Hydrochloric Acid → 2-propyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amine

HRID 549242Notes

Reaction equation

HRID 549242 reaction equation
Cl.C(OC([NH:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].Br[C:26]1[C:27]([C:41]#[N:42])=[N:28][N:29]([CH2:38][CH2:39][CH3:40])[C:30]=1[CH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH2:38]([N:29]1[C:30]([CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[C:26]2[C:27]([C:41]([NH2:42])=[N:9][C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:28]1)[CH2:39][CH3:40]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 22135186(2-[(tert-Butoxycarbonyl)amino]pyridin-3-yl)boronic acidHCID 671583524-bromo-1-propyl-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carbonitrile

Product 1

HCID 119504992-propyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amineYield 24.3%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

Hydrochloric acid (10 mL of 1M) was added to a solution of 2-tert-butoxycarbonylamino-3-pyridylboronic acid (2.59 g, 10.9 mmol), and the resulting mixture was heated at 80° C. for 45 minutes and allowed to cool to room temperature. Potassium carbonate (3.87 g, 27.95 mmol) was added with stirring, and then DME (20 mL), 4-bromo-1-propyl-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carbonitrile (1.70 g, 5.44 mmol), and dichlorobis(triphenylphosphine)palladium(II) (190 mg, 0.27 mmol) were added. The flask was placed under vacuum and back-filled with nitrogen three times. The reaction was heated under a nitrogen atmosphere at 95° C. overnight. The reaction was allowed to cool to room temperature, and the volatiles were removed under reduced pressure. The residue was dissolved in chloroform (100 mL), and the resulting solution was washed with water (100 mL), dried over magnesium sulfate, filtered, and concentrated to yield a light yellow solid. The crude product was purified by automated flash chromatography (eluting with 0% to 30% CMA in chloroform) followed by recrystallization from acetonitrile (30 mL). The crystals were washed with cold acetonitrile and dried overnight in a vacuum oven at 60° C. to provide 0.43 g of 2-propyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amine as white needles, mp 252-255° C.

Workup

  1. temperatureto cool to room temperature
  2. additionback-filled with nitrogen three times
  3. temperatureThe reaction was heated under a nitrogen atmosphere at 95° C. overnight
  4. temperatureto cool to room temperature
  5. customthe volatiles were removed under reduced pressure
  6. dissolutionThe residue was dissolved in chloroform (100 mL)
  7. washthe resulting solution was washed with water (100 mL)
  8. dry with materialdried over magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto yield a light yellow solid
  12. customThe crude product was purified by automated flash chromatography (eluting with 0% to 30% CMA in chloroform)
  13. customfollowed by recrystallization from acetonitrile (30 mL)
  14. washThe crystals were washed with cold acetonitrile
  15. customdried overnight in a vacuum oven at 60° C.

Sources & evidence

ORD record
ord-b08f305585524a61ba56cfa2cc85083e
Source dataset
uspto-grants-2011_05
Patent number
US07943636B2

Reaction notes

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