반응 #640623

반응 방정식

2-methyl-3-methoxy-6-acetyl-aniline

Oxalyl chloride

4-isopropyl-thiazole-2-carboxylic acid

Diisopropylethylamine

→

title compound

수율 91.3%

1-Acetyl-2-[(4-isopropyl-thiazol-2-yl)-carbonylamino]-3-methyl-4-methoxy-benzene

수율 91.3%

용매

toluene

반응 조건

후처리

1. 1
   기타was continued at ambient temperature until the bubbling
2. 2
   온도The reaction mixture was then heated
3. 3
   온도under reflux for a further 1 hour
4. 4
   기타LCMS analysis of an aliquot quenched with methanol revealed full conversion of the acid to the acid chloride
5. 5
   workup.WAITThe reaction mixture was left
6. 6
   기타the solvent removed under vacuum
7. 7
   workup.ADDITIONThe residue was diluted with dry dioxane (40 mL)
8. 8
   workup.STIRRINGThe reaction mixture was stirred at ambient temperature for 15 hours
9. 9
   기타The solvent was removed under vacuum
10. 10
    workup.DISSOLUTIONthe residue dissolved with ethyl acetate (75 mL)
11. 11
    세척The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL), water (50 mL), and brine (50 mL)
12. 12
    건조dried over sodium sulphate
13. 13
    여과filtered
14. 14
    기타the solvent removed under vacuum
15. 15
    기타The residue was purified by flash column chromatography
16. 16
    기타the solvent removed under vacuum

실험 절차

Oxalyl chloride (5.71 g, 45 mmol., 3.0 eq) was added dropwise, at ambient temperature, to a solution of 4-isopropyl-thiazole-2-carboxylic acid (3.85 g, 22.5 mmol., 1.5 eq) in toluene (40 mL). Stirring was continued at ambient temperature until the bubbling stopped. The reaction mixture was then heated under reflux for a further 1 hour. LCMS analysis of an aliquot quenched with methanol revealed full conversion of the acid to the acid chloride. The reaction mixture was left to cool to ambient temperature and the solvent removed under vacuum. The residue was diluted with dry dioxane (40 mL). Diisopropylethylamine (3.9 g, 30 mmol., 2 eq.) was added dropwise followed by 2-methyl-3-methoxy-6-acetyl-aniline (2.7 g, 15.0 mmol., 1.0 eq). The reaction mixture was stirred at ambient temperature for 15 hours. LCMS analysis showed full conversion of the starting material to product. The solvent was removed under vacuum and the residue dissolved with ethyl acetate (75 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL), water (50 mL), and brine (50 mL), dried over sodium sulphate, filtered and the solvent removed under vacuum. The residue was purified by flash column chromatography using a gradient of heptanes:ethyl acetate (4:1 to 6:4). The relevant fractions were combined and the solvent removed under vacuum to give 4.55 g (91%) of the title compound as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 11.28 (br. s, 1 H), 7.76 (d, J=8.70 Hz, 1 H), 7.17 (s, 1 H), 6.79 (d, J=8.70 Hz, 1 H), 3.94 (s, 3 H), 3.23 (spt, J=6.89 Hz, 1 H), 2.59 (s, 3 H), 2.17 (s, 3 H), 1.42 (d, J=6.87 Hz, 6 H). LC-MS: 99% (UV), tR 2.24 min, m/z [M+1]+ 333.05.

출처