N-Hydroxyphthalimide → 2-(cyclopropylmethoxy)-1H-isoindole-1,3(2H)-dione

Temperature

6 °C

To a stirring solution/suspension comprised of N-hydroxyphthalimide (Aldrich, 57.15 g, 339.8 mmol), cyclopropanemethanol (Aldrich, 25.10 g, 341.1 mmol), and triphenylphosphine (“DEAD,” Aldrich, 91.0 g, 344 mmol) in 1.00 L of tetrahydrofuran under a nitrogen atmosphere and cooled to 6° C. (internal mixture temperature) with an ice-water bath was added diethyl azodicarboxylate (Aldrich, 56 ml, 356 mmol) dropwise over 20 minutes via addition funnel. The reaction mixture temperature was kept below 20° C. during the addition. Following addition of the DEAD, the cold bath was removed and the reaction mixture was stirred for 15 hours. The mixture was concentrated to a paste under reduced pressure. Chloroform (ca. 300 ml) was added and the mixture swirled to loosen all solids. Vacuum filtration removed the insolubles. The filtrate was likewise filtered to remove white precipitate that formed and to give a clear filtrate. Concentration under reduced pressure afforded a clear oil. Flash filtration through silica gel (100% chloroform) gave filtrates containing unseparated product. These filtrates were combined and concentrated under reduced pressure to afford 127.4 g of a clear oil. The oil was dissolved in absolute ethanol (400 ml) and the solution was refrigerated for two hours. A white crystalline solid had precipitated and was subsequently collected by vacuum filtration. The product was dried in the vacuum oven (60° C.) to afford 42.66 g (58%) of the desired material; m.p. 71-77° C.; 1H-NMR (400 MHz; CDCl3 signal offset to δ6.96) δ7.54-7.43 (m, 4H), 3.74 (d, 2H, J=7.6 Hz), 1.02-0.95 (m, 1H), 0.34-0.30 (m, 1H) 0.04-0.00 (m, 1H).

1. additionvia addition funnel
2. additionThe reaction mixture temperature was kept below 20° C. during the addition
3. customthe cold bath was removed
4. concentrationThe mixture was concentrated to a paste under reduced pressure
5. additionChloroform (ca. 300 ml) was added
6. filtrationVacuum filtration
7. customremoved the insolubles
8. filtrationThe filtrate was likewise filtered
9. customto remove white precipitate
10. customthat formed
11. customto give a clear filtrate
12. concentrationConcentration under reduced pressure
13. customafforded a clear oil
14. filtrationFlash filtration through silica gel (100% chloroform)
15. customgave filtrates
16. additioncontaining unseparated product
17. concentrationconcentrated under reduced pressure

ORD record

ord-60e15d71f6de410681a189b3540c5a61

Source dataset

uspto-grants-2002_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06469004B1