Water → 1,2-Dimethylpiperidin-4-one

Temperature

-15 °C

A 1 M solution of TiCl4 in CH2Cl2 (23 mL, 23 mmol, 1.0 equiv) was added to a flask under Ar and cooled to −15° C. with a MeOH/ice water bath. 3-[(2-Methoxycarbonyl-ethyl)-methyl-amino]-butyric acid methyl ester (5 g, 23 mmol, 1.0 equiv) was added dropwise over a 25 min period as a solution in 75 mL of dry CH2Cl2 to give a dark red mixture that was difficult to stir with a magnetic stir bar. Stirring was continued an additional 1 h and then Et3N (5.1 g, 50.6 mmol, 2.2 equiv) was added dropwise over a 30 min period and then the reaction was stirred an additional 1.5 h at −15° C. The reaction mix was poured into 150 mL of brine and 150 mL of CH2Cl2 was added. After thorough mixing, the pH of the water was brought to 8-9 with Et3N. The mix was filtered and the gel-like solid was washed 3×100 mL CH2Cl2. The filtrate layers were separated and the aqueous layer was washed 3×50 mL CH2Cl2. All of the organic layers were combined and concentrated to a thick red oil. The residue was taken up in 150 mL of concentrated HCl and the solution was refluxed 4 h. The cooled reaction solution was evaporated to dryness and the residue was dissolved in 200 mL of saturated sodium bicarbonate solution. The product ketone was extracted with 2×100 mL of EtOAc. The organic layers were combined and dried over Na2SO4. The product was purified by flash chromatography on SiO2 using pure CH2Cl2 to 4% MeOH in CH2Cl2 as eluent. The product was isolated as an orange oil (1.23 g, 42%); MS, m/z 128=M+1.

1. customto give a dark red mixture that
2. stirringStirring
3. stirringthe reaction was stirred an additional 1.5 h at −15° C
4. additionThe reaction mix
5. additionwas added
6. filtrationThe mix was filtered
7. washthe gel-like solid was washed 3×100 mL CH2Cl2
8. customThe filtrate layers were separated
9. washthe aqueous layer was washed 3×50 mL CH2Cl2
10. concentrationconcentrated to a thick red oil
11. temperaturethe solution was refluxed 4 h
12. customThe cooled reaction solution
13. customwas evaporated to dryness
14. dissolutionthe residue was dissolved in 200 mL of saturated sodium bicarbonate solution
15. extractionThe product ketone was extracted with 2×100 mL of EtOAc
16. dry with materialdried over Na2SO4
17. customThe product was purified by flash chromatography on SiO2 using pure CH2Cl2 to 4% MeOH in CH2Cl2 as eluent

ORD record

ord-cf8afffd70b04915a540834eb78bf7b8

Source dataset

uspto-grants-2007_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07279472B2