| 61.6% |
Stage #1: With N-benzyl-N,N,N-triethylammonium chloride; <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In acetonitrile at 80℃; for 16 h;
Stage #2: With hydrogenchloride In water; ethyl acetate
Stage #3: With sodium hydrogencarbonate In water; ethyl acetate |
The stirred solution of pyrrolo[l,2-f][l,2,4]triazin-4-ol 12f (1 g, 7.40 mmol),benzyltriethylammomum chloride (3.29 g, 14.80 mmol), and N,N-dimethylaniline (1.35 g, 1 1.10 mmol) in acetonitrile (25 mL) was heated to 80 °C and at this temperature phosphorous oxy chloride (6.88 g, 44.40 mmol) was added and stirred at 80 °C for 16 h. The reaction was concentrated to remove acetonitrile and phosphorus oxy chloride. The reaction was quenched by adding ice water (20 mL) and extracted with ethyl acetate (2 x 100 mL). The combined ethyl acetate extracts were washed with hydrochloric acid (1 N, 30 mL) water (50 mL), saturated sodium bicarbonate (1 x 20 mL), water (50 mL), brine (20 mL) dried and concentrated. The crude residue was purified by flash chromatography [silica gel, eluting with ethyl acetate in hexanes (0 to 5 percent)] to furnish pure 4-chloropyrrolo[l,2-f][l,2,4]triazine 12g (0.7 g, 61.6 percent) as a colorless oil, which solidified on standing in refrigerator. 1H NMR (300 MHz, DMSO) δ 8.44 (s, 1H), 8.27 (dd, J = 1.5, 2.5, 1H), 7.12 (qd, J= 2.0, 4.6, 2H). |
| 61.6% |
With N-benzyl-N,N,N-triethylammonium chloride; <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In acetonitrile at 80℃; for 16 h; |
Step 1:To a stirred solution of tert-butyl hydrazinecarboxylate 22b (50 g, 412.37 mmol) and 2,5-dimethoxytetrahydrofuran 22a (54.5 g, 412.37 mmol) in dioxane (300 mL) was added aqueous hydrochloric acid (5 mL, 2N). The reaction was set up using a dean-stark apparatus and heated at 90 °C for 20 h. Reaction mixture was cooled to 20 °C, neutralized with saturated sodium bicarbonate (18 mL) and filtered to remove inorganics. The filtrate was concentrated in vacuum and triturated with ether. The solid obtained was collected by filtration to furnish on drying tert-butyl lH-pyrrol-l-ylcarbamate 22c (43 g, 57.2percent) as a yellow brown solid. 1H NMR (300 MHz, CD3OD) ? 6.62 (t, J= 2.3, 2H), 6.02 (t, J= 2.3, 2H), 1.48 (s, 9H); MS (ES+): 181.1 (M _1). Analysis: Calculated for C9Hi4N202: C, 59.32; H, 7.74; N, 15.37. Found: C, 59.32; H, 7.65; N, 15.02. Step 2:To a stirred solution of tert-butyl lH-pyrrol-l-ylcarbamate 22c (40 g, 219.52 mmol), in acetonitrile (350 mL) was added chlorosulfonyl isocyanate (32.62 g, 230.50 mmol) slowly at 0 °C and continued stirring at 0 °C for 30 min. To the solution N, N-dimethyl formamide (40 mL) was added below 5 °C and continued stirring at 0 °C for 1 hr. The reaction mixture was poured into a mixture of crushed ice (1 L) and ethyl acetate (1 L). The layers were separated and the organic layer was washed with water (500 mL), brine (250 mL), dried and concentrated in vacuum to furnish crude (43 g) product. The crude was purified by flash chromatography (silica gel, eluting with ethyl acetate in hexane0-50percent) to afford pure tert-butyl 2-cyano-lH-pyrrol-l-ylcarbamate 22d (30 g, 66 percent>) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) ? 10.80 (s, 1H, D20 exchangeable), 7.23 (dd, J= 1.7, 2.9, 1H), 6.94 (dd, J= 1.7, 4.3, 1H), 6.20 (dd, J= 2.9, 4.3, 1H), 1.45 (s, 9H). Analysis: Calculated for Ci0Hi3N3O2: C, 57.95; H, 6.32; N, 20.27. Found: C, 58.02; H, 6.45; N, 20.18. Step 3:To a stirred solution of tert-butyl 2-cyano-lH-pyrrol-l-ylcarbamate 22d (5 g, 24.12 mmol) in ethyl alcohol (100 mL) was added concentrated aqueous ammonium hydroxide solution (50 mL) at 20 °C followed by hydrogen peroxide (7.4 mL, 72.38 mmol, 30 percent in water) slowly at 20 °C and stirred at the same temperature for 16 h. Reaction mixture was concentrated in vacuum and diluted with ethyl acetate (150 mL), washed with water (2 x 50 mL). The aqueous layer was extracted with ethyl acetate (150 mL). The combined ethyl acetate layers were washed with water (100 mL), brine (50 mL), dried, filtered, and concentrated in vacuum. The residue obtained was crystallized from diisopropyl ether and hexane to afford tert-butyl 2-carbamoyl-lH-pyrrol-l-ylcarbamate 22e (4.0 g, 73.6percent) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) ? 