DOPA, resolution

Resolution of compounds made as diastereoisomeric mixtures The synthesis of Jacobsen s Mn(III) epoxidation catalyst by resolution Resolution with half an equivalent of resolving agent Physical Separation of Enantiomers Chromatography on chiral columns Resolution of triazole fungicides by HPLC A commercial drug separation by chiral HPLC Differential Crystallisation or Entrainment of Racemates Conglomerates and racemic compounds Typical procedure for differential crystallisation (entrainment) Conventional resolution ofL-methyl DOPA Resolution ofL-methyl DOPA by differential crystallisation Finding a differential crystallisation approach to fenfluramine Resolution with Racemisation... 

Crystallization Method. Such methods as mechanical separation, preferential crystallisation, and substitution crystallisation procedures are included in this category. The preferential crystallisation method is the most popular. The general procedure is to inoculate a saturated solution of the racemic mixture with a seed of the desired enantiomer. Resolutions by this method have been reported for histidine (43), glutamic acid (44), DOPA (45), threonine (46), A/-acetyl phenylalanine (47), and others. In the case of glutamic acid, the method had been used for industrial manufacture (48). 

Finally, as an old example of kinetic resolution of racemic mixtures, mention must be made on the report of Kise and Tomiuchi on the significant effect of acetonitrile on the enantioselectivity of different proteases toward the kinetic resolution of aromatic amino acid ethyl esters (5-8). For instance, (l)-DOPA (8) was obtained with 99% ee in the presence of 90% v/v acetonitrile [9]. 

Gubitz, G., Jellenz, W., and Schonleber, D., High performance liquid chromatographic resolution of the optical isomers of D,L-tryptophane, D,L-5-hydroxytryptophan and D,L-dopa on cellulose columns, J. High Resolut. Chromatogr. Chromatogr. Commun., 3, 31, 1980. 

Cellulose was the first sorbent for which the resolution of racemic amino acids was demonstrated [23]. From this beginning, derivatives such as microcrystalline triacetylcellulose and /3-cyclodextrin bonded to silica were developed. The most popular sorbent for the control of optical purity is a reversed-phase silica gel impregnated with a chiral selector (a proline derivative) and copper (II) ions. Separations are possible if the analytes of interest form chelate complexes with the copper ions such as D,L-Dopa and D.L-penicillamine [24], Silica gel has also been impregnated with (-) brucine for resolving enantiomeric mixtures of amino acids [25] and a number of amino alcohol adrenergic blockers were resolved with another chiral selector [26]. A worthwhile review on enantiomer separations by TLC has been published [27],... 

DSM has developed a general, industrial-scale process for the production of either l- or D-amino acids through the hydrolysis of the amide (Scheme 2.22).75 78 The product amino acid and untouched amide are easily separated. The amide can be recycled. The resolution method has been extended to a,a-disubstituted of which L-methyl-dopa (14) is an example.79... 

Preferential crystallization. Preferential crystallization is one of the oldest methods for the resolution of racemates. It involves seeding of the racemate solution with pure crystals of the desired enantiomer which induce the preferential crystallization of that isomer from the solution. The technology is used in the commercial production of a-methyl-L-dopa (7). 

In the mid-1960s, it was discovered that L-DOPA was useful in treating Parkinson s disease. L-DOPA is the common name for the amino acid (S)-3,4-dihydroxyphenylalanine, which is the biologically active enantiomer. Its industrial synthesis was formerly achieved by resolution of a racemic intermediate which, in turn, was prepared by heterogeneous hydrogenation of an enamide according to Figure 11a. 

Hydrolases - Chymotrypsin is the best documented hydrolase. It has a very broad and predictable stereospecificlty and is widely used in resolution of racemic esters.1 L-DOPA has been prepared in this way.41 Several esterases also exhibit enantiotopic specificity. This is exploited in the synthesis of R-mevalonolactone 22 from 21.42... 

The synthesis of L-methyl DOPA 80 by the Strecker reaction was straightforward and of course produced racemic material. A conventional resolution by crystallising the menthyl ester 83 from hexane and hydrolysis of acetal, ester and amide in 48% HBr (note that no racemisation by enolisation can occur) gives good yields.19... 

A particularly interesting use of seeds is in the resolution of the isomers of methy l-dopa as practiced by Merck Co., Inc. In this process two fluidized beds operate in tandem, each of which is seeded with one of the optical isomers. Supersaturation is controlled to minimize nucleation so that growth of each isomer occurs on the existing crystals in their respective beds (see Section... 

Further studies on proteins have been carried out by Haas et al. (1951a) using low-temperature techniques to improve the resolution of the fine-structure. These methods made it possible to recognize the absorption maximum of dopa (3 4-dihydroxyphenylalanine) at 2820 A. which appears in the spectrum as a progressive enhancement of the tyrosine fine-structure maximum at the same wavelength dopa is apparently a characteristic intermediate in the oxidation of combined tyrosine or tyrosine derivatives, though not of free tyrosine. 

A complementary approach is to use reverse phase silica gel impregnated with a chiral selector [55,56]. Chiral plates comprising reverse phase Cjg impregnated with copper A,Ar-dialkyl-a-amino acids, e.g. proline have been used successfully for the separation of a variety of enantiomeric mixtures, e.g. d- and L-dopa. The resolution is based on ligand exchange, the enantiomers to be separated forming chelate complexes with the copper ion of differing stabilities. 

The thalidomide tragedy, described in chapter 7, started to focus the pharmaceutical industry on synthesis of single enantiomers rather than racemic mixtures. Even if there are no antagonistic or undesirable side effects from the other enantiomer, a racemic mixture may waste 50 percent of the mass of a drug. Optically pure compounds such as vitamin B]2, morphine, and L-dopa are available naturally. In some cases (e.g., vitamin B12), the natural source is really the only practical source. For simpler compounds like L-dopa, chemical synthesis is very practical but resolution of enantiomers may double the production cost. 

The a-amino acids prepared by the synthetic methods just described are racemic unless a resolution step is included, enantiomerically enriched reactants are used, or the reaction is modified so as to become enantioselective. Considerable progress has been made in the last of these methods, allowing chemists to prepare not only L-amino acids, but also their much rarer D-enantiomers. We have already seen one example of this approach in the synthesis of the anti-parkinsonism drug L-dopa by enantioselective hydrogenation (see Section 14.14). A variation of the Strecker synthesis using a chiral catalyst has recently been developed that gives a-amino acids with greater than 99% enantioselectivity. 

Direct crystallisation techniques are widely used for industrial scale resolution, e.g. the manufacture of a-methyl-L-dopa [21] and chloramphenicol [22]. 

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