Methyl Nicotinate → Methyl 4-(3-ethoxy-3-oxopropyl)nicotinate

Temperature

80 °C

Under an argon gas atmosphere, a mixture of zinc (21.0 g, 321 mmol) and 1,2-dibromoethane (1.40 mL, 16.2 mmol) in tetrahydrofuran (105 mL) was stirred at 80° C. for 20 min. After cooling to room temperature, chlorotrimethylsilane (400 μL, 3.13 mmol) was added at room temperature, and the mixture was stirred for 30 min. A solution of ethyl 3-iodopropanoate (60.0 g, 263 mmol) in tetrahydrofuran (53 mL) was added dropwise to the mixture at room temperature, and the mixture was stirred at 40° C. for 3 hr. A solution of copper(I) cyanide (19.2 g, 214 mmol) and lithium chloride (18.3 g, 432 mmol) in tetrahydrofuran (50 mL) was added dropwise to the mixture at 0° C., and the mixture was stirred for 30 min. This mixture was added dropwise at −78° C. under an argon gas atmosphere to a mixture obtained by stirring a solution of ethyl chlorocarbonate (19.4 mL, 203 mmol) and methyl nicotinate (27.8 g, 203 mmol) in tetrahydrofuran (105 mL) at 0° C. for 30 min, and the mixture was stirred for 12 hr while heating to room temperature. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the insoluble material was filtered off. The filtrate was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Xylene (105 mL) and sulfur (20.0 g, 624 mmol) were added to the residue, and the mixture was stirred at 140° C. for 12 hr. After cooling to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (20.5 g, yield 43%).

1. temperatureAfter cooling to room temperature
2. stirringthe mixture was stirred for 30 min
3. stirringthe mixture was stirred at 40° C. for 3 hr
4. stirringthe mixture was stirred for 30 min
5. additionThis mixture was added dropwise at −78° C. under an argon gas atmosphere to a mixture
6. customobtained
7. stirringthe mixture was stirred for 12 hr
8. temperaturewhile heating to room temperature
9. filtrationthe mixture was filtered
10. concentrationThe filtrate was concentrated under reduced pressure
11. filtrationthe insoluble material was filtered off
12. extractionThe filtrate was extracted with ethyl acetate
13. dry with materialthe extract was dried over anhydrous sodium sulfate
14. customThe solvent was evaporated under reduced pressure
15. stirringthe mixture was stirred at 140° C. for 12 hr
16. temperatureAfter cooling to room temperature
17. filtrationthe insoluble material was filtered off
18. concentrationthe filtrate was concentrated under reduced pressure
19. customThe residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70)

ORD record

ord-789b8ebdfb1a437cb9de87fdee22423e

Source dataset

uspto-grants-2012_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08247429B2