Sulfuric Acid → HCID 45257655, compound

Temperature

40 °C

In a nitrogen gas atmosphere, a solution composed of (S)-N-(ethoxycarbonyl)phenylalanine methyl ester (35.0 g, 139 mmol), sodium monochloroacetate (24.2 g, 208 mmol), magnesium chloride (19.9 g, 208 mmol) and tetrahydrofuran (125 ml) was stirred at 40° C. for 3 hours (solution A). Separately, in a nitrogen atmosphere, diisopropylamine (65.0 g, 642 mmol) was added dropwise at 40° C. over 30 minutes to n-butylmagnesium chloride (2 M THF solution, 278 ml, 556 mmol) and the resulting mixture was further stirred at 40° C. for 2 hours (solution B). Solution B was added at about 10° C. (inside temperature) over about 30 minutes to solution A. After completion of the addition, the inside temperature was raised to 40° C. and stirring was continued for further 2 hours. Then, the reaction mixture was mixed with 900 ml of an ice-cooled mixed solution composed of 10% (w/v) aqueous solution of sulfuric acid and 550 ml of ethyl acetate with stirring. After thorough mixing, the mixture was allowed to separate into layers. The organic layer was washed in sequence with a saturated aqueous solution of sodium hydrogen carbonate (300 ml) and a saturated solution of sodium chloride (300 ml) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, 30 ml of isopropanol was added to the residue, the mixture was heated to 60 to effect dissolution, 600 ml of hexane was then added, and the mixture was gradually cooled to 5° C. for allowing crystallization. The precipitate crystals were collected by filtration, washed with hexane and dried under reduced pressure to give 28.5 g of white needle crystals. 1H NMR (400 MHz, CDCl3): δ7.35 to 7.16 (m, 5H), 5.17 (d, 1H), 4.75 (q, 1H), 4.17 to 4.08 (m, 2H), 4.00 to 3.96 (ds, 2H), 3.09 to 3.07 (m, 2H), 1.23 (t, 3H)

1. additionAfter completion of the addition
2. temperaturecooled
3. additionmixed solution
4. stirringwith stirring
5. customto separate into layers
6. washThe organic layer was washed in sequence with a saturated aqueous solution of sodium hydrogen carbonate (300 ml)
7. dry with materiala saturated solution of sodium chloride (300 ml) and then dried over anhydrous sodium sulfate
8. distillationThe solvent was distilled off under reduced pressure, 30 ml of isopropanol
9. additionwas added to the residue
10. temperaturethe mixture was heated to 60
11. dissolutiondissolution, 600 ml of hexane
12. additionwas then added
13. temperaturethe mixture was gradually cooled to 5° C.
14. customcrystallization
15. filtrationThe precipitate crystals were collected by filtration
16. washwashed with hexane
17. customdried under reduced pressure

ORD record

ord-f6eb26858921478aaad3f78f423cf154

Source dataset

uspto-grants-2000_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06020518