Patent GB-1343975-A (GB)
Title: 16beta-difluoromethyl and 16-fifluoromethylene steroids and processes for their preparation
IPC: C07J75/00
Filed: 1971-04-19
Abstract: 1343975 16-Difluoromethylene and 16#- difluoromethyl steroids SYNTEX CORP 19 April 1971 [24 Feb 1970] 20637/71 Heading C2U 16-Difluoromethylene and 16#-difluoro methyl steroids are prepared by treating a steroid of the pregnane or 19-nor-pregnane series having, as the only site of keto conjugated unsaturation, a #<SP>16</SP>-20-keto grouping, with difluoromethylphenylsulphone and a C 4-8  alkali metal t-alkoxide to aive a 16α-benzenesulphonyldifluoromethyl-20-keto-steroid and (a) treating this with a C 4-8  alkali metal t-alkoxide to give a 16-difluoromethyl-#<SP>16</SP>-20-keto-steroid and hydrogenating this to give a 16#-difluoromethyl-20-keto-steroid or (b) reducing it to give a 16α-benzenesulphonyl difluoromethyl-20- hydroxy-steroid, treating this with a C 4-8  alkali metal t-alkoxide to give a 16-difluoromethylene 20-hydroxy-steroid and oxidizing this to a 16-difluoromethylene-20-keto-steroid. This lastnamed product may, by the action of potassium t-butoxide in t-butanol, sodium methoxide in methanol or hydrogen chloride in methanol be converted into the first product of process (a) above. The final products of processes (a) and (b) may subsequently be hydroxylated to give 17α-hydroxy derivatives. Novel products have the formulµ wherein R is C(α-H)(#-CHF 2 ) or C=CF 2 ; R<SP>1</SP> is H, OH or Oacyl; R<SP>2</SP> is H, GH 3 , Cl or F; R<SP>3</SP> is O or H(#-R<SP>8</SP>) in which R<SP>8</SP> is OH or O acyl; R<SP>4</SP> is H or CH 3 ; R<SP>6</SP> is OH, O acyl, Br, Cl or F; R<SP>6</SP> is H, Cl or F; R<SP>9</SP> is O or H(#-R 9 ) xhere R<SP>9</SP> is OH or Cl, and when R is Cl, R<SP>8</SP> is Cl; Z<SP>1</SP> is an optional double bond or methylene or difluoromethylene group; Z<SP>2</SP> is an optional double bond; and R<SP>4</SP> is H only when Z<SP>1</SP> at the 1,2-position is absent. The products of the process or intermediates therein may, when applicable, be further treated according to standard procedures to (1) introduce keto conjugated unsaturation in rings A and B; (2) introduce an 11#-OH group; (3) introduce an 11-keto group; (4) elaborate the 17α- and/or 21-position(s); (5) introduce halogen at the 9- and 11-positions; (6) introduce a 6-halo or -methyl substituent or a 6,6-difluoro grouping for example by a process involving conversion of a 3-alkoxy-3,5-diene to a 6#-halo-#<SP>1</SP>-3-one followed by epimerization of this to a 6α-halo-#<SP>4</SP>-3-one; (7) introduce 1,2- and/or 6,7-methylene or -difluoromethylene substituents; (8) reduce 3-keto to 3-OH; (9) esterify an OH group, e.g. a 3-OH group; (10) introduce #<SP>9(11)</SP>-unsaturation, a 9,11-oxidogroup and then a 9α-halo-11#-OH grouping; (11) protect a 3-OH group by ether, e.g. alkyl or tetrahydropyranyl ether, formation, with subsequent hydrolysis to re-form the 3-OH group, and, when required, oxidation to form a 3-keto group; and (12) protect a 3-keto group as an alkylene ketal, with subsequent hydrolysis to re-form the said keto group. The novel steroids are stated variously to possess progestational and anti-inflammatory activity.