3-Amino-4-bromo-6-chloropyridazine

To a solution of3-amino-6-chloropyridazine ([CAS 5469-69-2], (200 g, 1538 mmol)and NaHC03 (258 g, 3076 mmol) in CH30H (2000 mL) was added Br2 ([CAS 7726-95-6], 369 g, 2308 mmol) dropwise at 0oc and the mixture was stirred overnight atroom temperature. Then water (2000 mL) was added and the solid precipitate was filtered and washedwith water. The solid was dried under vacuum to give intermediate 1 (260 g, 81.7percent).To a solution of 3-amino-6-chloropyridazine ([CAS 5469-69-2], (200 g, 1538 mmol) and NaHCOTo a 250 mL round-bottomed flask was added 6-chloropyridazin-3 -amine (3.92 g, 30.3 mmol), sodium bicarbonate (5.08 g, 60.5 mmol) and ethanol (20 mL). To the resulting solution, bromine (1.559 mL, 30.3 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 hours. The solution was filtered and then concentrated in vacuo. The residue was dissolved in water and the product extracted with ethyl acetate (3x). The organic layers were combined, dried IA: Preparation of 4-bromo-6-chloropyridazin-3 -amine[00228] To a 250 mL round-bottomed flask was added 6-chloropyridazin-3 -amine (3.92 g, 30.3 mmol), sodium bicarbonate (5.08 g, 60.5 mmol) and ethanol (20 mL). To the resulting solution, bromine (1.559 mL, 30.3 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 hours. The solution was filtered and then concentrated in vacuo. The residue was dissolved in water, and the product extracted with ethyl acetate (3 times). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give IA (4.5 g, 71.3 percent yield). HPLC: Rt = 1.25 min (Waters Sunfire C18 column (4.6 x 50 mm). 10- 90percent aqueous methanol containing 0.1percent TFA, 4 min gradient, flow rate = 4 mL/min, detection at 254 nm). MS (ES): m/z = 207.88 [M+H]To a suspension of 6-chloropyridazin-3-amine (30 g, 232 mmol), NaHCOTo a suspension of 6-chloropyridazin-3 -amine (30 g, 232 mmol), NaHC0Example AlPreparation of intermediate 1 : 4-Bromo-6-chloro-pyridazin-3-ylamineBromine (7.9 ml, 154.3 mmol) was added to a stirred suspension of 6-chloro-pyridazin- 3-ylamine (20 g, 154.3 mmol) and sodium hydro gencarbonate (25.9 g, 308.8 mol) in methanol (500 ml). The mixture was stirred at room temperature for 16 h, then filtered. The filtrate was diluted with ethyl acetate and washed with a saturated solution of sodium thiosulfate, water and a saturated solution of sodium carbonate. The organic layer was separated, dried (NaGeneral procedure: To a solution of pyridazine derivative 5 or 6 (0.75 mmol) in MeOH (7 mL) was added NaHCOTo a solution of C2 (1.45g, 11.2mmol) in methanol (2OmL) was added NaHCOSodium bicarbonate (13.0 g, 155 mmol) and bromine (4.0 mL, 78 mmol) were added to a solution of 3-amino-6-chloropyridazine (10.0 g, 78 mmol) in methanol (150 mL) at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was filtered, and the solvent was evaporated. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with a 10percent aqueous sodium thiosulfate solution, an aqueous saturated sodium bicarbonate solution and a brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) to give the title compound (8.6 g, 53percent) as tan crystals. 1H NMR (400MHz, CDCl3) δ 5.35 (br s, 2H), 7.54 (s, 1H) .Step 1: To a solution of 6-chloropyridazin-3-amine (1.0 equiv) in MeOH (1M) at room temperature was added sodium bicarbonate (2.0 equiv.) and the resulting suspension was stirred at room temperature for 30 min before the dropwise addition of bromine (1.0 equiv.). The reaction mixture was stirred for 20 h. Upon concentration under vacuo, the crude residue was purified via silica gel column chromatography eluting with 100percent heptanes to 80percent ethyl acetate:heptanes to yield 4-bromo-6-chloropyridazin-3-amine in 50percent yield. LCMS (m/z) (M+H)=207.8/209.8, Rt=0.47 min. To a mixture of 3-amino-6-chloropyridazine (45.0 g, 347.0 mmol) and sodium bicarbonate (58.4 g, 695.0 mmol) in MeOH (1000.0 mL) was added bromine (55.5 g, 347.0 mmol) dropwise. The resultant mixture was stirred at room temp for 16 h and then filtered. Water (500.0 mL) was added to the filtrate and the solution was extracted with EtOAc. The organic layers were combined and concentrated in vacuo. The resulting residue was purified by flash chromatography to give 4-bromo-6-chloropyridazin-3- amine (35.0 g, 48.3percent). MS (ESI) calcd for CTo a solution of 6-chloropyridazin-3-amine (16 g, 0.124 mol, Preparation No.25) in methanol (200 mL) was added NaHCOExample I(1)[A] 4-Bromo-6-chloropyridazin-3-amine[0244][0245]To a stirred mixture solution of 6-chloropyridazin-3-amine (50 g 387.6 mmol) and NaHCOTo a solution of 6-Chloro-pyridazin-3-ylamine (4 g, 31 mmol) in methanol (60 mL) was added NaHCOs (5.2 g, 62 mmol). The reaction mixture was stirred for 30 minutes at RT then BrEXAMPLE 43;Tert-butyl 4-(8-(2-fluoro-4-(methylsulfonyl)phenylamino)imidazo[l, 2-b] pyridazin-3-yl)-5, 6-dihydropyridine-l(2H)-carboxylateStep 1: 4-Bromo-6-chloropyridazin-3 -amine[0368] A 500-ml round-bottomed flask was charged with a solution of 6- chloropyridazin-3-amine (90 g, 697.67 mmol, 1.00 equiv) in methanol (2500 ml) and sodium bicarbonate (117.2 g, 1.40 mol, 1.84 equiv). To this mixture was added BrTo a solution of 6-Chloro-pyridazin-3-ylamine (4 g, 31 mmol) in methanol (60 mL) was added NaHCOTo a solution of 6-chloropyridazin-3-amine (5.0 g, 38.6 mmol) in MeOH (200 mL) sodium bicarbonate (6.48 g, 77 mmol) was added and stirred at roomtemperature for 10 mm. Bromine (1.988 mL, 38.6 mmol) was added dropwise to the reaction mixture and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure at 30 ° C. To the residue was added water (150 mL) and the mixture stirred for 10 mm. The brown solid that precipitated out was collected by vacuum filtration and dried under vacuumovernight to afford 4-bromo-6-chloropyridazin-3-amine (3.75 g, 13.85 mmol, 36percent yield). LCMS (ESI) m/e 208.4; 210.4 (bromo pattern) [(M+H) , calcd for C4H4BrC1N3 208.01; LC/MS retention time (method B): tR = 0.58 mm.To a solution of A2 (284g, 2.19mol) in methanol (3.5L) was added NaHC0To a solution of A2 (284g, 2.19mol) in methanol (3.5L) was added NaHC0To a solution of A2 (284g, 2.19mol) in methanol (3.5L) was added NaHCO4-Bromo-6-chloropyridazin-3-amine Intermediate 1-11To a mixture of 3-amino-6-chloropyridazine (5 g, 38.59 mmol) and NaHC0

Molecular Weight:208.44
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:206.91989
Monoisotopic Mass:206.91989
Topological Polar Surface Area:51.8
Heavy Atom Count:9
Complexity:102
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes