Process for the resolution of certain octahydrobenzocycloheptapyridoisoquinolinols
AssigneeAyerst McKenna and Harrison Ltd.
InventorsKarel Pelz, Francois T. Bruderlein, Leslie G. Humber
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Abstract
An efficient, commercially feasible process for the resolution of the organic bases, (.+-.)-(4a,13b-trans)-(3-hydroxy,13b-trans)-3-isopropyl-2,3,4,4a,8,9,13b,1 4-octahydro-1H-benzo[6,7]cyclohepta[1,2,-3-de)pyrido[2,1-a]isoquinolin-3-ol and (.+-.)-(4a,13b-trans)-(3-hydroxy,13b-trans)-3-tert-butyl-2,3,4,4a,8,9,13b, 14-octahydro-1H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolin-3-ol , known neuroleptic agents, is disclosed. The process comprises resolving the racemic organic bases with L-(+)-tartaric acid to obtain directly the pure L-(+) tartrate of the (+)-enantiomer and converting the latter salt to the corresponding (+)-enantiomer free base.
Claims4
A process for resolving (.+-.)-(4a,13b-trans)-(3-hydroxy,13b-trans)-3-isopropyl-2,3,4,4a,8,9,13b,1 4-octahydro-1H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolin-3-ol and (.+-.)-(4a,13b-trans)-(3-hydroxy,13b-trans)-3-tert-butyl-2,3,4,4a,8,9,13b1 4-octahydro-1H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolin-3-ol, which consists of dissolving one part by weight of a racemic mixture of the (.+-.)-(4a,13b-trans)-(3-hydroxy,13b-trans)-3-isopropyl-2,3,4,4a,8,9,1 3b,14-octahydro-1H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolin-3 -ol or (.+-.)-(4a,13b-trans)-(3-hydroxy,13b-trans)-3-tert-butyl-2,3,4,4a,8, -9,13b,14-octahydro-1H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquino lin-3-ol and 1.0 to 1.3 parts by weight of L-(+)-tartaric acid in 4 to 6 parts by volume of methanol at 20.degree. to 40.degree. C, diluting the solution with 1 to 3 parts of volume of acetone or ether at 15.degree. to 25.degree. C to crystallize the corresponding L-(+)-tartrate of the (+)-enantiomer of the compound;
- dissolving one part by weight of the L-(+)-tartrate in a mixture of 5 to 8 parts by volume of water and 5 to 8 parts by volume of a water-immiscible organic solvent containing 5 to 10 parts by weight of alkali;
- separating the water-immiscible solvent from the aqueous phase, and isolating the corresponding (+)-enantiomer free base from the water-immiscible solvent.
Dependencies are inferred from the claim text.