Co-crystallization process

Details Co-crystallization process Co-crystallization process

2001-08-31

2003-05-27

Ford, John M. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Sulfonic acids or salts thereof

C023S300000, C564S304000

Reexamination Certificate

active

06570036

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a process for isolating enantiomer components from a mixture of enantiomers, as well as to separating a racemate into its enantiomeric components. Separated, single enantiomers are extremely important in certain fields of use, since they contain desired properties whereas their enantiomer pair may contain undesirable properties.
Isolation of enantiomers from a mixture of enantiomers is typically difficult because the enantiomers generally have identical physical properties, such as melting and boiling points, or other such properties typically used for separation. Moreover they tend to crystallize as racemic crystals rather than as a conglomerate consisting of a mixture of pure enantiomer crystals which would be separable by preferential crystallization. Thus, a common way today to obtain enantiomers is not through isolating individual enantiomers from a mixture, but rather through asymmetric synthesis of the enantiomer.
Techniques for isolating enantiomers in use today include various embodiments of chromatography, such as simulated moving bed chromatography (SMB). Chromatography-based methods, however, to date are not capable of isolating some enantiomers and/or cannot isolate some enantiomers economically in commercial quantities.
Various crystallization methods have also been proposed for separating enantiomers from a mixture, including preferential crystallization, co-crystallization and emulsion-crystallization. C.f. EP 0 548 028 A1; WO 97/32644; EP 0 838 448 A1; U.S. Pat. No. 5,898,075. While these methods overcome many of the shortcomings in crystallization, they also have some shortcomings. Preferential crystallization works only with racemates forming conglomerates. Furthermore, it is difficult to conduct with many conglomerates, since the systems tolerate only a small degree of super-saturation before spontaneous nucleation of the unwanted isomer occurs.
In co-crystallization, the yields of the enantiomer to be isolated and its co-crystallization agent are often poor (<95%), and it is normally difficult to recover the other enantiomer of the mixture in pure form. Furthermore, it can be difficult to identify a suitable co-crystallization agent that is inexpensive and readily accessible, and which enables crystallization of the desired enantiomer in high yield. Through emulsion crystallization some racemates forming racemic crystals (i.e. conglomerates and especially racemic compounds; see R. A. Sheldon,
Chirotechnology,
Marcel Dekker, Inc. 1993 (p. 174) for general definitions of terminology) can be separated, however the majority of the racemic crystals forming racemates cannot be separated even by normal emulsion crystallization.
It has now been found that the aforementioned problem can be avoided through the use of two co-crystallization agents which selectively form co-crystals with the (R) and (S) enantiomers of a mixture of enantiomers. The co-crystals so-formed can then be readily isolated and subsequently treated to yield the desired enantiomers.
In a second aspect of the invention, one or more enantiomers can be isolated from a mixture of enantiomers through co-crystallization from an emulsion. Use of an emulsion lends additional benefits characteristic of emulsion crystallization to the present invention.
SUMMARY OF THE INVENTION
The present invention provides a process for isolating enantiomer components from a mixture of enantiomers through co-crystallization comprising the steps of (a) forming a solution comprising the mixture of enantiomers (R) and (S) and co-crystallization agents C
1
and C
2
, wherein C
1
and C
2
are chiral or achiral, with the proviso that at least one of C
1
and C
2
is chiral and C
1
and C
2
do not form an enantiomeric pair, whereby C
1
forms a co-crystal with (R) and C
2
forms a co-crystal with (S); (b) super-saturating the solution in C
1*
(R) and C
2 *
(S); (c) inducing crystallization of co-crystals of C
1*
(R) and C
2*
(S); and (d) isolating the C
1*
(R) co-crystals and C
2*
(S) co-crystals.
A second aspect of the present invention provides a process for isolating one or more enantiomers from a mixture of enantiomers through co-crystallization from an emulsion comprising the steps of (a) forming an emulsion of organic liquid droplets in a continuous water phase, which emulsion contains the mixture of enantiomers and a co-crystallization agent for each enantiomer to be isolated, wherein the co-crystallization agents are chiral or achiral, with the proviso that at least one co-crystallization agent is chiral, whereby the co-crystallization agent forms a co-crystal with its corresponding enantiomer; (b) super-saturating the emulsion in (co-crystallization agent)
*
(enantiomer); (c) inducing crystallization of co-crystals of (co-crystallization agent)
*
(enantiomer), whereby crystallization takes place in the water phase; and (d) isolating the co-crystals of (co-crystallization agent)
*
(enantiomer).
DETAILED DESCRIPTION OF THE INVENTION
Crystallization processes are known and need not be described in detail here. Their basic premise is that a solution is formed containing the desired substance, the solution is supersaturated by conventional techniques such as cooling of the solution, and then crystallization of the desired substance is induced, either spontaneously or by seeding with seed crystals of the desired substance. The present extends this technology through the judicious choice of co-crystallization agents which will form co-crystals with the enantiomers of a mixture of enantiomers. The solution accordingly contains the enantiomers and the co-crystallization agents, is super-saturated, and then crystallization of co-crystals of the enantiomers and co-crystallization agents is induced.
Co-crystals of the co-crystallization agents and the enantiomers are indicated in the present invention according to the convention ‘(co-crystallization agent)
*
(enantiomer)’. In a typical embodiment of the invention, two co-crystallization agents, C
1
and C
2
, will be employed. They will, accordingly, selectively form co-crystals with the (R) and (S) enantiomers of the mixture of enantiomers, as indicated by ‘C
1*
(R)’ and ‘C
2*
(S)’. All stoichiometries are intended to be covered with this nomenclature, i.e., ‘C
1*
(R)’ should be understood to include 1 C
1*
(R); 2 C
1*
(R); 1 C
1*2
(R); 2 C
1*
3(R); etc.
(R) and (S) may be present in the enantiomeric mixture in any ratio, including a 50/50 ratio, i.e. as a racemate. The mixture may comprise more than one pair of (R) and (S) enantiomers. The enantiomers can be bases in which case the co-crystallization agents typically will be acids. Or, the enantiomers can be acids in which case the co-crystallization agents typically will be bases. Bases will typically be amines. Alternatively, the enantiomers and/or co-crystallization agents can be neutral co-crystal-forming compounds.
The enantiomers can be pharmaceutical or agrochemical substances, fragrances, food additives, chemical intermediates or the like.
Co-crystallization agents are compounds that selectively form co-crystals with the (R) and (S) enantiomers. Co-crystallization agents may be either chiral or achiral, though at least one of them must be chiral. Preferably, both are chiral. Co-crystallization agents can not form an enantiomeric pair as this could lead to formation of a racemic co-crystal consisting of C
1*
C
2*
R
*
S.
An exception to the limitations on the co-crystallization agents applies to the case of co-crystallization from an emulsion (later described). In this case, the process of the present invention can be carried out using one co-crystallization agent to isolate a single enantiomer (R) or (S) from the mixture of enantiomers. The co-crystallization agent must be chiral. Where two co-crystallization agents are used to isolate both enantiomers, the co-crystallization agents can be chiral or achiral, with the proviso that at least one is chiral. In the case both are chiral they can form an enantiomeric pair. Typically, however, the condition

Affiliated with

Also associated with

Rating

Co-crystallization process does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Co-crystallization process, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Co-crystallization process will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3040056