Sulfuric Acid → ethyl 4(R)-amino-4-phenylbutyrate

Temperature

-78 °C

To a stirred solution of 2,4,4-trimethyl-2-oxazoline (620 μL, 4.8 mmol) in 10 mL of anhydrous tetrahydrofuran was added a 2.5 M solution of butyllithium (1.76 mL, 4.4 mmol) in hexane at -78° C. under an argon atmosphere. The reaction mixture was stirred at -78° C. for 30 min. A solution of N-(tert-Butoxycarbonyl)-2-(S)phenylglycinbromide (14) (1.08 g, 3.6 mmol) in 25 mL of anhydrous THF was added dropwise over a period of 10 min. The reaction mixture was stirred at -78° C. for 30 min, then at room temperature for 45 min, quenched with cold saturated sodium chloride aqueous solution, extracted with ether (5×5 mL). The combined ether extracts were washed with water, brine, dried over anhydrous MgSO4, concentrated under reduced pressure to give a crude 4,4-dimethyl-2-[3(R)-phenyl-3-(tert-butoxycarbamidyl)propyl-2-oxazoline. 1H NMR (CDCl3) δ 1.256 (s, 6H, 2CH3), 1.398 (s, 9H, tert-Bu), 2.05-2.35 (m, 4H), 3.879 (s, 2H), 4.670 (d, 1H, J=3.6 Hz), 5.614 (d, 1H, J=7.2 Hz), 7.20-7.34 (m, 5H); 13C NMR (CDCl3) δ 24.97, 28.18, 32.52, 54.68, 66.72, 78.80, 126.03, 126.95, 128.32, 142.34, 155.09, 165.53. To a stirred solution of this crude 4,4-dimethyl-2-[3(R)-phenyl-3-(tert-butoxycarbamidyl)propyl-2-oxazoline (1.0 g, 3.01 mmol) in 20 mL of 95% ethanol was added a solution of 2.0 mL of concentrated sulfuric acid in 18 mL of 95% ethanol at room temperature. The reaction mixture was heated to reflux for 15 h, cooled to room temperature, concentrated at reduced pressure. The residue was neutralized with 5% sodium bicarbonate solution, then basified with saturated sodium carbonate solution, extracted with methylene chloride (4×20 mL). The combined methylene chloride extracts were washed with brine, dried over anhydrous MgSO4, concentrated under reduced pressure to give 580 mg of product (76% yield for two steps) as a thick oil. 1H NMR (CDCl3) δ 1.220 (t, 3H, J=7.2 Hz, CH3), 1.694 (br, 2H, NH2), 1.92-2.04 (m, 2H), 2.24-2.34 (m, 2H), 3.901 (t, 1H, J=6.9 Hz, benzyl), 4.082 (q, 2H, J=7.2 Hz, OCH2), 7.20-7.45 (m, 5H, aryl); 13C NMR (CDCl3) δ 14.00, 31.11, 34.13, 55.25, 60.08, 126.08, 126.93, 128.33, 145.44, 173.25.

1. stirringThe reaction mixture was stirred at -78° C. for 30 min
2. waitat room temperature for 45 min
3. customquenched with cold saturated sodium chloride aqueous solution
4. extractionextracted with ether (5×5 mL)
5. washThe combined ether extracts were washed with water, brine
6. dry with materialdried over anhydrous MgSO4
7. concentrationconcentrated under reduced pressure
8. customto give a crude 4,4-dimethyl-2-[3(R)-phenyl-3-(tert-butoxycarbamidyl)propyl-2-oxazoline
9. temperatureThe reaction mixture was heated
10. temperatureto reflux for 15 h
11. temperaturecooled to room temperature
12. concentrationconcentrated at reduced pressure
13. extractionextracted with methylene chloride (4×20 mL)
14. washThe combined methylene chloride extracts were washed with brine
15. dry with materialdried over anhydrous MgSO4
16. concentrationconcentrated under reduced pressure

ORD record

ord-dcf4b55293c94e3aa0ad9cb5bc6575a1

Source dataset

uspto-grants-2000_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06162417