Quinine acetate

Fluorination of cinchona alkaloids has also been investigated. For instance, fluorination of quinine acetate under similar superacidic conditions (HF—SbFs/CHCls) affords a mixture of difluorocompounds in the 10 position that are ephners in 3 (60% yield, 1 1 ratio). This reaction involves a mechanism similar to the one described earlier (protonation, isomerization of carbenium ions, and Cl— F exchange). Curiously, when the reaction is performed on quinine itself, fluorination does not occur and an unprecedented rearrangement takes place (Figure 4.51). ... 

Low cost Organocatalysts from Nature, such as proline and quinine acetate, are inexpensive and bio-renewable... 

Economic and practical reasons, in addition to green concerns, have meant that many of the first generation of asymmetric organocatalysts have been either natural molecules, such as nomicotine [52] and proline [40], derived directly from the chiral pool (Figure 7.1), or simple derivatives thereof, such as quinine acetate [53] and 5,5-dimethyl thiazolidinium-4-carboxylate (DMTC) [54], which are expected to be either biodegradable or biotransformable, with little impact on the environment. [54]. 

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... 

It was found, during a study of synthetic routes leading to quinine analogues, that oxidation of a specific bicydic pyrazoline derivative with mercuric acetate gives an enamine-like pyrazole (87b). 

Irreversible reaction of [18] iodine with acetylsalicylic acid, aethaverine, amidopyrine, ascorbic acid, benzo-caine, quinine, dihydrocodeine, fluorescein, glycine, hydrocortisone acetate, isoni-azid, metamizole, papaverine, paracetamol, phenacetin, phenol-phthalein, piperazine, resorcinol, salicylic acid, salicylamide, sulfaguanidine, thymol, triethanolamine, tris buffer detection by reaction chromatography... 

Bohman and Allenmark resolved a series of sulphoxide derivatives of unsaturated malonic acids of the general structure 228. The classical method of resolution via formation of diastereoisomeric salts with cinchonine and quinine has also been used by Kapovits and coworkers " to resolve sulphoxides 229, 230, 231 and 232 which are precursors of chiral sulphuranes. Miko/ajczyk and his coworkers achieved optical resolution of sulphoxide 233 by utilizing the phosphonic acid moiety for salt formation with quinine. The racemic sulphinylacetic acid 234, which has a second centre of chirality on the a-carbon atom, was resolved into pure diastereoisomers by Holmberg. Racemic 2-hydroxy- and 4-hydroxyphenyl alkyl sulphoxides were separated via the diastereoisomeric 2- or 4-(tetra-0-acetyl-D-glucopyranosyloxy)phenyl alkyl sulphoxides 235. The optically active sulphoxides were recovered from the isolated diastereoisomers 235 by deacetylation with base and cleavage of the acetal. Racemic 1,3-dithian-l-oxide 236... 

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],... 

The first attempt to effect the asymmetric cw-dihydroxylation of olefins with osmium tetroxide was reported in 1980 by Hentges and Sharpless.54 Taking into consideration that the rate of osmium(VI) ester formation can be accelerated by nucleophilic ligands such as pyridine, Hentges and Sharpless used 1-2-(2-menthyl)-pyridine as a chiral ligand. However, the diols obtained in this way were of low enantiomeric excess (3-18% ee only). The low ee was attributed to the instability of the osmium tetroxide chiral pyridine complexes. As a result, the naturally occurring cinchona alkaloids quinine and quinidine were derived to dihydroquinine and dihydroquinidine acetate and were selected as chiral... 

FIGURE 1.5 pH -effect on retention factors k and separation factors a. CSP 0-9- tert-butylcarbamoyl)quinine bonded to sihca column dimension, 150 x 4 mm ID eluent, methanol-ammonium acetate buffer (80 20, v/v) (adjusted with acetic acid) temperature, 25°C 1 mL min sample, N-benzoyl-leucine (Bz-Leu). (Reproduced from M. Lammerhofer et al., American Laboratory, 30 71 (1998). With permission.)... 

FIGURE 1.6 Effect of organic modifier (methanol) percentage in the elnent on the retention factors (a) and observed enantioselectivities (b) of Af-(2,4-dinitrophenyl)-a-(2-chlorobenzyl)-proline employing an 0-9-[(2,6-diisopropylphenyl)carbamoyl]quinine-based CSP. Experimental conditions Elnent, ammonium acetate buffer-methanol (total ionic strength = 25 mM pHj, = 6.5), methanol content varied between 60 and 90%, while ionic strength and apparent pH were kept constant temperature, 40 C flow rate, 0.8 mLmin . (Reproduced from A. Peter et al., J. Sep. ScL, 26 1125 (2003). With permission.)... 

FIGURE 1.10 Comparison of enantiomer separations of DNB-Leu on quinine (QN) based and 0-9-(terf-butylcarbamoyl)quinine (tBuCQN) based CSPs. 1, ionic interaction 2, jt-7T-interaction 3, hydrogen bonding 4, steric interaction. Experimental conditions Eluent, methanol-0.1 M ammonium acetate (80 20 v/v) (pHa = 6.0) flowrate, 1 mLmin temperature, 25°C column dimension, 150 x 4 mm ID detection, UV 250 nm. Selector loadings, 0.37 and 0.30 mmol g l for QN- and tBuCQN-based CSPs, respectively. (Reproduced from A. Mandl et ah, J. Chromatogr. A, 858 1 (1999). With permission.)... 

