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Sertraline represented Pfizer's first product with stereocenters not derived from natural sources, as was the case with azithromycin and beta-lactam products. Discovery chemists employed chromatography and classical resolution to secure the active agent's two stereocenters. Investigations to identify a commercial route comprised a number of synthetic approaches, including enantioselective ketone reduction, SN2 displacement of an activated alcohol to transfer chirality, and continuous chromatography. The challenges of adopting new technology in the pharmaceutical industry are discussed in the context of sertraline's development. The successful outcome employed continuous chromatography, and the potential for this technology to shift the development paradigm for any development candidate or commercial product is described.

Methyl 4,5,7,8-Tetra-0-acetyl-2-O-benzyl-3-deoxy-o-manno -2octulopyranosonate (23). A solution of the acid 22 (127 mg, 0.254 mmol) in ether (5 mL) was treated with an excess of etheral diazomethane. After 10 min, the solution was concentrated in vacuo. Flash chromatography (35% ethyl acetate/hexane, Rf0.35) provided 124 mg (95%) of the title compound as a colorless glass: ,8-Penta-0-acetyl-3-deoxy-~-~anno-2-octulopyranosonate (24). A mixture of the benzyl ether 23 (111 mg, 0.217 mmol), 10% palladium on carbon (20 mg), and ethanol (3 mL) was stirred under a balloon of hydrogen for 20 h then filtered through Celite, washing with dichloromethane. The filtrate was concentrated in vacuo to give the crude alcohol, which was dissolved in dichloromethane (2 mL) and treated with acetic anhydride (44 mg, 0.43 mmol), pyridine (34 mg, 0.43 mmol) and 4-(dimethylamino)pyridine (2 mg). After 3 h, the solution was washed with 10% aqueous hydrochloric acid and saturated aqueous sodium bicarbonate, then dried (MgS04), and concentrated in vacuo to provide 93.1 mg (93%) of the title compound as a colorless solid, mp 129.&129.5 "C (ethyl acetate/hexane) lit. mp25 for (+)-24 155-158 "C, which was identical with material prepared from (+)-NH4 KDO (Sigma) according to Unger2' with regard to its TLC behavior (Rf0.25, 40% ethyl acetate/hexane) and its IR, IH N M R (250 MHz), and mass spectra: (26). (*)-Ammonium 3-Deoxy-o-msnno -2-octulopyranosonate (( f)-NH, KDO) (1). A solution of the acid 22 (203 mg, 0.409 mmol) in methanol 451 (M -C02H, 2), 390 (12), 141 (24), 112 (12), 91 (100).(4 mL) was stirred with sodium methoxide (1 11 mg, 2.05 mmol) for 6 h, then neutralized with methanol-washed Dowex 50-8x (20-50 mesh) ion-exchange resin. The mixture was filtered, washing the resin with small portions of methanol. Palladium (10% on charcoal, 50 mg) was added to the filtrate and the mixture was stirred under a balloon of hydrogen for 16 h then filtered through Celite, washing with methanol. The filtrate was treated with excess anhydrous methanolic ammonia, and the solution was concentrated in vacuo to provide 96.0 mg (92%) of the title compound as a colorless, amophous solid (mp 119-122 "C) whose 250-MHz 'H N M R spectrum in D 2 0 was essentially identical with that of an authentic sample of (+)-NH, KDO (Sigma, mp 122-1 24 "C) with the exception of a few very minor impurities, which were absent after recrystallization. Mobility by TLC was identical with that of an authentic sample, Rf 0.58 (10:10:3 methanol/chloroform/water, p-anisaldehyde/sulfuric acid visualization). Slow crystallization from aqueous ethanol provided pure (*)-NH4 KDO (1) as colorless plates, mp 122.5-124.0 'C (lit. mp2sa of (+)-1 122-125 "C); 'H NMR (250 MHz, D20, Me4Si reference) 6 4.47-4.37 (m), 4.10 (m), 4.03-3.92 (m), 3.88-3.49 (m), 2.50 (dd, J = 14, 7 Hz), 2.25 (ni), 2.03-1.76 (m).Peracetylation and diazomethane esterification of 7.1 mg (0.028 mmol) of the crude product according to the literature procedure2' afforded 10.4 mg (81%) of (*)-24 as a colorless solid (mp 128-1...

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