1,4-Dioxane → 1-Piperidinecarboxylic acid, 3-(cyclopropylcarbonyl)-4-oxo-, 1,1-dimethylethyl ester

N,N-Diisopropylethylamine (4.14 mL, 23.8 mmol) was added to a solution of tert-butyl 4-pyrrolidin-1-yl-3,6-dihydropyridine-1(2H)-carboxylate (5.00 g, 19.8 mmol) in 1,4-dioxane (10 mL). The reaction mixture was cooled in an ice bath and treated drop-wise with a solution of cyclopropanecarbonyl chloride (2.18 mL, 23.8 mmol) in 1,4-dioxane (3 mL). The mixture was allowed to stir at room temperature for 16 hours; water (10 mL) was added, and the solution was heated at reflux for 30 minutes. After cooling, the reaction was diluted with additional water (10 mL), and extracted with diethyl ether. The combined organic layers were washed sequentially with water, with 5% aqueous citric acid solution and with saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification using silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided the product as a yellow oil. Yield: 4.23 g, 15.8 mmol, 80%. 1H NMR (400 MHz, CDCl3) δ 4.39 (br s, 2H), 3.59 (br dd, J=5.9, 5.9 Hz, 2H), 2.43 (br dd, J=5.7, 5.9 Hz, 2H), 1.74-1.85 (br m, 1H), 1.50 (s, 9H), 1.17-1.22 (m, 2H), 0.96-1.02 (m, 2H).

1. temperatureThe reaction mixture was cooled in an ice bath
2. temperaturethe solution was heated
3. temperatureat reflux for 30 minutes
4. temperatureAfter cooling
5. extractionextracted with diethyl ether
6. washThe combined organic layers were washed sequentially with water, with 5% aqueous citric acid solution and with saturated aqueous sodium chloride solution
7. dry with materialThe organic layer was dried over magnesium sulfate
8. filtrationfiltered
9. concentrationconcentrated in vacuo
10. customPurification

ORD record

ord-4d6b1db343a7478eb5a033427c59c743

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09296761B2