Methyl 2-(4-bromophenyl)acetate → tert-butyl 4-(4-carbamoyl-3-{[4-(2-methoxy-2-oxoethyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

HRID 1852481Notes

Reaction equation

HRID 1852481 reaction equation
[NH2:1][C:2]1[C:6]([C:7](=[O:9])[NH2:8])=[CH:5][N:4]([C:10]2([CH2:23][C:24]#[N:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:3]=1.CC([O-])=O.[K+].Br[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:34][CH:33]=1.C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C>CCOC(C)=O.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].CC(O)C>[C:7]([C:6]1[C:2]([NH:1][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:34][CH:33]=2)=[N:3][N:4]([C:10]2([CH2:23][C:24]#[N:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]2)[CH:5]=1)(=[O:9])[NH2:8]

Participants

8

Reactant 4

HCID 316783Methyl 2-(4-bromophenyl)acetateHCID 517044Potassium AcetateHCID 866523322-Di-t-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-tri-1-propylbiphenylHCID 86729368tert-Butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate2×

Product 1

HCID 86729389tert-butyl 4-(4-carbamoyl-3-{[4-(2-methoxy-2-oxoethyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 3776IsopropanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
95 °C

Procedure

To a microwave vessel was added tert-butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (Intermediate 47-1, 0.30 g, 0.86 mmol), KOAc (127 mg, 1.29 mmol), methyl (4-bromophenyl)acetate (237 mg, 1.03 mmol) and 2-propanol (4.3 mL). The mixture was degassed for 5 minutes by bubbling argon gas. Pd2(dba)3 (39 mg, 0.04 mmol) and 2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-1-propylbiphenyl (83 mg, 0.17 mmol) were added, the vial was sealed and heated at 95° C. for 18 hours. The mixture was cooled to ambient temperature, then diluted with EtOAc and washed with H2O. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 50-100% EtOAc/hexanes) to afford the title compound. 1H NMR (600 MHz, Acetone-d6): δ 9.17 (s, 1H), 8.45 (s, 1H), 7.52-7.55 (m, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.14 (brs, 1H), 6.51 (brs, 1H), 3.80-3.90 (m, 2H), 3.60 (s, 3H), 3.53 (s, 2H), 3.15 (s, 2H), 3.00-3.18 (m, 2H), 2.52-2.60 (m, 2H), 2.04-2.12 (m, 2H), 1.42 (s, 9H).

Workup

  1. customThe mixture was degassed for 5 minutes
  2. customby bubbling argon gas
  3. customthe vial was sealed
  4. temperatureThe mixture was cooled to ambient temperature
  5. washwashed with H2O
  6. customThe organic layer was separated
  7. washwashed with brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified by MPLC on silica gel (
  12. washa gradient elution of 50-100% EtOAc/hexanes)

Sources & evidence

ORD record
ord-f55888d4b87c406eb62476edd09230b6
Source dataset
uspto-grants-2015_02
Patent number
US08962608B2

Reaction notes

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