Réaction #605413

Équation de réaction

(E)-3-{1′-(4-Fluoro-benzyl)-3,4-dihydro-3-methyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester

EDC

HOBT

NH2OTHP

HCl

NaOH

→

(E)-3-{1′-(4-fluoro-benzyl)-3,4-dihydro-3-methyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-hydroxy-acrylamide hydrochloride

Rendement 80.0%

Solvants

dioxane

water

Conditions de réaction

Traitement

1. 1
   Autrethe solvent was removed
2. 2
   workup.DISSOLUTIONThe resulting acid was dissolved in DCM (10 ml)
3. 3
   workup.STIRRINGThe mixture was stirred for 6 h at RT
4. 4
   Autrepartitioned between 5% aqueous NaHCO3 and DCM
5. 5
   SéchageThe organic layer was dried over Na2SO4
6. 6
   Autreevaporated
7. 7
   AutreThe crude product was purified by column chromatography (eluent: DCM/MeOH 97:3)
8. 8
   workup.DISSOLUTIONthe resulting compound was dissolved in DCM
9. 9
   workup.ADDITIONtreated with 4 M HCl in dioxane for 4 h
10. 10
    FiltrationThe precipitate was filtered

Mode opératoire

(E)-3-{1′-(4-Fluoro-benzyl)-3,4-dihydro-3-methyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (520 mg, 1.22 mmol) was suspended in dioxane (20 ml) and water (10 ml). 1 M NaOH (1.59 ml) was added and the resulting mixture was stirred at RT for 5 h. The mixture was neutralized with 1 M HCl and the solvent was removed. The resulting acid was dissolved in DCM (10 ml) and TEA (0.338 ml, 2.44 mmol). EDC (350 mg, 1.83 mmol), HOBT (247 mg, 1.83 mmol) and NH2OTHP (172 mg, 1.46 mmol) were added to the resulting solution. The mixture was stirred for 6 h at RT and then partitioned between 5% aqueous NaHCO3 and DCM. The organic layer was dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (eluent: DCM/MeOH 97:3) and the resulting compound was dissolved in DCM and treated with 4 M HCl in dioxane for 4 h. The precipitate was filtered to give (E)-3-{1′-(4-fluoro-benzyl)-3,4-dihydro-3-methyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-hydroxy-acrylamide hydrochloride (451 mg) as a white solid.

Source