Ethyl chloroacetate → 3-{4-[2-(Tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-hydroxy-propionic acid ethyl ester

To a solution of [2-(4-formyl-phenyl)-ethyl]-heptyl-carbamic acid tert-butyl ester (8 g crude, ˜18.4 mmol) and ethyl chloroacetate (27.7 mmol, 2.73 mL) dissolved in anhydrous tetrahydrofuran (50 mL) was added NaH (60% oil dispersion, 27.7 mmol, 1.1 g). The mixture was allowed to stir at room temperature for 1 h, then was refluxed for 10 minutes. The mixture was cooled to room temperature and quenched by the addition of ethanol. The solution was diluted with water and extracted with ethyl acetate (3×). The organic layers were combined, washed with saturated brine (2×), dried over Na2SO4 and concentrated to a crude oil. The oil was dissolved in methanol (150 mL). To this solution was added ammonium formate (34.2 mmol; 2.16 g) and 10% Pd/C (170 mg). The mixture was heated to reflux for 2 h, then cooled to room temperature and filtered through Celite®. The filtrate was concentrated to a tan solid and redissolved in water. The aqueous solution was extracted with ethyl acetate (3×). The organic layers were combined, washed with brine (2×), dried over Na2SO4, and concentrated to a crude oil. The oil was purified by chromatography on silica gel (Merck silica gel 60, art#9385-3) eluting with 35% ethyl acetate in hexanes to give 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}2-hydroxy-propionic acid ethyl ester as a clear oil (3.17 g, 41%).

1. temperaturewas refluxed for 10 minutes
2. temperatureThe mixture was cooled to room temperature
3. customquenched by the addition of ethanol
4. additionThe solution was diluted with water
5. extractionextracted with ethyl acetate (3×)
6. washwashed with saturated brine (2×)
7. dry with materialdried over Na2SO4
8. concentrationconcentrated to a crude oil
9. dissolutionThe oil was dissolved in methanol (150 mL)
10. temperatureThe mixture was heated
11. temperatureto reflux for 2 h
12. temperaturecooled to room temperature
13. filtrationfiltered through Celite®
14. concentrationThe filtrate was concentrated to a tan solid
15. dissolutionredissolved in water
16. extractionThe aqueous solution was extracted with ethyl acetate (3×)
17. washwashed with brine (2×)
18. dry with materialdried over Na2SO4
19. concentrationconcentrated to a crude oil
20. customThe oil was purified by chromatography on silica gel (Merck silica gel 60, art#9385-3)
21. washeluting with 35% ethyl acetate in hexanes

ORD record

ord-02d35f7677ba489f85c51e8f633e3115

Source dataset

uspto-grants-2004_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06699904B2