Papaverinium salts

As a means of decreasing side reactions in the dehydrogenation of tertiary amines with mercuric acetate, Knabe studied the oxidation of alkaloids of the type of papaverine (1) in the presence of an equivalent amount of the sequestering agent ethylenediamine tetraacetic acid (EDTA) as the disodium salt. The products were the papaverinium salt (2) and the dihydro salt (3) in the yields noted- In the absence of the complexing agent, papaverine is cleaved at the methylene bridge. 

Most of the reactions of laudanosine have been carried out with the racemic mixture obtainable by reduction of quaternary papaverinium salts (p. 36). For instance, Gadamer and Kondo (79) obtained by oxidation with mercuric acetate, veratraldehyde and 4,5-dimethoxy-2-( 3-methyl-aminoethyl) benzaldehyde (XLVI) (or its ring-chain tautomer, laudaline), which resembles cotarnine in its properties. The same products are formed when manganese dioxide is chosen as the oxidizing agent (80). In both... 

As mentioned above, quaternary papaverinium salts were reduced to DL-laudanosine (XIII) under a variety of conditions (17, 28, 29, 30, 76). Alternatively, tetrahydropapaverine may be treated with methyl iodide to give DL-laudanosine hydriodide (85). The route from papaverine via protopapaverine and DL-laudanosoline 3, 4-dimethyl ether (LVII) has already been mentioned. Methylprotopapaverinium iodide can be reduced to DL-codamine (XXII), which can be methylated to DL-laudanosine. Not only DL-codamine but its three phenolic isomers (p. 53) can be converted to DL-laudanosine by the action of diazomethane (33, 83, 86). 

A patent for the preparation of quaternary salts of papaverine from C5, Ce, and Cg halides been published. N-Alkyl-papaverinium salts have been found to undergo oxidation by oxygen either photolytically or in the presence of cuprous chloride, to give the isoquinolones (25). The corresponding dihydro-papaverinium salts (26), with oxygen and cuprous chloride, do not suffer fission, and oxidation of the N-methyl compound (26 R = Me) in this way, followed by reduction of the product with sodium borohydride, affords a- and -hydroxy-laudanosines 21) The n.m.r. spectrum of laudanosine has been studied in detail. 

Quaternary papaverinium salts (22) have been converted into enamines (23), which have been oxidised by singlet oxygen or by oxygen and cuprous chloride with fission to the quinolones (24). N-methyl-3,4-dihydropapaverinium salts... 

Alkylpapaverinium salts, often called papaverine methochloride, etho-sulfate, etc., are prepared readily from the base and alkyl halides, sulfates, etc., by standard methods. Their reduction furnishes iV-alkyltetrahydro-papaverines (21, 27, 28). For example, iV-methylpapaverinium sulfate yields DL-laudanosine (XIII) on cathodic reduction (29) another publication records an almost quantitative yield of XIII by reduction of methyl-papaverinium chloride with zinc-cadmium alloy and acetic-formic acid (28). 

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