1,8-Diazabicyclo(5.4.0)undec-7-ene → HCID 66704943, compound

HRID 424759Notes

Reaction equation

HRID 424759 reaction equation
Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[CH:8][N:9]2[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[F:22].[CH:23]1([NH:26][CH2:27][C@@H:28]2[C@H:32]([F:33])[CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24]1.N12CCCN=C1CCCCC2>C(#N)C>[CH:23]1([NH:26][CH2:27][C@@H:28]2[C@H:32]([F:33])[CH2:31][N:30]([C:2]3[N:11]=[C:10]4[C:5]([C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][N:9]4[C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:4][C:3]=3[F:22])[CH2:29]2)[CH2:25][CH2:24]1

Participants

5

Reactant 3

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 11147857N-(((3R,4S)-4-Fluoropyrrolidin-3-yl)methyl)cyclopropanamineHCID 11844477HCID 11844477, compound

Product 1

HCID 66704943HCID 66704943, compoundYield 33.5%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

Ethyl 7-chloro-6-fluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-1,8-naphthyridine-3-carboxylate (327 mg), (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (160 mg) and acetonitrile (5 mL) were mixed together. The reaction mixture was stirred at 80° C. for 1 hour and was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (30 ml), washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane:acetone=2:1->1:1->dichloromethane:methanol=10:1). The eluted pale yellow solid was dissolved in ethanol (4 mL), followed by addition of a 10% aqueous solution of sodium hydroxide (4 mL), stirring at 60° C. for 70 min, and concentration under reduced pressure. The resulting residue was diluted with water (10 mL), neutralized with 1 mol/L hydrochloric acid (pH 7.5), and extracted with dichloromethane (2×30 mL). The dichloromethane extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane:methanol=10:1) to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid as white crystals (141 mg).

Workup

  1. concentrationwas concentrated under reduced pressure
  2. dissolutionThe resulting residue was dissolved in dichloromethane (30 ml)
  3. washwashed sequentially with water and saturated brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customThe resulting residue was purified by silica gel column chromatography (eluant: dichloromethane:acetone=2:1->1:1->dichloromethane:methanol=10:1)
  7. dissolutionThe eluted pale yellow solid was dissolved in ethanol (4 mL)
  8. additionfollowed by addition of a 10% aqueous solution of sodium hydroxide (4 mL)
  9. stirringstirring at 60° C. for 70 min
  10. concentrationconcentration under reduced pressure
  11. additionThe resulting residue was diluted with water (10 mL)
  12. extractionextracted with dichloromethane (2×30 mL)
  13. washwashed with saturated brine
  14. dry with materialdried over anhydrous sodium sulfate
  15. concentrationconcentrated under reduced pressure
  16. customThe resulting residue was purified by silica gel column chromatography (eluant: dichloromethane:methanol=10:1)

Sources & evidence

ORD record
ord-b79924730fe04d5f84c026f1e8a32040
Source dataset
uspto-grants-2012_01
Patent number
US08106072B2

Reaction notes

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