Sodium Hydroxide → (4S)-6-chloro-1,1-dioxo-3,4-dihydro-2H-thieno(3,2-e)thiazin-4-ol

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Reaction Conditions

Reaction Steps

A 50-L, 5-necked flask equipped with a mechanical stirrer and a thermometer was flushed with nitrogen overnight. Working under nitrogen, the flask was charged with 3-bromoacetyl-5-chloro-2-thiophenesulfonamide (4, 855 g, 2.68 mol) and t-butyl methyl ether (12.5 L). The stirred suspension was cooled to -40° C. using a dry-ice/2-propanol bath and (+)-β-chlorodiisopinocampheylborane (4.5 L of a 1.2M solution in t-butyl methyl ether, 5.4 mol, 2 eq) was added via a cannula over 30 minutes, causing the temperature to rise to -32° C. The reaction mixture was maintained between -25° to -20° C. for 3.5 hours, after which TLC analysis indicated complete reduction. The mixture was warmed to 0° C. and 1M aqueous sodium hydroxide (11 L) was added from an addition funnel over 10 minutes, causing the temperature to rise to 22° C. The biphasic mixture was stirred vigorously at ambient temperature for 2 hours, after which TLC analysis indicated complete cyclization. The phases were split and the dark aqueous layer was extracted with t-butyl methyl ether (3 L), acidified to pH 1 using concentrated hydrochloric acid, and extracted with ethyl acetate (2×4 L). The combined ethyl acetate extracts were washed with saturated aqueous sodium chloride (3 L), dried over sodium sulfate (1 kg), filtered, and concentrated to a volume of about 1 liter by rotary evaporation, at which point toluene (2 L) was added. As the remainder of the ethyl acetate was stripped, the product crystallized from toluene. It was collected by filtration, washed with toluene (2 L) and methylene chloride (2 L), and dried in air at ambient temperature to a constant weight of 498 grams (77%) of 5: mp 126°-127° C.; IR (KBr) 3550, 3230, 1430, 1410, 1320, 1170, 860, 720, 550, 470 cm-1 ; 1H NMR (DMSO-d6) δ8.18-8.11 (m, 1H), 7.19 (s, 1H), 5.8 (br, 1H), 4.60-4.54 (m, 1H), 3.68-3.55 (m, 1H), 3.50-3.35 (m, 1H); [α]25D -5.9° (c=1, CH3OH); Analysis for C6H6ClNO3S2 : Calcd: C, 30.06; H, 2.52; N, 5.84. Found: C, 30.14; H, 2.56; N, 5.80.

Provenance & Evidence