Dimethylformamide → Ethyl 3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylate

In a flame-dried scintillation vial, to a suspension of zinc (0.0998 g, 1.53 mmol) in N,N-dimethylformamide (1.36 mL, 17.6 mmol) were added 1,2-dibromoethane (0.003279 mL, 0.03805 mmol) and chlorotrimethylsilane (0.004830 mL, 0.03805 mmol). Stirred at room temperature for 15 min, at which point a solution of 3-fluoro-4-chlorobenzylbromide (0.341 g, 1.53 mmol) in N,N-dimethylformamide (1.36 mL, 17.6 mmol) was added. The resulting suspension was stirred at room temperature for 16 hours. A scintillation vial containing ethyl 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylate (199 mg, 0.507 mmol and bis(tri-t-butylphosphine)palladium(0) (12.96 mg, 0.02537 mmol) was purged via vacuum/backfilling with argon. To this was added the organozinc solution from above, and the resulting solution was stirred at 45° C. for 6 hours, at which point LC/MS showed complete conversion to a single new peak with mass representing desired product. The reaction mixture was transferred to a separatory funnel containing saturated NaHCO3 (aq., 10 mL) and water (10 mL), and then diluted with EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted 2×30 mL with EtOAc. The combined organic layers were washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford crude ethyl 3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylate as a brown oil that was used without further purification. LCMS: (FA) ES+ 409, 411

1. additionwas added
2. customwas purged via vacuum/backfilling with argon
3. additionTo this was added the organozinc solution from above, and the resulting solution
4. stirringwas stirred at 45° C. for 6 hours, at which point LC/MS
5. customThe reaction mixture was transferred to a separatory funnel
6. additioncontaining saturated NaHCO3 (aq., 10 mL) and water (10 mL)
7. additiondiluted with EtOAc (40 mL)
8. customThe layers were separated
9. extractionthe aqueous layer was extracted 2×30 mL with EtOAc
10. washThe combined organic layers were washed 1× brine
11. dry with materialdried over Na2SO4
12. filtrationfiltered
13. concentrationconcentrated in vacuo

ORD record

ord-2b7c013673a74579a699bef3f7d84718

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08796268B2