1377608 3α - Hydroxy - pregnane 21 - ethers and their 3-esters GLAXO LABORATORIES Ltd 16 Dec 1971 [17 Dec 1970] 60065/70 Heading C2U [Also in Division A5] Novel 3α-hydroxy steroids of the pregnane and 19-nor-pregnane series and their C 1-5  alkanoyl esters in which the ester group may be substituted by halogen, carboxy or amino, which contain a 21-etherified hydroxy group, a 20- keto or -hydroxy group, a 17α- hydrogen atom and a 5α- or 5#-hydrogen atom are prepared (1) for the 20-ones, by reaction of 21-ols or their reactive derivatives with alcohols or phenols or their reactive derivatives; (2) for the 20-ones of the 5α-pregnane series, by stereospecific reduction of 3-keto compounds using a phosphorous acid ester and an iridium compound, to give the 3α-ols; (3) for the 3α-acyloxy-20- ones, by reaction of the corresponding 3#- hydrocarbonsulphonates with a salt of an appropriate carboxylic acid; or (4) by reaction of 20,21- epoxides (prepared for example by reduction of 20-ones having a readily eliminatable group at the 20-position using a borohydride reducing agent followed by epoxide formation under basic conditions) containing a 3α- or 3#-hydroxy group, a protected 3α-hydroxy group or a keto group with an alcohol or phenol to form a 20-ol- 21-ether, followed when required by oxidation to a 20-keto-21-ether and, when required, by process (2). In process (1) and, as indicated, in process (4) a protected 3α-ol may be used, in which case the protecting group is subsequently removed unless it is a required ester-forming group. Resulting 3α-ols may subsequently be esterified. Products containing a nitro group in the 21-ether group may subsequently be reduced to the corresponding amines; products containing a readily eliminatable group in the 21-ether group may subsequently be reacted with ammonia or an amine to replace the readily eliminatable group by an amino or substituted amino (including heterocyclic amino) group; and products containing a cyano group in the 21-ether group may be solvolysed, preferably in the presence of an alcohol to give the corresponding esters which may subsequently be hydrolysed. Products containing a substituent capable of forming a salt with an acid or base may be salified. The 21-ether substituent is preferably an alkoxy, cycloalkoxy, aralkoxy or aryloxy group which may be substituted. Substituents may be introduced into the steroid nucleus by standard methods before or after 21- ether formation, e.g. a 3α-ol may be tosylated and detosylated to give a #<SP>2</SP>-compound, this epoxidized and this reacted with a compound ZH or a compound furnishing an anion Z- and a cation to form a 3α-hydroxy-2#-Z-compound directly or via a metal derivative of the 3α-ol. A 20-oxo-#<SP>16</SP>-steroid may be reacted with a lithium dialkyl cuprate to form a 16α-alkyl-20- oxo steroid.  21-Bromo-steroids used as starting materials are prepared by halogenation of the corresponding 21-unsubstituted-20-keto pregnanes. 21-Hyd roxy steroid starting materials are prepared by lead tetracylate oxidation of the 21-unsubstituted steroids followed by hydrolysis. In these reactions the 3α-hydroxy group is preferably protected, e.g. as a nitro-oxy group. 21 - Hydroxy - 3α - nitro - oxy - 5α - pregnane- 11,20-dione is prepared from 3α-hydroxy-21- acetoxy-5α-pregnane-11,20-dione by nitration followed by hydrolysis. 3α-Nitro-oxy-11-oxo- 5α - androstane - 17# - carboxylic acid is prepared by oxidative degradation of 3α-nitro-oxy- 21-hydroxy-5α-pregnane-11,20-dione; it is subsequently converted to 21-diazo-3α-nitro-oxy- 5α - pregnane - 11,20 - dione via 17# - chlorocarbonyl - 3α - nitro - oxy - 5α - androstan - 11- one. 21-Bromo-3α-nitro-oxy-5α-pregnane-11,20- dione is prepared by nitration of the 3α-ol. The novel 20-keto-steroids are stated to possess anaesthetic, sedative and hypnotic properties, and they may be made up into pharmaceutical compositions with suitable carriers.