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With sodium carbonate In DMF (N,N-dimethyl-formamide) at 20℃;
To a suspension of 4-amino-2-nitrobenzoic acid (200 mg, 1.10 mmol) synthesized in accordance with the synthesis method described in W096/35666 and sodium carbonate (349 mg, 3.29 mmol) in dimethylformamide (5.5 mL), methyl iodide (0.21 ml) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and extraction was carried out with ethyl acetate, and the combined organic layer was washed with a saturated ammonium chloride aqueous solution and a saturated sodium chloride aqueous solution, followed by drying over anhydrous sodium sulfate. By concentrating the obtained organic layer, 216 mg of the desired product was obtained as a yellow solid (yield 100percent). ^-NMR (ppm in CDC13)5 7.69 (d, J= 8.5 Hz, 1H), 6.85 (d, J= 2.4 Hz, 1H), 6.77 (dd, J= 2.4, 8.5 Hz, 1H), 4.31 (bs, 2H), 3.84 (s, 3H). LC/MS (ESI) 196.
With sodium carbonate; In DMF (N,N-dimethyl-formamide); at 20.0℃;
To a suspension of <strong>[610-36-6]4-amino-2-nitrobenzoic acid</strong> (200 mg, 1.10 mmol) synthesized in accordance with the synthesis method described in W096/35666 and sodium carbonate (349 mg, 3.29 mmol) in dimethylformamide (5.5 mL), methyl iodide (0.21 ml) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and extraction was carried out with ethyl acetate, and the combined organic layer was washed with a saturated ammonium chloride aqueous solution and a saturated sodium chloride aqueous solution, followed by drying over anhydrous sodium sulfate. By concentrating the obtained organic layer, 216 mg of the desired product was obtained as a yellow solid (yield 100%). ^-NMR (ppm in CDC13)5 7.69 (d, J= 8.5 Hz, 1H), 6.85 (d, J= 2.4 Hz, 1H), 6.77 (dd, J= 2.4, 8.5 Hz, 1H), 4.31 (bs, 2H), 3.84 (s, 3H). LC/MS (ESI) 196.
A solution of the above synthesized <strong>[84228-45-5]methyl 4-amino-2-nitrobenzoate</strong> (50 mg, 0.25 mmol) and 1,1'-thiocarbonyldi-2(1H)-pyridone (59 mg, 0.25 mmol) in dichloromethane (4.2 ml) was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was evaporated, followed by purification with a silica gel column chromatography to obtain 42 mg of the desired product as a colorless oil (yield 69%). hl-NMR (ppm in CDC13)<5 7.79 (d, J= 8.3 Hz, 1H) , 7.66 (d, J= 2.1 Hz, 1H) , 7.47 (dd, J= 2.1, 8.3 Hz, 1H) , 3.92 (s, 3H) . LC/MS (ES~) 224 (M+-CH2)
2-nitro-4-[(2',6'-di-tert-butylpyrid-4'-yl)carbamoyl]benzoic acid[ No CAS ]
2,6-difluoro-4-[(2',6'-di-tert-butylpyrid-4'yl)carbamoyl]benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2-Nitro-4-[(2',6'-di-t-butylpyrid-4'-yl)carbamoyl]benzoic Acid (Compound 54) Using the same procedure as for the preparation of 2,6-difluoro-4-[(2',6'-di-t-butylpyrid-4'yl)carbamoyl]benzoic acid (Compound 50) but using 2,6-di-t-butylisonicotinic acid (40 mg, 0.17 mmol) and <strong>[84228-45-5]methyl 2-nitro-4-aminobenzoate</strong> (Compound F1, 33 mg, 0.17 mmol), the title compound was obtained as a light yellow oil. 1 H NMR delta (acetone-d6) 10.25 (b, 1H), 8.32 (s, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.93 (b, 1H), 7.70 (s, 2H), 1.36 (s, 18H).
With triethanolamine; In methanol; thionyl chloride;
Methyl 2-Nitro-4-aminobenzoate (Compound K) <strong>[610-36-6]2-Nitro-4-aminobenzoic acid</strong> (261 mg, 1.43 mmol) was dissolved in 1 ml of SOCl2. The solution was refluxed for 1 hour. Excess SOCl2 was removed under reduced pressure and 5 ml of CH2 Cl2, 1 ml of MeOH and TEA (0.24 ml, 1.7 mmol) were added to the residue. The reaction mixture was stirred at room temperature for 2 hours. Excess MeOH and TEA were removed and the residue was purified by column chromatography with ethyl acetate/hexane (1/3) to yield the title compound as a yellow solid (316 mg). 1 H NMR delta 7.69 (d, J=8.5 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 6.67 (dd, J=8.3; 2.1 Hz, 1H), 4.31 (b, 2H), 3.94 (s, 3H).
