Pilocarpine synthesis

Pilosinine (31) is a naturally occurring alkaloid in P. microphyllus, structurally, it resembles pilocarpine (27) since it lacks the ethyl substituent at C2 [8]. This substance plays an important role in pilocarpine synthesis as a key intermediate as indicated by recent works [30, 31]. Tandem mass spectroscopy studies indicated that P. carajaensis, P. spicatus A. St. Hil., P. trachyllophus, P. pennatifolius, P. jaborandi, and P. racemosus accumulated 2,3-dehydropilosinine (32). Confirmatory fragmentation pattern was made by comparison with that described to the synthetic derivative. 

Roylance showed that pilocarpidine on -methylation yielded two products, pilocarpine and neopilocarpine (see below), thus confirming Hamack s suggestion that pilocarpidine is the imino-base corresponding to pilocarpine, Spath and Kunz showed that pilocarpidine, on treatment with alcoholic sodium ethoxide, is converted into isopilocarpidine (nitrate, m.p. 109-111°), which, on quaternary methylation, yields isopilocarpine metho-salts (methopicrate, m.p. 119-120°). The confirmation of these observations by the synthesis of pilocarpidine and isopilocarpidine and their conversion into pilocarpine and isopilocarpine has been described already. 

The foregoing formula has been confirmed by the synthesis of pilosinine by Poljakova and V. A. and N. A. Preobrashenski, who followed the process used for the synthesis of pilocarpine and the allied alkaloids see p. 625), starting with diethyl formylsuccinate to produce pilosinie acid,... 

Zhang68 has applied the cyclization of esters to the formation of a-methylene-y-butyrolactones, thus offering a novel and enantioselective entry to these substructures. The importance of this unsaturated lactone is evidenced by its ubiquitous presence in nearly a third of all naturally occurring secondary metabolites. The Alder-ene reaction has been applied to a formal total synthesis of (+)-pilocarpine, a leading therapeutic reagent for the treatment of narrow and wide glaucoma. Zhang intersected Btichi s synthetic intermediate (i )-181 (Scheme 47) in only two steps with a 99% ee and a 91% overall yield. In comparison, Biichi synthesized (i )-181 in five steps with a 92% ee and a 20% overall yield. 

H. Bundgaard, E. Falch, C. Larsen, G. L. Mosher, T. J. Mikkelson, Pilocarpine Prodrugs. II. Synthesis, Stability, Bioconversion, and Physicochemical Properties of Sequentially Labile Pilocarpine Acid Diesters , J. Pharm. Sci. 1986, 75, 775 - 783. 

When (R,R)-Me-Duphos, (R,R,R,R)-BICPO [9] or BINAP [10] is used, the rhodium-catalyzed asymmetric cycloisomerization of 3 affords 4 with up to >99.5% enantiomeric excess (Scheme 7 2). This methodology was applied to the synthesis of functionalized a-methylene-y-butyrolactone derivatives 6 such as (-i-)-pilocarpine 7 (Scheme 7.3) [11]. 

The basic alkaloid in Pilocarpus jaborandi (Rutaceae) is pilocarpine, a molecule of which contains an imidazole nucleus and is also used as a clinical drug. During alkaloid synthesis, L-histidine can produce the manzamine nucleus (Figure 27). These alkaloids are quite widespread, though they were first isolated in the late 1980s in marine sponges. They have an unusual polycyclic system and a very broad range of bioactivities. Common alkaloids with this nucleus include manzamine A, manzamine B, manzamine X, manzamine Y, sextomanzamine A and so on. 

Bundgaard, H., Falch, E., Larsen, C., and Mikkelson, T. J. Pilocarpine prodrugs I. Synthesis, physicochemical properties and kinetics of lactonization of pilocarpic acid esters. J. Pharm. Sci. 75 36-43, 1986. 

Jarvinen, T., Suhonen, P, Auriola, S., Vepsalainen, J., Peura, P, et al. (1991), 0,0 -( 1,4-Xylylene)bispilocarpic acid esters as new potential double prodrugs of pilocarpine for improved ocular delivery. Part 1. Synthesis and analysis, Int. I. Pharm., 75(2-3), 249-258. 

