Chlorotrimethylsilane → (E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid methyl ester

温度

25 °C

A mixture of zinc dust (330 mg, 5 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane (187 mg, 1 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (108 mg, 1 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (440 mg, 1.5 mmol) in dry tetrahydrofuran (1 mL). The resulting reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (3 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (27 mg, 0.05 mmol) and triphenylphosphine (52 mg, 0.2 mmol) in dry tetrahydrofuran (4 mL) was stirred at 25° C. under argon for 10 min and then treated with 1-(4-bromo-2-methanesulfonyl-phenyl)-5-methyl-1H-tetrazole (297 mg, 0.94 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was stirred at 40-45° C. over the weekend. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (30 mL), and the organic compound was extracted into ethyl acetate (3×25 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid methyl ester (289 mg, 78%) as an amorphous yellow solid: EI-HRMS Tile calcd for C18H22N4O4S (M+) 390.1362, found 390.1363.

1. temperatureto cool
2. temperatureheated again
3. customThe resulting reaction mixture
4. stirringwas then stirred at 40-45° C. for 1 h
5. stirringstirred overnight at 25° C
6. custom(˜2 h)
7. stirringwas stirred at 25° C. under argon for 10 min
8. stirringThe resulting brick red solution was stirred at 40-45° C. over the weekend
9. temperatureThe reaction mixture was cooled to 25° C.
10. extractionthe organic compound was extracted into ethyl acetate (3×25 mL)
11. washThe combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×50 mL)
12. dry with materialdried over anhydrous magnesium sulfate
13. filtrationfiltered
14. concentrationconcentrated in vacuo

ORDレコード

ord-0b3c4569e39746c6892ca4fe7fe29229

出典データセット

uspto-grants-2002_08

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US06441180B1