Racemate resolution-classical

The initial medicinal chemistry route to the azabicyclo[3.3.0]octane-3-carboxylic acid produced the azabicyclo system in a diastereoselective but racemic manner, and required a classical resolution to achieve enantioenriched material (Teetz et al., 1984a, b 1988). Reaction of (R)-methyl 2-acetamido-3-chloropropanoate (43) and 1-cyclopentenylpyrrolidine (44) in DMF followed by an aqueous acidic work-up provided racemic keto ester 45 in 84% yield (Scheme 10.11). Cyclization of 45 in refluxing aqueous hydrochloric acid provided the bicyclic imine, which was immediately reduced under acidic hydrogenation conditions. The desired cis-endo product 46 was obtained upon recrystaUization. The acid was protected as the benzyl ester using thionyl chloride and benzyl alcohol, providing subunit 47 as the racemate. Resolution of 47 was accomplished by crystallization with benzyloxy-carbonyl-L-phenylalanine or L-dibenzoyl-tartaric acid. 

Resolution Methods. Chiral pharmaceuticals of high enantiomeric purity may be produced by resolution methodologies, asymmetric synthesis, or the use of commercially available optically pure starting materials. Resolution refers to the separation of a racemic mixture. Classical resolutions involve the construction of a diastcrcomcr by reaction of the racemic substrate with an enantiomerically pure compound. The two diastereomers formed possess different physical properties and may be separated by crystallization, chromatography, or distillation. A disadvantage of the use of resolutions is that the best yield obtainable is. 50%, which is rarely approached. However, the yield may he improved by repeated raccmization of the undcsired enantiomer and subsequent resolution of the racemate. Resolutions are commonly used in industrial preparations of homochiral compounds. 

After the first preparation of enantiomerically pure (27 ,2 7 )-t/zreo-methylphenidate hydrochloride (1) in 1958, it is only recently that a great deal of interest has been demonstrated in the synthesis of this molecule. Various approaches to the preparation of enantiomerically pure (2R,2>R)-(-i-)-t/zreo-methylpheni-date hydrochloride (1) are reviewed. These approaches include synthesis using enantiomerically pure precursors obtained by resolution, classical and enzyme-based resolution approaches, enantioselective synthesis approaches, and approaches based on enantioselective synthesis of 2S, 2 Ryerythro-methylphenidate followed by epimerization at the 2-position. Classical resolution approaches have been successfully upscaled to produce 1 on a multi-kilo-gram scale due to the ready availability of racemic ( )-t/zreo-methylphenidate hydrochloride (10). VVfiiIt some enantioselective approaches are short, they do not provide 1 of the desired enantiomeric purity necessary for drug development. Enantioselective synthesis approaches to produce 1, however, will be-... 

Resolution of racemates by classical separation of diastereomeric salts remains a valid alternative to enantioselective synthesis. A simple but ingenious idea has recently been proposed and shown to work successfully the use of families of resolving agents that would work as a library on the racemate to be resolved, so that the least soluble salt would crystallize out. As a matter of fact, Broxterman [21] has shown that a mixture of acylated tartaric acids like 6a-c of Fig. 8, gave immediate crystallization in 97 out of 100 amine racemates studied, allowing a more rapid choice of resolving agents to be made in a more suitable manner than was previously possible. 

The optical enrichment of halothan, CFjCHBrCl 41), using a-cyclodextrin (26) is the only known strategy hitherto for racemate resolution of this substance. This is a good example to demonstrate the independency of the inclusion method on functional groups, even if the optical yield is only low as yet. These are indispensable when classical methods of resolution, e.g. use of diastereomeric salts, are applied consequently their application field is very restricted. 

If alkaloids are mentioned in connection with racemate resolution, one is usually inclined to think at first of the classical methods of resolution using diastereomeric salt formation by combination of the alkaloid base and an organic acid. 

Enantiomerically pure propeneoxide can be obtained in three steps from lactic acid. Its reaction with prenyl cuprate directly yields sulcatol [9, 10]. Even with such a convincing route at hand, one should not fail to evaluate routes via a racemate. A classical resolution via the formation of a hemiphthalate and crystallization of its brucine salt appears circumstantial. Yet kinetic resolution using enzymes, e.g.. Upases, appears more attractive (Scheme 10.7) [11]. 