9.89 (s, 1H, D20 exchangeable), 7.31 (d, J = 38.5, 1H), 6.84 (dd, J= 1.9, 2.8, 2H, lH is D20 exchangeable), 6.76 (dd, J = 1.9, 4.2, 1H), 5.97 (dd, J= 2.8, 4.2, 1H), 1.40 (s, 9H); Analysis: Calculated for Ci0Hi5N3O3: C, 53.32; H, 6.71 ; N, 18.65. Found: C, 53.40; H, 6.74; N, 18.55. Step 4:To a solution of tert-butyl 2-carbamoyl-lH-pyrrol-l-ylcarbamate 22e (2g, 8.87 mmol) in dichloromethane (15 mL) was added trifluoro acetic acid (15 mL) at 20 °C and stirred for 30 min. The reaction mixture was concentrated to dryness to remove excess trifluoroacetic acid and diluted with dichloromethane. Triethylorthoformate (30 mL) was added to the residue and was heated to 79 °C overnight. Reaction mixture was concentrated to dryness and triturated with hexanes, the solid obtained was collected by filtration dried in vacuum to give crude pyrrolo[l ,2-f][l ,2,4]triazin-4-ol 22f (1.1 g, 91percent) as a dark brown solid. 1H NMR (300 MHz, DMSO-d6) ? 11.63 (s, 1H, D20 exchangeable), 7.83 (d, J= 4.0, 1H), 7.59 (dd, J= 1.7, 2.6, 1H), 6.89 (dd, J= 1.6, 4.3, 1H), 6.54 (dd, J = 2.7, 4.3, 1H); MS (ES+): 136.2 (M + l). Step 5:The stirred solution of pyrrolo[l ,2-f][l ,2,4]triazin-4-ol 22f (1 g, 7.40 mmol), benzyltriethylammonium chloride (3.29 g, 14.80 mmol), and N,N-dimethylaniline (1.35 g, 1 1.10 mmol) in acetonitrile (25 mL) was heated to 80 °C and at this temperature phosphorous oxy chloride (6.88 g, 44.40 mmol) was added and stirred at 80 °C for 16 h. The reaction was concentrated to remove acetonitrile and phosphorus oxy chloride. The reaction was quenched by adding ice water (20 mL) and extracted with ethyl acetate (2 x 100 mL). The ethyl acetate extracts were combined washed with hydrochloric acid (1 N, 30 mL), water (50 mL), saturated sodium bicarbonate (1 x 20 mL), water (50 mL), brine (20 mL) dried and concentrated. The crude residue was purified by flash chromatography (silica gel, eluting with ethyl acetate in hexanes (0 to 5 percent)) to furnish pure4-chloropyrrolo[l,2-fJ[l,2,4]triazine 22g (0.7 g, 61.6 percent) as a colorless oil, which solidified on standing in refrigerator. 1H NMR (300 MHz, DMSO-d6) ? 8.44 (s, 1H), 8.27 (dd, J = 1.5, 2.5, 1H), 7.12 (qd, J= 2.0, 4.6, 2H). Step 6:A solution of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (10m) (2.3 g, 9.8 mmol) and 4-chloropyrrolo[l,2-f][l,2,4]triazine (22g) (1.5 g, 9.8 mmol) in DMF (90 mL) was degassed with nitrogen for 15 min followed by addition of sodium carbonate (3.615 g, 34.2 mmol) in water (17 mL) under a continuous flow of nitrogenpalladium(II)bis(triphenyl phosphine) dichloride (0.69 g, 0.98 mmol) was added to the reaction mixture. The reaction mixture was stirred at 80 °C for 1 h and diluted with H20 (100 mL). The product was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with water (2 x 100 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 100percent)) to furnish 2-(pyrrolo[l,2-f][l,2,4]triazin-4- yl)aniline (22h) (0.584 g, 28 percent yield) as a yellow solid. ? NMR (300 MHz, DMSO- 6) ? 8.53 (s, 1H), 8.10 (dd, J = 2.2, 1.8 Hz, 1H), 7.81 (dd, J = 7.9, 1.5 Hz, 1H), 7.25 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.09 - 7.00 (m, 2H), 6.87 (dd, J = 8.3, 1.0 Hz, 1H), 6.69 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 6.62 (s, 2H, D20 exchangeable); MS (ES+) 233.1 (M+Na), (ES-) 208.9 (M-1). Analysis calculated for Ci2Hi0N4: C, 68.56; H, 4.79; N, 26.65. Found: C, 68.53; H, 4.83; N, 26.57. |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
