Patent GB-1495513-A (GB)
Title: Steroid compounds of the 20(22)-cardenolide series
IPC: C07J9/00
Filed: 1974-11-20
Abstract: 1495513 20(22)-Cardenolides STEELE CHEMICALS CO Ltd 20 Nov 1974 [29 Nov 1973] 50262/74 Heading C2U The invention comprises: (A) a process for preparing compounds of Formula I infra from II by reaction with ZCH 2 CO 2 H or a functional derivative thereof to give III, base-inducec cyclization of which yields I R 1  is H, oxo, OH, OMe, OCOH, OCOMe, OCOCH 2 P(O)(OEt) 2 , OCOCH 2 CO 2 H, OCH 2 Ph, OCH 2 C#CH, or tetrahydropyran - 2 - yloxy; R 2  is CH 3 , CHO, CH 2 Cl, CH 2 OH, CH 2 OMe, CH 2 OCOH, CH 2 OCOMe, CH 2 OCOCH(Me) (OH), CH 2 OCO(CH 2 OH) 2 CO 2 H, CH 2 OCOCH 2 CO 2 H, CH 2 OCH 2 C#CH; tetrahydropyran-2-yloxymethyl, or R 3  is H, CN, CO 2 Me, CO 2 CH 2 Ph, CO 2 CH 2 C # CH, or CO 2 CH 2 CH 2 OH; R 6  (when present) is α-H, #-H, α-Cl, α-Br or α-OH; R 7  is H, or R 2  and R 7  together are -CH 2 -O- (the -O- of which is attached to C 6 ); R 8  is H, or R 2  and R 8  together are -CH 2 -O-, -CO-O-, or -CH(OH)-O- (the -O- of which is attached to C 8 ); X-Y is C(#-OH)-CH 2 , C(α-H)-CH 2 , C(#-H)-CH 2 , C=CH, C(#-OH)-CH(α-Q 1 ) or C(#-OCOQ 2 )-CH 2 -, Q 1  being Br, Cl, OCOMe or OCOBu<SP>t</SP>, and Q 2  being H or Me; Z is a substituent which enhances the acidity of the adjacent CH 2  (Z generally being retained in the product as R 3  except for Z=P(O)(OEt) 2  which results in R 3  = H); and the dotted lines in the ring, represent optional #<SP>4</SP>, #<SP>5</SP> or #<SP>4,6</SP>-ethylenic unsaturation; and (B) the following compounds per se: 3# - acetoxy - 8, 19 - epoxy - 5α - carda - 14,20- (22) - dienolide; 3# - acetoxy - 22 - (benzyloxycarbonyl) - 8,19 - epoxy - 5α - carda - 14,20- (22) - dienolide; 3# - acetoxy - 22 - cyano - 8,19- epoxy - 5α - carda - 14,20(22) - dienolide; 22- cyano - 3# - hydroxy - 8,19 - epoxy - 5α - carda- 14,20(22) - dienolide; 19 - acetoxy - 3 - oxo- 14α - carda - 4,6,20(22 - trienolide; 3 - oxo - 8, 19 - epoxy - 14α - carda - 4,20(22) - dienolide; 3# - [(diethylphosphono)acetoxy] - 14α - carda- 5,20(22) - dienolide; 3# - acetoxy - 22 - cyano- 14α - carda - 5, 20(22) - dienolide; 3# - hydroxy- 22 - cyano - 14α - carda - 5, 20(22) - dienolide; 8,19 - epoxy - 5α - carda - 14,20(22) - dienolide; 19 - formyloxy - 5α - carda - 14,20(22) - dienolide*; 3# - acetoxy - 19 - hydroxy - 5α - carda- 14,20(22) - dienolide*; 3# - acetoxy - 15α- bromo - 19 - formyloxy - 14# - hydroxy - 5α- card - 20(22) - enolide*; coroglaucigenin 3- acetate 19 - formate*; 3# - acetoxy - 19 - formyloxy - 14#,15# - epoxy - 5α - card - 20(22)- enolide*; 3# - acetoxy - 14#, 19 - dihydroxy- 5α - card - 20(22) - enolide*; 14#, 19 - dihydroxy - 5α - card - 20(22) - enolide 19- formate*; 19 - formyloxy - 14,15# - epoxy- 5α,14# - card - 20(22) - enolide*: and 3 - oxo - 6,19 - epoxy - 14α - carda - 4,20(22) - dienolide; all of these being immediate products of process (A) followed in some cases by hydrolysis of 3-ester groups, with the exception of those marked * which are produced in subsequent process steps infra. When the cardenolides produced by the process (A) are 8,19-epoxy-14-enes, subsequent cleavage of the epoxy group with Zn/HCHO (optionally followed by acetylation) yields a 19-hydroxy-14-ene or formate or acetate thereof, reaction of which with N-bromoacetamide yields the corresponding 19-oxygenated-14#- hydroxy-15α-bromo compound, reaction of which with Raney nickel, NH 4 OH or t-butylamine yields the corresponding 19-oxygenated- 14# - hydroxy - 15 - unsubstituted or 19- oxygenated - 14#,15# - epoxy compound, whereafter 3- and 19-ester groups may be hydrolysed and 19-OH oxidized to oxo. These after-processes, which are the subject of Examples 14--28, give both known and novel (supra) compounds.