Sodium Chloride → 1-methyl-2,3-dihydro-1H-inden-2-one

Temperature

-55 °C

A solution of 1-(1H-inden-2-yl)pyrrolidine (1.00 g, 5.40 mmol) in anhydrous 2-methyltetrahydrofuran (13.3 mL) was cooled to −55° C. and treated with a solution of n-BuLi (1.6 M in hexanes, 4.0 mL, 6.4 mmol) dropwise. The mixture was then stirred at −55° C. for 15 min. Iodomethane (0.4 mL, 6.3 mmol) was added and, after stirring for 5 min, the mixture was quenched by addition of 1 N HCl (6.7 mL). The solvent was removed in vacuo, water (17 mL) was added and the mixture was heated at reflux for 10 min. The mixture was then cooled to ambient temperature and extracted with diethyl ether. The organic layer was washed with brine, and the combined aqueous layers were saturated with NaCl and extracted twice more with diethyl ether. The combined organic extracts were dried (Na2SO4), filtered and concentrated to give an oil, which was treated with TFA (2.5 mL) in CH2Cl2 (2.5 mL) for 5 min. The mixture was concentrated in vacuo and the residue purified by reverse phase preparative HPLC eluting with a gradient of 90:10 to 0:100 A:B where A=0.1% TFA in H2O and B=0.1% TFA in CH3CN). The fractions containing product were combined and concentrated to give an aqueous residue which was saturated with NaCl and extracted with EtOAc (3×). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound. MS: m/z=147.1 (M+1).

1. stirringafter stirring for 5 min
2. customthe mixture was quenched by addition of 1 N HCl (6.7 mL)
3. customThe solvent was removed in vacuo, water (17 mL)
4. additionwas added
5. temperaturethe mixture was heated
6. temperatureat reflux for 10 min
7. temperatureThe mixture was then cooled to ambient temperature
8. extractionextracted with diethyl ether
9. washThe organic layer was washed with brine
10. extractionextracted twice more with diethyl ether
11. dry with materialThe combined organic extracts were dried (Na2SO4)
12. filtrationfiltered
13. concentrationconcentrated
14. customto give an oil, which
15. concentrationThe mixture was concentrated in vacuo
16. customthe residue purified by reverse phase preparative HPLC
17. washeluting with a gradient of 90:10 to 0:100 A:B where A=0.1% TFA in H2O and B=0.1% TFA in CH3CN)
18. additionThe fractions containing product
19. concentrationconcentrated
20. customto give an aqueous residue which
21. extractionextracted with EtOAc (3×)
22. dry with materialThe combined organic extracts were dried (Na2SO4)
23. filtrationfiltered
24. concentrationconcentrated in vacuo

ORD record

ord-081c20da38764032a6a2723a61a44efb

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09296750B2