Sodium Chloride → (4S)-6-chloro-2-(3-methoxypropyl)-1,1-dioxo-3,4-dihydrothieno(3,2-e)thiazin-4-ol

A 5-L, 4-necked flask equipped with a mechanical stirrer, a thermometer, and a 250-mL addition funnel was charged with (S)-3,4-dihydro-6-chloro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide (5, 350 g, 1.46 mol), dimethylsulfoxide (1.75 L), and potassium carbonate (605 g, 4.38 mol). 1-Bromo-3-methoxypropane (268 g, 1.75 mol, 1.2 eq) was added via the addition funnel in eight equal portions spaced 1 hour apart. Each addition caused a small rise in temperature, amounting to a 10° C. increase over 8 hours. TLC analysis 1.5 hours after the final addition indicated complete reaction. The reaction mixture was poured into a 50-L flask equipped with a mechanical stirrer containing saturated aqueous sodium chloride (18 L). The original reaction vessel was rinsed with both water and t-butyl methyl ether. The aqueous solution was extracted with t-butyl methyl ether (2×4 L) and the combined extracts were washed with 1M aqueous sodium hydroxide (2 L), 1:1 bleach/water (2 L), and saturated aqueous sodium chloride (2 L). The t-butyl methyl ether solution was dried over sodium sulfate (500 g), filtered, and stripped of solvent by rotary evaporation. The residual oil was transferred to a 2-L flask and trace solvent was removed by rotary evaporation at 50° C., first under water aspirator, then under high vacuum for 6 hours to provide 427 grams (94%) of (S)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide as a light yellow syrup: IR (film) 3500, 2931, 2878, 1422, 1336, 1167, 1114, 1071, 1028, 690 cm-1 ; 1H NMR (CDCl3) δ6.96 (s, 1H), 4.64 (br s, 1H), 4.08 (dd, 1H, J=4 and 15 Hz), 3.81-3.28 (m, 6H), 3.25 (s, 3H), 2.04-1.83 (m, 2H); [α]25D +11.4° (c=1, CH3OH); Analysis for C10H14ClNO4S2 : Calcd: C, 38.52; H, 4.53; N, 4.49. Found: C, 38.65; H, 4.54; N, 4.47.

1. additiona thermometer, and a 250-mL addition funnel
2. additionEach addition
3. customto a 10° C.
4. temperatureincrease over 8 hours
5. additionTLC analysis 1.5 hours after the final addition
6. customreaction
7. additionThe reaction mixture was poured into a 50-L flask
8. customequipped with a mechanical stirrer
9. washThe original reaction vessel was rinsed with both water and t-butyl methyl ether
10. extractionThe aqueous solution was extracted with t-butyl methyl ether (2×4 L)
11. washthe combined extracts were washed with 1M aqueous sodium hydroxide (2 L), 1:1 bleach/water (2 L), and saturated aqueous sodium chloride (2 L)
12. dry with materialThe t-butyl methyl ether solution was dried over sodium sulfate (500 g)
13. filtrationfiltered
14. customstripped of solvent by rotary evaporation
15. customThe residual oil was transferred to a 2-L flask
16. customtrace solvent was removed by rotary evaporation at 50° C., first under water

ORD record

ord-8e9a57d6b6e14950bb3d8f5ee7d0f8f2

Source dataset

uspto-grants-1994_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05344929