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With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere;
Step A: N-(2-amino-5-(trifluoromethyl)phenyn-4-chloro-2,5-difluorobenzamide A suspension of <strong>[132794-07-1]4-chloro-2,5-difluorobenzoic acid</strong> (1.00 g, 5.19 mmol), 3,4- diaminobenzotrifluoride (1.006 g, 5.71 mmol) and PyBOP (2.97 g, 5.71 mmol) in DMF (15.0 ml) under a N2 atmosphere was stirred at room temperature for 5 min. DIEA (2.72 ml, 15.58 mmol) was then added via a syringe and the mixture stirred at roomtemperature for 4 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgS04) and concentrated. Purification on the CombiFlash Companion, on a 40 g column eluting with 10 to 30 % EtOAc / Hexane afforded 652 mg of N-(2-amino-5-(trifluoromethyl)phenyl)-4-chloro-2,5-difluorobenzamide as a cream crystalline solid. LC- S (M+l) = 351.
With hydrogenchloride; In water; at 100 - 120℃; for 5.0h;
12 M HCI (1 ml, 12 mmol) was added to a mixture of 4-(trifluoromethyl)benzene-1 ,2-diamine (1 g, 5.68 mmol) and chloroacetic acid (0.590 g, 6.25 mmol) in water (20 ml) and the mixture was heated at 100C for 2 h. Further 12 M HCI (4 ml, 48 mmol) was added and the reaction mixture heated at 120C for 3 h. The mixture was then cooled to room temperature and quenched by addition of 7 M ammonia in MeOH until basic, extracted with EtOAc (3 x 20 ml) and the combined organic layers were washed with brine (20 ml), dried (MgSC), filtered and evaporated in vacuo. Flash column chromatography (eluting with a gradient 5- 50% EtOAc / heptane) afforded the crude title compound as a purple solid (0.571 g, 24%, 56% purity) which was used without further purification. HPLCMS (Method E): [m/z]: 234.85 [M+H]+
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 60℃; for 16h;
General procedure: The title compounds were prepared in parallel format using thefollowing protocol: Step 1: To 4-alkyl-1, 2-diaminobenzene (100 mumol,1 eq) was added a solution of the required amino acid in DMF (0.2 M,500 muL, 100 mumol, 1 eq) followed by TEA (28 muL, 200 mumol, 2 eq) and asolution of HATU in DMF (0.2 M, 500 muL, 100 mumol, 1 eq). The reactionwas shaken at 60 °C for 16 h before cooling and concentrating in vacuoto afford crude uncyclised intermediate. Step 2: To crude uncyclizedintermediate was added acetic acid (1000 muL) and the reaction wasshaken at 80 °C for 1 h. The reaction was cooled, concentrated in vacuoand dissolved in DMSO. The solution was filtered and purified usingpreparative HPLC to afford the intermediate benzimidazole. Step 3: Tothe intermediate benzimidazole was added CH2Cl2 (1800 mumol) followedby 4M HCI in dioxane (200 muL) and the reaction was shaken at30 °C for 1.5 h. The reaction was concentrated in vacuo to afford productas the HCl salt.
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