2,6-Dihydro-4H-pyrrolo[3,4-c] pyrazole-5-carb

A solution of tert-butyl 3-[(dimethylamino)methylidene]-4-oxopyrrohdine-1-carboxylate ( 1 g, 4.16 mmol, 1.00 equiv) and hydrazine hydrate (340 mg, 6.79 rnrnol, 1 , 63 equiv) in ethanol (10 mL) was stirred for 5 h at rt. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 :5 to 1 2) to give 250 mg (29percent) of tert-butyl 2H, 4H, 5H, 6H-pyrrolo[3, 4-c]pyrazole-5-carboxylate as a yellow sol id LC/MS (Method C, ESI ): RT = 1.30 min, m/z - 210.0 [M+H](0090) 37.2g white solid obtained from the last step was dissolved in methanol, 5N hydrochloric acid was added, stirred at room temperature for 6h, ammonia methanol solution (2N) was added after concentration, the pH was adjusted to a slightly alkaline state, 200mL dichloromethane was added, 40mL triethylamine was added, dichloromethane solution (40mL) of 64g di-tert-butyl dicarbonate was added drop by drop at room temperature, after the reaction was carried out for half an hour, the solution was concentrated to dry under vacuum, then subjected to column chromatography (methanol: aqueous ammonia: ethyl acetate=135:15:350) to obtain 20g white solid. Dissolve 2, 6-dihydropyrrolo[3, 4-c]pyrazole-5(4H)-tert-butyl carboxylate (3.3 g, 15.8 mmol) in acetonitrile (40 mL) and add 3-bromo-4-fluorobenzyl bromide 7a (5 g, 18.9 mmol) and cesium carbonate (18 g, 55.3 mmol), replaced with nitrogen 3 times, Place in 80 C oil bath for 3 hours. The reaction solution was filtered, and the filtrate was concentrated.The residue was purified by column chromatography (petroleum ether: ethyl acetate = 2: 1), 2-(3-Bromo-4-fluorobenzyl)-2, 6-dihydropyrrolo[3, 4-c]pyrazole-5(4H)-tert-butyl carboxylic acid 7b (6.1 g, yellow solid ), Yield: 97.7%.Dissolve 2, 6-dihydropyrrolo [3, 4-c] pyrazole-5 (4H) -tert-butyl carboxylate (4.5 g, 21.5 mmol) in acetonitrile (40 mL) and add 3, 5- Dichlorobenzyl chloride 6a (5 g, 25.8 mmol) and cesium carbonate (24.5 g, 75.3 mmol) were replaced 3 times with nitrogen.Place in 80 C oil bath for 3 hours. The reaction solution was filtered, and the filtrate was concentrated.The residue was purified by column chromatography (petroleum ether: ethyl acetate = 2: 1), Obtained 2-(3, 5-dichlorobenzyl)-2, 6-dihydropyrrolo[3, 4-c]pyrazole-5(4H)-tert-butyl carboxylic acid 6b (7.9 g, yellow-brown solid ), Yield: 100%.Dissolve 2, 6-dihydropyrrolo [3, 4-c] pyrazole-5(4H)-tert-butyl carboxylate (12 g, 56.7 mmol) in acetonitrile (100 mL), Add 1-bromo-3- (bromomethyl) -5-methoxybenzene 4b (19 g, 68.1 mmol), Cesium carbonate (64.8 g, 199 mmol), Nitrogen was replaced 3 times, and the reaction was performed in an 80 C oil bath for 3 hours. Filtering the reaction solution, The filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain 2-(3-bromo-5-methoxybenzyl)-2, 6-dihydropyrrolo[3, 4-c]pyrazole-5(4H)-tert-butyl carboxylate 4c (23 g, yellow oil), yield: 82.9%.Dissolve 2, 6-dihydropyrrolo[3, 4-c]pyrazole-5(4H)-tert-butyl carboxylate 3a (2.8 g, 13.5 mmol) in acetonitrile (50 mL) and add 3-chloro Benzyl bromide (3.3 g, 16.2 mmol) and cesium carbonate (32.5 g, 47 mmol) were vented 3 times under nitrogen and placed in an 80 C oil bath for 3 hours. The reaction solution was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain 2-(3-chlorobenzyl)-2, 6-dihydropyrrolo[3, 4-c]pyrazole-5(4H)-tert-butyl carboxylic acid 3b (4.1 g, yellow oil), yield 91%.Dissolve 2, 6-dihydropyrrolo[3, 4-c]pyrazole-5(4H)-tert-butyl carboxylate (2.8 g, 13.5 mmol) in acetonitrile (50 mL), Add 2-bromo-4-(bromomethyl)-1-methoxybenzene 1b (4.5 g, 16.2 mmol) and cesium carbonate (32.5 g, 47 mmol), ventilate 3 times with nitrogen, and place in 80 C oil bath Medium reaction for 3 hours. The reaction solution was filtered, and the filtrate was concentrated.The residue was purified by column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain 2-(3-bromo-4-methoxybenzyl)-2, 6-dihydropyrrolo [3, 4-c] pyrazole-5(4H)-tert-butyl carboxylic acid 1c (6 g, yellow oil), yield: 91%.