Carbamate → tetrahydro-2H-pyran-4-yl 4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate

HRID 539718Notes

Reaction equation

HRID 539718 reaction equation
[F:1][C:2]1[C:21]([NH:22][C:23]([NH:25]C2C=CN=C(C)C=2)=[O:24])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])C)=[O:12])[CH2:7][CH2:6]1.Cl.CCN(CC)CC.[CH:41]1[C:46]([N+:47]([O-])=O)=[CH:45][CH:44]=[C:43]([Cl-]C([O-])=O)[CH:42]=1.OC1C[CH2:59][O:58][CH2:57]C1.[H-].[Na+].C(=O)([O-])N>CO.O1CCOCC1.C(Cl)Cl>[O:58]1[CH2:59][CH2:16][CH:14]([O:13][C:11]([N:8]2[CH2:7][CH2:6][N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[C:21]([NH:22][C:23]([NH:25][C:43]4[CH:42]=[N:47][C:46]([CH3:41])=[CH:45][CH:44]=4)=[O:24])[C:2]=3[F:1])[CH2:10][CH2:9]2)=[O:12])[CH2:17][CH2:57]1

Participants

10

Reactant 6

HCID 276CarbamateHCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 24758Sodium hydrideHCID 74956Tetrahydro-4H-pyran-4-olHCID 58919226Tert-butyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)piperazine-1-carboxylate

Product 1

HCID 23641368tetrahydro-2H-pyran-4-yl 4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylateYield 39%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of tert-butyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)piperazine-1-carboxylate (1.0 g, 2.26 mmol, 1.0 equiv) in MeOH (10 mL) was added HCl (71 (4N in dioxane, 10 mL, 40 mmol, 17.7 equiv). The mixture was stirred for 30 min, and the solvent was then removed in vacuo. The residue was suspended in dry DCM (20 mL) and Et3N (1.64 mL, 11.79 mmol, 5.2 equiv). To the resulting mixture was added 4-nitrophenylchloroformate (500 mg, 2.49 mmol, 1.1 equiv). The resulting solution was stirred for 30 min, diluted with DCM, washed with aq NH4Cl and brine and concentrated in vacuo. The resulting residue was divided into three equal portions for subsequent derivitization. To a solution of 4-hydroxytetrahydropyran (190 μL, 2 mmol, 2.65 equiv) was added NaH (120 mg of 60% dispersion in mineral oil, 3.0 mmol, 4 equiv) after stirring for 10 minutes, the activated carbamate was added to the reaction mixture, and the reaction was stirred at room temperature overnight. The excess NaH was quenched by the careful addition of water, and the reaction mixture was diluted with ethyl acetate. The organic layer was washed repeatedly with water and once with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by preparative reverse phase HPLC provided tetrahydro-2H-pyran-4-yl4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate (140 mg, 39%). LCMS m/z (APCI)=472.2 (M+H).

Workup

  1. customthe solvent was then removed in vacuo
  2. stirringThe resulting solution was stirred for 30 min
  3. washwashed with aq NH4Cl and brine
  4. concentrationconcentrated in vacuo
  5. stirringafter stirring for 10 minutes
  6. stirringthe reaction was stirred at room temperature overnight
  7. customThe excess NaH was quenched by the careful addition of water
  8. additionthe reaction mixture was diluted with ethyl acetate
  9. washThe organic layer was washed repeatedly with water and once with brine
  10. dry with materialdried over sodium sulfate
  11. concentrationconcentrated in vacuo
  12. customPurification by preparative reverse phase HPLC

Sources & evidence

ORD record
ord-965b19c93a47433882be3412985adcd9
Source dataset
uspto-grants-2014_10
Patent number
US08871768B2

Reaction notes

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