Iodine → HCID 70664304, compound

HRID 874717Notes

Reaction equation

HRID 874717 reaction equation
C(OC1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6]C=1Br)C.[Mg].II.[Cl:15][C:16]1[CH:27]=[CH:26][C:19]2[N:20]=[C:21]([CH3:25])[O:22][C:23](=[O:24])[C:18]=2[CH:17]=1.[CH2:28]1[CH2:32][O:31][CH2:30][CH2:29]1>>[Cl:15][C:16]1[CH:27]=[CH:26][C:19]([NH:20][C:21](=[O:22])[CH3:25])=[C:18]([C:23](=[O:24])[C:6]2[CH:7]=[C:8]([F:10])[CH:9]=[CH:29][C:30]=2[O:31][CH2:32][CH3:28])[CH:17]=1

Participants

6

Reactant 5

HCID 807IodineHCID 8028Tetrahydrofuran2×HCID 2911346-Chloro-2-methyl-4H-3,1-benzoxazin-4-oneHCID 5462224MagnesiumHCID 447549131-Bromo-2-ethoxy-4-fluorobenzene

Product 1

HCID 70664304HCID 70664304, compoundYield 58%

Conditions

Temperature
-20 °C

Procedure

Making Grignard reagent: A solution of 2-ethoxy-4-fluorophenyl bromide (30 g, 138 mmol) in THF (140 ml) was added dropwisely into a stirred mixture of magnesium flake and catalytically amount of iodine under nitrogen. The result mixture was heated to reflux for 15 minutes and cooled to room temperature (Grignard reagent). In a separated flask, 6-chloro-2-methyl-4H-benzo[d][1,3]oxazin-4-one (25 g, 128 mmole) was dissolved into THF (200 ml) and stirred under nitrogen. The Grignard reagent was transferred slowly into the flask during 30 minutes. The reaction temperature was kept below 55° C. during addition. The result mixture was stirred for further 2 hours under nitrogen. The reaction was quenched by slowly addition of aqueous solution of ammonium chloride (30 g/300 ml). The reaction was extracted into MTBE (500 ml). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated on a rotary evaporator to solid. The solid was sonicated for 5 minutes in ethyl acetate (250 ml) and filtered. The filtrate was concentrated on a rotary evaporator to about 70 ml and cooled at −20° C. for 4 hours. During this time, crystallized product came out and was collected by filtration (25 g, yield: 58%). 1H NMR (CDCl3): 11.2 (br, 1H), 8.73 (d, J=22 Hz, 1H), 7.49 (dd, J=24 Hz, 7 Hz, 1H), 7.38 (d, J=6 Hz, 1H), 7.2 (m, 1H), 7.07 (dd, J=20 Hz, 8 Hz, 1H), 6.93 (m, 1H), 3.97 (q, J=17 Hz, 2H), 2.27 (s, 1H), 1.13 (tr, J=17 Hz, 3H).

Workup

  1. temperatureThe result mixture was heated
  2. temperatureto reflux for 15 minutes
  3. additionThe reaction temperature was kept below 55° C. during addition
  4. stirringThe result mixture was stirred for further 2 hours under nitrogen
  5. customThe reaction was quenched by slowly addition of aqueous solution of ammonium chloride (30 g/300 ml)
  6. extractionThe reaction was extracted into MTBE (500 ml)
  7. washThe organic layer was washed with brine
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated on a rotary evaporator to solid
  11. customThe solid was sonicated for 5 minutes in ethyl acetate (250 ml)
  12. filtrationfiltered
  13. concentrationThe filtrate was concentrated on a rotary evaporator to about 70 ml
  14. customDuring this time, crystallized product
  15. filtrationwas collected by filtration (25 g, yield: 58%)

Sources & evidence

ORD record
ord-20d42f1672a042a8bcb2c95de317a179
Source dataset
uspto-grants-2015_03
Patent number
US08980926B2

Reaction notes

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