(S)-3,4-Dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide

1245550-91-7

154127-42-1

The general procedure for the synthesis of (S)-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide from the compound (CAS: 1245550-91-7) is as follows: the cyclization reaction of the compound (VI) can be carried out with a chiral reductant, e.g., (+)-diisopropylphenylborane (DIPCI) to obtain a single isomer of the target compound (VII) by stereoselective reduction. The procedure was as follows: compound (VI) (210 g, 0.484 mol) was suspended in tert-butyl methyl ether (15 v/v) and stirred under nitrogen protection. The suspension was cooled to -40 °C and (+)-diisopropylaminoborane (DIPCI) (762 g, 60-65% hexane solution, 1.063 mol) was slowly added through a cannula over 30 min. The temperature was raised to -30 °C during the reaction. The reaction mixture was maintained at -25 to -20 °C for 3.0 to 4.0 h. The reaction progress was monitored by TLC (mobile phase: ethyl acetate:hexane = 3:7). After completion of the reduction reaction, 1M aqueous sodium hydroxide solution (20 vol) was added through the addition funnel within 15-20 minutes. The reaction mixture was stirred at 25-30°C overnight and the completion of the reaction was monitored by TLC (mobile phase: ethyl acetate:hexane=1:1). Upon completion of the reaction, the aqueous and organic phases were separated, and the aqueous phase was extracted with tert-butyl methyl ether (4.0 v/v), followed by acidification to pH 1 with 5N hydrochloric acid solution, and extraction with ethyl acetate (3 x 6.0 v/v). The ethyl acetate extracts were combined, washed with saturated brine solution (2 x 2.5 volumes), dried over sodium sulfate and filtered. The organic layer was completely distilled under reduced pressure (at a temperature below 50°C) to give a light yellow syrupy crude product. The yield of compound (VII) was 112 g (65.2% yield). Alternatively, step (f) can be carried out using a non-chiral reducing agent such as sodium tetrahydroborane, subject to a subsequent optical splitting step to remove unwanted isomers.