Patent GB-1380246-A (GB)
Title: 3alpha-hydroxy-androstanes and esters thereof
IPC: A61K31/573
Filed: 1970-12-17
Abstract: 1380246 3α-Hydroxy-androstane compounds and esters thereof GLAXO LABORATORIES Ltd 16 Dec 1971 [17 Dec 1970 (2)] 60064/70 and 60070/70 Headings C2U and C2C Novel 3α-hydroxy-5α-androstanes and 3α- hydroxy-#<SP>4</SP>-androstenes which possess essentially an 11-oxo group, a 17α-hydrogen atom and a 17#-carboxyl, esterified carboxyl, carbamoyl, mono- or di-substituted carbamoyl, cyano, formyl or acetalized formyl group, and which optionally possess further ring double bonds and/or substituents and 3-esters thereof, are prepared (i) when the 17#-substituent R is to be CO 2 H, by oxidation of pregnanes containing 17#-acetyl group; (ii) when R is to be esterified CO 2 H, by esterification of the products of (i); (iii) when R is to be CONH 2 , optionally substituted, by reaction of the products of (i) or derivatives thereof, such as esters and halides, with ammonia or appropriate amines; (iv) when R is to be CHO, by reduction of compounds wherein R is -COhal, or by oxidation of 20,21- dihydroxy-pregnanes; and (v) when R is to be CN, by dehydration of the products of (iii). These products may be esterified in the 3-position, and the 17-formyl compounds may be converted into acetals. #<SP>4</SP>-3α-Ols and their acylates may be prepared by neucleophilic displacement by an OH or O acyl group of an allylically replaceable substituent at the 3#- position. Also, 3α-ols may be prepared by stereospecific reduction of 3-ones; 3α-acyloxy compounds may be prepared by reacting 3#- hydrocarbonsulphonyloxy-5α-androstan-11-ones with carboxylic acids or salts thereof; 3#- alkyl-3α-ols may be prepared by reaction of 3-ones with metal alkyl derivatives; or by reaction of 3-spiro-2<SP>1</SP>-oxiranes with a complex metal hydride (giving 3#-methyl products) or a metal alkyl; products possessing a 2#-substituent, Z may be prepared by re acting 2α,3α-epoxides with a compound ZH furnishing an anion Z-, followed, where a metal derivative of the 3α-ol is first formed, by treatment with a proton source; products having a #<SP>1</SP>-double bond may be prepared by dehydrohalogenation of 2#-halo compounds, with possible protection of the 3α-OH groups as a tetrahydropyranyl ether; products containing an amino substituent in a side chain of an ester may be prepared by esterifying an OH group with an alcohol containing a readily eliminatable substituent such as a halogen atom and then reacting the product with ammonia or an appropriate amine; and 3α-acyloxy products may be hydrolysed to 3α-ols. If an 11-oxo group is reduced in any of these processes it must subsequently be reoxidized. The foregoing processes may also be effected on corresponding pregnanes which are then oxidized as described above. 16α-Alkyl substituents may be insertedinto #<SP>16</SP>-compounds by standard procedures. If protection of the 3α-OH group is needed in any of these processes this may be effected by conversion to an ether or ester, particularly the nitrate ester, with subsequent hydrolysis. Any of the foregoing processes may also be effected on the starting materials and intermediates described below where appropriate. 17#-Halocarbonyl-steroid-starting materials are prepared :from the corresponding 17#-carboxylic acids by standard procedures. 2α,3α-Epoxy-steroid starting materials are prepared by converting 3-ols to their tosylates, converting these to #<SP>2</SP>-steroids and epoxidizing these. 3α,20#,21 - Trihydroxy - 5α - -pregnan - 11 - one is prepared by reduction 3α,21-dihydroxy-5α- pregnene-11,20-dione, prepared in turn by hydrolysis of the 21-acetate. 3# - Hydroxy - 17# - methoxycarbonyl - androst- 4-en-11-one is prepared by reduction of the 3-one, and is subsequently converted to the corresponding 3#-dichloroacetoxy compound. 3α - Hydroxy - 19 - nor - 5α - pregnane -11,20- dione is prepared from 11α, 17α-dihydroxy-19- norpregn-4-ene-3,20-dione via 11α-hydroxy-19- norpregna - 4,16 - diene - 3,20 - dione, 19 - nor- 5α - pregnane - 3,11,20 - trione, and 3#,11α,20#- trihydroxy - 19 - nor - 5α - pregnane. 20,20- Ethylenedioxy-3#-methyl-5α-pregnane-3α-11#-diol is prepared from 5α-pregnane-3,11,20-trione-20- ketal via (3R)-20,20-ethylenedioxy-11-oxo-5α- pregnane-3-spiro-2<SP>1</SP>-oxirane. N - ethyl - N - (2 - hydroxy ethyl) - p - anisidine is prepared from N-ethyl-p-anisidine and ethylene chlorohydrin. The novel 3α-ols (except those containing a free 17#-carboxyl or carbamoyl group) are anaesthetics and may be made up into pharmaceutical compositions with suitable carriers.