Hydrochloric Acid → methyl (3R,4R)-1-[2-(cyclohexylthio)ethyl]-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate dihydrochloride

Temperature

10 °C

0.42 g of sodium borohydride was added portionwise for approximately 1 hour with stirring and under an inert atmosphere, to a solution cooled to a temperature in the region of 15° C., of 3.5 g of methyl (3R,4R)-1-[2-(cyclohexylthio)ethyl]-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate in 50 cm3 of methanol to which had been added 1 drop of 5N sodium hydroxide solution. The mixture was stirred for 2 hours at this temperature and then cooled to approximately 10° C. 10 cm3 of water were then added dropwise. The mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 45° C. After adding 100 cm3 of water to the residue obtained, the mixture was extracted with 2 times 100 cm3 of ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and concentrated as above. An oil was obtained, which product was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 3 cm; height 35 cm), elution was carried out with ethyl acetate, and 30-cm3 fractions were collected. Fractions 19 to 42 were combined and concentrated as under the above conditions 2.44 g of a product were obtained, the hydrochloride of which was prepared in the following way: 0.5 g of product was dissolved in 10 cm3 of diethyl ether and then the solution was poured into 5 cm3 of a 1 N solution of hydrochloric acid in ether. 10 cm3 of ether were added and then the mixture was left to act for 1 hour at a temperature in the region of 20° C. The mixture was filtered and the cake was washed with 2 times 10 cm3 of diethyl ether and dried under reduced pressure (5 kPa) at a temperature in the region of 20° C. and then in an oven under reduced pressure (10 Pa) at a temperature in the region of 60° C. 0.46 g of methyl (3R,4R)-1-[2-(cyclohexylthio)ethyl]-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate dihydrochloride was obtained in the form of a solid with a pale pink color melting at 80° C. while softening.

1. stirringThe mixture was stirred for 2 hours at this temperature
2. concentrationThe mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 45° C
3. additionAfter adding 100 cm3 of water to the residue
4. customobtained
5. extractionthe mixture was extracted with 2 times 100 cm3 of ethyl acetate
6. dry with materialThe combined extracts were dried over sodium sulfate
7. filtrationfiltered
8. concentrationconcentrated as above
9. customAn oil was obtained
10. customwhich product was purified by chromatography under a nitrogen pressure of 50 kPa
11. washon a column of silica gel (particle size 20-45 μm; diameter 3 cm; height 35 cm), elution
12. customwere collected
13. concentrationconcentrated as under the above conditions 2.44 g of a product
14. customwere obtained
15. customthe hydrochloride of which was prepared in the following way
16. waitthe mixture was left
17. filtrationThe mixture was filtered
18. washthe cake was washed with 2 times 10 cm3 of diethyl ether
19. customdried under reduced pressure (5 kPa) at a temperature in the region of 20° C.
20. customin the region of 60° C

ORD record

ord-6043d7bfca8649b3a97f4c72d6d17562

Source dataset

uspto-grants-2002_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06403610B1