Cinchona preparation

Cinchona preparations were introduced into medical use in Europe in the early seventeenth century, and were popularized through the efforts of the wife of the then Spanish Viceroy of Peru, the Countess of Chinchon, who in 1638 was successfully treated for malaria throu administration of the hitherto little known remedy. Almost two hundred years later, one of the most intensive chemical investigations of the nineteenth century began, with the isolation of a crude mixture of crystalline alkaloids from the bark by Gomes in Portugal in 1810, and of pure quinine and cinchonine by Pelletier and Caventou in 1820 (3). Subsequently, upwards of two dozen further bases have been isolated from Cinchona and Bemijia species of these only quinidine (van Hejningen, 4) and cinchonidine (Winckler, 5) need be mentioned here. 

As the re-introduction of mixtures of cinchona alkaloids for use in medicine has given rise to some discussion, a list of the principal papers on this subject is given. Several of these provide analyses of locally produced totaquina. Applezweig and Ronzone have described an ion exchange process for the preparation of totaquina. 

Analyses of Cinchona Barks. For galenical preparations, pharmacopoeia recognition is usually restricted to barks of cultivated cinchona species known to yield total alkaloids satisfactory in composition thus, the British Pharmacopoeia 1932 prescribes the varieties to be used, and specifies not less than 6 per cent, of total alkaloids, of which at least half must be quinine and cinchonidine, determined by the process prescribed. Numerous other processes have been published and references to the more important of these are given under the following headings —identifica-... 

Cmchonine, C19H22ON2. This alkaloid is usually present in cinchona and cuprea barks. One of the best sources is Cinchona micrantha bark. It occurs in the crude quinine sulphate mother liquors. The mixed alkaloids recovered from these may be extracted with ether to remove quinidine and cinchonidine and the insoluble residue boiled with successive small quantities of alcohol, from which cinchonine crystallises on cooling. The crude alkaloid is neutralised with dilute sulphuric acid and the sulphate recrystallised from boiling water. Cinchonine so prepared contains quinidine, from which it may be freed by crystallisation from boiling alcohol until it ceases to exhibit fluorescence in dilute sulphuric acid. It will then still contain 10 to 15 per cent, of dihydrocinchonine, which may be removed by reprecipitation as the cuprichloride, B. 2HC1. CuClj, or by the simpler mercuric acetate process of Thron and Dirscherl. ... 

The cinchona alkaloids on degradation break down into derivatives of (1) quinoline and (2) quinuclidine and the synthesis of any one of them involves the preparation of each of these two halves in a form suitable for combination. 

Work also prepared a series of carbinolamines and polyamines without a quinoline nucleus but, in other respects, conforming in type and range of molecular weight, with quinoline compounds known to possess plasmocidal activity. As none of these were active, it seems clear that the quinoline nucleus in the cinchona alkaloids and in certain synthetic anti-malarials is a potent factor in the production of plasmocidal action. Later the same author made (1942) a series of lepidylamine derivatives of the form R. Q. CHj. NH[CH2] . NEtj, which were found to be inactive, in spite of their similarity to the active examples of the type R. Q. NH[CH2] . NEt2 prepared by Magidson and Rubtzow. Rubtzow (1939) has also shown that an isomeride of dihydroquinine (II) with the quinuclidine nucleus attached via the carbinol group at C in the quinoline nucleus was inactive in an infection of Plasmodium prcecox in finches. 

A notable change in methods of isolating alkaloids from plant materials has been described by Applezweig, depending on the use of a suitable ion-exchange material and capable of application on a semi-micro scale or for industrial use. It has been applied to the preparation of the total alkaloids of cinchona bark (totaquina) and according to Sussman, Mindler and Wood, is also used industrially for the recovery of hyoscine. 

Small chiral molecules. These CSPs were introduced by Pirkle about two decades ago [31, 32]. The original brush -phases included selectors that contained a chiral amino acid moiety carrying aromatic 7t-electron acceptor or tt-electron donor functionality attached to porous silica beads. In addition to the amino acids, a large variety of other chiral scaffolds such as 1,2-disubstituted cyclohexanes [33] and cinchona alkaloids [34] have also been used for the preparation of various brush CSPs. 

Azirines (three-membered cyclic imines) are related to aziridines by a single redox step, and these reagents can therefore function as precursors to aziridines by way of addition reactions. The addition of carbon nucleophiles has been known for some time [52], but has recently undergone a renaissance, attracting the interest of several research groups. The cyclization of 2-(0-tosyl)oximino carbonyl compounds - the Neber reaction [53] - is the oldest known azirine synthesis, and asymmetric variants have been reported. Zwanenburg et ah, for example, prepared nonracemic chiral azirines from oximes of 3-ketoesters, using cinchona alkaloids as catalysts (Scheme 4.37) [54]. 

