Binap, (A+-)- → HCID 90041496, compound

HRID 523020Notes

Reaction equation

HRID 523020 reaction equation
[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][C:13]([CH3:18])=[C:14](Br)[N:15]=2)[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][C:13]([CH3:18])=[C:14]([NH:33][C:31]3[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=3)[N:15]=2)[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 634876Binap, (A+-)-HCID 47709901-methyl-1H-pyrazol-4-amineHCID 23676156Sodium t-butoxideHCID 90041146HCID 90041146, compound

Product 1

HCID 90041496HCID 90041496, compound

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (0.110 g, 0.25 mmol), 1-methyl-1H-pyrazol-4-ylamine 1.35-HCl salt (0.073 g, 0.5 mmol), tris(dibenzylideneacetone)dipalladium (0.011 g, 0.0125 mmol), racemic BINAP [rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl](0.023 g, 0.038 mmol) and sodium tert-butoxide (0.094 g, 0.98 mmol) in toluene (2½ mL), under an argon atmosphere, was heated and stirred in a sealed vessel at 110° C. for 18.5 h. The cooled reaction mixture was diluted with ethyl acetate, washed once with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica, 70% ethyl acetate in hexanes) gave 0.104 g of slightly impure 3-methyl-2-(1-methyl-1H-pyrazol-4-ylamino)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a yellow-brown solid. This material was combined with 0.022 g of partially purified product obtained from a separate, lower yielding, coupling reaction (palladium acetate was used in place of tris(dibenzylideneacetone)dipalladium), and purified by chromatography (silica, ethyl acetate) to give 3-methyl-2-(1-methyl-1H-pyrazol-4-ylamino)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (0.112 g) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.08 (s, 9H), 0.83 (t, J=8.2 Hz, 2H), 1.38 (s, 9H), 2.54 (s, 3H), 3.51 (t, J=8.2 Hz, 2H), 3.80 (s, 3H), 5.55 (s, 2H), 7.61 (s, 1H), 7.68 (s, 1H), 7.85 (s, 1H), 8.01 (s, 1H), 8.19 (s, 1H); MS (EI/CI) m/z: 458 [M+H].

Workup

  1. customThe cooled reaction mixture
  2. washwashed once with brine
  3. dry with materialdried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customPurification by chromatography (silica, 70% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-cc64551657eb4949a0b62572a7c844d3
Source dataset
uspto-grants-2016_05
Patent number
US09334278B2

Reaction notes

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