Chlorotrimethylsilane → HCID 86677796, compound

Temperature

70 °C

Zinc (5.0 g, 77 mmol) and oven dried Celite (520 mg) was added to a flask and the flask was heated with a heat gun while under high-vac for 5 min and then back-filled with nitrogen. N,N-dimethylacetamide (53 mL) was added, followed by 1,2-dibromoethane (400 μL, 4.6 mmol) and the mixture was heated at 70° C. for 15 min and then cooled to room temperature. The reaction mixture was treated with chlorotrimethylsilane (580 μL, 4.6 mmol) dropwise and stirred at room temperature for 1 h. The reaction mixture was treated with a solution of tert-butyl 3-iodoazetidine-1-carboxylate (16 g, 58 mmol) in N,N-dimethylacetamide (26 mL) dropwise (internal temperature was kept below 40° C. with a water bath) and heated at 40° C. for 2 h. The zinc-iodo reagent (transferred via canula) was filtered through a plastic filter (that was appropriately sealed to avoid atmospheric exposure) directly into a clean, dry flask that was flushed with nitrogen. The reaction mixture was treated with tris(dibenzylideneacetone)dipalladium(0) (670 mg, 0.73 mmol) and tri-(2-furyl)phosphine (340 mg, 1.5 mmol) and degassed with nitrogen for a few minutes. The reaction mixture was treated with a solution of 4-acetyl-6-chloro-2-iodo-3-methoxybenzonitrile (13 g, 39 mmol) in N,N-dimethylacetamide (120 mL) (degassed with nitrogen) quickly and heated at 70° C. for 2 h. The reaction mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with water (4×500 mL) and brine (1×500 mL), dried with magnesium sulfate, filtered, and concentrated to a crude dark oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (5%-40%) to give the desired product (12 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 4.39-4.29 (m, 1H), 4.28-4.11 (m, 4H), 3.68 (s, 3H), 2.58 (s, 3H), 1.38 (s, 9H).

1. additionwas added to a flask
2. temperaturethe flask was heated with a heat gun while under high-vac for 5 min
3. additionback-filled with nitrogen
4. temperaturecooled to room temperature
5. temperatureheated at 40° C. for 2 h
6. filtrationThe zinc-iodo reagent (transferred via canula) was filtered through a plastic
7. filtrationfilter (that
8. customwas appropriately sealed
9. customdry flask that
10. customwas flushed with nitrogen
11. customdegassed with nitrogen for a few minutes
12. temperatureheated at 70° C. for 2 h
13. extractionextracted with ethyl acetate (3×300 mL)
14. washThe combined organic extracts were washed with water (4×500 mL) and brine (1×500 mL)
15. dry with materialdried with magnesium sulfate
16. filtrationfiltered
17. concentrationconcentrated to a crude dark oil
18. customThe crude material was purified by flash column chromatography

ORD record

ord-0081bbb7f24d4ed690f2b6dc85d013ca

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09199982B2