| ~ 100% |
With hydrogen;5% palladium over charcoal; In tetrahydrofuran; methanol; at 50℃; under 2625.26 Torr; for 6.0h;Product distribution / selectivity; |
A mixture of <strong>[918321-18-3]methyl 2,4-diamino-3-fluoro-5-nitrobenzoate</strong> (5) (40.0 g, 173.7 mmol) and 5% Pd/C (3.0 g, Type 487; 0.4 mol% Pd relative to starting material), in methanol (300.0 rnL) and tetrahydrofuran (300.0 mL) was stirred at 2000 RPM, under hydrogen (-3.5 bar), at 50 0C in a 1.5 L hydrogenation vessel. After 6 hours the vessel was purged with nitrogen and HPLC analysis indicated that no starting material remained. The mixture was then filtered under nitrogen pressure and the filter washed through with THF (160 mL), to give a clear yellow solution. The solvent was removed by rotary evaporation, to provide methyl 2,4,5-triamino-3-fluorobenzoate (9) 37.5 g (93.3% w/w by NMR) as a solid, yield -100%. 1H NMR (400 MHz, d6 DMSO) delta 3.69 (3H, s, NMe), 4.20 (2H, br s, NH2), 5.24 (2H, br s, NH2), 5.70 (2H, br s, NH2), 6.83 (IH5 d, J 1, Ar-H). 13C NMR (100 MHz, d6 DMSO) delta 51 (CH3), 98 (C, d, J 5), 110 (CH, d, J 2), 125 (C, d, J 6), 131 (C, d, J 12), 133 (C, d, J 12), 139 (CF, d, J 225), 166 (C=O). vmax/cm-1 3480, 3461, 3373, 3356, 3280, 3163, 1679, 1655, 1314. MS APCI (+) m/z 200 (M+l) detected. |
| ~ 96% |
With hydrogen;palladium over charcoal; In tetrahydrofuran; methanol; at 20 - 55℃; under 3000.3 Torr; for 7.75h;Product distribution / selectivity; |
A nitrogen purged hydro genation vessel was charged with palladium on carbon (5.53 g, 1.30 mmol), and to this was added a solution of methyl 2,4-diamino-3-fluoro- EPO <DP n="67"/>5-nitrobenzoate (5) (100 g, 419 mmol) in tetrahydrofuran (1.3 L) 15.98, followed by methanol (700 mL). The mixture was then stirred, purged with nitrogen, and heated to 55 C. Stirring was then paused while the system was purged with hydrogen (4 bar), and stirring was then recommenced at 750 rpm. After 6.75 hours observable hydrogen uptake had ceased and 29.1 L of hydrogen had been taken up. The system was then purged with nitrogen and allowed to cool to 20 C. HPLC analysis indicated that all starting material had been reacted and that the solution yield of the desired triamine product was approximately 96%. The mixture was then filtered using a Whatman 1 mu in-line filter to remove the catalyst and the system was washed with tetrahydrofuran (400 mL). Solvent was then distilled off until a total of 1400 mL had been collected and the mixture was allowed to cool to ambient temperature. Acetonitrile (1.0 L) was added to the mixture, followed by removal of solvent (1 L) by distillation, then two additional 500 mL aliquots of acetonitrile were added, followed each time by removal of solvent (2 x 500 mL) by distillation.[00324] Following the solvent swap procedure above, the stirred mixture was cooled to60 0C and a solution of p-toluenesulfonic acid monohydrate (87.7 g, 461 mmol) in acetonitrile (175 mL) and water (7.6 mL, 419 mmol) was added slowly, followed by diethoxymethane (95.98 g, 921.59 mmol). After 3 hours, HPLC analysis indicated incomplete reaction and the temperature was raised to 65 C for an additional 1 hour, after which time the reaction was complete by HPLC analysis. Pyridine (66.3 g, 838 mmol) was added over 10 minutes and the reaction mixture was cooled to 20 C over about 30 minutes and held at this temperature for 2.5 hours. The resultant slurry was then filtered and the solid was washed with acetonitrile (2 x 200 mL), and then dried at 45 C in a vacuum oven, to provide 73.65 g of 6-amino-7-fluoro-3-methyl-3/i-benzoimidazole-5-carboxylic acid methyl ester (6) as a pale brown solid (assay 95.3%), yield at 100%, 75%. 1H NMR (400 MHz, d6 DMSO) delta 3.79 (3H, s, NMe), 3.87, (3H, s, OMe), 6.04 (2H, br, NH2), 7.82 (IH, s, ArH), 8.23 (IH, s, Ar-H). 13C NMR (100 MHz, d6 DMSO) delta 33 (NCH3), 52 (OMe), 110 (CH, d J 5), 111 (C, d J4), 124 (C, d J5), 125 (C, d J 14), 136 (C, d J 11), 137 (CF, d J 242), 145 (CH), 167 (C=O). vmjcm l 3455, 3283, 3166, 3096, 2950, 2361, 2342, 1689, 1608, 1228. MS APCI (+) m/z 224 (M+l) detected. |
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