Phenylacetic Acid → HCID 178468614, compound

Dimethylformamide (DMF) (8.1 g, 8.6 mL, 110 mmol) was added dropwise to 13.8 g (8.4 mL, 90 mmol) of phosphorus oxychloride, while the internal temperature was maintained at 25°-30° C. using an ice bath. After stirring for 5 minutes at ambient temperature, phenylacetic acid (4.1 g, 30 mmol) was added dropwise as a solution in 15 mL of DMF. The mixture was heated at 70° C. overnight. The resultant brown solution was poured onto 125 g of ice and neutralized by the careful addition of potassium carbonate. The solution was heated to 50° C., and 36 mL of 50% aqueous sodium hydroxide was added at a rate to maintain the internal temperature in the 50°-60° C. range. The reaction mixture was heated at 50° C. for 2 hours and then cooled to ambient temperature. Water was added, and the aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered through Celite and concentrated in vacuo. The crude product was combined with 3.4 g of ethyl cyanoacetate (3.2 mL, 30 mmol) and 0.3 mL piperidine in 7 mL of ethanol. The solution was stirred for 72 hours at ambient temperature. Diisopropylethylamine (1 mL) was added, and the mixture was heated at reflux for 24 hours. The solvents were removed in vacuo, and the residue was chromatographed on silica gel using 5% methanol/0.5% acetic acid in chloroform to isolate the desired product (blue spot under 254 nM UV light). Final purification by ether precipitation gave the product as a white solid. 1H NMR (CDCl3, 300 MHz) δ 1.43 (t, J=7 Hz, 3H), 4.44 (q, J=7 Hz, 2H), 7.35-7.53 (m, 6H); 8.20 (bs, 1H), 8.50 (d, J=3 Hz, 2H). MS (DCl/NH3) m/e 244 (M+H)+.

1. temperaturewas maintained at 25°-30° C.
2. temperatureThe mixture was heated at 70° C. overnight
3. temperatureThe solution was heated to 50° C.
4. temperatureto maintain the internal temperature in the 50°-60° C. range
5. temperatureThe reaction mixture was heated at 50° C. for 2 hours
6. temperaturecooled to ambient temperature
7. extractionthe aqueous mixture was extracted twice with ethyl acetate
8. dry with materialThe combined organic extracts were dried over sodium sulfate
9. filtrationfiltered through Celite
10. concentrationconcentrated in vacuo
11. stirringThe solution was stirred for 72 hours at ambient temperature
12. temperaturethe mixture was heated
13. temperatureat reflux for 24 hours
14. customThe solvents were removed in vacuo
15. customthe residue was chromatographed on silica gel using 5% methanol/0.5% acetic acid in chloroform

ORD record

ord-84487aa089884ab19a8d2e3de671136d

Source dataset

uspto-grants-1993_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05250548