Triethylamine → 2-(Cyclopropylmethyl)benzoxazole-4-carboxylic acid

To an ice-cold solution of 2-cyclopropyl acetic acid (321 mg, 3.21 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.29 mL, 3.21 mmol) dropwise and a few drops of DMF. The ice bath was removed and stirring was continued for 1 h. 2-Amino-3-hydroxybenzoic acid hydrobromide (750 mg, 3.21 mmol) was added followed by triethylamine (0.90 mL, 6.42 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with aqueous 1 N HCl (25 mL) until the solution reached pH 1. The reaction mixture was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated to a brown solid. The crude was dissolved in toluene (10 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (735 mg, 3.87 mmol). The reaction mixture was then heated to reflux for 3 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water (5×50 mL) and brine, dried (Na2SO4), filtered, and concentrated. The crude was purified by recrystallization from diethyl ether and hexanes to afford 2-(cyclopropylmethyl)benzoxazole-4-carboxylic acid (441 mg, 63%) as a light brown solid: 1H NMR (500 MHz, DMSO-d6) δ 13.04 (br s, 1H), 7.94 (dd, J=8.1, 0.9 Hz, 1H), 7.81 (dd, J=7.8, 0.9 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 2.92 (d, J=7.0 Hz, 2H), 1.27-1.16 (m, 1H), 0.60-0.54 (m, 2H), 0.36-0.30 (m, 2H); MS (ESI+) m/z 218 (M+H).

1. customThe ice bath was removed
2. customThe resulting reaction mixture
3. stirringwas stirred at room temperature overnight
4. customThe reaction was quenched with aqueous 1 N HCl (25 mL) until the solution
5. extractionThe reaction mixture was extracted with dichloromethane
6. dry with materialThe combined organic layers were dried over Na2SO4
7. filtrationfiltered
8. concentrationconcentrated to a brown solid
9. dissolutionThe crude was dissolved in toluene (10 mL)
10. temperatureThe reaction mixture was then heated
11. temperatureto reflux for 3 h
12. extractionextracted with ethyl acetate
13. customThe organic layer was separated
14. washwashed with water (5×50 mL) and brine
15. dry with materialdried (Na2SO4)
16. filtrationfiltered
17. concentrationconcentrated
18. customThe crude was purified by recrystallization from diethyl ether and hexanes

ORD record

ord-b822b961b6614ecda5199f366de9679b

Source dataset

uspto-grants-2009_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07553846B2