Stereoselective and useful preparation of 3-substituted 4-aryl piperidine compounds
AssigneeBrantford Chemicals Inc.
InventorsK. S. Keshava Murthy, Allan W. Rey
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Abstract
This invention relates to new stereoselective processes for preparing 3-substituted-4-aryl piperidines and methods for controlling the absolute stereochemistry at the C-3 and C-4 positions of the piperidine ring. Compounds of this type are key intermediates in the preparation of paroxetine, femoxetine, and other medicaments.
Claims23
A process for the preparation of a compound of formula VII:
- ##STR18## wherein Ar is a group of formula IX, ##STR19## in which X is hydrogen, alkyl having 1-4 carbon atoms, C.sub.1-6 alkoxy, trifluoro C.sub.1-6 alkyl, hydroxy, methylthio, or halogen and R is a chiral auxiliary selected from substituted menthol-, substituted camphor-, substituted and unsubstituted ephedrine-, carbohydrate-, amino acid-, substituted and unsubstituted binapthyl-, chiral diol-, and substituted oxazolidinone-based auxiliaries which process comprises contacting a compound of formula V:
- ##STR20## wherein R is as defined above, with an organometallic of formula VI:
- ##STR21## wherein X is as defined above, and M is a lithium, cuprate, or Grignard substituent.
A process for the preparation of a compound of formula VIII:
- ##STR22## wherein Ar is a group of formula IX, ##STR23## in which X is hydrogen, alkyl having 1-4 carbon atoms, C.sub.1-6 alkoxy, trifluoro C.sub.1-6 alkyl, hydroxy, methylthio, or halogen and R is a chiral auxiliary selected from substituted menthol-, substituted camphor-, substituted and unsubstituted ephedrine-, carbohydrate-, amino acid-, substituted and unsubstituted binapthyl-, chiral diol-, and substituted oxazolidinone-based auxiliaries which process comprises contacting a compound of formula V:
- ##STR24## wherein R is as defined above, with an organometallic of formula VI. ##STR25## wherein X is as defined above, and M is a lithium, cuprate, or Grignard substituent.
Process for the synthesis of paroxetine according to the following Scheme:
- ##STR26## wherein R is a chiral auxiliary selected from substituted menthol-, substituted camphor-, substituted and unsubstituted ephedrine-, carbohydrate-, amino acid-, substituted and unsubstituted binapthyl-, chiral diol-, and substituted oxazolidinone-based auxiliaries, M is a lithium, cuprate or Grignard substituent, and Ar is 4-fluorophenyl.
Process for the synthesis of paroxetine according to the following Scheme:
- ##STR27## wherein R is a chiral auxiliary selected from substituted menthol-, substituted camphor-, substituted and unsubstituted ephedrine-, carbohydrate-, amino acid-, substituted and unsubstituted binapthyl-, chiral diol-, and substituted oxazolidinone-based auxiliaries, M is a lithium, cuprate, or Grignard substituent, and Ar is 4-fluorophenyl.
Process for the synthesis of femoxetine according to the following Scheme:
- ##STR28## wherein R is a chiral auxiliary selected from substituted menthol-, substituted camphor-, substituted and unsubstituted ephedrine-, carbohydrate-, amino acid-, substituted and unsubstituted binapthyl-, chiral diol-, and substituted oxazolidinone-based auxiliaries, M is a lithium, cuprate or Grignard substituent, and Ar is phenyl.
Process for the synthesis of femoxetine according to the following Scheme:
- ##STR29## wherein R is a chiral auxiliary selected from substituted menthol-, substituted camphor-, substituted and unsubstituted ephedrine-, carbohydrate-, amino acid-, substituted and unsubstituted binapthyl-, chiral diol-, and substituted oxazolidinone-based auxiliaries, M is a lithium, cuprate or Grignard substituent, and Ar is phenyl.
Dependencies are inferred from the claim text.