反应详情

A solution of cis-methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate, from a preparation of Example 20, Step 1 (1.28 g, 3.62 mmol) in MeOH (3 mL) was added dropwise to a solution of NaOH (0.159 g) in MeOH/H2O (3 mL/0.2 mL) at −30° C. After stirring for 10 minutes a solution of hydroxylamine hydrochloride (0.50 g, 7.24 mmol) and NaOH (0.29 g, 7.24 mmol) in methanol/water (5 mL/5 mL) was added at −30° C. Stirring was continued for 30 minutes at −30° C. The solution was added dropwise to HCl (6M) at 80° C. Stirred 30 minutes at 80° C. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was isolated, dried with Na2SO4, filtered through Celite® and the solvent was evaporated. Acidic reversed phase chromatography, gradient 35% to 75% acetonitrile gave cis-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.62 g, 53.1%). Chiral separation using Chiralpac IC, mobile phase heptane/isopropyl alcohol 80/20 at the temperature 40° C. gave (2R,4R)-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.28 g), e.e. 98.5% and (2S,4S)-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.27 g), e.e 98.5%. 1H NMR (600 MHz, cdcl3, RR) δ 0.67-0.88 (m, 2H), 0.98-1.20 (m, 5H), 1.28 (dd, 1H), 1.56 (dd, 5H), 1.75-1.86 (m, 2H), 1.92-2.06 (m, 2H), 2.87-2.99 (m, 1H), 3.02-3.15 (m, 1H), 3.65 (s, 3H), 3.88 (dd, 1H), 4.15 (p, 1H), 5.65 (d, 1H). [α]20D −30.7 (MeCN, c=1); 1H NMR (600 MHz, cdcl3, SS) δ 0.70-0.87 (m, 2H), 0.97-1.20 (m, 5H), 1.28 (dd, 1H), 1.51-1.65 (m, 5H), 1.77-1.85 (m, 2H), 1.96-2.05 (m, 2H), 2.87-2.96 (m, 1H), 3.03-3.14 (m, 1H), 3.65 (s, 3H), 3.88 (dd, 1H), 4.15 (p, 1H), 5.65 (d, 1H) [α]20D +29.9 (MeCN, c=1).

1. additionwas added at −30° C
2. stirringStirred 30 minutes at 80° C
3. customThe reaction mixture was partitioned between water and ethyl acetate
4. customThe organic phase was isolated
5. dry with materialdried with Na2SO4
6. filtrationfiltered through Celite®
7. customthe solvent was evaporated