632 
Synthesis  of  Pilocarpine. 
Am.  Jour.  Pharm. 
Dec,  1887. 
SYNTHESIS  OF  PILOCARPINE.1 
By  Haedy  and  Calmels. 
The  synthesis  of  pilocarpine  was  effected  by  converting  /2-pyridine- 
a-lactic  acid  into  pilocarpidine,  which  was  then  transformed  into  pilo- 
carpine by  oxidation. 
One  gram  /3-pyridine-a-lactic  acid  was  mixed  with  100  grams  of 
carbon  bisulphide  and  10  grams  of  phosphorous  bromide  and  dis- 
tilled to  dryness.  The  residue  was  extracted  with  water,  the  solution 
neutralized  with  baryta,  the  excess  of  baryta  removed  by  means  of 
carbonic  anhydride,  and  the  solution  evaporated  to  dryness  at  a  tem- 
perature not  exceeding  60°.  The  residue  thus  obtained  was  purified 
by  repeated  treatment  with  alcohol,  and  then  mixed  with  hydrobro- 
mic  acid  and  auric  chloride,  when  crimson  plates  of  the  normal  auro- 
bromide  of  /9-pyridine-a-bromopropionic  acid  are  obtained.  The  gold 
is  removed  by  means  of  hydrogen  sulphide,  and  the  free  acid  is  heated 
in  sealed  tubes  at  150°  for  several  hours  with  excess  of  triethyl amine. 
The  product  is  treated  with  an  aqueous  solution  of  potassium  carbo- 
nate, and  the  oily  drops  of  the  liberated  alkaloid  are  dissolved  in 
ether  alcohol,  and  purified  by  treatment  with  animal  charcoal.  When 
mixed  with  auric  chloride,  it  yields  the  modified  aurochloride  of  pilo- 
carpidine,  AuCl3,C10H14N2O2,  melting  at  144°. 
In  order  to  convert  pilocarpidine  into  pilocarpine,  the  extra-pyridic 
nitrogen  of  the  former  must  be  rendered  pentavalent  by  the  addition 
of  a  methyl-group,  whilst  the  pyridic  nitrogen  remains  trivalent. 
When  pilocarpidine  is  mixed  with  methyl  iodide  in  alcoholic  solu- 
tion at  60-100°,  it  combines  with  1  mol.  of  methyl  iodide,  forming 
a  compound  which  crystallizes  with  difficulty.  If  this  compound  is 
mixed  with  auric  chloride  an  oily  precipitate  is  formed  and  gradually 
changes  to  large  prismatic  needles  which  melt  at  152-153°,  and  have 
the  composition  AuCl4Me,C10H14N2O2.  This  compound  readily  loses 
methyl  chloride  when  fused,  and  yields  modified  pilocarpidine  auro- 
chloride, melting  at  144°.  Pilocarpidine  mixed  with  excess  of  methyl 
iodide  in  concentrated  methylic  solution,  and  then  with  fragments  of 
solid  potassium  hydroxide,  care  being  taken  that  the  temperature  does 
not  rise  too  high,  combines  with  methyl  iodide  (1),  and  methyl  hy- 
droxide (2),  and  if  this  product  is  treated  with  carbonic  anhydride, 
1  Compt.  rend.,  105,  68-71.  Eeprinted  from  Jour.  Chem.  Soc,  November, 
1887. 
