Anthranilic acid derivatives

Ubiquinones are prenylated benzoquinone derivatives carrying a side chain of 5-10 isoprene residues. Ubiquinone 50 (coenzyme Qio) for instance, has a side chain of fifty carbon atoms (=10 isoprene units). 

The Ubiquinones participate in cell respiration (E 2.1). They are attached with the hydrophobic side chain to the lipid components of the membranes, whereas the quinoid ring undergoes oxidoreductions. 

Threlfall, D. R. Polyprenols and terpenoid quinones and chromanols. In Encyclopedia of Plant Physiology, New Series, Vol. 8 Secondary Plant Products (E. A. Bell, B. V. Charlwood, eds.), pp. 288-308. Springer, Berlin-Heidelberg-New York 1980 Threlfall, D. R., Whistance, G. R. Biosynthesis of isoprenoid quinones and chromanols. In Aspects of Terpenoid Chemistry and Biochemistry (T. W. Goodwin, ed.), pp. 357-404. Academic Press, London 1971 

The secondary products derived from anthranilic acid (o-amino benzoic acid) may carry additional substituents at the aromatic ring, e.g., hydroxy groups (see formula for hydroxyanthranilic acid) or at the carboxyl and the amino group. The latter substituents may form additional rings. 

Anthranilic acid and anthranilic acid derivatives are formed in microorganisms, plants and animals. 

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The benzoic acid derivative 457 is formed by the carbonylation of iodoben-zene in aqueous DMF (1 1) without using a phosphine ligand at room temperature and 1 atm[311]. As optimum conditions for the technical synthesis of the anthranilic acid derivative 458, it has been found that A-acetyl protection, which has a chelating effect, is important[312]. Phase-transfer catalysis is combined with the Pd-catalyzed carbonylation of halides[3l3]. Carbonylation of 1,1-dibromoalkenes in the presence of a phase-transfer catalyst gives the gem-inal dicarboxylic acid 459. Use of a polar solvent is important[314]. Interestingly, addition of trimethylsilyl chloride (2 equiv.) increased yield of the lactone 460 remarkabiy[3l5]. Formate esters as a CO source and NaOR are used for the carbonylation of aryl iodides under a nitrogen atmosphere without using CO[316]. Chlorobenzene coordinated by Cr(CO)j is carbonylated with ethyl formate[3l7]. 

Similar instability is found for 3-unsubstituted 2,1-benzisoxazole in the presence of base, ring opening to anthranilic acid derivatives occurring readily (see Section 4.16.3.1.6). 

Dicarbonylimidazole reacted with the anthranilic acid derivative (498) to produce the fused isoxazolone IV-oxide (499) (77ZOR462). Methyl nitroacetate reacted with indole-3-carbaldehyde to produce (500) (70KGS1505). Treatment of (501) with base gave 3,4,5-triphenyl-2-isoxazoline IV-oxide (Scheme 142) (69JOC984). The reaction was reported to be a direct displacement as (502) did not give a product and no incorporation of deuterium was found using DOMe. 

The carcinogenic properties of tricycloquinazoline (60) were studied in detail because of its possible formation from anthranilic acid derivatives in nature. It possessed stronger carcinogenic activity toward mice (72%) than rats (27%). Its action resembled that of embedded plastic materials, because it was recovered unmetabolized. ... 

Nucleophilic aromatic substitution of the anthranilic acid derivatives, 72, on ortho-bromonitrobenzene affords the diphenyl-amine, 73. The ester is then saponified and the nitro group reduced to the amine (74). Cyclization of the resulting amino acid by heat affords the lactam (75). Alkylation on the amide nitrogen with 2-dimethylaminoethyl chloride by means of sodium amide affords dibenzepine (76). ... 

Most condensations of this type start with 2-aminobenzoic acid (anthranilic acid) derivatives. In an early, extensive work on the synthesis and chemistry of dianthranilides", acid chlorides 1 were used as starting materials.2... 

Simple heating of various other anthranilic acid derivatives often leads to the 1,5-diazocine derivatives (Table 3).3 "12... 

Table 3. Benzannulated 1,5-Diazocines by the Condensation of Anthranilic Acid Derivatives...

Anthranilic acid derivatives, such as flufenamic acid (35), constitute another effective series of non-steroidal antiinflammatory agents. Homologation... 

