Anthranilic acid, reduction

Reduction of anthranilic acid (5) to o-aminobenzylalcohol (6). The expensive LiAlH4 can be used as reducing agent for valuable fine chemicals, e.g. pharmaceuticals [31]. 

Reduction of aromatic carboxylic acids to alcohols can be achieved by hydrides and complex hydrides, e.g. lithium aluminum hydride 968], sodium aluminum hydride [55] and sodium bis 2-methoxyethoxy)aluminum hydride [544, 969, 970], and with borane (diborane) [976] prepared from sodium borohydride and boron trifluoride etherate [971, 977] or aluminum chloride [755, 975] in diglyme. Sodium borohydride alone does not reduce free carboxylic acids. Anthranilic acid was reduced to the corresponding alcohol by electroreduction in sulfuric acid at 20-30° in 69-78% yield [979],... 

The above procedure is essentially that of Ullmann and Bleier.2 2-Aminobenzophenone has also been prepared by reduction of 2-nitrobenzophenone,3 by the Hofmann reaction of the amide of o-benzoylbenzoic acid with sodium hypobromite,4 by the action of an excess of benzoyl chloride on aniline at 220°,6 and by hydrolysis of the acetyl derivative which is obtained by the action of phenylmagnesium bromide on 2-methyl-3,l,4-benzoxaz-4-one (from anthranilic acid and acetic anhydride).6 Various methods for the preparation of 2-aminobenzophenones have been summarized critically by Simpson, Atkinson, Schofield, and Stephenson.7... 

The discovery that the cyclization of one of the sulfonamide groups and the adjacent amine in classic monocyclic diuretics leads to an increase in potency is discussed in the next section. A similar increase in potency is also observed in the anthranilic acid based diuretics. Thus the fusion of anthranilic acid (87-1), which may show diuretic activity in its own right, with propionamide leads to the ring closure and formation of (87-2). Reduction of the unsaturation in the heterocyclic ring then affords the diuretic quinethazone (87-3) [97]. 

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). 

Diphenic acid has been prepared by the reduction of diazotized anthranilic acid with cuprous ion,5 Ullman coupling of potassium... 

An alternative but equally cumbersome synthesis utilizes the more accessible bis(2-carboxyphenyl)disulfide, easily prepared from anthranilic acid. Byconversion to the corresponding anilide, then by successive reduction with zinc dust and acetic acid (yielding 2-mercaptobenzoyl anilide) and lithium aluminum hydride, the aldehyde (6) is obtained in fair overall yield.Although... 

Examples of this ring system (263) were prepared by cyclocondensation of anthranilic acid with the 1,3-thiazole derivatives 262 (82MI1 83AP394). Reductive cyclization of the 4-ethylamino-3-(2-nitrobenzyl)thiazolidines (264) was affected by heating with iron filings and acetic acid to give 4//-3,3a-dihydrothiazolo[4,3- >]quinazoline (265) (87JHC107). 

On the other hand, the two heterocyclic rings of the title compounds (587) were formed upon synthesis from anthranilic acids and 2-nitrophenoxyacetyl chloride (585) followed by reduction and cyclization (84J1C721). 

Of the several methods described for the production of thiosalicylic acid, only the following are of preparative interest heating of o-halogenated benzoic acids with an alkaline hydrosulfide at i50-200° in the presence of copper or copper salts,1 5 or by substitution of sodium sulfide at 200° 2 by reduction of dithiosalicylic add with glucose,3 or metals 4,5 in alkaline solution. The dithiosalicylic add is prepared by treating diazo-tized anthranilic acid with sodium disulfide in alkaline solution.4... 

The stirrers are started, the current (no volt D.C.) turned on, and the resistance so adjusted that the ammeter records io-i 2 amperes. The temperature of the solution in the cells is maintained at 20-30° by surrounding them with a bath of cool water (Note 4). The reduction is complete after 60-70 ampere-hours. This fact is indicated by the increased evolution of hydrogen and the complete solution of the anthranilic acid. 

The anthranilic acid derivative 4, prepared from isatoic anhydride and L-proline, on Birch reduction and alkylation affords pure 5, which is hydrolyzed by acid to the aminolactone 6, with the absolute configuration opposite to that of 3. 

Reductive removal of the Nj-oxide oxygen atom of the triazinium betaines (76) can be readily accomplished either by heating the betaine N-oxides in ethanol, or, more efficiently, by treatment with stannous chloride. Further reduction of the resultant betaines (77) with tin/hydrochloric acid results in ring cleavage and formation of arylhydrazides or anthranilic acid.87... 

Diphenic acid has been prepared by the reduction of diazotized anthranilic acid with cuprous ion,6 Ullman coupling of potassium o-bromobenzoate,6 and oxidation of phenanthrene or phen-anthrenequinone with various oxidizing agents.7 The latter methods have been reviewed recently.7 The ozonolysis method has also been carried out in solvents 8 that do not react with the zwitterion intermediate. ... 

