Cesium carbonate → 5-(5-Methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole

HRID 1475239Notes

Reaction equation

HRID 1475239 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[CH3:31][S:32]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:31][S:32]([CH:35]1[CH2:40][CH2:39][N:38]([C:2]2[CH:30]=[CH:29][CH:28]=[C:4]([CH2:5][N:6]3[C:10]([CH3:11])=[N:9][C:8]([C:12]4[O:16][N:15]=[C:14]([C:17]5[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=5)[N:13]=4)=[N:7]3)[CH:3]=2)[CH2:37][CH2:36]1)(=[O:34])=[O:33]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 222750384-(Methanesulfonyl)piperidineHCID 86711906HCID 86711906, compound

Product 1

HCID 867119315-(5-Methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
140 °C

Procedure

A mixture of 5-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (Example 11, Step 1; 165 mg, 0.34 mmol), 4-(methylsulfonyl)piperidine (62 mg, 0.38 mmol), and Cs2CO3 (224 mg, 0.69 mmol) in toluene (2 mL) was degassed with argon for 5 min. Pd2(dba)3 (0.15 mg, 0.017 mmol) and dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (33 mg, 069 mmol) were added and the reaction mixture was degassed a second time with argon for 5 min, then heated to 140° C. for 18 h. The mixture was then cooled to RT, diluted with EtOAc (15 mL), filtered through a pad of Celite, and concentrated under reduced pressure. The crude product was purified by prep-HPLC (Mobile phase: A=0.1% TFA/H2O, B=0.1% TFA/MeCN; Gradient: B=40%-80% in 12 min; Column: C18) to give the title compound as a white solid; MS (ES+) C25H25F3N6O4S requires: 562. found: 563 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 8.22 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.2 Hz, 2H), 7.21 (t, J=7.9 Hz, 1H), 6.97 (bs, 1H), 6.94 (dd, J=8.3, 2.4 Hz, 1H), 6.64 (d, J=7.5 Hz, 1H), 5.48 (s, 2H), 3.86 (bd, J=13.4 Hz, 2H), 3.28 (m, 1H), 2.94 (s, 3H), 2.76 (m, 2H), 2.57 (s, 3H), 2.06 (bd, J=13.4 Hz, 2H), 1.68 (ddd, J=16.5, 12.5, 4.1 Hz, 2H); 19F NMR (282 MHz, DMSO-d6) δ −56.6.

Workup

  1. customwas degassed with argon for 5 min
  2. customthe reaction mixture was degassed a second time with argon for 5 min
  3. temperatureThe mixture was then cooled to RT
  4. additiondiluted with EtOAc (15 mL)
  5. filtrationfiltered through a pad of Celite
  6. concentrationconcentrated under reduced pressure
  7. customThe crude product was purified by prep-HPLC (Mobile phase

Sources & evidence

ORD record
ord-1f2e771ef39240df9efa255128a11795
Source dataset
uspto-grants-2015_04
Patent number
US09018380B2

Reaction notes

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