| 99% |
at 190℃; for 0.5h; |
Example 9Preparation of 2-(4-(3-chloro-4-fluorophenylamino) quinazolin-6-yloxy)-N-hydroxyacetamide (Compound 13); Step 9a. 6-Hydroxyquinazolin-4(3H)-one (compound 0202)To a solution of <strong>[394-31-0]2-amino-5-hydroxybenzoic acid</strong> 0201 (30.6 g, 0.2 mol) in formamide was stirred and heated to 190 C. for 0.5 h. The mixture was allowed to cool to room temperature. The precipitate was isolated, washed with ether and dried to obtain title compound 0202 (32 g, brown solid, yield: 99%): LC-MS m/z 163 [M+1]; 1H NMR (DMSO-d6): delta7.25 (dd, 1H), 7.40 (d, 1H), 7.46 (d, 1H), 7.88 (s, 1H) |
| 75% |
at 190℃; for 0.5h; |
2-Amino-5-hydroxybenzoic acid (2.00?g, 13.1?mmol) and formamide (9.37?mL, 235?mmol) were mixed and stirred for 30?min at 190?C. At room temperature, the solid was filtered, triturated with H2O and washed with diethyl ether to afford 14 as a brown solid (1.60?g, 75%). Mp: 338?C (dec.); IR (ATR, ZnSe): nu (cm-1) 2900, 1660, 1601, 1397, 1242, 884, 833, 752, 718; 1H NMR (400?MHz, DMSO-d6): delta (ppm) 12.03 (s, 1H), 10.07 (s, 1H), 7.89 (s, 1H), 7.53 (d, J?=?8.8?Hz, 1H), 7.40 (d, J?=?2.9?Hz, 1H), 7.25 (dd, J?=?8.8, 2.9?Hz, 1H); 13C NMR (126?MHz, DMSO-d6): delta (ppm) 160.6, 156.2, 142.2, 142.0, 128.9, 123.7, 123.7, 108.8; HRMS-ESI calcd for C8H7N2O2 [M+H]+ 163.0502 found 163.0499. |
| 68% |
at 140℃; |
General procedure: To a three necked flask, substituted anthranilic acid (1 meq.) was added in excess of formamide (6 meq). The reaction mixture was then heated at 140 C for 4-6 h. The reaction was monitored with thin layer chromatography and upon completion; ice was added to the reaction mixture. The resultant solid was filtered, washed with water, dissolved in ethyl acetate, dried over MgSO4 and concentrated to obtain the pure desired product. Where product did not precipitate on addition of ice, the reaction mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated to obtain the desired quinazolin-4(3H)-one derivatives 1-9, 11-15, 17-21 and 23-25.The amino derivatives 10, 16 and 22 were prepared using the following general procedure:To a reaction flask, substituted nitroquinazolin-4(3H)-one derivative (0.3 g, 1.56 mmol) was added followed by addition of 6 mL ethyl acetate and SnCl2·2H2O (2.12 g, 9.42 mmol), then reaction mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution, followed by repeated extraction with ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated to obtain the desired amino substituted quinazolin-4(3H)-one derivatives 10, 16 and 22.The substituted anthranilic acid (1 g) was dissolved in excess acetic anhydride (10 mL) and the resulting reaction mixture was stirred at room temperature for 4-7 h. The reaction was monitored for completion using thin layer chromatography. The solvent was evaporated under vacuum and the resultant residue was stirred with ammonia solution for 7 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3 × 10 mL), the organic extracts were combined, dried over MgSO4 and evaporated to obtain compounds 26-30, 31a and 32. The 2-methyl-8-nitroquinazolin-4(3H)-one intermediate (31a) was reduced to compound 31 using the same procedure as reported in Scheme 1 for the synthesis of compounds 10, 16 and 22. |
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