Phenyl chloroformate → 4-(Azetidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide

HRID 492998Notes

Reaction equation

HRID 492998 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[N: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[N: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 231530124-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidineHCID 231533864-(Azetidin-1-ylmethyl)piperidine dihydrochloride

Product 1

HCID 576776554-(Azetidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent2×

Procedure

6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-ylamine (200 mg) was dissolved in tetrahydrofuran (8 ml) under a nitrogen atmosphere, and then triethylamine (0.335 ml) and phenyl chloroformate (0.300 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 30 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) 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 (600 mg) and triethylamine (0.781 ml) were added thereto, followed by stirring for 7 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, heptane:ethyl acetate=1:8, then ethyl acetate). Fractions containing the target compound were concentrated to provide a crude product of the titled compound (340 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) 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 7 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) in this order
  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-13948159976c4c4a93c657361114c4e1
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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