4-Methylmorpholine → 4-[2-(2,4-Difluoro-phenyl)-1-methoxycarbonyl-2-oxo-ethylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester

HRID 2288969Notes

Reaction equation

HRID 2288969 reaction equation
C[N:2]1[CH2:7][CH2:6]O[CH2:4][CH2:3]1.Cl[C:9]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10].Cl.[CH3:17][O:18][C:19](=[O:32])[CH:20]([NH2:31])[C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30])=[O:22]>O1CCCC1>[CH2:12]([O:11][C:9]([N:2]1[CH2:3][CH2:4][CH:20]([C:19](=[O:18])[NH:31][CH:20]([C:19]([O:18][CH3:17])=[O:32])[C:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])=[O:22])[CH2:6][CH2:7]1)=[O:10])[C:13]1[CH:15]=[CH:24][CH:23]=[CH:21][CH:14]=1

Participants

5

Reactant 3

HCID 79724-Methylmorpholine2×HCID 62365Isobutyl chloroformateHCID 1317218882-Amino-3-(2,4-difluoro-phenyl)-3-oxo-propionic acid methyl ester, hydrochloride

Product 1

HCID 538667984-[2-(2,4-Difluoro-phenyl)-1-methoxycarbonyl-2-oxo-ethylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
20 °C

Procedure

To a three neck 1 liter round bottom flash fitted with mechanical stirrer, nitrogen inlet and dropping funnel are added n-carbobenzyloxy-isonipecotic acid (22.64 g, 86.2 mmol). 550 mL of dry tetrahydrofuran, and N-methyl morpholine, (19 mL, 712.4 mmol). The mixture is cooled to negative 20° C. and then isobutyl chloroformate (11.2 mls, 86.2 mmol in 90 mL of dry tetrahydrofuran) is added dropwise while maintaining the internal temperature at negative 20° C. After 1 hour at negative 20° C., the 2-Amino-3-(2,4-difluoro-phenyl)-3-oxo-propionic acid methyl ester, hydrochloride (22.89 g, 86.2 mmol) is added, followed by N-methyl morpholine, 9.5 mL. The reaction is allowed to come to room temperature is stirred for an additional 16 hours. The reaction is concentrated to a thick slurry and then extracted with dichloromethane, 350 mL, and water, 300 mL. The organic layer is washed with additional water. The aqueous layers are combined and washed with dichloromethane. The organic layers are combined and washed with brine and then dried with magnesium sulfate, filtered, and concentrated to give an oil. The oil is purified by preparative high performance liquid chromatography to give upon concentration of the desired fractions to yield the title compound.

Workup

  1. customTo a three neck 1 liter round bottom flash fitted with mechanical stirrer, nitrogen inlet
  2. temperaturewhile maintaining the internal temperature at negative 20° C
  3. customto come to room temperature
  4. concentrationThe reaction is concentrated to a thick slurry
  5. extractionextracted with dichloromethane, 350 mL, and water, 300 mL
  6. washThe organic layer is washed with additional water
  7. washwashed with dichloromethane
  8. washwashed with brine
  9. dry with materialdried with magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customto give an oil
  13. customThe oil is purified by preparative high performance liquid chromatography
  14. customto give upon concentration of the desired fractions

Sources & evidence

ORD record
ord-e111289248e84e198ba1e52ee4a5ffe7
Source dataset
uspto-grants-2000_07
Patent number
US06090825

Reaction notes

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