Water → 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

HRID 2186389Notes

Reaction equation

HRID 2186389 reaction equation
Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[OH:10][CH:11]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:12][CH2:13][C@@H:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]#[CH:22])[CH2:16][C@@H:15]1[C:23]([O:25][CH3:26])=[O:24].O>C(N(CC)CC)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:10][CH:11]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:12][CH2:13][C@@H:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]#[C:22][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)[CH2:16][C@@H:15]1[C:23]([O:25][CH3:26])=[O:24]

Participants

7

Reactant 3

HCID 962WaterHCID 1363131-Bromo-3,5-difluorobenzeneHCID 131723275methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate

Product 1

HCID 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

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

0.138 g of tetrakis(triphenylphosphine)palladium, 0.046 g of cuprous iodide, and 0.42 cm3 of 1-bromo-3,5-difluorobenzene were added to a mixture, stirred at a temperature in the region of 20° C. under an inert atmosphere, of 0.95 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine -3-carboxylate in 9.5 cm3 of triethylamine. The mixture was heated at a temperature in the region of 80° C. for 3 hours. After cooling to approximately 20° C., the reaction mixture was taken up in 30 cm3 of ethyl acetate and 30 cm3 of water and stirred for 5 minutes. The organic phase was separated by settling, while the aqueous layer was extracted with 2 times 30 cm3 of ethyl acetate. The organic extracts were combined, washed with 3 times 30 cm3 of water, dried over sodium sulfate, filtered, and concentrated 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 2.3 cm; 40 g), elution was carried out with pure ethyl acetate. 2 fractions of 100 cm3 were first collected and then 20-cm3 fractions were obtained. Fractions 8 to 40 were combined and evaporated under the above conditions. 0.967 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 was obtained in the form of a foam with an orange color.

Workup

  1. temperatureAfter cooling to approximately 20° C.
  2. customThe organic phase was separated
  3. extractionwas extracted with 2 times 30 cm3 of ethyl acetate
  4. washwashed with 3 times 30 cm3 of water
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C
  8. customThe residue obtained
  9. customwas purified by chromatography under a nitrogen pressure of 50 kPa
  10. washon a column of silica gel (particle size 20-45 μm; diameter 2.3 cm; 40 g), elution
  11. custom2 fractions of 100 cm3 were first collected
  12. custom20-cm3 fractions were obtained
  13. customevaporated under the above conditions

Sources & evidence

ORD record
ord-5df2a06598a947f0b28a6dd80f773f5f
Source dataset
uspto-grants-2002_06
Patent number
US06403610B1

Reaction notes

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