Sodium Carbonate → 2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-[1-[2-fluoro-4'-[(methylsulfonyl)amino]-4-biphenylyl]-2-(4-morpholinyl)ethyl]-N-methylacetamide

HRID 2114444Notes

Reaction equation

HRID 2114444 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]([CH3:33])[C:17](=[O:32])[CH2:18][N:19]2[C:24]3[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:23]=3[O:22][CH2:21][C:20]2=[O:31])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[F:34].[CH3:35][S:36]([NH:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)(=[O:38])=[O:37].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:30][C:26]1[C:27]([Cl:29])=[CH:28][C:23]2[O:22][CH2:21][C:20](=[O:31])[N:19]([CH2:18][C:17]([N:16]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:43]4[CH:42]=[CH:41][C:40]([NH:39][S:36]([CH3:35])(=[O:37])=[O:38])=[CH:45][CH:44]=4)=[C:3]([F:34])[CH:4]=3)[CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH3:33])=[O:32])[C:24]=2[CH:25]=1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 2773537(4-Methanesulfonamidophenyl)boronic acidHCID 57489052N-[1-(4-bromo-3-fluorophenyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide

Product 1

HCID 574890542-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-[1-[2-fluoro-4'-[(methylsulfonyl)amino]-4-biphenylyl]-2-(4-morpholinyl)ethyl]-N-methylacetamideYield 9.5%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a room temperature solution under nitrogen containing 0.20 g of N-[1-(4-bromo-3-fluorophenyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (0.348 mmols) in 3.5 mL of dry DMF was added 0.09 g of {4-[(methylsulfonyl)amino]phenyl}boronic acid (0.418 mmols), 0.014 g of (dppf)PdCl2 (0.017 mmols), and 0.70 mL of Na2CO3 solution (2M in water). The reaction mixture was heated to 80° C. After 18 h the reaction was cooled to ambient temperature and filtered through a 0.2 □m syringe filter. The resulting DMF solution was purified by preparative HPLC (Phenomenex 50×100 mm column, 90 mL/min flow rate, A: 0.1% TFA in acetonitrile B: 0.1% TFA in water, A: 10 to 100% over 15 min, UV detection at 215 nm) to give 0.022 g (9%) of the title compound as a light brown solid. MS (ES) m/e 666, 667 [M+H]+.

Workup

  1. temperatureAfter 18 h the reaction was cooled to ambient temperature
  2. filtrationfiltered through a 0.2 □m syringe
  3. filtrationfilter
  4. customThe resulting DMF solution was purified by preparative HPLC (Phenomenex 50×100 mm column, 90 mL/min flow rate

Sources & evidence

ORD record
ord-f6743db07d7a4f1c84f214819afc0e00
Source dataset
uspto-grants-2008_10
Patent number
US07432258B2

Reaction notes

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