Triethylamine → Ethyl 4'-[(1R)-1-[[(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetyl](methyl)amino]-2-(4-morpholinyl)ethyl]-4-biphenylcarboxylate

HRID 2114429Notes

Reaction equation

HRID 2114429 reaction equation
[CH3:1][NH:2][C@H:3]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:28][C:29]1[C:30]([Cl:44])=[CH:31][C:32]2[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][C:40]([OH:42])=O)[C:33]=2[CH:43]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:28][C:29]1[C:30]([Cl:44])=[CH:31][C:32]2[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][C:40]([N:2]([CH3:1])[C@H:3]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)[CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[O:42])[C:33]=2[CH:43]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 574888462-(6,7-Dichloro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)acetic acidHCID 57488870Ethyl 4'-[(1R)-1-(methylamino)-2-(4-morpholinyl)ethyl]-4-biphenylcarboxylate

Product 1

HCID 57488871Ethyl 4'-[(1R)-1-[[(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetyl](methyl)amino]-2-(4-morpholinyl)ethyl]-4-biphenylcarboxylateYield 43.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Ethyl 4′-[(1R)-1-(methylamino)-2-(4-morpholinyl)ethyl]-4-biphenylcarboxylate (59.7 mg, 0.16 mmol) was dissolved in 10 mL of DMF at room temperature with magnetic stirring. The resulting solution was treated with (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid (63.8 mg, 0.18 mmol, with 23 wt % LiCl) followed by triethylamine (32.4 mg, 0.32 mmol) and BOP (78.7 mg, 0.18 mmol), and then the reaction mixture was maintained at room temperature for 16 h. The reaction mixture was concentrated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer was washed by brine, dried over MgSO4, filtered and then concentrated. The residue was dissolved in 2 mL of DMSO and purified by preparative HPLC (Xterra Prep RP, 30×100 mm, 25 mL/min, A: acetonitrile with 0.1% TFA, B: water with 0.1% TFA, A: 15% to 90% during 20 min, UV detection at 214 nm) to ive 44 mg (37% yield) of the title compound as a yellow solid. MS (ES) m/e 626 [M+H]+.

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customthe residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution
  3. washThe organic layer was washed by brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. dissolutionThe residue was dissolved in 2 mL of DMSO
  8. custompurified by preparative HPLC (Xterra Prep RP, 30×100 mm, 25 mL/min

Sources & evidence

ORD record
ord-52a05d2558c64c9992319446708544cb
Source dataset
uspto-grants-2008_10
Patent number
US07432258B2

Reaction notes

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