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

HRID 1767104Notes

Reaction equation

HRID 1767104 reaction equation
[O:1]=[C: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].Br[C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[C:32]=1[F:39].C(OCC)(=O)C.O>C(N(CC)CC)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:1]=[C: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:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[C:32]=2[F:39])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15]

Participants

7

Reactant 4

HCID 962WaterHCID 8857Ethyl AcetateHCID 27363991-Bromo-2,3,5-trifluorobenzeneHCID 71699959(3R,4R)-Methyl 4-(3-(6-methoxyquinolin-4-yl)-3-oxo-propyl)-1-(prop-2-ynyl)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-carboxylateYield 93.7%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8471TriethylamineSolvent

Conditions

Temperature
20 °C

Procedure

A mixture of 17.28 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)-piperidine-3-carboxylate in 173 cm3 of triethylamine is stirred for 5 minutes under an inert atmosphere at a temperature in the region of 20° C. 4.05 g of tetrakis(triphenylphosphine)palladium, 0.834 g of cuprous iodide and 7.9 g of 1-bromo-2,3,5-trifluorobenzene are added. The mixture is stirred for 2 hours at a temperature in the region of 80° C. After cooling to approximately 20° C., 150 cm3 of ethyl acetate and 150 cm3 of water are added to the reaction mixture, which is then separated after settling out. The aqueous phase is extracted with 3 times 150 cm3 of ethyl acetate. The organic phases are pooled, washed with 5 times 150 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 is purified by chromatography under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20–45μ; diameter 7 cm; 600 g), eluting with pure ethyl acetate and collecting first a fraction of 2.5 1, and then fractions of 250 cm3. Fractions 2 to 29 are pooled and then concentrated as above. 18.4 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]-piperidine-3-carboxylate, in the form of a yellow oil, are obtained.

Workup

  1. stirringThe mixture is stirred for 2 hours at a temperature in the region of 80° C
  2. temperatureAfter cooling to approximately 20° C.
  3. customis then separated
  4. extractionThe aqueous phase is extracted with 3 times 150 cm3 of ethyl acetate
  5. washwashed with 5 times 150 cm3 of water
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C
  9. customThe residue obtained
  10. customis purified by chromatography under a nitrogen pressure of 50 kPa
  11. washon a column of silica gel (particle size 20–45μ; diameter 7 cm; 600 g), eluting with pure ethyl acetate
  12. customcollecting first a fraction of 2.5 1
  13. concentrationconcentrated as above

Sources & evidence

ORD record
ord-16f39e41526c415988e755b107770d29
Source dataset
uspto-grants-2007_06
Patent number
US07232834B2

Reaction notes

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