The most common synthetic method towards quinazolin-4-ones is the Niementowski reaction, a cyclocondensation of anthranilic acid with for-mamide which requires high temperatures (130-150 °C) and long reaction times (6 hours). It is noteworthy that a remarkable reduction of the reaction time (20 min) was achieved under microwave heating conditions (150 °C) [123]. Moreover, microwave-accelerated reactions were cleaner and afforded higher yields than those under conventional thermal conditions (Scheme 48). 

The moist cake is mixed with 27 g. of zinc dust and 300 cc. of glacial acetic acid in a i-l. round-bottom flask, and the mixture is refluxed vigorously for about four hours (Note 4). When the reduction is complete, the mixture is cooled and filtered with suction. The filter cake is washed once with water and then transferred to a i-l. beaker. The cake is suspended in 200 cc. of water and the suspension is heated to boiling. The hot solution is made strongly alkaline by the addition of about 40 cc. of 33 per cent aqueous sodium hydroxide solution. The alkaline solution is boiled for about twenty minutes to insure complete extraction of the product from the filter cake, filtered from the insoluble material (Note 5) and the thiosalicylic acid is then precipitated by the addition of sufficient concentrated hydrochloric acid to make the solution acid to Congo red paper. The product is filtered with suction, washed once with water and dried in an oven at 100-110°. The yield of a product which melts at 162-163° is 110-130 g. (71-85 per cent of the theoretical amount based on the anthranilic acid). 

The material of the glower is mostly without any influence on the reaction. Platinum, platinum-iridium, nickel, iron and carbon gave qualitatively equal results only copper wires are not applicable for the preparation of anthranilic acid. They primarily cause a reduction to o-toluidine and then complete combustion is brought about by the copper oxide which is formed. 

For the preparation of 4-(1.2.3.4-tetrahydroquinolino)-phenol 17 three different procedures were worked out [Eqs. (6)-(8)]. 17 was prepared by reacting N-p-methoxyphenyl-anthranilic acid with acetic anhydride and subsequent saponification to l-p-methoxyphenyl-4-hydroxy-2-quinolone, reaction withPOCl3 to form l-p-methoxyphenyl-4-chloro-2-quinolone, hydrogenation to l-(p-methoxy-phenyl)-3.4-dihydro-2-quinolone, splitting the ether with HBr to l-(p-hydroxy-phenyl)3.4-dihydro-2-quinolone, and reduction with LiAlH4 [Eq. (6)J. Another synthetic possibility was the reaction of p-anilinophenol with (3-propiolactone and subsequent cyclization to l-(p-acetoxyphenyl)2.3-dihydro-4-quinolone 18. The next step, the Wolff-Kishner reduction, led directly to the desired product [Eq. (7)]. The third way, the direct amination of p-iodoanisole with 1.2.3.4-tetrahydro-quinoline and the subsequent splitting of 4-(1.2.3.4-tetrahydro-quinolino)-anisol with HBr was the best one [Eq. (8)]. Saponification of l-(p-acetoxyphenyl>2.3-... 

Table 2 Selected anthranilic acid derivatives prepared by reductive alkylation of the Step 2 amine intermediate using 4-pyridinecarboxaldehyde and their corresponding melting points. 111-NMR data supplied by author...

The ring of anthranilic acid, like that of prephenic acid, is derived, in appropriate bacterial extracts, from shikimate 5-phosphate, the amino group originating in the amide nitrogen of glutamine. An oxidation-reduction appears to be involved in this synthesis, since diphosphopyridine nucleotide is a required cofactor. At least one other cofactor, present in yeast extract and so far unidentified, is also required. 

The first anthranil ( azo-opianic acid ) was made by this method in 1881,113 but was not recognized as such. In 1882 Friedlander and Henriques109 prepared the parent compound, by reduction of o-nitrobenzaldehyde with tin and acetic acid. They thought it to be the anhydride of anthranilic acid, and hence arose the name anthranil. It has been shown, using O18, that the carbonyl oxygen is lost, and the cyclic oxygen atom is derived from the nitro group, in the reductive cyclization.141... 

The haloalkoxy substitution reaction has been applied to 6-nitroanthroxanic acid [Eq. (22)], but 6-nitroanthranil decomposes to the anthranilic acid under the basic conditions of the reaction.347 Reduction of 207 with ferrous sulfate and ammonia yields the corresponding isatin. 

Kynurenine Hydroxylase Kynurenine hydroxylase is an FAD-dependent mixed-function oxidase of the outer mitochondrial membrane, which uses NADPH as the reductant. The activity of kynurenine hydroxylase in the liver of riboflavin-deficient rats is only 30% to 50% of that in control animals, and deficient rats excrete abnormally large amounts of kynurenic and anthranilic acids after the administration of a loading dose of tryptophan, and, correspondingly lower amounts of quinolinate and niacin metabolites. Riboflavin deficiency may thus be a contributory factor in the etiology of pellagra when intakes of tryptophan and niacin are marginal (Section 8.5.1). 

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