2-Methylpropan-2-olate → 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene

HRID 708055Notes

Reaction equation

HRID 708055 reaction equation
Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[F:29][C:30]([F:39])([F:38])[CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([N:35]5[CH2:34][CH2:33][N:32]([CH2:31][C:30]([F:38])([F:39])[F:29])[CH2:37][CH2:36]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1

Participants

7

Reactant 4

HCID 45749132-Methylpropan-2-olateHCID 95339211-(2,2,2-Trifluoroethyl)piperazineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 579003099-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene

Product 1

HCID 582038022-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azuleneYield 28%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
125 °C

Procedure

A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (20 mg, 0.1 mmol), 1-(2,2,2-Trifluoro-ethyl)-piperazine (175 mg, 1.44 mmol), X-phos (70 mg, 0.144 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 125° C. for 9 min under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 110 mg of 309. (yield=28%). 1H NMR (CDCl3, 400 MHz): δ8.08 (s, 1H), 7.57-7.51 (m, 1H), 7.16-7.06 (m, 4H), 6.52 (d, J=8.8 Hz, 1H), 4.25-4.23 (m, 2H), 3.47-3.44 (m, 4H), 3.12-3.02 (m, 4H), 2.80-2.77 (m, 4H). LC-MS (ESI): m/z=549 [M+H]+

Workup

  1. customwas bubbled N2 for 10 min
  2. filtrationThe mixture was filtered over ceilite
  3. concentrationThe filtrate was concentrated to dryness
  4. custompurified by pre-HPLC

Sources & evidence

ORD record
ord-27bdc7c252334723924ceaa0d4ef6768
Source dataset
uspto-grants-2015_11
Patent number
US09175009B2

Reaction notes

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