Mandelic acid resolution

In 1997, chemists from the Process Exploration Labs at Bristol-Myers Squibb Company reported their development of a simple asymmetric synthesis of d-sotalol 105, a Class III antiarrythmia compound, utilising a CBS reduction as the key step (Scheme 14.34). ° Previous efforts towards synthesis of d-sotalol had utilised techniques such as mandelic acid resolution, chiral chromatography and use of chiral homogeneous hydrogenation. The synthesis of d-sotalol via a CBS reduction is of interest as the molecule contains a methanesulfonamide NH proton, which clearly does not interfere with the yield or enantioselectivity of the process despite the acidic nature of this substituent. The authors discuss the various elements of the reduction process that they investigated and conclude that the optimal procedure involves addition of 1 M BH3 THE over a few minutes to a mixture of the (5 )-2-MeCBS catalyst and substrate ketone 102 in MTBE held at room temperature. Under these reaction conditions (on a 1.8 mmol scale), alcohol 103 was obtained in 92% yield with 96% ee. In this instance, the enantiomeric excess was calculated by conversion of the alcohol product to... 

The present method is adapted from that of Loven. The resolution has been carried out with d-a-bromocamphor-TT-sulfonic acid (f-form) 2.3 with /-and d/-malic acids (d- and /-forms) with /-quinic acid and d-tartaric acid (d- and /-forms) and with d- and /-6,6 -dinitrodiphenic acids (d- and /-forms). Methods employing d-benzyimethylacetyl chloride, d-oxymeth-ylenecamphor, /-quinic acid, and d-camphoric anhydride are of theoretical interest only. The d/-amine is not resolved by the active camphor-lo-sulfonic acids or mandelic acids. ... 

A patent procedure for formation of compounds 19 from simple tartaric acid derivatives has appeared <06USP047129> and various new routes to chiral dioxolanones include synthesis of dioxolan-2-ones either by transition metal-mediated asymmetric synthesis <06T1864> or enzyme-mediated kinetic resolution <06H(68)1329> and a new synthesis of the chiral dioxolan-4-ones 21 from lactic or mandelic acid involving initial formation of intermediates 20 with trimethyl orthoformate in cyclohexane followed by reaction with pivalaldehyde <06S3915>. 

The use of dissociable diastereomers for enantiomer resolution may be illustrated by the case where racemic mandelic acid is resolved using en-antiomerically pure a-methylbenzylamine. The n and p salts of a-methylbenzyl-amine mandelate have aqueous solubilities of 49.1 and 180 g/L, respectively, at 25°C [153], A more recent example, which focuses on the crystallographic origin of the solubility differences, is provided by the resolution of ( )-mandelic acid with (-)-ephedrine in water or methanol solution [154], In general, the relative solubilities of the n and p salt pairs are strongly influenced by the choice of solvent medium and temperature, which provide considerable flexiblity in optimizing the crystallization conditions and the efficiency of resolution. This process may be facilitated by the development of a full solubility phase diagram. 

Optically active substances are preferentially adsorbed by some optically active adsorbent. Thus Broadly and Easty (1951) found wool and casein to adsorb (+) mandelic acid from its aqueous solution. Some workers also successfully carried out resolution without using an active adsorbent. The alumina was found to be suitable for resolving diastereoisomers of (-) menthyl ( ) mandelate. 

Enzymes exhibit specificity as regards their behaviour towards stereo-isomerides. Pasteur s biological resolution of racemic acid with moulds depends on this fact, and such moulds may also be used for the resolution of racemic mandelic acid, for the partial digestion of racemic polypeptides according to E. Fischer s method, and in numerous other processes. 

Miyazawa, T., Kurita, S., Ueji, S., Yamada, T. and Shigeru, K., Resolution of mandelic acids by lipase-catalyzed transesterifications in organic media inversion of enantioselectivity mediated by the acyl donor. J. Chem. Soc. Perkin Trans. 1, 1992, 18, 2253-2255. 

The original synthesis of duloxetine (3) is relatively straightforward, involving a four-step sequence from readily available 2-acetylthiophene 30 (Scheme 14.7). Understandably, the main synthetic challenge stems from the presence of a chiral center, because duloxetine (3) is marketed as the (5)-enantiomer as shown. Thus, a Mannich reaction between 30 and dimethylamine generated ketone amine 31, which was then reduced to provide intermediate racemic alcohol amine 32. The desired optically active (5)-alcohol 32a was accessed via resolution of racemate 32 with (5)-(+)-mandelic acid, which provided the necessary substrate for etherihcation with 1-fluoronaphthalene to afford optically active amine 33. Finally, A -demethylation with 2,2,2-trichloroethyl chloroformate and cleavage of the intermediate carbamate with zinc powder and formic acid led to the desired target duloxetine (3). 

