Chemistry: molecular biology and microbiology – Process of utilizing an enzyme or micro-organism to destroy... – Resolution of optical isomers or purification of organic...
Reexamination Certificate
1999-10-26
2003-07-08
Marx, Irene (Department: 1651)
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
C435S252100, C435S170000, C435S171000, C435S254800
Reexamination Certificate
active
06589777
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel processes for preparing the (4S) enantiomer of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone (hereinafter also referred to as “chiral tetralone” or “(4S) tetralone”) and, more specifically, relates to the stereoselective microbial reduction of racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone (hereinafter also referred to as “racemic tetralone”) to chiral tetralone.
BACKGROUND OF THE INVENTION
The chiral tetralone prepared by the processes of the present invention may be further reacted to prepare pure cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine, commonly referred to as sertraline. Sertraline is well known to be useful, for example, as an antidepressant and anorectic agent, and in the treatment of chemical dependencies, anxiety-related disorders, premature ejaculation, cancer and post-myocardial infarction.
Methods are known in the art for preparing sertraline, such as, for example, those described in U.S. Pat. Nos. 4,536,518; 4,777,288; 4,839,104; 4,855,500; 4,940,731; 4,962,128; 5,082,970; 5,130,338; 5,196,607; 5,248,699; 5,442,116; 5,463,126; 5,466,880; 5,597,826; and 5,750,794; and, in the paper of W. M. Welch, Jr. et al., appearing in the
Journal of Medicinal Chemistry
, Vol. 27, No. 11, p. 1508 (1984).
Several of the aforementioned patents relate to the synthesis of mixtures of cis- and trans-isomers of racemic N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine. As described therein, the cis- and trans-isomers, as well as their (S) and (R) enantiomers, may be separated by methods known to those skilled in the art including, for example, fractional crystallization or chromatography.
It is also known to select for the ultimately desired chirality earlier on in the synthesis of sertraline. For example, the aforementioned U.S. Pat. No. 5,750,794 discloses a process for preparing chiral tetralone by reacting racemic tetralone with an asymmetric ketone reducing agent to yield the corresponding cis- or trans-alcohols depending upon the chirality of the asymmetric reagent employed, and then separating the alcohols and oxidizing the (1S,4S) and/or (1R,4S) alcohols to (4S)-tetralone.
It is also known in the art that chiral compounds can be synthesized using microorganisms, such as, fungi, e.g., yeast. For example, the use of yeasts to reduce ketones to chiral alcohols is well known. However, as is appreciated by those of skill in the relevant art, the chemical and optical yields, e.g., particular enantiomers and amounts thereof, of such microbial reductions generally vary substantially depending on, for example, the particular microorganism chosen, as well as the substituents of the starting material.
U.S. Pat. No. 5,049,497 discloses a process for resolving a racemic derivative of bicyclo[4.2.0]octane by contacting the derivative with Baker's Yeast under conditions sufficient to give a mixture of a ketone and an alcohol of high enantiomeric purity. As described therein, only one enantiomer of the subject racemic ketone is reduced to give an alcohol.
U.S. Pat. No. 5,580,764 discloses an asymmetric reduction process which uses an intact microorganism, or a broken cell preparation thereof, to convert a cyclic ketone to the corresponding chiral alcohol.
U.S. Pat. No. 5,618,707 discloses a process for the stereoselective reduction of ketone substrates by adding the substrates to a culture broth of either
Zygosaccharomyces bailii
ATCC (American Type Culture Collection) No. 38924 or
Schizosaccharomyces octosporus
ATCC No. 2479, incubating the resultant mixture, and isolating the hydroxy compound through conventional means such as, for example, extraction with organic solvents, adsorption to resins, or chromatography for subsequent use as an intermediate in the preparation of a serum cholesterol lowering agent. The isolated hydroxy compound described therein was analyzed by chiral high performance liquid chromatography (HPLC), reverse-phase HPLC, or both. Consistent with what would be understood by one of skill in the relevant art, as described therein, many of the large number of microorganisms which were investigated for their ability to reduce the ketone group of the selected substrate failed to reduce the ketone group with the desired specificity or productivity.
It has now been unexpectedly found that a range of microorganisms, including fungi, e.g., yeasts, and actinomycetes, substantially stereoselectively reduce a racemic tetralone. More specifically, the subject stereoselective microbial reduction selectively reduces the (4R) tetralone of the racemic mixture while leaving the (4S) tetralone substantially unreacted. Moreover, the unwanted (4R) tetralol produced by the subject process can be oxidized and then racemized to racemic tetralone and the subject process repeated to yield even more (4S) tetralone. The (4S) tetralone produced by the subject process can be used in the synthesis of sertraline.
All of the documents cited herein, including the foregoing, are incorporated by reference herein in their entireties.
SUMMARY OF THE INVENTION
The present invention relates to microbiological reduction of carbonyl groups which comprises contacting a ketone compound, the racemic tetralone of formula (I), with a microorganism, or an enzyme reduction system capable of accomplishing the subject reduction comprising an enzyme derived from said microorganism and a co-factor for said enzyme, and incubating the resultant mixture under suitable conditions such that a compound having a hydroxy group, specifically, the (4R) tetralol of formula (II) can be formed and accumulated in the medium, and a compound having the desired stereochemistry, the (4S) tetralone of formula (V) below, remains substantially unreacted. The (4S) tetralone of formula (V) below, i.e., chiral tetralone, can then be isolated by any suitable method, e.g., chromatography or crystallization. In addition, the (4R) tetralol of formula (II) can be separated from the compounds of formulae (III)-(V), oxidized and racemized to racemic tetralone and the subject stereoselective microbial reduction repeated to result in even more of the desired chiral ketone.
Accordingly, the present invention provides processes for carrying out the following stereospecific microbial reduction:
which comprises: contacting a compound of formula (I) with a microorganism, or an enzyme reduction system capable of accomplishing the subject reduction comprising an enzyme derived from said microorganism and a co-factor for said enzyme, and incubating the resulting mixture under conditions sufficient to yield more of the compound of formula (II) than the compound of formula (III), thus leaving more of the compound of formula (V) unreacted than the compound of formula (IV) unreacted.
The subject stereospecific reduction may also be represented by:
which comprises: contacting a compound of formula (I) with a microorganism, or an enzyme reduction system capable of accomplishing the subject reduction comprising an enzyme derived from said microorganism and a co-factor for said enzyme, and incubating the resulting mixture under conditions sufficient to yield the (4R) tetralol of formula (II) and to leave substantially unreacted the (4S) tetralone of formula (V).
The stereoselective reduction further optionally comprises the separation of the (4S) tetralone of formula (V) from the (4R) tetralol of formula (II). The (4R) tetralol may then be oxidized to produce the (4R) tetralone, which is then reacted, e.g., with a base, to produce racemic tetralone of formula (I) and the subject stereoselective microbial reduction may be repeated to result in even more of the desired (4S) tetralone of formula (V), i.e., the (4S) enantiomer of the racemic tetralone of formula (I).
The present invention provides processes which comprise the stereoselective microbial reduction of a compound of formula (I) to a compound of formula (II) by: contacting a compound of formula (I) with a microorganism, or an enzyme reduction s
Morse Brook K.
Truesdell Susan J.
Wong John W.
Benson Gregg C.
Kispert Jennifer A.
Marx Irene
Pfizer Inc.
Richardson Peter C.
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