1,2-Dichloroethane → 1-[7-fluoro-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-3-[(1R)-1-phenylethyl]urea

HRID 571402Notes

Reaction equation

HRID 571402 reaction equation
[F:1][C:2]1[C:3]2[N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:10]=[C:9]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[NH2:8].[C:38]([N:45]1[CH:49]=[CH:48]N=C1)(N1C=CN=C1)=[O:39].N1[CH:54]=[CH:53]N=C1.Cl[CH2:56][CH2:57]Cl.[CH3:59][CH2:60]OC(C)=O>C([O-])(O)=O.[Na+]>[F:1][C:2]1[C:3]2[NH:11][N:10]=[C:9]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[NH:8][C:38]([NH:45][C@@H:49]([C:57]1[CH:56]=[CH:54][CH:53]=[CH:60][CH:59]=1)[CH3:48])=[O:39]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 795ImidazoleHCID 8857Ethyl AcetateHCID 682631,1'-CarbonyldiimidazoleHCID 895259467-fluoro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine

Product 1

HCID 715550911-[7-fluoro-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-3-[(1R)-1-phenylethyl]ureaYield 37%

Reagents, catalysts & solvents 1

HCID 516892Sodium BicarbonateSolvent

Procedure

A flask was charged with the mono-TFA salt of 7-fluoro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (30.0 mg, 0.050 mmol), 1,1′-carbonyldiimidazole (48.7 mg, 0.30 mmol) and imidazole (17.0 mg, 0.25 mmol). The flask was put under an atmosphere of argon and 1,2-dichloroethane was injected (1 mL). The mixture was stirred 3 h at room temperature, warmed to 40° C. for 16 h, allowed to cool to room temperature and treated with (R)-methyl-benzylamine (0.1 mL). The reaction was stirred for 2 hours at room temperature and then diluted with 50% NaHCO3 (3 mL) and EtOAc (5 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was dissolved in a mixture of DCM, TFA and triethylsilane (3:2:0.1 mL). After 2 h the reaction was filtered, concentrated under reduced pressure and the crude residue was purified by MS-directed reverse phase preparative-HPLC (C-18 stationary phase, eluting with a H2O/MeCN gradient with 0.1% TFA) to yield 1-[7-fluoro-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-3-[(1R)-1-phenylethyl]urea as a white solid (9 mg, 0.019 mmol, 37%).

Workup

  1. temperaturewarmed to 40° C. for 16 h
  2. temperatureto cool to room temperature
  3. stirringThe reaction was stirred for 2 hours at room temperature
  4. customThe organic phase was separated
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. dissolutionThe resulting residue was dissolved in a mixture of DCM, TFA and triethylsilane (3:2:0.1 mL)
  9. filtrationAfter 2 h the reaction was filtered
  10. concentrationconcentrated under reduced pressure
  11. customthe crude residue was purified by MS-directed reverse phase preparative-HPLC (C-18 stationary phase
  12. washeluting with a H2O/MeCN gradient with 0.1% TFA)

Sources & evidence

ORD record
ord-af511fa8e7534f88b2b357928d42026a
Source dataset
uspto-grants-2015_05
Patent number
US09023865B2

Reaction notes

Loading…