Isatoic Anhydrides

Fig. 2. Synthesis of uma2enil (18). The isonitrosoacetanihde is synthesized from 4-f1iioroani1ine. Cyclization using sulfuric acid is followed by oxidization using peracetic acid to the isatoic anhydride. Reaction of sarcosine in DMF and acetic acid leads to the benzodiazepine-2,5-dione. Deprotonation, phosphorylation, and subsequent reaction with diethyl malonate leads to the diester. After selective hydrolysis and decarboxylation the resulting monoester is nitrosated and catalyticaHy hydrogenated to the aminoester. Introduction of the final carbon atom is accompHshed by reaction of triethyl orthoformate to...

These formulae explain the scission products of the two alkaloids and the conversion of evodiamine into rutaecarpine, and were accepted by Asahina. A partial synthesis of rutaecarpine was effected by Asahina, Irie and Ohta, who prepared the o-nitrobenzoyl derivative of 3-)3-amino-ethylindole-2-carboxylic acid, and reduced this to the corresponding amine (partial formula I), which on warming with phosphorus oxychloride in carbon tetrachloride solution furnished rutaecarpine. This synthesis was completed in 1928 by the same authors by the preparation of 3-)S-amino-ethylindole-2-carboxylic acid by the action of alcoholic potassium hydroxide on 2-keto-2 3 4 5-tetrahydro-3-carboline. An equally simple synthesis was effected almost simultaneously by Asahina, Manske and Robinson, who condensed methyl anthranilate with 2-keto-2 3 4 5-tetrahydro-3-carboline (for notation, see p. 492) by the use of phosphorus trichloride (see partial formulae II). Ohta has also synthesised rutaecarpine by heating a mixture of 2-keto-2 3 4 5-tetrahydrocarboline with isatoic anhydride at 195° for 20 minutes. 

The substance represented by formula (IV), viz., 4-hydroxy-3-allyl-3 4-dihydroqviinazoline, m.p. 130°, was synthesised by Reynolds and Robinson, and proved to be different from vasicine. Spath and Kuffner established the identity of the degradation product (V), upon which formula (IV) for vasicine was chiefly based by synthesis from isatoic anhydride, which, on treatment with glycine ester hydrochloride and sodium meth-oxide, gave the substituted Wppuric acid (VI), and this, on heating with... 

It was found inadvisable to use more than four molecules of form-amide [ (47) when R = H] per molecule of anthranilic acid and the condensation produces best results when the mixture is heated at 120 -130°C for 2 hr followed by further heating at 170°-180 C for 2 hr. Other variants of this reaction involve the use of ammonium o-acylaminobenzoates, anthranilic acid in the presence of nitriles and acetic anhydride, o-acetamidonitrile with acetic anhydride or hydrogen peroxide, anthranilic esters and aliphatic or aromatic amides or amidines, isatoic anhydride with amides or amidines, and anthranilic esters with aryl iminochlorides in acetoned The mechanism proposed by Bogert and Gotthelf has had experimental supporR and is represented in Scheme 12. 

Treatment of isatoic anhydrides with thionyl chloride furnishes the isocyanates 22, which react with methylhydrazine to yield Ihe benzotriazepinediones 23.362... 

The benzodiazepine nucleus is extremely important, as it is the base of several drugs and other biologically active compounds with different properties. A facile synthesis of 2-methyl-l,4-benzodiazepin-5-ones has been described by Santagada and co-workers [162]. Isatoic anhydride 254 was reacted with M-substituted allylamines under microwave irradiation to give compound 255... 

A more highly oxidized derivative of quinazoline forms the heterocyclic moiety of a compound with CNS activity. Condensation of the aminopropylpiperazine 141 with isatoic anhydride gives the anthranilamide 142. Reaction of that amide with phosgene gives directly the heterocyclic ring. (The reaction may proceed by initial formation of the carbamoyl chloride ... 

As noted above, a convenient pathway to cinno-lines consists of intramolecular condensation of a diazonium group with a ketonic methyl group, or alternately with a double bond. The analogous reaction with an amide nitrogen leads to 1,2,3-benzotriazines, such as 198. Reaction of isatoic anhydride with N-aminomorpholine affords the hydrazide 196 then, treatment with nitrous acid yields initially the diazonium salt (197). Under the reaction conditions... 

Syntheses from [4+2] atom fragments from an aniline and a pyrimidine derivative as sources of the heteroatoms have also been utilized. Heating isatoic anhydride 202 and 2-methylthio-l,4,5,6-tetrahydropyrimidine in DMF yielded 203 (Equation 22) <2000T8735>. 

The first representative of the [l,2,4]triazino[5,6-fc]diazepin-8-ones 583 was obtained by reaction of 6-amino-3-(p-tolyl)[l, 2,4]triazin-5(2//)-thione 581 with 2//-1,3-oxazine-2,6(3//)-dione [85LA(3)640]. The benzo analogue [l,2,4]triazino[5,6-b][l,4]benzodiazepinones 582 were similarly obtained by reaction of 581 with isatoic anhydride. 

It is clear from Table 44 that the E2/SN2 ratios observed for reactions of crown ether-separated KOt-Bu ion pairs will greatly depend on the type of substrate and solvent. Di Biase and Gokel (1978) have recently reported many examples of the use of this reagent either as a nucleophile [for example, in its reaction with benzyl chloride and in the reaction with isatoic anhydride (34)] or as a strong base [for example, in the basic oxidation of fluorene to 2-carboxybiphenyl (35)]. 

Although the 3,l-perhydrobenzoxazine-2,4-diones are the saturated analogs of the versatile synthon isatoic anhydride, few articles deal with the synthesis of these derivatives. 

One of the early steps in an allergic reaction consists in the release of a series of endogenous compounds referred to as mediators from sensitized cells. The finding in the early 1960s that cromolyn sodium, still the only approved drug of this class, blunts this reaction has led to an intense search for additional examples. It is of interest that a relatively simple anthranilic acid derivative has shown mediator-release inhibiting activity. Reaction of 3,4-dimethoxybenzalde-hyde (167) with isatoic anhydride 168 gives the condensation product 169, which, upon hydrolysis, affords tranilast (170) (43]. 

---