Trifluoroacetic acid → 6-((3R,4R)-3-amino-tetrahydropyran-4-ylamino)-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide

HRID 1396336Notes

Reaction equation

HRID 1396336 reaction equation
[C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)[CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13]1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 86689706tert-butyl (3R,4R)-4-(6-carbamoyl-5-(6-methylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate

Product 1

HCID 716268186-((3R,4R)-3-amino-tetrahydropyran-4-ylamino)-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amideYield 28.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

tert-butyl (3R,4R)-4-(6-carbamoyl-5-(6-methylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (60 mg, 83% pure, 0.112 mmol) was dissolved in dichloromethane (0.85 mL) and cooled to 0° C. Trifluoroacetic acid (0.35 mL, 4.49 mmol) was added drop-wise, then the mixture was warmed to room temperature. After 3 h, the mixture was concentrated in vacuo then water, sodium bicarbonate solution and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate. Sodium chloride was added to the aqueous layer and it was further extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by chromatography (silica, 0-10% methanol in dichloromethane) gave 6-((3R,4R)-3-amino-tetrahydropyran-4-ylamino)-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (11 mg, 28%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.61 (s, 1H) 8.39 (br. s., 1H) 8.12 (s, 1H) 7.65 (br. s., 1H) 7.60 (t, J=7.7 Hz, 1H) 6.95 (d, J=7.2 Hz, 1H) 6.85 (d, J=7.6 Hz, 1H) 6.75 (d, J=8.3 Hz, 1H) 4.10 (br. s., 1H) 3.79-3.89 (m, 1H) 3.66-3.75 (m, 1H) 3.49-3.57 (m, 1H) 3.37-3.47 (m, 1H) 3.00-3.08 (m, 1H) 1.94-2.12 (m, 1H) 1.76-1.92 (m, 1H) 1.63-1.73 (m, 1H). MS (EI/CI) m/z: 344 [M+H].

Workup

  1. temperaturethe mixture was warmed to room temperature
  2. concentrationthe mixture was concentrated in vacuo
  3. additionwater, sodium bicarbonate solution and ethyl acetate were added
  4. extractionThe aqueous phase was extracted with ethyl acetate
  5. additionSodium chloride was added to the aqueous layer and it
  6. extractionwas further extracted with ethyl acetate
  7. washThe combined organic extracts were washed with saturated aqueous sodium chloride solution
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customPurification by chromatography (silica, 0-10% methanol in dichloromethane)

Sources & evidence

ORD record
ord-5a736a2fd8434d6eb56aee2a21236cea
Source dataset
uspto-grants-2014_12
Patent number
US08901124B2

Reaction notes

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