4-Methylmorpholine → Phenylmethyl (3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-4-hydroxybutanoate

Temperature

-7.5 °C

N-(tert-butoxycarbonyl)-L-aspartic acid 4-benzyl ester (1.23 g, 3.80 mmol) was dissolved in dimethoxyethane (3.6 mL) in a flame-dried flask. The solution was cooled to −5 to −10° C. N-methylmorpholine (0.422 mL, 3.84 mmol) was then added dropwise, followed by a slow addition of isobutyl chloroformate (0.525 mL, 3.9 mmol) while the reaction temperature was maintained below −10° C. The mixture was aged for 30 minutes. The solids were quickly filtered and washed with dimethoxyethane (3.6 mL). The filtrate was cooled to −50° C. and a solution of sodium borohydride (0.18 g, 4.76 mmol) in water (1.8 mL) was added slowly while the reaction temperature was maintained between −30° C. and −15° C. Water (20 mL) was then added such that the reaction mixture temperature was maintained below −15° C. The reaction mixture was extracted with ethyl acetate (3×5 mL), washed with cold 0.1N HCl, then saturated sodium bicarbonate solution and then brine. The organic phase was dried with magnesium sulfate. Evaporated to dryness to yield an oil that crystallizes upon standing. LC-MS m/z=332 (M+Na+).

1. temperaturewas maintained below −10° C
2. filtrationThe solids were quickly filtered
3. washwashed with dimethoxyethane (3.6 mL)
4. temperatureThe filtrate was cooled to −50° C.
5. temperaturewas maintained between −30° C. and −15° C
6. temperaturewas maintained below −15° C
7. extractionThe reaction mixture was extracted with ethyl acetate (3×5 mL)
8. washwashed with cold 0.1N HCl
9. dry with materialThe organic phase was dried with magnesium sulfate
10. customEvaporated to dryness
11. customto yield an oil that
12. customcrystallizes

ORD record

ord-b066ecb8fe544e5e827691bda7e4db43

Source dataset

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08791162B2