4-Methylmorpholine → tert-butyl 1-(3-chloro-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate

HRID 1775054Notes

Reaction equation

HRID 1775054 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:10]=2)=[N:6][C:7]=1F.[C:32]([NH:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].CN1CCOCC1.CN1CCCC1=O>CCOC(C)=O>[Cl:1][C:2]1[C:7]([N:43]2[CH2:42][CH2:41][CH:40]([NH:39][C:32](=[O:33])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:45][CH2:44]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:10]=2)=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 13387N-methyl-2-pyrrolidoneHCID 7238334-(N-Boc-amino)piperidineHCID 71253589HCID 71253589, compound

Product 1

HCID 71253367tert-butyl 1-(3-chloro-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

In a pressure tube was charged with 3-(5-chloro-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (103.4 mg, 0.2268 mmol), 4-(N-Boc-amino)-piperidine (136.24 mg, 0.6803 mmol), 4-Methylmorpholine (249.30 uL, 10 mmol), and N-Methylpyrrolidinone (3 mL). The mixture was heated at 120° C. overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed 3 times with water. The organic layer was dried with MgSO4, and then concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in DCM to afford tert-butyl 1-(3-chloro-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate. It was dissolved in 1,4-Dioxane (5 mL) and treated with 4.0 M of Hydrogen chloride in 1,4-Dioxane (5 mL) overnight. The mixture was concentrated, and the residue was purified by reverse phase HPLC to afford 241 as an off-white solid (8.7 mg, 19%). 1H NMR (400 MHz, DMSO) δ 9.24 (d, J=10.3 Hz, 2H), 8.99 (s, 1H), 8.61 (s, 1H), 8.42 (d, J=7.5 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.56 (d, J=4.4 Hz, 1H), 3.99 (d, J=12.0 Hz, 2H), 3.09 (d, J=12.4 Hz, 3H), 1.94 (d, J=11.6 Hz, 2H), 1.56 (d, J=11.1 Hz, 2H). ESI MS m/z=406.1 (M+1)

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. washwashed 3 times with water
  3. dry with materialThe organic layer was dried with MgSO4
  4. concentrationconcentrated
  5. customThe residue was purified on silica
  6. washeluted with 0 to 100% EtOAc in DCM

Sources & evidence

ORD record
ord-94bc8cd020c546e2b2f385b480e1f5dc
Source dataset
uspto-grants-2016_02
Patent number
US09260425B2

Reaction notes

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