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B. Synthesis of 7-fluoro-3-hydroquinazolin-4-one (0245) To a suspension of ethyl 2-amino-4-fluorobenzoate (1.73 g, 9.45 mmol) in formamide (8 mL) was added ammonium formate (0.9 g, 14 mmol). The reaction mixture was stirred at 140 °C for 24 hr, with additional ammonium formate (0.92 g, 15 mmol) at 6 hr. The reaction was dilute with EtOAc, washed with water, back-extracted with EtOAc, dried and concentrated in vacuo to give 7-fluoro-3-hydroquinazolin-4-one (2.82 g) which contains some formamide. ES-MS (M+H)+ = 165.
Reference：
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3772 - 3793
[2] Patent: EP2314593, 2016, B1, . Location in patent: Paragraph 0245
A. Synthesis of ethyl 2-amino-4-fluorobenzoate To a chilled solution of 2-amino-4-fluorobenzoic acid (1.57 g, 10.1 mmol) in absolute ethanol (20 mL) was added neat thionyl chloride (4.4 mL, 60 mmol). The reaction mixture was refluxed for 4 days total, with addition of more SOCl2 (8 mL, 110 mmol), then concentrated, diluted with EtOAc, washed with 2N NaOH, dried and concentrated in vacuo to give ethyl 2-amino-4-fluorobenzoate (1.73 g, 94percent).
94%
With thionyl chloride In ethanol
A. Synthesis of ethyl 2-amino-4-fluorobenzoate To a chilled solution of 2-amino-4-fluorobenzoic acid (1.57 g, 10.1 mmol) in absolute ethanol (20 mL) was added neat thionyl chloride (4.4 mL, 60 mmol). The reaction mixture was refluxed for 4 days total, with addition of more SOCl2 (8 mL, 110 mmol), then concentrated, diluted with EtOAc, washed with 2N NaOH, dried and concentrated in vacuo to give ethyl 2-amino-4-fluorobenzoate (1.73 g, 94percent).
A. Synthesis of ethyl 2-amino-4-fluorobenzoate (0244) To a chilled solution of 2-amino-4-fluorobenzoic acid (1.57 g, 10.1 mmol) in absolute ethanol (20 mL) was added neat thionyl chloride (4.4 mL, 60 mmol). The reaction mixture was refluxed for 4 days total, with addition of more SOCl2 (8 mL, 110 mmol), then concentrated, diluted with EtOAc, washed with 2N NaOH, dried and concentrated in vacuo to give ethyl 2-amino-4-fluorobenzoate (1.73 g, 94percent).
Reference：
[1] Patent: EP2314593, 2016, B1, . Location in patent: Paragraph 0243; 0244
[2] Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3772 - 3793
[3] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 10, p. 5803 - 5814
A. Synthesis of ethyl 2-amino-4-fluorobenzoate (0244) To a chilled solution of 2-amino-4-fluorobenzoic acid (1.57 g, 10.1 mmol) in absolute ethanol (20 mL) was added neat thionyl chloride (4.4 mL, 60 mmol). The reaction mixture was refluxed for 4 days total, with addition of more SOCl2 (8 mL, 110 mmol), then concentrated, diluted with EtOAc, washed with 2N NaOH, dried and concentrated in vacuo to give ethyl 2-amino-4-fluorobenzoate (1.73 g, 94%).
B. Synthesis of 7-fluoro-3-hydroquinazolin-4-one (0245) To a suspension of <strong>[117324-05-7]ethyl 2-amino-4-fluorobenzoate</strong> (1.73 g, 9.45 mmol) in formamide (8 mL) was added ammonium formate (0.9 g, 14 mmol). The reaction mixture was stirred at 140 C for 24 hr, with additional ammonium formate (0.92 g, 15 mmol) at 6 hr. The reaction was dilute with EtOAc, washed with water, back-extracted with EtOAc, dried and concentrated in vacuo to give 7-fluoro-3-hydroquinazolin-4-one (2.82 g) which contains some formamide. ES-MS (M+H)+ = 165.
