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-c9b92b6690c941cdbe8c948577debe60

Source dataset

uspto-grants-2006_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07056915B2