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Into a 25-mL round-bottom flask, was placed 3,5-dichloropyridazine (1 g, 6.71 mmol, 1 equiv), ammonia (8 mL), dioxane (2 mL). The resulting solution was stirred overnight at 100 °C. The solids were collected by filtration. This resulted in 570 mg (62percent) of the title compound as a brown solid. Analytical Data: LC-MS: (ES, m/z): RT= 0.434 min, LCMS 53, m/z = 130 [M+l].
[0512] Compound 487A was prepared by an analogous method as that of 473B, except using compound <strong>[29049-45-4]3-chloro-5-aminopyridazine</strong> in place of compound 2-bromo-6-aminopyridine.
Step B: 4-amino-6-chloropyridazine A stirred solution of 1.2 grams of 3-hydrazino-4-amino-6-chloropyridazine and 15 ml of aqueous 8percent sodium hydroxide solution is heated under reflux for 30 minutes. The reaction mixture is treated with decolorizing carbon and filtered. The filtrate is neutralized with aqueous 50percent acetic acid and the resultant precipitate is collected by filtration. The filter cake is recrystallized from water to yield 0.8 gram of 4-amino-6-chloropyridazine, m.p. 153°-154.5° C.
N-(6-chloro-4-pyridazinyl)-N'-(1-methylethyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N-methyl-acetamide; water;
Step C: N-(6-Chloro-4-pyridazinyl)-N'-(1-methylethyl)urea To a stirred solution of 0.8 gram of 4-amino-6-chloro-pyridazine in 30 ml of dimethylformamide is added 0.2 gram of 1,4-diazabicyclo[2.2.2]octane, followed by 0.6 gram of 1-methylethyl isocyanate. The reaction mixture is stirred at ambient temperature for 18 hours, then at 60 C. for six hours. The majority of the dimethylformamide is removed under reduced pressure, and the residue is slurried in water. The resultant solid is collected by filtration and dried to yield N-(6-chloro-4-pyridazinyl)-N'-(1-methylethyl)urea.
(R)-6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridazin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41.7%
To a stirred suspension of potassium tert-butoxide (7.80 g, 69.5 mmol) inl,4-Dioxane (50 mL) was added (R)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol (5.20 mL, 41.7 mmol) at 0 C and the reaction mixture was stirred at 25 C for 1 h. under Nitrogen atmosphere. Then <strong>[29049-45-4]6-chloropyridazin-4-amine</strong> (3 g, 23.16 mmol) was added to the reaction mixture and the resulting reaction mixture was stirred at 1 10 C for 16 h. (TLC System Ethyl acetate, Rf: 0.3). The reaction mixture was poured into ice cold water (40 ml) and extracted with EtOAc (2x80 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to get crude compound. The crude product was purified by flash column chromatography (Neutral alumina, Eluent: 65% Ethyl acetate in Pet ether) to afford the desired product (R)- 6-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)pyridazin-4-amine (2.2 g, 9.66 mmol, 41.7 % yield) as an off white solid. LCMS (m/z): 226.05 [M+H]+, Rt = 1.00 min.
(S)-6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridazin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
To a stirred suspension of potassium tert-butoxide (3.90 g, 34.7 mmol) in 1,4-Dioxane (50 mL) was added a mixture of (,S)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol (2.75 g, 20.84 mmol) at 0 C and the reaction mixture was stirred at 25 C for 1 h. under Nitrogen atmosphere, then <strong>[29049-45-4]6-chloropyridazin-4-amine</strong> (1.5 g, 1 1.58 mmol) was added to the reaction mixture and the resulted reaction mixture was stirred at 1 10 C for 16 h. (TLC System: Neat Ethyl acetate, Rf: 0.3). The reaction mixture was poured in to ice cold water (40 ml) and extracted with EtOAc (2x80 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to get crude compound. The crude material was purified by flash column chromatography (Neutral alumina, Eluent: 65% Ethyl acetate in Pet ether) to afford the desired product (,S)-6-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)pyridazin-4-amine (1.0 g, 4.28 mmol, 37.0 % yield) as a white solid. LCMS (m/z): 226.20 [M+H]+.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; water; toluene; at 90℃; for 14h;Sealed tube; Inert atmosphere;
General procedure: A mixture of 4-chloropyridin-2-amine (64 g, 498 mmol), phenyl boronic acid (61 g, 500 mmol), Na2CO3 (159 g, 1.5 mol), Pd(PPh3)4 (6.4 g) in H20/EtOH/toluene (500 mL) was heated to 90 C in sealed vessel for 14 h. The crude mixture was cooled, filtered, and concentrated under reduced pressure. Purification (FCC, 5i02,PE:EtOAc (100:1) afforded the title Compound (64 g, 75%).
