Patent ID: 6022409
Filing Date: 2000-02-08
Classification: C07B,C07C,C07D

Abstract:
A method for the alternate, batch-wise resolution of two optical enantiomers by preferential crystallization which comprises:a) preparing a racemic mixture of crystals in conglomerate form, of the first enantiomer and a solvent, the figurative point E of which, defined by the variables concentrations and temperature Tg, is situated in the two-phase domain of the first enantiomer in excess, with its saturated solution;b) cooling the two phase mixture of step (a) in accordance with a temperature kinetic schedule, so that the mother liquor retains a slight supersaturation that promotes the growth of the first enantiomer present in crystal form, while preventing the spontaneous nucleation of the second enantiomer present in the solution;c) using during the entire duration of the crystalline growth of step (b) an agitation rate that increases slightly as a function of time such that this rate is at all times sufficiently slow to favor the growth of the first enantiomer while avoiding the generation of excessively high striction forces that would induce uncontrolled nucleation, and sufficiently rapid so as to create a homogeneous suspension and rapid renewal of the mother liquor around each crystallite of the first enantiomer;d) harvesting the crystals of the first enantiomer:e) adding the racemic mixture of crystals in conglomerate form to the mother liquors resulting from the harvest of the crystals of the first enantiomer performed in step (d) and bringing the mixture to a temperature threshold T.sub.B for the time required to with E in relation to the plane of the racemic-mixtures of the solvent system enantiomer (-), enantiomer (+), with said point E' being situated in the two-phase domain of the second enantiomer in excess and in thermodynamic equilibrium with its saturated solution;f) cooling in accordance with the temperature kinetic schedule the two-phase mixture of step (e) containing the second enantiomer, so that the mother liquors retain a slight supersaturation during the crystallization that promotes the growth of the second enantiomer present in the crystal form while preventing the spontaneous nucleation of the first enantiomer present in the solution;g) using during the entire duration of the crystalline growth of step (f) an agitation rate that increases slightly as a function of time such that this rate is at all times sufficiently slow to favor the growth of the second enantiomer while avoiding the generation of excessively high striction forces that would induce uncontrolled nucleation, and sufficiently rapid so as to create a homogeneous suspension and rapid renewal of the mother liquor around each crystallite;h) harvesting the crystals of the second enantiomer;i) adding to the racemic mixture crystals in conglomerate form the mother liquors resulting from the harvest of the crystals of the second enantiomer formed in step (h) and bringing the mixture to a temperature threshold T.sub.B for the time required to reach the thermodynamic equilibrium so that the figurative point E' is symmetrical with E in relation to the plane of the racemic mixtures of the solvent system, whereby the results a mixture which is identical to the initial mixture of (a); andj) repeating steps (a), (b), (c), (d), (e), (f), (g), (h) and (i) so as to obtain successively the one and then the other of the two enantiomers.