Oxalyl chloride → N-(6-Acetyl-3-methoxy-2-methylphenyl)-4-(propan-2-yl)-1,3-thiazole-2-carboxamide

HRID 553441Notes

Reaction equation

HRID 553441 reaction equation
C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[N:11]=[C:12]([C:15]([OH:17])=O)[S:13][CH:14]=1)([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C.[CH3:27][C:28]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([C:37](=[O:39])[CH3:38])[C:29]=1[NH2:30]>C1(C)C=CC=CC=1>[C:37]([C:31]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:28]([CH3:27])[C:29]=1[NH:30][C:15]([C:12]1[S:13][CH:14]=[C:10]([CH:7]([CH3:8])[CH3:9])[N:11]=1)=[O:17])(=[O:39])[CH3:38]

Participants

6

Reactant 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 224993072-Thiazolecarboxylic acid, 4-(1-methylethyl)-HCID 250673162'-Amino-3'-methyl-4'-methoxyacetophenone

Product 1

HCID 53482122N-(6-Acetyl-3-methoxy-2-methylphenyl)-4-(propan-2-yl)-1,3-thiazole-2-carboxamideYield 91.3%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

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.

Workup

  1. customwas continued at ambient temperature until the bubbling
  2. temperatureThe reaction mixture was then heated
  3. temperatureunder reflux for a further 1 hour
  4. customLCMS analysis of an aliquot quenched with methanol revealed full conversion of the acid to the acid chloride
  5. waitThe reaction mixture was left
  6. customthe solvent removed under vacuum
  7. additionThe residue was diluted with dry dioxane (40 mL)
  8. stirringThe reaction mixture was stirred at ambient temperature for 15 hours
  9. customThe solvent was removed under vacuum
  10. dissolutionthe residue dissolved with ethyl acetate (75 mL)
  11. washThe organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL), water (50 mL), and brine (50 mL)
  12. dry with materialdried over sodium sulphate
  13. filtrationfiltered
  14. customthe solvent removed under vacuum
  15. customThe residue was purified by flash column chromatography
  16. customthe solvent removed under vacuum

Sources & evidence

ORD record
ord-6e201bc2331a46e8a0f7bbabb24aa589
Source dataset
uspto-grants-2011_11
Patent number
US08048862B2

Reaction notes

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