Papaverine alkaloids syntheses

A number of pharmaceuticals are derived from isoquinoline. The long-known isoquinoline alkaloid papaverine 56 (synthesis on p 344) is still important as a spasmolytic. The antidepressant nomifensin 88 and the antibilharzia drug praziquantel 89 are derived from 1,2,3,4-tetrahydroisoquinoline. 

Review Problem 4 This compound (TM 78) is an important intermediate in the synthesis of alkaloids Treatment with POCI3 gives the poppy alkaloid papaverine. How would you make TM 78 from simple starting materials ... 

Special Reactions of Papaverine. Papaverine undergoes a number of reactions, which are of interest as providing methods of synthesis for other alkaloids, of which examples will be found under laudanosine, laudanine, laudanidine, codamine (pp. 187-195), berberine (p. 331), corydaline (p. 284), and glaucine (p. 311). 

On treatment of N-methylpapaverine, formed by the lithium aluminum hydride reduction of papaverine methiodide with phosphoric acid, N-methylpavine is formed which is identical with the racemic alkaloid argemonine. This reaction was used for the synthesis of the alkaloid (-h)-coreximine (268) (174) and similar compounds containing the proto-berberine grouping in the molecule (269,270). 

The opiate alkaloid, papaverine, from Papaver somniferum is an anti-spasmodic, vasodilator, and smooth muscle relaxant. Its total synthesis has been studied since Pictet and Gams early work in 1909 and has since been followed up by various industrial syntheses up till the early 1950s using important industrial commodities as vanillin, acetovanillone, veratraldehyde (methylvanillin), and homoveratric acid as starting materials (see Figure 4.50). Table 4.23 summarizes the results of the five synthetic plans for this natural product. All are convergent... 

Isoquinoline synthesis Bischler-Napieralski synthesis is used to synthesize isoquinolines. (3-phenylethylamine is acylated, and then cyclodehy-drated using phosphoryl chloride, phosphorus pentoxide or other Lewis acids to yield dihydroisoquinoline, which can be aromatized by dehydrogenation with palladium, for example in the synthesis of papaverine, a pharmacologically active isoquinoline alkaloid. 

A synthesis of sevanine (16) by Bischler-Napieralski ring-closure of the amide (17) followed by hydrogenolysis and dehydrogenation has been reported.27 The alkaloid has also been prepared from papaverine by demethylation and methyl-enation with dichloromethane.27... 

In 1803 the German pharmacist Seturner achieved the isolation of morphine as one of the active ingredients of opium. He named the compound after Morpheus, Ovid s god of dreams, the son of sleep. Among the other alkaloids of opium are codeine, isolated in 1832, thebaine, narceine, narcotine, and papaverine. From the isolation of pure morphine to the elucidation of its structure by first Gulland and Robinson(1,2) and later Schopf(3) took another 120 years. A total synthesis by Gates and Tschudi(4,5) confirmed the structure in the early 1950s. 

II. The stmctuie of papaverine, C2oH2i04N, one of the opium alkaloids, has been established by the following synthesis ... 

A rational total synthesis is used for some simple alkaloids (adrenaline, theophylline, papaverine), low molecnlar peptide hormones (oxytocin, vasopressin), vitamins (biotin, folk acid, thiamine, riboflavin), phenolic acids (sahcyhc acid). It should, however, be observed that the synthetic substances are all racemic forms, whereas many natural products occur in the 1-form. 

Papaverine is an alkaloid from opium it is a smooth-muscle relaxant and thus useful as a coronary vasodilator - the synthesis illustrates the Pictet-Gams variation of the Bischler-Napieralski sequence. 

Bischler-Napieralski and Pictet Spengler reactions continue to serve well for benzylisoquinoline syntheses.76,77 In the latter reaction, use of a-formylphenyl-acetic esters for the non-nitrogen-containing component appears to be advantageous.77 An interesting sequence of reactions (43)—>—>(44) (Scheme 4) has apparently been applied to the synthesis of papaverine [44 R = 3,4-(MeO)2-C6H3CH2 ] and related alkaloids.78 An attempt to convert ( )-reticuline (37 R = H) into a morphinandienone-type alkaloid by enzymic oxidation with... 

