1- ethylamine resolution

Acetophenone similarly gives an oxime, CHjCCgHjlCtNOH, of m.p. 59° owing to its lower m.p. and its greater solubility in most liquids, it is not as suitable as the phenylhydrazone for characterising the ketone. Its chief use is for the preparation of 1-phenyl-ethylamine, CHjCCgHslCHNHj, which can be readily obtained by the reduction of the oxime or by the Leuckart reaction (p. 223), and which can then be resolved by d-tartaric acid and /-malic acid into optically active forms. The optically active amine is frequently used in turn for the resolution of racemic acids. 

S(-)-x-(l-Naphthyl)ethylamine has been prepared by resolution of the racemic amine with camphoric acid in unspecified yield.2,3... 

Resolution, of ketones with a-phenyl-ethylamine bisulfite complex, 49, 97... 

Optica] resolution of these and related carboxylic acids were achieved using salt formation with alkaloids (strychnine, brucine, cinchonidine) 33,39,44 or with optically active amines [1-phenyl- or l-( 3-naphthyl)ethylamine]4o,44). The following rotations [a]D have been reported [8]paracyclophanecarboxylic acid (13) +18° (chloroform)441 [10]homologue (14) +80° (chloroform)39 and +67° (chloroform)40 its methyl-derivative (75) —28° (methanol)44 . Dioxa[10]paracyclophanecarboxylic acid (16) + 104° (ethanol)36 and bromo-dioxa[12]paracyclophanecarboxylic acid (79) —37° (acetone)33). 

Abou-Basha and Aboul-Enein [22] presented an isocratic and simple HPLC method for the direct resolution of the clenbuterol enantiomers. The method involved the use of a urea-type CSP made of hS )-indoline-2-carboxylic acid and (R)-1 -(naphthyl) ethylamine known as the Chirex 3022 column. The separation factor (a) obtained was 1.27 and the resolution factor (Rs) was 4.2 when using a mobile phase composed of hexane-1,2-dichloroethane-ethanol (80 10 10, v/v/v). The (+)-enantiomer eluted first with a capacity factor (k) of 2.67 followed by a (—)-enantiomer with a k of 3.38. Biesel et al. [23] resolved 1-benzylcyclohexane-1,2-diamine hydrochloride on a Chirex D-penicillamine column. Gasparrini et al. [24] synthesized a series of the chiral selectors based on /ra s -1,2 - d i a m i n o eye I o hexane. The developed CSPs were used for the chiral resolution of arylacetic acids, alcohols, sulfoxides, selenoxides, phosphinates, tertiary phosphine oxides, and benzodiazepines. In another study, the same authors [25] described the chiral resolution of /i-aminocstcrs enantiomers on synthetic CSPs based on a re-acidic derivatives of trans- 1,2-diaminocyclohexane... 

For example, in the optical resolution of diltiazem, a benzothiazepin derivative, with optically active mandelic acid, one of the diastereomeric salts with the same stereochemical sign (+) (+) or (-) (-) is crystallized from ethyl acetate whereas another with the opposite stereochemical sign (+) ( ) or (-) (+) is obtained from a mixed solvent of ethyl acetate and benzene (1 1).21 In the resolution of 1-phenyl-2-(p-tolyl)ethylamine with the same chiral acid, the same sign salt crystallizes from 50 % aqueous methanol and the opposite one from 2-propanol.22... 

Nohira, H., Kai, M., Nohira, M., Nishikawa, J., Hoshiko, T. and Saigo, K. (1981) Optical resolution of a-methylbenzylamine and l-phenyl-2-(/ -tolyl)ethylamine by preferential crystallization, Chem. Lett., 1981, 951-952. 

Sakai, K., Yoshida, S., Hashimoto, Y., Kinbara, K., Saigo, K. and Nohira, H. (1998) Reciprocal resolution of l-(4-methylphenyl)ethylamine and 2-hydroxy-4-phenylbutyric acid, and habit modification of a less-soluble diastereomeric salt with a chiral additive, Enantiomer 3, 23-35. 

Nohira H., Murata, H., Asakura, I., and Terunuma, D. (1984) Optical resolution of l-phenyl-2-)p-tolyl)ethylamine, Jpn. Kokai Tokkyo Koho JP59-110656 Chem. Abstr. 102 5896 (1984). 

