Ethyl Acetate → 4-[6-Bromo-8-(methylsulfanyl)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzamide

HRID 925592Notes

Reaction equation

HRID 925592 reaction equation
[Br:1][C:2]1[N:3]=[C:4]([S:12][CH3:13])[C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:22]1([NH:25][C:26]([C:28]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=2)=[O:27])[CH2:24][CH2:23]1.C(OCC)(=O)C>C1COCC1.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]>[Br:1][C:2]1[N:3]=[C:4]([S:12][CH3:13])[C:5]2[N:6]([C:8]([C:31]3[CH:32]=[CH:33][C:28]([C:26]([NH:25][CH:22]4[CH2:23][CH2:24]4)=[O:27])=[CH:29][CH:30]=3)=[CH:9][N:10]=2)[CH:7]=1

Participants

8

Reactant 4

HCID 8857Ethyl AcetateHCID 62657Potassium Phosphate, TribasicHCID 2773359(4-(Cyclopropylcarbamoyl)phenyl)boronic acidHCID 575996096-Bromo-3-iodo-8-(methylthio)imidazo[1,2-a]pyrazine

Product 1

HCID 533898994-[6-Bromo-8-(methylsulfanyl)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzamideYield 56.26%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
45 °C

Procedure

To a stirred solution of intermediate example 3-1 6-bromo-3-iodo-8-methylsulfanyl-imidazo[1,2-a]pyrazine (25.00 g, 67.6 mmol) in THF (214 mL) and water (100 mL) was subsequently added 43 g tripotassium phosphate (203 mmol, 3 eq), 18.01 g [4-[(cyclopropylamino)carbonyl]phenyl]-boronic acid (87.8 mmol, 1.3 eq) and 5.52 g Pd(dppf)Cl2 (6.8 mmol, 0.1 eq) in one portion at rt under argon atmosphere. After stirring overnight at 45° C., ethyl acetate was added and the organic phase was washed with sat. sodium chloride solution, dried over sodium sulphate and filtered. After removal of the solvent, purification by flash chromatography (n-hexane/ethyl acetate 85:15) yielded 15.33 g (56.26%) 4-(6-bromo-8-methylsulfanyl-imidazo[1,2-a]pyrazin-3-yl)-N-cyclopropyl-benzamide: 1H-NMR (300 MHz, CDCl3): δ =8.07 (1H, s), 7.92 (2H, d), 7.77 (1H, s), 7.60 (2H, d), 6.32 (1H, bs), 2.95 (1H, m), 2.70 (3H, s), 0.92 (2H, m), 0.67 (2H, m) ppm. UPLC-MS: RT=1.12 min; m/z 404.3 [MH+]; required MW=403.3.

Workup

  1. customat rt
  2. washthe organic phase was washed with sat. sodium chloride solution
  3. dry with materialdried over sodium sulphate
  4. filtrationfiltered
  5. customAfter removal of the solvent, purification by flash chromatography (n-hexane/ethyl acetate 85:15)

Sources & evidence

ORD record
ord-07614bb77b474457a20330800c0b1b26
Source dataset
uspto-grants-2016_03
Patent number
US09284317B2

Reaction notes

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