Triethylamine → (R)-tert-butyl 2-((5-chloro-2-cyanopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate

Temperature

80 °C

To a stirred solution of (R)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-5-chloropyridine 1-oxide (610 mg, 1.855 mmol, EXAMPLE 29 Step 2) and triethylamine (1.56 mL, 11.13 mmol) in acetonitrile was added trimethylsilyl cyanide (TMSCN) (1.24 mL, 9.28 mmol) at ambient temperature and the mixture was heated at 80° C. After being stirred at 80° C. for 15 h, the mixture was cooled to room temperature. 1.24 mL of TMSCN (9.28 mmol) and 1.56 mL of triethylamine (11.13 mmol) were added to the mixture and the mixture was heated at 80° C. further 6 h. After cooling to room temperature, the mixture was concentrated in vacuo to give a dark brown oil. The residual oil was dissolved with ethyl acetate and 2 N aq. sodium hydroxide. The mixture was extracted with ethyl acetate twice and washed with water, 2 N hydrochloric acid, and brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to afford an oil. The residual oil was purified by silica gel column chromatography (hexane to ethyl acetate/hexane 1:4) to afford 364 mg (58%) of the title compound as a waxy solid.

1. temperaturethe mixture was cooled to room temperature
2. temperaturethe mixture was heated at 80° C. further 6 h
3. temperatureAfter cooling to room temperature
4. concentrationthe mixture was concentrated in vacuo
5. customto give a dark brown oil
6. extractionThe mixture was extracted with ethyl acetate twice
7. washwashed with water, 2 N hydrochloric acid, and brine
8. dry with materialdried over sodium sulfate
9. concentrationconcentrated in vacuo
10. customto afford an oil
11. customThe residual oil was purified by silica gel column chromatography (hexane to ethyl acetate/hexane 1:4)

ORD record

ord-1521fca0122746b883562431ad7f862d

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08969383B2