Papaverine oxidation

CgHjoO,. A compound of largely historical interest for its role in establishing the structure of many natural products. Methylation of vanillin gives veratraldehyde which may be oxidized to veratric acid. Veratric acid was identified as a degradation product of the alkaloid papaverine. 

In this, the first serious and successful work on the structure of a complex alkaloid, there was naturally at first some confusion between Moquinoline and the better-known quinoline. The 6 7-dimethoxy-woquinolinecarboxylic acid was thought to be a dimethoxycinchoninic acid. It known, however, that quinoline benzylchloride on oxidation furnished formylbenzylanthranilic acid, CjH4(COOH)—N(C,H,)—CHO, whereas various papaverine alkyl halides gave what were presumed to be... 

The position in which the veratryl residue is attached to this isoquinoline nueleus in papaveraldine and papaverine is determined by the formation of pyridine-2 3 4-tricarboxylic acid in the oxidation of papaverine by hot permanganate. On the basis of these results, Goldschmiedt assigned the following formula to papaveraldine —... 

Papaverinic acid, CieHjjO N. HjO, crystallises in small tablets, m.p. 233°. It is dibasic, readily forms an anhydride, furnishes an oxime and a phenylhydrazone, contains two methoxyl groups, and on oxidation yields veratric and pyridine-2 3 4-tricarboxylic acids, and hence is represented by the following formula —... 

CeH3(OCH3)a. CHOH. CHa. NH. CO. CHg. CeH3(OCH3)2, which when boiled with phosphoric oxide in xylene solution lost 2 mols. of water and formed papaverine (IV). ... 

Although this isoquinoline at first bears little structural resemblance to morphine (108), careful rearrangement of the structure (A) shows the narcotic to possess the benzylisoquinoline fragment within its framework. Indeed, research on the biogenesis of morphine has shown that the molecule is formed by oxidative coupling of a phenol closely related to papaverine. 

Introduction of a hydroxyl group into the protoberberine skeleton was successfully carried out by the hydroboration-oxidation method. Dihydro-berberine (90) was converted to ( )-epiophiocarpine (91) as a major product along with ( )-ophiocarpine (92) (Scheme 22) (71). 5-Hydroxyprotober-berines 94 and 95 were obtained from the 5,6-dehydro compound 93 (50) synthesized from papaverine via 54 (72). 

The aromatic dibenzopyrrocoline dimer 33 was obtained by Hess etal. (22) by electrochemical oxidation of papaverine at a platinum anode in methanolic so-... 

Compound 378 has been made by oxidation of 6 -nitro-3,4-dihydro-papaverine (379) to the A-oxide 380 using hot ethanolic iodine solution... 

The yellow crystalline azaberbinone (388) has been prepared by several, closely related methods. Dehydrogenation of betaine 378 (Section III,E,2) with dichlorodicyanoquinone gives compound 388 directly. Alternatively, this compound (388) has been prepared in three ways from 6 -nitropapaverine (385) (Scheme 15) (i) Treatment of compound 385 with triethyl phosphite gives a low yield of betaine 388 directly (ii) compound 385 in methanolic KOH at reflux temperature gives the anthranil 386 which rearranges to the betaine 388 in hot triethyl phosphite and (iii) iodine oxidation of 6 -nitro-papaverine (385) generates the A-oxide 387 which is reduced to the betaine 388 by sodium bisulfite. The chemistry of compound 388 remains unexplored. 

Anodic oxidation of papaverine (244) in an aqueous medium at pH 3-7, using a divided cell, gave papaverinol (245) and papaveraldine (246) in 40-60% and 10-20% yield, respectively.380 Oxidation of 244 in an undivided cell resulted in better yield (70-75%) of 245 [Eq. (131)]. 

R3R2 = O), with rat liver enzymes gives 6,7-dimethoxy-2-methyltetra-hydroisoquinolone as the main metabolite, whereas papaverine is oxidized to the N-oxide under the same conditions.108... 

