1,2-Dichloroethane → 1-(1-Methylethyl)-N-{[6-methyl-4-(1-methylethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

HRID 475960Notes

Reaction equation

HRID 475960 reaction equation
[CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13](O)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:34])[NH:26][C:27]([CH3:33])=[CH:28][C:29]=1[CH:30]([CH3:32])[CH3:31].C(O)(C(F)(F)F)=O.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CCOC(C)=O.O.CN(C=O)C>[CH3:3][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:11]=[C:12]([C:13]([NH:22][CH2:23][C:24]3[C:25](=[O:34])[NH:26][C:27]([CH3:33])=[CH:28][C:29]=3[CH:30]([CH3:31])[CH3:32])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:1]

Participants

10

Reactant 6

HCID 111,2-DichloroethaneHCID 6422Trifluoroacetic acidHCID 79724-MethylmorpholineHCID 181649HOAtHCID 201146251-(1-Methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acidHCID 671243373-(aminomethyl)-4-isopropyl-6-methylpyridin-2(1H)-one

Product 1

HCID 565974311-(1-Methylethyl)-N-{[6-methyl-4-(1-methylethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamideYield 27%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A DMF solution (6 mL) of 1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (288 mg, 1.019 mmol), 3-(aminomethyl)-6-methyl-4-(1-methylethyl)-2(1H)-pyridinone.TFA (300 mg, 1.019 mmol), HOAT (208 mg, 1.529 mmol), EDC (782 mg, 4.08 mmol), and N-methylmorpholine (0.448 mL, 4.08 mmol) was stirred overnight at 40° C. After cooling to room temperature, the reaction mixture was poured into H2O (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAC (2×50 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DMSO and purified by reverse phase (15-40% ACN in H2O, 0.1% TFA). The product fractions were poured into sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a white solid (123 mg, 27% yield). LCMS E-S (M+H)=445.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (m, 6H), 1.56 (m, 6H), 2.17 (s, 3H), 3.17-3.28 (m, 1H), 4.45-4.56 (m, 2H), 5.29-5.43 (m, 1H), 5.99-6.12 (m, 1H), 8.16-8.23 (m, 2H), 8.24-8.29 (m, 1H), 8.40-8.46 (m, 1H), 8.71-8.82 (m, 2H), 8.96-9.04 (m, 1H), 11.53-11.63 (m, 1H).

Workup

  1. extractionThe aqueous layer was extracted with EtOAC (2×50 mL)
  2. dry with materialThe organic layers were dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. dissolutionThe residue was dissolved in DMSO
  6. custompurified by reverse phase (15-40% ACN in H2O, 0.1% TFA)
  7. additionThe product fractions were poured into sodium bicarbonate
  8. extractionextracted with ethyl acetate
  9. dry with materialThe organic layer was dried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-9b685f803b58496ca9aa656068caedc8
Source dataset
uspto-grants-2014_01
Patent number
US08637509B2

Reaction notes

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