Acetic Acid → methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate

HRID 1050461Notes

Reaction equation

HRID 1050461 reaction equation
[NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.C([O-])(O)=O.[Na+]>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]

Participants

8

Reactant 4

HCID 176Acetic AcidHCID 121599Tetrahydro-4H-pyran-4-oneHCID 5049666Sodium triacetoxyborohydride2×HCID 24729181Methyl 3-Amino-5-bromo-2-methylbenzoate

Product 1

HCID 70872676methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoateYield 75%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 962WaterSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A 1 L round-bottomed flask was charged with methyl 3-amino-5-bromo-2-methylbenzoate (15.26 g, 62.5 mmol) and dihydro-2H-pyran-4(3H)-one (9.39 g, 94 mmol) in 1,2-dichloroethane (DCE) (250 mL) to give a yellow solution at room temperature under nitrogen. Acetic acid (21.47 mL, 375 mmol) was added to the reaction mixture. After 30 min, sodium triacetoxyborohydride (39.8 g, 188 mmol) was added to the reaction mixture. After 3 h, sodium triacetoxyborohydride (39.8 g, 188 mmol) was added to the reaction mixture. The reaction was stirred overnight, at which time it was diluted with water and neutralized with NaHCO3 to pH 7. The reaction mixture was extracted with EtOAc (3×). The combined EtOAc layers were stirred with Na2SO4 and activated carbon darco for 30 min, then filtered through a pad of SiO2 (2″×1″) and concentrated. The solids were stirred with ether and filtered to obtain methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (15.4 g, 46.9 mmol, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.98 (d, J=2.02 Hz, 1 H), 6.94 (d, J=1.77 Hz, 1 H), 5.03 (d, J=8.08 Hz, 1 H), 3.94-3.84 (m, 2 H), 3.80 (s, 3 H), 3.64-3.51 (m, 1 H), 3.44 (td, J=11.68, 1.89 Hz, 2 H) 2.15 (s, 3 H), 1.84 (dd, J=12.63, 2.02 Hz, 2 H), 1.43-1.69 (m, 2 H). MS(ES) [M+H]+ 328, 330.

Workup

  1. customto give a yellow solution at room temperature under nitrogen
  2. waitAfter 3 h
  3. extractionThe reaction mixture was extracted with EtOAc (3×)
  4. stirringThe combined EtOAc layers were stirred with Na2SO4 and activated carbon darco for 30 min
  5. filtrationfiltered through a pad of SiO2 (2″×1″) and
  6. concentrationconcentrated
  7. stirringThe solids were stirred with ether
  8. filtrationfiltered

Sources & evidence

ORD record
ord-4abb9ab443934658b0e5588246524a34
Source dataset
uspto-grants-2016_07
Patent number
US09382234B2

Reaction notes

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