Sertraline, preparation

Few methodologies have either the diversity of synthetic transformations or the high level of product selectivity as catalytic reactions with the intermediate involvement of metal carbenes [ 1-5]. They provide synthetic opportunities that are clearly demonstrated in the preparation of the antidepressant sertraline (1)... 

The vinylcyclopropane 10 is a useful chiral building block for organic synthesis, as the vinyl group can be oxidatively cleaved if desired and further functionahzed (Scheme 14.1). Either diastereomer 20 or 21 of the cyclopropane analog of phenylalanine can be readily prepared from 10 [40]. Corey has reported another elegant appHcation of the vinylcyclopropane 10 in the asymmetric synthesis of the antidepressant (-i-)-sertraline 22 [52]. 

Sertraline [60], chiral 1,4-cycloheptadienes [61], and select cyclopentenes [62] have been prepared by using these catalysts and vinyldiazocarboxylates, and this approach has also been applied to the enantioselective synthesis of functionalized tropanes [63] and of the four stereoisomers of 2-phenylcyclopropane-l-amino acid [64]. 

Sertraline is an antidepressant that is sold as a single enantiomer and prepared commercially through a resolution of a racemate. The starting material for the resolution step is the hydrochloride salt of racemic sertraline (13.22) (Scheme 13.3). The hydrochloride salts are first neutralized through the addition of NaOH to form the racemic free amine (13.23). The amine is then reacted with 1.0 equivalents of d-(— )-mandelic acid (13.24) in ethanol to form diastereomeric salts. The solution of the salts in ethanol is allowed to stand at room temperature, and a solid consisting of predominantly diastereomer 13.25 precipitates. Filtration of the solid followed by recrystallization from ethanol affords essentially... 

Antidepressant stability after three freeze-thaw cycles was evaluated in triplicate at low and high concentrations. Calculated concentrations in the samples subjected to these conditions (stability samples) were compared to those obtained in freshly prepared samples (control samples). Stability and control samples were quantified with a calibration curve prepared on the day of the analysis. All analytes were stable under these conditions, except sertraline, for which a slight signal decrease was observed at 250 ng/mL in oral fluid (MRE = -33.4% %CV = 6.0%). 

Equally successful has been the group of Quallich at Pfizer46 who reported the preparation of a substituted dihydronaphthalenone, a pivotal intermediate in the preparation of the antidepressant sertraline (Lustral ) (10) (Scheme 16.6). In this synthesis, the new chiral center created subsequently determines the absolute stereochemistry of the final product (see Chapter 31). 

Sertraline (cis-(lS)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphtha-leneamine) in the hydrochloride salt is an antidepressant marketed as Zoloft . U.S. 4,536,518 (to Pfizer, Inc.) describes the preparation of the API. Estimate the cost of production of the APL... 

Asymmetric transfer hydrogenation with a chiral ruthenium complex is an alternative option for preparation of substituted phenethyl alcohols, which are important building blocks for the agricultural fungicide, (S)-MA20565 [47]. In the enantioselective synthesis of antidepressant sertraline (50), different chiral secondary alcohols have been proposed as pivotal intermediates (Scheme 14). Reduction of the keto ester 46 catdyzed by oxazaborolidine 45 provides chiral intermediate 47 in 90% ee [48]. Alternatively, reductive fragmentation of C2-symmetric oxa-tricyclic alkene 48 with DIBAL catalyzed by a BINAP-Ni complex generates a novel intermediate 49 in 88 % yield with 91% ee [49]. 

When the compound itself contains more than one chiral centre the question of diastereoisomers takes precedence over that of enantiomers. Resolution is normally performed on the wanted diastereoisomer rather than on the mixture. In the case of sertraline 45, an anti-depressant that affects serotonin levels in the brain, the active isomer was not known when both diastereoisomers were prepared by a unselective route.8 The starting material 41 was made by a Friedel-Crafts reaction between 1,2-dichlorobenzene and succinic anhydride. 

Taber, G. P. Pfisterer, D. M. Colberg, J. C. A New and Simplified Process for Preparing N-[4-(3,4-Dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenyl-idene]methanamine and a Telescoped Process for the Synthesis of (IS-cis)-4-(3,4-Dichlorophenol)-1,2,3,4-tetrahydro-N-methyL 1 -naphthalenamine Mandelate Key Intermediates in the Synthesis of Sertraline Hydrochloride. Org. Proa Res. Dev. 2004, [Pg.431]

Both (RJi) and (S,S) enantiomers of ethylenebis(rf-tetrahydroindenyl)titanium difluoride (EBTHI)TiF2, were developed by Buchwald et al. and used in many efficient enantioselective hydrogenations of ketones [15] and imines [16]. The utility of this process was demonstrated in the enantio- and diastereo-selective preparation of sertraline according to Scheme 7.2. The enantioselectivity and yield in this reaction ranged between 90 and 96% e.e. and 40-50%, respectively. The yield is based on the racemic 5, and amounts to 76-96% when based on the (4S)-enantiomer. Workup in this reaction requires chromatographic separation of (15,45 )-1, from the (4i )-ketone 4. Later, in Sect. 7.5.4, we shall discuss an independent research project that resulted in the efficient recycling of the wrong enantiomer of this ketone. 

The use of chiral columns of various types has exploded since the 1980s, as the need for laboratory-scale and preparative-scale separation of enantiomers has increased. A number of chiral drugs are prepared for commercial purposes using chiral chromatography, for example, the antidepressant Zoloft (chemical name S-sertraline) [26]. Its absolute structure is shown in Figure 5.19 [27]. 

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