Production of enantiomerically pure a-arylpropanoic acids, also known as profens, is of critical importance to the pharmaceutical industry because they constitute a major class of antiinflammatory agents. One of the most practical approaches to preparing optically pure a-arylpropanoic acids is by resolution with chiral amines. Notable examples include brucine, quinidine, cinchonidine, morphine, ephedrine, and a-(l-naphthyl)ethylamine. For instance, (.Sj-a-methylbenzylaminc and... 

Resolution of Carboxylic Acids. The enantiomers of 1-(1-naphthyl)ethylamine are used to resolve racemic carboxylic acids by selective crystallization of diastereomeric salts. For example, crystallization of racemic 3-bromobutyric acid with (R)-(+)-NEA followed by acidification of the diastereomeric salt afforded (S)-(+)-3-bromobutyric acid (eq 1). In the same manner, resolution with (5)-(-)-NEA yielded (R)-(-)-3-bromobutyric acid after liberation of the amine (eq 1). ... 

Chromatographic Resolutions. 1-(1-Naphthyl)ethylamine serves as a chiral derivatization agent useful in preparing diastereomeric amides from racemic acids for chromatographic resolution. For example, various terpenoid acids, after conversion to the diastereomeric amides using (R)-(+)-NEA, were analyzed by HPLC to define the enantiomeric composition (eq 4). Application of the procedure has been used to analyze the enantiomeric purity of several carboxylic acid derivatives. ... 

Platinum complexes incorporating an optically active amine have been employed for resolution of racemic mixtures of optically active olefins by reaction of the olefin with dichloro-platinum(II). The differing solubility of the diastereoisomers permits separation by fractional crystallization and the olefin can be recovered by reaction of the complex with aqueous alkali cyanide. Using either (-f)-l-phenyl-2-aminopropane (Dexedrine) or (-f)- or (—)-a-phenyl-ethylamine. Cope and co-workers have resolved the optical isomers of trans double bond coordinated and, with (—)-phenylethyl-amine)dichloroplatinum(II), a bridged complex with each double bond coordinated to a different platinum atom. 

Planar chiral compounds should also be accessible from the chiral pool. An example (with limited stereoselectivity) of such an approach is the formation of a ferrocene derivative from a -pinene-derived cyclopentadiene (see Sect. 4.3.1.3 [81]). A Cj-symmetric binuclear compound (although not strictly from the chiral pool, but obtained by resolution) has also been mentioned [86]. Another possibility should be to use the central chiral tertiary amines derived from menthone or pinene (see Sect. 4.3.1.3 [75, 76]) as starting materials for the lithiation reaction. In these compounds, the methyl group at the chiral carbon of iV,iV-dimethyl-l-ferrocenyl-ethylamine is replaced by bulky terpene moieties, e.g., the menthane system (Fig. 4-2 le). It was expected that the increase in steric bulk would also increase the enantioselectivity over the 96 4 ratio, as indicated by the results with the isopropyl substituent [118]. However, the opposite was observed almost all selectivity was lost, and lithiation also occurred in the position 3 and in the other ring [134]. Obviously, there exists a limit in bulkiness, where blocking of the 2-position prevents the chelate stabilization of the lithium by the lone pair of the nitrogen. 

Amidation. Resolution by selective acetylation of l-(heteroaryl)ethylamines is successful. Lipases have also been used to catalyze aminolysis of a-oxygenated esters. 

First, the solvent effect in the enantioseparation of racemic l-(4-methylpheny-l)ethylamine with (R)-2-hydroxy-4-phenylbutyric acid was examined. The system using 2-butanone, 2-propanol, or water as a solvent was found to give higher total resolution efficiency, whereas their mixed solvents resulted in lower total resolution efficiency (Table 5.12). For industrial-scale production, the use of a single solvent is better, and water is the best solvent for both economic and environmental reasons. Therefore, water was selected as a solvent, although 2-butanone gave the best total resolution efficiency... 

In the next stage, the enantioseparation of racemic 2-hydroxy-4-phenylbutyric acid with (T)-l-(4-methylphenyl)ethylamine was tried several solvents (dioxane, 4-methyl-2-pentanone, and water) were tried and a relatively higher resolution efficiency was observed with water which is economically and environmentally favorable. The addition of NaOH was also effective, and the highest resolution efficiency (0.76, 78% yield, 98% enantiomeric excess) was achieved when the molar ratio of the basic resolving agent/NaOH was 1/1 for racemate/water = 1/2.8. 

