4-tert-Butyl-3,6-dichloropyridazine

Colourless Oil

Synthesis of Compound J.1. A flask was charged with 3, 6-dichloropyridazine (1.49 g, 0.01 mol, 1.0 equiv), silver nitrate (0.17 g, 0.001 mol, 0.1 equiv), water (30 mL), pivalic acid (3.57 g, 0.035 mol, 3.5 equiv), and sulfuric acid (1.6 mL, 0.03 mol, 3.0 equiv). The mixture was heated to 70° C. and a solution of ammonium persulfate (2.28 g, 0.01 mol, 1.0 equiv) in water (10 mL) was added dropwise over ten minutes. The reaction was stirred at 70° C. for one hour and then cooled to RT. The reaction mixture was poured into ice water and then adjusted to pH 8 with aqueous ammonium hydroxide. The aqueous mixture was extracted with CHA flask was charged with 3, 6-dichloropyridazine (1.49 g, 0.01 mol, 1.0 equiv), silver nitrate (0.17 g, 0.001 mol, 0.1 equiv), water (30 mL), pivalic acid (3.57 g, 0.035 mol, 3.5 equiv), and sulfuric acid (1.6 mL, 0.03 mol, 3.0 equiv). The mixture was heated to 70° C. and a solution of ammonium persulfate (2.28 g, 0.01 mol, 1.0 equiv) in water (10 mL) was added dropwise over ten minutes. The reaction was stirred at 70° C. for one hr and then cooled to RT. The reaction mixture was poured into ice water and then adjusted to pH 8 with aqueous ammonium hydroxide. The aqueous mixture was extracted with CHa Synthesis of Compound J.1. A flask was charged with 3, 6-dichloropyridazine (1.49 g, 0.01 mol, 1.0 equiv), silver nitrate (0.17 g, 0.001 mol, 0.1 equiv), water (30 mL), pivalic acid (3.57 g, 0.035 mol, 3.5 equiv), and sulfuric acid (1.6 mL, 0.03 mol, 3.0 equiv). The mixture was heated to 70° C. and a solution of ammonium persulfate (2.28 g, 0.01 mol, 1.0 equiv) in water (10 mL) was added dropwise over ten minutes. The reaction was stirred at 70° C. for one hour and then cooled to RT. The reaction mixture was poured into ice water and then adjusted to pH 8 with aqueous ammonium hydroxide. The aqueous mixture was extracted with CHA flask was charged with 3, 6-dichloropyridazine (1.49 g, 0.01 mol, 1.0 equiv), silver nitrate (0.17 g, 0.001 mol, 0.1 equiv), water (30 mL), pivalic acid (3.57 g, 0.035 mol, 3.5 equiv), and sulfuric acid (1.6 mL, 0.03 mol, 3.0 equiv). The mixture was heated to 70° C. and a solution of ammonium persulfate (2.28 g, 0.01 mol, 1.0 equiv) in water (10 mL) was added dropwise over ten minutes. The reaction was stirred at 70° C. for one hr and then cooled to RT. The reaction mixture was poured into ice water and then adjusted to pH 8 with aqueous ammonium hydroxide. The aqueous mixture was extracted with CHa Preparation 6 3, 6-dichloro-4-t-butylpyridazine A 375 g. portion of 3, 6-dichloropyridazine was slurried with 578 g. of pivalic acid in 367 g. of sulfuric acid and 1500 ml. of water, and the mixture was warmed to 40. Then 48.2 g. of silver nitrate was added, and the mixture was heated to 62. To it was added 1 kg. of ammonium persulfate in 2 liters of water over a period of 1 hour. The temperature rose exothermically, and was controlled at 80 maximum. After the addition, the mixture was stirred for 15 minutes, and was then cooled to 15 with an ice-water bath. The mixture was then cooled further by the addition of ice, and its pH was adjusted to 9 with ammonium hydroxide. It was then stirred vigorously for 1 hour, while gummy material was scraped from the sides of the vessel as needed. It was then filtered, and the solids were washed with 2 liters of water and dried on the filter pad. The solids were then slurried in 5 liters of diethyl ether and the slurry was filtered. The filtrate was washed three times