Narcotine was isolated by Derosne (592) and Robiquet (593) from opium. It has a mild antitussic and a relaxant effect on smooth muscles (similar to those of papaverine). The relaxant effect is about ten times smaller than that of papaverine (594-597). LaBarre and Plisnier (598, 599) found that narcotine is a better antitussic than codeine. j8-Narcotine proved to be much more effective than a-narcotine (600) the effect of the N-oxides of the two isomers was more marked than that of the base. /3-Narcotine N-oxide was much more effective than dihydrocodeine. Those substances did not increase the analgesic effect of morphine. Contrary to codeine they did not cause obstipation (601). The therapeutic dose of the hydrochloride is 25-50 mg three times daily for adults and 25 mg three times daily per os for children. For the effect of narcotine upon the cough reflex and upon the bronchial muscle, see (602-613). 

Papaverine.—The biosynthesis of the simple benzylisoquinoline papaverine (89) is known to proceed via nor-reticuline (48) and tetrahydropapaverine (88).71 Dehydrogenation of the latter affords papaverine, and examination of the stereochemistry of the processes involved has led to the conclusion72 that loss of the proton at C-3 [in nor-reticuline (48)] is stereospecific (loss of the pro-S hydrogen atom) but removal of the C-4 proton is essentially non-stereospecific. These observations are perhaps best explained if enzyme-catalysed oxidation of (88) occurs to give (90), subsequent non-stereospecific imine-enamine isomerization occurring without enzyme participation to give (91). A further amine to imine oxidation then occurs to give papaverine (89).72... 

The cyclization product is still an amino acid and it can be decarboxylated by pyridoxal. Now we have something quite like papaverine but it lacks the methyl groups and the aromatic heterocyclic ring. Methylation needs SAM and is done in two stages for a reason we will discover soon. The final oxidation should again remind you of the closing stages of the tropinone route. 

A more interesting series of alkaloids arises when benzyl isoquinoline alkaloids cyclize by radical reactions. Phenols easily form radicals when treated with oxidizing agents such as Fe(III), and benzyl isoquinoline alkaloids with free phenolic hydroxyl groups undergo radical reactions in an intramolecular fashion through a similar mechanism. Here are the details of some methylations of a class of alkaloids closely related to papaverine. 

The initial attack in the anodic oxidation of papaverine [75] probably involves a similar attack further oxidation and dimerization leads to the isolated product, 12,12 -bis-(2,3,9,10-tetramethoxyindolo[2,l-fl]isoquinolyl). An analogous reaction is the electrooxidation of a tetramethoxy-substituted 2-methyl-l-phenethyl-l,2,3,4-tetrahydroisoquinoline to a dibenzoquinolizinium derivative [76] and the oxidation of A,A -triphenyl-( -phenyle-nediamine to 9,10-diphenylphenazine [77]. Intramolecular Michel addition of nitrogen in a tetrahydroquinoline derivative to an o-quinone moity have resulted in the formation of a 5,6-dihydrodibenz[6,d]indolizine derivative [78]. A similar ring closure occurs during the oxidation of various catecholamines [79] and similar compounds [79] to indoles. Cyclic a-carbonylazo compounds, generated by anodic oxidation of the hydrazines, may be trapped by reaction with dienes to the expected heterocycles [80]. 

The gasiroinie.slinal (Gl) aniispasmodic properties of bisaboloi and its oxides are well known. In fact, bisaboloi is said to be as potent as papaverine in tests of muscle spasticity. Besides bisaboloi. the flavone and coumarin components have -antispasmodic activities. The blue compound chamazulene posse.sses both anti-inflammatory and antiallcigenic ac-tivitic.s. as do the water-soluble components (the flavonoids). Apigenin and lutcolin possess anti-inflammatory potencies similar to that of indtimethacin. These flavonoids possess acidic phenolic groups, a. spacer, and an aromatic moiety that could fit into the COX receptor. None of the.se effects has been unequivocally documented in humans. The essential oil posse.s.ses low water. solubility, but teas used over a long period of time provide a cumulative medicinal effect. Typically. I teaspoon (3 g) of flower head is boiled in hot water for IS minutes. 4 times a day. 

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