Patent GB-1350730-A (GB)
Title: B,d-seco-delta4 and delta5,10-steroidal compounds
IPC: C07D309/10
Filed: 1972-06-16
Abstract: 1350730 B,D - diseco - #<SP>4</SP> and #<SP>5(10)</SP> - steroids SYNTEX CORP 16 June 1972 [20 July 1971] 28318/72 Heading C2C [Also in Division C7] Novel disecosteroids of the estrane series having the formulµ (wherein R<SP>1</SP> is free or esterified -CO 2 H, -COCH 3  or C 1-4  alkyl or is -CH 2 OH in which the OH group may be etherified or esterified and in which the -CH 2 - group may be substituted by one or two C 1-4  alkyl groups or by one C 1-4  alkyl group and a phenyl group) are prepared as illustrated in the following reaction scheme wherein R<SP>3</SP> and R<SP>5</SP> are C 1-4  alkyl, R<SP>4</SP> is C 1-4  alkyl or phenyl and R<SP>6</SP> is H or C 1-4  alkyl. (I) is reduced with a double metal hydride to (II), this is Birch reduced to a 3-methoxy-#<SP>2,5(10)</SP>- diene and this is hydrolysed to (III), mild hydrolysis giving a #<SP>5(10)</SP>-3-one and hydrolysis with a strong acid giving a #<SP>4</SP>-3-one. (III) is oxidized with CrO 3  to (IV) (R<SP>6</SP>=H) which may then be esterified. (I) with an alkyl Grignard reagent gives (V) and (VI) (R<SP>4</SP>=alkyl), and (V) with a phenyl alkali metal compound gives (VI) (R<SP>4</SP>=phenyl). Birch reduction and hydrolysis of (V) and (VI) gives (VII) and (IX) respectively via #<SP>2,5(10)</SP>-3-methoxy compounds. Oxidation of (II) with CrO 3  gives (VIII), which on electro chemical or chemical reduction gives (X) (R<SP>5</SP>=CH 3 ). Birch reduction and hydrolysis of (X) gives (XI) via #<SP>2,5(10)</SP>-3-methoxy compounds. Electro chemical or chemical reduction of (V) similarly gives (X) (R<SP>5</SP> = C 2-4  alkyl). Oxidation of (VII) gives XII). Products containing free OH groups can be esterified or etherified. The #<SP>5(10)</SP>-compounds (IX) are esterified by reduction to the corresponding diols, diesterification, selective saponification and oxidation. The starting materials for the foregoing process are prepared as illustrated in the following reaction scheme (1) is reacted with vinyl magnesium bromide to give 4 - (4<SP>1</SP> - methoxyphenyl) - 4 - hydroxyhex-5-ene, this is reacted with thiourea in acetic acid to give (2), this is converted to (3) as illustrated, this by acid-catalysed cyclization in boiling xylene gives (4) and small amounts of 3 - methoxy - 14(α and #) - hydroxy - 15- methyl - 16 - oxa - 5,6 - secoestra - 1,3,5(10),8- tetraen - 17 - one, treatment of (4) with sodium hydroxide in methanol for 1-3 hours gives (5), in equilibrium with (5A), (5) with CH 3 I gives (6), electro chemical reduction of this gives (7) and catalytic reduction of this gives (8). Prolonged alkaline treatment of (4) gives predominantly (9) which is converted to (10) via intermediates similar to (6) and (7). (I) wherein R<SP>2</SP> is CH 3  is obtained by reducing 1,2-dimethyl- 3 - ethyl - 4 - (p - anisyl) - cyclohex - 4 - ene carboxylic acid with Li/C.NH 3  to give 3- methoxy - 5,6; 16,17 - diseco - 16 - norestra- 1,3,5(10) - trien - 17 - oic acid and esterifying this. The novel compounds possess antiandrogenic activity and may be made up into pharmaceutical compositions with suitable carriers.