Sodium Hydroxide → (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid

HRID 2186388Notes

Reaction equation

HRID 2186388 reaction equation
[OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH2:7][C@@H:6]1[C:22]([O:24]C)=[O:23].[OH-].[Na+]>O1CCOCC1.ClCCl>[OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH2:7][C@@H:6]1[C:22]([OH:24])=[O:23]

Participants

5

Reactant 2

HCID 14798Sodium HydroxideHCID 131723286methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate

Product 1

HCID 69353757(3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acidYield 61.2%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 0.89 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate in 9 cm3 of dioxane to which had been added 1.41 cm3 of 5N aqueous sodium hydroxide solution was stirred for 18 hours at a temperature in the region of 60° C. After cooling to approximately 20° C., the reaction mixture was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 3.3 cm; mass 56 g), elution first was carried out with a dichloromethane/methanol (95/5 by volume) mixture. A fraction of 100 cm3 was first collected and then 16-cm3 fractions. Fractions 1 to 36 were separated. Elution was subsequently carried out with a dichloromethane/methanol (75/25 by volume) mixture. A first fraction of 200 cm3 a second of 150 cm3, and then a third of 100 cm3 were obtained. The latter two were combined and concentrated as above. The residue obtained was taken up in dichloromethane and filtered. The filtrate was evaporated as above and then the new residue obtained was triturated in 25 cm3 of a diisopropyl ether/pentane (50/50 by volume) mixture. The product which crystallized was filtered off and washed with 2 times 10 cm3 of the same mixture and then 3 times 10 cm3 of pentane. 0.53 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid was obtained in the form of solid with a cream color melting at 106° C.

Workup

  1. temperatureAfter cooling to approximately 20° C.
  2. customthe reaction mixture was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C
  3. customThe residue obtained
  4. customwas purified by chromatography under a nitrogen pressure of 50 kPa
  5. washon a column of silica gel (particle size 20-45 μm; diameter 3.3 cm; mass 56 g), elution
  6. customA fraction of 100 cm3 was first collected
  7. customFractions 1 to 36 were separated
  8. washElution
  9. customA first fraction of 200 cm3 a second of 150 cm3, and then a third of 100 cm3 were obtained
  10. concentrationconcentrated as above
  11. customThe residue obtained
  12. filtrationfiltered
  13. customThe filtrate was evaporated as above and then the new residue
  14. customobtained
  15. customwas triturated in 25 cm3 of a diisopropyl ether/pentane (50/50 by volume) mixture
  16. customThe product which crystallized
  17. filtrationwas filtered off
  18. washwashed with 2 times 10 cm3 of the same mixture

Sources & evidence

ORD record
ord-d2786c6d7ced4998a5e12f76580a0e7d
Source dataset
uspto-grants-2002_06
Patent number
US06403610B1

Reaction notes

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