Chirality classical resolution

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... 

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. 

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. 

At least one group attempted to synthesize enantio-enriched 1 via as5munetric reduction of 8 with modest success (Krasik and Alper, 1992). The classical resolution of racemic 1 (via the bis-tartrate salt, for example) (Nabenhaur, 1942) remains as the simplest and most economical method for preparing chiral amphetamine (1) on a large scale. 

Step 3 isolation purification In this step, again there are major energy savings with the energy use being reduced from 27.7 to 7.2 MJ/kg. The reasons are that in the classical process there now needs to be a classical resolution and saltbreaking operation, whereas in the enzymatic process the substrate is already chirally pure, and the process is just a simple purification operation. 

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. 

Cram finished his synthesis by making and reducing the amide 6. Both steps go in excellent yield and, more importantly, without any racemisation as the chiral centre is not involved in either step. These principles are involved in all classical resolutions. 

An overwhelming majority of classic resolutions still involve the formation of diastereomeric salts of the racemate with a chiral acid or base (Table 6.1). These chiral-resolving agents are relatively inexpensive and readily available in large quantities (Table 6.2). They also tend to form salts with good crystalline properties.8... 

Another classic resolution process developed by Ethyl Corp. for (S)-ibuprofen production uses (S)-(-)-a-methylbenzylamine (MAB) as the chiral base for diastereomeric salt formation 49 The difference in solubility between (S)- and (ft)-ibuprofen MAB salts is so substantial that only half an equivalent of MAB is used for each mole of racemic ibuprofen, and no seeding is needed. The process can also be performed in a wide range of solvents, and the unwanted (ft)-ibuprofen can be recycled conveniently by heating the mother liquor in sodium hydroxide or hydrochloric acid. Other designer amines have been developed for resolution of ibuprofen with good stereoselectivities,50 but these chiral amines were prepared specifically for ibuprofen resolution and are thus unlikely to be economical for industrial production. 

A second example is the reciprocal DR of (R,S)-alaninol. Both (R)- and (,S )-alaninol are interesting chiral intermediates used in recent drug developments28 but are difficult to obtain by classical resolution.29 Alaninol is also one of the few examples that resisted the standard DR procedure. However, resolution of (f ,. S )-alaninol could be achieved with mandelic acid in isopro-panol/water (19 1) in the presence of enantiopure 2-amino-1-butanol.30 Whereas the latter amine... 

Overall recovery of the auxiliary was 64%. On cost estimates for scale up work it was found that the previously mentioned chiral auxiliary route exceeded the desired cost by a factor of six, primarily as a result of the cost of the chiral oxazolidinone and a yield of 33% over 10 steps. The route was ultimately replaced with a classical resolution protocol using mandelic acid, and this has been superseded by asymmetric approaches (see Chapter 12). 

The preparation of homochiral compounds by formation and separation of diastereoisomers or by kinetic resolution of racemates, at or near the end of a total synthesis, has been a method of choice. This avoids the possibility of racemization should chirality be introduced earlier. However, the costs are high because only half by weight of the homochiral compound is theoretically possible from the racemate unless the optical antipode can also be easily inverted to the desired product. Indeed, previous methods for producing levomethadone based on the classical resolution at the end, or at the penultimate stage of the synthesis, were costly and not very effective. Levomethadone hydrochloride has previously been marketed as L-Polamidon and Levadone16 but was subsequently withdrawn because of the high cost of production. 

Recent work by Katz and coworkers led to the development of very efficient nonphotochemical, gram-scale syntheses of functionalized enantiopure [n]heli-cenes (n = 5, 6 and 7). These approaches were based on racemic syntheses and classical resolutions with a chiral auxiliary [31, 32]. 

Our biotransformation group (Drs. David Dodds, Alex Zaks, and Brian Morgan) contributed to most of our chiral synthesis projects, although in most cases enzyme-based routes were not selected over chiral induction or classical resolution processes for the short-term needs in API synthesis. This area, however, remains one of huge promise with the prospect of working in water being one of its most appealing attractions. 

Testing the concept required the preparation of pure samples of each of the four enantiomers. These were prepared by Gold et al.3 and Chemical Development using classical resolution and chiral synthesis methods. It was quickly found that the RR enantiomer, later named dilevalol, was virtually free of a-adrenergic receptor blocking activity and also possessed superior vasodilator properties versus labetalol. 

A classical resolution using dibenzoyl tartrate affords an even simpler synthesis of the chiral phenyl glycine intermediate 35. 

The relatively high optical purities obtained with the Rh-NMDPP system are particularly interesting from a practical viewpoint since the NMDPP ligand is prepared from an inexpensive, commercially available, chiral precursor, (-)-menthol (17). Tertiary phosphines chiral at phosphorus, on the other hand, are much less accessible and require a classic resolution step (see later discussion for details Section II. B). 

Chromatography on a chiral stationary phase is especially important when the compounds being resolved have no functional groups suitable for making the derivatives (usually esters or salts) needed for the more classical resolutions described above. For example, the two enantiomers of an analogue of the tranquillizer Valium were found to have quite different biological activities. 

As mentioned, asymmetrically pure compounds are important for many applications, and many different strategies are pursued. However, in spite of many methods being developed, the classic resolution technique of diastereomeric crystallization is still preferentially used to prepare optically active pure compounds in bulk quantity. Crystallization is commonly used in the last purification steps for solid compounds because it is the most economic technique for purification and resolution. Attempts to achieve crystallization after completed reaction without workup and extraction is called a direct isolation process. This technique can be cost-effective even though the product yield obtained is lower. Special conditions may be needed in this case, and the diastereomers can be classified into two types diastereomeric salts and covalent diastereomeric compounds, respectively. Diastereomeric salts can, for example, be used in the crystallization of a desired amine from its racemic mixture using a chiral acid. Covalent diastereomers can, on the other hand, be separated by chromatography, but are more difficult to prepare. Another advantage of crystallization is the possibility of combining in situ racemi-zation reactions and diastereomeric formation reactions to get the desired pure compounds. This crystallization-induced resolution technique is still under development because of its requirements for optimized conditions [55, 56],... 

Classical Resolution and Variants. Resolution is the process by which a chiral recemic molecule is combined with a second chiral, but enantiomerically homogeneous, molecule. The resultant mixture of diastereomers is separated and the appropriate diastereomer is then cleaved to recover the resolving agent and the desired enantiomer. As opposed to enantiomers, diastereomers have different physical properties, for example, melting points and solubilities, thus allowing for separation. 

The most classical of resolutions is exemplified by the separation, by crystallization, of the diastereomeric salts formed by treatment of a racemic acid with one enantiomer of a chiral base, typically an alkaloid such as quinine. Unfortunately, despite significant recent advances (3,6), the relative solubilities of two diastereomers, and thus the probability for success of a classical resolution, are difficult to predict. It thus remains, for most chemists, a largely empirical method. On the other hand, a successful resolution often provides both enantiomers, even when both enantiomers of the resolving agent are not at hand, by recovery from the enriched... 

Second-Order Asymmetric Transformations. A modification of the classical resolution occurs in the specific case where equilibration of the chiral center can be achieved during the resolution. By judicious choice of reaction conditions, one diastereomeric salt can be induced to crystallize under the equilibration conditions. As this material precipitates, solution equilibrium is reestablished by racemization of the now-major isomer remaining. In the best cases, over 90% of a single diastereomeric salt can be obtained. 

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