The angularly fused pyridazino[l,6- ]quinazolines were prepared by tandem [6+0 (a), 6+0 (7)] cyclization of functionalized, diazotized anthranilic acid derivatives. Depending on the order of reacting ethyl benzoylacetate, malonitrile, and the diazotized anthranilonitrile, the pyridazino[l,6- ]quinazolines 103 or 105 were obtained by alkaline or thermal cyclizations, respectively (Scheme 11) <2001T1813>. 

Anthranilic acid derivatives of genus D that possess carbamate and urea linkers (W contains an oxygen or nitrogen atom directly linked to the carbonyl carbon, e.g., compounds 18 and 19 respectively) were claimed as GPR109A agonists in a patent application [65]. 

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 biogenetic pathway proposed by Chakraborty for the formation of carbazole (1) and 3-methylcarbazole (2) proceeds through Af-phenylated anthranilic acid (406). This hypothesis is based on aromatic C-methylation of aniline with methionine, and originates from anthranilic acid (397) and prephenic acid (404). Until now, there are no N-phenylated anthranilic acid derivatives known naturally, therefore, this hypothesis is lacking substantial biogenetic evidence. However, the isolation of carbazole (1), 3-methylcarbazole (2), and several derivatives of 3-methylcarbazole... 

Anthranilic acid-derived Zygophyllaceae Peganum harmala Harmin... 

Anthranilic Anthranilic acid-derived True alkaloids... 

Diazotization of anthranilamide and its derivatives is the most common and widely exploited reaction for the preparation of 1,2,3-benzo-triazine derivatives. The reasons for this are 3-fold (i) many nuclear substituted anthranilic acid derivatives are readily available (ii) the diazotization reactions generally proceed smoothly and in high yield, and the product triazinones are usually very stable and easily handled and (iii) many 3-substituted l,2,3-benzotriazin-4(3i/)-ones have been found to possess a wide range of pronounced pharmacological activity, while others undergo a number of very interesting chemical transformations, and hence a very large number of these compounds have been prepared. 

Hydrolysis of 3-alkyl-l,2,3-benzotriazin-4(3i/)-ones (10, R = alkyl) with cold, aqueous potassium hydroxide leads to anthranilic acid derivatives. The related 3-aryl-l,2,3-benzotriazin-4(3H)-ones (10, R = aryl) react less readily, but on treatment with hot aqueous or alcoholic potassium hydroxide are converted into 3-aryltriazenes (53, R = aryl) which, on further reaction, give anthranilic acids. ... 

Fluorinated NSAIDs are present in all the main families of nonspecific COX inhibitors arylacetic acid derivatives, anthranilic acid derivatives, and salicylic acid derivatives. 

Floctafenine and glifanine are also anthranilic acid derivatives. However, while they are analgesics, they are not NSAIDs. 

A common method for the preparation of 2(177),4(3//)-quinazolinediones consists of the fusion of anthranilic acid derivatives 853 with urea, and a microwave-assisted procedure has now been developed that produces the quinazo-linediones 854 in excellent yields <2005CL1438>. 

Condensations of anthranilic acid derivatives lead to the 6,12-diamino- and 6,12-dioxo-dibenzodiazocines, and the dichloro compound (279) is available from the latter (54JCS3429). Reduction of (279) via the dihydrazino compound was used to prepare the parent dibenzo[6,/][l,5]diazocine (280) (67CC1077). The NMR value (5 8.53 p.p.m.) of the 6(12) proton is indicative of the diazocine structure, presumably in a tub form, rather than the valence isomeric dibenzodiazapentalene (281). 

In a follow-up communication,26 similar chemistry was used for the production of 2-substituted benzofurans beginning not with an anthranilic acid derivative, but with a resin-bound ortho-hydroxy aryl iodide 3. In the solid-phase work, depicted in Scheme 5, the relevant carboxylic acid was linked to TentaGel via a Mitsunobu reaction, and after deprotection was seen to undergo smooth Heck coupling and cyclization, giving essentially pure compounds in 40-70% overall yield after cleavage. 

Pyrrolo[2, l-b]quinazolines (49) were obtained through the formation of their diazine ring by condensation of an anthranilic acid derivative with a pyrrole derivative such as O-alkylbutyrolactimes (48) [60GEPI088968 ... 

The published work on the synthesis of this system involved the reaction of anthranilic acid with a reactive pyrimidine derivative. Thus, 4-chloropyrimidines (520) condense with 2-aminobenzaldehyde (47JCS726) or an anthranilic acid derivative [66T(S)227 68ZC103 89MI2] to give the pyrimido-[6,1 -b]quinazolines (521). 

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