Ethyl chloroformate → 3-(4-Bromo-2-fluoro-benzyl)-7-methoxy benzo[e][1,3]oxazine-2,4-dione

HRID 457942

Reaction equation

HRID 457942 reaction equation
[OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(C(C)C)CC)(C)C.Cl[C:23](OCC)=[O:24].[F:28][C:29]1[CH:36]=[C:35]([Br:37])[CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>O1CCCC1.C(OCC)(=O)C>[Br:37][C:35]1[CH:34]=[CH:33][C:30]([CH2:31][N:32]2[C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=3[O:1][C:23]2=[O:24])=[C:29]([F:28])[CH:36]=1

Participants

7

Reactant 4

HCID 10928Ethyl chloroformateHCID 752314-Methoxysalicylic AcidHCID 81531Diisopropylethylamine2×HCID 3770848(4-Bromo-2-fluorophenyl)methanamine

Product 1

HCID 184681743-(4-Bromo-2-fluoro-benzyl)-7-methoxy benzo[e][1,3]oxazine-2,4-dioneYield 36.5%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A solution of 2-hydroxy-4-methoxybenzoic acid (2.04 g, 12.2 mmol) in tetrahydrofuran (20 mL, 0.6 M)was cooled to 0° C. After being treated with diisopropylethylamine (4.4 mL, 25.3 mmol), and ethyl chloroformate (2.4 mL, 25.1 mmol), the mixture was stirred at room temperature for 1 h and subsequently treated with a solution of 2-fluoro-4-bromobenzylamine (2.92 g, 12.1 mmol) and diisopropylethylamine (4.4 mL, 25.3 mmol) in tetrahydrofuran (15 mL). After stirring at room temperature for 22 h, the reaction mixture was diluted ethyl acetate and successively washed with 2 N HCl, saturated aq NaHCO3 and saturated aq NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The crude solid was purified by recrystallization with heptane and ethyl acetate to give 3-(4-bromo-2-fluoro-benzyl)-7-methoxy benzo[e][1,31 oxazine-2,4-dione (1.68 g, 36%): 1H NMR (DMSO-d6, 300 MHz) δ 7.87 (d, J=8.4 Hz, 1 H), 7.53 (dd, J1=10.5 Hz, J2=1.1 Hz, 1 H), 7.33–7.34 (m, 2 H), 7.03–6.99 (m, 2 H), 5.02 (s, 2 H), 3.87 (s, 3 H).

Workup

  1. stirringAfter stirring at room temperature for 22 h
  2. washsuccessively washed with 2 N HCl, saturated aq NaHCO3 and saturated aq NaCl
  3. dry with materialThe organic layer was dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude solid was purified by recrystallization with heptane and ethyl acetate

Sources & evidence

ORD record
ord-dc8a6168e7e541e286a4605e93058656
Source dataset
uspto-grants-2007_03
Patent number
US07189749B2

Linked notes

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