Resolution of optical isomers

J. Jaques, A. CoUet, and S. WiUen, Enantiomers, Racemate, and Resolutions,]o m Wiley Sons, Inc., New York, 1981 The Chemical Society of Japan, eds., Kikan Kagaku Sosetsu (No. 6, Resolution of Optical Isomers), Gakkai Shuppan Senta, Tokyo, Japan, 1989 G. C. Barrett ia Ref. 1, Chapt. 10, pp. 338—353 S. Otsuka and T. Mukaiyama, Progress of ylsymmetric Synthesis and Optical Resolution (ia Japanese), Kagaku Dojia, Kyoto, Japan, 1982. 

N. Oi ia Chemical Society of Japan, eds., Kagaku Sosetsu (No. 6, Resolution of Optical Isomers), Gakkai Shuppan Senta, Tokyo, Japan, 1989,... 

Fanali, S., Ossicini, L., Foret, F., and Bocek, R, Resolution of optical isomers by capillary zone electrophoresis study of enantiomeric and distereoisomeric cobalt (III) complexes with ethylenediamine and amino acid ligands, /. Microcol. Sep., 1, 190, 1989. 

The synthesis of optically active polyamides, or nylons, is a growing area of interest. From 1980 to 1991 there have been many citations in Chemical Abstracts on this subject. For example, optically active polyamides have been prepared for the resolution of optical isomers. The polyamides are prepared from optically active amines or dicarboxylic acids. One polyamide was prepared from (-)-(ram-l,2-diaminocyclohexane and terephthaloyl chloride and was used to resolve 2,2 -dihydroxy-6,6 -dimethylbiphenyl [31]. These optically active polyamides can be used in chromatography applications to resolve other optically active compositions. 

Geometrical (cis-trans) isomers of benz-omorphans result from the cyclization step in their synthesis when the bond to C-6 is formed (Scheme 2). When this is considered a transaddition to the double bond the preponderance of the cis or form is easily explained (10). Resolution of optical isomers from both cis and trans forms has been reported (7,19.20). The norpentazocine precursor in the cis form crystallized first as the (-) base with (+) tartaric acid which would give the twenty-fold more active (-) pentazocine. The (+) base (-) tartarate was recovered from resolution liquors. Quinic acid salts were formed for resolution of the trans isomers. 

W. Pirkle and J. Hauske, Broad spectrum methods for the resolution of optical isomers. A discussion of the reasons underlying the chromatographic separability of some diastereomeric carbamates, J. Organ. Chem., 42 1839-1844 (1977). 

K. Gunther, J. Martens, and M. Schickendanz, Resolution of optical isomers by thin-layer chromatography, enantiomeric purity of D-penicillamine, Arch. Pharm. (Weinheim), 579 461 (1986). 

W. H. Pirkle, D. W. House, and J. E. Finn, Broad spectrum resolution of optical isomers using chiral high-performance liquid chromatographic bonded phase, J. Chromatogr., 792 143 (1980). 

E. Gordis, Gas-chromatographic resolution of optical isomers in microgram samples of amphetamine, Biochem. Pharmacol., 15 2124(1966). 

K. Shimizu, T. Kakimoto, K. Ishi, Y. Fujimoto, H. Nishi, and N. Tsumagari, New derivatization reagent for the resolution of optical isomers in diltiazem hydrochloride by high-performance liquid chromatography, J. Chromotogr., 357 119 (1986). 

The OTCEC capillaries described in this chapter have been fabricated in a manner so that the major problems associated with packed capillaries are not present. The open tubular approach greatly reduces the likelihood of bubble formation so that pressurization of the system is not necessary. The other major problem, strong adsorption of basic compounds on the typical support material, is eliminated through the modification scheme, silanization/ hydrosilation, that removes silanols and replaces them with hydride groups. This type of separation medium also eliminates the need for any additives in the mobile phase to suppress adsorption of basic compounds, a technique that is often used in packed capillaries as the only means to elute such analytes. Therefore, the bulk of the applications developed to date have centered on the elution characteristics of compounds and separation of mixtures that are difficult to obtain in the packed capillary format. The major exception is the resolution of optical isomers that often can be done equally as well or often better with packed capillaries. The main objective of the chiral separations is to illustrate the presence of... 

