Synthesis Of Intermediate Of SUN-C8257

The heart cerebral diseases, such as hypertension and antherosclerosis, endanger humanity's health seriously. In recent years, the incidence rate of hypertension disease in our country assumed the trend of escalation year by year. Nowadays, many countries are still researching and developing new anti-hypertension drugs, and making great effort in looking for new target. Much attention has been paid to chymase inhibitor in cardiovascular drug research.Prehypertension is hydrolyzed in blood plasma by renin, where angiotensinⅠ(AngⅠ) is produced. Angiotensin- converting enzyme(ACE), which exsists in blood plasma and tissue, is able to convert AngⅠinto AngⅡ. In the developing process of hypertension, chronic cardiac insufficiency and acute myocardial infarction, AngⅡplays an important role. AngⅡcauses the ascension of blood pressure by affecting AngⅡreceptor. Besides the pathway of ACE, there are several other ways of AngⅡproduction. Chymase is an important enzyme which converts AngⅠinto AngⅡ. This discovery has provided new mechanism for pathology physiology of certain cardiovascular diseases, and also provides reasonable explanation for the finiteness of ACE inhibitor treatment.Chymase inhibitor is a new kind of medicine, which is different with the traditional cardiovascular medicine. There are two types of chymase inhibitor, peptidic and nonpeptidic. Research of long-lasting nonpeptidic and selective chymase inhibitor is being concerned in cardiovascular medicine development.SUN-C8257, also named as 3-[(3-amino-4-carboxy) phenyl- sulfonyl]-7-chloroquinazoline-2,4(1H, 3H)-dione, is the first orally stable chymase inhibitor. Experiment indicated that it can suppress the deposition of lipin in aorta obviously, and is helpful in antherosclerosis retrogression, so as to eliminate hidden danger of hypertension and other cardiovascular diseases.Benzyl 4-chloro-2-N-phenoxycarbonylanthranilate and t-butyl 4-sulfonyl-2-[[(phenylmethoxy)carbonyl]amino]benzoa- te are two important intermediates on the synthesis of SUN-C8257, the synthetic methods of which were not reported and were not commercially available.Objective1 To synthesis several intermediates of SUN-C8257①4-chloro-2-[(phenoxycarbonyl)amino] benzoic acid;②benzyl 4-chloro-2-N-phenoxycarbonylanthranilate;③4-sulfo-2-[[(phenylmethoxy)carbonyl]amino]benzoic acid;④t-butyl 4-sulfo-2-[[(phenylmethoxy)carbonyl]amino] benzo- ate;⑤t-butyl 4-sulfonyl-2-[[(phenylmethoxy)carbonyl]amino] benz- oate.2 To design and evaluate the best synthetic methods of the compounds mentioned above.Methods1 Synthesis of several intermediates①4-chloro-2-[(phenoxycarbonyl)amino]benzoic acid was prepared by reaction with 4-chloro-2-aminobenzoic acid and phenyl chloroformate;②4-chloro-2-N-phenoxycarbonylanthranilate was prepared by esterification with 4-chloro-2-[(phenoxycarbonyl)amino] benzoic acid and benzyl alcohol, in which way the carboxyl group was protected;③4-sulfo-2-[[(phenylmethoxy)carbonyl]amino]benzoic acid was systhesized by reaction with 4-sulfoanthranilic and benzyl chloroformate, in which way the amino group was protected;④to get t-butyl 4-sulfo-2-[[(phenylmethoxy)carbonyl] amino]benzoate by reaction with 4-sulfo-2-[[(phenylmethoxy) carbonyl]amino]benzoic acid and t-butyl alcohol;⑤to prepare benzenesulfonyl chloride by reaction with t-butyl 4-sulfo-2-[[(phenylmethoxy)carbonyl] amino]benzoate and thionyl chloride, and then to get t-butyl 4-sulfonyl-2- [[(phenylmethoxy)carbonyl] amino]benzoate via aminolysis of benzensulfonyl chloride.2 The purity of the products was checked by TLC and HPLC.3 The structures of the products were characterized by 1H-NMR, 13C-NMR, MS and element analysis. Result1 Three intermediates were synthesized①4-chloro-2- [(phenoxycarbonyl)amino]benzoic acid, m.p.>360℃, the structure was characterized by 1H-NMR, 13C-NMR and MS;②benzyl 4-chloro-2-N-phenoxycarbonylanthranilate, m.p .88.6 -89.3℃, the structure was characterized by element analysis, 1H-NMR and 13C-NMR;③4-sulfo-2-[[(phenylmethoxy)carbonyl]amino]benzoic acid, m.p. > 300℃, the structure was characterized by element analysis, 1H-NMR and 13C-NMR.2 We've ascertained the best react conditions about the synthesis of 4-chloro-2-[(phenoxycarbonyl)amino]benzoic acid and benzyl 4-chloro-2-N-phenoxycarbonylanthranilate. 3 We've tried to explore synthetic method of t-butyl 4-sulfonyl-2-[[(phenylmethoxy)carbonyl]amino]benzoate but failed at last. Probable causes have been analyzed.Conclusion1 Three intermediates of SUN-C8257 were synthesized: 4-chloro-2-[(phenoxycarbonyl)amino]benzoic acid, benzyl 4- chloro-2-N-phenoxycarbonylanthranilate, 4-sulfo-2-[[(phenyl- methoxy)carbonyl]amino]benzoic acid, the structures of which were characterized to be right.2 Different synthetic methods of the compounds mentioned above were designed. Best react conditions were determined, which were easily to operate. 3 Failed to get t-butyl 4-sulfo-2-[[(phenylmethoxy)carbonyl] amino]benzoate. The possible reason is that t-butyl alcohol was turned to be alkene by elimination reaction.