Sodium Carbonate → N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine

HRID 928099Notes

Reaction equation

HRID 928099 reaction equation
[CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[S:33][CH:32]=[N:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6]([C:29]2[S:33][CH:32]=[N:31][CH:30]=2)[CH:7]=1

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 5460595-BromothiazoleHCID 58456089N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine

Product 1

HCID 58456403N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (80 g, 211.08 mmol) in 1,4-dioxane (800 mL) was added 5-bromo-1,3-thiazole (28 g, 171.78 mmol), Pd(dppf)Cl2 (8 g, 10.62 mmol) and a solution of sodium carbonate (44.7 g, 421.70 mmol) in water (447 mL). The resulting solution was heated to reflux for 1 hour. Then it was allowed to cool to room temperature and was concentrated in vacuo. The residue was diluted with EtOAc (500 mL) and filtered. The filtrate was washed with brine (2×300 mL) and water (2×300 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was recrystallized from EtOAc:DCM in the ratio of 1:5 to afford a portion of product. The mother liquor was applied onto a silica gel column and eluted with dichloromethane/ethyl acetate (2:1) to afford N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine as a pale yellow solid. MS ESI calc'd for C15H12F3N4S [M+H]+ 337. found 337. 1H NMR (400 MHz, CD3COCD3) δ 9.21 (1H, s), 8.97 (1H, s), 8.84 (1H, d, J=4.8 Hz), 8.21 (2H, m), 7.64 (1H, s), 7.25-7.26 (2H, m), 2.41 (3H, s). rhSyk activity=+++.

Workup

  1. temperatureThe resulting solution was heated
  2. temperatureto reflux for 1 hour
  3. concentrationwas concentrated in vacuo
  4. additionThe residue was diluted with EtOAc (500 mL)
  5. filtrationfiltered
  6. washThe filtrate was washed with brine (2×300 mL) and water (2×300 mL)
  7. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  8. concentrationconcentrated in vacuo
  9. customThe crude product was recrystallized from EtOAc
  10. customDCM in the ratio of 1:5 to afford a portion of product
  11. washeluted with dichloromethane/ethyl acetate (2:1)

Sources & evidence

ORD record
ord-d09ca0ae411b4ab1bf31f669f0222583
Source dataset
uspto-grants-2016_03
Patent number
US09290490B2

Reaction notes

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