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

HRID 2186409Notes

Reaction equation

HRID 2186409 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].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>[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: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 131723275methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate

Product 1

HCID 131723296methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylateYield 50.2%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8471TriethylamineSolvent

Conditions

Temperature
20 °C

Procedure

A mixture of 1.95 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate in 20 cm3 of triethylamine was stirred for 5 minutes under an inert atmosphere at a temperature in the region of 20° C. 0.284 g of tetrakis(triphenylphosphine)palladium, 0.094 9 of cuprous iodide, and 1.56 g of 1-bromo-2,3,5-trifluorobenzene were added. The mixture was stirred for 2 hours 30 minutes at a temperature in the region of 80° C. After cooling to approximately 20° C., the reaction mixture had 60 cm3 of ethyl acetate and 60 cm3 of water added. After stirring for 30 minutes, the mixture was separated by settling. After separating off the organic phase, the aqueous layer was extracted with 3 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 4 cm; 80 g), elution was carried out with pure ethyl acetate, and first a fraction of 100 cm3 was collected, followed by 20-cm3 fractions. Fractions 23 to 27 were combined and concentrated as above. 1.3 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylate were obtained in the form of a foam.

Workup

  1. stirringThe mixture was stirred for 2 hours 30 minutes at a temperature in the region of 80° C
  2. temperatureAfter cooling to approximately 20° C.
  3. additionadded
  4. stirringAfter stirring for 30 minutes
  5. customthe mixture was separated
  6. customAfter separating off the organic phase
  7. extractionthe aqueous layer was extracted with 3 times 30 cm3 of ethyl acetate
  8. washwashed with 3 times 30 cm3 of water
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C
  12. customThe residue obtained
  13. customwas purified by chromatography under a nitrogen pressure of 50 kPa
  14. washon a column of silica gel (particle size 20-45 μm, diameter 4 cm; 80 g), elution
  15. customfirst a fraction of 100 cm3 was collected
  16. concentrationconcentrated as above

Sources & evidence

ORD record
ord-e5d49d168eef45188b9a2a47a77d5fd2
Source dataset
uspto-grants-2002_06
Patent number
US06403610B1

Reaction notes

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