Iodine → HCID 178433768, compound

Temperature

140 °C

A microwave tube equipped with a magnetic stir bar and a rubber septum was charged with lithium chloride (44.9 mg, 1.06 mmol). The vial was heated at 140° C. for 10 min under high vacuum and backfilled with nitrogen after cooling to room temperature. Zinc (69.3 mg, 1.06 mmol) was added and the vial was heated at 140° C. for 10 min under high vacuum and backfilled with nitrogen. After cooling to room temperature, THF (0.6 mL) and 1,2-dibromoethane (3.4 μL, 0.040 mmol) was added via syringe. The mixture was heated at 60° C. for 10 min and then cooled to room temperature. Chlorotrimethylsilane (0.99 μL, 0.0078 mmol) and iodine (1.0 mg, 0.0039 mmol) in THF (0.2 mL) was added and stirred at 60° C. for 10 min and cooled to room temperature. (trans-4-Iodocyclohexyl)acetonitrile (132 mg, 0.53 mmol) in THF (0.2 mL) was then added, and the mixture stirred at 50° C. overnight. 9-Bromo-8-methylpyrazolo[1,5-c]thieno[2,3-e]pyrimidine (80.2 mg, 0.299 mmol), 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (29 mg, 0.072 mmol) in toluene (0.2 mL) were added to a microwave vial. The vial was evacuated under high vacuum and backfilled with nitrogen. The mixture was cooled to 0° C. and the zinc reagent was added slowly via syringe. After addition, the reaction was heated to 60° C. overnight and partitioned between EtOAc and saturated NH4Cl solution. The layers were separated and the aqueous extracted further with ethyl acetate (2×). The combined organics were washed with water and brine, dried over MgSO4, and concentrated. The residue was dissolved in methanol and purified with preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give a colorless solid (5.3 mg, 5.7%). LCMS calculated for C17H19N4S (M+H)+: m/z=311.1. Found: 311.1. 1H NMR (500 MHz, CDCl3) δ 8.96 (s, 1H), 7.59 (m, 1H), 7.49 (m, 1H), 2.90 (m, 1H), 2.51 (s, 3H), 2.36 (d, J=6.5 Hz, 2H), 2.06 (m, 2H), 1.97-1.88 (m, 5H), 1.37 (m, 2H). ppm.

1. customA microwave tube equipped with a magnetic stir bar
2. temperatureafter cooling to room temperature
3. temperaturethe vial 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. temperaturecooled to room temperature
8. stirringthe mixture stirred at 50° C. overnight
9. customThe vial was evacuated under high vacuum
10. temperatureThe mixture was cooled to 0° C.
11. additionthe zinc reagent was added slowly via syringe
12. additionAfter addition
13. temperaturethe reaction was heated to 60° C. overnight
14. custompartitioned between EtOAc and saturated NH4Cl solution
15. customThe layers were separated
16. extractionthe aqueous extracted further with ethyl acetate (2×)
17. washThe combined organics were washed with water and brine
18. dry with materialdried over MgSO4
19. concentrationconcentrated
20. dissolutionThe residue was dissolved in methanol
21. custompurified with preparative LCMS (XBridge C18 column
22. washeluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min)

ORD record

ord-04e6d42288dd43769c5bc68d99dde47c

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09181271B2