Crystallization chiral resolution

Some chiral ILs have been designed and synthesized. They have already been applied in different fields snch as asymmetric synthesis, stereoselective polymerization, chiral chromatography, liquid crystals, chiral resolution, and NMR shift reagents [20,106, 107]. Chiral solvents have been reported in asymmetric syntheses. In the BayUs-HUlman reaction of benzaldehyde and methyl acrylate in the presence of bases, chiral ILs demonstrate their ability in the transfer of chirality, even if the enantiomeric excesses (ee) are stiU moderate. The presence of an alcoholic functional group on the Af-alkyl-fV methylephedrinium is primordial and acts as a fixing point of the chiral IL on the reactants. It is assumed that the OH is connected... 

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. 

Amphetamine (1) is a very simple phenethylamine, described in the chemical literature as early as 1887 (Edeleano, 1887). Smith, Kline and French (now GSK) filed a patent on the synthesis and use of amphetamine in 1930 (Nabenhauer, 1930), and the enantiomers were assigned in 1932 (Leithe, 1932 V-Braun and Friehmelt, 1933). Not surprisingly, early access to chiral material relied on classical crystallization-based resolutions (Gillingham, 1962 Nabenhaur, 1942). The early, racemic syntheses of amphetamine fall into four major classifications according to the method used to make the C-N bond ... 

Abstract It is well known that spontaneous deracemization or spontaneous chiral resolution occasionally occurs when racemic molecules are crystallized. However, it is not easy to believe such phenomenon will occur when forming liquid crystal phases. Spontaneous chiral domain formation is introduced, when molecules form particular liquid crystal phases. Such molecules possess no chiral carbon but may have axial chirality. However, the potential barrier between two chiral states is low enough to allow mutual transformation even at room temperature. Therefore the systems are essentially not racemic but nonchiral or achiral. First, enhanced chirality by doping chiral nematic liquid crystals with nonchiral molecules is described. Emphasis is made on ester molecules for their anomalous behavior. Second, spontaneous chiral resolution is discussed. Three examples with rod-, bent-, and diskshaped molecules are shown to give such phenomena. Particular attention will be paid to controlling enantiomeric excess (ee). Actually, almost 100% ee was obtained by applying some external chiral stimuli. This is very noteworthy in the sense that we can create chiral molecules (chiral field) without using any chiral species. 

As described in the Introduction, Pasteur showed beautifully that racemic molecules resolve spontaneously into chiral forms when they crystallize. We call them conglomerates, in which molecules form condensates comprised of only one enantiomer. The condensation into conglomerates can now be observed not only in crystals but in monolayers, fibers, and supramolecules self-assembled in solution [35]. The researches became possible because of the development of microscopic observation techniques at the nanometer scale. However, in crystals we still do not know what kinds of molecules show spontaneous resolution. Hence, observation of chiral resolution in soft matter may provide important information on the general question. 

A group at Industrial Research Limited in New Zealand recently reported the results of a study to determine if a cross-linked enzyme crystal-catalyzed resolution can compete with alternative chiral technologies in the pharmaceutical and chemical process industries. The group used the enantioselective hydrolysis of a-phenylethyl acetate catalyzed by ChiroCLEC -PC as a model system (Fig. 13). Based on their results with 270 kg of racemate, they evaluated the economics of mnning the process at the 600-kg batch scale and concluded that this process is economically feasible [38],... 

AM Collins, C Maslin, RJ Davies. Scale-up of a chiral resolution using cross-linked enzyme crystals. Org Process Res Dev 2 400-406, 1998. 

R,R)-TA crystallizes in different enantiomorphous superstructures on Cu( 110), but at a coverage of 0.25 molecules per substrate atom, the monotartrate species forms an achiral c(4 x 2) or (4 0,2 1) structure [71]. In contrast to the bitartrate in its sawhorse geometry, only a single molecular site is connected to the substrate and chirality is not transferred into the lattice structure. Under these conditions, chiral resolution cannot be expected (see below) [72],... 

Optically active diols have been used for several asymmetric syntheses [67] and chiral resolutions [68]. In 1990, Kawashima and co-workers [69] reported the first example of direct optical resolution of racemic 2,2 -dihydroxy-l,l -binaphthyl (34) with (R,R)-29. In this procedure equimolar amounts of racemic 34 and (R,R)-29 were added in benzene and the mixture was heated to a homogeneous solution and then cooled to room temperature. After crystallization of the precipitate and treatment with hydrochloric acid, (R)-(+)-34 was obtained with an optical purity of 94% and in a yield of 86% based on the amount of enantiomer presents in the racemate (Scheme 23). 

