Acetic Acid → Methyl 3-bromo-2-fluoro-6-methyl-5-[(oxan-4-yl)amino]benzoate

HRID 1616458Notes

Reaction equation

HRID 1616458 reaction equation
[NH2:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]([F:13])=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Br:12][C:10]1[C:9]([F:13])=[C:4]([C:3]([CH3:14])=[C:2]([NH:1][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 121599Tetrahydro-4H-pyran-4-oneHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 84076173Methyl 3-amino-5-bromo-6-fluoro-2-methylbenzoate

Product 1

HCID 86672662Methyl 3-bromo-2-fluoro-6-methyl-5-[(oxan-4-yl)amino]benzoateYield 82.2%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 962WaterSolvent

Procedure

To a solution of methyl 3-amino-5-bromo-6-fluoro-2-methylbenzoate (2.23 g, 8.08 mmol) in 1,2-Dichloroethane (32 ml) at room temperature and under nitrogen was added oxan-4-one (1.49 ml, 16.17 mmol) followed by acetic acid (2.78 ml, 48.5 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (5.14 g, 24.25 mmol) at room temperature. After stirring for 5.5 hours there was no unreacted starting material present by LCMS. Deionized water (32 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×32 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 6:4 Heptane:EtOAc) to give 2.3 g (82%) of methyl 3-bromo-2-fluoro-6-methyl-5-[(oxan-4-yl)amino]benzoate as a off-white solid. LC-MS 99%, 2.13 min (3 minute LC-MS method), m/z=245.9/247.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 6.78 (d, J=5.9 Hz, 1H), 4.01 (dt, J=11.9, 3.4 Hz, 2H), 3.93 (s, 3H), 3.53 (td, J=11.7, 2.1 Hz, 2H), 3.49-3.42 (m, 1H), 3.34 (s, 1H), 2.04 (s, 5H), 1.48 (qd, J=11.0, 4.2 Hz, 2H).

Workup

  1. customThe phases were separated
  2. extractionthe aqueous layer was extracted with EtOAc (2×32 ml)
  3. dry with materialThe combined organic extracts were dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 6:4 Heptane:EtOAc)

Sources & evidence

ORD record
ord-f410515baf354f7bae92f78bedfb52b6
Source dataset
uspto-grants-2014_07
Patent number
US08765732B2

Reaction notes

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