Papaverine synthesis

Table 4.23 Summary of reaction metrics and synthesis tree parameters for papaverine synthesis plans ranked according to overall kernel (maximum) RME. ...

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 ... 

At about the same time, Vogtle and Frensch reported the synthesis of a similar bis-crown based on the papaverine nucleus. This synthesis also was executed in the Williamson fashion using doubly-demethylated papaverine and tetraethylene glycol dichloride. The base, if used, was not specified but it was noted that the high dilution technique was not used. It was presumed that the major product was 10, shown below, but there was also evidence of other components, presumably 11 and 12. 

In an attempted synthesis of papaverine based on Rugheimer s preparation of 6 7-dimethoxyisoquinoline from veratrylaminoacetal (McO)2—CjHg—NH—CH2(OEt)2, Allen and Buck reduced deoxy-veratroin oxime, (MeO)2—CgHg—C(NOH)—CHj—C6H3(OMe)2, to a 3-di-(3 4-dimethoxy)-phenylethylamine,... 

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 initial synthesis of papaverine is due to Pictet, and fittingly enough involved as its key step the name reaction. Acylation of veratrylamine (109) with dimethoxyphenylacetylchlo-ride affords the amide (110). Cyclization by means of phosphorus oxychloride constitutes the same reaction and affords the dihy-droisoquinoline (111). Dehydrogenation by means of a noble metal catalyst affords papaverine (107). ... 

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... 

Figure 4.50 Synthesis map showing starting materials used for the synthesis of papaverine.

Figure 4.51 Synthesis tree for synthesis of papaverine by the Pictet-Cams method.

Kindler, K. Peschke, K. (1934) New and Improved Methods for the Synthesis of Pharmacologically Important Amines. IX. Synthesis of Papaverine and Tetrahydropapaverine. Archiv fur... 

The Pictet-Gams modification of the Bischler-Napieralski synthesis has also been reviewed (5loR(6)74, 81HC(38-l)l6i). As shown in equation (32), the additional unsaturation is achieved by elimination of ROH before the cyclization. The commonest examples use j8-hydroxy or /3-methoxy substituents on the phenethylamide. Papaverine (107) is an example of an isoquinoline obtained from both precursors (09CB2943, 27AP(265)l). The precursors can be made from 5-aryloxazolines by reaction with an acid chloride and... 

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. 

Scheme 5 Steps involved in the synthesis of papaverine proposed by Pictet and Gams [2,21]...

The optical resolution of pavine (I) (obtained by synthesis from papaverine) and Trdger s base (II) on a microcrystalline triacetylcellulose (MCTC) column has been demonstrated [20]. 

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... 

PictetGams preparation of isoquinolines from iV-acylated 2-hydroxyphenethylamines, e.g., the synthesis of papaverine 180 (Scheme 107), utilizes similar conditions. 

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. 

In all the above-mentioned cases, the active component itself had to be determined. However, polarography often serves to determine toxic decomposition products or reaction intermediates in pharmaceutical synthesis. Besides the presence of codeinone in dihydrocodeinone [189], one can detect the presence and amount of toxic ketones in chloramphenicol [221] or of papaveraldine in papaverine [222]. 

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

The shortest synthesis of papaverine was achieved in the laboratory of R. Hirsenkom starting from racemic stilbene oxide and using a modified Pomeranz-Fritsch reaction The aminolysis of the stilbene oxide led to the formation of the cyclization precursor, which upon treatment with excess benzoyl chloride, underwent cyclization to give the N-benzoyl 1,2-dihydroisoquinoline derivative. Reduction under Wolff-Kishner conditions afforded papaverine. 

Hirsenkorn, R. Short-cut in the Pomeranz-Fritsch synthesis of 1-benzylisoquinolines short and efficient syntheses of norreticuline derivatives and of papaverine. Tetrahedron Lett. 1991, 32,1775-1778. 

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