Sodium Carbonate → N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-yl)-5-methylthiazol-2-amine

HRID 473176Notes

Reaction equation

HRID 473176 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.[CH3:64][C:65]1[S:69][C:68]([NH2:70])=[N:67][CH:66]=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:70][C:68]2[S:69][C:65]([CH3:64])=[CH:66][N:67]=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 3517702-Amino-5-methylthiazoleHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866626934-Chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline

Product 1

HCID 56848561N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-yl)-5-methylthiazol-2-amineYield 5%

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), 5-methylthiazol-2-amine (51 mg, 0.45 mmol), and Na2CO3 (48 mg, 0.45 mmol) was added toluene (3 mL). The mixture was evacuated and flushed with argon three times and then heated at 110° C. for 2 h. The mixture was diluted with MeOH, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O) to afford N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-yl)-5-methylthiazol-2-amine (6 mg, 5%). 1H NMR (300 MHz, DMSO-d6) δ 12.45 (br s, 1H), 8.64 (d, J=2.4 Hz, 2H), 7.88-8.15 (m, 4H), 7.66-7.76 (m, 1H), 7.19 (s, 1H), 2.28 (s, 3H). LCMS (ESI) m/z 388 (M+H)+.

Workup

  1. customThe mixture was evacuated
  2. customflushed with argon three times
  3. additionThe mixture was diluted with MeOH
  4. filtrationfiltered
  5. concentrationthe filtrate was concentrated under reduced pressure
  6. customThe residue was purified by preparative HPLC (Varian diphenyl reverse phase column
  7. washeluted with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O)

Sources & evidence

ORD record
ord-afc8f4360eda4364bb00340f8523a404
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

Loading…