Water → N,2-dihydroxy-4-methoxybenzamide

HRID 1246565Notes

Reaction equation

HRID 1246565 reaction equation
Cl.[NH2:2][OH:3].O.[OH-].[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:19])[C:12](=[CH:17][CH:18]=1)[C:13](OC)=[O:14]>CCOCC>[OH:19][C:11]1[CH:10]=[C:9]([O:8][CH3:7])[CH:18]=[CH:17][C:12]=1[C:13]([NH:2][OH:3])=[O:14]

Participants

6

Reactant 4

HCID 962Water2×HCID 14798Sodium HydroxideHCID 79523Methyl 4-methoxysalicylateHCID 443297Hydroxyamine hydrochloride

Product 1

HCID 10171294N,2-dihydroxy-4-methoxybenzamideYield 77.4%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Conditions

Temperature
0 °C

Procedure

Prepare 4-(6-methoxybenzo[d]isoxzaol-3-yl)piperazine by slowly adding a solution of hydroxylamine hydrochloride (57.2 g, 0.823 mol) and water (600 mL) to a solution of sodium hydroxide (76.9 g, 1.92 mol) and water (300 mL). Then add a solution of methyl 4-methoxysalicylate (100 g, 0.55 mol, Aldrich Chemical Co.) and ether (800 mL), stir overnight, evaporate the ether, acidify with dilute hydrochloric acid, cool to 0° C., and filter. Recrystallize the filter cake from methanol to afford the 2-hydroxy-p-anisohydroxamic acid (78 g). Treat a warm (50° C.) solution of the hydroxamic acid (78 g) and tetrahydrofuran (500 mL) under nitrogen with a solution of carbonyldiimidazole (138.1 g, 0.85 mol) and tetrahydrofuran (500 mL), reflux for 3.5 hours, quench by addition of water (1000 mL), acidify to pH 3, add water (1000 mL) and refrigerate overnight. Collect the solid, wash with water and recrystallize from methanol to afford 54 g of 3-hydroxy-6-methoxy-1,2-benzisoxazole. Heat a stirred mixture of 3-hydroxy-6-methoxy-1,2-benzisoxazole (54 g) and POCl3 (100.3 g, d 1.645) at 95° C. under nitrogen, cool to 30° C., add triethylamine (33 g), heat at 140° C. overnight, quench with stirring into ice water and filter. Dissolve the filter cake in cyclohexane (2000 mL), filter, concentrate and recrystallize the residue from petroleum ether to give 3-chloro-6-methoxy-1,2-benzisoxzole (33 g). Treat this product with piperazine as described in U.S. Pat. No. 5,852,022, the contents of which are herein incorporated by reference, to afford 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole.

Workup

  1. customevaporate the ether
  2. filtrationfilter
  3. customRecrystallize the filter cake from methanol

Sources & evidence

ORD record
ord-4ac487058352481a9dd64971af0dad5f
Source dataset
uspto-grants-2006_10
Patent number
US07125903B1

Reaction notes

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