Papaveraldine. (6,7 Dimethoxy l isoquinolinyl) 13,4-dimeihoxyphenyl)meihanone 6,7-dimethoxy-l-isoquin-olyl 3,4-dimethoxyphenyt ketone 6,7-dimethoxy-l -veratro-ylisoquinoline xanthaline. CwH NOd mol wt 353.36. C 67.98%, H 5.42%, N 3.96%, O 22.64%. The old name pa-paveraldine is retained to avoid confusion. Prom opium whether papaveraldine occurs as such in the poppy plant, or h formed during the process of extraction, has not been investigated. Oxidation of papaverine to papaveraldine by SeOj Menon, Proc. Indian Acad. Sci. 19A, 21 (1944), For older references see Small, Luca, Chemistry of the Opium Alkaloids, V.S. Public Health Reports. Suppl. No. 103, Washington (1932). Synthesis from Reissert cotnpds Popp, McEwen, J Am. Chem. Soc. 79, 3773 (1957). 

The synthesis of the alkaloid papaverine 56 serves as an example of the two synthetic methods ... 

Prior to this synthesis, Pictet and Finkelstein (22) had attempted a synthesis of the alkaloid by way of its 3,4-dihydro derivative but were unable to remove the two extra hydrogen atoms from its pyridine ring. Spath and Burger (19) completed this synthesis by dehydrogenating 3,4-dihydro-papaverine with palladized asbestos at 200°. Homoveratrylamine and homoveratroyl chloride were condensed, and the amide (XXXIII) converted to 3,4-dihydropapaverine (XXXIV) by a Bischler-Napieralski iso-... 

Since papaveraldine (II) is reduced to papaverine (p. 33), this constitutes another synthesis of the parent alkaloid. It should be mentioned that the alkaloid xanthaline, first isolated from opium mother liquors by T. and H. Smith Co. (54), has been identified with papaveraldine by Dobson and Perkin (55). 

A second commercial synthesis of papaverine was performed by Wahl (62) in 1947 but not published until three years later. 3,4-Dimethoxy-phenylpyruvic acid (XXXVIII), prepared from veratraldehyde and hip-puric acid, was treated with ammonium hydroxide at 100° under pressure, and the resultant diamide (XXXIX) was hydrolyzed to the corresponding 3- (3,4- dimethoxyphenyl)- a- (3,4- dimethoxyphenylacetamido) propionic acid. The methyl ester of this compound was cyclized readily with phosphorus oxychloride, and the resulting ester was saponified to 3,4-dihydro-papa verine-3-carboxylic acid (XL). The latter was decarboxylated at 140° in tetralin solution to 3,4-dihydropapaverine, and addition of palladium-on-carbon catalyst to the reaction mixture furnished papaverine, four parts of vanillin leading to one part of the alkaloid in over-all yield. 

Since papaverine has been synthesized by different methods, these reactions constitute syntheses of DL-laudanosine. Pictet and Athanasescu (76) completed the synthesis of the optically active opium alkaloid by resolution of the racemic mixture with quinic acid. 

Structure. The structure of glaucine was arrived at by Gadamer (12) by a process of intuitive reasoning supplemented by a synthesis. Co-rytuberine dimethyl ether and glaucine were known to be isomeric, and if a relation to papaverine were admitted only two structures were available for the two alkaloids. Pschorr (13), utilizing his well-known phenanthrene synthesis, had attempted to convert papaverine into an aporphine (IV) via the nitro (II) and the amino (III) derivatives. When papaverine is nitrated it yields 6 -nitropapaverine (II), from which the methochloride... 

Many stmctures are found in the isoquinoline family of alkaloids (see section 3.2), and the Bischler-Napieralski method has been of considerable value in synthesizing some of them. An example is the synthesis of papaverine, 4.20 (Scheme 4.18, where Ar refers to the dimethoxyphenyl substituent). 

Suau, R., Rico-Gomez, R., Souto-Bachiller, F.A., Rodriguez-Rodriguez, L.A., and Ruiz, M.L., Efficient photoinduced electron transfer in papaverine N-oxide regioselective intramolecular hydroxylation of papaverine as an alternative disconnection for the synthesis of cularine alkaloids. 

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