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With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; for 1 h;
To a solution of 2-amino-4-methoxybenzoic acid (4.00 g, 23.93 mmol) in DMF (120 mL) at 0 °C was added NBS (4.68 g, 26.3 mmol). The cooling bath was removedand the reaction mixture was warmed up to room temperature and was stirred at room temperature for 1 h. The mixture was cooled to 0 °C and was treated with saturated sodium sulfite solution (25 mL) and was stirred for 5 mm. The pH of the mixture was adjusted to pH = 3 using conc. HC1 (ca. 10-15 mL was added). The reaction mixture was transferred to a separatory funnel containing water (100 mL). Theaqueous layer was extracted with ether (1 x 250 mL then 4 x 100 mL). The combined organic layers were washed with water (3 x 50 mL), brine (50 mL), dried over MgSO4, filtered, and concentrated to afford 2-amino-5-bromo-4- methoxybenzoic acid (5.90 g, 100percent yield) as a solid: ‘H NMR (400 MHz, DMSOd6) ö 7.78 (s, 1H), 6.43 (s, 1H), 3.81 (s, 3H), 2.90 (s, 1H), 2.74 (s, 1H); MS (ESI) m/e228.0 [(M+H-H2O), calcd for C8H7BrNO2 228.0].
77%
at 20 - 40℃; for 18 h;
2-amino-5-bromo-4-methoxybenzoic acid 2-amino-4-methoxybenzoic acid (5 g, 30 mmol) was suspended in acetic acid (100 mL) and bromine (0.57 mL, 11.25 mmol) added at RT. The mixture was stirred approx. 15 h at RT, then additional bromine (0.2 mL, 3.75 mmol) was added and the reaction mixture held at 40° C. for 3 hours. The reaction course was tracked by thin-film chromatography, the product filtered out and washed with a little water. (Yield: 5.63 g, 77percent)
1.3 g
With N-Bromosuccinimide In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 4 h;
To a mixture of 4-methoxyanthranilic acid (0.67 g, 4.0 mmol) in DCM (10 mL) and DMF (3 mL) was added NBS (0.71 g, 4.0 mmol) at 0 °C. The mixture was stirred at room temperature for 4 h, then concentrated and subjected to silica gel chromatography (5-100percent EtOAc/Heptane) to provide 2-amino-5-bromo-4-methoxybenzoic acid as a beige solid (1 .30 g, containing 1 equivalent succinamide). MS (M-1 ) = 244.3/246.3. 1H NMR (DMSO-d6) δ 7.76 (s, 1 H), 6.42 (s, 1 H), 3.79 (s, 3H). This material was used without further purification.
6-bromo-7-methoxyquinazoline-4(3H)-one <strong>[169045-04-9]2-amino-5-bromo-4-methoxybenzoic acid</strong> (type T) (5.63 g, 23 mmol) was dissolved in EtOH (100 mL), formamidine acetate (4.76 g, 46 mmol) added and refluxed for 1 d. Water (200 mL) was then added, the precipitated product filtered out and washed with 70% ethanol. (Yield: 4.14 g, 71%)
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.0h;
To a solution of 2-amino-4-methoxybenzoic acid (4.00 g, 23.93 mmol) in DMF (120 mL) at 0 C was added NBS (4.68 g, 26.3 mmol). The cooling bath was removedand the reaction mixture was warmed up to room temperature and was stirred at room temperature for 1 h. The mixture was cooled to 0 C and was treated with saturated sodium sulfite solution (25 mL) and was stirred for 5 mm. The pH of the mixture was adjusted to pH = 3 using conc. HC1 (ca. 10-15 mL was added). The reaction mixture was transferred to a separatory funnel containing water (100 mL). Theaqueous layer was extracted with ether (1 x 250 mL then 4 x 100 mL). The combined organic layers were washed with water (3 x 50 mL), brine (50 mL), dried over MgSO4, filtered, and concentrated to afford 2-amino-5-bromo-4- methoxybenzoic acid (5.90 g, 100% yield) as a solid: ?H NMR (400 MHz, DMSOd6) oe 7.78 (s, 1H), 6.43 (s, 1H), 3.81 (s, 3H), 2.90 (s, 1H), 2.74 (s, 1H); MS (ESI) m/e228.0 [(M+H-H2O), calcd for C8H7BrNO2 228.0].