A total of 3.84 g of <strong>[117324-05-7]2-amino-4-fluoro-benzoic acid ethyl ester</strong> obtained in Production Example II-7-a was dissolved in 50 ml of pyridine, 1.64 ml of acetyl chloride was added under ice-cooling, and the mixture was stirred for 1 hours. The reaction mixture was diluted with water and was extracted with diethyl ether. The resulting organic layer was washed with 1 N hydrochloric acid and brine, dried over magnesium sulfate, and then evaporated, to give 4.0 g of the title compound.1H-NMR ( 400 MHz, CDCl3 ) d 1.41 ( 3H, t, J = 6.8 Hz ), 2.14 ( 3H, s ), 4.38 ( 2H, q, J = 6.8 Hz ), 6.73 - 6.81 ( 1H, m ), 8.06 ( 1H, dd, J = 8.8, 6.4 Hz ), 8.53 ( 1H, dd, J = 12.0, 2.4 Hz ), 11.3 ( 1H, brs )
A. Synthesis of ethyl 2-amino-4-fluorobenzoate To a chilled solution of 2-amino-4-fluorobenzoic acid (1.57 g, 10.1 mmol) in absolute ethanol (20 mL) was added neat thionyl chloride (4.4 mL, 60 mmol). The reaction mixture was refluxed for 4 days total, with addition of more SOCl2 (8 mL, 110 mmol), then concentrated, diluted with EtOAc, washed with 2N NaOH, dried and concentrated in vacuo to give ethyl 2-amino-4-fluorobenzoate (1.73 g, 94%).
94%
With thionyl chloride; In ethanol;
A. Synthesis of ethyl 2-amino-4-fluorobenzoate To a chilled solution of 2-amino-4-fluorobenzoic acid (1.57 g, 10.1 mmol) in absolute ethanol (20 mL) was added neat thionyl chloride (4.4 mL, 60 mmol). The reaction mixture was refluxed for 4 days total, with addition of more SOCl2 (8 mL, 110 mmol), then concentrated, diluted with EtOAc, washed with 2N NaOH, dried and concentrated in vacuo to give ethyl 2-amino-4-fluorobenzoate (1.73 g, 94%).
With sulfuric acid; In ethanol; for 11.0h;Heating / reflux;
A total of 10 g of 2-amino-4-fluoro-benzoic acid was dissolved in 129 ml of ethanol, 6.45 ml of sulfuric acid was added and the mixture was heated under reflux for 11 hours. After cooling to room temperature, the solvent was evaporated to about half. Water was added and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane = 1:5), to give 7.57 g of the title compound as a pale yellow oil.1H-NMR ( 400 MHz, CDCl3 ) d 1.38 ( 3H, t, J = 6.8 Hz ), 4.32 ( 2H, q, J = 6.8 Hz ), 5.88 ( 2H, brs ), 6.28 - 6.38 ( 2H, m ), 7.88 ( 1H, dd, J = 8.8, 6.8 Hz )
B. Synthesis of 7-fluoro-3-hydroquinazolin-4-one To a suspension of <strong>[117324-05-7]ethyl 2-amino-4-fluorobenzoate</strong> (1.73 g, 9.45 mmol) in formamide (8 mL) was added ammonium formate (0.9 g, 14 mmol). The reaction mixture was stirred at 140 C. for 24 hr, with additional ammonium formate (0.92 g, 15 mmol) at 6 hr. The reaction was dilute with EtOAc, washed with water, back-extracted with EtOAc, dried and concentrated in vacuo to give 7-fluoro-3-hydroquinazolin-4-one (2.82 g) which contains some formamide. ES-MS (M+H)+=165.
With ammonium formate; In formamide;
B. Synthesis of 7-fluoro-3-hydroquinazolin-4-one To a suspension of <strong>[117324-05-7]ethyl 2-amino-4-fluorobenzoate</strong> (1.73 g, 9.45 mmol) in formamide (8 mL) was added ammonium formate (0.9 g, 14 mmol). The reaction mixture was stirred at 140 C. for 24 hr, with additional ammonium formate (0.92 g, 15 mmol) at 6 hr. The reaction was dilute with EtOAc, washed with water, back-extracted with EtOAc, dried and concentrated in vacuo to give 7-fluoro-3-hydroquinazolin-4-one (2.82 g) which contains some formamide. ES-MS (M+H)+=165.
Step B: To the formamide (6 mL) solution of <strong>[117324-05-7]ethyl-2-amino-4-fluorobenzoate</strong> (811 mg, 4.43 mmol) added ammonium formate (0.450 g, 7.14 mmol) and the reaction mixture was heated at 140 C. overnight. After cooling added water and ethyl acetate. The layers were separated, the EtOAc layer was dried, filtered and evaporated to give desired quinazolinone (1 g, quantitative). MS (ES) 165 (M+H)
With sodium hydride; In 5,5-dimethyl-1,3-cyclohexadiene; at 130.0℃; for 2.0h;Inert atmosphere;
General procedure: To a solution of 3,3'-((4-methoxybenzyl)azanediyl)dipropanenitrile (130 mg, 0.535 mmol) inxylene (0.3 mL) in a 5 mL reaction tube, the appropriate cyanamide (0.36 mmol) and tBuOK were rapidly added (20 mg, 0.18 mmol). The reaction was heated to 130 C for 2 h andfollowed by TLC using CH2Cl2/MeOH as eluant. After cooling to room temperature, thesolvent was removed and the residue was purified by flash chromatography or HPLC.
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