Isatoic anhydride , condensation with

Isatoic anhydride condensed with 3,4-dihydroisoquinazolines (471) to give the partially reduced title compounds (472) (70USP3497499). 

Isatoic anhydride condensed with the sodium salt of 2-aminothiophenol to give the intermediate benzamide (607), which underwent double ring closure with a-haloketones to quinazolino[2,3-c]l,4-benzothiazoles (608) (72IJC476). 

N-Substituted isatoic anhydrides condensed with S-methylthioureas to form 1-substituted 2-amino-quinazolin-4-ones in good yields. When S-N,N -trimethylthiourea was used, l,3-disubstituted-2-methylimino-l,2-dihydro-quinazolin-4-one was formed. ... 

The condensation of isatoic anhydride 1 with the diamines 31 in acetic acid led to the substituted benzimidazoles 32 (yields 62-70%) [16],... 

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. 

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. 

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... 

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]. 

The use of activated anthranihc acid derivatives facUitates the preparation of the amides in those cases where the amines are either umeactive or difficult to obtain. Thus, reaction of (87-1) with phosgene gives the reactive the isatoic anhydride (89-1). Condensation of that with ortho-toluidine leads to the acylation product (89-2) formed with a simultaneous loss of carbon dioxide. This is then converted to the quinazolone (89-3) by heating with acetic anhydride. Reaction with sodium borohydride in the presence of aluminum chloride selectively reduces the double bond to yield the diuretic agent metolazone (89-4) [99]. 

Performing a Vilsmeier-Haack reaction on 3-benzoyloxy-2-methyl-quinazolin-4-one (184) afforded the isoxazolo[3,2- ]quinazolinone (185) [86IJC(B)709]. This ring system (187) was also synthesized by cyclocondensation of anthranilic acids or isatoic anhydrides with the isoxazolin-3-ones (186) (77AF766 83MIP1), or by condensation of methyl anthrani-late with 3-chloropropanoyl chloride followed by cyclization with hydroxylamine hydrochloride (77AF766). 

Benzoxazine-2,4-diones (43) (isatoic anhydrides) have proved useful synthons for various new heterocycles. For example, a base-catalyzed condensation with the oxindole (44) affords tetracycles (45) (80JHC1785), whereas the parent compound (43 R = H) and 3-hydroxyisothiazole give the quinazolinone (46) (69AJC2497). 

In a simple microwave-assisted and solvent-free approach, substituted isatoic anhydrides were reacted with 4-substituted prolines to afford fused 1,4-benzodiazepine derivatives67. The reactions proceeded in less than 3 min and the fused 1,4-benzo-diazepine products were obtained in very good yields (Scheme 3.42). This condensation reaction represents a practical alternative approach to the typical traditional methods. 

Isatoic anhydride can be condensed with proline in polar aprotic solvents at high temperature, or in a reaction catalyzed by the enzyme catalase, to yield a pyrrolo[l,4]benzodiazepine ring, a structural pattern found in some antineoplasic antibiotics188 (Scheme 40). 

Mandelaldehyde, PhCH(OH)CHO, can be condensed with 7V-phenyl-ethanolamine under acid catalysis to afford the 5,6-dihydro-1,4-oxazine (393) (80%) none of the isomeric oxazolidine is formed.""" Oxidation of isatins with peroxodisulphate gives excellent yields of 2,3-dioxo-benzo[Z>]-l,4-oxazines (394), in contrast to the formation of isatoic anhydrides by oxidation with a peroxide." Benzo[f>]-l,4-oxazines that are functionalized with methylene at position 2, i.e. (395), are obtained in good yields by the mercuric-oxide-promoted cyclization of o-(propargylamino)phenols." ... 

Many examples of the formation of new six-membered rings containing a nitrogen atom in the reaction of isatoic anhydrides with ketones, diketones, various ether derivatives, lactones, and organometallic compounds are known. Thus, the anhydrides 2 and 34 condense with acetophenones and co-methoxyacetophenones in the presence of lithium diisopropylamide at low temperatures with the formation of derivatives of quinolone 35 [17, 18],... 

The reaction of isatoic anhydrides with cyclic ketones and diketones leads to condensed tri- and tetracyclic compounds. For example, the reaction of the anhydrides 2 or 42 with cyclohexen-2-one in the presence of lithium diisopropylamide gave 28-49% yields of the acridine derivatives 43 [25],... 

The derivatives of anthranilic acid 179 (the products from the condensation of primary amines and the respective isatoic anhydrides) were treated with orthocarbonic ester, and the obtained compounds 180 were cyclized to the derivatives of 2,4-quinazolinedione 181 by the action of an alcohol solution of potassium hydroxide [67, 96, 104, 105],... 

The ripe fruits of E. rutaecarpa contain d two new alkaloids, i.e. dihydro-rutaecarpine (23) and its 14-formyl derivative (24), in addition to evodiamine and rutaecarpine. The racemic forms of the new bases, (23) and (24), were readily synthesized by condensation of 3,4-dihydro-/3-carboline with isatoic anhydride (25) [- ( )-(23)], followed by formylation (Scheme 4). 

The synthesis of rutaecarpine (26) itself from the sulphur analogue (27) of isatoic anhydride and 3,4-dihydro-/3-carboline is reported to proceed in 80% yield " however, the corresponding condensation with isatoic anhydride (25) is unsatisfactory, presumably owing to the instability of 3,4-dihydro-/3-carboline at the high temperature used. This may be circumvented by condensation of (25) with the more stable l-oxo-l,2,3,4-tetrahydro-/S-carboline (28), which affords rutaecarpine directly, a spontaneous dehydrogenation step obviously not being required in this reaction. ... 

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