1-Bromo-2,3,5-trifluorobenzene → (3R,4R)-methyl 4-(3-(6-methoxyquinolin-4-yl)-3-oxopropyl)-1-(3-(2,3,5-trifluorophenyl)prop-2-ynyl)piperidine-3-carboxylate

HRID 393218Notes

Reaction equation

HRID 393218 reaction equation
Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10].[CH3:11][C:12]#[C:13][N:14]1[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][C:22](=[O:35])[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)[C@@H:16]([C:36]([O:38][CH3:39])=[O:37])[CH2:15]1>C(N(CC)CC)C.O.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>[F:10][C:3]1[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[C:11]#[C:12][CH2:13][N:14]1[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][C:22](=[O:35])[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)[C@@H:16]([C:36]([O:38][CH3:39])=[O:37])[CH2:15]1

Participants

6

Reactant 2

HCID 27363991-Bromo-2,3,5-trifluorobenzeneHCID 86591491methyl (3R,4R)-1-(3-prop-2-ynyl)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate

Product 1

HCID 86591490(3R,4R)-methyl 4-(3-(6-methoxyquinolin-4-yl)-3-oxopropyl)-1-(3-(2,3,5-trifluorophenyl)prop-2-ynyl)piperidine-3-carboxylate

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
80 °C

Procedure

4.05 g of tetrakis(triphenylphosphine)palladium, 0.834 g of cuprous iodide and 7.9 cm3 of 1-bromo-2,3,5-trifluorobenzene are added at a temperature in the region of 20° C., with stirring and under an inert atmosphere, to a solution of 17.28 g of methyl (3R,4R)-1-(3-prop-2-ynyl)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 173 cm3 of triethylamine. After heating for 2 hours at a temperature in the region of 80° C., the reaction mixture is cooled to approximately 20° C., diluted with 100 cm3 of water and then extracted with 4 times 150 cm3 of ethyl acetate. The organic extracts are combined, washed with 5 times 100 cm3 of water, dried over sodium sulfate, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue is purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45μ; diameter 7 cm; mass 600 g), elution being carried out with ethyl acetate. Fractions 3 to 11 are combined and then concentrated under the above conditions. 18.4 g of methyl (3R,4R)-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate are obtained.

Workup

  1. temperaturethe reaction mixture is cooled to approximately 20° C.
  2. extractionextracted with 4 times 150 cm3 of ethyl acetate
  3. washwashed with 5 times 100 cm3 of water
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C
  7. customThe residue is purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45μ; diameter 7 cm; mass 600 g), elution
  8. concentrationconcentrated under the above conditions

Sources & evidence

ORD record
ord-6fa1a6ee0bf849569b0c9901c9559e20
Source dataset
uspto-grants-2004_10
Patent number
US06806277B2

Reaction notes

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