Chirality resolution screening

A Practical Workflow for Chiral Resolution Screening by Diastereomeric Sait Formation... 

To identify an optimal system for efficient chiral resolution, a comprehensive chiral resolution screening that includes different chiral resolving agents and different solvents can be typically performed according to the workflow illustrated in Figure 56.5. Based on the authors experience. 

FIGURE 56.5. Schematic diagram of workflow for chiral resolution screening hy diastereomeric salt formation. 

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. 

Introduction Since we had already developed the novel asymmetric addition of lithium acetylide to ketimine 5, we did not spend any time on investigating any chiral resolution methods for Efavirenz . Our previous method was applied to 41. In the presence of the lithium alkoxide of cinchona alkaloids, the reaction proceeded to afford the desired alcohol 45, as expected, but the enantiomeric excess of 45 was only in the range 50-60%. After screening various readily accessible chiral amino alcohols, it was found that a derivative of ephedrine, (1J ,2S) l-phenyl-2-(l-pyrrolidinyl)propan-l-ol (46), provided the best enantiomeric excess of 45 (as high as 98%) with an excellent yield (vide infra). Prior to the development of asymmetric addition in detail, we had to prepare two additional reagents, the chiral modifier 46 and cyclopropylacetylene (37). 

Kennedy et al. [57] have described the use of an intelligent chiral resolution system using a rapid screening of conditions on polysaccharide CSP, aiming to transfer the separation to preparative LC afterward. For the analytical part of the strategy, lO-pm particles were used for the preparative section, the particles had a 20-ttm diameter. The screening performs 11 experiments on analytical columns, which are displayed in Table 3.3. Chiralpak AD, Chiralcel OD, Chiralcel OJ, and Chiralpak AS are the considered stationary phases, and they are analyzed either in POSC or NPLC mode. The... 

A single CSP cannot be used for the chiral resolution of all racemic compounds. Therefore, different CSPs were used for the chiral resolution of different racemates. To make this part easy and clear, Table 1 includes the names of 20 CSPs and their most frequent applications. However, some other interesting applications are possible. Upon screening about 510 racemic compounds described in the literature, we observed that 229 of them resolved completely and 86 partially on cellulose tris(3,5-dimethylphenylcarbamate), and the rest not at all. For amylose tris(3,5-dimethylphenylcarbamate) CSP, we screened 384 racemic compounds and observed that 107 resolved completely and 102 partially. Clearly, cellulose and amylose tris(3,5-diphenylcarbamate) CSPs have the ability to resolve about 80% of the racemic compounds investigated. 

Finally, libraries aimed to chiral resolution of racemates will be covered here in particular, the use of chiral stationary phases (CSPs) has recently been reported for the identification of materials to be used for chiral separation of racemates by HPLC. The group of Frechet reported the selection of two macroporous poly methacrylate-supported 4-aryl-1,4-dihydropyrimidines (DHPs) as CSPs for the separation of amino acid, anti-inflammatory drugs, and DHP racemates from an 140-member discrete DHP library (214,215) as well as a deconvolutive approach for the identification of the best selector phase from a 36-member pool library of macroporous polymethacrylate-grafted amino acid anilides (216,217). Welch and co-workers (218,219) reported the selection of the best CSP for the separation of a racemic amino acid amide from a 50-member discrete dipeptide iV-3,5-dinitrobenzoyl amide hbrary and the follow-up, focused 71-member library (220). Wang and Li (221) reported the synthesis and the Circular Dichroism- (CD) based screening of a 16-member library of CSPs for the HPLC resolution of a leucine ester. Welch et al. recentiy reviewed the field of combinatorial libraries for the discovery of novel CSPs (222). Dyer et al. (223) reported an automated synthetic and screening procedure based on Differential Scanning Calorimetry (DSC) for the selection of chiral diastereomeric salts to resolve racemic mixtures by crystallization. Clark Still rejxrrted another example which is discussed in detail in Section 9.5.4. 

Initial results on the attempted resolution screen of racemic UK-350,926 with our in-house collection of chiral amines were not encouraging due to the propensity of the highly crystalhne racemic free acid to preferentially precipitate from solution. The only success in the initial screen was with the chiral amine brucine hydrate 19. Crystalhzation of a stoichiometric brucine salt from hot acetone gave the desired diastereoisomer in 92% recovery and 40% d.e (Scheme 10.5). 

Screening kits/sets containing samples of the normal commercially available enzymes are also provided by other enzyme suppliers, such as Boehringer Mannheim/Roche (Chirazyme sets for lipases/esterases, aldol reaction kits), Altus Biologies (ChiroScreen Kits TE and EH (based on CLECs, see section 5) for the chiral resolution of alcohols, amines, and esters), Biocatalysts (kits with alcohol dehydrogenases), Enzymatix (lipase biotransformation research kit), and others. 

Derivatization of channel walls has also been reported for the successful incorporation of biocatalytic surfaces in microreactors. Such a reactor has been used in the chiral resolution of a variety of substrates (Scheme 6.20). Such methodology may be used to screen substrates rapidly for enzymatic evaluation. In a manner comparable with chemical catalysts, the use of immobilized enzymes is a cost-effective method for their recycle and reuse. Other examples of continuous flow resolutions have been demonstrated... 

Zhang T, Nguyen D, Franco P. Enantiomer resolution screening strategy using multiple immobilised polysaccharide-based chiral stationary phases. J. Chromatogr. A 2008 1191 214-222. 

Tan H, Cui S, Gahm K, Luu V, Walker SD. Rational screening approach for classical chiral resolution under thermodynamic equilibrium a case study of diphenyl-substituted Af-methyl-piperazine. Org. Process Res. Dev. 2011 15 53-63. 

Method development remains the most challenging aspect of chiral chromatographic analysis, and the need for rapid method development is particularly acute in the pharmaceutical industry. To complicate matters, even structurally similar compounds may not be resolved under the same chromatographic conditions, or even on the same CSP. Rapid column equilibration in SFC speeds the column screening process, and automated systems accommodating multiple CSPs and modifiers now permit unattended method optimization in SFC [36]. Because more compounds are likely to be resolved with a single set of parameters in SFC than in LC, the analyst stands a greater chance of success on the first try in SFC [37]. The increased resolution obtained in SFC may also reduce the number of columns that must be evaluated to achieve the desired separation. 

The low-temperature method was then applied to the resolution of ( )-2-hydroxy-2-(pentafluorophenyl)acetonitrile (7) (Fig. which is usahle for the syntheses of a variety of ethane diols, amino alcohols containing CgFj groups as novel chiral ligands. After screening lipases such as Amano PS and AK, lipase LIP Pseudomonas aeruginosa lipase immobilized on Hyflo Super-Cel, Toyobo,... 

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