Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-05-18
2004-08-03
Shippen, Michael L. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S100000, C560S106000, C560S145000
Reexamination Certificate
active
06770775
ABSTRACT:
The present invention is directed to the synthesis of highly optically enriched &agr;-halo-esters, and, in particular, to a synthesis method using acid halides, cinchona alkaloid catalysts and substituted halogenated quinones to produce &agr;-halo-ketoesters.
BACKGROUND OF THE INVENTION
In the prior art, much effort is being expended into developing optically pure products as building blocks for the synthesis of various chemical, pharmaceutical, and agricultural products. These enantiomerically pure products exhibit high enantiomeric excess and are highly prized for their ability to serve as useful precursors for making optically active compounds such as amines, amides, ethers, and sulfides. Consequently, there is a need for improved methods for making these types of products, particularly halogen-containing products.
In the past, &agr;-halogenation reactions have not been catalyzed due to the use of diatomic halides as halogenation reagents. These reagents can be highly reactive and in some cases very non-selective. However, since halocarbon products are desirable as intermediates, a need exists to produce chiral, optically active &agr;-carbonyl halides for precursor use.
The present invention responds to this need by providing an asymmetric halogenation process to produce &agr;-halo-esters. The process employs simple but effective catalyst and halogenation reagents, while producing an &agr;-halo-ester having high enantiomeric excess.
SUMMARY OF THE INVENTION
It is a first object of the present invention to provide a method of making highly optically enriched &agr;-halo-esters.
Another object of the invention is the product of the method of making the &agr;-halo-esters.
Still another object of the invention is a method, which uses a double-sided flask in conjunction with the reaction sequences.
One other object of the invention is a composition comprising &agr;-halo-esters having high enantiomeric excess, especially &agr;-halo-ketoesters.
Other objects and advantages of the present invention will become apparent as a description thereof proceeds.
In satisfaction of the foregoing objects and advantages, the present invention provides a method of synthesizing an &agr;-halo-ester by first reacting a solution containing a cinchona alkaloid catalyst, a base, and an acid chloride at low temperatures to produce an intermediate ketene solution. Then, a substituted halogenated quinone derivative is reacted with the ketene solution in the presence of the catalyst to produce the &agr;-halo-ester having high enantiomeric excess. The catalyst is preferably one of benzoylquinine or benzoylquinidine, or their respective pseudoenantiomers, benzoylcinchonine or benzoylcinchonidine. The base can be a proton sponge, an inorganic salt, or a triaminophosphoamide immine. The inorganic salts can include potassium carbonate, potassium hydride, sodium carbonate, and sodium hydride and combinations thereof, or other first or second row carbonates.
In one mode, the intermediate ketene solution is filtered prior to conducting the halogenating reaction. The reaction and filtering can be done using a double-sided flask having two flasks separated by a filter. The ketene solution can be formed in one flask and then canted to the other flask through the filter for halogenation. The filter can be any type but is preferably a fritted disc filter disposed in a glass-tube connecting the two flasks.
The reaction to form the ketenes is controlled at a low temperature, preferably no higher than about −42° C. Low temperatures can be attained by cooling baths such as dry ice/acetone mixtures (−78° C.) or other equivalent means. Preferably, the reaction is conducted in a double-sided flask that is surrounded by another enclosing flask for precise control of temperature and atmosphere.
The invention also provides a new and novel highly optically pure/enriched composition and a product made from the inventive process. The (&agr;-halo-ester composition has high enantiomeric excess, e.g., up to 99%, making it an ideal building block in other synthesis processes, wherein other optically pure products such as amides, sulfides, etc. can be made.
The inventive method also provides a unique halogenation synthesis process wherein the inorganic salts are used as a base. This mode offers significant advantages in terms of economics since the base materials are much less expensive than other base materials such as resins or the like.
REFERENCES:
patent: 4728458 (1988-03-01), Higuchi et al.
patent: 5021454 (1991-06-01), Sharma
patent: 2701706 (1994-08-01), None
patent: WO 00/29505 (2000-05-01), None
Wack et al Journal of the American Chemical Society 2001, 123, pp. 1531-1532. + Supporting Information.*
Oppolzer et al Tetrahedron Letters 1985, 26(41), pp. 5037-5040.*
Hafez et al Organic Letters 2001, 3(13) pp. 3963-3965. Abstract Only.
Shippen Michael L.
Stevens Davis Miller & Mosher LLP
Zucker Paul A.
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