran, tetrahydrofuran, a lower alkanol and the like). ring D of the steroid compounds is brought about by For example, the reduction is conveniently carried out by 5 intimately contacting these compounds with a base, such reacting compound VI with lithium aluminum hydride in as triethylamine, an alkali metal, an alkalimetal alkoxide, tetrahydrofuran at room temperature for sufficient time an alkali metal hydride, or an alkaline earth metal al to complete the reaction. The reduction can be effected koxide (inter alia, sodium, prtassium sodium methoxide, in shorter time by heating the reactants at temperatures potassium tertiary butoxide, sodium isopropoxide, sodi up to about 150° C. After the reduction with the lithium 20 um hydride, and the like). The reaction is conveniently aluminum hydride is complete, the desired product is carried out in a suitable solvent medium such as a lower readily recovered by adding water to the reaction mix alkalnol, benzene, toluene, ether or the like. Generally, ture, filtering, and evaporating the filtrate under dimin we prefer to effect this ring closure by reacting Com ished pressure. pound IX or Compound.XIII with a sodium or potassium As indicated above, dodecahydrophenanthrene com 25 alkoxide in a lower alkanol, since these reactants are pounds having either a 1-carboxymethyl substituent or an readily available and their use...results in good yields of esterified carboxymethyl substituent can be reduced in the desired steriod compounds. Thus, the ring closure accordance with our process to obtain the corresponding is conveniently effected by reacting Compounds IX or dodecahydrophenanthrene compound having at position 1 XIII with sodium methoxide in methanolic solution at a 2-hydroxyethyl substituent. Lower alkyl esters such as 30 room temperature for sufficient time to complete the re carbomethyoxymethyl, carboethoxymethyl, and carbopro action. The resulting steroid compound is recovered by poxymethyl which are readily prepared are most conven diluting the resulting reaction mixture... with water, ex iently reduced by our process. tracting the desired product with a water immiscible * In the second step of our process, the 1-(2-hydroxy solvent such as chloroform, and concentrating the result ethyl)-dodecahydrophenanthrene compound is converted 35 ing extract under diminished pressure. The producti’so to the corresponding sulfonic acid derivative (VIII) by obtained can be further purified, if desired, by chroma reaction with an alkyl, aryl, or aralkyl sulfonyl halide in tography over acid washed alumina. the presence of a tertiary amine.