Hydrochloric Acid → 2-(3-Chloro-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile

tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 82 g, 0.42 mol) was added to THF (850 mL) and the resulting solution was cooled to 0° C. before a 4 M HCl solution in 1,4-dioxane (850 mL, 3.38 mol, 8.0 equiv) was added over 1 h while keeping the temperature<5° C. The resulting reaction mixture was slowly warmed to room temperature and stirred at room temperature for 18 h. When the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure and the residue was placed under high vacuum for an additional 3 h before being treated with THF (900 mL) and diisopropylethyl amine (183 mL, 1.06 mol, 2.5 equiv) at room temperature. The resulting solution was then cooled to 0° C. and ethanesulfonyl chloride (56 mL, 0.59 mol, 1.4 equiv) was added while keeping the reaction temperature<5° C. The ice bath was removed and the reaction was stirred at room temperature for 18 h. When TLC indicated the reaction was complete, the reaction mixture was diluted with ethyl acetate (1 L) and washed with saturated brine (1 L). The aqueous layer was extracted with ethyl acetate (2×500 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was diluted with dichloromethane and absorbed onto silica gel (150 g). This mixture was purified by column chromatography (1.5 Kg silica gel) eluting with heptane (4 L), 10% EtOAc in heptane (4 L), 20% EtOAc in heptane (8L), 30% EtOAc in heptane (12 L), and finally with 40% EtOAc in heptane (12 L) to afford 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (4) and 2-(3-chloro-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (4B) as a off-white solid (58.1 g, 68% yield), which was found to be an approximately one to one mixture of compound 4 and 4B. For 4: 1H NMR (300 MHz, CDCl3) δ 1.38 (t, 3H), 3.05 (q, 2H), 4.72 (m, 2H), 4.79 (m, 2H), 5.41 (m, 1H); MS: m/z calcd. 187.05; found: 187.1. For 4B: 1H NMR (300 MHz, CDCl3) δ 1.38 (t, 3H), 3.05 (q, 2H), 3.1 (s, 2H), 4.15 (d, 2H), 4.37 (d, 2H); MS: m/z calcd. 222.9; found: 222.9.

1. additionwas added over 1 h
2. customthe temperature<5° C
3. customThe resulting reaction mixture
4. concentrationthe reaction mixture was concentrated under reduced pressure
5. waitthe residue was placed under high vacuum for an additional 3 h
6. temperatureThe resulting solution was then cooled to 0° C.
7. customthe reaction temperature<5° C
8. customThe ice bath was removed
9. stirringthe reaction was stirred at room temperature for 18 h
10. additionthe reaction mixture was diluted with ethyl acetate (1 L)
11. washwashed with saturated brine (1 L)
12. extractionThe aqueous layer was extracted with ethyl acetate (2×500 mL)
13. dry with materialThe combined organic layers were dried over sodium sulphate
14. concentrationconcentrated under reduced pressure
15. additionThe residue was diluted with dichloromethane
16. customabsorbed onto silica gel (150 g)
17. customThis mixture was purified by column chromatography (1.5 Kg silica gel)
18. washeluting with heptane (4 L), 10% EtOAc in heptane (4 L), 20% EtOAc in heptane (8L)

ORD record

ord-7306a0e4e2c9499d94bdd99cf8a0ac24

Source dataset

uspto-grants-2012_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08158616B2