Chumachenko et al. (50,51) confirmed the structure of pilocarpine by their synthesis of homopilopic acid, a degradation product of pilocarpine (Section III,F). Inch and Lewis (52) also gave structural evidence by their synthesis of (+)-(/ )- l-acetoxy-2,3-(bisacetoxymethyl)pentane (14), which... 

The syntheses of pilocarpine via homopilopic acid by Preobrazhenski et al. and Dey have been discussed previously (1). In 1968, Chumachenko et al. (50,51) reported the synthesis of homopilopic acid, starting from furfural. A few years later, DeGraw (85) also reported on a synthesis of homopilopic acid his approach to the problem was similar to Chumachenko s work. 

A stereoselective synthesis of (+)-pilocarpine (7) starting from L-histidine (2) has been worked out by Noordam et al. (88 - 90). Use was made of the S configuration of the amino acid, which is the same as that of C-3 of the lactone ring in both (+)-pilocarpine and (+)-isopilocarpine. Furthermore, regioselective N-alkylation reactions of the imidazole nucleus of histidine had been developed by Beyerman et al. (29,91). Schemes 3 and 4 depict the different ways of the regioselective alkylations. For the synthesis of pilocarpine, the N7I-methylation has been performed via Nb-protection with the 4-nitrobenzenesulfonyl group, instead of the benzoyl group (29). 

The Jaborandi alkaloid pilocarpidine (49) is the A -nor lower homolog of pilocarpine. No new reports on the occurrence of pilocarpidine have been published since the last review in this series (1). The synthesis of pilocarpidine that terminates with the N -methylation of the imidazole nucleus is likewise the synthesis of pilocarpidine (Section III,F). 

In 1972 Link and Bernauer (69) published a synthesis of (+)-isopilosine and of (+)-pilocarpine, and then obtained (—)-epiisopilosine as a by-product. The readily available ester 53 was converted in two steps to the aldehyde (54), which on Stobbe condensation with succinic ester gave the half-ester acid salt 55. Lithium borohydride reduction followed by prolonged acid treatment gave ( )-pilosinine [( )-32], together with 2,3-dehydropilosin-... 

Q6 Pilocarpine eyedrops are suitable. In severe conditions, in addition to the eyedrops, intravenous acetazolamide and intravenous hypertonic mannitol (an osmotic agent) may be used to reduce pressure. Acetazolamide prevents the actions of carbonic anhydrase in the ciliary body and inhibits bicarbonate synthesis. This causes reduction in sodium transport and aqueous humour formation since there is a link between bicarbonate and sodium transport. 

The earliest method of this type, developed by Marckwald, employed the reaction of a-aminocarbonyl compounds (or their acetals) with cyanates, thiocyanates or isothiocyanates to give 3//-imidazoline-2-thiones. These compounds can be converted readily into imidazoles by oxidation or dehydrogenation. The major limitations of this synthetic procedure are the difficulty of synthesis of a wide variety of the a-aminocarbonyl compounds, and the limited range of 2-substituents which are introduced. The reduction of a-amino acids with aluminum amalgam provides one source of starting materials. The method has been applied to the preparation of 4,5-trimethyleneimidazole (83) from 2-bromocyclopentanone (70AHC(12)103), and to the synthesis of pilocarpine (84 Scheme 47) (80AHC(27)24l). If esters of a-amino acids react with cyanates or thiocyanates, the products are hydantoins and 2-thiohydantoins, respectively. 

An adaptation of the old Marckwald synthesis has allowed an improved preparation of pilocarpine (30) (see Scheme 8). 

A general review on the use of electrochemical methods for the synthesis of N-heterocycles and natural products includes a section on imidazole derivatives. Thin-layer chromatographic methods for the separation of imidazole alkaloids have been briefly reviewed. Pharmacological effects of pilocarpine (15) have been summarized as part of an excellent review on convulsant alkaloids. ... 

The synthesis of its isosteric carbamate (Figure 41.3), which is as effective as pilocarpine, has greatly improved the stability of the former lactonic ring. °... 

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