Pyridine → HCID 11087723, compound

HRID 1603840Notes

Reaction equation

HRID 1603840 reaction equation
[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][NH2:19])[O:15][N:14]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:26](=[O:28])[CH3:27])[O:15][N:14]=3)=[CH:11][CH:12]=2)=[CH:5][CH:6]=1

Participants

5

Reactant 3

HCID 1049PyridineHCID 7918Acetic AnhydrideHCID 68867113HCID 68867113, compound

Product 1

HCID 11087723HCID 11087723, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a flame dried flask containing (R)-4,5-Dihydro[3-[4-(4-pyridinyl)phenyl]-5-(hydroxymethyl)]isoxazole (440 mg, 1.73 mmol) in methylene chloride (20 mL) at 0° C. under an inert atmosphere is added triethylamine (0.36 mL, 2.60 mmol) and methanesulfonyl chloride (0.14 mL, 1.82 mmol). The reaction is slowly warmed to ambient temperature, stirred 3 hours, and quenched with water (25 mL). The organic phase is separated, washed with saturated NaHCO3 (25 mL) and saline (25 mL), dried over sodium sulfate and concentrated in vacuo to give crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-[[(methylsulfonyl)oxy]methyl]isoxazole. The crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-[[(methylsulfonyl)oxy]-methyl]isoxazole (580 mg, 1.73 mmol) is dissolved in tetrahydrofuran (4 mL), isopropanol (4 mL), and concentrated ammonium hydroxide (4 mL) in a thick wall resealable vessel and heated to 100-110° C. for 15 hours. The reaction is cooled to ambient temperature, diluted with ethyl acetate (50 mL), washed with saline (20 mL), dried over sodium sulfate and concentrated in vacuo to give crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-(aminomethyl)isoxazole. The crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-(aminomethyl)isoxazole (320 mg, 1.57 mmol) is dissolved in methylene chloride (15 mL) and cooled to 0° C. under an inert atmosphere. Pyridine (0.31 mL, 3.78 mmol) and acetic anhydride (0.15 mL, 1.57 mmol) are added to the cooled solution and stirred 20 hours at ambient temperature. The reaction is concentrated in vacuo, diluted with methylene chloride (50 mL), washed with saline (25 mL), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 200 mL), eluting with chloroform/methanol (97/3). The appropriate fractions are combined (Rf =0.14, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 244-245° C.

Workup

  1. concentrationThe reaction is concentrated in vacuo
  2. additiondiluted with methylene chloride (50 mL)
  3. washwashed with saline (25 mL)
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated in vacuo
  6. customchromatographed on silica gel (230-400 mesh, 200 mL)
  7. washeluting with chloroform/methanol (97/3)
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-4c85fb3e3ee649bd90feb01a0448433f
Source dataset
uspto-grants-1999_11
Patent number
US05990136

Reaction notes

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