Citric Acid → Ethyl 3-[((3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidin-1-yl)-2,5-difluoro-3-methylphenyl]-3-oxopropionate

HRID 1253431Notes

Reaction equation

HRID 1253431 reaction equation
C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][C@H:21]1[C@@H:25]([CH3:26])[CH2:24][N:23]([C:27]2[C:35]([F:36])=[CH:34][C:30]([C:31]([OH:33])=O)=[C:29]([F:37])[C:28]=2[CH3:38])[CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:39]([O:45][CH2:46][CH3:47])(=[O:44])[CH2:40]C([O-])=O.[K+].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([NH:20][C@H:21]1[C@@H:25]([CH3:26])[CH2:24][N:23]([C:27]2[C:35]([F:36])=[CH:34][C:30]([C:31](=[O:33])[CH2:40][C:39]([O:45][CH2:46][CH3:47])=[O:44])=[C:29]([F:37])[C:28]=2[CH3:38])[CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]

Participants

9

Reactant 6

HCID 311Citric AcidHCID 8471TriethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 86618516HCID 86618516, compound

Product 1

HCID 86618517Ethyl 3-[((3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidin-1-yl)-2,5-difluoro-3-methylphenyl]-3-oxopropionateYield 93%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

1,1′-carbonyldiimidazole (1.46 g, 9.00 mmol) was added to a solution of 4-[(3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidin-1-yl]-2,5-difluoro-3-methylbenzoic acid (2.20 g, 6.30 mmol) in tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 3 hours. Separately, a magnesium salt was prepared potassium ethyl malonate (3.40 g, 20.0 mmol), magnesium chloride (2.38 g, 25.0 mmol), and triethylamine (4.18 mL, 30.0 mmol), and the salt was dissolved in ethyl acetate (40 mL). The reaction mixture was added dropwise to the solution under cooling with ice, followed by stirring at an external temperature of 50° C. for 16 hours. Under cooling with ice, a 10% aqueous citric acid solution was added thereto, and the resultant mixture was extracted with ethyl acetate (200 mL×2), washed by saturated sodium hydrogencarbonate (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield the title compound (2.58 g, 93.0%).

Workup

  1. additionThe reaction mixture was added dropwise to the solution
  2. temperatureunder cooling with ice
  3. stirringby stirring at an external temperature of 50° C. for 16 hours
  4. temperatureUnder cooling with ice
  5. extractionthe resultant mixture was extracted with ethyl acetate (200 mL×2)
  6. washwashed by saturated sodium hydrogencarbonate (100 mL) and saturated brine (100 mL)
  7. dry with materialdried over anhydrous sodium sulfate
  8. filtrationAfter filtration
  9. concentrationthe filtrate was concentrated under reduced pressure
  10. customthe obtained residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=4:1)

Sources & evidence

ORD record
ord-c90bc09c18a24a85868f4e1e28337f0e
Source dataset
uspto-grants-2013_06
Patent number
US08455482B2

Reaction notes

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