Hydrochloric Acid → HCID 178505980, compound

HRID 1028454Notes

Reaction equation

HRID 1028454 reaction equation
CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl[C:44]1[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[C:46]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[Cl:60])[N:45]=1.[F:61][C:62]1[CH:63]=[C:64]2[C:70]([NH2:71])=[N:69][N:68](COCC[Si](C)(C)C)[C:65]2=[N:66][CH:67]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[Cl:60][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=1[C:46]1[N:45]=[C:44]([NH:71][C:70]2[C:64]3[C:65](=[N:66][CH:67]=[C:62]([F:61])[CH:63]=3)[NH:68][N:69]=2)[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=1

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 66878659HCID 66878659, compoundHCID 86650329HCID 86650329, compound

Product 1

HCID 178505980HCID 178505980, compoundYield 11.3%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent3×

Procedure

Xantphos (37.7 mg, 0.065 mmol) was added to Pd(OAc)2 (7.3 mg, 0.033 mmol) in dioxane (2 mL). After 3 min, this solution was added (with the aid of 1 mL dioxane) to a mixture of 2-chloro-6-(2-chlorophenyl)-4-(trifluoromethyl)pyridine (85.4 mg, 0.359 mmol), 5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-amine (92 mg, 0.326 mmol) and potassium carbonate (225 mg, 1.63 mmol) in dioxane (15 mL) under nitrogen. The reaction mixture was heated and stirred at reflux for 80 min. EtOAc was added, the solids were filtered off and the filtrate was concentrated. Purification by column chromatography (1/2 Petroleum ether/EtOAc) gave a residue that was dissolved in THF (2 mL) and treated with aq. HCl (2M, 8 mL). After 90 min at 100° C., the mixture was concentrated. The residue was partitioned between EtOAc and aq. sat. NaHCO3. The organic layer was separated, dried (MgSO4), filtered and concentrated. The residue was purified by Fractionlynx mass-directed prep. HPLC (with aq. TFA/MeCN mixtures) and the fractions passed through a bicarbonate Stratosphere cartridge. Concentration gave the aminopyridine (15 mg, 11%) as a white solid. 1H NMR (400 MHz, DMSO): 7.36 (1H, s), 7.48-7.51 (2H, m), 7.60-7.64 (2H, m), 8.31 (1H, s), 8.43 (1H, d), 8.56 (1H, s), 10.61 (1H, s), 13.17 (1H, s).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux for 80 min
  3. filtrationthe solids were filtered off
  4. concentrationthe filtrate was concentrated
  5. customPurification by column chromatography (1/2 Petroleum ether/EtOAc)
  6. customgave a residue that
  7. waitAfter 90 min at 100° C.
  8. concentrationthe mixture was concentrated
  9. customThe residue was partitioned between EtOAc and aq. sat. NaHCO3
  10. customThe organic layer was separated
  11. dry with materialdried (MgSO4)
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe residue was purified by Fractionlynx mass-directed prep
  15. concentrationConcentration

Sources & evidence

ORD record
ord-99de9ac0a4c645428217a57415cd1374
Source dataset
uspto-grants-2014_05
Patent number
US08735593B2

Reaction notes

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