Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-11-10
2003-01-14
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S308000, C564S415000
Reexamination Certificate
active
06506940
ABSTRACT:
INTRODUCTION
The present invention relates to a novel process for the conversion of (1R,4R) N-methyl-4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthaleneamine of formula 2, hereinafter referred to as cis (1R,4R) isomer, or trans (1S,4R), isomer of formula 3, or trans (1R,4S) isomer of formula 4, or mixtures thereof, to (1S,4S) N-methyl-4-(3,4-dichlorophenyl)-3,4-dihydro-1,2,3,4-tetrahydro-1-naphthaleneamine of formula 1, commonly known as sertraline (INN Name).
These aforesaid isomers of formulas 2, 3 and 4 are undesired stereoisomers of sertraline of formula 1, and are invariably co-produced during the manufacture of this drug by known processes such as that disclosed in U.S. Pat. No. 4,536,518, which is incorporated herein by reference. More particularly, the present invention relates to a novel process for recycling the undesired stercoisomers, both the trans isomers as well as the cis (1R,4R) isomer, to obtain sertraline in asymptotic amounts through an iterative process. Sertraline hydrochloride (commonly known as Zoloft®) is an important drug useful in the treatment of depression, obsessive-compulsive disorder and panic disorder.
BACKGROUND OF THE INVENTION
Sertraline has two chiral centres and hence has four stercoisomeric forms, namely, the (1R,4R), (1S,4S), (1R,4S), and (1S,4R) isomeric forms of setraline. Of these, the active stercoisomer for therapeutic purpose is the cis (1S,4S) isomer of formula 1.
U.S. Pat. Nos. 4,536,518 and 4,556,676, assigned to Pfizer, disclose a multi-step process for synthesis of pure (1S,4S) N-methyl-4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthaleneamine from 3,4-dichlorobenzophenone. The process proceeds via racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone, a compound of formula 6.
The ketone is condensed with methylamine to form a racemic imine mixture of formula 5c (shown below). The racemic imine is then reduced by means of catalytic hydrogenation or by the use of a metal hydride complex to N-methyl-4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthaleneamine, which is a racemic mixture of the cis and trans isomers. Trans isomers are separated from the cis isomers by fractional crystallization. Resolution of the separated cis racemate with optically active precipitant acid, such as D-(−)-mandelic acid in a classical manner, finally affords the desired cis-(1S,4S)-enantiomer (sertraline). The process has the disadvantage that large amounts of the undesired isomers of formulas 2, 3, and 4 are co-produced thereby lowering the overall yield of sertraline and increasing the production cost.
U.S. Pat. Nos. 4,777,288 and 4,839,104, assigned to Pfizer, disclose processes for the preparation of 4-(3,4-dichlorophenyl)-4-ketobutanoic acid in pure form and in high yield. The 4-(3,4-dichlorophenyl)-4-ketobutanoic acid is converted to racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone, the compound of formula 6. Also, PCT International Publication No. WO 98/15516 discloses a process to prepare a compound of formula 6 in pure form by reacting &agr;-naphthol and o-dichlorobenzene wherein the amount of by-product 4-(2,3-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone is decreased below 1%. The racemic tetralone obtained by the processes of U.S. Pat. Nos. 4,777,288; 4,839,104, and WO 98/15516 may be converted to sertraline by the process disclosed in U.S. Pat. Nos. 4,536,518 and 4,556,676. The processes thus carry with them the prior art disadvantage in that large amounts of the undesired isomers of formulas 2, 3, and 4 are co-produced thereby lowering the overall yield of sertralille and increasing the production cost. U.S. Pat. No. 5,196,607 assigned to Pfizer discloses a multi-step process for preparing chiral (4S)-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-napthalenone of formula 6a in pure form and high yield.
Yet another method is described in U.S. Pat. No. 5,466,880 whereby the chiral tetralone is prepared in an elaborate five-step process starting from 4-(3,4-dichlorophenyl)-4-ketobutanoic acid.
