(R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine → (2S,5R)-2-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine

温度

0 °C

Commercially available (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine (2.0 g, 10.86 mmol) in dry THF (12 ml) under argon was cooled to −75° C. n-BuLi (8 ml, 13.03 mmol, 1.6M solution in hexanes) was added slowly and stirring was continued for 30 min. After that 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (3.628 g, 13.03 mmol), (preparation described in J. Med. Chem. 2005, 4511-4525; Bioorg. Med. Chem. Lett. 2004, 4191-4195), in THF (15 ml) was added dropwise under stirring and stirring was continued for 30 min at −75° C. Then the mixture was warmed to 0° C. and stirred for 1 h before it was quenched with sat. aq. NaHCO3-solution. The mixture was extracted with ethyl acetate, the organic layers were combined and dried with MgSO4, filtered and evaporated to dryness. A crude oil was obtained (4.1 g) and the diastereomeric excess (d.e.: 88%) was determined by H-NMR from that crude mixture. The mixture was separated by column chromatography on silica gel (n-heptane-ethyl acetate 6:1). Yield: 3.3 g, 80%.

1. additionwas added slowly
2. stirringunder stirring
3. stirringstirring
4. waitwas continued for 30 min at −75° C
5. stirringstirred for 1 h before it
6. customwas quenched with sat. aq. NaHCO3-solution
7. extractionThe mixture was extracted with ethyl acetate
8. dry with materialdried with MgSO4
9. filtrationfiltered
10. customevaporated to dryness
11. customA crude oil was obtained (4.1 g)
12. customThe mixture was separated by column chromatography on silica gel (n-heptane-ethyl acetate 6:1)

ORDレコード

ord-3cf530bc8bf34a4ea744b83c3ee592ac

出典データセット

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08835653B2