Quinine preparations

Bitters are substances taken before meals to improve appetite. They have not been scientifically investigated. They include gentian, nux vomica and quinine. Preparations can be found in formularies and at wine merchants (Duboimet, Campari). 

Licorice extracts are used extensively as ingredients in cough drops and syrups, tonics, laxatives, antismoking lozenges (see lobelia), and other preparations. They are also used as flavoring agents to mask bitter, nauseous, or other undesirable tastes in certain medicines (e.g., cascara, ammonium chloride, and quinine preparations). 

One approach is to prepare a sample blank using urine known to be free of quinine. The fluorescent signal for the sample blank is subtracted from the urine sample s measured fluorescence. 

The antimalarial properties attributed to preparations from Dichroa febrifuga by the Chinese were confirmed about 1944 and two alkaloids, febrifugine (999) and isofebrifugine (1000), were isolated eventually. After difficult structural elucidations, syntheses of ( )-febrifugine followed it proved to be half as active as the natural material, itself far better than quinine, but the therapeutic index was disappointingly low (67HC(24-l)490). 

Much of the bark collected in S. America was of low alkaloidal content, but proved suitable for the preparation of totaquina (p. 420). Among other interesting developments was the discovery by Steere of large stands of a race of Remijia pedunculaia on the western slopes of the Andes north of Bucaramanga, the bark of which yielded 3 per cent, of quinine sulphate. " ... 

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. ... 

Hydroquinine (Dihydroquinine), C20H26O2N2.2H2O. This base was isolated by Hesse from the mother liquors of quinine sulphate manufacture and is present to the extent of 5 to 6 per cent, in commercial sulphate of quinine, from which it is best isolated by the mercuric acetate process. The demand for hydroquinine as such and as a material for the preparation of hydrocupreine has led to its manufacture from quinine by catalytic hydrogenation. It crystallises from ether or benzene in needles, m.p. 173 5° (dry), — 235 7° (c = M/40, N/10 H2SO4) or... 

Prelog and Zalan have investigated the spatial distribution about positions C3, C4 and Cg and have shown that cincholoipon ethyl ester (V), whether prepared from cinchonine or quinine, has 16-7° and... 

The important role played by the quinicines (rubatoxanones, quina-toxines) in the syntheses of the dihydrocinchona alkaloids and the possibility that such substances might be used for the preparation of products approaching quinine in therapeutical interest, has led to the production of a large number of quinolyl ketones of various types and the corresponding secondary alcohols, and other derivatives obtainable from them, of which mention may be made of Rubtzov s syntheses of several isomerides of dihydroquinine. ... 

Woodward achieved his first signal success of a lifetime devoted to the preparation of increasingly complex natural products by total synthesis by the successful preparation of quinine. Despite its elegance, this synthesis did not provide a commercially viable alternative to isolation of the drug from chincona bark. A rather short synthesis for this drug from readily available starting materials has been only recently developed by the group at Hoffmann-LaRoche. (The economics of this synthesis are,... 

Now prepare test solutions containing, say, 0.00025 and 0.00045 mg quinine per mL. Determine their concentrations by measuring the fluorescence on the instrument and using the calibration curve (see Note). 

To determine the quinine content of tonic water it is first necessary to de-gas the sample either by leaving the bottle open to the atmosphere for a prolonged period or by stirring it vigorously in a beaker for several minutes. Take 12.5 mL of the de-gassed tonic water and make up to 25 mL in a graduated flask with 0.1M sulphuric acid. From this solution prepare other dilutions with 0.05M... 

Following Uskokovic s seminal quinine synthesis [40], Jacobsen has very recently reported the first catalytic asymmetric synthesis of quinine and quinidine. The stereospecific construction of the bicyclic framework, introducing the relative and absolute stereochemistry at the Cg- and expositions, was achieved by way of the enantiomerically enriched trans epoxide 87, prepared from olefin 86 by SAD (AD-mix (3) and subsequent one-pot cyclization of the corresponding diol [2b], The key intramolecular SN2 reaction between the Ni- and the Cg-positions was accomplished by removal of the benzyl carbamate with Et2AlCl/thioanisole and subsequent thermal cyclization to give the desired quinudidine skeleton (Scheme 8.22) [41],... 

Quinidine, a natural product epimeric with quinine at Cg and C9, was accessed through the diastereoisomeric trans epoxide prepared from 86 by SAD, in this case by using AD-mix a [2b, 41]. 

Quinine Lafran (Lafran as hydrochloride) numerous eombination preparations... 

Sulfoxides without amino or carboxyl groups have also been resolved. Compound 3 was separated into enantiomers via salt formation between the phosphonic acid group and quinine . Separation of these diastereomeric salts was achieved by fractional crystallization from acetone. Upon passage through an acidic ion exchange column, each salt was converted to the free acid 3. Finally, the tetra-ammonium salt of each enantiomer of 3 was methylated with methyl iodide to give sulfoxide 4. The levorotatory enantiomer was shown to be completely optically pure by the use of chiral shift reagents and by comparison with a sample prepared by stereospecific synthesis (see Section II.B.l). The dextrorotatory enantiomer was found to be 70% optically pure. 

The next milestone in the development of organic synthesis was the preparation of the first synthetic dye, mauveine (aniline purple) by Perkin in 1856 Perkin, 1856, 1862). This is generally regarded as the first industrial organic synthesis. It is also a remarkable example of serendipity. Perkin s goal was the synthesis of the antimalarial drug quinine by oxidation of N-allyl toluidine (Fig. 2.4). 

Taking Tomioka s pioneering work [8] as a precedent, we have screened 13-amino alcohols as chiral modifiers [9] in the nucleophilic addition of lithium 2-pyridinylacetylide 6 to the pMB protected ketimine 5. We were pleased to discover that when 5 was treated with a mixture prepared from 1.07 equiv each of quinine and 2-ethynylpyridine by addition of 2.13 equiv of n-BuLi in THF at -40 to -20 °C, the desired adduct 19 was obtained in 84% yield with maximum 64% ee. Soon after, we found selection of the nitrogen protective group had great influence on the outcome of the asymmetric addition and the ANM (9-anthranylmethyl)... 

A complex naturally occurring amino acid 5-hydroxypiperazic acid (5HyPip) 100 was prepared by a multistep procedure that included Diels-Alder addition of 2,4-pentadienoic acid to phthalazinedione 83a as a first step (Scheme 24). Adduct 97 was esterified and oxidized with mercuric acetate to 98, which on hydrogenation over rhodium on alumina and subsequent hydrolysis provided a mixture of enantiomers from which the required enantiomer 99 was obtained by resolution with quinine. Its hydrazinolysis provided 100 [71JCS(C)514 77H119],... 

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