Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2000-11-03
2002-06-25
Raymond, Richard L (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C558S415000, C568S319000, C568S322000, C568S327000
Reexamination Certificate
active
06410794
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, pertinent to the subject matter of this invention, is the class of compounds having Formula I. An important member of this class is the antidepressant sertraline (available as Zoloft™), which has Formula II:
Useful precursors to compounds of Formula I are represented by tetralones having Formula III which are generally referred to as “tetralones” or where racemic, “racemic tetralones”. A valuable synthetic precursor to sertraline is a tetralone, specifically, one enantiomer of the compound 4-(3,4-dichlorophenyl-3,4-dihydro-1(2H)-naphthalenone and, more specifically, (4S)-(3,4-dichlorophenyl-3,4-dihydro-1(2H)-naphthalenone with the structure IV:
Thus, G. J. Quallich and T. M. Woodall,
Tetrahedron
, Vol. 48, No.47, p. 10239, (1992) used SN2 cuprate displacement of an activated chiral benzylic alcohol, followed by intramolecular Friedel-Crafts acylation of a diaryl carboxylic acid to yield the chiral tetralone of structure IV. Other documents relate to the synthesis of sertraline and to chiral tetralone, including U.S. Pat. No. 5,750,794; U.S. Pat. No. 4,536,518 ; U.S. Pat. No. 4,556,676; U.S. Pat. No. 4,777,288; and U.S. Pat. No. 4,839,104. Other asymmetric methods of synthesis have been employed by those skilled in the art, such as those described by W. M. Whitesides, et. al,
Journal of the American Chemical Society
, Vol. 91, No. 17, p. 4871 (1969); K. Mori et. al.,
Synthesis
, p. 752 (1982); and B. H. Lipshutz et. al.,
Journal of Organic Chemistry
, Vol. 49, p. 3928, (1984).
The foregoing are examples of enantioselective synthesis relevant to the chiral tetralone precursor (structure IV) to sertraline. 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 3-chloro-1-phenyl-1-propanol (CPP) via enzymatic hydrolysis of the racemic acetate in the presence of a lipase from
Pseudornonas 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 serotonin-uptake inhibitors fluoxetine (whose racemate is available as Prozac™), tomoxetine, 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 by product 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 a process for the preparation of the more desirable enantiomer of tetralones. The invention comprises resolution of racemic tetralones by simulated moving bed chromatography using a chiral adsorbent to afford at least one substantially pure enantiomer of tetralones, utilization of the substantially pure tetralone enantiomer in the synthesis of sertraline or sertraline analogs, racemization of the enantiomer not further used in synthesis, with recycle thereof to the resolution stage. In a specific embodiment (4S)-(3,4-dichlorophenyl-3,4-dihydro-1(2H)-naphthalenone is utilized as the substantially pure enantiomer.
Another embodiment comprises the reduction of tetralones to the corresponding racemic alcohols, conversion of the racemic alcohols to the corresponding racemic hydroxyl-protected alcohols, resolution of racemic hydroxyl-protected alcohols by simulated moving bed chromatography using a chiral adsorbent to afford at least one substantially pure enantiomer of the hydroxyl-protected alcohols, de-protection of a selected hydroxyl-protected alcohol enantiomer to the corresponding alcohol, oxidation of said alcohol to the corresponding tetralone enantiomer, utilization of the substantially pure tetralone enantiomer in the synthesis of sertraline or sertraline analogs, and racemization of the other hydroxyl-protected alcohol enantiomer with its recycle to the resolution stage.
Yet another embodiment comprises the conversion of tetralones to the corresponding carbonyl-protected tetralones, resolution of carbonyl-protected tetralones by simulated moving bed chromatography using a chiral adsorbent to afford at least one substantially pure enantiomer of the carbonyl-prot
Gattuso Mark J.
Zinnen Herman A.
Maas Maryann
Molinaro Frank S.
Raymond Richard L
Tolomei John G.
UOP LLC
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