77%
With bromine; acetic acid; at 20 - 40℃; for 18.0h;
2-amino-5-bromo-4-methoxybenzoic acid 2-amino-4-methoxybenzoic acid (5 g, 30 mmol) was suspended in acetic acid (100 mL) and bromine (0.57 mL, 11.25 mmol) added at RT. The mixture was stirred approx. 15 h at RT, then additional bromine (0.2 mL, 3.75 mmol) was added and the reaction mixture held at 40 C. for 3 hours. The reaction course was tracked by thin-film chromatography, the product filtered out and washed with a little water. (Yield: 5.63 g, 77%)
With bromine; In acetic acid; at 0 - 20℃; for 8.0h;
Step 1: 2-Amino-5-bromo-4-methoxybenzoic acidTo a stirred suspension of 2-amino-4-methoxybenzoic acid (5 g, 0.029 mol) in acetic acid (100 mL) was added bromine (1.23 mL, 0.023 mol) dropwise at 0C. The reaction mixture was stirred at room temperature for 8 h. The separated solid was filtered, washed with water (30 mL) and dried under vacuum to afford the product as white solid (6.3 g, 86 %). As per the LC-MS data this solid contains 14% of starting material, 22% of dibromo byproduct and 61% of desired compound.1H NMR (400 MHz, DMSO-de) : delta 7.76 (s, 1H), 6.42 (s, 1H), 3.72 (s, 3H); ESI-MS: Calculated mass: 244.97; Observed mass LC-MS: 246.0 [M + H]+RT: 2.07 min.
1.3 g
With N-Bromosuccinimide; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 4.0h;
To a mixture of 4-methoxyanthranilic acid (0.67 g, 4.0 mmol) in DCM (10 mL) and DMF (3 mL) was added NBS (0.71 g, 4.0 mmol) at 0 C. The mixture was stirred at room temperature for 4 h, then concentrated and subjected to silica gel chromatography (5-100% EtOAc/Heptane) to provide 2-amino-5-bromo-4-methoxybenzoic acid as a beige solid (1 .30 g, containing 1 equivalent succinamide). MS (M-1 ) = 244.3/246.3. 1H NMR (DMSO-d6) delta 7.76 (s, 1 H), 6.42 (s, 1 H), 3.79 (s, 3H). This material was used without further purification.
With bromine; acetic acid; In acetonitrile; at 0 - 20℃; for 1.0h;Inert atmosphere;
2-Amino-4-methoxybenzoic acid (5.00 g, 29.91 mmol) was dissolved in acetic acid (10 mL) and acetonitrile (100 mL), slowly added dropwise with liquid bromine (4.78 g, 29.91 mmol) at 0 C and under nitrogen protection,, and stirred at 20 C for 1 hour. TLC showed that the reaction was complete. After the reaction solution was concentrated, water (100 ml) and petroleum ether (100 ml) were successively used for making a slurry, which was vaccum dried to obtain compound 1A. 1H NMR (400MHz, DMSO-d6) delta= 7.76 (s, 1H), 6.41 (s, 1H), 3.79 (s, 3H).
With piperidine; In methanol; for 1.0h;Heating / reflux;
6-Bromo-7-methoxy-3H-quinazolin-4-one 2-Amino-5-bromo-4-methoxybenzoic acid (1.56 g, 6.34 mmol) is dissolved in methanol (15 ml), treated with piperidine (0.063 ml, 0.63 mmol) and 1,3,5-triazine (772 mg, 9.5 mmol) and refluxed for one hour. After cooling to room temperature, the resulting crystals are filtered off with suction and washed with methanol. The desired product is obtained in 63% yield (1.01 g). 1H-NMR (300 MHz, DMSO-d6): delta 3.95 (s, 3H), 7.20 (s, 1H), 8.08 (s, 1H), 8.16 (s, 1H), 12.2 (br, 1H).