with 500 ml. portions of 1N sodium hydroxide, and the washes were combined and extracted with 500 ml. of diethyl ether. That ether was combined with the first ether filtrate, and was washed with 500 ml. of brine. The organic layer was dried over magnesium sulfate and carbon treated at the reflux temperature. It was then cooled and filtered through diatomaceous earth, and the filtrate was evaporated under vacuum to obtain 449 g. of the desired intermediate.EXAMPLE 10 3, 6-dichloro-4-(1-iodomethyl-1-methylethyl)pyridazine A 10.3 g. portion of the product of Preparation 6 was combined with 11.25 g. of N-iodosuccinimide and 100 mg. of benzoyl peroxide in 500 ml. of carbon tetrachloride, and the mixture was irradiated with a 250-watt infrared lamp about 15 cm. from the Pyrex flask. The mixture was stirred under gentle reflux for about 1.25 hours, and then 10 drops of sulfuryl chloride were added. After 2.25 hours, 20 drops more of sulfuryl chloride were added, and reflux was continued. After 4.5 hours, a second lamp of the same type was also placed 15 cm. from the flask. After 7.25 hours, another 5 g. of N-iodosuccinimide was added and reaction was continued for a total of 25 hours, when the mixture was cooled and filtered.EXAMPLE 8 3, 6-dichloro-4-(1-chloromethyl-2-chloro-1-methylethyl)pyridazine Two g. of the product of Preparation 6 above was combined with 2.6 g. of sulfuryl chloride and 50 mg. of benzoyl peroxide in 2.5 ml. of carbon tetrachloride, and the mixture was stirred with irradiation from a 250-watt infrared reflector lamp for 2 hours. Then 0.66 g. of additional sulfuryl chloride was added, and the reaction was continued for another 2 hours. The mixture was then evaporated under vacuum to obtain 2.3 g. of oil, which was chromtographed by high performance liquid chromatography, eluding with 9:1 heptane:ethyl acetate. About 0.9 g. of the desired product in impure form was collected, and was re-chromatographed with 19:1 heptane:ethyl acetate. About 0.6 g. of impure product was obtained, which was re-treated with 0.67 g. of sulfuryl chloride and benzoyl peroxide, with irradiation as before.3, 6-dichloro-4-(1-chloromethyl-2, 2-dichloro-1-methylethyl)pyridazine Fifty g. of the product of Preparation 6 above was combined with 99 g. of sulfuryl chloride and 25 mg. of benzoyl peroxide in 125 ml. of carbon tetrachloride, and the mixture was irradiated with an infrared lamp as described in the examples above. After 20 hours, an additional 99 g. of sulfuryl chloride was added, and irradiation was continued for 7 hours more.Cs2C03 (1.023 g, 3.14 mmol), XantPhos (0.191 g, 0.33 mmol) and pyrazin-2- amine (0.149 g, 1.57 mmol) were placed under an argon atmosphere. Intermediate 1 (0.321 g, 1.57 mmol) was added as a solution in 1 , 4-dioxane (8 mL). The reaction mixture was degassed and placed under an argon atmosphere. Pd2(dba)3 (0.0137 g, 0.15 mmol) was added and the reaction mixture heated to 101 C for 5.5 h. After cooling the reaction mixture was poured into water (15 mL) and extracted with CH2CI2 (30 mL) twice. The combined organic fractions were dried over MgS04, filtered and the solvent removed by evaporation in vacuo. Purification by trituration with EtOAc yielded intermediate 2 (0.172 g, 42%). (1656) LCMS (ESI): Found 264.1 [M+Hf.PREPARATION A N'-[4-[[6-Chloro-5-(1, 1-dimethylethyl)-3-pyridazinyl]oxy]phenyl]-N, N-dimethylurea A solution of 5.23 grams (g) (0.029 mole) of N'-(4-hydroxyphenyl)-N, N-dimethylurea in 125 milliliters (ml) of ethanol was added to a solution of 0.607 g (0.0264 mole) of sodium