Resolving Agents

In order to set up practical process for the separation of diastereoisomeric salts, initially a system forming a eutectic must be selected. This leads to the choice of the resolving agent and of the solvent. Next the crystallization conditions are optimized by means of phase diagrams along the lines discussed above. A classical resolving agent is a chiral acid or base available in bulk quantities at low price, and which has a propensity to form crystalline diastereoisomers when combined with racemic bases or acids. Table 1 lists some of the most common resolving agents for salt formation. Other, more specialized, resolving agents for the separation of

Table 1 Common resolving agents

Acids

Bases

Tartaric acid (#), (-) Dibenzoyltartaric acid (#), (-) Mandelic acid (#), (-) Camphoric acid (#) Malic acid (#), (-) 10-Camphorsulfonicacid (#), (-) a-Bromo-rc-camphorsulfonicacid (#), (-) Glutamic acid (#), (-) Aspartic acid (#), (-) «-Camphanic acid (#), (-) 1,1 '-Binaphthyl-2,2'-diyl-hydrogen phosphate (#), (-)

a-Methylbenzylamine (#), (-) Ephedrine (#), (-) 2-Amino-1-butanol (#), (-) Quinine (- ) Quinidine (#) Cinchonine (#) Cinchonidine (-) Brucine (-) Yohimbine (#) Dehydroabietylamine (#) N-Methyl-D-glucamine (- )

diastereoisomers by chromatography or for analytical purposes (nuclear magnetic resonance spectroscopy) are not mentioned here. For important commercial applications, it may be appropriate to design new resolving agents: for example, the N-alkyl-d-glucamine family (prepared from d-glucose) has been developed by Syntex as a substitute for cinchonidine for the large-scale resolution of naproxen (over 1000 tonnes per year). There are no clear guidelines allowing the prediction of a good resolving agent for a given substrate. This is not really a serious problem because the number of available resolving agents, being very limited, generally allows systematized protocols to identify the best ones very quickly.

Salts usually need polar solvents to crystallize, and a statistical survey of solvents used in over 800 such resolutions indicate that anhydrous or aqueous acetone and alcohols (ethanol, methanol, 1- and 2-propanol, 1-butanol), and water feature in 80% of cases. The presence of water may be necessary whenever the salts crystallize as hydrates. This is why 95% ethanol (rather than absolute ethanol) is to be preferred during the selection of a resolving agent.

Interesting achievements in the area of chiral host lattices have been reported during the last decade. A small number of chiral substances that form dia-stereoisomeric crystalline inclusion complexes with a variety of guests have been identified. In addition to the alkaloid brucine, which has been utilized for resolving, at least partially, chiral halogenoalkanes (including CHFClBr) and, more recently, acetylenic alcohols and cyanohydrins, several new hosts have been discovered, among which readily available diols prepared from tartaric acid seem to have the greatest potential as resolving agents.

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