Racemic resolution processes

For the preparation of the (S)-enantiomer an enzymatic racemic resolution process using Aspergillus oryzae protease was developed by Sepracor ... 

A 27 73 mixture of (A)-4 (/f)-4 is suspended in eight volumes ethylene glycol and stabilized at 30°C for 2 h. The reaction mixture is filtered, and the filtrate is transferred into a second reactor, preheated to 170°C. After 15 min, the solution is allowed to flow back to the first reactor and is stabilized at 20 to 25°C for about 1.5 h. The suspension is filtered, and the filtrate is submitted to the next racemization step. The racemization-resolution process is repeated 13 times to afford a 79 21 mixture of crystals (5)-4 (/ )-4 in 66% yield. 

Though this method has given satisfactory results in many cases, it has the disadvantage of depending on functional groups (acid function). However, beside salt formation in some cases formation of clathrates of alkaloids plays a decisive role in racemate resolution processes. As an example the enantiomeric enrichment of bromochlorofluoromethane (CHClBrF) was achieved successfully by means of brucine Typically enough measurement of the enantiomeric excess (ee) of this interesting anaesthetic was achieved by differentiation of the enantiomers in a cavity of the cyclophane type (cf. section 2.6). 

In racemic resolution processes a racemic mixture of the desired product is produced first. There are several techniques by which this mixture can be separated into its two enantiomers. A favorable option is to react the racemic mixture with another chiral compound to form diastereomers. The latter have different physicochemical properties and thus they can be separated, for example, by chromatographic or crystallization processes. After separation of the diasteromers the chiral auxiliary compound is split-off and separated to re-obtain the desired compound as pure enantiomer. In an alternative concept, called kinetic racemic resolution, the initial racemic mixture is reacted with a chiral reactant or in the presence of a chiral catalyst (e.g., an enzyme) and only one of the two enantiomers of the desired product is transformed into a new compound. The reacted and non-reacted enantiomers are usually easily separated. All processes of racemic resolution have the common disadvantage that both enantiomers, the desired and the undesired one, have to be synthesized initially. Consequently, half of the initial racemic mixture is the undesired enantiomer, which usually has no or very little commercial value. This problem is partialy solved by applying racemization processes in which after separation the pure wrong enantiomer is re-converted into the racemic mixture. The latter is then applied in another round of racemic resolution again to increase the final yield of the desired enantiomer. 

Resolution of diastereomer mixtures by retro-aldolization under kinetic control for preparation of enantiomerically pure phenylserines, and racemate resolution process for a synthetic intermediate of an antiparkinsonism drug. 

Large volumes of organic solvents (often harmful to the environment) are used in the process. However, chemists are now using supercritical carbon dioxide as a solvent, which is much safer. At 31 °C and 73 atmospheres pressure, CO is a suitable non-polar solvent for many drug derivatives in the racemic resolution process. The solubility of the derivatives can be changed, simply by varying the density of the solvent. The solvent, which is... 

In a catalytic asymmetric reaction, a small amount of an enantio-merically pure catalyst, either an enzyme or a synthetic, soluble transition metal complex, is used to produce large quantities of an optically active compound from a precursor that may be chiral or achiral. In recent years, synthetic chemists have developed numerous catalytic asymmetric reaction processes that transform prochiral substrates into chiral products with impressive margins of enantio-selectivity, feats that were once the exclusive domain of enzymes.56 These developments have had an enormous impact on academic and industrial organic synthesis. In the pharmaceutical industry, where there is a great emphasis on the production of enantiomeri-cally pure compounds, effective catalytic asymmetric reactions are particularly valuable because one molecule of an enantiomerically pure catalyst can, in principle, direct the stereoselective formation of millions of chiral product molecules. Such reactions are thus highly productive and economical, and, when applicable, they make the wasteful practice of racemate resolution obsolete. 

Moreover, it is possible to open racemic azlactones by acyl bond cleavage to form protected amino acids in a dynamic kinetic resolution process. As azlactones suffer a fast racemization under the reaction conditions, eventually all starting material is converted [115]. 

Of course, kinetic resolution processes are not optimal. In order to obtain >50% molar yields, racemization and recycling loops are required which often have a negative impact on solvent and/or energy consumption, as well as on waste production. Obviously, better... 

The resolution process developed by Syntex is almost ideal (Pope Peachy resolution), with an efficient racemization and recycling of the unwanted (R) -enantiomer (yield >95% of (S)-naproxen from the racemate) and the chiral auxiliary (recovery >98%). 

After some early examples of bio-chemo combinations in the 1980s, there was then over a decade of silence , followed by clearly increasing interest from the mid-1990s in the field of dynamic kinetic resolution processes (i.e., chemocata-lyzed racemization combined with enantioselective enzymatic conversion, giving, in principle, 100% yield of an optically pure compound). 

