| 81% |
With acetic acid In methanol at 20℃; for 16h; |
5.2 Preparation of methyl (4-(2-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)carbamate (17e)
Step 1:To a solution of ethyl pyrrole-2-carboxylate 10b (5 g, 98%, 35.21 mmol) in DMF (300 mL) cooled to -10 °C was added dropwise LiHMDS (1 M in THF, 42.3 mL) and stirred at -10 °C for 15 min. To the cold reaction mixture was added O- (diphenylphosphoryl)hydroxylamine 10c (15 g, 64.32 mmol) and stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (800 mL) washed with water (2 x 400 mL), brine (200 mL), dried over MgS04 and filtered. The filtrate was concentrated in vacuo and the residue obtained was purified by column chromatography (silica gel 200 g, eluting with hexanes/ethyl acetate, 1 :0 to 4: 1 , product Rf = 0.46 in hexanes/ethyl acetate = 4: 1 ) to furnish ethyl l-amino-lH-pyrrole-2-carboxylate (lOd), (3.868 g, 71%) as a light yellow oil. 1H NMR (300 MHz, DMSC ?): ? 7.01 (t, J= 2.3 Hz, 1H), 6.70 (dd, J= 2.0, 4.3 Hz, 1H), 6.26 (s, 2H), 5.97 (dd, J= 2.6, 4.3 Hz, 1H), 4.22 (q, J= 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). Step 2:To a solution of methyl 1 -amino- lH-pyrrole-2-carboxylate (lOd) (0.29 g, 2.1 mmol) in methanol/ AcOH (5 mL/0.6 mL) was added S-methyl bis(methoxycarbonyl)thiourea(17a) (0.47 g, 2.28 mmol) and stirred at room temperature for 16 h. The reaction mixture was diluted with ether (5 mL) and hexane (15 mL). The solid obtained was collected by filtration, washed with hexane and dried under vacuum to furnish methyl l-(2,3- bis(methoxycarbonyl)guanidino)-lH-pyrrole-2-carboxylate (17b) (0.5 g, 81%) as a white solid; mp 160.3 °C. 1H NMR (300 MHz, OMSO-d6) ? 11.17-10.23 (m, 1H), 10.16-9.48 (m, 1H), 7.10-6.86 (m, 1H), 6.79 (s, 1H), 6.11 (s, 1H), 3.70 (s, 3H), 3.66 (s, 3H), 3.49 (s, 3H). MS ES(+) 299.1 (M+l); ES(-) 296.9 (M-l). Analysis: Calcd for CnHi4N406: C, 44.30; H, 4.73; N, 18.79. Found: C, 44.21; H, 4.76; N, 18.72. Step 3:To a solution of methyl l-(2,3-bis(methoxycarbonyl)guanidino)-lH-pyrrole-2- carboxylate (17b) (0.145 g, 0.5 mmol) in methanol (5 mL) was added NaOMe (25% wt, 1.08 mL, 5 mmol) and stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum and the residue obtained was triturated with water. The solid obtained was collected by filtration and dried under vacuum to furnish methyl4-hydroxypyrrolo[l,2-/][l,2,4]triazin-2-ylcarbamate (17c) (0.087 g, 84%>) as an off-white solid; mp 232.4 °C. 1H NMR (300 MHz, DMSO-Analysis: Calculated for C8H8N403: C, 46.16; H, 3.87; N, 26.91. Found: C, 46.07; H, 3.85; N, 26.88. Step 4:To a solution of methyl 4-hydroxypyrrolo[l,2: ][l,2,4]triazin-2-ylcarbamate (17c) (1.9 g, 9.12 mmol) in acetonitrile (75mL) was added benzyltriethylammonium chloride (4.15 g, 18.24 mmol) and N,N-diethylaniline (2.17 g, 14.6 mmol). The reaction mixture was heated to 80 °C, to the heat reaction mixture was added dropwise POCI3 (11.18 g, 72.96 mmol) and continued heating for 15 h. The reaction mixture was cooled to room temperature and concentrated in vacuum to dryness. The residue obtained was taken in ethyl acetate (400 mL), washed with aqueous NaHC03 (IN, 200 mL), water (200 mL), brine (100 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel, eluting with ethylacetate/hexanes) to afford methyl (4-chloropyrrolo[2,l-f][l,2,4]triazin-2-yl)carbamate (17d) (1.05 g, 50%) as a light yellow solid. 1H NMR (300 MHz, DMSC ?) ? 10.55 (s, 1H), 8.10 (dd, J= 2.5, 1.5 Hz, 1H), 7.04 (dd, J= 4.7, 1.5 Hz, 1H), 6.98 (dd, J = 4.7, 2.5 Hz, 1H), 3.68 (s, 3H); MS (ES+) 227.1 (M+l). Step 5:A solution of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (10m) (0.329 g, 1.5 mmol) and methyl (4-chloropyrrolo[2,l-f][l,2,4]triazin-2-yl)carbamate (17d) (0.227 g, 1.0 mmol) in DMF (10 mL) was degassed with nitrogen for 15 min followed by addition of sodium carbonate (1.75 mL, 3.5 mmol) in water (1.6 mL) under a continuous flow of nitrogen palladium(II)bis(triphenyl phosphine) dichloride (0.070 g, 0.1 mmol) was added to the reaction mixture. The reaction mixture was stirred at 80 °C for 2 h and diluted with H20 (25 mL). The product was extracted with ethyl acetate (3 x 25 mL). The organic layers were combined, washed with water (2 x 25 mL), dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography ((silica gel 12 g, eluting with hexane: ethyl acetate (0 to 100%)) to furnish methyl 4-(2- aminophenyl)pyrrolo[l,2-f][l,2,4]triazin-2-ylcarbamate 17e (0.2 g, 71 % yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) ? 10.47 (s, 1H), 7.95 - 7.89 (m, 2H), 7.30 - 7.20 (m, 1H), 7.14 (s, 2H), 7.07 (dd, J = 4.7, 1.4 Hz, 1H), 6.93 (dd, J = 4.6, 2.5 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.70 - 6.61 (m, 1H), 3.70 (s, 3H). Analysis: Calculated for Ci4Hi3N502: C, 59.36; H, 4.63; N, 24.72. Found: C, 59.08; H, 4.51; N, 24.34. |
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