2-nitro-4-[(2',6'-di-tert-butylpyrid-4'-yl)carbamoyl]benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2-Nitro-4-[(2',6'-di-t-butylpyrid-4'-yl)carbamoyl]benzoic Acid (Compound 14) Using the same procedure as for the preparation of 2,6-difluoro-4-[(2',6'-di-t-butylpyrid-4yl)carbamoyl]benzoic acid (Compound 10)(Compound 10) but using 2,6-di-t-butylisonicotinic acid (40 mg, 0.17 mmol) and <strong>[84228-45-5]methyl 2-nitro-4-aminobenzoate</strong> (Compound K, 33 mg, 0.17 mmol), the title compound was obtained as a light yellow oil. 1 H NMR delta (acetone-d6) 10.25 (b, 1H), 8.32 (s, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.93 (b, 1H), 7.70 (s, 2H), 1.36 (s, 18H).
The benzoic acid used as starting material was obtained as follows: A mixture of <strong>[84228-45-5]methyl-p-amino-o-nitrobenzoate</strong> (The Dictionary of Organic Compounds, Volume 1, page 285: Chapman and Hall, 1982: 1 g), ethyl iodide (0.8 g), 2,6 -lutidine (2.7 g) and dimethylformamide (5 ml) was stirred and heated to 80 C. for 18 hours, cooled and evaporated. A mixture of the residue, 2,6-lutidine (2.7 g), 6-bromomethyl-3,4-dihydro-2-methylquinazolin-4-one (1.3 g) and dimethylformamide (10 ml) was stirred at 85 C. for 5 hours, cooled, poured into water (100 ml) and extracted with ethyl acetate (3*70 ml). The combined extracts were washed with a saturaed aqueous sodium chloride solution (70 ml), dried over magnesium sulphate, filtered and evaporated. The residue was purified by chromatography on a silica gel column using a 50:1 v/v mixture of ethyl acetate and methanol as eluent. There was thus obtained methyl p-[N(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) N-ethylamino]-o-nitrobenzoate (0.35 g).
With benzoic acid; In N-methyl-acetamide;
The benzoic acid used as starting material was obtained as follows:- A mixture of methyl- p -amino- o -nitrobenzoate (The Dictionary of Organic Compounds, Volume 1, page 285; Chapman and Hall, 1982; 1 g), ethyl iodide (0.8 g), 2,6-lutidine (2.7 g) and dimethylformamide (5 ml) was stirred and heated to 80C for 18 hours, cooled and evaporated. A mixture of the residue, 2,6-lutidine (2.7 g), 6-bromomethyl-3,4-dihydro-2-methylquinazolin-4-one (1.3 g) and dimethylformamide (10 ml) was stirred at 85C for 5 hours, cooled, poured into water (100 ml) and extracted with ethyl acetate (3 x 70 ml). The combined extracts were washed with a saturaed aqueous sodium chloride solution (70 ml), dried over magnesium sulphate, filtered and evaporated. The residue was purified by chromatography on a silica gel column using a 50:1 v/v mixture of ethyl acetate and methanol as eluent. There was thus obtained methyl p -[ N -(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)- N -ethylamino]- o -nitrobenzoate (0.35 g).
The p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-o-nitrobenzoic acid, used as a starting material, was obtained as follows: A mixture of <strong>[84228-45-5]methyl 4-amino-2-nitrobenzoate</strong> (10.6 g; Chem. Abs., 98, 143133e), 2,6-lutidine (8.14 ml), prop-2-ynyl bromide (80% w/w solution in toluene; 7.82 ml) and dimethylacetamide (50 ml) was heated to 80 C. for 4 hours. A second portion of prop-2-ynyl bromide solution (7.82 ml) was added and the mixture was heated to 80 C. for 5 hours. The mixture was cooled to laboratory temperature and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel using methylene chloride as eluent. There was thus obtained methyl 2-nitro-4-(prop-2-ynylamino)benzoate (6.58 g), m.p. 134-135 C.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110.0℃;Inert atmosphere; Sealed tube;
General procedure: To a mixture of (4-amino-2-nitrophenyl)(morpholino)methanone(1.21 g, 4.85 mmol) in dioxane (15 mL) was added 3,5-dibromo-1-methylpyridin-2(1H)-one (1.29 g, 4.85 mmol),Pd2(dba)3 (444 mg, 0.485 mmol), Xantphos (281 mg, 0.485 mmol)and Cs2CO3 (4.74 g, 14.5 mmol). The reaction mixture was stirred at110 C overnight under argon, and then concentrated to remove thedioxane. The residue was diluted with water (100 mL) andextracted with DCM (3 x 80 mL). The organic phase was concentratedand purified with flash column chromatography (0-5%MeOH in DCM) to afford S4b (1.80 g, 85%) as a solid.