Binap, (A+-)- → HCID 90041121, compound

HRID 523022Notes

Reaction equation

HRID 523022 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].Cl.[CH3:28][C:29]1[CH:33]=[C:32]([NH2:34])[S:31][N:30]=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:34][C:32]3[S:31][N:30]=[C:29]([CH3:28])[CH:33]=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 27239183-Methylisothiazol-5-ylamine hydrochlorideHCID 23676156Sodium t-butoxideHCID 90041146HCID 90041146, compound

Product 1

HCID 90041121HCID 90041121, compoundYield 43%

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 (0.221 g, 0.5 mmol), 3-methyl-isothiazol-5-ylamine hydrochloride (0.151 g, 1 mmol), tris(dibenzylideneacetone)dipalladium (0.023 g, 0.025 mmol), racemic BINAP [rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl](0.047 g, 0.075 mmol) and sodium tert-butoxide (0.144 g, 1.5 mmol) in toluene (3.5 mL), under an argon atmosphere, was heated and stirred in a sealed vessel at 110° C. for 19 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, 75% ethyl acetate in hexanes, then repeated with 50% ethyl acetate in hexanes, and again with 40% ethyl acetate I hexanes) gave 3-methyl-2-(3-methyl-isothiazol-5-ylamino)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (0.101 g, 43%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.08 (s, 9H), 0.84 (t, J=8.0 Hz, 2H), 1.55 (s, 9H), 2.35 (s, 3H), 2.67 (s, 3H), 3.53 (t, J=8.0 Hz, 2H), 5.61 (s, 2H), 6.94 (s, 1H), 7.34 (s, 1H), 8.25 (s, 1H), 10.49 (s, 1H). MS (EI/CI) m/z: 475 [M+H].

Workup

  1. temperatureunder an argon atmosphere, was heated
  2. customThe cooled reaction mixture
  3. washwashed once with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customPurification by chromatography (silica, 75% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-ebcde746096e4e62910fc7ec495c7895
Source dataset
uspto-grants-2016_05
Patent number
US09334278B2

Reaction notes

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