Hemipinic acid

In a similar attempt, Decker and Eichler reduced A -methylnor-papaverinium phenolbetaine (VIII) with tin and hydrochloric acid and obtained i/i-laudanine, m.p. 112°, pierate, m.p. 162-3°, which was subsequently investigated by Spath and Epstein, who showed that on methylation it furnished dMaudanosine and that the ethyl ether on energetic oxidation yielded veratric acid (3 4-dimethoxybenzoic acid) and the methyl ethyl ether of nor-m-hemipinic acid. This clearly indicated that the free hydroxyl group was in the woquinoline nucleus, and its position was determined by the fact that on mild oxidation 7-methoxy-6-ethoxy-l-keto-2-methyl-l 2 3 4-tetrahydrowoquinoline, m.p. 95-6°, was produced, and on this basis these authors assigned formula (IX R = H R = CH3) to -laudanine. 

This with potassium hydroxide in methanol forms de-OiV-dimethylarmepavine, m.p. 86-7°, (B. HCl, m.p. 229-30°) of which the methiodide, m.p. 233-4°, on treatment with alkali decomposes into trimetHylamine and a -p-anisyl-/3-(3 4-dimethoxy- 6 - vinylphenyl) -ethylene, m.p. 79°. The latter is oxidised by permanganate in acetone to anisic and m-hemipinic acids. With ethyl sulphate and alkali, armepavine gives 0-ethylarmepavine, an oil, which permanganate oxidises to p-ethoxybenzoic acid. Armepavine is similarly oxidised to p-hydroxybenzoic acid and l-keto-6 7-dimethoxy-2-methyl-1 2 3 4-tetiahydrowoquinoline and is therefore 6 7-dimethoxy-l-p-hydroxybenzyI-2-methyI-l 2 3 4-tetrahydrowoquinoline, i.e., it is laudanosine (p. 187) with MeO. at C replaced by H and MeO at C changed to HO. ... 

Oxynarcotine, CjjHjaOgN. This alkaloid was separated by Mayer, and later by Beckett and Wright, from crude narceine. It crystallises from hot alcohol in small needles. Its close relationship to narcotine is shown by the formation of cotarnine, C12H15O4N (p. 201), and hemipinic acid when it is oxidised by ferric chloride narcotine under these circumstances furnishing cotarnine and opianic acid. Rabe and McMillan regard oxynarcotine and nomarceine as identical. 

Berberilic acid, CgoHjgOgN, m.p. 177-82°, is dibasic, and furnishes a dimethyl ester, m.p. 173°. When heated to about 180°, the acid passes into ANHYDROBERBERiLic ACID, CjgHjjOgN, colourless needles, m.p. 236°, soluble in alkali carbonate solutions with the formation of berberilates. When ammonium berberilate is dried under reduced pressure, a molecular proportion of ammonia is lost with the formation of the ammonium salt of the anhydro-acid, from which other salts, and the methyl ester, m.p. 178°, have been obtained. Berberilic acid is hydrolysed by hot dilute sulphuric acid to hemipinic acid (I) and oi-aminoethylpiperonylic acid (II), large tabular crystals, m.p. 180-2°. Berberilic acid is therefore represented by (III). 

Capaurine, Ci,Hj2N(OH)(OMe)4. (Items 9, 16, 17, 22 list, p. 170.) M.p. 164°. Yields an 0-methyl ether, m.p. 152°, which on oxidation by iodine to the quaternary iodide, followed by reduction to the tetrahydro-base forms capauridine methyl ether, m.p. 142° capauridine must therefore be dZ-capaurine. Capaurine ethyl ether, C23H29O5N, m.p. 134°, on oxidation furnishes 3-ethoxy-4 5-dimethoxyphthalic acid. The methyl ether on oxidation by potassium permanganate gives hemipinic acid... 

It has been reported (111) that permanganate oxidation of deoxytubulo-sine (17) yielded m-hemipinic acid (124), whereas selenium dehydrogenation and zinc dust distillation of 17 and alangimarckine (18) produced harman (125). 

Groups other than halogen or nitro in the two ortho positions also can influence the mode of reaction. For example, while opianic acid can be transformed in good yield into hemipinic acid and meconine, pseudo-opianic acid loses the formyl group imder the influence of strong alkali. ... 

