4-AMINOPYRIDAZINE

yellow powder

4-(3-Phenyl-1, 2, 4-thiadiazol-5-yl)-N-pyridazin-4-ylpiperazine-1-carboxamide; (1) Pyridazine-4-amine; A mixture of 3, 6-dichloropyridazine-4-amine (5.00 g, 18.2 mmol), tetrahydrofuran (100 ml), sodium hydroxide (8.00 g, 200 mmol), water (32 ml) and 10percent palladium-carbon (500 mg) was stirred under a hydrogen atmosphere at room temperature for 2 days, insolubles were filtered off and the filtrate was concentrated. The residue was dissolved in methanol (100 ml), insolubles were filtered off and the filtrate was concentrated to obtain the desired product quantitatively as a solid. 50 mL of ammonia was condensed in a 200 mL, 3-NECK flask equipped with dry ice condenser. After the addition of a crystal of Fe (N03) 3, potassium (468 mg, 12.0 mmol) was added in small pieces AT-78 C. The cooling bath was removed and the intense dark blue mixture was brought to a gentle reflux until a light grey slurry was obtained. After cooling TO-78 C, 0.35 mL (4.80 mmol) of pyridazine was added and the mixture was stirred for 10 minutes. Solid KM : NO4 (2. 65 g, 16. 8 mmol) was added in small portions, the cooling bath was removed, and the mixture was stirred for 10 minutes The reaction was carefully quenched with 1.2 g of solid ammonium chloride. 20 mL of methanol was added and the ammonia was left to evaporate in the hood. The black mixture was filtered through CELIEZ filter aid, the filtrate was concentrated in vacuo, and the resulting black solid was purified on SI02 (100percent CH2CL2 to 10percent MeOH in CH2C12, gradient) to yield pyridazin-4-ylamine as a brownish solid (380 mg; 83percent yield). Bromination of pyridazin-4-ylamine was performed in the same manner as for the preparation of 4-amino-3-bromo-2, 6-dimethylpyridine. Chromatography on Si02 (20percent ethyl acetate in hexanes to 100percent ethyl acetate, gradient, followed by 2percent methanol in ethyl acetate) yielded 4- amino-3-bromopyridazine (first eluting: 15percent yield) and 4-amino-5-bromopyridazine (second eluting: 5percent yield) as tan solids.To a stirred solution of 7-bromo-4-(3-(3, 4-dihydroisoquinolin-2(lH)-yl)- 2-hydroxypropyl)-3, 4-dihydrobenzo[f][l, 4]oxazepin-5(2H)-one (1.51 g, 3.5 mmol, 1.0 eq) in l, 4-dioxnae (20 ml) was added General procedure: A microwave tube was charged with 6'-bromo-8'-chloro-2'H-spiro[cyclohexane-1, 3'-imidazo[1, 5-a]pyridine]-1', 5'-dione 3 (1.00 eq.), amine (1.00 eq.), Cs2CO3 (2.00 eq.), Pd2(dba)3 (0.10 eq.), xantphos (0.10 eq.) and 1, 4-dioxane (4 mL). The reaction mixture was heated under microwave irradiation at 130 C for 30 min, concentrated under reduced pressure, and purified by flash column chromatography (silica gel, DCM ramping to DCM/CH3OH = 9:1) to yield the desired product.To a solution of 166 mg of compound 1-3 in 30 mL THF at 20 to 25C was added 95 mg A mixture of l-(3-chloro-5-methyl-5H-chromeno[4, 3-c]pyridin-8-yl)pynOlidin-2- one (80 mg, 0.25 mmol), General procedure: Aniline (62mul, 0.68 mmol), 2, 4-dichloropyridine (100 mg, 0.68 mmol), cesium carbonate (442 mg, 1.36 mmol), xantphos (47 mg, 0.08 mmol) and Pd(OAc)2 (12 mg, 0.05 mmol) were combined in a microwave tube, sealed and purged with nitrogen. Dioxane (3 mL) was then added and the reaction solution degassed with nitrogen prior to heating at 100C for 30 minutes. The reaction mixture was then filtered and the filtrate was purified by reverse phase chromatography, utilizing a 20-65% gradient over 9 mins, with 0.5% ammonia as modifier to afford 4-chloro-N-phenyl-pyridin-2-amineTo solution of phenyl {4-[(3-chloro-1 -{[2-(trimethylsilyl)ethoxy]methyl}-1 H-pyrrolo[2, 3-b]pyridin- 4-yl)oxy]-3, 5-difluorophenyl}carbamate (90 mg, 0.16 mmol, intermediate 44) in DMF (1 mL) was added General procedure: To a slurry of 6?-bromo-8?-methyl-2'H-spiro[cyclohexane-1, 3?-imidazo[1, 5-a]pyridine]-1?, 5?-dione (12) and aromatic aminederivatives (1.2 eq) in 1, 4-dioxane was added Cs2CO3 (3 eq). Themixture was stirred at room temperature for 20 min under nitrogen.To the mixture was then added Pd(OAc)2 (0.1 eq) and Xantphos(0.2 eq). After stirred at room temperature for additional 20 minunder nitrogen, the mixture was heated at 95 C for 12 h undernitrogen. The mixture was concentrated in vacuo, added with water, stirred and filtered. The filter cake was dried and purified by flashcolumn chromatography.TDI01236-1 (700 mg, 2.78 mmol) and N, N-dimethylformamide (5 mL) were added to a 50 mL flask, HATU (1.59 g, 4.17 mmol) was cautiously added under stirring, and the reaction was stirred at room temperature for half an hour. Pyridazin-4-amino (290 mg, 3.16 mmol) and diisopropylethylamine (898 mg, 6.95 mmol) were then sequentially added, and the reaction was further stirred at room temperature for 4 h. After the reaction was complete, the reaction solution was slowly added dropwise to water (20 mL) under stirring. A large amount of solid precipitated, and was filtered after being stirred for 30 min. The solid was successively washed with water (5 mL*2) and petrolem ether (5 mL*2), to afford TDI01236-2 (900 mg, yellow solid, yield: 98.4%) 1H NMR (400 MHz, DMSO-d6) delta 11.36 (s, 1H), 9.75 (d, J = 2.0 Hz, 1H), 9.16 (d, J = 5.9 Hz, 1H), 8.72 (d, J = 8.5 Hz, 1H), 8.48 (s, 1H), 8.30-8.27 (m, 2H), 8.14 (d, J = 8.8 Hz, 1H), 7.95 (dd, J = 8.7, 1.8 Hz, 1H). MS m/z (ESI): 329.0 [M+H].

Molecular Weight:95.10
XLogP3:-0.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:95.048347172
Monoisotopic Mass:95.048347172
Topological Polar Surface Area:51.8
Heavy Atom Count:7
Complexity:54.9
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes