反应详情

温度

80 °C

To a stirred solution of 2-hydroxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester (800 mg, 1.79 mmol), in anhydrous pyridine (20 mL) under a nitrogen atmosphere is added phenyl chloroformate (0.566 mL, 4.5 mmol) in one lot. A gelatinous, white precipitate is formed. The stirred reaction mixture is heated to 80° C. After 45 minutes TLC/LCMS analysis indicates completion of the reaction. The reaction is allowed to cool and evaporated in vacuo to dryness. The residue is partitioned between ethyl acetate and 2 M HCl. The organic phase is separated, dried over anhydrous Na2SO4, and evaporated to give an off-white foam which is dried at high vacuum. The foam is dissolved in anhydrous THF (10 mL) and ethanolamine (2 mL, 33 mmol) is added. The reaction mixture is stirred overnight at room temperature under argon. TLC/LCMS analysis indicates completion of the reaction. The reaction mixture is evaporated in vacuo to dryness and the residue is partitioned between dichloromethane and 2 M HCl. The organic phase is separated, dried over anhydrous Na2SO4 and evaporated in vacuo to give an orange oil. Purification by flash chromatography on silica (gradient elution with ethyl acetate, 50% to 70% to 90%, in cyclohexane) provides the title compound as colourless crystals after drying at high vacuum (872 mg, 1.64 mmol, 91%). Mp 122-125° C.; 1H NMR (400 MHz, CDCl3) 1.41 (3 H, t, J=7 Hz), 2.30 (1 H, bm), 2.43 (3 H, s), 2.67 (3 H, d, J=5 Hz), 2.74 (3 H, s), 3.27 (2 H, m), 3.66 (2 H, bm), 4.45 (2 H, q, J=7 Hz), 4.73 (2 H, m), 4.97 (1 H, bm), 5.31 (1 H, bm), 7.45 (1 H, d, J=8 Hz), 7.49 (1 H, s), 7.71 (1 H, t, J=8 Hz), 7.79 (1 H, m), 8.10 (1 H, d, J=8 Hz); MS m/z (ES+) 533.2 (M+1, 100%); HPLC: retention time=4.313 min, >99%, column Phenomex-Kingsorb C18, 3 cm×4.6 mm ID, solvent system MeCN/H2O (0.1% TFA), gradient 10 to 90% MeCN, 10 min; Detection 254 nm.

1. customA gelatinous, white precipitate is formed
2. customThe stirred reaction mixture
3. customcompletion of the reaction
4. temperatureto cool
5. customevaporated in vacuo to dryness
6. customThe residue is partitioned between ethyl acetate and 2 M HCl
7. customThe organic phase is separated
8. dry with materialdried over anhydrous Na2SO4
9. customevaporated
10. customto give an off-white foam which
11. customis dried at high vacuum
12. dissolutionThe foam is dissolved in anhydrous THF (10 mL)
13. customcompletion of the reaction
14. customThe reaction mixture is evaporated in vacuo to dryness
15. customthe residue is partitioned between dichloromethane and 2 M HCl
16. customThe organic phase is separated
17. dry with materialdried over anhydrous Na2SO4
18. customevaporated in vacuo
19. customto give an orange oil
20. customPurification by flash chromatography on silica (gradient elution with ethyl acetate, 50% to 70% to 90%, in cyclohexane)