FIGURE 1.30 Micro-HPLC separation of all 4 stereoisomers of the dipeptide alanyl-alanine as FMOC derivatives (a) and DNP-derivatives (b), respectively, on a 0-9-(tert-butylcarbamoyl)quinine-based CSP. Experimental conditions Column dimension, 150 X 0.5 mm ID mobile phase (a) acetonitrile-methanol (80 20 v/v) containing 400 mM acetic acid and 4 mM triethylamine, and (b) methanol-0.5 M ammonium acetate buffer (80 20 v/v) (pHa 6.0) flow rate, 10 ixLmin temperature, 25 C injection volume, 250 nL detection, UV at 250 nm. (Reproduced fromC. Czerwenka et al., J. Pharm. Biomed. Anal., 30 1789 (2003). With permission.)... 

In a recent study, chiral separations for pyrethroic acids, which are the chiral building blocks of synthetic pyrethroids and the primary metabolites of the acid part of these potent ester insecticides, have been developed [62], For example, a polar-organic mobile phase allowed the complete baseline resolution of all four stereoisomers of chrysanthemic acid (2,2-dimethyl-3-(2-methylprop-l-enyl)-cyclopropanecarboxylic acid) on a 0-9-(tcrt-butylcarbamoyl)quinine-based CSP(acjj = 1.20, oLtrans = 1-35, critical Rs = 3.03) (Figure 1,32a). This chiral acid is the precursor of pyrethroids like allethrin, phenothrin, resmethrin, and tetramethrin but not excreted as metabolite. The primary acid metabolite of these pyrethroids is chrysanthemum dicarboxylic acid (3-[(l )-2-carboxyprop-l-enyl]-2,2-dimethylcyclopropanecarboxylic acid) the stereoisomers of which could also be resolved with a reversed-phase eluent (acetonitrile— 30-mM ammonium acetate buffer 90 10, v/v pHa = 6.0) and employing an O-9-(2,6-diisopropylphenylcarbamoyl)quinine-based CSP ads = 1-09, atrans = 1-50,... 

FIGURE 1.32 Stereoisomer separations of chrysanthemic acid (a) and fenvaleric acid (b) employing an 0-9-(tert-bntylcarbamoyl)qninine-based CSP in the polar-organic mode (a) and an 0-9-(2,6-diisopropylphenylcarbamoyl)quinine based CSP (b). Experimental conditions Column dimensions, 150 mm x 4mmID eluents(a)0.06%aceticacidin acetonitrile-methanol (95 5 v/v) (b) acetonitrile-0.3 M ammoninm acetate buffer (90 10 v/v) (pHa 6.0) flow rate, 0.65 mLmin temperature, 25°C detection, UV at 230 nm. (Reproduced from W. Bicker et al., J. Chromatogr. A, 1035 37 (2004). With permission.)... 

Further, [2.2]paracyclophane-4-acetic acid, a potential drug candidate tested for its anti-inflammatory activity (NSAID could be resolved on the 0-9-(tert-butylcarbamoyl)quinine-based CSP with a = 1.12 Rs = 2.6) and elution order (R)-(-)- before (5)-(- -)-enantiomer [125]. Samples that were assessed to be enan-tiomerically pure by an enantioselective H-NMR spectroscopic method contained 6% and 8% enantiomeric impurity in S- and/ -enantiomers, respectively. This clearly reveals that enantioselective HPLC is a more powerful technique than NMR-methods to assess stereoisomeric purity, in particular, if the enantiomeric impurity amounts to less than 10%. 

Aryl-, aryloxy- and arylthiocarboxylic acids, N-derivatized amino acids Quinine and quinidine carbamates Methanol—0.1 M 194 ammonium acetate, pH 6.0 (80 20)... 

Mepivacine, bupivacine, doxapram, quinine, quinidine, atenolol, metoprolol, propranolol, pethidine, methadone (5)-N-(3,5-dinitro-benzoyl) tyrosine Acetonitrile—ammo 208 nium acetate (60 40)... 

S. Debarge, S. Thibaudeau, B. Violeau, A. Martin-Mingot, M.P. Jouannetaud, J.C. Jacquesy, A. Cousson, Rearrangement or gem-difluorination of quinine and 9-epiquinine and their acetates in superacid. Tetrahedron 61 (2005) 2065-2073. 

A 10 mL round-bottomed flask was charged with (5)-6,6 -[oxybis(ethylene) dioxy]biphenyl-2,2 -diol (1) (98% ee, 225.6 mg, 0.78 mmol), quinine (127.0 mg, 0.39 mmol) and ethanol (2mL). The mixture was warmed until the mixture suspension turned to a clear solution, and was allowed to settle for 12 h. The solid residue [crystals of (5)-l-quinine complex] was collected by filtration. To a mixture of aqueous 1 M HCl and ether was added the obtained crystals of (5 )-l-qumine complex. This was stirred for 15 min at room temperature, and the solution was extracted with ether (twice). The combined organic layers were washed with brine, and dried over sodium sulfate. After concentration in vacuo, the residue was purified by silica gel flash column chromatography (hexane/ethyl acetate = 20/1-3/1) to give optically pure (5)-l (167.8 mg, 74%, 99% ee) as a colourless solid. The enantiomeric excess of (5)-l was determined by chiral stationary-phase HPLC analysis DAICEL CHIRALCEL... 

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