N-(9-Fluorenylmethoxycarbonyloxy)succinimide → 1-{[(9H-Fluoren-9-yl)methoxy]carbonyl}piperidine-2-carboxylic acid

Temperature

0 °C

The carboxylate salt 2-16 (0.084 g, 0.204 mmol) was dissolved in THF/MeOH/H2O (6:3:1, 9 mL) and the solution cooled to 0° C. LiOH.H2O (0.045 g, 1.07 mmol) dissolved in 0.4 mL H2O was added. The mixture was stirred at 0° C. for 20 hours. The solvent was removed under reduced pressure to give a white solid (Rf=0.31, CH2Cl2:MeOH 10:1). The white solid was dissolved in MeOH followed by addition of ammonium formate (0.106 g, 1.68 mmol) and Pd/C (10%, 0.049 g) under N2. The mixture was refluxed for 3 hours. The solution was then cooled, filtered through celite and syringe filter and the filtrate concentrated on a rotary evaporator to afford a white solid. The solid was dissolved in acetone/H2O (2:1, 9 mL) and cooled to 0° C., followed by the addition of Fmoc-OSu (0.067 g, 0.199 mmol) and NaHCO3 (0.16 g, 1.90 mmol). The turbid reaction mixture was stirred at 0° C. for 1 hour and was then allowed to stir at room temperature overnight. Acetone was mostly removed under reduced pressure. The aqueous residue was diluted with H2O (2 mL), diethyl ether (9 mL) added and the mixture stirred at room temperature for 1 hour. The layers were separated and the ether layer was washed three times with saturated NaHCO3. The aqueous phases were combined, acidified with 1N HCl and extracted three times with ethyl acetate (75 mL total volume). The combined organic extracts were dried over MgSO4, concentrated on a rotary evaporator, and dried under vacuum to afford a white solid. The crude product was purified by three crystallizations from n-hexane/chloroform to afford 0.05 g (53% yield) of 2-18 as white fluffy crystals: m.p. 206-208° C.; Rf=0.44, 10:1 CH2Cl2:MeOH; [α]23D=−36.0 (c 0.50, acetone); 1H NMR (300 MHz, CDCl3/CD3OD) δ 7.77 (d, J=7.5 Hz, 2H, ArH), 7.62 (d, J=6.9 Hz, 2H, ArH), 7.43-7.29 (m, 4H, ArH), 4.36-4.22 (m, 3H), 4.07-4.02 (m, 1H), 3.93-3.86 (m, 1H), 3.09-2.82 (m, 2H), 2.44-2.38 (m, 1H), 2.02-1.97 (m, 1H), 1.50-1.43 (m, 1H), 1.47 (s, 9H); 13C NMR (75 MHz, CDCl3/CD3OD) δ 173.38 (C), 155.83 (C), 154.21 (C), 143.23 (C), 140.69 (C), 127.07 (CH), 126.46 (CH), 124.42 (CH), 119.27 (CH), 80.00 (C), 66.35 (CH2), 49.73 (CH), 47.77 (CH), 46.57 (CH), 44.33 (CH2), 41.68 (CH2), 30.63 (CH2), 27.51 (CH3); MS-ESI m/z 243.1 [M−Fmoc]−, 465.1 [M−H]−, 931.2 [2M−H]−.

1. additionwas added
2. customThe solvent was removed under reduced pressure
3. customto give a white solid (Rf=0.31, CH2Cl2:MeOH 10:1)
4. temperatureThe mixture was refluxed for 3 hours
5. temperatureThe solution was then cooled
6. filtrationfiltered through celite and syringe
7. filtrationfilter
8. concentrationthe filtrate concentrated on a rotary evaporator
9. customto afford a white solid
10. temperaturecooled to 0° C.
11. customThe turbid reaction mixture
12. stirringwas stirred at 0° C. for 1 hour
13. stirringto stir at room temperature overnight
14. customAcetone was mostly removed under reduced pressure
15. additionThe aqueous residue was diluted with H2O (2 mL), diethyl ether (9 mL)
16. additionadded
17. stirringthe mixture stirred at room temperature for 1 hour
18. customThe layers were separated
19. washthe ether layer was washed three times with saturated NaHCO3
20. extractionextracted three times with ethyl acetate (75 mL total volume)
21. dry with materialThe combined organic extracts were dried over MgSO4
22. concentrationconcentrated on a rotary evaporator
23. customdried under vacuum
24. customto afford a white solid
25. customThe crude product was purified by three crystallizations from n-hexane/chloroform

ORD record

ord-8441db41bdd54662a095c3c2442e91f4

Source dataset

uspto-grants-2010_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07858737B2