Diethyl Malonate → Diethyl 2-(4-(3-bromo-4-methoxyphenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate

Temperature

0 °C

A mixture of diethyl malonate (2.8 g, 17 mmol) in 50 mL ACN was stirred at 0° C. This mixture was treated with MgCl2 (1.7 g, 17 mmol) in one portion and dropwise with TEA (3.9 g, 38 mmol). The resulting mixture was then stirred at room temperature for 2.5 hours. A mixture of 4-(3-bromo-4-methoxyphenyl)-tetrahydro-2H-pyran-4-carboxylic acid (5.5 g, 17 mmol) in thionyl chloride (21 g, 175 mmol) was refluxed for 2 hours and then concentrated in vacuo. The residue was diluted with 10 mL ACN and added dropwise to the above mixture. The mixture was stirred at 50° C. for 15 hours, M−1=455/457. The mixture was cooled to room temperature, diluted with 100 mL ether, washed with H2O (2×50 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-20% EtOAc/hexane to give 1.25 g of the intermediate as a pale yellow oil. MS m/e=455/457 (M+H)+.

1. stirringThe resulting mixture was then stirred at room temperature for 2.5 hours
2. temperaturewas refluxed for 2 hours
3. concentrationconcentrated in vacuo
4. additionThe residue was diluted with 10 mL ACN
5. additionadded dropwise to the above mixture
6. stirringThe mixture was stirred at 50° C. for 15 hours
7. temperatureThe mixture was cooled to room temperature
8. additiondiluted with 100 mL ether
9. washwashed with H2O (2×50 mL) and brine (20 mL)
10. dry with materialdried over anhydrous Na2SO4
11. concentrationconcentrated in vacuo
12. customThe crude product was purified by column chromatography
13. washeluting with 10-20% EtOAc/hexane

ORD record

ord-bacdced54ffd4bb0ab1f9543b9aad735

Source dataset

uspto-grants-2009_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07635715B2