Triethylamine → 2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methyl-N-[(1R)-1-[3'-(methyloxy)-4-biphenylyl]-2-(4-morpholinyl)ethyl]acetamide

HRID 2354417Notes

Reaction equation

HRID 2354417 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][CH:20]=[C:19]([O:23][CH3:24])[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:25][C:26]1[C:27]([Cl:41])=[CH:28][C:29]2[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][C:37]([OH:39])=O)[C:30]=2[CH:40]=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:25][C:26]1[C:27]([Cl:41])=[CH:28][C:29]2[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][C:37]([N:2]([CH3:1])[C@H:3]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[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:39])[C:30]=2[CH:40]=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 57488867(1R)-N-Methyl-1-[3'-(methyloxy)-4-biphenylyl]-2-(4-morpholinyl)ethanamine

Product 1

HCID 574888662-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methyl-N-[(1R)-1-[3'-(methyloxy)-4-biphenylyl]-2-(4-morpholinyl)ethyl]acetamideYield 46.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(1R)—N-Methyl-1-[3′-(methyloxy)-4-biphenylyl]-2-(4-morpholinyl)ethanamine (3.3 g, 10 mmol) was dissolved in 100 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 (4.3 g, 12 mmol, with 23 wt % LiCl) followed by triethylamine (2.8 mL, 20 mmol) and BOP (5.3 g, 12 mmol). The reaction mixture was maintained at room temperature for 16 h. The reaction mixture was filtered and the filtrate was added slowly to of H2O (300 mL) with vigorous stirring. The precipitate which formed was collected by filtration and further purified by silica gel chromatography (120 g Redisep column, silica, 40 um, 60 Å, 80 mL/min, A: MeOH (with 10% NEt3), B: CH2Cl2, A: 1% for 20 min, 2% for 20 min, 5% for 10 min; detection at 254 nm). The combined fractions were concentrated, and the resulting residue was triturated with MeOH. The white solid was collected by filtration to give the title compound (2.7 g, 46%). MS (ES) m/e 585 [M+H]+.

Workup

  1. filtrationThe reaction mixture was filtered
  2. additionthe filtrate was added slowly to of H2O (300 mL) with vigorous stirring
  3. customThe precipitate which formed
  4. filtrationwas collected by filtration
  5. customfurther purified by silica gel chromatography (120 g Redisep column, silica, 40 um, 60 Å, 80 mL/min
  6. wait2% for 20 min
  7. wait5% for 10 min
  8. concentrationThe combined fractions were concentrated
  9. customthe resulting residue was triturated with MeOH
  10. filtrationThe white solid was collected by filtration

Sources & evidence

ORD record
ord-aea528d94fdf44008f88ff634f33cfa1
Source dataset
uspto-grants-2010_07
Patent number
US07749998B2

Reaction notes

Loading…