Ammonia → 3-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-acrylic acid tert-butyl ester

HRID 1773898Notes

Reaction equation

HRID 1773898 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:50]([O:54][C:55](=[O:58])[CH:56]=[CH2:57])([CH3:53])([CH3:52])[CH3:51].C(N(CC)CC)C.N>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:50]([O:54][C:55](=[O:58])[CH:56]=[CH:57][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)[C:9]=2[CH3:30])=[CH:6][CH:7]=1)([CH3:53])([CH3:52])[CH3:51]

Participants

9

Reactant 5

HCID 222AmmoniaHCID 8471TriethylamineHCID 11776TriphenylphosphineHCID 15458tert-Butyl acrylateHCID 726953822-(4-bromophenyl)-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene

Product 1

HCID 867039743-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-acrylic acid tert-butyl ester

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 2-(4-bromophenyl)-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 122A) (100 mg, 0.214 mmoles) in DMF (2.5 mL) in a screw-capped vial under argon are added Pd(OAc)2 (5 mg, 10.7 μmole), PPh3 (14 mg, 53.5 μmole), tert-butylacrylate (196 μL, 1.07 mmole) and triethylamine (115 μL, 0.856 mmole). The reaction mixture is heated at 100° C. overnight. Water is added to the reaction mixture and pH adjusted to 9-10 by adding concentrated ammonia solution. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (98:2:0.1) to (96.5:3.5:0.35) and the residue is submitted to a preparative thin-layer chromatography eluting with (CH2Cl2:MeOH:NH4OH) (9:1:1) to afford 3-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-acrylic acid tert-butyl ester melting at 185° C.

Workup

  1. extractionThe aqueous phase is extracted three times with CH2Cl2
  2. dry with materialThe organic phase is dried over magnesium sulphate
  3. filtrationfiltered
  4. customthe solvent is removed under reduced pressure
  5. customThe residue is pre-purified by silica gel chromatography
  6. washeluting with (CH2Cl2:MeOH:NH4OH) (9:1:1)

Sources & evidence

ORD record
ord-4e99342f236149378f9b40b749515b57
Source dataset
uspto-grants-2016_02
Patent number
US09255101B2

Reaction notes

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