1 United  States  Patent  Office  3,716,528  Patented  Feb.  13, 1973  1  2  DERIVATIVES  OF  IBOGAMINE,  IBOGAINE  AND  IBOGALINE  LACTAMS  ABSTRACT  OF THE  DISCLOSURE  Wataru Nagata,  Nishinomiya,  and Shoichi  Hirai, lbaraki,  Japan, assignors  to  Shionogi  &  Co., Ltd.,  Osaka, Japan  No  Drawing.  Original application  May 28, 1968,  Ser. No.  732,520,  now Patent  No.  3,663,940.  Divided and  this  application  Oct. 14, 1970,  Ser. No.  80,806  Claims priority,  application  Japan, June  3, 1967,  42/35,647;  Feb. 7, 1968,  43/7,620  Int. Cl. C07d  43/38  U.S. Cl.  260-239.3  P  10 Claims  Lactams  of  ibogamine,  ibogaine  and  ibogaline  com› pounds,  such as  4-desethyl-18-p-toluensulfonyloxyibog› amine lactam,  are  provided,  which are  useful  as inter› mediates  in  preparing  isoquinuclidine  alkaloids  useful  as  medicaments.  This  application  is a  drvision  of Ser. No.  732,520  filed  May 28,  1968, now  U.S. Pat.  No.  3,663,940.  The present  invention  relates  to a  process for  the prep› aration  of a series  of  known and  useful alkaloids  of  isoquinuclidine-type,  particularly  the  components  of the  iboga plants  such as  ibogamine,  ibogaine,  ibogaline,  or  the  homologues,  which  is  characterized  by totally  syn› thesizing  the said  compounds  briefly and  stereospecifically  utilizing  the  peculiar  and  advantageous  reactivity  of novel  and unusual  cyclic  compounds,  i.e.  1-azatricyclo,[3.2.  1.02- 7 ]octanes  and the  homologues  (I)  which have  been  prepared  by the  present inventors.  Most  advantageously  the present  invention  provides  an  improved  method  for  the  preparation  of these  a1kaloids  useful  as  medicaments.  The process  of the  present invention  comprises  inter- acting  a  starting aziridine  compound  (I) with  an indole› acetic  acid.anhydride  (II)  followed  by  hydrolysis  to give  an  isoquinuclidine  (UI) [the  1st step],  oxidizing  the lat› ter to give  a  compound  (IV) [the  2nd step],  interacting  the latter  with an  organic acid  to give a  compound  (V)  [the  3rd step],  subjecting  to  solvolysis  the latter  to give  a  compound  (VI)  [the 4th  step], reducing  the latter  with  a  metal hydride  to give  a vinyl  amine  (VII)  [the 5th  step],  catalytically  hydrogenating  the latter  to give  a  compound  (VIII) [the  6th step],  and then  treating  ilie  latter  with a metal  hydride  to give the  final  compound  (.IX) [the  7th step],  or,  alternatively  in the 3rd  step in  the  above-described  process,  interacting  the  compound  (IV) with  an acid  in the  presence  of a lower  alcohol  directly  to give the  compound  (VI)  corresponding  to the  product  of the 4th  step [the  3rd step],  or in the  4th step,  reducing  the  compound  (V) with  an  aluminum  hydride  represented  by the  general formula  AIH•Z•Z’  (wherein  Z and Z’  are the same  or  different  and each  is a  hydrogen  atom,  a  lower alkyl  group, e.g.  methyl,  ethyl, propyl,  i-propyl,  butyl, i-butyl,  a  lower alkoxy  group, e.g.  me› thoxy, ethoxy,  propoxy,  i-propoxy,  butoxy,  i-butoxy,  t-butoxy,  or a  halogen  atom, e.g.  chlorine,  bromine,  iodine)  directly  to give the  final  compound  (IX)  [4’th  step] and/or  the  intermediate  (X),  being  catalytically  hydrogenated  to the final  compound  (IX)  [  4"th step].  The reaction  sequence  is  represented  by the  following  reaction  scheme.  3,716,528  R"~N)  r  lt  O  ~ 