Acidic dmgs, separations

AGP columns have wide appHcation for the direct separation of enantiomers of many different classes of dmgs, amines, acids, and nonprotolytic compounds (18,23). Acidic dmgs resolved include ibuprofen [15687-27-17, C 2H g02, ketoprofen [22071 -15 ] and naproxen [22204-53-17,... 

The antihistamine dmg cetirizine, which is a piperazine derivative, is a racemic mixture, and has been used in the treatment of rhinitis and hay fever. It is available over the counter as the well-known ZYRTEC (McNeil-PPC, Inc). However the levo-rotatory R-enantiomer (10.29) was later found to be the more active form and is now on the market as the prescription dmg XYZAL (Sanofi-Aventis U.S. LLC). An approach for the synthesis of the enantiomers of cetirizine is expressed by Scheme 10.11, wherein chiralty in the dmg is introduced at an early stage in the synthesis. Thus, compound 10.28 was synthesized in racemic form then converted into diastereoisomeric salts with an optically active tartaric acid. To procure the (—)-enantiomer of 10.28, the resolution was performed with (-l-)-tartaric acid for the (-l-)-enantiomer, the resolution employed (—)-tartaric acid. After separation of the salts by crystallization, the 10.28 enantiomers were released by treatment with base and each then converted to optically active cetirizine enantiomers or related compounds by use of the general reaction suggested by Scheme 10.11 for the synthesis of the (R)-isomer of cetirizine. 

Because cationic amines are also required for the condensation of anionic nucleic acid dmgs, some polymer-based carriers separate the functions of condensation and endosomal dismption in moieties with high and low pK, respectively. For example, the PLL block in the ABC-type block copolymer, PEG-6-poly [(3-morpholinopropyl)aspartamide]-b-poly(L-lysine) (PEG-PMPA-PLL), condenses... 

The need for low levels of 3-isomer in 2-thiophenecarboxyhc acid [527-72-0] which is produced by oxidation of 2-acetylthiophene [88-15-3] and used in dmg appHcations, has been the driving force to find improved acylation catalysts. The most widely used oxidant is sodium hypochlorite, which produces a quantity of chloroform as by-product, a consequence that detracts from its simplicity. Separation of the phases and acidification of the aqueous phase precipitate the product which is filtered off. Alternative oxidants have included sodium nitrite in acid solution, which has some advantages, but, like the hypochlorite method, also involves very dilute solutions and low throughput volumes. 

An hplc assay was developed suitable for the analysis of enantiomers of ketoprofen (KT), a 2-arylpropionic acid nonsteroidal antiinflammatory dmg (NSAID), in plasma and urine (59). Following the addition of racemic fenprofen as internal standard (IS), plasma containing the KT enantiomers and IS was extracted by Hquid-Hquid extraction at an acidic pH. After evaporation of the organic layer, the dmg and IS were reconstituted in the mobile phase and injected onto the hplc column. The enantiomers were separated at ambient temperature on a commercially available 250 x 4.6 mm amylose carbamate-packed chiral column (chiral AD) with hexane—isopropyl alcohol—trifluoroacetic acid (80 19.9 0.1) as the mobile phase pumped at 1.0 mL/min. The enantiomers of KT were quantified by uv detection with the wavelength set at 254 nm. The assay allows direct quantitation of KT enantiomers in clinical studies in human plasma and urine after adrninistration of therapeutic doses. 

The first partial chiral resolution reported in CCC dates from 1982 [120]. The separation of the two enantiomers of norephedrine was partially achieved, in almost 4 days, using (/ ,/ )-di-5-nonyltartrate as a chiral selector in the organic stationary phase. In 1984, the complete resolution of d,l-isoleucine was described, with N-dodecyl-L-proline as a selector in a two-phase buffered n-butanol/water system containing a copper (II) salt, in approximately 2 days [121]. A few partial resolutions of amino acids and dmg enantiomers with proteic selectors were also published [122, 123]. 

Cyclosporine A itself and a number of other cyclosporines have been completely synthesized. Many stmctural analogs have also been synthesized, and a few patterns have been discovered in terms of their structure and activity. It is known that the activity of the dmg is determined by the entire cyclic stmcture, and not by its separate fragments. Likewise, it is also clear, that the structure of amino acids at position 1 is an important factor of... 

Applications. Various N-derivatives of amino acids (qv) are resolvable on BSA columns. These A/-amino acid derivatives include benzenesulfonyl-, phthalimido-, 5-dimethylamino-l-naphthalenesulfonyl- (DANSYL-), 2,4-dinitrophenyl- (DNP-), and 2,3,6-trinitrophenyl- (TNP-) derivatives (30). Amines such as Prilocain, (+)-2-(propylamino)-0-propiono-toluidide, a local anesthetic (Astra Pharm. Co.), are also resolved on BSA. The aromatic amino acids DL-tryptophan, 5-hydroxy-DL-tryptophan, DL-kynurenine [343-65-7], C10H12N2O3, and 3-hydroxy-m.-kynurenine [484-78-6], and dmgs such as warfarin, phenprocoumon, and benzodiazepine derivatives can be separated on BSA as well. 

The synthetic polymers based on N-acryloyl amino acid-derivatives developed by Blaschke in the 1970 and transferred to silica-bonded phases in the 1980 are especially useful for the separation of 5- and 6-membered N- and O-heterocycles with chiral centers (Review in Kinkel, 1994). Their wide chemical variety has been intensively exploited by Bayer Healthcare for their portfolio of chiral molecules. One example of this approach has been published in a joint work of Merck and Bayer (Schulte, 2002). This work explicitly shows how important it is to screen different intermediates in addition to the final dmg compound. Due to different selectivities and solubilities, the productivity for the preparative separation can be dramatically different. 

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