Cinchonidine resolution

Thus, racemic acid 12 (R = H) was obtained by [3+2] cycloaddition in 90-95% yield (Scheme 5.9) [28]. Its resolution into enantiomers could be achieved either by chiral preparative HPLC, or by fractional crystallization of its cinchonidine salts. Better results were obtained upon enzymatic kinetic resolution of its iso-butyl ester 12 (R = i-Bu) [29]. However, further work showed that racemic thiolester 13, which... 

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). 

R)-1,1 -Bi-2-naphthol was prepared by resolution employing the N-benzylammonium chloride salt of (-)-cinchonidine to form separable diastereomeric clathrate complexes. Hu, Q-S. Vitharama, D. Pu, L. Tetrahedron Asymmetry 1995, 6, 2123. 

For racemic resolution of naproxen the use of cinchonidine, A/-alkyl-D-glucamine, dehydroabietylamine or (S)-a-phenylethylamine has been described. 

The cinchonidine-catalyzed addition of 4-tert-butylthiophenol reported by Wynberg and Hiemstra has also been used for kinetic resolution of racemic 5-methyl -2-cyclohexen-l-one At an enone/thiophenol ratio of 2 1, the remaining enone had an optical purity of 36% [54], A similar procedure was employed by Asaoka et al. for kinetic resolution of 5-trimethylsilyl-2-cyclohexen-l-one, affording 50% of the trans adduct (57% ee, enantiomerically pure after recrystallization) with 41% of the starting enone (59% ee) [55a]. 

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... 

Three chiral stationary phases that were prepared by derivatizing y-mercaptopropylsilanized silica gel with quinine (CSP II), quinidine (CSP III), and cinchonidine (CSP IV), have been used for the successful resolution of N-acyl derivatives of fl-hydroxyphenethylamines [25]. UV and CD detectors set at 270 nm were used in series. The effectiveness of the separation and the detection are illustrated in Figure 6 for the resolution of the N-(3,5-dinitrobenzoyl) derivative of phenylethanolamine on CSP III. 

Diastereoselective 1,4-addition of cuprates to enones. 5-Trimethylcyclohex-enone (1) has been resolved by kinetic resolution via the adduct with p-toluenethiol by cinchonidine. It undergoes highly diastereoselective addition with cuprates in the presence of ClSi(CH3)3 and HMPT to furnish only the trans-1,4-adducts in 88-95% yield. ... 

This approach was also successfully applied to the kinetic resolution of 5-/crf-butyl-2-cyclo-hexenonel3. Thus, cinchonidine catalyzed addition of thiophenol to racemic enone 15 in benzene affords the mms-addition product tram-16 contaminated with small amounts of the r/y-adduct and unreacted, partially resolved cyclohexenone. The latter has 20% ee and 29% when the thiol/enone ratio is 0.5 and 0.4, respectively. 

As mentioned above, one of the limitations of using naturally occurring resolving agents is that only one enantiomer of the compound being resolved may be readily accessible by resolution. However, many examples have been described where brucine and some other alkaloid favor crystallization with opposite enantiomers of a given acid. For example, resolution of acid (6) with brucine yields the (+)-enantiomer, while cinchonidine provides material that is enriched in the (—)-enantiomerof the acid. Similarly, diacid (7) is resolved into its (—)-enantiomer by brucine and into its (+)-enantiomer by strychnine. The (+)-enantiomer of acid (8) can be obtained with brucine, while the (—)-enantiomer crystallizes with cinchonidine. Additional examples of the same phenomenon can be found in the literature. ... 

Perhaps, one of the most important industrial processes using cinchonidine (or quinidine) as the resolving agent was the production of (S)-naproxen (3) by resolution of racemic naproxen. It is not clear whether it is still in use (Figure 13.4) [12],... 

The X-ray-determined structure of the complex of 16 and 19 with quaternary salt 15 revealed that the primary discriminative forces leading to an efficient resolution are the formation of directional hydrogen bonds of hydroxy groups of cinchonidine and BINOL with the halide anion as well as aryl-aryl interaction between the naphthyl and the quinoline rings [40]. 

