反应详情

Combine 2-isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acid amide (47.5 g, 155 mmol) and 2-dichloroethane (475 mL) and stir at rt under N2 as a dark solution. Pour POCl3 (14.5 mL, 155 mmol) into the solution, and heat the reaction to reflux (80–83° C.) for 2–3 h until complete by HPLC (Zorbax SB C18 25 cm, 60:40/ACN:0.1% TFA in water, 233 nm, 1.0 L/min). Coolthe reaction to rt, cool further to 0–5° C. Adjust the pH to 8–9 by adding aqueous 2N NaOH (275 mL) at such a rate to maintain the temperature below 20° C. Separate the layers, extract the aqueous layer with CH2Cl2 (2×100 mL). Combine the organic layer, wash with brine (2×100 mL), dry (MgSO4), filter, and concentrate the filtrate in vacuo to a dark oil/solid residue (40 g). Purify the crude product by silica gel chromatography (1200 g silica gel 60, CH2Cl2) to afford 29.4 g (66%) of the title compound as a red solid: 1H NMR (300 MHz, DMSO-d6) δ 9.78 (bs, 1h), 8.15 (dd, 1H, J=6.95 Hz, 1.46 Hz), 7.67 (dt, 1H, J=7.32 Hz, 1.46 Hz), 7.26 (dd, 1H, J=7.32 Hz, 1.10 Hz), 7.15 (dt, 1H, J=6.95 Hz, 1.10 Hz), 3.26 (dq, 1H, J=6.95 Hz), 1.33 (d, 6H, J=6.95 Hz). 13C NMR (75 MHz, DMSO-d6) δ 171.85, 150.83, 139.10, 136.22, 136.00, 126.05, 121.41, 118.64, 116.09, 113.73, 33.01, 22.07(2). IR (CHCl3) 3311, 3021, 2970, 2928, 2868, 2223, 1613, 1583, 1518, 1492, 1448, 1403, 1341 cm−1. HRMS (ES) M/z calculated for C13H12N4O2S 289.0759, found 289.0744.

1. customthe reaction
2. customCoolthe reaction to rt
3. temperaturecool further to 0–5° C
4. temperatureto maintain the temperature below 20° C
5. customSeparate the layers
6. extractionextract the aqueous layer with CH2Cl2 (2×100 mL)
7. washCombine the organic layer, wash with brine (2×100 mL)
8. dry with materialdry (MgSO4)
9. filtrationfilter
10. concentrationconcentrate the filtrate in vacuo to a dark oil/solid residue (40 g)
11. customPurify the crude product by silica gel chromatography (1200 g silica gel 60, CH2Cl2)