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

HRID 1959269Notes

Reaction equation

HRID 1959269 reaction equation
[Br:1][C:2]1[C:3]([F:20])=[C:4]([C:9]([CH3:19])=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Br:1][C:2]1[C:3]([F:20])=[C:4]([C:9]([CH3:19])=[C:10]([N:12]([CH2:21][CH3:22])[CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 177AcetaldehydeHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 86672662Methyl 3-bromo-2-fluoro-6-methyl-5-[(oxan-4-yl)amino]benzoate

Product 1

HCID 86672663Methyl 3-bromo-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzoateYield 96.3%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 962WaterSolvent

Procedure

To a solution of methyl 3-bromo-2-fluoro-6-methyl-5-[(oxan-4-yl)amino]benzoate (500 mg, 1.44 mmol) in 1,2-Dichloroethane (15 ml) at room temperature and under nitrogen was added acetaldehyde (0.81 ml, 14.44 mmol) followed by acetic acid (0.5 ml, 8.67 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (3.06 g, 14.44 mmol) at room temperature. After stirring for 2 hours deionized water (20 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 85:15 Heptane:EtOAc) to give 519 mg (96%) of methyl 3-bromo-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzoate as a pale yellow oil that solidified upon standing. LC-MS 94%, 2.45 min (3 minute LC-MS method), m/z=373.9/375.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.33 (d, J=6.6 Hz, 1H), 3.95 (s, 5H), 3.32 (td, J=11.7, 2.1 Hz, 2H), 3.00 (q, J=7.1 Hz, 2H), 2.88 (tt, J=10.9, 4.0 Hz, 1H), 2.25 (s, 3H), 1.73-1.54 (m, 4H), 0.85 (t, J=7.1 Hz, 3H).

Workup

  1. additionwas added
  2. customThe phases were separated
  3. extractionthe aqueous layer was extracted with EtOAc (2×20 ml)
  4. dry with materialThe combined organic extracts were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 85:15 Heptane:EtOAc)

Sources & evidence

ORD record
ord-800e92dfca7c42b89e23aad9b4889782
Source dataset
uspto-grants-2013_04
Patent number
US08410088B2

Reaction notes

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