Azirines can be prepared in optically enriched form by the asymmetric Neber reaction mediated by Cinchona alkaloids. Thus, ketoxime tosylates 173, derived from 3-oxocarhoxylic esters, are converted to the azirine carboxylic esters 174 in the presence of a large excess of potassium carbonate and a catalytic amount of quinidine. The asymmetric bias is believed to be conferred on the substrate by strong hydrogen bonding via the catalyst hydroxyl group <96JA8491>. 

The hydrogenation of methyl pyruvate proceeded over 4% Pd/Fe20 at 293 K and 10 bar when the catalyst was prepared by reduction at room temperature Racemic product was obtained over utunodified catalyst, modification of the catalyst with a cinchona alkaloid reduced reaction rate and rendered the reaction enantioselective. S-lactate was formed in excess when the modifier was cinchonidine, and R-lactate when the modifier was cinchonine... 

Introduction Since we had already developed the novel asymmetric addition of lithium acetylide to ketimine 5, we did not spend any time on investigating any chiral resolution methods for Efavirenz . Our previous method was applied to 41. In the presence of the lithium alkoxide of cinchona alkaloids, the reaction proceeded to afford the desired alcohol 45, as expected, but the enantiomeric excess of 45 was only in the range 50-60%. After screening various readily accessible chiral amino alcohols, it was found that a derivative of ephedrine, (1J ,2S) l-phenyl-2-(l-pyrrolidinyl)propan-l-ol (46), provided the best enantiomeric excess of 45 (as high as 98%) with an excellent yield (vide infra). Prior to the development of asymmetric addition in detail, we had to prepare two additional reagents, the chiral modifier 46 and cyclopropylacetylene (37). 

In order to evaluate the catalytic characteristics of colloidal platinum, a comparison of the efficiency of Pt nanoparticles in the quasi-homogeneous reaction shown in Equation 3.7, with that of supported colloids of the same charge and of a conventional heterogeneous platinum catalyst was performed. The quasi-homogeneous colloidal system surpassed the conventional catalyst in turnover frequency by a factor of 3 [157], Enantioselectivity of the reaction (Equation 3.7) in the presence of polyvinyl-pyrrolidone as stabilizer has been studied by Bradley et al. [158,159], who observed that the presence of HC1 in as-prepared cinchona alkaloids modified Pt sols had a marked effect on the rate and reproducibility [158], Removal of HC1 by dialysis improved the performance of the catalysts in both rate and reproducibility. These purified colloidal catalysts can serve as reliable... 

Since the reaction has been reviewed recently (12) only a few additional facts will be mentioned. Many optically active cyanohydrins can be prepared (33) with e.e. s of 84 to 100% by the use of the flavopnotein D-oxynitrilase adsorbed on special (34) cellulose ion-exchange resins. Although the enzyme is stable, permitting the use of a continuously operating column, naturally only one enantiomer, usually the R isomer, is produced in excess. This (reversible) enzyme-catalyzed reaction is very rapid (34). Nonenzymic catalysts, such as the cinchona alkaloids, permit either enantiomer to be prepared in excess. 

Figure 1.12). It is beyond the scope of the present review article to discuss all of the findings of these studies in detail. However, in general, it can be stated that also these CSPs may reveal valuable complementary selectivity profiles for particular classes of chiral solutes. This may apply to an even greater extent to CSPs based on Sharpless phthalazine-derived cinchona alkaloids (see Figure 1.9) (type IV CSPs bottom) [38,59] and mutants thereof (N.M. Maier and W. Lindner, in preparation). They partly showed exceptionally high enantioselectivities for some specific applications (vide infra). 

It is also worthwhile to outline at this place the immobilization procedure that was used for the preparation of type I CSPs A bifunctional linker with a terminal isocyanate on one side and a triethoxysilyl group on the other end (3-isocyanatopropyl triethoxysilane) was reacted with the native cinchona alkaloids quinine and quinidine and subsequently the resultant carbamate derivative in a second step with silica [30], Remaining silanols have been capped with silane reagents, yet, are less detrimental for acidic solutes because of the repulsive nature of such electrostatic interactions. CSPs prepared in such a way lack the hydrophobic basic layer of the thiol-silica-based CSPs mentioned earlier, which may be advantageous for the separation of certain analytes. 

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