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With N-ethyl-N,N-diisopropylamine In ethanol at 20℃; for 3.5 h;
A solution of 2-Ethyl-2-thiopsuedourea hydrobromide (1.52 g, 8.19 mmol),(Ethoxymethylene)malononitrile (1.0 g, 8.19 mmol) and N,N-diisopropylethylamine (3.57 mL, 20.05 mmol) in ethanol (20 mL) was stirred at room temperature for 3.5 hours. The resultant solid was collected, washed with ethanol, and the dried under vacuum to provide the title compound as a light yellow solid (580 mg, 39percent).
Reference：
[1] Patent: WO2008/133753, 2008, A2, . Location in patent: Page/Page column 115
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 6, p. 2212 - 2215
With sodium carbonate; In water; at 20 - 80℃; for 25.5h;
To a solution of ethyl imidothiocarbamate hydrobromide (2,59 g) in water (25 mL) were added sodium carbonate (1.48 g) and methyl 4-oxotetrahydro-3-furancarboxylate (1.44 g), then the mixture was stirred for 3.5 hours at room temperature, 18 hours at 70C, then 4 hours at 80C. The reaction mixture was cooled to room temperature, the precipitate was collected, washed with water and diisopropyl ether sequentially to give the title compound (744 mg) having the following physical data. The former water layer was washed with ethyl acetate, extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated. The obtained residue was added by diisopropyl ether, the precipitated solid was collected to give the title compound (139 mg) having the following physical data. TLC: Rf0.65 (ethyl acetate); 1H NMR (CDCl3): delta 1.38 (t, J = 7.36 Hz, 3 H), 3.20 (q, J = 7.36 Hz, 2 H), 4.80 - 4.97 (m, 2 H), 4.98 - 5.15 (m, 2 H), 11.62 - 12.25 (m, 1 H).
With sodium carbonate; In water; for 72h;Darkness;
Step (iii)To a solution of S-ethyl isothiouronium bromide (6.06 g, 32.7 mmol) in water (60 mL) was added sodium carbonate (3.64 g, 34.33 mmol) and methyl 3-oxo-tetrahydrothiophene-2-carboxylate (5.00 g, 31.20 mmol) dropwise. The mixture was stirred in the dark for 3 days. The solid precipitate in the resulting mixture was collected by filtration, washed with water, ether and ethyl acetate, and then dried under vaccum to obtain 2-(ethylthio)-6,7-dihydrothieno[3,2-d]pyrimidin-4(3H)-one as a white soild, (2.8 g, 42.4%). Without further purification, the crude product was used directly in the next step.LC-MS (Method A), (ES+)215, RT = 4.51 min.
N-(2-fluoro-5-trifluoromethylbenzoyl)-S-ethylthiourea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With triethylamine; In dichloromethane; at 20℃; for 1h;Cooling with ice;
[Example 15] Preparation of 3-(4-chlorobenzyl)-2-(3-chloro-4-isopropoxyphenylamino)-6-trifluoromethylquinazoline -4(3H)-one (I-211) To a mixture of S-ethylisothiourea hydrobromide (0.817 g, 4.41 mmol), triethylamine (0.447 g, 4.41 mmol) and dichloromethane (15 mL) was added 2-fluoro-5-trifluoromethylbenzoyl chloride (0.67 ml, 4.4 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give N-(2-fluoro-5-trifluoromethylbenzoyl)-S-ethylthiourea (1.21 g, Yield: 93%) as white solid. 1H-NMR (δ ppm TMS/CDCl3): 1.42 (3H, t, J=7.3 Hz), 3.19 (2H, q, J=7.3 Hz), 7.21 (1H, m), 7.69 (1H, m), 8.42 (1H, dd, J=6.9, 2.4 Hz).
93%
With triethylamine; In dichloromethane; at 20℃; for 1h;Cooling with ice;
EXAMPLE 15 Preparation of 3-(4-chlorobenzyl)-2-(3-chloro-4-isopropoxyphenylamino)-6-trifluoromethylquinazoline-4(3H)-one (I-211) To a mixture of S-ethylisothiourea hydrobromide (0.817 g, 4.41 mmol), triethylamine (0.447 g, 4.41 mmol) and dichloromethane (15 mL) was added 2-fluoro-5-trifluoromethylbenzoyl chloride (0.67 ml, 4.4 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give N-(2-fluoro-5-trifluoromethylbenzoyl)-S-ethylthiourea (1.21 g, Yield 93%) as white solid. 1H-NMR (δ ppm TMS/CDCl3): 1.42 (3H, t, J=7.3 Hz), 3.19 (2H, q, J=7.3 Hz), 7.21 (1H, m), 7.69 (1H, m), 8.42 (1H, dd, J=6.9, 2.4 Hz).
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