Application of the Hofmann and Emde reactions to tylophorinine did not lead to any useful result. Vigorous oxidation of tylophorinine gave m-hemipinic acid as the only isolable product. Mild oxidation of the methiodide yielded an imide, C19H15O5N (mp 297°), and an acid readily converted to an anhydride and yielding with diazomethane a crystalline diester, C21H20O7 (mp 160°-162°). The identity of the imide as 2,3,6-trimethoxyphenanthrene-9,10-dicarboxylimide (XIII) was established by comparison with a synthetic specimen obtained by oxidation of the dihydroisoquinoline (XIV) synthesized by the standard route from 2,3,6-trimethoxyphenanthrene-9-aldehyde. Further, the diester was shown... 

The presence of a phenanthroindolizidine ring system can be assumed on the basis of the UV- and mass-spectra. Oxidation of the alkaloid with alkaline hydrogen peroxide yielded m-hemipinic acid as the only isolable product. On the basis of its IR-spectrum and biogenetic considerations, the methoxyl groups can be assigned to the 2,3,6- or 3,6,7-positions on the phenanthroindolizidine system leading to the alternate structures XVa and XVI. It is of interest that racemic forms of both the possible structures have already been synthesized (12, 18). 

Hasubanonine has the composition C H OgN, is non-phenolic, contains one carbonyl group and four methoxyl groups. On distillation with zinc-dust it gives phenanthrene, and on oxidation it yields hemipinic acid [90]. 

Pluviine gave m-hemipinic acid on permanganate oxidation and the red, phenolic betaine (LXXVII) under Oppenauer conditions (87). The structure of this betaine was indicated by the virtual identity of... 

The derivatives of the synthetic oily base were identical with those of naturally occurring carnegine and pectenine. Furthermore, the possible alternate structure (the product of ring closure in o-position to one of the methoxy groups) was excluded by the observation that permanganate oxidation of the dihydro compound gave m-hemipinic and not hemipinic acid. 

Methylsalsoline, oxidized with permanganate, yields m-hemipinic acid. The position of the hydroxyl group was established by Spath, Orekhov and Kuffner (39) by synthesis, starting from isovanillin. Salsolidine was synthesized by Spath and Dengel (38). 

Permanganate oxidation of papaverine in neutral medium furnishes m-hemipinic acid (V), veratric acid (VI), papaverinic acid (a-veratroylcincho-meronic acid) (VII), and pyridine-2,3,4-tricarboxylic acid (VIII). The last-named product (VIII) may serve as evidence for the point of attachment of the nitrogen-free portion of the isoquinoline system. Dimethoxy-isoquinolines are oxidized to pyridine-3,4-dicarboxylic (cinchomeronic) acid, but papaverine yields VIII under analogous conditions, thus marking position 1 as the connecting point. 

Since fusion with alkali splits papaverine to 6,7-dimethoxyisoquinoline and 3,4-dimethoxytoluene (dimethylhomocatechol), it is likely that the latter is linked to the 1-position of the isoquinoline by way of the methyl group. The structure of the isoquinoline follows from its oxidation to m-hemipinic acid (V) and that of the dimethoxytoluene from its conversion to veratric acid (VI). 

Structure. Reduction of palmatine yields di-tetrahydropalmatine, and this can readily be reoxidized to palmatine. It differs from berberine in having four methoxyls, the methylenedioxy group of the latter being replaced by two methoxyls in the former. Since it yields corydaldine and hemipinic acid on oxidation with permanganate Feist and Sandstede (223) suggested structure XXIX, which should be rewritten to conform to the carbinol form analogous to XVII for berberine. Like berberine it forms... 

Complete oxidation of capaurine with permanganate yields hemipinic acid and the 0-methyl ether yields a mixture of 3,4,5-trimethoxyphthalic... 

Furthermore, corydaline, like tetrahydropalmatine, has four methoxyls, but its formula contains CH2 more, which indicates that it should be a C-methyl derivative of the latter. The final products of its oxidation by permanganate are hemipinic and m-hemipinic acid, and it is possible to isolate, along with a number of other products, the compound called coryd-aldine (LIII) (246), the structure of which has been adequately proved by... 

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