Sodium hydride → HCID 68312825, compound

HRID 1530382Notes

Reaction equation

HRID 1530382 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[C:18]1[CH:37]=[CH:36][C:21]2[C:22]3[N:26]([CH2:27][CH2:28][O:29][C:20]=2[CH:19]=1)[CH:25]=[C:24]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[N:23]=3>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]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:18]2[CH:37]=[CH:36][C:21]3[C:22]4[N:26]([CH2:27][CH2:28][O:29][C:20]=3[CH:19]=2)[CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[N:23]=4)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 5456991-Boc-3-hydroxypiperidineHCID 68312888HCID 68312888, compound

Product 1

HCID 68312825HCID 68312825, compound

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
70 °C

Procedure

To a solution of 3-hydroxypiperidine-1-carboxylic acid tertbutyl ester (176 mg, 0.88 mmol) in toluene (3 mL) was added NaH (60% in mineral oil, 35 mg, 0.88 mmol) and the mixture was heated at 70° C. for 15 min. After cooling to RT, 8-bromo-2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (200 mg, 0.58 mmol), Pd2 dba3 (11 mg, 0.001 mmol) and tertbutylXantphos (20 mg, 0.08 mmol) were added and the mixture was heated at 95° C. for 18 h. The reaction mixture was then partitioned between EtOAc and brine and the aqueous phase was further extracted with EtOAc (×3). The combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% 2M NH3/MeOH in DCM followed by Si-PCC, gradient 0-10% 2M NH3/MeOH in EtOAc) affording 3-(2-Pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy)piperidine-1-carboxylic acid tertbutyl ester as a colorless oil, taken forward in the next step without further purification. LCMS: RT 2.68 min [M+H]+ 463.2

Workup

  1. temperatureAfter cooling to RT
  2. temperaturethe mixture was heated at 95° C. for 18 h
  3. customThe reaction mixture was then partitioned between EtOAc and brine
  4. extractionthe aqueous phase was further extracted with EtOAc (×3)
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated in vacuo
  8. customThe resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% 2M NH3/MeOH in DCM followed by Si-PCC, gradient 0-10% 2M NH3/MeOH in EtOAc)

Sources & evidence

ORD record
ord-1711e246c3274e1f988cf678d729aaa7
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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