Patent GB-1441519-A (GB)
Title: Cinchonidine and cinchonidine derivatives
IPC: C07D215/12
Filed: 1974-12-06
Abstract: 1441519 Cinchonidine and cinchonine derivatives F HOFFMANN-LA ROCHE & CO AG 6 Dec 1974 [7 Dec 1973] 52843/74 Heading C2C Novel compounds of the Formulµ I and II wherein R 1  is halogen or CF 3  and R 2  is ethyl or vinyl, enantiomers and racemates and acid addition salts thereof may be prepared by (a) reacting a compound of the Formula III or an enantiomer or a racemate thereof with a compound of the Formula IV (b) reducing a compound of the Formula V or an enantiomer or a racemate thereof, (c) hydroxylating a compound of the Formula VI or (d) cyclising a compound of the Formula VII or an enantiomer or racemate thereof and optionally reducing a vinyl group at R 2  if present to an ethyl group, resolving a racemate, forming an acid addition salt from a free base or from another acid addition salt or forming a base from an acid-addition salt. Intermediates of Formula III are prepared by cyclizing a 1,1 - dichloro - 3[3(ethyl or vinyl)- 4-piperidinyl]propan-2-ol. Intermediates of the Formula IV are prepared by cyclizing an R 1  substituted aniline with ethyl 4,4,4-trifluoroacetoacetate to yield an R 1 -substituted - 2 - trifluoromethyl - 4 - quinolinol followed by bromination to an R 1 -substituted-2- trifluoromethyl - 4 - bromoquinoline and thereafter formation of the lithium compound in situ. 2<SP>1</SP>,8<SP>1</SP> - Bis(trifluoromethyl) - dihydrocinchonidinone racemate and 2<SP>1</SP>,8<SP>1 </SP>- bis(trifluoromethyl) - dihydrocinchoninone racemate are prepared by cyclizing isomeric erythro-1,1- dichloro - 3 - (3 - ethyl - 4 - piperidinyl) - propan - 2# - ol hydrochlorides by treatment with base, silver nitrate and then ethanol and hydrogen chloride to yield racemic ethyl 4,5-erythro-5- ethyl - quininelidine - 2# - carboxylate which on reaction with 2,8-bis(trifluoromethyl)-4-quinolyl lithium, generated in situ from the 4-bromo compound, yields the required intermediates. 21,81 - Bis(trifluoromethyl) - desorydihydrocinchonidine and 2<SP>1</SP>,8<SP>1</SP> - bis(trifluoromethyl)- desoxydihydrocinchonine are prepared by cyclizing 2-trifluoromethylaniline with 1,1,1-trifluoro- 2,4 - pentanedione to form. 2,8 - Bis(trifluoromethyl)lepidine which on reaction with a lithium compound and then methyl 3(R)-ethyl-4(5)- piperidine acetate yields 2,8-bis(trifluoromethyl)- 4 - [3 - (3(R) - ethyl - 4(S) - piperidyl) - 2 - oxopropyl] - quinoline which is reduced to an epimeric mixture of 2,8-bis(trifluoromethyl)-4- [3 - (3(R) - ethyl - 4(S) - piperidyl) - 2# - hydroxy propyl] - quinolines which is esterified to an epimeric mixture of 2,8-bis(trifluoromethyl)-4- [3 - (3(R) - ethyl - 4(S) - piperidyl) - 2# - acetoxypropropyl]quinolines which is cyclized to the required compounds. Diasteromeric 2,8 - bis(trifluoromethyl) - 4 - [3 - (3(R) - ethyl - 4(S) - piperidyl) - 1#,2#- oxapropylquinolines are prepared by reacting 2,8-bis(trifluoromethyl)-lepidine with a lithium compound followed by N-benzoyl-cincholoipan ethyl ester to yield 2,8-bis(trifluoromethyl) - 4- [3 - (1 - benzoyl - 3(R) - ethyl - 4(S) - piperidyl)- 2 - oxopropyl] - quinoline which is brominated under free radical conditions to yield a mixture of epimine 2,8-bis(trifluoromethyl)-4- [3 - (1 - benzoyl) - 3(R) - ethyl - 4(S) - piperidyl)- 1# - bromo - 2 - oxopropyl] - quinolines which are cyclized to a mixture of diastereomeric 2,8- bis(trifluoromethyl)- 4 - [3 - (1 - benzoyl - 3(R)- ethyl - 4(S) - piperidyl) - 1#,2# - oxapropyl]- quinolines which are reduced to the required compounds. Pharmaceutical compositions of the compounds I and II with the usual excipients show antimalarial activity when administered orally parenterally or rectally.