A’-Acetylanthranilic acid

A-Acetylanthranilic acid [89-52-1] M 179.1, m 182-184 , 185-186 , 190 (dec), pK 3.61. Wash with distilled H2O and recrystallise from aqueous AcOH, dry and recrystallise again from EtOAc. Also recryst from water or EtOH. [J Chem Soc 2495 7957 J Am Chem Soc ll 6698 7955.]... 

Acetylacetanilid, a24 Acetyl acetate, a22 Acetylacetone, p34 A-Acetylanthranilic acid, all Acetylbenzene, a31 Acetylcyclopropane, c410 Acetylene dichloride, d228, d229... 

Japan A -acetylanthranilic acid, ephedrine, ergometrine, ergotamine, isosafrole, lysergic acid, 3,4-methylenedioxyphenyl-2-propanone, l-phenyl-2-propanone, piperonal, pseudoephedrine and safrole 17 December 1999... 

Acetic anhydride A -Acetylanthranilic acid Ephedrine Ergometrine Ergotamine Isosafrole Lysergic acid 3,4-Methylenedioxyphenyl-2-propanone Norephedrine 1 -Phenyl-2-propanone Piperonal Potassium permanganate Pseudoephedrine Safrole Acetone Anthranilic acid Ethyl ether Hydrochloric acid" Methyl ethyl ketone Phenylacetic acid Piperidine Sulphuric acid" Toluene... 

Following large seizures of methaqualone in Southern Africa that were believed to have originated in China, Chinese authorities seized 10 tons of A-acetylanthranilic acid, a direct precursor of methaqualone. Asian authorities should remain particularly alert with regard to precursors of methaqualone. 

The biosynthesis of quinazoline alkaloids is not resolved, but anthranilic acid, probably as A -acetylanthranilic acid, is a precursor (Cordell, 1981, Groger, 1980). Both anthranilic acid and phenylalanine serve as precursors for arborine (5) in Glycosmis arborea (Cordell, 1981). 

More recent studies of the mechanism of this reaction by Patel and Patel in 1965 suggested an alternate reaction pathway for the conversion of 10 to 12. They found that heating A -acetylanthranilic acid (10) in the presence of a slight excess of formamide or acetamide resulted in the formation of 4-quinazolone 14. Since ammonia is not generated under these reaction conditions, they proposed that the conversion of 10 to amide 12 proceeded by way of a transamidoylation reaction. Experimental support for this reaction pathway was found in the observation that formic acid was detected when heating 10 with formamide at 160 °C (shown below), and acetic acid was detected when heating 10 with acetamide at 180 °C. In both cases, the same 4-quinazolone product (14) was formed. 

The carbonylation reaction was carried out by mixing an aqueous solution of NaOH with a xylene solution of the Pd(PPh3)4 in the presence of salt, PhCH2NEt3Cl. Tilley reported the synthesis of anthranilic acid using this method. Pd-catalyzed carbonylation of 2-bromoaniline did not afford anthranilic acid 2e (Scheme 6), but N-acetylated 2-bromoaniline la afforded the desired A -acetylanthranilic acid 2a in high yield. Carbonylation of aqueous media under 1 atm pressure in the presence of palladium complexes without phosphine ligand and some bases leads to the formation of aromatic acid. ... 

Preparation of Intermediate Compound 4-Chloro-5-Sulfamyl-N-Acetylanthranilic Acid To a hot solution (80°C) of 366 g (1.482 mols) of magnesium sulfate (Epsom salts) in 2.8 liters of water was added 130 g (0.495 mol) of powdered 5-chloro-2-methyl-4-sulfamyl-acetanilide. With stirring and maintaining the temperature at 83°C, 234 g (1.482 mols) of potassium permanganate was added portionwise over a period of 2 hours. The mixture was then kept at 85°C with stirring for an additional 3 hours. By this time the pink color of the permanganate had been discharged. 

