Triethylamine → methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate

HRID 2186391Notes

Reaction equation

HRID 2186391 reaction equation
[OH:1][CH:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[CH:13])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C.Br[C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[F:45].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.O>[OH:1][CH:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=2[F:45])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 8857Ethyl AcetateHCID 678622-Bromo-1,4-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 131723287methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 1.1 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate, 11 cm3 of triethylamine, 0.16 cm3 of tetrakis(triphenylphosphine)palladium, 0.053 g of cuprous iodide, and 0.47 cm3 of 1-bromo-2,5-difluorobenzene was stirred for 3 hours 15 minutes under an inert atmosphere at a temperature in the region of 80° C. After cooling to approximately 20° C., the reaction mixture had 30 cm3 of ethyl acetate and 30 cm3 of water added with stirring. The organic phase was separated, while the aqueous phase was extracted with 2 times 30 cm3 of ethyl acetate. The organic extracts were combined, washed with 3 times 25 cm3 of water, dried over sodium sulfate, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. A product 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 3.3 cm; 50 g), elution was carried out with ethyl acetate, and a fraction of 300 cm3 first was collected, followed by 32-cm3 fractions. Fractions 7 to 22 were combined and then concentrated under the above conditions. 0.91 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate was obtained in the form of a foam with an off-white color.

Workup

  1. temperatureAfter cooling to approximately 20° C.
  2. additionadded
  3. stirringwith stirring
  4. customThe organic phase was separated, while the aqueous phase
  5. extractionwas extracted with 2 times 30 cm3 of ethyl acetate
  6. washwashed with 3 times 25 cm3 of water
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C
  9. customA product 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 3.3 cm; 50 g), elution
  12. customa fraction of 300 cm3 first was collected
  13. concentrationconcentrated under the above conditions

Sources & evidence

ORD record
ord-6a462b65bf164c0683ab46df19aea52c
Source dataset
uspto-grants-2002_06
Patent number
US06403610B1

Reaction notes

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