Diisopropylamine → Ethyl 8-(cyanomethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate

Temperature

-40 °C

To a stirred solution of diisopropylamine (10.09 ml, 69.76 mmol) in THF (150 ml) was added nBuLi (1.9 M solution in hexane, 26.09 ml, 51.1 mmol) drop wise at −40° C. followed by HMPA (31.0 ml, 178.0 mmol) under nitrogen atmosphere, and the reaction mixture was stirred for 30 minutes at −40° C. It was then cooled further to −78° C., and a solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (10 g, 46.5 mmol) in THF (20 ml) was added keeping the temperature below −70° C. throughout the addition. After stirring for 25 min at −78° C., bromoacetonitrile (3.8 ml, 55.8 mmol) was added slowly, and the reaction mixture was then allowed to warm to 25° C. The mixture was poured into cold water (100 ml) and the aqueous layer was extracted with EtOAc (5×70 ml). The combined organic layer was washed successively with saturated aqueous solution of NH4Cl (3×50 ml), H2O (2×50 ml) and then with brine (1×40 ml), dried (Na2SO4), filtered and evaporated in vacuo. The crude compound obtained was purified by column chromatography over silica gel (22-25% EtOAc/hexane) to give the title compound (6 g) as a pale yellow liquid. MS (m/e): 254.2 [MH+].

1. temperatureIt was then cooled further to −78° C.
2. customthe temperature below −70° C.
3. additionthroughout the addition
4. stirringAfter stirring for 25 min at −78° C.
5. temperatureto warm to 25° C
6. extractionthe aqueous layer was extracted with EtOAc (5×70 ml)
7. washThe combined organic layer was washed successively with saturated aqueous solution of NH4Cl (3×50 ml), H2O (2×50 ml)
8. dry with materialwith brine (1×40 ml), dried (Na2SO4)
9. filtrationfiltered
10. customevaporated in vacuo
11. customThe crude compound obtained
12. customwas purified by column chromatography over silica gel (22-25% EtOAc/hexane)

ORD record

ord-5cd3c1b47b4147a7a03d1dc3f4d97165

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08703807B2