The resolution of racemates constitutes the main method for industrial preparation of pure enantiomers. Methods for such resolution include: direct preferential crystallization; crystallization of the diastereomeric salts and kinetic resolution. Pure enantiomers may also be produced by asymmetric synthesis (reaction of a chiral reagent or catalyst with a prochiral substrate).
Also referred to as resolution by entrainment, preferential crystallization is widely used on an industrial scale; for example, in the manufacture of .alpha.-methyl-L-dopa and chloramphenicol. It is technically feasible only with racemates which are so-called conglomerates. Unfortunately, less than 20 percent of all racemates are conglomerates. The rest are racemic compounds which cannot be separated by preferential crystallization.
If the racemate is not a conglomerate, a homogeneous solid phase of the two enantiomers co-exists in the same unit cell. These materials may be separated via diastereomer crystallization, which generally involves reaction of the racemate with an optically pure acid or base (the resolving agent) to form a mixture of diastereomeric salts which are then separated by crystallization. Ibuprofen, for example, is such a compound.
Diastereomer crystallization is widely used for the industrial synthesis of pure enantiomers. A typical example is the Andeno process for the manufacture of (D)-(-)-phenylglycine, an antibiotic intermediate, using optically pure camphor sulfonic acid as the resolving agent. Also see U.S. Pat. No. 4,752,417 for a diastereomeric procedure for resolving certain phenylacetic acid derivatives and U.S. Pat. No. 4,973,745 for resolving 2-arylpropionic acids.
The theoretical once-through yield of a resolution via diastereomer crystallization is 50 percent. However, in practice, a single recrystallization produces a composition that is simply enantiomerically enriched.
Another method for the resolution of racemates is kinetic resolution, the success of which depends on the fact that the two enantiomers react at different rates with a chiral addend.
Kinetic resolution can also be effected using chiral metal complexes as chemocatalysts, e.g., the enantioselective rhodium-BINAP-catalyzed isomerization of chiral allylic alcohols to the analogous prostaglandin intermediates reported by Noyori.
The enantioselective conversion of a prochiral substrate to an optically active product, by reaction with a chiral addend, is referred to as an asymmetric synthesis. From an economic viewpoint, the chiral addend functions in catalytic quantities. This may involve a simple chemocatalyst or a biocatalyst. An example of the former is the well-known Monsanto process for the manufacture of L-dopa by catalytic asymmetric hydrogenation. See Knowles, et al., J. Am. Chem. Soc., 97, 2567 (1975). An example of the latter is the Genex process for the synthesis of L-phenylalanine by the addition of ammonia to transcinnamic acid in the presence of L-phenylalanine ammonia lyase (PAL). See Hamilton et al., Trends in Biotechnology, 3, 64-68, (1985). Also see Jacques et al., Enantiomers, Racemates and Resolutions, Chapter 3 (1981) incorporated herein by reference.
With the exception of the preferential crystallization process when applied to true conglomerates, the prior art processes typically produce a first mixture that is enantiomerically enriched. A number of crystallizations are required to obtain a substantially pure enantiomer.
USPTO Backgrounds
USPTO Backgrounds