Sertraline-tetralone

Quallich, Process for the production of enantiomerically pure or optically enriched sertraline-tetralone using continuous chromatography. US Patent 6,444,854 (2002). 

The method was shown to be useful by its application to an asymmetric synthesis of (S)-sertraline tetralone, a precursor of Zoloft and perhaps for analogues. Their future work is focused on the development of enantio-selective nickel-catalysed methods for cross-coupling allqrl electrophiles (Scheme 16.25). 

The intramolecular C-H insertion reaction of phenyldiazoacetates on cyclohexadiene, utilizing the catalyst Rh2(S-DOSP)4, leads to the asymmetric synthesis of diarylacetates (Scheme 8). Utilizing the phenyl di azoacetate 38 and cyclohexadiene, the C-H insertion product 39 was produced in 59% yield and 99% ee. Oxidative aromatization of 39 with DDQ followed by catalytic hydrogenation gave the diarylester 40 in 96% ee. Ester hydrolysis followed by intramolecular Friedel-Crafts gave the tetralone 31 (96% ee) and represents a formal synthesis of sertraline (5). Later studies utilized the catalyst on a pyridine functionalized highly cross-linked polystyrene resin. ... 

Sertraline is the active pharmaceutical ingredient (API) in Pfizer s antidepressant Zoloft [25]. The developed commercial process employs an SMB chromatographic resolution of tetralone (Scheme 13.10) in >99% ee followed by diastereoselective reductive amination to give 95% sertraline (cis-isomer) and 5% trans-isomer the (4R)-tetralone can be racemized with an alkoxide base [8]. Asymmetric processes to sertraline have been described [26]. Our studies started with the original patented process involving palladium-catalyzed reductive amination of a tetralone to give a mixture of 80% racemic-cis and 20% racemic-trans diastereomers [27]. The cis-diastereomer can be purified by selective crystallization from toluene followed by diastereomeric crystallization of the (lS,4S)-enantiomer using (R)-... 

Sertraline (16) is an antidepressant that inhibits the uptake of serotonin in the central nervous system.148 It is marketed by Pfizer under the name Zoloft.149 One methodology that can be used relies on an asymmetric reduction (see also Chapter 16) (Scheme 31.11).150-156 The lactone can be used as a chiral starting material for the Friedel-Crafts reaction. The established stereogenic center in the tetralone controls the reduction of the imine.157 The alternative is a resolution approach (Scheme 31.12).148-153-158-161... 

In this process (Fig. 22), ketone 61 underwent reduction with an over-stoichiometric amount of borane in THF in the presence of 5 mol % of the proline-derived Corey s oxa-zaborolidine 62 to afford alcohol 63 in 100% yield and 92% e.e. SN2 displacement carried out on the alcohol mesylate with a higher-order cuprate gave adduct 64, that was transformed first into tetralone 65 by a triflic acid-promoted Friedel-Crafts-type reaction, and then into sertraline 66 (86% e.e.) by imine formation and borohydride reduction. 

On comparing Pfizer G3 and Pfizer G2 plans, the overall yield increased 2.8-fold, 64% less tetralone and methylamine are used, but 22.5% more (+)-mandelic acid is used. Table 2.6 shows a reduction in the E-aux contribution from solvents and auxiliary materials of 58%, a reduction of 65% in the E-kernel contribution from raw materials, and a reduction in E-total of 60%. The difference in E-total factors is over 436 units of waste per unit of sertraline produced. 

The search for a cost-effective synthetic method for the production of (4S)-tetralone 4, the intermediate on the pathway to sertraline, was shifted to technology that is still new to the pharmaceutical industry - continuous chromatographic separation... 

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