Synthesis of NSC‐341,964: An unexpected study on the stability of 2‐aryl‐4H‐3,1‐benzoxazin‐4‐ones

Abstract

Resynthesis of NSC 341,964, which had been assigned structure 1 (1-[[3-(7-chloro-4-oxo-4H-3,l-benzoxazin-2-yl)phenyl]methyl]pyridinium chloride) was approached via 7-chloro-2-(3-methylphenyl~4H-3,1-benzoxazin-4one (5) obtained from 3-methylbenzoyl chloride (2) and 2-amino-4-chlorobenzoic acid (3) followed by dehydration in acetic anhydride. Radical bromination provided 6 which with pyridine afforded the bromide analog 7 of 1. Ion exchange, however, gave ring-opened henzoic acid 8 rather than 1. The original sample of NSC 341,964 also proved to be ring-opened material. However, 7 upon standing exhibited slow hydrolysis to 8 so that the structure of the original NSC 341,964 remains uncertain. A more direct route to compound 8 is also described. Chern., 23, 249 (1986). J. HeterocyclicIn order to provide the National Cancer Institute with additional material for biological evaluation, we were asked to prepare NSC-341,964. This compound had been assigned the structure 1-[[3-(7-chloro-4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]methyI]pyridinium chloride (1, Scheme I) by

7-Nitro-2-phenyl-4H-3,1-benzoxazin-4-one

“…For related literature, see: Allen et al (1987); Bain & Smalley (1968); Bernstein et al (1995); Bouillant et al (1983); Colson et al (2005); El-Din (2000); Fenton et al (1989); Francis et al (2000); Gutschow et al (1998); Hamprecht et al (2004); Hauteville et al (1988); Hodson et al (2000); Johnson & Pattison (1986); Kakuta et al (2001); Krantz et al (1990); Mayama et al (1981); Pavlidis & Perry (1994); Ponchet et al (1984); Shalaby et al (2000); Ulrich (1991); Uejima et al (1993). Table 1 Hydrogen-bond geometry (Å , ).…”

“…2-Substituted-4H-3,1-benzoxazin-4-one base has been utilized as potent inhibitors of human leukocyte elastase (Krantz et al, 1990) and serine proteases (Gutschow et al, 1998). The National Cancer Institute, Washington, USA has also shown interest in 1-[3-(7-chloro-4-oxo-3,1-benzoxazin-4-yl) phenyl] methyl pyridinium chloride (NSC-341, 964) (Johnson & Pattison, 1986), evaluating its anti-neoplastic activity. Initial studies on 2-substituted-4H-3,1-benzoxazin-4-one showed good cytotoxic activity (Pavlidis & Perry, 1994) and herbicidal properties (Hamprecht et al, 2004).…”