Salts cinchonidine

A solution of p-nitro-N-phthaloyl-DL-phenylalanine (1.0 g) in methanol (25 ml) and a solution of cinchonidine (0.865 g) in methanol (30 ml) were mixed. Crystallization soon set in. The mixture was left overnight, and the colorless needles (0,97 g), MP 209° to 210°C, collected. After two recrystallizations from methanol the cinchonidine salt of the D-acid had MP 211°C,... 

MP 191° to 192,5°C, Two recrystallizations from aqueous ethanol gave the cinchonidine salt of the L-acid, MP 192,5° to 194°C. To the salt (2.9 g) in warm ethanol (50 ml) was added water (50 ml) and a slight excess (ca 10 ml) of N aqueous sodium hydroxide. The mixture was diluted with water, cooled, filtered from the precipitated base and the filtrate acidified with hydrochloric acid. Refluxing with 2 N ethanolic hydrogen chloride yielded p-nitro-N-phthaloyl-L-phenylalanine ethyl ester, according to U.S. Patent 3,032,585. 

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... 

The absolute configurations at C-8-C-9 of the alkaloids govern the absolute configurations of the products that is, when a quinine or cinchonidine salt (both salts have SS,9R configurations) is used, the epoxide produced... 

The replacement of the oxygen atom in sulfoxides by nitrogen leads to a new class of chiral sulfur compounds, namely, sulfimides, which recently have attracted considerable attention in connection with the stereochemistry of sulfoxide-sulfimide-sulfoximide conversion reactions and with the steric course of nucleophilic substitution at sulfur. The first examples of chiral sulfimides, 88 and 89, were prepared and resolved into enantiomers by Phillips (127,128) by means of the brucine and cinchonidine salts as early as 1927. In the same way, Kresze and Wustrow (129) were able to separate the enantiomers of other structurally related sulfimides. 

A chiral quartemary ammonium salt works as a chiral-phase transfer catalyst, and this chemistry has been applied to asymmetric Michael reaction by Corey et al. (Scheme 8D.16) [33]. It has been shown that the cinchonidine salt 28, which has been designed by rigidifying... 

The filtered precipitate was partially dried for several hours under vacuum, and reprecipitated twice from boiling methanolic solution by means of four volumes of ethyl acetate (analytical grade), to yield overnight a pure, white product (about 12 g., together with 2-3 g. of an impure Becond crop). A weighed sample (20-25 mg.) was boiled with 100 ml. of 2 N hydrochloric acid for 2.5 hr. (to complete hydrolysis), neutralized with alkali, made up to standard volume, and the phenolphthalein estimated colorimetrically (theoretical content, 38.8% for the cinchonidine salt of the monoglucuronide). ... 

The cinchonidine salt (1.58 g.) of the glucuronide was suspended in 64 ml. of water and 40 ml. of ethyl acetate (analytical grade), and 2.4 ml. of concentrated hydrochloric acid (or 11 N sulfuric acid) was stirred in until dissolution was complete. After quantitative transfer to a separating funnel and shaking, the aqueous layer was reextracted four times (with 20 ml. of ethyl acetate each time). The combined ethyl acetate solutions were filtered, evaporated rapidly under diminished pressure, and dried thoroughly under diminished pressure. The residue was redissolved in 70 ml. 

The 1-alcohol also can be purified by fractionation of the cinchonidine salts of the hydrogen succinate.63 For this purpose the alcohol is recovered from the mother liquors of the brucine salt and converted to the hydrogen succinate by the general procedures previously outlined (p. 393). The oily succinate is oombined with one molecular proportion of cinchonidine in acetone. The very soluble cinchonidine Z-s-butyl succinate is purified by five or six crystallizations and then has m.p. 54-55° [a]D — 85° (c = 5, 95% ethanol). The alcohol is recovered from the pure salt in the usual way. 

The quinine salt of p-arsanilic acid forms white needles, M.pt. 202° C., and the cinchonidine salt small prisms, decomposing at 180° C., both compounds being soluble in alcohol. ... 

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]. 

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. ... 

Dicarboxy-2,2, 5,5 -tetraethyl-3,3 -bithienyl (70) was resolved into enantiomers (67AK115). The dextrorotatory form was obtained through fractional crystallization of the cinchonidine salt from ethanol. Some remarkable features were associated to the optically active forms. The melting behavior favors the existence of liquid crystals. 

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. 

Pasteur converted rf-tartaric acid into paratartaric acid (and hence to the /-form) by heating the /-cinchonidine salt to 170 C and extracting the resulting mass with water. He also found that a fourth form of the acid, mesotartaric acid, was formed in this process. This was optically inactive but could not be resolved into enantiomers. 

EHsubstituted (—)-a-methyl-a-ethyl-]3-thiolactone (IX) was synthesized by Jerman and Fles [7 ] from (+)-methyl-ethylmalonic acid monoethyl ester (V), which was prepared by fractional crystallization of diastereomeric quinine salt for the (+)-antipode and cinchonidine salt for the (—)-antipode. Monoester (V) was converted to a-methyl-a-ethyl-/3-bromopropionic acid (VI) using essentially the method described by Sweeney and Casey [4] for the racemic compound. Optically active a-methyl-a-ethyl-j3-fiiiolactone (IX) was synthesized either via the dehydration of the /3-mercapto derivative (VII) or by debenzylation of the jS-benzyl-... 

Jamison and Turner (52) have worked intensively on optical activation of various substituted i f-benzoyIdiphenylamines by means of alkaloids and have achieved particularly interesting results with the acid, iV-benzoyl-2,4,4 -tribromodiphenylamine-6-carboxylicacid (X). Conditions were here suitable for demonstrating the fairly marked temperature coefficient of the inversion process, for the acid in acetone solution is optically labile at room temperature, but stable at — 15°C. Crystallization of an equimolecular solution of the dl acid and cinchonidine from acetone at room temperature led to separation of pure cinchonidine (-I-) salt in almost 100% yield, a typical second-order asymmetric transformation. However, the same process at — 15°C. led to crystallization of cinchonidine (-I-) salt in only about 50% yield, and the residue on evaporation of the cold filtrate in vacuo was about two-thirds cinchonidine (—) salt—in other words, a typical resolution by the classical salt-formation method. 

Resolving agent for bases, amino acids, and helicenes. Resolved via strychnine, cinchonine, or cinchonidine salts. 

Figure 4.14 Polymeric chiral quaternary ammonium cinchonidine salts for asymmetric allylation.

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