An alternative approach17 is to attach a chiral auxiliary, (phenyl ethylamine, available by resolution, chapter 22, and used repeatedly in chapters 22-28, to the anhydride 100 in the form of a chiral imide 108. This auxiliary is very close to the two carbonyl groups of the anhydride in 108 and directs the achiral Grignard reagent 109 to one of them to give adduct 110 immediately reduced and hydrolysed to the lactone 106. One recrystallisation gives 106 in >98% ee. This time a Horner-Wadsworth-Emmons reaction (chapter 15) adds the side chain as a conjugated unsaturated acid reduced to the saturated side chain in 111, a common intermediate in most syntheses of ifetroban. The formation of the oxazole and the rest of the synthesis is described by R. N. Misra and the Bristol-Meyers Squibb team.16... 

The lipase catalyzes the kinetic resolution of racemic amines, e.g. 1-phenyl-ethylamine (Fig. 19-21)[11. Products are intermediates for pharmaceuticals and pesticides. They can also be used as chiral synthons in asymmetric synthesis. As acylating agent ethylmethoxyacetate is used, because the reaction rate is more than 100 times faster than that with butyl acetate. Probably an enhanced carbonyl activity induced by the electronegative a-substituents accounts for the activating effect of the methoxy group. The lipase is immobilized on polyacrylate. The lowered activity caused by use of in organic solvent (tert-methylbutylether = MTBE) can be increased... 

A very large amount of NMR spectroscopic data has been collected during the year under review. The presentation of data in addition to data is now almost routine. NMR spectroscopic studies have now been presented for phosphonocarboxylic acids and their esters,some new phosphinic amides, and for Lawesson s reagent (solid and solution data). A spectroscopic study of the dimer of the nitrile oxide (401) suggested the structure (402). 1-(1-Naphthalenyl)ethylamine and ephedrine are recommended for the NMR spectroscopic determination of the enantiomeric composition of (1-aminoalkyl)-phosphonates, but of quinine and rert-butylphenylphosphinothioic acid, only the former was effective for the chiral resolution of the diethyl esters in the determination of e.e.s of (2-hydroxyalkyl)phosphonates. Conformational analyses, based on NMR spectroscopic data, have been carried out for dialkyl (2-hydroxyalkyl)phosphonates. ... 

The theory and experiment of direct crystallization of enantiomers is quite well understood at present [10]. There are a number of variables which affect the resolution by direct crystallization in practice. Several technological schemes based on this principle are realized on the commercial scale. These are, for example, the Merck process used for the production of antihypertensive drug methyldopa [11], a process developed by Harman and Reimer for (-)-menthol, which is separated as an ester [12], the process patented by Industria Chimica Profarmaco for the resolution of naproxen enantiomers as the ethylamine salt [13], the production of L-glutamic acid by the Japanese company Ajinomoto on a scale in excess of 10000 tons annually as early as the 1960s [14], etc. In general, it seems that spontaneous crystallization is a very useful technique for the enantioseparation of the naturally occurring a-amino acids. All of them may be resolved either directly or as derivatives [10]. 

Resolution of amines. The preparation of this acid and its use for resolution of a variety of amines were first disclosed in a patent. One advantage of this reagent is that it is water-insoluble and thus can be recovered in 91-947o vWd-An example of its use is the resolution of -(l-naphthyl)ethylamine to obtain the S-(—) isomer in 85-90% yield. ... 

Kinetic resolution of secondary allylic alcohols by Sharpless asymmetric epoxidation using fert-butylhydroperoxide in the presence of a chiral titanium-tartrate catalyst has been widely used in the synthesis of chiral natural products. As an extension of this synthetic procedure, the kinetic resolution of a-(2-furfuryl)alkylamides with a modified Sharpless reagent has been used . Thus treatment of racemic A-p-toluenesulphonyl-a-(2-furfuryl)ethylamine [( )-74] with fert-butylhydroperoxide, titanium isopropoxide [Ti(OPr-/)4], calcium hydride (CaHa), silica gel and L-(+)-diisopropyl tartrate [l-(+)-DIPT] gave (S)-Al-p-toluenesulphonyl-a-(2-furfuryl)ethylamine [(S)-74] in high chemical yield and enantiomeric excess . Similarly prepared were the (S)-Al-p-toluenesulphonyl-a-(2-furfuryl)-n-propylamine and other homologues of (S)-74 using l-(+)-D1PT. When D-(—)-DIPT was used, the enantiomers were formed . ... 

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