Preparation of Intermediate Compound 2-Methyl-3-o-Tolyl-6-Sulfamyl-7-Chloro-4(3H)-Quinazoiinone Set up a 5-liter 3-necked flask fitted with a stirrer, condenser and a drying tube. To a stirred mixture of 100 g (0.342 mol) of powdered 4-chloro-5-sulfamyl-N-acetylanthranilic acid, 40.2 g (0.376 mol) of o-toluidine and 2.0 liters of dry toluene was added dropwise, over a period of 15 minutes, 21.7 ml (34.1 g) (0.248 mol) of phosphorus trichloride. The mixture was then refluxed for 10 hours. The solid turned somewhat gummy towards the latter part of the first hour. The mixture then became more free flowing as heating was continued. Let stand overnight. The yellow solid was filtered, washed with toluene and dried. The toluene filtrate was discarded. The dried solid was triturated with 1.5 liters of 10% sodium bicarbonate, filtered and the cake washed with water. The filtrate on acidification yielded 11.5 g of the starting acid. The damp product was dissolved in 4,5 liters of 95% ethanol and the solution treated with charcoal and filtered. On cooling filtrate yielded 69.5 g (55.5%) of the title compound, MP 271.5° to 274°C. 

This indoline derivative has antihypertensive and diuretic actions. Indapamide (233) in methanol under nitrogen was irradiated with a medium-pressure mercury lamp through a copper sulphate filter solution for 12 h. The filter removed wavelengths below 300 nm. Products were separated by preparative TLC and identified as 2-methylindoline (234), the formylhydrazide (235), the amide (237) and semicarbazide. The procedure was repeated under oxygen to give the above products plus the urethane (236), acid (238), ester (239) and TV-acetylanthranilic acid [146]. 

Lappaconitine has been found to occur in Aconitum septentrionale Koelle(i59), A. orientate 160), and A. excelsum Popov 161). Saponification of lappaconitine (C32H44NO8) gives lappaconine C23H37NO6) and acetylanthranilic acid. The molecular formula of lappaconine has been... 

Lappaconitine (C32H44N208) has been isolated from A. septentrionale Koelle (103), A. orientale (104), and A. excelsum Popov (105). Alkaline hydrolysis of lappaconitine yielded the parent alkamine, lappaconine (C23H37NO6), and the N-acetylanthranilic acid. On the basis of extensive chemical studies, in 1969 Marion and his co-workers (106) assigned structure 86 to lappaconine. Meanwhile, Birnbaum reported (107,108) an X-ray analysis of lappaconine hydrobromide and confirmed the proposed structure for lappaconine. Subsequently, the Soviet workers assigned (109) the -acetylanthranilic ester moiety of lappaconitine (87) to the C-4 position. 

In the latter pathway anthranilic acid and aspartic acid are used to construct peganine. In accord with this it has been shown recently that anthranoylaspartic acid (155) is a fairly specific precursor for peganine (154) in A. vasica N-Acetylanthranilic acid (153) is built into peganine intact, so perhaps the most important precursor for peganine may be (156). 

Lappaconitine (crystalline) and septentrionaline (amorphous) are the two alkaloids isolated (83) from A. septentrionale Koelle that have been examined in some detail (84, 85, 86). Both alkaloids are monoesters of the parent amino alcohols with derivatives of anthranilic acid, but whilst the acid esterifying the parent lappaconine has been firmly identified as iV-acetylanthranilic acid (85), that (m.p. 126°) forming part of septentrionaline has been erroneously formulated (85) as CgHgOsN (see also below) its constitution is therefore unknown. 

The Bischler synthesis, first described in 1893, involves the fusion of A-acylanthranilic acid and ammonia to generate the corresponding 2-substituted quinazolinone, which exists in equilibrium with the 4-hydroxy quinazoline tautomer. Bischler s original synthesis, shown below, involved direct conversion of ammonium-A-acetylanthranilate to the corresponding 2-alkyl-2,3,4-dihydro-4-quinazolinone under thermal conditions. 

In 1905, Bogert and Chambers described the synthesis of 32 via the acetanthranil intermediate 31, which was formed by heating 2-amino-6-nitrobenzoic acid (30) with acetic anhydride." It was reported that the yield for this reaction was nearly quantitative. This modification was compared to other variations known at that time, including heating the ammonium salt of anthranilic acid with formamide and heating the ammonium salt of N-acetylanthranilic acid, and proved to be superior. A 4-quinazolone without a substituent at the 3-position (35) has also been prepared by this method. ... 

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