Tetrahydro anthranilic acid

Replacement of the phenyl group of anthranilic acid by a cycloalkene represents another strategy to obtain intellectual property. This endeavor resulted in three consecutive patent applications [73-75] and a publication [76]. The advantages of tetrahydro anthranilic acid as a surrogate for anthranilic acid include reduced CYP2C8 and 2C9 inhibition and improved oral exposure in mice (analogs 25 vs. 12). Ultimately, a pre-clinical candidate, MK-6892 (26), was selected from this series due to its... 

Tripeptides with N-terminal anthranilic acid part were used as starting materials in the solid-phase synthesis carried out on TentaGel resin to prepare 1,4,11,1 l -tetrahydro-2//-pyrazino[2,l-3]quinazoline-3,6-diones with various N-l and N-3 substituents <2003EPP1471066>. Tandem cyclization from [6+0] atom fragments took place in the solid-phase synthesis of 143 from 142. Intermediate 141 was built on bromoacetal resin (Scheme 17) <1998JOC3162>. 

The first-suggested structure of rutaecarpine was based upon an erroneous identification of one of the products of its fission with alkali (2, 3). The fission fragment ultimately proved to be tryptamine (7), and this led to the correct structure (I), since the second fragment had already been recognized as anthranilic acid. An early synthesis was achieved by condensing l-keto-l,2,3,4-tetrahydro-2-carboline with methylanthra-... 

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-... 

With respect to time and cost, this method is superior to the five-step synthesis from anthranilic acid. Older literature sources have been cited in an earlier volume of Organic Syntheses. Indazole has also been prepared recently by the reaction of 2-hy-droxymethylenecydohexanone with hydrazine and dehydrogenation of the 5,6,7,8-tetrahydro derivative. ... 

Reaction of 2-halopyridines, their 3,4,5,6-tetrahydro derivatives, or their 5,6-benzologue with 3-aminoacrylates, anthranilic acids and their esters afforded derivatives of (12) <5UCS55i, 72CPB142), its... 

The action of a solution of potash in amyl alcohol on rutaecarpine produces anthranilic acid and a second acid which, when boiled with hydrochloric acid, is readily decarboxylated to tryptamine (6, 25, 94, 134, 135, 169). A close relationship between rutaecarpine and evodiamine was demonstrated by fusion of isoevodiamine hydrochloride. Rutaecarpine was formed with liberation of chloromethane. A number of syntheses of (63) have been reported 101, 135, 161), including some under so-called physiological conditions. Some of the more recent examples will be mentioned. Kametani et al. 102,108) obtained (63) in 80% yield through a regiospecificH s+n s cycloaddition of a keteneimine (generated in situ by extrusion of sulfur dioxide from the sulfmamide anhydride of anthranilic acid) with 3,4-dihydro-p-carboline or with 1,2,3,4-tetrahydro-l-keto-P-carboline 109) (also called 1,2,3,4-tetrahydronorharman-l-one or, as in Chemical Abstracts, 2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-l-one) ac-... 

Euxylophoricine F (90) exhibits the same uv spectrum as the other euxylophoricines. Methylation with methyl iodide and potassium carbonate yields Ni3-methyleuxylophoricine A, indicating that euxylophoricine F is a 2,3-disubstituted rutaecarpine derivative. The structure was confirmed by synthesis. Condensation of 4-benzyloxy-5-methoxy-anthranilic acid methyl ester with 1,2,3,4-tetrahydro-l-keto-p-carboline in the presence of phosphorus oxychloride and subsequent hydrogenolysis gave (90). 

The alkaloid rutaecarpine (111) was synthesized from l-oxo-1,2,3,4-tetrahydro-j8-carboline (183 R = H) by condensation with methyl anthranilate in the presence of phosphorous chloride or by heating with isatoic anhydride at 195°. The alkaloid was also obtained by boiling l-methoxy-3,4-dihydro-j8-oarboline (152 R = H, R = CHg) with anthranilic acid in methanol. In this connection might be... 

The same general intermediate (342 X = OOH) may be invoked in the reaction of tetrahydro-jS-carboUne derivatives with perbenzoic acid and ozone. From the reaction [342 (X = OOH) 353-> 353a] a cyclic lactam (353a) may be isolated. Such a structure is presumably the intermediate in the oxidative degradation of numerous complex tetrahydro-)S-carboline alkaloids, which yields A-oxalyl-anthranilic acid derivatives (354). The lactam can undergo base-... 

The angular isomers, viz. tetrahydro-5H-benzothiazolo[3,2-a]quin-azolines (295), arise in the condensation of 2-thiocyanatocyclohexanone and anthranilic acid. ... 

Amino-2,1,3-benzothiadiazole (237) is convertible into its anthranilic acid derivative (238), which is cyclized by phosphorus oxychloride to 6-chloro-[l,2,5]thiadiazolo[3,4-c]acridine (239). Replacement of its 6-halogeno-substituent produces derivatives such as (240). An analogous series of reactions provides 7,8,9,10-tetrahydro-analogues. The condensation of (237) and alkyl 2-oxocyclopentanecarboxylate yields derivatives of the [1,2,5]-thiadiazolo[3,4-h]quinoline ring system such as (241)—(243). Electrophilic substitutions of naphtho[l,2-d][2,l,3]thiadiazole (244) have been studied in some detail. Nitration produces a mixture of the 6- and... 

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. 

About 300 volatile compounds are present in honey and more than 200 have been identified. There are esters of aliphatic and aromatic acids, aldehydes, ketones and alcohols. Of importance are especially P-damascenone and phenylacetaldehyde, which have a honey-like odor and taste. Methyl anthranilate is typical of the honey from citrus varieties and lavender and 2,4,5,7a-tetrahydro-3, 6-dimethylbenzofuran (Formula 19.4, linden ether) is typical of linden honey. 

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