Triethylamine → 4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide

HRID 492957Notes

Reaction equation

HRID 492957 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.C(N(CC)CC)C.Cl[C:27](OC1C=CC=CC=1)=[O:28].Cl.Cl.[N:38]1([CH2:43][CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:42][CH2:41][CH2:40][CH2:39]1>O1CCCC1>[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:27]([N:47]2[CH2:48][CH2:49][CH:44]([CH2:43][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:45][CH2:46]2)=[O:28])[CH:6]=1

Participants

6

Reactant 4

HCID 8471Triethylamine2×HCID 15891Phenyl chloroformateHCID 231530214-(1-Pyrrolidinylmethyl)piperidine dihydrochlorideHCID 231531982-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine

Product 1

HCID 866021734-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

4-(2-Fluoro-4-nitrophenoxy)pyridin-2-ylamine (160 mg) was dissolved in tetrahydrofuran (7 ml) under a nitrogen atmosphere, and then triethylamine (0.268 ml) and phenyl chloroformate (0.242 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (200 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (100 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, and N,N-dimethylformamide (7 ml) was added thereto. And then 4-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride (619 mg) and triethylamine (0.716 ml) were added thereto, followed by stirring for 4 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) in this order, 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, eluent; heptane:ethyl acetate=1:1, then ethyl acetate). Fractions containing a target compound were concentrated to provide a crude product of 4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide (290 mg) as pale yellow oil.

Workup

  1. temperaturewhile cooling in an ice water bath
  2. customThe reaction mixture was partitioned between ethyl acetate (200 ml)
  3. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (100 ml) in this order
  4. dry with materialdried over anhydrous sodium sulfate
  5. customThe solvent was evaporated
  6. customto give a residue, and N,N-dimethylformamide (7 ml)
  7. additionwas added
  8. stirringby stirring for 4 hrs
  9. customThe reaction mixture was partitioned between ethyl acetate (100 ml)
  10. washThe organic layer was washed with a saturated aqueous solution of ammonium chloride (50 ml), water (50 ml) and brine (50 ml) in this order
  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, eluent
  15. additionFractions containing a target compound
  16. concentrationwere concentrated

Sources & evidence

ORD record
ord-78ef5d1f12614a318289c47fa253477d
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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