Triethylamine → 2-(1-Acetylpiperidin-4-yl)benzoxazole-4-carboxylic acid

HRID 1987987Notes

Reaction equation

HRID 1987987 reaction equation
Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].C(N(CC)CC)C.Cl.[C:21]([N:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=O)[CH2:26][CH2:25]1)(=[O:23])[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.C1(C)C=CC=CC=1.O>[C:21]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[O:12][C:11]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:2]=2)[CH2:26][CH2:25]1)(=[O:23])[CH3:22]

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 521998p-Toluenesulfonic acid monohydrateHCID 534308101-Acetylpiperidine-4-carbonyl chloride hydrochlorideHCID 668807402-Amino-3-hydroxybenzoic acid hydrobromide

Product 1

HCID 689953362-(1-Acetylpiperidin-4-yl)benzoxazole-4-carboxylic acidYield 21.4%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Procedure

To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide (2.0 g, 8.5 mmol) in dichloromethane (25 mL) was added triethylamine (4.77 mL, 34.2 mmol) followed by 1-acetylpiperidine-4-carbonyl chloride hydrochloride (1.93 g, 8.55 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 17 h. The reaction was quenched with aqueous 2 N HCl (50 mL). The reaction mixture was extracted with dichloromethane (3×250 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated to afford a light yellow solid. The crude solid was dissolved in toluene (20 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (2.08 g, 10.9 mmol). The reaction mixture was then heated to reflux under nitrogen for 10 h. The reaction was cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic phase was washed with water (2×100 mL), brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, 9:1 to 7:3 ethyl acetate/methanol) to afford 2-(1-acetylpiperidin-4-yl)benzoxazole-4-carboxylic acid (524 mg, 21%) as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 10.81 (br s, 1H), 7.48 (dd, J=7.7, 1.6 Hz, 1H), 6.94 (t, J=7.8 Hz, 1H), 6.89 (dd, J=7.7, 1.6 Hz, 1H), 4.45-4.34 (m, 2H), 3.92-3.82 (m, 2H), 3.18-3.05 (m, 1H), 2.07-2.02 (m, 2H), 2.02 (s, 3H), 1.92-1.82 (m, 2H); MS (ESI+) m/z 289 (M+H).

Workup

  1. customThe resulting reaction mixture
  2. customThe reaction was quenched with aqueous 2 N HCl (50 mL)
  3. extractionThe reaction mixture was extracted with dichloromethane (3×250 mL)
  4. dry with materialThe combined organic phase was dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto afford a light yellow solid
  8. temperatureThe reaction mixture was then heated
  9. temperatureto reflux under nitrogen for 10 h
  10. temperatureThe reaction was cooled to room temperature
  11. extractionextracted with ethyl acetate (3×150 mL)
  12. washThe combined organic phase was washed with water (2×100 mL), brine
  13. dry with materialdried (Na2SO4)
  14. filtrationfiltered
  15. concentrationconcentrated
  16. customThe crude product was purified by column chromatography (silica gel, 9:1 to 7:3 ethyl acetate/methanol)

Sources & evidence

ORD record
ord-cea5ae51d35344b9ae681c24e89b58f4
Source dataset
uspto-grants-2009_06
Patent number
US07553846B2

Reaction notes

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