Sodium Carbonate → HCID 178505732, compound

HRID 473177Notes

Reaction equation

HRID 473177 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:21])([F:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[N:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[NH:64]1[CH:68]=[N:67][C:66]([NH2:69])=[N:65]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:4]1[N:3]=[C:2]([NH:69][C:66]2[N:67]=[CH:68][NH:64][N:65]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1

Participants

6

Reactant 4

HCID 10340Sodium CarbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866626934-Chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolineHCID 178418311HCID 178418311, compound

Product 1

HCID 178505732HCID 178505732, compoundYield 14%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

To a mixture of 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline from Example 4 Step A (100 mg, 0.32 mmol), Pd2(dibenzylideneacetone)3 (12 mg, 0.013 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 0.04 mmol), SEM protected 1,2,4-triazol-3-amine (97 mg, 0.45 mmol), and Na2CO3 (48 mg, 0.45 mmol) was added toluene (3 mL), and the mixture was evacuated and flushed with argon three times. The mixture was heated at 110° C. for 2 h, and then diluted with DCM and filtered. To the filtrate was added TFA (3 mL) and the mixture was stirred at rt for 2 h and then concentrated under reduced pressured. To the residue was added MeOH and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex C-18 reverse phase column eluting with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O). The obtained material was triturated with diethyl ether to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(1H-1,2,4-triazol-3-yl)quinazolin-4-amine (16 mg, 14%). 1H NMR (300 MHz, methanol-d4) δ 8.68 (br s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.90-8.15 (m, 4H), 7.71-7.88 (m, 2H). LCMS (ESI) m/z 358 (M+H)+.

Workup

  1. customthe mixture was evacuated
  2. customflushed with argon three times
  3. additiondiluted with DCM
  4. filtrationfiltered
  5. additionTo the filtrate was added TFA (3 mL)
  6. concentrationconcentrated under reduced pressured
  7. additionTo the residue was added MeOH
  8. concentrationthe mixture was concentrated under reduced pressure
  9. customThe residue was purified by preparative HPLC (Phenomenex C-18 reverse phase column
  10. washeluting with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O)
  11. customThe obtained material was triturated with diethyl ether

Sources & evidence

ORD record
ord-173d6f475df44c1ca8d6e9c1aee166c0
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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