The development of the catalytic hydrogenation system based on RhCl(PPh3)3 and methods for the resolution of optical isomers of tertiary phosphines occurred around the same time (1965), and this led to the possibility of asymmetric catalytic hydrogenation of prochiral unsaturated substances with C=C, C=0, and C=N bonds using transition metal complexes with chiral phosphine ligands. Such tertiary phosphines are of three types ... 

Bis (benzoylacetonato) diphenyltin (IV) is a white solid, which is soluble in benzene and toluene and only slightly soluble in petroleum ether. The infrared spectrum (KBr disk) has peaks centered at 1570,1550,1520, and 1374 cm.. The ultraviolet absorption spectrum (benzene) has a band centered at 308 mpi (e = 4.42 X 10 ). Attempts to effect resolution of optical isomers by a chromatographic technique (n-lactose) were unsuccessful, and it has been suggested that the phenyl groups are in trans positions. ... 

R.M. Secor, Resolution of optical isomers by crystallization procedures, Chem. Rev. 63 (1963) 297-309. 

L-Amino acids Aminoacylase (resolution of optical isomers) Japan 65 days n.a. 

A primary example is the resolution of optical isomers by continuous crystallization in fluid beds. Control of low supersaturation by control of the temperature difference between the continuous feed and the seed bed is critical to maintaining an essentially all-growth regime in which the individual isomers grow on their respective seeds in separate crystalfi-zers. The seed beds in both crystallizers are massive in relation to the amount of racemic solution passing through in order to present sufficient seed area to maintain low supersaturation. Uncrystallized isomers in the overhead streams are recycled to dissolve additional racemic feed. Crystal size is maintained by sonication. See Examples 7-6 and L1-6 for a discussion of resolution of optical isomers by continuous crystallization. 

Although widely practiced for production of industrial chemicals, continuous evaporation for crystallization is rarely if ever used in pharmaceutical operations. Although continuous operation has the advantages of using massive seeding and increased control of supersaturation and the crystal surface area, the throughput necessary for its application is rarely, if ever, achieved for final bulk drug substances. In addition, continuous operation to achieve the conditions for crystallization (as discussed above for resolution of optical isomers) is often not... 

Metastability and induction time can play an interesting role in the kinetic resolution of optical isomers, such as of resolution of ibuprofen lysinate (see Example 7.4). On the one hand in order to maintain the optical purity of the desired isomer, it is necessary to keep the (undesired) isomer in its supersaturated state for the entire crystallization period. If the undesired isomer crystallizes out from the solution, the optical purity of the desired isomer will decrease. On the other hand, it is important to release the supersaturation of the desired isomer, which starts at the same initial level of supersaturation as the undesirable isomer. These are two conflicting requirements. To overcome this dilemma, it is critical to maintain a large amount of seed bed of the desired isomer to accelerate the release of super-saturation of the desired isomer, whereas the undesired isomer remains supersaturated. As mentioned, a detailed description of the resolution process of optical isomers is given in Example 7-4. 

Nucleation must also be minimized by tight control of supersaturation in processes involving resolution of optical isomers. In some cases, nucleation must be avoided to prevent the formation of undesired polymorphs. 

Massive (the seed is the product in a continuous or semicontinuous operation), to provide maximum opportunity for aU growth. (See Examples 7-6 and 11-6 on resolution of optical isomers.)... 

The most effective seeding is achieved in semicontinuous and continuous crystallizations by the nature of the operations themselves, in which the seed is always present and in large quantity. Although common in large industrial operations, these techniques have found more limited application in the pharmaceutical industry. Exceptions to this are detailed in Examples 7-6 and 11-6, on the continuous resolution of optical isomers in fluid bed crystal-fizers, and in Example 10-1, which presents a semicontinuous method of utilizing seed heel recycle in reactive crystallization to achieve primarily growth. 

Both continuous and semicontinuous operation can be utilized. This principle has been successfully applied in the resolution of optical isomers in which nucleation must be minimized, and preferably eliminated, to achieve isomer separation, as described by Midler (1970, 1975, 1976) and presented in Examples 7-6 and 11-6 in this book. Tools for monitoring PSD online, as mentioned in Section 2.10.2, are very applicable here. 

Resolution of optical isomers via preferential crystallization is outlined in Example 7-6 as an example of the use of tightly controlled supersaturation in a cooling crystallization. This process is discussed in greater detail in Example 11-6. 

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