Isatoic anhydride reaction

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...

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... 

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)]. 

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 synthesis of quinazoline derivatives by ring-opening and ring-closure reactions involving isatoic anhydrides and 3,l-benzoxazin-4-ones is covered in Section 8.02.9.2. 

The reaction of maleic anhydride with trimethylsilyl azide was reported to provide l,3-oxazine-2,6-dione in good yield. Control of the temperature proved essential in order to avoid a violent, exothermic reaction this could readily be accomplished by running the reaction in methylene chloride at 0°C <19950PP651>. Similar transformations of 3-substituted phthalic anhydrides 546 resulted in formation of 8- 547 or 5-substituted 548 isatoic anhydrides (Equation 66). The ratio of the regioisomeric products was strongly influenced by the substituent X while nitro and acetylamino derivatives 546 (X = NO2, NHAc) gave exclusively the 8-substituted isomers, only the 5-substituted product was formed from 3-aminophthalic anhydride 546 (X = NH2) <1998JOC6797>. 

Isatoic anhydride undergoes a one-step conversion to o-aminophenyloxazolines 2 with amino alcohols via elimination of carbon dioxide. The reaction is carried out in the presence of kaolinitic clay in refluxing chlorobenzene. These o-aminophenyloxazolines, in particular, those derived from chiral amino alcohols,... 

There are two important general types of reaction by which six-membered heterocycles containing two or more heteroatoms can be transformed into other six-membered heterocyclic systems, namely reactions which involve an ANRORC mechanism, and reactions which proceed by a Diels-Alder/retro-Diels-Alder type of mechanism. Transformation of 1,3-oxazinones and -thiazinones into pyrimidones (equations 193 and 194) has been extensively used, especially in the conversion of isatoic anhydride into quinazolinones (e.g. equation 195). 2,4-Diaryl-l,2,3,5-oxathiadiazines, which are readily accessible by reaction of sulfur trioxide with aryl isocyanates, are useful precursors to pyrimidines and 1,3,5-triazines (equation 196). 

The azathio isatoic anhydride 99 has been prepared by the reaction of 2-aminonicotinic acid 303 and thionyl chloride in ecu <2001JOC4413>, benzene, or cyclohexane as the solvent (Equation 40) <2004TL1377>. 

C8H9NO2, Mr 151.16, bp2w 135.5 °C, df 1.1682, ng 1.5815, occurs in a large number of blossom essential oils (e.g., neroli, ylang-ylang, and jasmin oils), grapes, and citrus oils. It occurs as white crystals mp 24-25 °C), or a yellowish liquid, that show blue fluorescence and have an orange blossom odor. Methyl anthranilate is prepared by esterification of anthranilic acid with methanol or by reaction of isatoic anhydride with methanol [163]. 

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). 

Reaction of isatoic anhydride with a-aminoalkynes gave 209, which cyclized to a mixture of the oxazolo[3,2-b]quinazolines (210) and 2-aminophenyloxazoles (211) upon treatment with phosgene (89JHC1495). 

Dihydro - 2,2,4 - trimethyl - 2H,6H -1,3,4-oxadiazino[2,3-6]quinazolines (654) were synthesized together with 2,3-dihydro-3-methyl-2-thioxo-6H-1,3,4-thiadiazolo[2,3-6]quinazolines by the reaction of isatoic anhydrides with l-[(2-hydroxy-2-methyl)propyl]hydrazine to give the corresponding anthranilic acid hydrazides (652), which were cyclized to the quinazoline intermediates 653 and then to 654 (79JHC1339). 

Dihydro-4-methyl-2//,6//-l, 3,4-thiadiazino[2,3-fc]quinazolines (655) were synthesized from isatoic anhydrides and 1-(2-hydroxymethyl)-1-methylhydrazine(79JHC1339). l,3,4-Thiadiazino[2,3- ]quinazolines(657) were also prepared by the reaction of 3-amino-2-mercaptoquinazolinones (656 with a-haloketones [81IJC(B)14 82M1145]. 

---