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

HRID 246443Notes

Reaction equation

HRID 246443 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.C(C1CN(C(=O)[C@H](NC(C2C3C(=NC=C([C:46]4[C:54]5[C:49](=[CH:50][C:51]([Cl:55])=[CH:52][CH:53]=5)[N:48](C)[N:47]=4)N=3)NC=2)=O)C)C1)#N>CN(C=O)C.C(OCC)(=O)C.[Cl-].[NH4+].[Cu]I.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>[Cl:55][C:51]1[CH:50]=[C:49]2[C:54]([C:46]([C:2]3[N:3]=[C:4]4[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]4=[N:6][CH:7]=3)=[N:47][NH:48]2)=[CH:53][CH:52]=1

Participants

8

Reactant 2

HCID 585222792-bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideHCID 712886022-(6-chloro-1-methylindazol-3-yl)-N-[(2R)-1-(3-cyanoazetidin-1-yl)-1-oxopropan-2-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

Product 1

HCID 712803652-(6-chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideYield 23.6%

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred solution of 2-bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (289 mg, 700 μmol) and 6-chloro-3-(tributylstannyl)-1H-indazole (see Example 4, 2.01 g, 4.55 mmol) in DMF at 20° C. was added copper(I) iodide (25.1 mg, 280 μmol) and then the mixture degassed with bubbling Argon for 15 min. Tetrakis(triphenylphosphine)palladium(0) (80.9 mg, 70.0 μmol) was added then the reaction mixture was heated to 80° C. After 15 h the mixture was cooled and diluted with ethyl acetate and saturated aqueous saturated ammonium chloride solution. The organic layer was separated and washed with brine, then dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by chromatography (silica, 40 g Analogix column, 20-50% ethyl acetate in hexanes, gradient over 15 min) to give 2-(6-chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.080 g) as a light brown oil. This was approximately 75% pure by 1H NMR with a single, major impurity tentatively assigned as 6,6′-dichloro-1H,1′H-[3,3′]biindazolyl and was used directly in the next step without further purification. MS (M−H)−=483; 1H NMR (CDCl3) δ: 8.41 (s, 1H), 8.35 (s, 1H), 8.07 (br. s, 1H), 7.64-7.77 (m, 2H), 7.52 (s, 1H), 7.16 (d, J=8.7 Hz, 1H), 5.64 (s, 2H), 4.23-4.47 (m, 1H), 3.45-3.58 (m, 2H), 1.34 (d, J=6.4 Hz, 6H), 0.93 (s, 2H), −0.05 (s, 9H)

Workup

  1. customthe mixture degassed with bubbling Argon for 15 min
  2. temperatureAfter 15 h the mixture was cooled
  3. customThe organic layer was separated
  4. washwashed with brine
  5. dry with materialdried (sodium sulfate)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by chromatography (silica, 40 g Analogix column, 20-50% ethyl acetate in hexanes, gradient over 15 min)

Sources & evidence

ORD record
ord-9dbf4e7f79d54b2da397043cb598ed23
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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