Acetic Acid → Methyl 5-chloro-2-ethyl-3-[(oxan-4-yl)amino]benzoate

HRID 2208863Notes

Reaction equation

HRID 2208863 reaction equation
[NH2:1][C:2]1[C:3]([CH2:13][CH3:14])=[C:4]([CH:9]=[C:10]([Cl: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>[Cl:12][C:10]1[CH:11]=[C:2]([NH:1][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[C:3]([CH2:13][CH3:14])=[C:4]([CH:9]=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 86672668Methyl 3-amino-5-chloro-2-ethylbenzoate

Product 1

HCID 70872938Methyl 5-chloro-2-ethyl-3-[(oxan-4-yl)amino]benzoate

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 962WaterSolvent

Procedure

To a solution of methyl 3-amino-5-chloro-2-ethylbenzoate (1.5 g, 7.02 mmol) in 1,2-dichloroethane (28 ml) at room temperature under nitrogen was added oxan-4-one (1.3 ml, 14. mmol) followed by acetic acid (2.41 ml, 42 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (4.46 g, 21 mmol) at room temperature. After stirring for 20 hours, deionized water (28 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×28 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 8:2 Heptane:EtOAc) to give 1.76 g of crude methyl 5-chloro-2-ethyl-3-[(oxan-4-yl)amino]benzoate as a white solid. The material was taken through the next step without further purification. LC-MS 60%, m/z=298.0/300.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.07 (d, J=2.0 Hz, 1H), 6.71 (d, J=1.9 Hz, 1H), 4.01 (dt, J=11.8, 3.4 Hz, 2H), 3.87 (s, 3H), 3.82-3.76 (m, 1H), 3.64-3.47 (m, 3H), 2.79-2.63 (m, 2H), 2.06 (d, J=13.2 Hz, 2H), 1.55-1.46 (m, 2H), 1.18 (t, J=7.5 Hz, 3H).

Workup

  1. customThe phases were separated
  2. extractionthe aqueous layer was extracted with EtOAc (2×28 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 8:2 Heptane:EtOAc)

Sources & evidence

ORD record
ord-381c8bd37a82428795ce3960d8d06e0b
Source dataset
uspto-grants-2016_06
Patent number
US09376422B2

Reaction notes

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