Patent GB-1127747-A (GB)
Title: Novel processes for the preparation of estratriene derivatives and compositions incorporating them
IPC: C07J1/00
Filed: 1966-09-02
Abstract: 1,127,747. Steroids. ROUSSEL UCLAF. 2 Sept., 1966 [3 Sept., 1965], No. 39322/66. Headings C2C and C2U. A novel 7α-methyl-estra-4,9,11-trien-3-one of the general formula wherein R represents a hydrogen atom or an acyl group and Y represents an unsaturated aliphatic hydrocarbon residue is obtained by reacting the corresponding 7α-methyl-estra- 5(10),9(11)-trien-3-one with a substituted pbenzoquinone to give the desired estra-4,9,11- trien-3-one. The 7α-methyl-estra-5(10),9(11)- dien starting compound is obtained in a process in which a 5-alkyleneketal-17#-acyloxy-des-A- estra-9(11)-ene (II) is hydrated to give the corresponding 5 - alkyleneketal - 11α - hydroxy - 17# - acyloxy - des A - estrane (III), the compound (III) is subjected to acid hydrolysis to give the corresponding 11α-hydroxy-17#-acyloxy - des A - estran - 5 - one (IV A ), which optionally is formylated to give the corresponding 11α - formyloxy - 17# - acyloxy - des A - estran - 5 - one (IV B ); the compound (IV A ) or (IV B ) is brominated to give the corresponding 11α-hydroxy or 11α-formyloxy-17#-acyloxy - 6 - bromo - des A - estran - 5 - one (V A ) or (V B ); the compound (V A ) or (V B ) is dehydrobrominated to give the corresponding 11α-hydroxy or 11α - formyloxy - 17# - acyloxy - des A - estr - 6 - en-5-one (VI A ) or (VI B ) and optionally the compound (VI B ) is hydrolysed to give the compound (VI A ); the compound (VIA) or (VI B ) is reacted with a methyl Grignard reagent, in the presence of a copper salt, to give the corresponding 11α - hydroxy - 17# - acyloxy - 7α - methyl - des - A - estran - 5 - one (VII); the compound (VII) is reacted with a functional derivative of a sulphonic organic acid to give the corresponding 11α-organo sulphonyloxy-17#- acyloxy - 7α - methyl - des - A - estran - 5 - one (VIII); the compound (VIII) is reacted with a lithium halide in the presence of a dialkylformamide to give the corresponding 17#-acyloxy - 7α - methyl - des A - estr - 9 - en - 5 - one (IX); the compound (IX) is saponified by an alkali metal hydroxide to give the corresponding 17# - hydroxy - 7α - methyl - des A - estr - 9 - en - 5-one (X), the compound (X) is oxidized to give the corresponding 7α - methyl - des A - estr - 9 - ene-5,17-dione (XI); the compound (XI) is reacted with a secondary amine to give the corresponding 5 - enamino - 7α - methyl - des A - estra - 5(10),9(11) - dien - 17 - one (XII); the compound (XII) is condensed with 1,3-dichlorobut-2-ene to give the corresponding 3-chloro- 7α - methyl - 4,5 - seco - estra - 2,9 - dien - 5,17 - dione (XIII); the compound (XIII) is hydrolysed in acid to give the corresponding 7α- methyl - 4,5 - seco - estr - 9 - ene - 3,5,17 - trione (XIV); the compound (XIV) is cyclized by reaction with a secondary amine to give the corresponding 3 - enamino - 7α - methyl - estra - 3,5(10),9(11)-trien-17-one (XV); the compound (XV) is de-enaminated by acid hydrolysis to give the corresponding 7α - methyl - estra - 5(10),9(11)-diene-3,17-dione (XVI); the compound (XVI) is reacted with a ketalizing agent to give the corresponding 3-ketal-7α-methylestra - 5(10),9(11) - dien - 17 - one (XVII); the compound (XVII) is reacted with an organometallic derivative to give the corresponding 3 - ketal - 7α - methyl - 17α - unsaturated hydrocarbonyl - 17# - hydroxy - estra - 5(10),9(11)- diene (XVIII); and the compound (XVIII) is hydrolysed in acid to give the corresponding 7α - methyl - 17α - unsaturated hydrocarbonyl - 17# - hydroxy - estra - 5(10),9(11) - dien - 3 - one (XIX). Pharmaceutical compositions having hypocholesterolemiant activities and containing the above compounds are employed orally, perlingually, transcutaneously or rectally.