Chloroacetyl chloride → (R)-4-Benzyl-5-oxo-3-morpholinecarboxylic Acid

HRID 1366409Notes

Reaction equation

HRID 1366409 reaction equation
[C:1]1([CH2:7][NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23](Cl)=[O:24].[OH-].[Na+]>C1COCC1.O>[O:24]=[C:23]1[N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][CH2:22]1

Participants

7

Reactant 4

HCID 6577Chloroacetyl chloride2×HCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 13543366(R)-2-(Benzylamino)-3-hydroxypropanoic acid

Product 1

HCID 13543371(R)-4-Benzyl-5-oxo-3-morpholinecarboxylic AcidYield 75.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

As per the procedures of WO2005058245, a solution of N-(phenylmethyl)-D-serine (79.51 g, 407.3 mmol) in THF (485 mL) was cooled to 0° C., and a precooled 0° C. solution of K2CO3 (168.87 g, 1222 mmol) in water (485 mL) was added. To the well-stirred mixture was added chloroacetyl chloride (45.4 mL, 570.0 mmol) slowly while keeping the internal temperature below 5° C. The mixture was vigorously stirred at 0° C. for 30 min, and then an additional portion of chloroacetyl chloride (4.54 mL, 57.0 mmol) was slowly added. The mixture was stirred for an additional 30 min at 0° C. To the mixture was added a sufficient quantity of precooled 0° C. aqueous NaOH (50% w/w) to adjust the pH>13.5 while keeping the internal temperature between 5° C. and 10° C. The mixture was stirred at 0° C. for 2 h, and then warmed to 20° C. The mixture was washed with heptane (165 mL) followed by a second portion of fresh heptane (240 mL). The aqueous phase was cooled to 0° C., and adjusted to pH<2 with concentrated aqueous HCl while keeping the internal temperature less than 10° C. The mixture was placed in a 0° C. freezer overnight, and the solid was collected by vacuum filtration. The solid was washed with water (2×300 mL) and dried in vacuo at 42° C. overnight. The resulting (3R)-5-oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid (72.20 g, 75%) was isolated as a white solid. LCMS: (M+H)+: 236.1.

Workup

  1. customthe internal temperature below 5° C
  2. stirringThe mixture was stirred for an additional 30 min at 0° C
  3. customthe internal temperature between 5° C. and 10° C
  4. stirringThe mixture was stirred at 0° C. for 2 h
  5. temperaturewarmed to 20° C
  6. washThe mixture was washed with heptane (165 mL)
  7. temperatureThe aqueous phase was cooled to 0° C.
  8. customthe internal temperature less than 10° C
  9. waitThe mixture was placed in a 0° C. freezer overnight
  10. filtrationthe solid was collected by vacuum filtration
  11. washThe solid was washed with water (2×300 mL)
  12. customdried in vacuo at 42° C. overnight

Sources & evidence

ORD record
ord-c220f7e9f18847b8a9ada3cf3ad3867e
Source dataset
uspto-grants-2011_02
Patent number
US07893056B2

Reaction notes

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