Process for the solid state synthesis of enantiopure...

Details Process for the solid state synthesis of enantiopure... Process for the solid state synthesis of enantiopure...

2000-03-24

2001-05-29

Barts, Samuel (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S351000

Reexamination Certificate

active

06239313

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the solid state synthesis of enantiopure &bgr;-aminoalcohols from racemic epoxides. More particularly, the present invention relates to a process for the solid state synthesis of enantiopure &bgr;-aminoalcohols from racemic epoxides by the dynamic kinetic resolution involving enantiodifferentiating racemisation in crystalline cyclodextrin complexes.
The novel phenomenon of converting racemic substrates to enantiopure products is illustrated by the synthesis of enantiopure &bgr;-aminoalcohols by dynamic kinetic resolution involving chiral cyclodextrins by supramolecular catalysis under solid state conditions.
BACKGROUND OF THE INVENTION
Dynamic kinetic resolution involves the conversion of racemic substrate into a single stereoisomer of the product by inter-conversion of the reactant isomers by racemisation, making removal of one of the isomers as the rate determining step. Dynamic kinetic resolution also overcomes the limitation of conventional kinetic resolution where the maximum yield of one stereoisomer of the starting material or product is only 50%. Dynamic kinetic resolution, though of great significance in asymmetric synthesis to get a single enantiomer of the product from racemic substrate, is not a widespread phenomenon. Only a few cases have been reported so far (R. S. Ward,
Tetrahedron Asymmetry,
1996, 1475). However, in these cases the substrates involved are made chirally labile either chemically, biochemically or thermally. There is also a stray reference by F. Toda and K. Tanaka in
Chem. Lett.,
1983, 661, of converting racemic cyanohydrin into a single enantiomer by complexation with brucine. However, there has been no attempt so far to involve chirally stable racemic epoxides by any means in dynamic kinetic resolution by reaction with amines for obtaining enantiopure &bgr;-aminoalcohols that have a high potential as intermediates for the synthesis of wide range of biologically active compounds and as precursors in asymmetric transformations. Until now dynamic kinetic resolution has not been carried out by supramolecular catalysis involving cyclodextrins.
Accordingly, studies were undertaken to see the possibility of involving chirally stable, easily accessible and inexpensive racemic epoxides for the synthesis of enantiopure &bgr;-aminoalcohols by dynamic kinetic resolution through supramolecular catalysis in cyclodextrins.
OBJECTS OF THE INVENTION
The main object of the invention is to provide a process for the synthesis of enantiopure &bgr;-aminoalcohols from racemic epoxides by creating conditions for enantiodifferentiating racemisation in cyclodextrin complexes.
It is another object of the invention to provide a process for the formation of enantiomerically pure products from racemic epoxides by dynamic kinetic resolution through supramolecular catalysis involving cyclodextrins by enantiodifferentiating racemisation since cyclodextrins are chiral and mimic enzymes.
It is another object of the invention to provide a process for the solid state synthesis of enantiopure &bgr;-aminoalcohols that overcomes the limitations of kinetic resolution.
SUMMARY OF THE INVENTION
The structures of &agr;-cyclodextrin, &bgr;-cyclodextrin and &ggr;-cylodextrin are indicated below in Table I and represented by reference numerals 1, 2 and 3 respectively.
TABLE 1


The following Table II discloses the reaction of cyclodextrin complex of racemic epoxides 1 with amines 2 and 3 to form enantiopure &bgr;-aminoalcohols 4 (4a, 4b, 4c and 4d) and 5(5a, 5b, 5c and 5d) respectively:
TABLE 2
The racemisation of aryloxyepoxides is shown in Table III below:
The present invention discloses a process for the solid state synthesis of enantiopure &bgr;-aminoalcohols from racemic epoxides by dynamic kinetic resolution involving enantiodifferentiating racemisation in crystalline cyclodextrin complexes, which comprises synthesis of various racemic aryloxyepoxides to obtain their inclusion complex with cyclodextrins, reacting the epoxide of the cyclodextrin complex with amines under solid state conditions, extracting the product with solvent, removing the solvent and amine in vacuo and purifying the product &bgr;-aminoalcohol by the formation of hydrochloride.
Accordingly the invention relates to a process for the solid state synthesis of enantiopure &bgr;-aminoalcohols of formula VI form racemic epoxides which comprises:
(a). preparing inclusion complexes of aryloxyepoxide with cyclodextrin by adding an epoxide in equimolar ratio in an organic solvent to an aqueous solution of cyclodextrin at a temperature ranging between 30-80° C.;
(b). reacting the cyclodextrin complex of aryloxyepoxide with a nucleophile in solid state by intimately grinding the mixture using a mortar and pestle;
(c). continuing the mixing till the starting epoxide disappeared on tlc within a period ranging between 3-12 hours;
(d). removing excess amines under vacuum;
(e). extracting the &bgr;-aminoalcohols of formula 4 or 5 with a solvent with yields of more than 50% and enantioselectivity of upto 100%.
In one embodiment of the invention the substrates forming the inclusion complexes with cyclodextrins are selected from aryloxy epoxides that are optionally substituted with halo, alkyl or substituted alkyl.
In another embodiment of the invention the cyclodextrins that form an inclusion complex with aryloxyepoxides are cyclic oligosaccharides comprising six glucose units (&agr;-cyclodextrin), seven glucose units (&bgr;-cyclodextrin) or eight glucose units (&ggr;-cyclodextrin).
In a yet another embodiment of the invention the epoxide cyclodextrin complexes may be prepared by adding the epoxide in equimolar ratio in solvents such as methanol, ethanol, acetone, etc. to an aqueous solution of cyclodextrin.
In a further embodiment of the invention, the reaction of cyclodextrin complex of the aryloxyepoxide with amines may be carried out in solid state by intimately grinding the mixture using mortar and pestle or in liquid state using water as a reaction medium.
In another embodiment of the invention, the solvents used for preparing inclusion complexes are selected from the group comprising of methanol, ethanol, and acetone.
In a further embodiment of the invention, the solvent used for extracting the aminoalcohols are selected from the group comprising of dichloromethane, chloroform, ethyl acetate and methanol.
In another embodiment of the invention, the nucleophiles used are amines.
As a result of intensive study with the aim of achieving the above-mentioned objectives, a new process for the synthesis of enantiopure &bgr;-aminoalcohols from racemic epoxides by dynamic kinetic resolution involving enantiodifferentiating racemisation in crystalline cyclodextrin complexes has been achieved for the first time under solid state conditions.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present investigation deals with a process for the solid state synthesis of enantiopure &bgr;-aminoalcohols of formula VI (as shown in Table IV below) from racemic epoxides by dynamic kinetic resolution by dynamic kinetic resolution through supramolecular catalysis in cyclodextrin complexes.
The synthesis of each compound is described hereinbelow in detail.
The first step in the process comprises formation of an inclusion complex of aryloxyepoxides of the general formula 1 with cyclodextrins as shown above in Table II.
The cyclodextrins of the general formulae 1, 2 and 3 shown above in Table I are cyclic oligosaccharides possessing hydrophobic cavities and mimic enzymes in their capability to bind substrates selectively and catalyse chemical reactions. They catalyse reactions by supramolecular catalysis involving reversible formation of Host: Guest complexes with substrates by non-covalent bonding as seen in enzymes. Since the cyclodextrin cavity is chiral in nature, it can induce asymmetric reactions. It can discriminate and form complexes with different enantiomers of racemates. The following criteria have to be fulfilled to ensure rigidity for chiral recognition by cyc

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