2-bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide → N-isopropyl-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

HRID 246354Notes

Reaction equation

HRID 246354 reaction equation
Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH3:25][N:26]1[C:34]2[CH2:33][C:32]([CH3:36])([CH3:35])[CH2:31][CH2:30][C:29]=2[C:28]([Sn](CCCC)(CCCC)CCCC)=[N:27]1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:29]4[CH2:30][CH2:31][C:32]([CH3:35])([CH3:36])[CH2:33][C:34]=4[N:26]([CH3:25])[N:27]=3)[N:3]=2)[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1)=[O:12])([CH3:16])[CH3:15]

Participants

6

Reactant 2

HCID 585222792-bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideHCID 712794751,6,6-trimethyl-3-tributylstannanyl-4,5,6,7-tetrahydro-1H-indazole

Product 1

HCID 71279665N-isopropyl-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideYield 70%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

2-Bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (107 mg, 259 μmol) and 1,6,6-trimethyl-3-(tributylstannyl)-4,5,6,7-tetrahydro-1H-indazole (see Example 70, 188 mg, 414 μmol.6) were dissolved in DMF (2.5 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (15.0 mg, 12.9 μmol) and CuI (4.64 mg, 51.8 μmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 2.5 h. The reaction mixture was concentrated under high vacuum and the residue was purified by chromatography (silica, 40 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 15 min) to give N-isopropyl-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (90 mg, 181 μmol, 70.0%) as a light yellow solid and of approximately 75% purity. MS (M+H)+=497.1; 1H NMR (CDCl3) δ: 9.10 (s, 1H), 8.26 (s, 1H), 8.18 (d, J=7.9 Hz, 1H), 5.68 (s, 2H), 4.34-4.60 (m, 1H), 3.82 (s, 3H), 3.48-3.61 (m, 2H), 3.03 (t, J=6.2 Hz, 2H), 2.41 (s, 2H), 1.61 (t, J=6.4 Hz, 2H), 1.33 (d, J=6.8 Hz, 6H), 1.09 (s, 6H), 0.83-0.97 (m, 2H), −0.06 (s, 9H). NMR and LCMS showed an impurity that was identified as the dimer of the tetrahydroindazole (MW 326.49) linked at the 3-position.

Workup

  1. customthe mixture sonicated for 5 min with bubbling argon
  2. concentrationThe reaction mixture was concentrated under high vacuum
  3. customthe residue was purified by chromatography (silica, 40 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 15 min)

Sources & evidence

ORD record
ord-bc6f5c6edfca41e58f5b3510a37d59a4
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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