Phenyl chloroformate → 4-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide

HRID 492989Notes

Reaction equation

HRID 492989 reaction equation
[F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].Cl.Cl.Cl.[N:32]1([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:35][CH2:34][CH2:33]1>O1CCCC1.CO.C(N(CC)CC)C>[F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:20]([N:41]2[CH2:40][CH2:39][N:38]([CH2:37][CH2:36][N:32]3[CH2:33][CH2:34][CH2:35]3)[CH2:43][CH2:42]2)=[O:21])[CH:6]=1

Participants

7

Reactant 3

HCID 15891Phenyl chloroformateHCID 231529971-[2-(Azetidin-1-yl)ethyl]piperazine trihydrochlorideHCID 231531982-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine

Product 1

HCID 576773874-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent2×

Procedure

4-(2-Fluoro-4-nitrophenoxy)pyridin-2-ylamine (60 mg) was dissolved in tetrahydrofuran (3 ml) under a nitrogen atmosphere. Triethylamine (0.101 ml) and phenyl chloroformate (0.0908 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 25 min. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, N,N-dimethylformamide (3 ml) was added thereto. Then an 1.0 M solution of 1-[2-(azetidin-1-yl)ethyl]piperazine trihydrochloride in methanol (0.819 ml) and triethylamine (0.343 ml) were added to the mixture, followed by stirring for 4 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (30 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (30 ml), water (30 ml), and brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to provide a crude product of the titled compound (114 mg) as a pale yellow oil.

Workup

  1. temperaturewhile cooling in an ice water bath
  2. customThe reaction mixture was partitioned between ethyl acetate (50 ml)
  3. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml)
  4. dry with materialdried over anhydrous sodium sulfate
  5. customThe solvent was evaporated
  6. customto give a residue, N,N-dimethylformamide (3 ml)
  7. additionwas added
  8. stirringby stirring for 4 hrs
  9. customThe reaction mixture was partitioned between ethyl acetate (50 ml)
  10. washThe organic layer was washed with a saturated aqueous solution of ammonium chloride (30 ml), water (30 ml), and brine (30 ml)
  11. dry with materialdried over anhydrous sodium sulfate
  12. customThe solvent was evaporated
  13. customto give a residue, which
  14. customwas then purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate
  15. additionFractions containing the target compound
  16. concentrationwere concentrated

Sources & evidence

ORD record
ord-d7845c5f59c346db97aafc3d29d3bf10
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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