Naproxen was introduced to the market by Syntex in 1976 as a nonsteroidal antiinflammatory drug in an optically pure form. The original manufacturing process (Scheme 1) before product launch started from P-naphthol (1) which was brominated in methylene chloride to produce 1,6-dibromonaphthol (2). The labile bromine at the 1-position was removed with bisulfite to give 2-bromo-6-hydroxy-naphthalene that was then methylated with methyl chloride in water-isopropanol to obtain 2-bromo-6-methoxynaphthalene (3) in 85-90% yield from p-naphthol. The bromo compound was treated with magnesium followed by zinc chloride. The resultant naphthylzinc was coupled with ethyl bromopropionate to give naproxen ethyl ester that was hydrolyzed to afford the racemic acid 4. The final optically active naproxen (5) was obtained by a classic resolution process. The racemic acid 4 was treated with cinchonidine to fonn diastereomeric salts. The S -naproxen-cinchonidine salt was crystallized and then released with acid to give S -naproxen (5) in 95% of the theoretical yield (48% chemical yield) [8,9]. 

Shortly after the product launch, the original process was modified (Scheme 2). Zinc chloride was removed from the coupling reaction, and ethyl bromopropionate was replaced with bromopropionic acid magnesium chloride salt. Most importantly, the resolution agent cinchonidine was replaced with A -alkylglucam-ine, which can be readily obtained from the reductive amination of o-glucose. 

Simple alcohols with only one hydroxy function and one asymmetric carbon atom are classical chiral chemicals. While they are often commercially available, they are relatively expensive. Until recently, they were obtained mainly by resolution of the racemates using a reliable but not very convenient technique. Reaction of the racemic alcohol with phthalic acid anhydride gave the monoester of phthalic acid, which was resolved by salt formation with a chiral base, usually brucine, or occasionally also strychnine or cinchonidine. The methyl carbinols from 2-butanol 1 to 2-tridecanol were first obtained by this method1,2 and this was later extended to 3,3-dimethyl-2-butanol3. When crystallization of the diastereomeric salts was performed in the presence of triethylamine, some other methyl carbinols could also be resolved, such as... 

For the alkylation of enolates, chromium tricarbonyl complexes of aromatic compounds (benchrotrenes) are useful, as they make simple aromatic compounds chiral. Thus, enantiomer-ically pure (indanone)tricarbonylchromium (2R)-25 has been prepared by resolution of the racemic benchrotrene derivative with cinchonidine and oxidation of the alcohol to the ketone with manganese dioxide60. The chiral ketone is alkylated diastereoselectively via the enolate, leading to the f.vo-2-methyl derivative (2/ )-25 which has been used in enolate alkylations and annulation reactions (Section D.1.5.2.4.). If necessary, complete isomerization to the endo-methyl compound can be achieved by treatment with base. 

Acetyl-6-methoxy-naphthalene may be prepared by the acylation of 6-methoxynaphthalene. The resulting product is then subjected to a series of reactions, namely Wilgerodt-Kindler reaction, esterification, alkylation and hydrolysis ultimately yields /)Z-Naproxen. Resolution of the resulting racemic mixture is caused through precipitation of the more potent /)-enantiomer as the cinchonidine salt. 

The resolution of BNP acid by crystallizing the (+)-acid-cinchonine salt, then the (-)-acid-cinchonidine salt, was first mentioned in a short paper and subsequently described in a patent. ... 

Naproxen is prepared (13) by the acylation of 6 substituted naphthalenes by AcCI forming the 2-acetyl derivative, which is further converted to 2-naphthyl acetic acid. Esterification and alkylation of 2-naphthyl acetic acid in the prescence of H2SO4, MeOH, NaH, Mel and with NaOH gave after hydrolysis the naphthyl propionic acid. Resolution of 2-(6-methoxy-2-naphthyl) propionic (Naproxen) was readily achieved by crystallization of the cinchonidine salt. 

In the early years of penem and carbapenem research, the easy preparation and commercial availability of azetidinone 10 prompted the devisal of several protocols for its conversion into an optically active equivalent (Scheme 1, F). Thus, acetate displacement with thioglycolic acid and resolution with d-( +)-ephedrine gave the 4/ -carboxymethylthio derivative 94, in turn elaborated to 95a [44], the 4R-enantiomer of the key intermediate of Woodward s first synthesis of racemic 6a-hydroxyethylpenems [45]. In another approach, analog 95b was obtained by diastereomer separation after displacement of 4-acetoxy-azetidinone with a chiral mercapto-alcohol [46]. Along a still different approach [43], optically active 93b was obtained from racemic 10 and thiophenol via asymmetric induction from the reaction medium (cinchonidine-containing benzene). 

For achiral molecules that, when coupling with a chiral molecule (mostly alkaloids, such as brucine, cinchonidine, and sparteine), form a pair of diastereomers with different physical properties that can be separated by the methods of fractional crystallization, column chromatography, etc., resulting in the enantiomeric resolution. No actual mechanism is necessary for this reaction. 

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