Dimethylformamide → 5-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine

HRID 634094Notes

Reaction equation

HRID 634094 reaction equation
Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)[N:3]=1.I[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[O:30][C:29]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)=[N:28][N:27]=3)[CH:24]=2)[N:19]([S:41]([C:44]2[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=2)(=[O:43])=[O:42])[CH:18]=1.CN(C=O)C>O1CCOCC1.CC(C)=O.CCOC(C)=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>[F:14][C:11]1([F:15])[CH2:12][CH2:13][N:8]([C:4]2[N:3]=[C:2]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]5[O:30][C:29]([NH:31][CH2:32][C:33]6[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=6)=[N:28][N:27]=5)[CH:24]=4)[N:19]([S:41]([C:44]4[CH:45]=[CH:46][C:47]([CH3:48])=[CH:49][CH:50]=4)(=[O:43])=[O:42])[CH:18]=3)[CH:7]=[N:6][CH:5]=2)[CH2:9][CH2:10]1

Participants

9

Reactant 3

HCID 6228DimethylformamideHCID 683283255-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amineHCID 867250902-Chloro-6-(4,4-difluoropiperidin-1-yl)pyrazine

Product 1

HCID 683288785-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amineYield 85.8%

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalyst2×HCID 180AcetoneSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
125 °C

Procedure

A glass microwave reaction vessel was charged with 2-chloro-6-(4,4-difluoropiperidin-1-yl)pyrazine (300 mg, 1.28 mmol) and (Me3Sn)2 (0.32 mL, 1.54 mmol) in p-dioxane (2.5 mL) followed by Pd(PPh3)4 (60 mg, 0.05 mmol). The reaction was heated in a microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 125° C. for 30 min. The mixture was cooled to RT and 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (0.615 g, 1.024 mmol) was added followed by DMF (1 mL), CuI (244 mg, 1.28 mmol) and Pd(PPh3)4 (59 mg, 0.05 mmol). The reaction was heated in a microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 125° C. for 0.5 h. It was diluted with 5 mL of acetone and 10 mL of EtOAc, filtered through a pad of Celite. The filtrate was concentrated. The residue was loaded on a silica gel column and eluted with 50% EtOAc in DCM followed by 10-20% MeOH in EtOAc to give 5-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (590 mg) as a brown amorphous solid that was used in the next step without further purification. MS (ESI, pos. ion) m/z 672.0 (M+1).

Workup

  1. customA glass microwave reaction vessel
  2. temperatureThe mixture was cooled to RT
  3. temperatureThe reaction was heated in a microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 125° C. for 0.5 h
  4. filtrationfiltered through a pad of Celite
  5. concentrationThe filtrate was concentrated
  6. washeluted with 50% EtOAc in DCM

Sources & evidence

ORD record
ord-6c554e79f4854dbba3c717c7f44b2b69
Source dataset
uspto-grants-2016_04
Patent number
US09321756B2

Reaction notes

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