The enantiomers of the silanes 10 and 11 were obtained from the corresponding racemic mixtures rac-10 (for its synthesis see Scheme 4) and rac-11 (for its synthesis see Scheme 5) by a classical racemate resolution using the enantiomers of 0,0 -di-p-toluoyltartaric acid and l,l -binaphthyl-2,2 -diyl hydrogen phosphate, respectively, as resolving agents (for resolution by fractional crystallization of diastereomeric salts see Scheme The silanes (/f)-10, (5)-10, (/J)-ll and (S)- were isolated as almost... 

Three general methods exist for the resolution of enantiomers by Hquid chromatography (qv) (47,48). Conversion of the enantiomers to diastereomers and subsequent column chromatography on an achiral stationary phase with an achiral eluant represents a classical method of resolution (49). Diastereomeric derivatization is problematic in that conversion back to the desired enantiomers can result in partial racemization. For example, (lR,23, 5R)-menthol (R)-mandelate (31) is readily separated from its diastereomer but ester hydrolysis under numerous reaction conditions produces (R)-(-)-mandehc acid (32) which is contaminated with (3)-(+)-mandehc acid (33). 

Diaziridines also show slow nitrogen inversion, and carbon-substituted compounds can be resolved into enantiomers, which typically racemize slowly at room temperature (when Af-substituted with alkyl and/or hydrogen). For example, l-methyl-3-benzyl-3-methyl-diaziridine in tetrachloroethylene showed a half-life at 70 °C of 431 min (69AG(E)212). Preparative resolution has been done both by classical methods, using chiral partners in salts (77DOK(232)108l), and by chromatography on triacetyl cellulose (Section 5.08.2.3.1). 

Schemes 3-7 describe the synthesis of cyanobromide 6, the A-D sector of vitamin Bi2. The synthesis commences with an alkylation of the magnesium salt of methoxydimethylindole 28 to give intermediate 29 (see Scheme 3a). The stereocenter created in this step plays a central role in directing the stereochemical course of the next reaction. Thus, exposure of 29 to methanol in the presence of BF3 and HgO results in the formation of tricyclic ketone 22 presumably through the intermediacy of the derived methyl enol ether 30. It is instructive to point out that the five-membered nitrogen-containing ring in 22, with its two adjacent methyl-bearing stereocenters, is destined to become ring A of vitamin Bi2. A classical resolution of racemic 22 with a-phenylethylisocyanate (31) furnishes tricyclic ketone 22 in enantiomerically pure form via diaster-eomer 32.

Catalytic kinetic resolution can be the method of choice for the preparation of enantioenriched materials, particularly when the racemate is inexpensive and readily available and direct asymmetric routes to the optically active compounds are lacking. However, several other criteria-induding catalyst selectivity, efficiency, and cost, stoichiometric reagent cost, waste generation, volumetric throughput, ease of product isolation, scalability, and the existence of viable alternatives from the chiral pool (or classical resolution)-must be taken into consideration as well... 

A different non-classical approach to the resolution of sulphoxides was reported by Mikolajczyk and Drabowicz269-281. It is based on the fact that sulphinyl compounds very easily form inclusion complexes with /1-cyclodextrin. Since /1-cyclodextrin as the host molecule is chiral, its inclusion complexes with racemic guest substances used in an excess are mixtures of diastereoisomers that should be formed in unequal amounts. In this way a series of alkyl phenyl, alkyl p-tolyl and alkyl benzyl sulphoxides has been resolved. However, the optical purities of the partially resolved sulphoxides do not exceed 22% after... 

The classical kinetic resolution of racemic substrate precursors allows only access to a theoretical 50% yield of the chiral ladone product, while the antipodal starting material remains unchanged in enantiomerically pure form. The regioseledivity for the enzymatic oxidation correlates to the chemical readion with preferred and exclusive migration of the more nucleophilic center (usually the higher substituted a-carbon). The majority of cydoketone converting BVMOs (in particular CHMOAdneto)... 