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],... 

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. 

Collins, A. M. Maslin, C. Davies, R. J., Scale-Up of a Chiral Resolution Using Cross-Linked Enzyme Crystals Org. Process Res. Dev 1998, 2, 400. 

As with ephedrine, chiral resolution can be achieved for 2,2 -ninaphthy 1-1,1 -diamine (DABN) (29) through diastereomer crystallization. Equal molar quantities (0.19mmol) of (i )-DABN, (5)-DABN, and (R)-camphorsulfonic acid (CSA) were first dissolved in methanol (40 mL). The resulting solution was pumped at low flow rates together with CO2 (10 mL/... 

BCSA The synthesis of enantiomerically pure oxazinone 1 used an efficient crystallization-induced resolution process however, the only chiral acid that could be used in this protocol was BCSA. Numerous attempts to find an alternative acid for the crystallization driven resolution were unsuccessful. As mentioned early, the recycling of BCSA was imperative. However, even with the recycle, enantiomerically pure BCSA... 

The product will have one enantiomer In excess [say, (AR) > (AS)]. When this product Is recrystalllzed from solution there are several pathways open to It the two enantiomers may crystallize In separate, chiral crystals (spontaneous resolution). These crystals cannot be of stack structures because of the bulkiness of the substituents nor can they be of pair structures, since In any one crystal all the molecules are homochlral, so that the symmetry elements of the crystal cannot Include a center of Inversion. The crystal structure must be such that adjacent parallel molecules are poorly overlapped (the stack axis sharply tilted with respect to the mean molecular plane). Crystals of this so-called Y typs structure are known to show monomer emission and. In general, to be nonphotodlmerlzlng. 

One interesting technology uses lipases in the form of cross-linked enzyme crystals (CLECs) (Margolin 1996). This immobilization method does not use any solid support and the lipase specific activity (units of activity/g of immobilized catalyst) of the immobilized lipase derivative can be enhanced by 10-fold because there is no inert support, that usually represent more than 90% of the catalyst weight in the case of carrier-bound enzymes. These cross-linked crystals have been used for the chiral resolution of commercially important organic compounds, such as ibuprofen. 

In conclusion, S-LMHA SAMs were used to stabilize the conglomerate form of DL-glutamic acid crystals. The results offer a powerful tool in the development of processes for controlling chiral polymorphic systems and can further develop into a novel method for chiral resolution by crystallization. 

We found that the kinetic resolution of racemic piperidines alkylated at the 2- or 3-p>osition was performed using the provisional enantiomeric conformation of naphthamide 3a derived from chiral crystals. ) Chiral crystals of naphthamide 3a were added to a THF solution of racemic lithium amides prep>ared by the reaction of substituted piperidines with w-BuLi at -80°C the reaction mixture was stirred for 5 hours at -20°C because the substitution reaction did not proceed below -20°C. 

C Racemic mixture Resolution - Crysullization (spontaneous resolution) - Chiral chromatography Crystallization (spontaneous resolution) coupled with an in situ fast racemization - Separation via diasteieomers - Kinetic resolution with or without creation of new chiral units - Asymmetric Transformation - Deracemization... 

Usually, atropisomers can be separated by chiral resolution methods (e.g., selective crystallization), selectively synthesized employing atropo-enantioselective or atropselective synthesis (e.g., in the presence of a chiral catalyst or by use of chiral auxiliaries), or obtained by the q)proaches based on thermodynamic equdibration when an isomerization reaction favors one atropisomer over the other. 

Several methods are known for the chiral resolution of racemates that are based on physical, chemical, or biological techniques, and they fall broadly into the following main classes crystallization methods (crystallization... 

Probably the most popular and the most preferred method for the resolution of organic acids or bases is a chiral resolution via diastereomeric salt formation. Ionic salts are easily formed and easily crystallized, and after the separation process, an enantiomerically pure separated compound may be easily isolated, and the resolving agent can be recovered and reused (Figure 1.37). Resolution via diastereomeric salt formation involves the acid-base reaction of a racemate with an enantiomerically pure resolving agent. The resulting two diastereomers have different physical properties e.g., the difference in solubility is used to separate them by crystallization. 

Among aU the possible areas discussed previously, the focus of this chapter will be on the two mainstream crystallization processes chiral separation through diastereomeric salts formation and chiral purification by crystallization. To complete the topic, chiral resolution by preference crystallization will also be reviewed and recent development in this area will be highlighted. 

Recentiy, an irmovative chiral resolution using enantio-specific co-crystallization from solution was reported by Springuel and Leyssens." In this new chiral resolution... 

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