Patent GB-1376892-A (GB)
Title: 2beta-substituted-3alpha-hydroxysteroids and their esters
IPC: C07J7/00
Filed: 1970-11-12
Abstract: 1376892 2# - Substituted - 3α - hydroxy and acyloxy-pregnanes GLAXO LABORATORIES Ltd 12 Nov 1971 [12 Nov 1970] 53911/70 Heading C2U Novel steroids of the pregnane and 19-norpregnane series which contain a 3α-hydroxy or -acyloxy group, hydrogen atoms at the 5α- and 17α-positions, two hydrogen atoms or an oxo group at the 11-position, a free or ketalized oxo group in the 20-position and in the 2#- position a substituent R which is a carboxylic acyloxy, C 1-6  alkanoylthio, tosyloxy, free or etherified hydroxy, etherified mercapto, alkyl, cycloalkyl, aryl, aralkyl, thiocyanato nitro-oxy or azido group or a halogen atom (with the exception of 2# - thiocyanato - 3α - hydroxy- 5α-pregnan-20-one and of mixtures of 2#-chloro- 3α-hydroxy-5α-pregnan-20-one or the corresponding 11-oxo compound with both the corresponding 2α - chloro - 3 - oxo - and 2α- hydroxy-3#-chloro-compounds) are prepared by reacting a corresponding 2α,3α-epoxide or a 16,17-dehydro-derivative thereof with an appropriate compound RH or a reaction system producing R- and a cation followed when necessary by protonization of a deprotonated 3α-hydroxy group and/or hydrogenation of a #<SP>16</SP>-double bond, and when a 3-ester is required, by esterification of the 3α-ol. Reagents RH include halogen hydracids, haloethanols (these may produce a mixture of 2#-halo and 2#-haloethoxy products), alcohols, carboxylic acids (chloroacetic acid may give a significant proportion of 2#,3α-dichloroacetoxy steroid; and the use of α-halocarboxylic acids in the presence of tetrahydrofuran produces 2#-[delta-(α-haloacyloxy)- butoxy]-compounds in addition to 2#-(α-haloacyloxy) - compounds), thiols, thiocarboxylic acids, nitric acid, thiocyanic acid and its salts, lithium dihydrocarbyl cuprates, aqueous acids (to form 2#,3α-diols), alkali metal azides and ptoluenesulphonic acid. Halogen atoms in resulting side chains may be replaced by other halogen atoms or by amino (including cyclic amino) groups; a cyano group in a 2#-cyanoalkoxy group may be converted via an iminoether salt into a 2#-(esterified carboxy-alkoxy)- group; and a 2# - [delta - (α - haloacyloxy)- butoxy]-group may be hydrolysed to a 2#- (delta-hydroxy butoxy)-group. 2#-Tosyloxycompounds may be converted to 2#-azido compounds by reaction with alkali metal azides. These processes may be effected on #<SP>16</SP>-steroids and the double bond subsequently hydrogenated, or reacted with a lithium dialkyl cuprate to insert a 16α-alkyl group or with reagents suitable for inserting a chloro- or alkoxy-substituent. Resulting 21-unsubstituted compounds may be converted to 21-halo or 21-acyloxy steroids by known methods. A 20-keto group may be protected during the foregoing processes by ketal formation and subsequently released. 2α,3α - Epoxy - 19 - nor - 5α - pregnane - 11,20- dione is prepared by epoxidation of 19-nor-5α- pregn - 2 - ene - 11,20 - dione, itself prepared from 3α - hydroxy - 19 - nor - 5α - pregnane- 11,20-dione via the corresponding tosylate. 2α,3α- Epoxy - 5α - pregn - 16 - ene - 11,20 - dione is similarly prepared by #<SP>2</SP>-epoxidation, as is 2α,3α - epoxy - 5α - pregn - 16 - en - 20 - one, the starting 5α - pregna - 2,16 - dien - 20 - one being prepared from 3#-hydroxy-5α-pregn-16-en-20- one via the corresponding tosylate. 3#-Hydroxy- 5α - pregn - 16 - ene - 11,20 - dione is prepared by hydrolysis of the 3#-acetoxy compound and is subsequently converted to the 3#-tosylate which is then converted to 3α-hydroxy-5α-pregn- 16-ene-11,20-dione and 5α-pregna-2,16-diene- 11,20-dione. The last-named compound with diazomethane gives (16#-H)-1<SP>1</SP>-pyrazglino-(4<SP>1</SP>,3<SP>1</SP>: 16α,17α) - 5α - pregn - 2 - ene - 11,20 - dione, this on pyrolysis gives 16-methyl-5α-pregna-2,16- diene-11,20-dione and this is epoxidized to 2α,3α- epoxy - 16 - methyl 5α - pregn - 16 - ene - 11,20- dione. 11α - Hydroxy - 19 - nor - pregna - 4,16- diene-3,20-dione is prepared from 11α,17α- dihydroxy - 19 - norpregn - 4 - ene - 3,20 - dione via the 20-semicarbazone and is subsequently converted to 19 - nor - 5α - pregnant - 3,11,20 - trione via 3#,11α,20# - trihydroxy - 19 - nor - 5α- pregnane; on reduction the product yields 3α- hydroxy-19-nor-5α-pregnane-11,20-dione. The novel steroids have anaesthetic properties and may be made up, into pharmaceutica compositions with suitable carriers. Reference has been directed by the Comptroller to Specification 943,220.