Dichloromethane → 4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-(1,4-dimethyl-1H-Pyrazol-5-yl)-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one

HRID 577572Notes

Reaction equation

HRID 577572 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]3[C:14](=[O:21])[NH:15][C:16]([CH3:20])=[CH:17][C:18]=3[CH3:19])[C:7](=[O:22])[C:6]=2[C:23]=1[CH3:24].[CH3:25][N:26]1[C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([CH3:40])[CH:28]=[N:27]1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>O1CCOCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].C(Cl)Cl>[CH3:19][C:18]1[CH:17]=[C:16]([CH3:20])[NH:15][C:14](=[O:21])[C:13]=1[CH2:12][N:8]1[C:7](=[O:22])[C:6]2[C:23]([CH3:24])=[C:2]([C:30]3[N:26]([CH3:25])[N:27]=[CH:28][C:29]=3[CH3:40])[CH:3]=[CH:4][C:5]=2[O:11][CH2:10][CH2:9]1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 578266761,4-dimethyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 867237977-bromo-4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one

Product 1

HCID 867237994-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-(1,4-dimethyl-1H-Pyrazol-5-yl)-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-oneYield 19%

Reagents, catalysts & solvents 2

HCID 178478472(1,1'-Bis(diphenylphosphino)ferrocene)dichloropalladium-dichloromethane (1:1)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A suspension of 7-bromo-4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (126d, 36 mg), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (34 mg, 0.092 mmol), and sodium carbonate (2M aq, 32 mg, 0.30 mmol) in 1,4-dioxane (3 mL) was degassed with N2 for 10 minutes. The reaction mixture was treated with PdCl2(DPPF)-DCM (8.2 mg, 0.010 mmol) and heated at 100° C. in the microwave for 1 hour, then at 120° C. in the microwave for an additional 1 hour. The reaction mixture was poured into DCM (25 mL) and washed with water (3×25 mL). The organic layer was concentrated under vacuum and the residue was purified by preparative HPLC to give the title compound (Example 126, 7 mg, 19% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.33 (s, 1H), 7.23 (d, J=8.07 Hz, 1H), 6.99 (d, J=8.19 Hz, 1H), 5.93 (s, 1H), 4.66 (s, 2H), 4.09 (t, J=5.44 Hz, 2H), 3.48 (s, 3H), 3.42-3.46 (m, 2H), 2.23 (s, 3H), 2.14 (s, 3H), 2.03 (s, 3H), 1.79 (s, 3H); MS 407.1 [M+1].

Workup

  1. customwas degassed with N2 for 10 minutes
  2. washwashed with water (3×25 mL)
  3. concentrationThe organic layer was concentrated under vacuum
  4. customthe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-75887a9c1c5c476d804591e410c45bd6
Source dataset
uspto-grants-2015_05
Patent number
US09040515B2

Reaction notes

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