Hydrochloric Acid → 1-(2-tert-Butoxycarbonyl-4-methoxy-3-oxo-butyl)-cyclopentane carboxylic acid

Participants

Reaction Conditions

Reaction Steps

A solution of diisopropylamine (35.0 ml, 250 mmol) in THF (70 ml) was cooled to −15° C. under nitrogen. n-Butyllithium (2.5 M, 100 ml, 250 mmol) was then added dropwise, whilst maintaining the temperature below −10° C. To the resultant solution was added a solution of 1-(3-tert-butoxy-3-oxopropyl)cyclopentane carboxylic acid (see EP274234B1, example 35) (27.52 g, 113.6 mmol) in THF (50 ml) and the reaction was then stirred at −10 to −15° C. for 1 h. To the reaction mixture was then added a solution of methyl methoxyacetate (18.0 ml) in THF (20 ml), and the resultant mixture was then allowed to warm to room temperature and then stirred for 19 hours. To the reaction mixture was added tert-butyl methyl ether (300 ml) and deionised water (300 ml), and the aqueous phase was then acidified with 2M hydrochloric acid to pH 3 with stirring. The phases were separated and the aqueous phase was then extracted with tert-butyl methyl ether (250 ml). The combined organic phases were then washed with water (250 ml) and then brine (250 ml), dried over magnesium sulfate, and the solvent was then removed under reduced pressure. The crude title compound was then purified by flash chromatography on silica gel using ethyl acetate/heptane (1:2 to 1:1) as the eluent to give the title compound (17.35 g, 55.2 mmol, 49% yield); 1H NMR (400 MHz, CDCl3) δ: 1.43 (s, 9H), 1.69-1.47 (m, 6H), 2.17-2.05 (m, 2H), 2.18 (dd, 1H), 2.32 (dd, 1H), 3.42 (s, 3H), 3.59 (t, 1H), 4.17 (q, 2H); 13C NMR (100 MHz, CDCl3) δ: 24.7, 27.8, 34.9, 35.8, 36.7, 53.2, 53.3, 59.2, 82.3, 168.3, 183.4, 203.2.

Provenance & Evidence