metal in 100 ml of 2B ethanol. The resulting mixture was concentrated to an oil, then diluted with benzene, and reconcentrated. The sodium salt obtained was dissolved in about 70 ml of DMSO and was added dropwise to a solution of 4.92 g (0.024 mole) of 3, 6-Dichloro-4-(1, 1-dimethylethyl)pyridazine Maintaining the temperature at 70, a solution of 2.28 grams (g) (0.01 mole, 1.0 equivalent) of ammonium peroxydisulfate in 10 milliliters (ml) of water was added dropwise with stirring over a 10-minute period to a mixture of 1.49 g (0.01 mole) of 3, 6-dichloropyridazine, 0.17 g (0.001 mole, 0.1 equivalent) of silver nitrate, 3.57 g (0.035 mole, 3.5 equivalents) of pivalic acid and 2.94 g (0.03 mole, 3.0 equivalents) of sulfuric acid in 30 ml of water. After the addition was completed, the mixture was kept at 70 for an additional hour and then poured on to ice-water. The pH of the solution was adjusted to 8 with concentrated ammonium hydroxide. After extraction with two 250-ml portions of methylene chloride, the resulting organic layers were combined, filtered, washed with 70 ml of 1N sodium hydroxide, and then dried with magnesium sulfate. Concentration afforded 1.9 g of an oil. This oil was purified over silica using a 80 to 20 ratio of hexanes to ethyl ether as the eluent. The product weighed 1.5 g (73%) and had a melting point (MP) of 37-40. Nuclear magnetic resonance (NMR), infrared (IR), and mass spectra were consistent with the structure of the desired product. The following elemental analysis was obtained: Calculated for C8 H10 Cl2 N2: Theory: C, 46.85; H, 4.91; N, 13.66; Cl, 34.57. Found: C, 46.73; H, 5.02; N, 13.38; Cl, 34.55.3-[6-Chloro-5-(1, 1-dimethylethyl)-3-pyridazinyl]-1-methyl-2-imidazolidinone Under a nitrogen purge, 0.3 g (0.0075 moles) of sodium hydride was washed twice with 10-ml portions of hexane. Twenty ml of toluene was added, followed by 0.75 g (0.0075 moles) of 1-methyl-2-imidazolidinone. After 15 minutes, 1.0 g (0.005 mole) of Synthesis of Compound J.2. To a solution of compound J.1 (1.32 g, 0.006 mol) in EtOH (1 mL) was added 50% aqueous ammonium hydroxide (10 mL). The reaction mixture was stirred at 140 C. for 19 hr, then additional aqueous ammonium hydroxide (10 mL) was added and the mixture was stirred at 130 C. for one hour. After cooling to RT, the reaction mixture was concentrated under reduced pressure and the resultant residue was suspended in water. The solid was filtered, washed with water and Et2O, and dried to afford compound J.2 as a peach solid (0.27 g, 23%). 1H NMR: (CDCl3) delta 7.01 (s, 1H), 1.5 (s, 9H); MS: m/z 186.1 [M+1]+.To a solution of compound J.1 (1.32 g, 0.006 mol) in EtOH (1 mL) was added 50% aqueous ammonium hydroxide (10 mL). The reaction mixture was stirred at 140 C. for 19 hr, then additional aqueous ammonium hydroxide (10 mL) was added and the mixture was stirred at 130 C. for one hr. After cooling to rt, the reaction mixture was concentrated under reduced pressure and the resultant residue was suspended in water. The solid was filtered, washed with water and Et2O, and dried to afford compound J.2 as a peach solid (0.27 g, 23%). 1H NMR: (CDCl3) delta 7.01 (s, 1 H), 1.5 (s, 9 H); LCMS: m/z 186.1 [M+1]+.Reference Example 66 Production of 3-amino-5-t-butyl-6-chloropyridazine Using 31.1 g of

Molecular Weight:205.08
XLogP3:3.4
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:204.0221037
Monoisotopic Mass:204.0221037
Topological Polar Surface Area:25.8
Heavy Atom Count:12
Complexity:156
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes