Sodium hydride → Ethyl 7-[(3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

HRID 1010571Notes

Reaction equation

HRID 1010571 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:20]([F:21])=[CH:19][C:18]([C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:17](F)[C:16]=2C)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:34](OC)[N:35]([CH3:37])C.[CH:40]1(N)C[CH2:41]1.[H-].[Na+].[Cl-].[NH4+]>C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:18]([C:22](=[O:29])[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:37][N:35]3[CH:34]3[CH2:41][CH2:40]3)=[CH:19][C:20]=2[F:21])[CH2:10]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]

Participants

7

Reactant 5

HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 69828CyclopropylamineHCID 78373Dimethylformamide dimethyl acetalHCID 86618517Ethyl 3-[((3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidin-1-yl)-2,5-difluoro-3-methylphenyl]-3-oxopropionate

Product 1

HCID 67308688Ethyl 7-[(3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylateYield 34.5%

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent

Procedure

A solution of ethyl 3-[((3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidin-1-yl)-2,5-difluoro-3-methylphenyl]-3-oxopropionate (2.58 g, 5.86 mmol) and N,N-dimethylformamide dimethylacetal (3.99 mL, 30.0 mmol) in benzene (40 mL) was refluxed for 4 hours. The temperature of the reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (20 mL), and cyclopropylamine (693 μL, 10.0 mmol) was added dropwise to the solution under cooling with ice, followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in 1,4-dioxane (30 mL), and 55% oily sodium hydride (436 mg, 10.0 mmol) was added to the solution at room temperature, followed by stirring for 2 hours. Subsequently, the resultant mixture was poured to an ice-cooling saturated aqueous ammonium chloride solution. The resultant mixture was extracted with ethyl acetate (200 mL×2), washed by saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified through silica gel column chromatography (chloroform:methanol=25:1), to thereby yield the title compound (957 mg, 33.4%).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. dissolutionThe obtained residue was dissolved in dichloromethane (20 mL)
  3. temperatureunder cooling with ice
  4. concentrationThe reaction mixture was concentrated under reduced pressure
  5. dissolutionThe obtained residue was dissolved in 1,4-dioxane (30 mL)
  6. stirringby stirring for 2 hours
  7. extractionThe resultant mixture was extracted with ethyl acetate (200 mL×2)
  8. washwashed by saturated brine (100 mL)
  9. dry with materialdried over anhydrous sodium sulfate
  10. filtrationAfter filtration
  11. concentrationthe filtrate was concentrated under reduced pressure
  12. customThe obtained residue was purified through silica gel column chromatography (chloroform:methanol=25:1)

Sources & evidence

ORD record
ord-f23dd97b26814c359004805117a22067
Source dataset
uspto-grants-2011_07
Patent number
US07977327B2

Reaction notes

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