Patent GB-1372175-A (GB)
Title: 3alpha-hydroxy-pregn-4-enes
IPC: A61K/
Filed: 1970-11-06
Abstract: 1372175 3α-Hydroxy-pregn-4-enes and their esters GLAXO LABORATORIES Ltd 5 Nov 1971 [6 Nov 1970] 53038/70 Heading C2U [Also in Division A5] Novel pregn-4-enes and 19-nor-pregn-4-enes, excluding 3α-hydroxypregn-4-en-20-one, possess a 3α-(free or esterified hydroxy group) group, a 17#-acetyl group together with a 17α-hydrogen atom, and in the 11-position two hydrogen atoms or an oxo group. The esterified hydroxy group is derived from an optionally carboxy- or halosubstituted C 1-5  alkanoic acid. The steroids may contain further substituents in undefined positions, particularly in the 2- and 16- positions, e.g. 16-CH 3  and 2#-(alkyl, alkoxy and halo). They may be prepared, for example, (a) by nucleophilic displacement of an allylically replaceable 3#-substituent in a suitable steroid containing a 2#-hydrogen atom by the required 3α-(free or esterified hydroxy group); or (b) for a product containing a 2#-substituent, by reacting an appropriate 2α,3α-epoxy-5α-ol with R<SP>2</SP>H (R<SP>2</SP> is C 1-5  alkyl, C 1-6  alkoxy or halogen) or a compound furnishing an anion R<SP>2-</SP> and a cation to give the corresponding 2#-R<SP>2</SP>-3α-ol (or a metal salt thereof) followed by treatment with a proton source when necessary and then dehydration to form the #<SP>4</SP>-double bond, the 3α-OH group being protected during dehydration and subsequently released. Resulting 3α-ols may subsequently be esterified. In one example 3#-dichloroacetoxypregn-4-en- 20-one (prepared from the free 3#-ol and dichloroacetyl chloride) is refluxed with an acetate buffer solution to give, in addition to the required 3α-ol, some 3#-hydrozy-pregn-4-en-20-one and 5α - hydroxy - pregn - 3 - en - 20 - one; the last-mentioned is separated from the 3α-ol by preparative T.L.C. and the 3#- and 3α-ols, and other similarly formed 3α- and 3#-ol mixtures, are separated via the digitonin complexes of the 3#-ols. In another example dehydration of 3α- acetoxy - 5α - hydroxy - 2# - methoxypregnan- 20-one gives not only the required #<SP>4</SP>-compound but also 3α-acetoxy-2#-methoxypregn-5-en-20- one. 3# - Hydroxypregn - 4 - ene - 11,20 - dione is prepared by converting 3-[pyrrolidin-1-yl)- pregna -3,5 - dien - 11,20 - dione (prepared from 11-oxo-progesterone and pyrrolidine) to the enaminium chloride, reacting this with ethyleneglycol and hydrolysing to give 20,20-ethylenedioxypregn - 4 - ene - 3,11 - dione, reducing this to 20,20-ethylenedioxy-3#-hydroxypregn-4- en-11-one and'hydrolysing this; the intermediate 3,11-dione may alternatively be prepared by oxidation of 20, 20-ethylenedioxy-11α-hydroxypregn-4-en-3-one, in turn prepared by converting 11α - hydroxypregn - 4 - ene - 3,20 - dione to 11α - hydroxy - 3 - (pyrrolidin - 1 - yl) - pregna- 3,5-dien-20-one, converting this to the enaminiurn chloride and reacting this with ethylene glycol and hydrolysing to the 3-one. 3#-Dichloroacetoxypregn - 4 - ene - 11,20 - dione and 3α - acetoxy - 5α - hydroxy - 2# - methoxypregnan- 20-one are prepared by esterification of the corresponding 3-ols, 3α,5α-dihdroxy-2#-methoxypregn-20-one being in turn prepared from 2α,3α- epoxy-5α-hydroxypregnan-20-one and methanol.