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

HRID 493004Notes

Reaction equation

HRID 493004 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.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.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: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 231530124-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine

Product 1

HCID 576774174-[2-(Azetidin-1-yl)ethyl]piperazine-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 (60 mg) was dissolved in tetrahydrofuran (3 ml) under a nitrogen atmosphere, and then triethylamine (0.100 ml) and phenyl chloroformate (0.0903 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 20 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). 1-[2-(Azetidin-1-yl)ethyl]piperazine trihydrochloride (214 mg) and triethylamine (0.234 ml) were added thereto, followed by stirring for 6 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) 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=1:1, ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated under reduced pressure to provide a crude product of the titled compound (110 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 6 hrs
  8. customThe reaction mixture was partitioned between ethyl acetate (50 ml)
  9. washThe organic layer was washed with a saturated aqueous solution of ammonium chloride (30 ml), water (30 ml), and brine (30 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 under reduced pressure

Sources & evidence

ORD record
ord-ddf0c9b45d2e4e42bffe93d67ed11b24
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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