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.0h;
Step 2: Methyl 2-amino-5-bromo-4-methoxybenzoateTo a stirred suspension of <strong>[169045-04-9]2-amino-5-bromo-4-methoxybenzoic acid</strong> (6.3 g, 0.025 mol) and potassium carbonate (7.06 g, 0.051 mol) in N,ll-dimethyl formamide (63 mL) was added methyl iodide (5.45 g, 0.038 mol) dropwise at 0C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The mixture was poured into ice cold water (500 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with water (100 mL) followed by brine solution, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using column chromatography (100-200 mesh silica gel, 20% EtOAc in hexane) to afford the title compound as white solid (5.5 g, 83% yield). *H NMR (400 MHz, DMSO-d6) : delta 7.78 (s, 1H), 6.85 (brs, 2H), 6.44 (s, 1H), 3.80 (s, 3H), 3.75 (s, 3H). ESI-MS: Calculated mass: 258.98; Observed mass: 258.3 [M-H]
A mixture of <strong>[169045-04-9]2-amino-5-bromo-4-methoxybenzoic acid</strong> (1 .25 g, 3.6 mmol) and formimidamide acetate (0.75 g, 7.2 mmol) in EtOH (15 mL) was refluxed for 24 h. The mixture was cooled to room temperature and the solid was filtered, washed with water, and dried to provide 6- bromo-7-methoxyquinazolin-4(1 H)-one as a white solid (0.858 g). MS (M+1 ) = 255.0/257.0. 1H NMR (DMSO-d6) delta 12.30 (br. s, 1 H), 8.21 (s, 1 H), 8.12 (s, 1 H), 7.25 (s, 1 H), 4.00 (s, 3H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1.0h;
EDC (5.42 g, 28.3 mmol) was added to a solution of 2-amino-5-bromo-4- methoxybenzoic acid (5.80 g, 23.57 mmol) in CH2C12 (120 mL). HOBT hydrate (4.33 g, 28.3 mmol) was added and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with 30% ammonium hydroxidesolution (58 mL) and stirring was continued for an additional 1 h. The reaction mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (150 mL). The aqueous layer was extracted with CH2C12 containing 5% MeOH (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over MgSO4, filtered, and concentrated to give 2-amino-5-bromo-4-methoxybenzamide (5.04 g, 87% yield) as a colorless solid: ?H NMR (400 MHz, DMSO-d6) oe 7.79 (s, 1H), 6.92 (s, 2H), 6.38 (s, 1H), 3.78 (s, 3H).
5-bromo-4-methoxy-2-[[(e)-2-nitrovinyl]amino]benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
Nitromethane (0.63 ml, 11.7 mmol) was added dropwise at room temperature to a solution of sodium hydroxide (14.7 g, 368 mmol) in water (33 ml) with stirring. The mixture was subsequently warmed slowly at 45 C. for 5 minutes with stirring. The reaction solution was then cooled to room temperature, and nitromethane (0.63 ml, 11.7 mmol) was again added dropwise. The reaction mixture was subsequently stirred for a further 10 minutes, during which a clear, reddish solution formed. After brief warming (5 minutes) at 50 C., the mixture was cooled to room temperature and decanted off onto ice (11 g). The aqueous solution was carefully acidified to pH<2 using conc. hydrochloric acid and subsequently immediately added to a solution of <strong>[169045-04-9]2-amino-5-bromo-4-methoxybenzoic acid</strong> (8.00 g, 32.5 mmol) in water (259 ml), acidified using conc. hydrochloric acid (126 ml, 2.75 mol), with stirring. The suspension obtained was stirred overnight and subsequently filtered. The residue was dried at 50, giving 9.60 g (93%) of 5-bromo-4-methoxy-2-[[(e)-2-nitrovinyl]amino]benzoic acid as colourless solid.
(3aR,6aS)-3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxotetrahydro-2H-pyrrol[3,4-d]oxazol-5(3H)-carboxylic acid tert-butyl ester[ No CAS ]
In 2-methoxy-ethanol; at 120℃; for 3.0h;Inert atmosphere;
Compound 1A (5.9 g, 18.94 mmol) and formamidine acetate (3.55 g, 34.10 mmol) were dissolved in ethylene glycol monomethyl ether (10 mL), and the reaction mixture was stirred under nitrogen protection at 120 C for 3 hours. TLC showed that the reaction was complete. The reaction solution was cooled down to room temperature, the solids were precipitated and filtered, and the filter cake was washed with EA (10 mL x 2), PE (20 mL x 3) and water (50 mL x 2), respectively. Compound 1B was obtained after drying. LCMS (ESI) (5-95AB): m/z: 254.9 [M+1].
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