Isobutylamine → 4-{6-bromo-8-[(2-methylpropyl)amino]imidazo[1,2-a]pyrazin-3-yl}-2-chloro-N-cyclopropylbenzamide

HRID 925591Notes

Reaction equation

HRID 925591 reaction equation
[Br:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[C:34](=[O:39])[NH:35][CH:36]1[CH2:38][CH2:37]1>C1COCC1.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]([NH:20][CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]2[N:6]([C:8]([C:30]3[CH:31]=[CH:32][C:33]([C:34]([NH:35][CH:36]4[CH2:38][CH2:37]4)=[O:39])=[C:28]([Cl:27])[CH:29]=3)=[CH:9][N:10]=2)[CH:7]=1

Participants

7

Reactant 4

HCID 6558IsobutylamineHCID 11430Potassium CarbonateHCID 441196493-Chloro-4-(cyclopropylcarbamoyl)benzeneboronic acidHCID 715340426-Bromo-3-iodo-8-(methylsulfonyl)imidazo[1,2-a]pyrazine

Product 1

HCID 866985544-{6-bromo-8-[(2-methylpropyl)amino]imidazo[1,2-a]pyrazin-3-yl}-2-chloro-N-cyclopropylbenzamideYield 62.2%

Reagents, catalysts & solvents 2

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

Procedure

To a stirred solution of 6-bromo-3-iodo-8-methanesulfonyl-imidazo[1,2-a]pyrazine (4.02 g, 10 mmol) in THF (50 mL) was added 1.47 g isobutylamine (20 mmol, 2 eq) in one portion at rt. After stirring overnight, 30 mL 1M potassium carbonate solution (30 mmol, 3 eq), 3.72 g [3-chloro-4-(cyclopropylcarbamoyl)phenyl]boronic acid (15 mmol, 1.5 eq) and 0.81 g Pd(dppf)Cl2 (1 mmol, 0.1 eq) were subsequently added at rt. After stirring for 96 h at 65° C., the mixture was concentrated in vaccuo, taken up in ethyl acetate and washed with water. After drying over sodium sulphate and filtration, the solvent was evaporated. Purification by flash chromatography (ethyl acetate/hexane) yielded 1.88 g (62.20%) 4-{6-bromo-8-[(2-methylpropyl)amino]imidazo[1,2-a]pyrazin-3-yl}-2-chloro-N-cyclopropylbenzamide. 1H-NMR (300 MHz, d6-DMSO): δ=8.51 (1H, d), 8.11 (1H, t), 7.77 (1H, s), 7.74 (1H, s), 7.71 (1H, s), 7.64 (1H, d), 7.51 (1H, d), 3.23 (2H, t), 2.80 (1H, m), 1.99 (1H, m), 0.87 (6H, d), 0.67 (2H, m), 0.50 (2H, m) ppm. UPLC-MS: RT=1.33 min; m/z 463.8 [MH+]; required MW=462.8.

Workup

  1. stirringAfter stirring for 96 h at 65° C.
  2. concentrationthe mixture was concentrated in vaccuo
  3. washwashed with water
  4. dry with materialAfter drying over sodium sulphate and filtration
  5. customthe solvent was evaporated
  6. customPurification by flash chromatography (ethyl acetate/hexane)

Sources & evidence

ORD record
ord-09ca8399f4914a10b78f545e8f3195ec
Source dataset
uspto-grants-2016_03
Patent number
US09284317B2

Reaction notes

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