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

HRID 492979Notes

Reaction equation

HRID 492979 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.[N:31]1([CH2:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:34][CH2:33][CH2:32]1>O1CCCC1.C(N(CC)CC)C.CN(C)C=O>[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:39]2[CH2:40][CH2:41][CH:36]([CH2:35][N:31]3[CH2:34][CH2:33][CH2:32]3)[CH2:37][CH2:38]2)=[O:21])[CH:6]=1

Participants

7

Reactant 3

HCID 15891Phenyl chloroformateHCID 231531982-Amino-4-(2-fluoro-4-nitrophenoxy)pyridineHCID 231533864-(Azetidin-1-ylmethyl)piperidine dihydrochloride

Product 1

HCID 576776814-(Azetidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent2×

Procedure

4-(2-Fluoro-4-nitrophenoxy)pyridin-2-ylamine (60 mg) was dissolved in tetrahydrofuran (3 ml) under a nitrogen atmosphere, and then 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 1.5 hrs. The solution 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) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which was added N,N-dimethylformamide (3 ml). 4-(Azetidin-1-ylmethyl)piperidine dihydrochloride (192 mg) and triethylamine (0.235 ml) were added thereto, followed by stirring for 8 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of ammonium chloride (50 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (50 ml), water (50 ml), and brine (50 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, heptane:ethyl acetate=1:1, then ethyl acetate). Fractions containing the target compound were concentrated to provide the titled compound (34 mg) as a pale yellow oil.

Workup

  1. temperaturewhile cooling in an ice water bath
  2. customThe solution 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) in this order
  4. dry with materialdried over anhydrous sodium sulfate
  5. customThe solvent was evaporated
  6. customto give a residue
  7. stirringby stirring for 8 hrs
  8. customThe reaction mixture was partitioned between ethyl acetate (100 ml)
  9. washThe organic layer was washed with a saturated aqueous solution of ammonium chloride (50 ml), water (50 ml), and brine (50 ml)
  10. dry with materialdried over anhydrous sodium sulfate
  11. customThe solvent was evaporated
  12. customto give a residue, which
  13. customwas then purified by silica gel column chromatography (Fuji Silysia NH, heptane
  14. additionFractions containing the target compound
  15. concentrationwere concentrated

Sources & evidence

ORD record
ord-468edff797df447c99a32638553f7e51
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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