Toluene → (S)-Benzyl (tetrahydro-2,5-dioxo-3-furyl)carbamate

In 15 mL of ethyl acetate was suspended 5.0 g (18.73 mmol) of N-benzyloxycarbonyl-L-aspartic acid (compound B′). This solution was stirred at room temperature in a nitrogen atmosphere. Thereto was added dropwise 1.76 g of acetyl chloride (98%, 22.48 mmol). The mixture was stirred at 60° C. for 2 hours. After completion of the reaction, 50 mL of toluene and 6 mL of dimethylformamide were added to the reaction mixture. The resultant mixture was heated to 90 to 103° C. to remove 20 mL of volatile ingredients including the ethyl acetate and the excess acetyl chloride by azeotropic distillation. The N-benzyloxycarbonyl-L-aspartic anhydride (compound 1) thus yielded was subjected to the subsequent step without being taken out. To the reaction mixture was added dropwise 2.0 g (18.69 mmol) of benzylamine at 44 to 54° C. Thereafter, a Dean Stark condenser was attached to the reactor, and the reaction mixture was heated with refluxing and stirring for 30 minutes. After the reaction mixture was cooled, 0.36 g (18.95 mmol) of p-toluenesulfonic acid monohydrate was added thereto and this mixture was heated at 110° C. with refluxing for 8 hours to conduct azeotropic dehydration (reaction yield, 80%; optical purity, 94%ee). The resultant reaction mixture was cooled and then, while being kept at 70° C., subjected twice to washing with 10 mL of saturated aqueous sodium hydrogen carbonate solution and then once to washing with 10 mL of saturated aqueous sodium chloride solution, followed by liquid separation each time. Subsequently, the organic layer obtained was heated with refluxing for 30 minutes to conduct azeotropic dehydration and then cooled to cause crystallization. Crystals began to separate out at 65° C. The organic layer was stirred for 1 hour with cooling to 20° C. and then further stirred at 10° C. or lower for 30 minutes. The crystals formed were isolated by filtration, washed with 20 mL of toluene, and then vacuum-dried to obtain 4.64 g of white crystals (13.73 mmol; isolation yield, 71.1%). The solid obtained was ascertained to be (3S)-1-benzyl-3-benzyloxycarbonylaminopyrrolidine-2,5-dione (compound 2′) by 1H-NMR spectroscopy. Analysis by HPLC revealed that this reaction product had a chemical purity of 100% and an optical purity of 100%ee.

1. stirringThe mixture was stirred at 60° C. for 2 hours
2. additionwere added to the reaction mixture
3. customto remove 20 mL of volatile ingredients
4. distillationthe excess acetyl chloride by azeotropic distillation

ORD record

ord-bf2aae41487842aa9ba8c5573750229a

Source dataset

uspto-grants-2003_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06531594B2