1,2-Dibromoethane → HCID 86677725, compound

Temperature

140 °C

A round-bottom flask equipped with a magnetic stir bar and a rubber septum was charged with lithium chloride (3.9 g, 91 mmol). The flask was heated at 140° C. for 10 min under high vacuum and backfilled with nitrogen after cooling to room temperature. Zinc (6.0 g, 91 mmol) was added and the flask was heated at 140° C. for 10 min under high vacuum and backfilled with nitrogen after cooling to room temperature. Tetrahydrofuran (THF) (38 mL) and 1,2-dibromoethane (233 μL, 2.70 mmol) were added via syringe. The mixture was heated at 60° C. for 10 min and then cooled to room temperature. Chlorotrimethylsilane (68 pt, 0.54 mmol) and iodine (69 mg, 0.27 mmol) in THF (1 mL) were added and the resulting mixture was stirred at 60° C. for 10 min then cooled to room temperature. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (12.17 g, 42.99 mmol) in THF (10 mL) was then added and the mixture stirred at 40° C. for 1 h and at room temperature for 1 h. Another flask charged with 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (13.0 g, 38.0 mmol), palladium acetate (170 mg, 0.76 mmol), 2′-(dicyclohexylphosphino)-N,N,N′,N′-tetramethylbiphenyl-2,6-diamine (660 mg, 1.5 mmol), and toluene (35 mL) was evacuated under high vacuum and backfilled with nitrogen. The mixture was cooled to 0° C. and the zinc reagent made above was added slowly via syringe. After addition, the reaction was heated to 50° C. overnight. The reaction solution was partitioned between EtOAc and sat. NH4Cl solution. The layers were separated and the aqueous extracted further with EtOAc (2×). The combined organics were washed with water, brine, then dried over MgSO4, and concentrated. The crude mixture was purified on silica gel column to give the desired product as an orange oil (6.3 g, 45%). LCMS calculated for C18H23ClFNO4Na (M+Na)+: m/z=394.1; Found: 394.1.

1. customA round-bottom flask equipped with a magnetic stir bar
2. temperatureafter cooling to room temperature
3. temperaturethe flask was heated at 140° C. for 10 min under high vacuum
4. temperatureafter cooling to room temperature
5. temperatureThe mixture was heated at 60° C. for 10 min
6. temperaturecooled to room temperature
7. temperaturethen cooled to room temperature
8. stirringthe mixture stirred at 40° C. for 1 h and at room temperature for 1 h
9. customwas evacuated under high vacuum
10. temperatureThe mixture was cooled to 0° C.
11. additionabove was added slowly via syringe
12. additionAfter addition
13. temperaturethe reaction was heated to 50° C. overnight
14. customThe reaction solution was partitioned between EtOAc and sat. NH4Cl solution
15. customThe layers were separated
16. extractionthe aqueous extracted further with EtOAc (2×)
17. washThe combined organics were washed with water, brine
18. dry with materialdried over MgSO4
19. concentrationconcentrated
20. customThe crude mixture was purified on silica gel column

ORD record

ord-4deb336ec1264cc58e4169c41e834e61

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09199982B2