Water → 3-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione

Participants

Reaction Conditions

Reaction Steps

A slurry of compound 2 was treated with 3-aminopiperidine-2,6-dione hydrochloride 3 (1.1 equiv.) in acetonitrile and a solution of 1-propanephosphonic acid cyclic anhydride (“T3P”) (2 equiv.) in ethyl acetate at 75-80° C. After 3 to 5 days, the total of compounds 1a and 2 was less than 1% area normalized (typically 0.05% area normalized). The reaction mixture was cooled to 55 to 65° C. Water was charged over 30 min, maintaining the temperature at 60° C. throughout the addition. During the first portion of water addition, an exotherm was observed. The mixture was further cooled to 20 to 30° C. over 1 hr. The resulting solid was filtered and washed with a mixture of acetonitrile and water (1:1). The solid was transferred back to the reactor and was agitated with a mixture of acetonitrile and water (1:1) between 20 to 30° C. for 1 hr. The mixture was filtered and the filter cake was washed with a mixture of acetonitrile and water (1:1). The filter cake was dried in a vacuum oven to afford compound 4 as a white solid: HPLC purity: 98.9 to 99.2%; yield: 89 to 93%; MS (m/e): 317 (M+1).

Provenance & Evidence