Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-22
2004-02-17
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S513000, C549S540000
Reexamination Certificate
active
06693206
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an improved process for hydrolytic kinetic resolution (HKR) of epoxides. More particularly, the present invention relates to an improved process for the preparation of non-racemic compounds using as a promoter a carboxylic acid, such as, electron deficient aromatic acid, activation of the catalyst with epoxides present and the use ammonium hydroxide during work-up.
2. Description of the Prior Art
The demand for enantiomerically pure compounds or non-racemic compounds having high optical purity, i.e., having an optical purity of at least 85% enantiomeric excess, has grown rapidly in recent years. The impetus for rapid growth has been the potential uses of such compounds as biologically active compounds or as intermediates in the synthesis of such biologically active compounds, particularly in the pharmaceutical and agrochemical industries.
It has become increasingly clear that enantiomerically pure drugs have numerous advantages over racemic drug mixtures including advantages, such as, fewer side effects and greater potency, which result in part from the ability of living systems to differentiate between enantiomeric compounds. Some of these advantages are summarized in a review article in
Chem. Eng. News,
pp. 46-79, Sep. 28, 1992.
U.S. Pat. No. 5,665,890 to Jacobsen et al. describes a stereoselective chemical synthesis by the reaction of a nucleophile and a chiral or prochiral cyclic substrate, such as an epoxide, in the presence of a non-racemic chiral catalyst, such as, chiral Co(salen)-catalyzed ring-opening reactions of racemic or enantiopure epoxides with nucleophiles.
U.S. Pat. No. 5,929,232, also to Jacobsen et al., describes a kinetic resolution of a cyclic substrate, such as an epoxide, in the presence of a non-racemic chiral catalyst.
U.S. Pat. Nos. 5,663,393 and 5,637,739, both to Jacobsen et al., describe catalysts that are useful in the above stereoselective chemical syntheses and kinetic resolution reactions.
Various aspects of kinetic resolution reactions, including ring opening of epoxides with nucleophiles has been mentioned by the following references: Annis and Jacobsen,
J. Am. Chem. Soc.,
121, 4147-4154 (1999); Ready and Jacobsen,
J. Am. Chem. Soc.,
121, 6086-6087 (1999); Jacobsen,
Acc. Chem. Res.
2000, 33, 421-431; and Tokunaga, Larrow, Kakiuchi, and Jacobsen,
Science
1997, 277, 936-938.
Existing hydrolytic kinetic resolution (HKR) technology requires pre-activation of the catalyst precursor, such as, Co(II)(salen), the structure of which is shown in Example 1, in dichloromethane with acetic acid promoter for 1 to 2 hours in the presence of air. The dichloromethane is then removed from the Co(III)(salen) catalyst, and the epoxide is added, followed by careful dosing of water. When the reaction is complete, the epoxide product is separated from the diol product by distillation.
Problems associated with the above process include the following:
(1) a separate catalyst activation step is required, the use of dichloromethane requires special equipment and additional expenses for handling and disposal and the exchange of dichloromethane for epoxide takes a significant amount of processing time;
(2) the process has moderate repeatability due to the use of a volatile and relatively reactive promoter, such as, acetic acid, which produces results that have poor reproducibility;
(3) the process has moderate efficiency due to high catalyst load required, which ranges from 0.2 mol % to 2 mol %, depending upon the epoxide; and
(4) the product is difficult to separate because the combination of heat and the presence of Co(II)(salen) during distillation can erode the enantiomeric excess of the epoxide, i.e., the epoxide can be entrained in the diol during distillation, leading to lower isolated yields of the high optical purity or enantiopure epoxide.
Thus, a more efficient catalyst activation method, better promoters, new separation techniques to isolate optically pure epoxide from diol, and a means of lowering Co(II)(salen) levels during work-up are very desirable.
None of the above references addresses these problems or provides a solution thereof. None of the above references discloses the preparation of non-racemic products using electron deficient aromatic acids as promoters, activation of the catalyst with epoxides present and the use of ammonium hydroxide during work-up.
Accordingly, the present invention provides a process for the preparation of enantiomerically pure epoxides or non-racemic epoxides and corresponding diols having high optical purity, i.e., having an optical purity of at least 85% enantiomeric excess, which can be useful as intermediate in the synthesis of a variety of widely used pharmaceutical and other products.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of an enantiomerically enriched non-racemic chiral diol and an enantiomerically enriched non-racemic chiral epoxy compound by a hydrolytic kinetic resolution reaction. The process includes the step of contacting oxygen and mixture including a racemic chiral epoxy compound, a non-racemic Co(II) complex catalyst, an aromatic carboxylic acid and water, at a temperature and length of time sufficient to produce a mixture of the non-racemic chiral diol and the non-racemic chiral epoxy compound.
The present invention further provides a process for the preparation of an enantiomerically enriched non-racemic chiral diol and an enantiomerically enriched non-racemic chiral epoxy compound by a hydrolytic kinetic resolution reaction. The process includes the step of: contacting a racemic chiral epoxy compound and water in the presence of a non-racemic complex of Co(III) having an aryl carboxylate counter-anion, at a temperature and length of time sufficient to produce a mixture of the non-racemic chiral diol and the non-racemic chiral epoxy compound.
The present invention still further provides a process for the preparation of an enantiomerically enriched non-racemic chiral diol and an enantiomerically enriched non-racemic chiral epoxy compound by a hydrolytic kinetic resolution reaction, including the step of:
contacting: (a) oxygen and a mixture including a racemic chiral epoxy compound, a non-racemic Co(II) complex catalyst, an aromatic carboxylic acid and water; or (b) a racemic chiral epoxy compound and water in the presence of a non-racemic complex of Co(III) having an aryl carboxylate counter-anion; wherein the contacting is carried out at a temperature and length of time sufficient to produce a mixture of the non-racemic chiral diol and the non-racemic chiral epoxy compound;
contacting the mixture and a nitrogenous base to produce a solution of the mixture; and
washing the solution of the mixture with water to separate the non-racemic chiral diol from the non-racemic chiral epoxy compound as an aqueous solution thereof.
The present invention also provides a process for the preparation of an enantiomerically enriched non-racemic chiral diol and an enantiomerically enriched non-racemic chiral epoxy compound by a hydrolytic kinetic resolution reaction. The process includes the steps of:
contacting oxygen and a mixture comprising a racemic chiral epoxy compound, a non-racemic Co(II) complex catalyst, a carboxylic acid and water, at a temperature and length of time sufficient to produce a mixture of said non-racemic chiral diol and said non-racemic chiral epoxy compound; and
contacting said mixture and a nitrogenous base to produce a solution of said mixture.
Lastly, the present invention provides a process for the preparation of an enantiomerically enriched non-racemic chiral diol and an enantiomerically enriched non-racemic chiral epoxy compound by a hydrolytic kinetic resolution reaction. The process includes the steps of:
contacting a racemic chiral epoxy compound and water in the presence of a non-racemic complex of Co(III) having an a carboxylate counter-anion, at a temperature and length of time sufficient to produce a mixture of said non-racemic chiral diol
DiMare Marcello
Jacobsen Eric N.
Jasmin Serge
Liu Yi
Marchese Salvatore Anthony
Ohlandt Greeley Ruggiero & Perle L.L.P.
Rhodia Chirex Inc.
Trinh Ba K.
LandOfFree
Hydrolytic kinetic resolution of epoxides does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Hydrolytic kinetic resolution of epoxides, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Hydrolytic kinetic resolution of epoxides will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3335941