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

HRID 634095Notes

Reaction equation

HRID 634095 reaction equation
[F:1][C:2]1([F:48])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[O:27][C:26]([NH:28]CC6C=CC(OC)=CC=6)=[N:25][N:24]=5)[CH:21]=4)[N:16]([S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:40])=[O:39])[CH:15]=3)[CH:11]=[N:10][CH:9]=2)[CH2:4][CH2:3]1>C(O)(C(F)(F)F)=O.O1CCOCC1>[F:48][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[O:27][C:26]([NH2:28])=[N:25][N:24]=5)[CH:21]=4)[N:16]([S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:40])=[O:39])[CH:15]=3)[CH:11]=[N:10][CH:9]=2)[CH2:4][CH2:3]1

Participants

4

Reactant 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-amine

Product 1

HCID 683281165-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amineYield 72.2%

Reagents, catalysts & solvents 2

HCID 6422Trifluoroacetic acidSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of 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) in TFA (5 mL) was heated in a microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 110° C. for 20 min. The volatiles were removed under reduced pressure. The brown residue was diluted with EtOAc and washed with 0.5 N NaOH. The EtOAc layer was concentrated. The off white solid was stirred with 5 mL Et2O, filtered, rinsed with 2×5 ml of Et2O to give 350 mg of crude material of 5-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine that was used without further purification. A glass microwave reaction vessel was charged with the above obtained 5-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (350 mg) in p-dioxane (3 mL) followed by 1 N NaOH (2 mL). The reaction was heated in a microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 105° C. for 20 min. The mixture was partitioned between 5 mL of H2O and 50 mL of EtOAc. The EtOAc layer was concentrated and the residue purified on a reverse phase HPLC, using a gradient of 10-90% [0.1% TFA in MeCN] in [0.1% TFA in H2O]. The desired fractions were collected, concentrated, the residue was extracted with EtOAc and washed with 0.5 N NaOH to give 5-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (20 mg, 5%) as an off white crystalline solid. MS (ESI, pos. ion) 398.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93 (1H, br. s.), 8.85 (1H, d, J=1.2 Hz), 8.45 (1H, s), 8.29 (1H, s), 8.19 (1H, s), 7.67 (1H, m), 8.57 (1H, d, J=8.6 Hz), 7.06 (2H, br. s.), 3.89 (4H, t, J=5.6 Hz), 2.12 (4H, m).

Workup

  1. customThe volatiles were removed under reduced pressure
  2. additionThe brown residue was diluted with EtOAc
  3. washwashed with 0.5 N NaOH
  4. concentrationThe EtOAc layer was concentrated
  5. filtrationfiltered
  6. washrinsed with 2×5 ml of Et2O
  7. customto give 350 mg of crude material of 5-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine that
  8. customwas used without further purification
  9. customA glass microwave reaction vessel
  10. additionwas charged with the

Sources & evidence

ORD record
ord-aabd4a30e43246d08655dd89384f31fb
Source dataset
uspto-grants-2016_04
Patent number
US09321756B2

Reaction notes

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