Water → tert-butyl (3R,4R)-4-(6-carbamoyl-5-(6-methylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate

HRID 1396335Notes

Reaction equation

HRID 1396335 reaction equation
Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:3]=1.[NH2:19][C@@H:20]1[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(N(CC)C(C)C)(C)C.O>O1CCOCC1.C(OCC)(=O)C>[C:29]([O:28][C:27](=[O:33])[NH:26][C@@H:21]1[C@H:20]([NH:19][C:2]2[N:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)[CH:3]=2)[CH2:25][CH2:24][O:23][CH2:22]1)([CH3:32])([CH3:30])[CH3:31]

Participants

7

Reactant 4

HCID 962WaterHCID 81531Diisopropylethylamine2×HCID 68077633tert-Butyl ((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamate2×HCID 866897076-Chloro-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide

Product 1

HCID 86689706tert-butyl (3R,4R)-4-(6-carbamoyl-5-(6-methylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamateYield 23.7%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
150 °C

Procedure

6-Chloro-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (150 mg, 0.57 mmol) and tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (185 mg, 0.85 mmol) were dissolved in 1,4-dioxane (2.8 mL) and N,N-diisopropylethylamine (0.25 mL, 1.4 mmol). The reaction mixture was stirred at 150° C. for 4 d. Further tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (50 mg, 0.23 mmol) and N,N-diisopropylethylamine (0.04 mL, 0.23 mmol) was added in four portions (every 36 h for 144 h). The mixture was cooled, and then water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After concentration, the residue was purified by chromatography (silica, 0 to 7% methanol in dichloromethane) to give {(3R,4R)-4-[6-carbamoyl-5-(6-methyl-pyridin-2-ylamino)-pyridazin-3-ylamino]-tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester (60 mg, 18%) as a clear amorphous residue. This was 83% pure and was used directly without further purification. MS (EI/CI) m/z: 444 [M+H].

Workup

  1. temperatureThe mixture was cooled
  2. extractionThe aqueous layer was extracted with ethyl acetate
  3. washthe combined organic layers were washed with sodium chloride solution
  4. dry with materialdried over sodium sulfate
  5. concentrationAfter concentration
  6. customthe residue was purified by chromatography (silica, 0 to 7% methanol in dichloromethane)

Sources & evidence

ORD record
ord-40e947aaa02441078a9d05ad414ad005
Source dataset
uspto-grants-2014_12
Patent number
US08901124B2

Reaction notes

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