Water → (3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-3-methylbutan-2-yl)-3-methylpiperidin-2-one

Temperature

0 °C

(S)-2-((2R,3R)-2-(3-Chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N—((S)-1-hydroxy-3-methylbutan-2-yl)-2-methylpent-4-enamide (example 261, step G) was transferred as a solution in anhydrous benzene to a pre-weighed, oven-dried 50 mL round bottom flask and stripped to dryness. Azeotropic distillation of benzene/water was performed twice more, and the residue was dried under high vacuum for 2 h, after which it weighed 550 mg. An oven-dried stir bar was added to the flask. The vessel was sealed and purged with nitrogen and then anhydrous dichloromethane (23 mL) was added, followed by triethylamine (1.3 mL, 9.33 mmol). The resulting stirred solution was cooled to 0° C. Methanesulfonyl chloride (0.270 mL, 3.49 mmol) was added dropwise by microsyringe. After 1 h, the reaction was quenched by addition of HCl (1.2M, 12 mL) and diluted in ethyl acetate. The organic layer was washed with 1.2 M HCl (30 mL), saturated sodium bicarbonate (2×25 mL), and sat. aq. NaCl solution. After drying over magnesium sulfate and concentration in vacuo an intermediate was obtained as an off-white foam (0.64 g,). 1,8-Bis(dimethylamino)naphthalene, 314 mg, 1.465 mmol) and water (0.104 mL, 5.75 mmol) were added to the intermediate, followed by dioxane (23 mL). The mixture was heated under nitrogen at 110° C. overnight. After cooling, the mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution.

1. customoven-dried 50 mL round bottom flask
2. distillationAzeotropic distillation of benzene/water
3. customthe residue was dried under high vacuum for 2 h
4. additionwas added to the flask
5. customThe vessel was sealed
6. custompurged with nitrogen
7. additionanhydrous dichloromethane (23 mL) was added
8. stirringThe resulting stirred solution
9. customthe reaction was quenched by addition of HCl (1.2M, 12 mL)
10. additiondiluted in ethyl acetate
11. washThe organic layer was washed with 1.2 M HCl (30 mL), saturated sodium bicarbonate (2×25 mL), and sat. aq. NaCl solution
12. dry with materialAfter drying over magnesium sulfate and concentration in vacuo an intermediate
13. customwas obtained as an off-white foam (0.64 g,)
14. temperatureThe mixture was heated under nitrogen at 110° C. overnight
15. temperatureAfter cooling
16. washwashed with saturated ammonium chloride solution

ORD record

ord-fd1082f49f964a488036886182d6ef10

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08569341B2