Patent GB-1225760-A (GB)
IPC: C07J5/00
Filed: 1967-10-05
Abstract: 1,225,760. Steroid eniminium salts. JOHN WYETH & BRO. Ltd. 10 Sept., 1968 [5 Oct., 1967; 22 March, 1968], Nos. 45473/67 and 13969/68. Heading C2U. A process for modifying a steroid containing both an α,# - unsaturated ketonic grouping and a functional group consisting of an ethylenic bond, an acetylenic bond, a carbonyl group or a functional derivative of a carbonyl group, the functional group being susceptible to reaction with an electrophilic reagent, comprises protecting the α,# - unsaturated ketonic grouping as an eniminium salt and then submitting this salt to an electrophilic reaction by reaction under acid or approximately neutral conditions with an electrophilic reagent to give a steroid in which the functional group is modified by addition or substitution by the electrophilic reagent. The α,# - unsaturated ketonic grouping can be protected by reaction with a primary or secondary amine to form the desired enamine, which is converted to a salt, preferably with a strong acid, possibly while also effecting the electrophilic reaction. Modifications include (a) reaction of an ethylenic or acetylenic bond with a halogen, halogen hydracid, hypohalous acid or peracid or its hydration, hydroboration or oxidation; (b) reaction of a compound containing a carbonyl group or its functional derivative with an electrophilic (including free radical) halogenating agent to introduce one or more halogen atoms on a carbon atom alpha to the carbonyl group (such halogen atoms may subsequently be replaced by, for example, an acyloxy group), or reaction with nitrous acid or an alkyl nitrite to introduce an oxime residue on an alpha carbon atom (which residue may subsequently be hydrolysed to an oxo group), or reaction with selenium dioxide to introduce ethylenic unsaturation α,# to the carbonyl group; (c) reaction of an enol ether or enol ester with a peracid to introduce an epoxide group (which may then be hydrolytically opened to introduce an hydroxyl group); (d) reaction of a compound containing a carbonyl group with a lead tetra-acylate in presence of an acid catalyst to introduce an acyloxy group on a carbon atom alpha to the carbonyl group; and (e) enol esterification of a carbonyl group with an acid anhydride and an acid. The protected keto group is released subsequent to these reactions by hydrolysis. Some of these processes are graphically described in Figs. 1 and 2 wherein R<SP>5</SP> is OH or Oaeyl, X is halogen or Oacyl and the other symbols have the meanings given below. Novel eniminium salts have the formulµ wherein each R is H, halogen or alkyl; R<SP>1</SP> is C 1-6  alkyl; R<SP>2</SP> is H or C 1-6  alkyl; R<SP>3</SP> is H and R<SP>4</SP> is an organic residue or both R<SP>3</SP> and R<SP>4</SP> are organic residues which may be joined together to form a heterocyclic ring with the N atom; U is H or C 1-6  alkyl; V is H, C 1-6  alkoxy or halogen; W is H, OH, = O, protected OH or protected = O; M is H or halogen; Y is H, C 1-6  alkyl, OH, = O, protected OH, protected = O, or halogen; T is 17(20) - ethylenic, bond or a 17α,20 - epoxide; Z- is an anion; and the #<SP>1</SP>- double bond is optional; provided that where M is H at least one of R, U, V and Y is not H and/or there is a #<SP>1</SP>-double bond and/or R<SP>2</SP> is H and/or R<SP>1</SP> is not CH 3 ; and provided that where in the 21-acyloxy compounds there is a 17α-OH group at least one of R, U, V and Y is not H and/or there is a #<SP>1</SP>-double bond, and/or R<SP>2</SP> is H and/or R<SP>1</SP> is not CH 3 . 16# - Methyl - pregn - 4 - ene - 3,20 - diane is prepared by reaction of 3# - acetoxy - pregna- 5,16 - dien - 20 - one with diazomethane, pyrolysis of the resulting pyrazoline to give 3# - acetoxy - 16 - methylpregn - 5,16 - dien - 20- one, catalytic hydrogenation of this to give 3# - acetoxy - 16# - methylpregn 5 - en - 20- one, hydrolysis to the 3 - ol and oxidation of this. 16α - Methyl - pregn - 4 - ene - 3,20 - dione is prepared by conversion of 3 - hydroxypregna. 5, 16 - dien - 20 - one to 3 - hydroxy - 16α- methyl - pregn - 5 - en - 20 - one and oxidation of this. Pregna - 4,16 - diene - 3,20 - dione is prepared by oxidation of 3 - hydroxypregna - 5,16- dien-20-one. Also described is the conversion of 21- acetoxy - 17α - hydroxy - 16# - methylpregn- 4 - ene - 3,20 - dione; the corresponding 16α- methyl compound; and 21 - bromo - 16α,17α- dihydroxypregn - 4 - ene - 3,20 - dione to betamethasone, dexamethasone and triamcinolone respectively by conventional processes. Specification 1,214,506 is referred to.