Methanone, [4-?(2-?amino-?4-?thiazolyl)?-?2-?(1H-?1,?2,?4-?triazol-?1-?yl)?phenyl]?(3,?4,?5-?trimethoxyphenyl)?- synthesis

Yield:1016543-77-3 48%

Reaction Conditions:

in ethanol; for 2 h;Heating / reflux;

Steps:

Compound 516; Synthesis of (4-(2-aminothiazol-4-ylV2-( 1 H- 1 ,2.4-triazol- 1 -vPphenvD(3A5-trimethoxyphenyl)methanone; In the same manner as in the synthesis of Compound 515, 1,2,4-triazole was added to Compound 21 of Reaction 6. Then, tributyl(l-ethoxyvinyl)tin was added to the mixture, and the resulting mixture was reacted to obtain (4-(l- ethoxyvinyl)-2-(lH-l,2,4-triazol-l-yl)phenyl)(3,4,5- trimethoxyphenyl)methanone. Thus obtained (4-(l-ethoxyvinyl)-2-( IH- 1,2,4- triazol-l-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone was dissolved in a mixed solution of tetrahydrofuran and water (1/1), and N-bromosuccinimide (NBS) was added thereto. The mixture was stirred for 3 hours at room temperature. After completion of the reaction, the reaction mixture was extracted with EtOAc. The organic layer was washed with a saturated aqueous Na₂SO₃ solution, water, and brine. The extracted organic layer was dried over anhydrous MgSO₄, and the solid substance was filtered off. The filtrate was vacuum evaporated to remove the solvent. The resulting residue was purified by column chromatography (SiO₂, n-Hex/EA=3/l→l/2) to obtain l-(3-(lH-l,2,4-triazol-l-yl)-4-(3,4,5- trimethoxybenzoyl)phenyl)-2-bromoethanone. Thus obtained 1 -(3-(I H- 1,2,4- triazol-l-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)-2-bromoethanone (65 mg, 0.14 mmol) was dissolved in 3 ml of 95% ethanol, and thiourea (16 mg) was added thereto. The mixture was refluxed for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and vacuum evaporated to remove the solvent. The resulting residue was purified by column chromatography (SiO₂, CH₂Cl₂/MeOH=30/l→10/l) to obtain Compound 516 (29.3 mg, 48%).¹H NMR (DMSO-J(J) δ 9.03 (s, IH), 8.15 (d, J = 1.5 Hz, IH), 8.05 (dd, J= 8.0, 1.5 Hz, IH), 7.96 (s, IH), 7.65 (d, J= 8.0 Hz, IH), 7.42 (s, IH), 6.85 (s, 2H), 3.72 (s, 6H), 3.70 (s, 3H). MS (ESI) m/z 438 (M⁺ + H).

References:

WO2008/38955,2008,A1 Location in patent:Page/Page column 106-107