Into a 50-mL round-bottom flask, was placed <strong>[29049-45-4]6-chloropyridazin-4-amine</strong> (570 mg, 4.40 mmol, 1 equiv), dioxane (20 mL), CH3NH2-H20 (4 mL). The resulting solution was stirred overnight at 140 C. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC A. This resulted in 320 mg (59%) of the title compound as a yellow solid. Analytical Data: LC-MS: (ES, m/z): RT= 0.187 min, LCMS 45, m/z = 125 [M+l].
Into a 25-mL round-bottom flask, was placed 3,5-dichloropyridazine (1 g, 6.71 mmol, 1 equiv), ammonia (8 mL), dioxane (2 mL). The resulting solution was stirred overnight at 100 C. The solids were collected by filtration. This resulted in 570 mg (62%) of the title compound as a brown solid. Analytical Data: LC-MS: (ES, m/z): RT= 0.434 min, LCMS 53, m/z = 130 [M+l].
Example 217 Synthesis of 6-chloropyridazin-4-amine. A solution of 3,5-dichloropyridazine (9 g, 60.8 mmol) in NH4OH (25%, 100 mL) was stirred at 120 C. for 16 h in sealed tube. Then the mixture was concentrated in vacuo and triturated with ether to give the 6-chloropyridazin-4-amine as a brown solid (7.3 g, yield: 93%). ESI-MS [M+H]+: 130.0.
Synthesis of 5-bromo-3-chloropyridazine. To a solution <strong>[29049-45-4]6-chloropyridazin-4-amine</strong> (2 g, 15 mmol), t-BuONO (2.4 g, 23 mmol) in MeCN (40 mL) was added CuBr2 (5 g, 23 mmol) at 0 C. The resulting mixture was stirred at RT for 16 h and then concentrated in vacuo. The mixture was diluted with EtOAc (50 mL) and added H2O (50 mL). After filtered through celite, the filtrate was extracted with EtOAc (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product which was purified by silica gel chromatography (PE/EA=20/1) to give 5-bromo-3-chloropyridazine (1.32 g, yield: 43%) as a brown oil. ESI-MS [M+H]+: 192.8, 194.8.
A suspension of <strong>[29049-45-4]4-amino-6-chloropyridazine</strong> (1) (2.59 g, 22.3 mmol, 1.0 eq) in CH2CI2 (65 ml_) was cooled to 0 C before the addition of triethylamine (10.9 ml_, 77.9 mmol, 3.5 eq) and di-fe/f-butyl dicarbonate (12.2 g, 55.7 mmol, 2.5 eq). The suspension was warmed to room temperature and stirred for 17.5 h then DMAP (277 mg, 2.23 mmol, 0.1 eq) and additional di-fe/f-butyl dicarbonate (4.86 g, 22.3 mmol, 1.0 eq) were added. The reaction was stirred for 2.5 h then concentrated in vacuo. Purification twice by silica gel chromatography using hexane/EtOAc (1 :0-4: 1 ) yielded intermediate 2 as an orange solid (3.40 g, 46%). (1299) LCMS (ES): Found 174.0 [M-C02fBu-fBu+3H]+. (1300) 1H NMR (300MHz, DMSO-cf6), d: 9.33 (d, J=2.1 Hz, 1 H), 8.14 (d, J=2.1 Hz, 1 H), 1.41 (s, 18H).
1.Q Synthetic Method Q: Synthesis of Example 136
A solution of R-21 (1.0 g, 7.75 mmol) in MeOH (20 ml) is added MeONa (1.255 g, 23.25 mmol), and then is stirred at 75 °C overnight. The mixture is concentrated under reduced pressure. The residue is purified by flash chromatography (S1O2 eluting with 65 % of EtOAc in petroleum ether) to give 1-7 (500 mg, 51%).
N-(6-chloropyridazin-4-yl)-2-fluoro-5-(trifluoromethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90 mg
With pyridine; In dichloromethane; for 24h;Inert atmosphere;
The crude compound 7b (393 mg, 1.73 mmol), 6-chloro-4-aminopyridazine (150 mg, 1.15 mmol) and pyridine (458 mg, 5.79 mmol) were dissolved in dichloromethane (5 mL), and the reaction solution was reacted for 24 hours. 50 mL ethyl acetate was added, and the reaction solution was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 7c (90 mg, yield: 24%). MS m/z (ESI):320.0 [M+1]