[(3R,3aS,6aR)-Hydroxyhexahydrofuro[2,3-β]furanyl Succinimidyl Carbonate

Chemical Properties

Pale-Yellow Solid

Uses

Darunavir intermediate.

Synthesis

1. 26.3 g of tert-butyl methyl ether, 35.09 g (135 mmol) of N,N'-disuccinimidyl carbonate, and 20.00 g (73.0% content) of (3R,3aS,6aR)-hexahydrofuro[2,3-B]furan-3-ol were mixed at room temperature, and the mixture was heated to 40 °C. 2. 11.89 g (150 mmol) of pyridine was added slowly and dropwise to the reaction mixture at 40 °C. 3. the reaction mixture was stirred at 40 °C for 22 hours. 4. Upon completion of the reaction, the reaction solution was cooled to 20 °C and 73.0 g of 2-propanol was slowly added dropwise at 20 °C to precipitate the target product 2,5-dioxopyrrolidin-1-yl ((3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl) carbonate. 5. The mixture was further cooled to 0-5°C and stirred at that temperature for 19 hours. 6. The precipitated target product was collected by filtration and washed with an appropriate solvent to give 27.83 g of product (97.8% content, 90% yield, enantiomeric excess >99.9% ee). 7. for the isolation of diastereoisomers, 30.0 g of tert-butyl methyl ether, 11.87 g of (3R,3aS,6aR)-hexahydrofuro[2,3-B]furan-3-ol containing 84.3% of the diastereoisomers, and the enzyme (CHIRAZYME L-2c, -flyo, Roche Diagnostics) were mixed at 25°C. 8. 3.31 g (38.4 mmol) of ethyl acetate was added dropwise to the mixture and the insoluble material was removed by filtration after stirring at 25 °C for 40 hours. 9. The filtrate was concentrated to give 12.73 g of a mixture containing (3R,3aS,6aR)-hexahydrofuro[2,3-B]furan-3-ol and its 3S,3aS,6aR isomer (90% yield, diastereoisomer ratio 100.0/0.0).

References

[1] Patent: JP2016/150901, 2016, A. Location in patent: Paragraph 0016; 0017; 0023; 0024
[2] Journal of Organic Chemistry, 2004, vol. 69, # 23, p. 7822 - 7829
[3] European Journal of Organic Chemistry, 2016, vol. 2016, # 10, p. 1874 - 1880
[4] Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 1813 - 1822
[5] Patent: WO2010/23322, 2010, A1. Location in patent: Page/Page column 29