Tetrahedron,
48(47), 10239 (1992), provides another method for preparing the chiral (4S) tetralone by reduction of 4-ketobutanoic acid ester with an asymmetric carbonyl reducing agent. The preparation of chiral tetralone allows for major improvement in the overall synthesis of sertraline in that the unwanted cis (1R,4R) isomer and trans (1S,4R) isomer are not co-produced when (4S) tetralone is converted to sertraline by methods described in U.S. Pat. Nos. 4,536,518; 4,556,676; 4,777,288; and 4,839,104.
PCT International Publication No. WO 95/15299 (Pfizer) describes a method for preparing chiral (4S)-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-napthalenone of formula 6a by asymmetric reduction of the corresponding racemic mixture with asymmetric ketone reducing agents, viz., chiral oxazaborolidine compounds to produce a mixture of cis and trans alcohols, from which the (4S) enantiomer is separated and oxidized to give the (4S) chiral tetralone.
The remaining mixtures of alcohols are oxidized to produce (4R) tetralone of formula 6b, which is then isomerized to racemic mixture of formula 6, with a base and recycled. The (4S) tetralone is then converted to sertraline by methods described in U.S. Pat. Nos. 4,536,518; 4,556,676; 4,777,288; and 4,839,104.
The PCT International Publication No. WO 98/27050 discloses a three step process for the preparation of a mixture of sertraline and its cis (1R,4R) isomer using a novel N-oxide intermediate.
In a recent publication (
Organic Lett.,
1(2), 293 (1999) an enantioselective synthesis of sertraline using an anionic imine ring closure methodology is described starting from dichlorocinnamic acid.
In all the methods described above, eventual isomer separation is inevitable however, none of the methods discussed above provides methods for recycling the unwanted stereoisomers of sertraline. A process for recycling trans isomer of sertraline is described in U.S. Pat. No. 5,082,970. The process involves refluxing the trans isomer or a mixture with about an equal part by weight of the corresponding cis isomer with about 2 molar equivalents of a base such as potassium tert-butoxide for 48 hours in an inert polar solvent to afford a cis-trans mixture in a ratio of about 2:1. However, this method appears to have certain drawbacks in that
i) an excess of base (2 mole equivalents) is used,
ii) it requires 48 hours of reflux, and, most importantly,
iii) the method is not exemplified with cis isomer containing (1R) center, which, incidentally, is the major unwanted isomer that is co-produced in equal amounts along with the desired cis-(1S) isomer. An experiment performed by the inventors herein on the cis (1R,4R) isomer, under the conditions described in the above-referred patent, did not result in isomerization at the C-1 center. This is understandable since the hydrogen at the C-1 position in sertraline isomers is not reactive under the conditions described, and hence is not susceptible to isomerization.
It is therefore, the object of the present invention to develop an alternate simple process whereby the unwanted isomers, both trans as well as the cis (1R,4R) isomer could be recycled to produce ultimately the desired cis (1S,4S) isomer in a simple manner which is commercially feasible.
SUMMARY OF THE INVENTION
The process of the present invention provides a method for converting the stereoisomers of sertraline into sertraline itself and comprises the steps of:
I. Converting cis (1R,4R) isomer of formula 2, or trans (IS,4R) isomer of formula 3, or mixtures thereof, to the corresponding (4R)-imine of formula 5a;
OR
Converting trans (1R,4S) isomer of formula 4 to the corresponding (4S)-imine of formula 5b;
OR
Converting a mixture of isomers of formulas 2 and 4, or a mixture of isomers of formulas 3 and 4, or a mixture of isomers of formula 2, 3 and 4, to the corresponding mixture of (4R)-said (4S)-imines of formula 5c;
II. Subjecting the (4R)-imine of formula 5a (if it has been produced in step I) to base catalyzed isomerization to produce a racemic imine mixture of formula 5c; and
III.
Chitturi Trinadha Rao
Jadav Kanaksinh J.
Thennati Rajamannar
Barts Samuel
Proskauer Rose LLP
Sun Pharmaceuticals Industries Ltd.
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