Tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-3-ylcarbamate → tert-butyl 3-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indole-1-carboxylate

HRID 1529294Notes

Reaction equation

HRID 1529294 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[C:12]2I.C([Sn](CCCC)(CCCC)[C:31]1[N:36]=[C:35]([N:37]2[CH2:42][CH2:41][CH2:40][CH:39]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:38]2)[CH:34]=[N:33][CH:32]=1)CCC>CN(C=O)C.C(Cl)Cl.O.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>[C:46]([O:45][C:44]([NH:43][CH:39]1[CH2:40][CH2:41][CH2:42][N:37]([C:35]2[N:36]=[C:31]([C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[CH:10]=4)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=3)[CH:32]=[N:33][CH:34]=2)[CH2:38]1)=[O:50])([CH3:49])([CH3:47])[CH3:48]

Participants

8

Reactant 2

HCID 67958112Tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-3-ylcarbamateHCID 67958266tert-butyl 5-(2,6-difluorophenyl)-3-iodo-1H-indole-1-carboxylate

Product 1

HCID 86709766tert-butyl 3-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indole-1-carboxylate

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
100 °C

Procedure

A glass microwave reaction vessel was charged with tert-butyl 5-(2,6-difluorophenyl)-3-iodo-1H-indole-1-carboxylate (350 mg, 0.769 mmol), tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-3-ylcarbamate (436 mg, 0.769 mmol), Pd(PPh3)4 (89 mg, 0.077 mmol), and CuI (15 mg, 0.077 mmol) in DMF (6 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 30 min. The mixture was diluted with DCM and water. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated to give the crude product, tert-butyl 3-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indole-1-carboxylate. MS (ESI, pos. ion) m/z: 606 (M+1). To a solution of tert-butyl 3-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indole-1-carboxylate (466 mg, 0.769 mmol) in DCM (6 mL) was added TFA (4 mL) and the reaction was stirred at RT for 3 h, then solvent was removed. The residue was diluted with DCM and washed with saturated NaHCO3 aqueous solution twice. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified with RP-HPLC to give 1-(6-(5-(2,6-difluorophenyl)-1H-indol-3-yl)pyrazin-2-yl)piperidin-3-amine as a light brown solid. MS (ESI, pos. ion) m/z: 406 (M+1).

Workup

  1. customA glass microwave reaction vessel
  2. customThe organic layer was separated
  3. washwashed with water and brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-a60e3562fa8f463e9fcb7966ca9ca05a
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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