Trifluoroacetic acid → 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide

HRID 1396351Notes

Reaction equation

HRID 1396351 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][C:15]([CH3:18])=[C:14]([CH3:19])[N:13]=2)[CH:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]1[NH:27]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O.C1CCCCC1>CN1CCCC1=O.ClCCl>[NH2:27][C@@H:22]1[C@H:21]([NH:20][C:2]2[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[N:13]=3)[CH:3]=2)[CH2:26][CH2:25][O:24][CH2:23]1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 8078CyclohexaneHCID 68077633tert-Butyl ((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamateHCID 866897206-Chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide

Product 1

HCID 716268236-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamideYield 12%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

6-Chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide (120 mg, 432 mmol) and tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (187 mg, 864 μmol) in N-methyl-2-pyrrolidinone (6 mL) was heated at 150° C. for 1.5 d. After solvent evaporation, the residue was dissolved in dichloromethane (2 mL) and TFA (370 mg, 250 μL, 3.24 mmol). The mixture was stirred at room temperature for 3 h, then the solvent was evaporated and the residue was purified by chromatography (spherical silica, 20-45 μm, 11 g, Versaflash from Supelco, 97:2.75:0.15 to 87:12.35:0.65 dichloromethane:MeOH:NH4OH, 20 min) to afford a brown solid. The brown solid was dissolved in dichloromethane and 10 mL of cyclohexane was added. After standing, a solid precipitate formed. The supernatant was decanted and the solid residue was dried under vacuum to give 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide (18 mg, 12% over two steps) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.23 (br. s., 1H) 8.29 (s, 1H) 8.03 (br. s., 1H) 7.36 (d, J=8.08 Hz, 1H) 6.67 (d, J=8.08 Hz, 1H) 5.68-5.79 (m, 1H) 5.39 (br. s., 1H) 4.02 (d, J=7.33 Hz, 1H) 3.88 (d, J=11.12 Hz, 1H) 3.69 (d, J=11.62 Hz, 1H) 3.55 (t, J=11.49 Hz, 1H) 3.10 (br. s., 1H) 2.49 (s, 3H) 2.25 (s, 3H) 2.02 (d, J=12.38 Hz, 1H) 1.42-1.84 (m, 3H); LCMS (EI/CI) m/z: 358 [M+H].

Workup

  1. customAfter solvent evaporation
  2. dissolutionthe residue was dissolved in dichloromethane (2 mL)
  3. customthe solvent was evaporated
  4. customthe residue was purified by chromatography (spherical silica, 20-45 μm, 11 g, Versaflash from Supelco, 97:2.75:0.15 to 87:12.35:0.65 dichloromethane:MeOH:NH4OH, 20 min)
  5. customto afford a brown solid
  6. customa solid precipitate formed
  7. customThe supernatant was decanted
  8. customthe solid residue was dried under vacuum

Sources & evidence

ORD record
ord-4e31a4e2de83484cb89019ad4685f730
Source dataset
uspto-grants-2014_12
Patent number
US08901124B2

Reaction notes

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