反应详情

温度

2.5 °C

To a stirred suspension of sodium hydride (60% w/w, 8.23 g, 205.7 mmol) in dry THF (350 mL) under an inert atmosphere was added 2-fluorobenzonitrile (20.34 g, 164.6 mmol) and the resulting mixture cooled to 2° C. (batch temperature). 2-(Methylamino)ethanol (16.04 mL, 197.5 mmol) was added at a rate commensurate with controlled hydrogen gas evolution. At the end of the addition, the mixture was allowed to warm to ambient temperature and held overnight. The reaction mixture was then concentrated in vacuo to ˜50 mL and partitioned between diethyl ether (200 mL) and water (200 mL). The aqueous phase was adjusted to pH 12 with aq. sodium hydroxide (1 M) and the phases separated. The aqueous fraction was re-extracted with diethyl ether (2×200 mL). Any interfacial gel was removed by filtration of the biphasic mixture through a short Celite pad before the phase separation. The organic fractions were combined, washed with brine (600 mL), dried over sodium sulfate and concentrated in vacuo to afford crude 2-[2-(methylamino)ethoxy]benzonitrile as an orange oil. This was dissolved in THF (195 mL) under an inert atmosphere and triethylamine (51.4 mL, 365 mmol) added. The stirred solution was cooled to 0-5° C. and benzyl chloroformate (37.0 mL, 238 mmol) added over 1 h. At the end of the addition, the mixture was allowed to warm slowly to ambient temperature where it was held overnight. Any residual benzyl chloroformate was then quenched through the addition of diethylamine (20 mL, 497 mmol). The resulting thick slurry was filtered through a short Celite pad, and the filtrate concentrated in vacuo. The residue was partitioned between aq. hydrochloric acid (0.2 M, 200 mL) and TBME (200 mL). The phases were separated and the organic phase washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to ˜120 mL. Isohexane was added slowly until cloudiness was observed whereupon the mixture was left to stir at ambient temperature overnight. The resulting slurry was filtered through 11 μm filter paper. The filter cake was washed with TBME/isohexane (1:1 v/v, 20 mL) and dried overnight (30° C., 400 mbar) to afford benzyl [2-[2-cyanophenoxy)ethyl]methylcarbamate (30.25 g). The mother liquors from the crystallisation and filtrate from the cake wash were combined, concentrated to dryness in vacuo and purified by chromatography on silica gel, eluting with an ethyl acetate/isohexane gradient, to afford further benzyl [2-[2-cyanophenoxy)ethyl]methylcarbamate (13.96 g). The solids were combined to give benzyl [2-(2-cyanophenoxy)ethyl]methylcarbamate (44.21 g, 99.9% w/w). Mp 52° C. (TBME/isohexane).

1. additionadded
2. additionAt the end of the addition
3. temperatureto warm slowly to ambient temperature where it
4. filtrationThe resulting thick slurry was filtered through a short Celite pad
5. concentrationthe filtrate concentrated in vacuo
6. customThe residue was partitioned between aq. hydrochloric acid (0.2 M, 200 mL) and TBME (200 mL)
7. customThe phases were separated
8. washthe organic phase washed with brine (100 mL)
9. dry with materialdried over sodium sulfate
10. concentrationconcentrated in vacuo to ˜120 mL
11. additionIsohexane was added slowly until cloudiness
12. waitwas left
13. filtrationThe resulting slurry was filtered through 11 μm
14. filtrationfilter paper
15. washThe filter cake was washed with TBME/isohexane (1:1 v/v, 20 mL)
16. customdried overnight (30° C., 400 mbar)