"In a 2L three-necked flask, tert-butyl 1H-pyrrolo [2,1-f ] [1,2,4] triazine-1-carboxylate was added, followed by tert-butoxycarbonylhydrazine carboxylate (100g, 0.76mol), 2,5-dimethoxytetrahydrofuran (108g, 0.83mol), and dioxane (700mL). The mixture was stirred, and then slowly added dropwise with dilute hydrochloric acid (2M, 10mL) to the solution."

-Deshangchemical-chemechemi

Step 1. In a 2L three-necked flask, tert-butyl 1H-pyrrolo [2,1-f ] [1,2,4] triazine-1-carboxylate was added, followed by tert-butoxycarbonylhydrazine carboxylate (100g, 0.76mol), 2,5-dimethoxytetrahydrofuran (108g, 0.83mol), and dioxane (700mL). The mixture was stirred, and then slowly added dropwise with dilute hydrochloric acid (2M, 10mL) to the solution. The mixture was heated to 100℃ for 48h. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was dissolved in EtOAc (500mL). The ester phase was successively washed with saturated Na2CO3 solution and saturated NaCl water solution, dried over anhydrous Na2SO4, and filtered before concentrating to obtain a yellow solid. The obtained solid was dispersed in EtOH (100mL), filtered, and the filter residue was washed with a small amount of EtOH and dried to obtain the target compound of 80g. The yield was 58%. LCMS(ESI): m/z = 183(M+H)+.

Step 2. In a 1L three-necked flask, tert-butyl 2-cyano-1H-pyrrolo [2,1-f ] [1,2,4] triazine-1-carboxylate was added, followed by tert-butyl 1H-pyrrolo [2,1-f ] [1,2,4] triazine-1-carboxylate (80g, 0.44mol) and anhydrous acetonitrile (500mL), and placed in an ice-water bath for cooling. The solution was slowly added dropwise with chlorosulfonyl isocyanate (65g, 0.46mol) at the maintained temperature for 1h. Then, DMF (40mL) was slowly added, and the mixture was maintained at the temperature for another 1h. After the reaction was completed, the reaction was quenched by adding ice water, and then adjusted to neutral with saturated Na2CO3 solution. The aqueous phase was extracted with EtOAc. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the product of 85g, which was directly used for the next reaction, with a yield of 95%. LCMS(ESI): m/z = 208(M+H)+.

Step 3. 1-Amino-1H-pyrrolo [2,1-f ] [1,2,4] triazine-2-carboxylic acid was added to a 1L round-bottomed flask, cooled under an ice bath, and then added tert-butyl 2-cyano-1H-pyrrolo [2,1-f ] [1,2,4] triazine-1-carboxylate (85g, 0.41mol) and hydrogen chloride dioxane solution (4M, 500mL) to the mixture. The mixture was allowed to rise to room temperature and react for 4h, resulting in the precipitation of white solid. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was dispersed in EtOAc (100mL). The filtrate was concentrated, and the residue was dissolved in EtOAc. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the solid of 50g, which was the salt of the target compound. LCMS(ESI): m/z = 108(M+H)+.

Step 4. Pyrrolo [1,2-f][1,2,4] triazine-4-amine was added to a 2L round-bottomed flask, followed by 1-Amino-1H-pyrrolo [2,1-f ] [1,2,4] triazine-2-carboxylate hydrochloride (50g), methylamine acetate (109g, 1.05mol), K3PO4 (222g, 1.05mol), and EtOH (800mL), and heated for reflux for 16h. After the reaction was completed, the filtrate was filtered, and the filter residue was washed with EtOH. The filtrate was concentrated, and the residue was dissolved in EtOAc. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a red solid. The obtained solid was dispersed in CH2Cl2, filtered, and the filter residue was washed with CH2Cl2 to obtain a pale yellow solid of 35g. LCMS(ESI): m/z = 135(M+H)+.

Step 5. 7-Iodo-pyrrolo [1,2-f][1,2,4] triazine-4-amine (35g, 0.26mol) was dissolved in anhydrous DMF (150mL) and placed in an ice-water bath for cooling. Add NIS (29g, 0.13 mol) to the upper solution and maintain the temperature for a reaction for 1 hour. Then add NIS (29g, 0.13 mol) and maintain the temperature for another 1 hour. After the reaction is completed, dilute with H2O. The aqueous phase is extracted with EtOAc. The obtained organic phase is successively washed with 5% Na2SO3 solution, saturated NH4Cl solution, and saturated NaCl solution, dried with anhydrous Na2SO4, filtered, and concentrated to obtain a dark yellow solid weighing 69g. The solid is dissolved in EtOAc, and activated carbon is added. Heat and reflux for decolorization for 5 hours, filter, and the filter residue is washed with EtOAc. The filtrate is concentrated, and the remaining substance is crystallized with EtOAc to obtain a light yellow solid weighing 50g, with a yield of 74%. LCMS(ESI): m/z = 261 (M+H)+.