Dicyclohexylamine → 4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

HRID 1629112Notes

Reaction equation

HRID 1629112 reaction equation
C1(NC2CCCCC2)CCCCC1.C([Li])CCC.[C:19]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].Br[C:38]1[CH:39]=[CH:40][C:41]2[O:50][CH2:49][CH2:48][C:47]3[C:43](=[N:44][N:45]([C:51]4[N:52]([C:56]5[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=5[F:63])[N:53]=[CH:54][N:55]=4)[CH:46]=3)[C:42]=2[CH:64]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1CCCCC1.C(OCC)(=O)C>[CH2:35]([O:34][C:32]([C:29]1([C:38]2[CH:39]=[CH:40][C:41]3[O:50][CH2:49][CH2:48][C:47]4[C:43](=[N:44][N:45]([C:51]5[N:52]([C:56]6[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=6[F:63])[N:53]=[CH:54][N:55]=5)[CH:46]=4)[C:42]=3[CH:64]=2)[CH2:30][CH2:31][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:27][CH2:28]1)=[O:33])[CH3:36]

Participants

9

Reactant 5

HCID 7582DicyclohexylamineHCID 2734635Tri-tert-butylphosphine tetrafluoroborateHCID 27588121-Tert-butyl 4-ethyl piperidine-1,4-dicarboxylateHCID 582044889-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azuleneHCID 178418339Butyllithium

Product 1

HCID 582046194-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl esterYield 29%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 8078CyclohexaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of dicyclohexylamine (291 L, 1.463 mmol) in anhydrous toluene (3 mL) was added 2.5M n-butyllithium in hexanes (563 L, 1.575 mmol) dropwise at RT under nitrogen. After complete addition the mixture was stirred at RT for 10 min then ethyl N-Boc-piperidine-4-carboxylate (305 L, 1.24 mmol) was added drop wise at RT and the mixture was stirred for 30 min. The mixture was added to 9-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (500 mg, 1.13 mmol), di(dibenzylideneacetone)-palladium (35 mg, 0.06 mmol), tri-tert-butylphosphonium tetrafluoroborate (17.4 mg, 0.06 mmol) at RT under nitrogen then heated to 100° C. After heating for 17 hr the mixture was allowed to cool to RT and subjected to flash chromatography (SiO2, gradient 0 to 50% ethyl acetate in cyclohexane) to afford the title compound (200 mg, 29%). LCMS RT=4.93 min, M+H+=621.

Workup

  1. additionAfter complete addition the mixture
  2. stirringthe mixture was stirred for 30 min
  3. temperaturethen heated to 100° C
  4. temperatureAfter heating for 17 hr the mixture
  5. temperatureto cool to RT

Sources & evidence

ORD record
ord-ee6186ba1ea443bfa9a0586356133eaf
Source dataset
uspto-grants-2014_07
Patent number
US08785626B2

Reaction notes

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