Patent GB-1268568-A (GB)
Title: NEW 18-NOR-14beta-PREGNANO-[13,14-F]-HEXAHYDRO-1,4-OXAZEPINES
IPC: C07J71/00
Filed: 1969-04-01
Abstract: 1,268,568. 18-Nor-14#-pregnano-[13,14-F]- hexahydro-1,4-oxazepines. SCHERING A.G. 1 April, 1969 [6 April, 1968], No. 16963/69. Heading C2U. The invention firstly comprises steroids of the formula (wherein X is a free or ketalized oxo group or H(α- or #-OR 2 ) in which R 2  is H, carboxylic acyl, alkyl or tetrahydropyranyl; R 1  is H, alkyl, alkenyl, alkynyl or carboxylic acyl; there is an optional 16(17)-double bond or 16,17-epoxy group present; Y is H, alkyl or OR 3  in which R 3  is H, carboxylic acyl, alkyl or tetrahydropyranyl, the alkyl or OR 3  group being α-oriented when the 16,17-bond is saturated; and W is the remainder of the steroid ring system, optionally substituted in rings A and/or B and/or C; and the alkyl groups may be substituted and, when forming part of an ether grouping, may also be interrupted by an additional oxygen atom); and acid-addition and quaternary ammonium salts thereof; and their preparation by cyclizing steroids of the formula (wherein T is H, carboxylic acyl, sulphonic acyl or tetrahydropyranyl; and Q is an α- or #-free or esterified hydroxyl group when a #<SP>8(14)</SP> or #<SP>14</SP> double bond is absent, or Q is absent when one of these double bonds is present) in a solvent and in the presence of a cyclization agent. The invention secondly comprises the compound 3α - acetoxy - N - methyl - 18 - nor - 17 - bromo- 5#,14# - pregnano[13,14 - f]hexahydro - 1<SP>1</SP>,4<SP>1</SP>- oxazepin-20-one, which is prepared by the action of cupric bromide on the corresponding 17-hydro compound (Example 7). Interconversions of compounds (I) are: (i) hydrolysis of functionally modified hydroxyl and hydrolysis of functionally modified hydroxyl and keto groups; (ii) esterification, etherification and oxidation of free hydroxy groups: (iii) reduction of keto groups and carbon-carbon double bonds; (iv) addition of R 3 OH across a 16,17- double bond; (v) 16,17-dehydrogenation; (vi) epoxidization of a double bond; (vii) cleavage of an epoxy group to form a double bond; (viii) 9α- chlorination or bromination; and (ix) salification. Preparation of compounds (II) is from the corresponding C- and D-ring-saturated 14- unsubstituted compounds (III). #<SP>35</SP>-Unsaturation is introduced by 17-bromination followed by 16,17-dehydrobromination. #<SP>14</SP>-Unsaturation is introduced into the #<SP>15</SP>-product by successive reactions with Br 2 /HOAc,NBS/azabis-isobutyronitrile and NaI. A 14#-hydroxy group (with a saturated D-ring) is introduced by 14,15- epoxidization of the #<SP>14,16</SP>-product followed by hydrobromination and then hydrogenation. A 14α-hydroxy group is introduced by microbial hydroxylation of compounds (III) with Curvularia lunata. #<SP>8(14)</SP>-Unsaturation is introduced by migration of a #<SP>7</SP>-double bond or by tert-butyl chromate oxidation of a #<SP>7</SP>-double bond to give an 8α-14α-epoxy-7-oxo compound (plus 8α,9α- epoxy-7-oxo isomer) which is reacted with Zn/HOAc to give a #<SP>8(14)</SP>-7-one. Preparation of compounds (III).-The 18- amine function is introduced by. photolysis of 20-nitrate to give an 18-hydroxyimino group which is reduced to NH 2  and alkylated. The 20- nitrite group is introduced from 20-hydroxy with nitrosyl chloride. 3#-Acetoxy-5α-pregn-7-en-20-ol is prepared by reduction of the 20-one. 20-Hydroxy-5#-pregn-7-en-3-one is prepared from 20-hydroxypregna-4,6-dien-3-one via 20- acetoxypregna-4,7-dien-3-one Compounds (I) and their acid-addition and quaternary salts are said to possess hypotensive, diuretic, positive inotropic and myotropic activity, and may be made up with carriers into pharmaceutical compositions for oral and parenteral administration.