Potassium Carbonate → 5-[4-(1-ethyl-1-{4-[5-(1-ethyl-1-hydroxy-propyl)-3-methyl-thiophen-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-4(R)-hydroxy-pentanoic Acid

A 0.96 M solution of ethylmagnesium bromide in tetrahydrofuran (0.08 mL, 0.077 mmol) was added to a solution of 5-(4-{1-[4-(t-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-4-methyl-thiophene-2-carboxylic acid methyl ester (Example 20-(2); 20 mg, 0.039 mmol) in tetrahydrofuran (0.1 mL) at 0° C., and the mixture was stirred at the same temperature for three hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. A 1.0 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (0.02 mL, 0.02 mmol) was added to a solution of the residue (7.8 mg) in tetrahydrofuran (0.4 mL), and the mixture was stirred at room temperature for one minute. Ethyl acetate was added to the reaction solution. The organic layer was sequentially washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. (R)-(−)-Dihydro-5-(p-tolyl-sulfonyloxymethyl)-2(3H)-furanone (5.8 mg, 0.022 mmol) and potassium carbonate (5 mg, 0.036 mmol) were added to a solution of the residue in N,N-dimethylformamide (0.1 mL) at room temperature, and the mixture was stirred at 105° C. for 11 hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane/methanol/triethylamine=70/10/0.4, developed three times) to give the title compound (1.5 mg, 56% in four steps).

1. washThe organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine
2. dry with materialdried over anhydrous magnesium sulfate
3. distillationthe solvent was distilled off under reduced pressure
4. stirringthe mixture was stirred at room temperature for one minute
5. washThe organic layer was sequentially washed with distilled water and brine
6. dry with materialdried over anhydrous magnesium sulfate
7. distillationthe solvent was distilled off under reduced pressure
8. stirringthe mixture was stirred at 105° C. for 11 hours
9. washThe organic layer was washed with brine
10. dry with materialdried over anhydrous magnesium sulfate
11. distillationthe solvent was distilled off under reduced pressure
12. customThe residue was purified by silica gel chromatography (dichloromethane/methanol/triethylamine=70/10/0.4, developed three times)

ORD record

ord-ba4cbbaf364145b9b4ba8cbfc7001984

Source dataset

uspto-grants-2011_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07935688B2