Enantiopure (R)- and (S)-nipecotic acid (Nip) derivatives 64 were obtained following classical resolution of ethyl nipecotate with either enantiomer of tartaric acid and successive recrystallization of the corresponding salts [153, 154, 156] or by resolution of racemic nipecotic acid with enantiomerically pure camphorsul-fonic acid [154]. N-Boc protected pyrrolidine-3-carboxylic acid (PCA) 65 for the synthesis of homo-ohgomers [155] was prepared by GeUman from trans-4-hydroxy-L-prohne according to a known procedure [157]. 

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... 

Our approach for chiral resolution is quite systematic. Instead of randomly screening different chiral acids with racemic 7, optically pure N-pMB 19 was prepared from 2, provided to us from Medicinal Chemistry. With 19, several salts with both enantiomers of chiral acids were prepared for evaluation of their crystallinity and solubility in various solvent systems. This is a more systematic way to discover an efficient classical resolution. First, a (+)-camphorsulfonic acid salt of 19 crystallized from EtOAc. One month later, a diastereomeric (-)-camphorsulfonic acid salt of 19 also crystallized. After several investigations on the two diastereomeric crystalline salts, it was determined that racemic 7 could be resolved nicely with (+)-camphorsulfonic acid from n-BuOAc kinetically. In practice, by heating racemic 7 with 1.3equiv (+)-camphorsulfonic acid in n-BuOAc under reflux for 30 min then slowly cooling to room temperature, a cmde diastereomeric mixture of the salt (59% ee) was obtained as a first crop. The first crop was recrystallized from n-BuOAc providing 95% ee salt 20 in 43% isolated yield. (The optical purity was further improved to -100% ee by additional recrystallization from n-BuOAc and the overall crystallization yield was 41%). This chiral resolution method was more efficient and economical than the original bis-camphanyl amide method. 

The target compound was obtained as a racemic mixture. Enantiomeric pure Efavirenz had to be isolated via a classical chiral resolution of a diastereo-mixture of (-) camphanate imide. 

Evaluation of the above route against our initial target objectives for the synthesis of taranabant indicated a high level of success, not just for the primary objectives of removing the tin chemistry and chiral chromatography, but for a number of other process improvements (Table 9.2). Of particular note was that the three crystalline intermediates were key for purification, first the phenethylamine salt 12 for the classical resolution, secondly the HC1 salt of amine 2 allowed for upgrade of diastereomeric purity, and finally the API allowed for upgrade of enantiomeric purity via initial removal of racemic material. 

In carrying out kinetic resolution, these in the standard approach are limited to 50% yield regarding the racemate. However, different approaches were developed [28] to overcome this limitation. The classical standard solution is to reracemize the unconverted enantiomer. A more advanced solution is the establishment of a dynamic kinetic resolution that has considerably expanded the synthetic scope of chemical processes. Here, the unconverted enantiomer is, in contrast to the latter method, racemized in situ. A great number of novel enzymatic methods have been developed [29]. Within this chapter, process solutions for enzymatic resolutions of racemic mixtures will be highlighted. 

Figure 4.6 Classical kinetic resolution with subsequent reracemization of unconverted enantiomer Synthesis of pantoic acid from pantolactone applying a stirred-tank reactor, extraction module and racemization step...

Figure 4.7 Classical kinetic resolution synthesis of L-methionine from IV-acetyl-methionine applying an ultrafiltration-membrane reactor and crystallization step as well as racemization step...

The catalytic RCM and kinetic resolution can be carried out in a single vessel as well. This is particularly important for the practical utility of the Zr-catalyzed resolution Because the best theoretical yield in a classical resolution is 50%, it is imperative that the racemic substrate is prepared readily (or 50% material loss will be too costly). In this instance, the racemic substrate is not only obtained efficiently, it is synthesized in a catalytic manner and need not even be isolated prior to the resolution. Two representative examples are illustrated in Scheme 4 [5a]. The tandem catalytic RCM, leading to rac-19 and its subsequent catalytic resolution proceeds with excellent efficiency the one-vessel, two-stage process... 

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