Dimethyl Sulfoxide → methyl (3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylsulfanyl)ethyl]piperidine-3-acetate

HRID 2414973Notes

Reaction equation

HRID 2414973 reaction equation
CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH3:48])[CH:45]=2)[N:40]=[CH:39][C:38]=1[F:49])[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[CH2:17][CH:16]1[CH2:32][C:33]([O:35][CH3:36])=[O:34].C(N(CC)CC)C>ClCCl.O>[O:11]=[C:12]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH3:48])[CH:45]=2)[N:40]=[CH:39][C:38]=1[F:49])[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[CH2:17][CH:16]1[CH2:32][C:33]([O:35][CH3:36])=[O:34]

Participants

7

Reactant 4

HCID 679Dimethyl SulfoxideHCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 131724011Methyl (3rs,4rs)-4-[3-(r,s)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylsulfanyl)ethyl]piperidine-3-acetate

Product 1

HCID 86589522methyl (3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylsulfanyl)ethyl]piperidine-3-acetateYield 80.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent4×

Conditions

Temperature
-70 °C

Procedure

1.88-cm3 of dimethyl sulfoxide in 6-cm3 of dichloromethane were poured, over 10 minutes, into a solution of 1.32-cm3 of oxalyl dichloride in 30-cm3 of dichloromethane cooled to −70° C., with stirring and under an inert atmosphere. After 10 minutes, a solution of 1.7 g of methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate in 15-cm3 of dichloromethane was poured in over 10 minutes. After 15 minutes, 8.4-cm3 of triethylamine in 10-cm3 of dichloromethane were added dropwise over 15 minutes and the reaction mixture was stirred for 45 minutes in the region of −70° C. and then for 20 hours in the region of 20° C. 50-cm3 of distilled water were poured over the reaction mixture, the organic phase was separated after settling out, washed with 50-cm3 of a saturated aqueous sodium hydrogen carbonate solution, twice with 30-cm3 of distilled water and 30-cm3 of a saturated aqueous sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3-cm), eluting with a cyclohexane-ethyl acetate (60/40 by volume) mixture and collecting 10-cm3 fractions. The fractions containing the expected product were combined and then concentrated to dryness according to the conditions described above. 1.37 g of methyl (3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate were obtained.

Workup

  1. waitAfter 15 minutes
  2. stirringthe reaction mixture was stirred for 45 minutes in the region of −70° C.
  3. waitfor 20 hours in the region of 20° C
  4. customthe organic phase was separated
  5. washwashed with 50-cm3 of a saturated aqueous sodium hydrogen carbonate solution, twice with 30-cm3 of distilled water and 30-cm3 of a saturated aqueous sodium chloride solution
  6. extractionThe organic extract
  7. dry with materialwas dried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C
  10. customThe residue obtained
  11. customwas purified by chromatography under an argon pressure of 50 kPa
  12. washon a column of silica gel (particle size 40-60 μm; diameter 3-cm), eluting with a cyclohexane-ethyl acetate (60/40 by volume) mixture
  13. customcollecting 10-cm3 fractions
  14. additionThe fractions containing the expected product
  15. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-b6eab95ba67842d3bd36377213d9d5e2
Source dataset
uspto-grants-2004_11
Patent number
US06815547B2

Reaction notes

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