1-Hydroxybenzotriazole hydrate → N-(2,3-dimethylpyridin-4-yl)-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

HRID 1253536Notes

Reaction equation

HRID 1253536 reaction equation
[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]([OH:20])=O)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.[CH3:21][C:22]1[C:27]([CH3:28])=[C:26]([NH2:29])[CH:25]=[CH:24][N:23]=1.O.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C.CN(C)C1C=CN=CC=1.CS(C)=O.O>[CH3:21][C:22]1[C:27]([CH3:28])=[C:26]([NH:29][C:18]([C:17]2[CH:16]=[N:15][N:5]3[CH:6]=[C:7]([C:9]4[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=4)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=23)=[O:20])[CH:25]=[CH:24][N:23]=1

Participants

7

Reactant 3

HCID 27960291-Hydroxybenzotriazole hydrateHCID 73304712,3-Dimethylpyridin-4-amine2×HCID 584048684-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Product 1

HCID 58404727N-(2,3-dimethylpyridin-4-yl)-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolventHCID 23503278(Methanesulfinyl)methane--water (1/1)Solvent

Conditions

Temperature
60 °C

Procedure

4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (30.0 mg, 0.110 mmol), 2,3-dimethyl-pyridin-4-ylamine (26.9 mg, 0.220 mmol), N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (31.7 mg, 0.165 mmol), and 1H-1,2,3-benzotriazol-1-ol hydrate (16.9 mg, 0.110 mmol) were suspended in DMF (1 ml). Diispropylethylamine (0.058 ml, 0.331 mmol) was added and the reaction mixture was allowed to stir. After 2 h, N,N-dimethylpyridin-4-amine (13.5 mg, 0.110 mmol) was added and the mixture was stirred overnight. After 16 h, the reaction mixture was heated to 60° C. for 4 h, after which additional 2,3-dimethyl-pyridin-4-ylamine (26.9 mg, 0.220 mmol) was added and the mixture was heated to 70° C. overnight. The reaction mixture was diluted in DMSO/water and filter through a 45 μm filter. The filtrate was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA to give a solid that was contaminated with trace impurities. Additional purification by column chromatography on silica gel (methanol/ethyl acetate gradient) afforded (N-(2,3-dimethylpyridin-4-yl)-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide. 1H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H); 8.83 (s, 1H); 8.41 (s, 1H); 8.37 (s, 1H); 8.19 (d, 1H); 8.10 (s, 1H); 7.82 (d, 1H); 7.28 (s, 1H); 4.13 (s, 3H); 3.88 (s, 3H); 2.47 (s, 3H); 2.24 (s, 3H). LRMS (ESI) calculated for C20H21N6O2 [M+H]+, 377.2; found 377.2.

Workup

  1. additionDiispropylethylamine (0.058 ml, 0.331 mmol) was added
  2. stirringthe mixture was stirred overnight
  3. waitAfter 16 h
  4. temperaturethe mixture was heated to 70° C. overnight
  5. filtrationfilter through a 45 μm
  6. filtrationfilter
  7. customThe filtrate was purified by preparative HPLC Reverse phase (C-18)
  8. washeluting with Acetonitrile/Water+0.05% TFA
  9. customto give a solid
  10. customAdditional purification by column chromatography on silica gel (methanol/ethyl acetate gradient)

Sources & evidence

ORD record
ord-08a671cd3c2949a0bef7e527ec57a674
Source dataset
uspto-grants-2013_06
Patent number
US08455477B2

Reaction notes

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