Binap, (A+-)- → N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

HRID 522978Notes

Reaction equation

HRID 522978 reaction equation
Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[O:12])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.Cl.[CH3:28][N:29]1[CH:33]=[C:32]([NH2:34])[CH:31]=[N:30]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:16][CH2:15][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:34][C:32]3[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=3)[N:3]=2)[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:12])([CH3:18])[CH3:17]

Participants

9

Reactant 4

HCID 634876Binap, (A+-)-HCID 173542681-methyl-1H-pyrazol-4-amineHCID 23676156Sodium t-butoxideHCID 715756472-Bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

Product 1

HCID 90041492N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideYield 18%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
140 °C

Procedure

A mixture of 2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 338 mol), 1-methyl-1H-pyrazol-4-amine hydrochloride (67.8 mg, 526 mol), BINAP (10.5 mg, 16.9 mol), palladium (II) acetate (19.0 mg, 84.6 mol) and sodium tert-butoxide (81.3 mg, 846 mol) in DMF (1 mL) and toluene (500 L) was heated in a microwave at 140° C. for 20 min. The reaction mixture was diluted with water then extracted into ethyl acetate (3×). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (silica, 20-65% of a 10:89.5:0.5 methanol:dichloromethane:ammonium hydroxide solution in dichloromethane) gave N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (28 mg, 60.9 mol, 18%) as a light yellow solid. (EI/CI) m/z: 460.3 [M+H].

Workup

  1. extractionthen extracted into ethyl acetate (3×)
  2. washThe combined organic extracts were washed with brine
  3. dry with materialthen dried over magnesium sulfate
  4. customPurification by chromatography (silica, 20-65% of a 10:89.5:0.5 methanol:dichloromethane:ammonium hydroxide solution in dichloromethane)

Sources & evidence

ORD record
ord-fab7d7c85f1a479488c3009e3e726bf7
Source dataset
uspto-grants-2016_05
Patent number
US09334278B2

Reaction notes

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