Dynamic kinetic resolution (DKR) is an extension to the kinetic resolution process, in which an enantioselective catalyst is usually used in tandem with a chemoselective catalyst. The chemoselective catalyst is used to racemize the starting material of the kinetic resolution process whilst leaving the product unchanged. As a consequence, the enantioselective catalyst is constantly supplied with fresh fast-reacting enantiomer so that the process can be driven to theoretical yields of up to 100 %. There are special cases where the starting material spontaneously racemizes under the reaction conditions and so a second catalyst is not required. 

Dynamic kinetic resolution (DKR) is a process in which the resolution process is coupled with in situ racemization of unreacted substrate. This has been shown to be a potential and feasible method to produce 100 % theoretical yield. We have developed a chemo-enzymatic DKR to obtain higher desired yield for (5)-ibuprofen. The combined base catalyst with lipase has resulted in high conversion and excellent ee of the product. 

The procedure shows that it is feasible to combine racemization with the kinetic resolution process (hence the DKR) of R,S)- ethoxyethyl ibuprofen ester. The chemical synthesis of the ester can be applied to any esters, as it is a common procedure. The immobilized lipase preparation procedure can also be used with any enzymes or support of choice. However, the enzyme loading will need to be optimized first. The procedures for the enzymatic kinetic resolution and DKR will need to be adjusted accordingly with different esters. Through this method, the enantiopurity of (5)-ibuprofen was found to be 99.4 % and the conversion was 85 %. It was demonstrated through our work that the synthesis of (5)-ibuprofen via DKR is highly dependent on the suitability of the reaction medium between enzymatic kinetic resolution and the racemization process. This is because the compatibility between both processes is crucial for the success of the DKR. The choice of base catalyst will vary from one reaction to another, but the basic procedures used in this work can be applied. DKRs of other profens have been reported by Lin and Tsai and Chen et al. ... 

A racemic alcohol may be converted into a racemic acid by reaction with one molar equivalent of phthalic anhydride the product is a half ester of a dicarboxylic acid (see Section 7.9.1). This can now be subjected to the resolution process for acids and, in due course, the alcohols can be regenerated by hydrolysis of the ester. 

The power of the rhodium(I)-catalyzed Alder-ene reaction is shown by a highly enan-tioselective kinetic resolution process [35]. The key result stems from an observation that a racemic mixture of 48, when treated with [Rh(COD)Cl]2 and ( )-BINAP, af forded roc49 (2i ,3S and 2S,3R, and not 2R,iR and 2S,3S Eq. (16). 

In practice, any of these four approaches might be the most effective for a given synthesis. If they are judged on the basis of absolute efficiency in the use of chiral material, the ranking is resolution < natural source < chiral auxiliary < enantioselective catalyst. A resolution process inherently employs only half of the original racemic material. A starting material from a natural source can, in principle, be used with 100% efficiency, but it is consumed and cannot be reused. A chiral auxiliary can, in principle, be recovered and reused, but it must be used in stoichiometric amount. A chiral catalyst can, in principle, produce an unlimited amount of an enantiomerically pure material. 

When a kinetic resolution process is carried ont, and no racemization occurs, one can derive from the mass balances of R- and S-enantiomers that there is a relation... 

Step 2 nitrile reduction In this step the two processes are very similar both are Raney nickel-catalyzed nitrile reductions using hydrogen. The reason the enzymatic process has an approximately halved energy is that it is being carried out in the enantiopure form, whereas in the classical resolution process this reaction is performed with a racemic substrate. 

Scheme 33 Racemic resolution of ibuprofen with hydrolase (Sepracor Process).

Dynamic Resolution of Chirally Labile Racemic Compounds. In ordinary kinetic resolution processes, however, the maximum yield of one enantiomer is 50%, and the ee value is affected by the extent of conversion. On the other hand, racemic compounds with a chirally labile stereogenic center may, under certain conditions, be converted to one major stereoisomer, for which the chemical yield may be 100% and the ee independent of conversion. As shown in Scheme 62, asymmetric hydrogenation of 2-substituted 3-oxo carboxylic esters provides the opportunity to produce one stereoisomer among four possible isomers in a diastereoselective and enantioselective manner. To accomplish this ideal second-order stereoselective synthesis, three conditions must be satisfied (1) racemization of the ketonic substrates must be sufficiently fast with respect to hydrogenation, (2) stereochemical control by chiral metal catalysts must be efficient, and (3) the C(2) stereogenic center must clearly differentiate between the syn and anti transition states. Systematic study has revealed that the efficiency of the dynamic kinetic resolution in the BINAP-Ru(H)-catalyzed hydrogenation is markedly influenced by the structures of the substrates and the reaction conditions, including choice of solvents. 

Compounds synthesised in the laboratory without the use of chiral reagents (see asymmetric synthesis p. 15) are always obtained as the racemate. In order to separate the individual enantiomers, a resolution process needs to be adopted. This aspect is considered in more detail in Section 5.19. 

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