Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-03
2002-10-01
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C562S401000, C562S402000, C564S302000, C564S303000, C564S304000, C564S347000, C564S349000
Reexamination Certificate
active
06458955
ABSTRACT:
BACKGROUND OF THE INVENTION
At the molecular level biological systems are highly asymmetric; enzymes, proteins, polysaccharides, nucleic acids, and many other fundamental components of life are present in optically active form. The implications of this are profound; as a general proposition the interaction of a chiral molecule with an optically active site is a diastereomeric interaction, and the two enantiomers properly should be viewed as distinct compounds capable of acting in different ways. (R)-Asparagine has a bitter taste, whereas the (S)-isomer is sweet. It has been known for some time that for medicinals having at least one chiral center the pharmacological effectiveness of the enantiomers of the racemic mixture may differ substantially, and in some cases the pharmacological action itself may differ. An extreme example is provided by propranolol, where the major pharmacological effect of the (R)-isomer is as a contraceptive, whereas the major pharmacological effect of the (S)-isomer is as a beta-blocker.
Although the recognition of the desirability of using the pharmacologically and pharmaceutically more acceptable enantiomer is old, nonetheless the use of optically pure medicinals generally is relatively new, simply because of the difficulty and cost of resolution of the racemic mixture and/or the difficulty and cost of asymmetric synthesis of the desired enantiomer. The importance of stereochemical purity may be exemplified by (S)-propranolol, which is known to be 100 times more potent as a beta-blocker than its (R)-enantiomer. Furthermore, optical purity is important since certain isomers actually may be deleterious rather than simply inert. For example, the R-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy. However, S-thalidomide was discovered to be a potent teratogen leaving in its wake a multitude of infants deformed at birth.
With recent chemical advances, especially in asymmetric synthesis, has come both an increase in the feasibility of selectively preparing the desired enantiomer of a given chiral medicinal, as well as increasing pressure on the pharmaceutical industry to make available only that enantiomer. An instructive example of the subject matter of this invention is the class of serotonin-uptake inhibitors represented by fluoxetine (whose racemate is available as Prozac™), tomoxetine, and nisoxetine, all of which have the structure (as the hydrochloride)
where R
3
=4-CF
3
, 2-CH
3
, and 2-C
2
H
5
O, respectively.
Thus, Skrebnik, Ramachandran & Brown,
J. Org. Chem.,
53, 2916, 1988, used chirally modified boron compounds in the asymmetric reduction of prochiral ketones. From 3-chloropropiophenone there was prepared S-3-chloro-1-phenyl-1-propanol in 97% enantiomeric purity which then was used as the starting material for the preparation of the corresponding enantiomers of S-tomoxetine and S-fluoxetine. Shortly thereafter, Gao & Sharpless,
J. Org. Chem.,
53, 4081, 1988, developed an enantioselective synthesis of both enantiomers of tomoxetine and of fluoxetine from cinnamyl alcohol via catalytic asymmetric epoxidation and regioselective reduction of the corresponding epoxycinnamyl alcohols. E. J. Corey and G. A. Reichard,
Tetrahedron Letters,
30, No. 39, 5207 (1989) outlined a 4-step synthesis of enantiomerically pure fluoxetine from 3-chloropropiophenone in 77-82% overall yield with the key step being the enantioselective catalytic reduction of the ketone to 3-chloro-1-phenyl-1-propanol (CPP) in 99% yield and with 94% enantiomeric selectivity. Recrystallization afforded material of 100% enantiomeric purity with 82% recovery. These authors have recognized that compounds such as CPP are extremely useful in syntheses. The patentees in U.S. Pat. No. 5,104,899 recognized that the S(+)isomer of fluoxetine was the more desirable enantiomer, since it was found not to have certain side effects of the racemate such as nervousness, anxiety, insomnia, and adverse psychological effects. The patentees also recognize that the S-enantiomer had a faster onset of action with a quicker response rate.
The foregoing are examples of enantioselective synthesis. Enantioselective synthesis depends on chiral reagents of high enantiomeric purity which often are quite expensive. Consequently, another general approach is based on the efficient resolution of a precursor early in the synthesis of a chiral material. Resolution is effected with high enantiomeric purity and is followed by subsequent conventional synthetic techniques which maintain high enantiomeric purity in intermediates through final product formation. This approach is exemplified by the work of Schneider and Goergens,
Tetrahedron: Asymmetry,
No. 4, 525, 1992. These authors effected enzymatic resolution of CPP via enzymatic hydrolysis of the racemic acetate in the presence of a lipase from
Pseudomonas fluorescens
under close pH control with a phosphate buffer. The hydrolysis was halted after about 50% conversion to afford the R-alcohol while leaving unchanged the S-acetate, which subsequently could be hydrolyzed with base to the S-alcohol. From the enantiomerically pure alcohols the enantiomerically pure tomoxetine, fluoxetine, and nisoxetine could be prepared.
The Schneider and Goergens approach highlights a characteristic of methods based on resolution of a racemate which requires our attention. The authors used both the R- and S-CPP to prepare both R- and S-fluoxetine in high optical purity, although one enantiomer is substantially more desirable than the other (see U.S. Pat. No. 5,104,899, supra). Consequently, in practice only, the more desirable enantiomer will be utilized in subsequent synthesis. There then results the economic burden of discarding the less desirable (or even undesirable) enantiomer—which is half of the raw material or (even worse) an intermediate in the synthesis of the desired enantiomer. Thus, it is imperative to somehow utilize the undesired enantiomer. Stated concisely, incident to a method of preparing medicinals of high optical purity based on using a raw material or intermediate of high enantiomeric purity obtained via resolution of its racemate is the requirement of utilizing the unwanted enantiomer produced as a byproduct in the resolution stage. Perhaps the most desirable utilization of the unwanted enantiomer would be to racemize it and recycle the racemate to the appropriate stage in the synthetic scheme; this application is directed precisely to such a process flow.
SUMMARY OF THE INVENTION
The purpose of the present invention is to present an improved process flow for the preparation of pharmaceutically desirable compounds of high enantiomeric purity. In such a process for producing one enantiomer of product compound where a racemic reactant is resolved into a first enantiomer of at least 95% enantiomeric purity and a second enantiomer and the first enantiomer is selectively converted into the product compound, the present invention provides the improvement that the racemic reactant is resolved by a simulated moving bed using a chiral adsorbent to afford the first enantiomer of at least 95% enantiomeric purity and the second enantiomer, the second enantiomer is racemized into the racemic reactant, and the racemic reactant is recycled to the resolution stage.
REFERENCES:
patent: 2985589 (1961-05-01), Broughton et la.
patent: 5104899 (1992-04-01), Young et al.
patent: 5889186 (1999-03-01), Gattuso
patent: 6162949 (2000-12-01), Gattuso
patent: WO 99-57089 (1999-11-01), None
Skrebnik, Ramachandran & Brown,J. Org. Chem.53, 2916, 1988.
Gao & Sharpless,J. Org. Chem53, 4081, 1988.
E. J. Corey and G.A. Reichard,Tetrahedron Letters, 30, No. 39, 5207 (1989).
Schneider and Goergens,Tetrahedron: Asymmetry, No. 4, 525, 1992.
Maas Maryann
Molinaro Frank S.
Raymond Richard L.
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