An improved route to the enantiomerically pure 5,6-diphenyltetrahydro-l,4-oxazin-2-ones is shown in Scheme 44 <2005SL693>. The starting amino alcohols are commercially available but can also be obtained by resolution of the (-)-mandelic acid salts of the two enantiomers. The reaction time was significantly shorter than with older methods and the yields over the three steps were 75% for the A-/-butoxycarbonyl oxazinone and 86% for the A -benzylox-ycarbonyl oxazinone. 

Compound (6) contains 3 centers of dissymmetry, and its resolution into separated enantiomers could effected using ( )-mandelic acid [7]. The least soluble diastereomer was found to be the (-)-mandelate salt (m.p. 164.5-164.8°C). Formation of the hydrochloride salts of both enantiomers gave (-i-)-isoxsuprine HCl (m.p. 196-196°C) and (-)-isoxsuprine HCl (m.p. 195-196°C). The two asymmetric centers at C-1 and C-2 were correlated with those of the erythro (p-OH-C6H4-CH(OH)-CH(CH3)-NH-) residue. 

Aminolysis with butylamine, rather than hydrolysis or transesterification, has been employed in the kinetic resolution of methyl mandelate (Figure 10.13) [123]. Enanhoselectivities in the kinetic resolution of mandelic acid via transesterification are generally low. Aminolysis (or ammoniolysis) may improve the resolution, as has been shown in some cases [124, 125], presumably by a shift of the ratedetermining step. Resolution with CaLB in conventional media afforded quite modest E ratios, which became near-quantitative when 10% [BMIm][BF4] was added to the medium [122]. 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

Following an initial resolution step with 0.5 mol equivalents (R)-mandelic acid in TBME, the crystalline product was filtered and tlie waste isomers in the mother liquors (39% ee) were washed with base and then subjected to racemization with the SCRAM catalyst. Upon completion, the catalyst precipitated and was screened, fresh racemic amine was added, and the whole was resolved a second time. The process was repeated several times, giving the results summarized in Table 13.2. 

Chiral acids, such as (+)-tartaric acid, (—)-malic acid, (—)-mandelic acid, and (+)-camphor-10-sulfonic acid, are used for the resolution of a racemic base. 

The alcoholic filtrate and washings from the above resolution can be united, split into two parts, and 20 gms. r-mandelic acid dissolved in one and 20 gms. of (—) ephedrine in the other. The two solutions are slowly mixed, warmed on a water bath for an hour, cooled, when (—) ephedrine (—) mandelate appears. This is treated as above and 10 gms. (—) mandelic should be obtained ([a]6461 = — 147° in acetone). With the... 

Pasteur s original chemical method of resolution, which is still widely used at the present time, involves the formation of diastereoisomeric salts from racemic acids or bases by neutralisation with available optically pure bases or acids respectively. The required optically pure reactants are often available from natural sources and include tartaric, malic and mandelic acids, and alkaloids such as brucine, strychnine, morphine and quinine. Ideally, by appropriate choice of the resolving reagent, the diastereoisomeric salts are crystalline and have solubilities sufficiently different to permit the separation and ready purification of the less soluble salt by fractional crystallisation from a suitable solvent. The regeneration of the optically pure enantiomorph, and incidentally the recovery of the resolving reagent, normally presents no problems. 

FIGURE 9 Chromatograms of enantiomeric resolution on cellulose triacetate CSPs. (a) /V-Benzoylalanine methyl ester, with hexane-ethanol (80 20, v/v) as the mobile phase, (b) Benzoin with hexane-2-propanol-water (70 27 3, v/v/v) as the mobile phase, (c) Mandelic acid with ethanol as the mobile phase. (From Ref. 9.)... 

In 1978, Harada et al. [17] used polymerized CD with gel support for the chiral resolution of mandelic acid and its derivatives. Later Zsadon et al. [18-21] used cyclodextrin-based CSPs for the chiral resolution of indole alkaloids, with aqueous buffers as the mobile phases. Today CD-based CSPs have a good reputation. In separate studies, Fujimura [22] and Kawaguchi [23] and their colleagues resolved the enantiomers of aromatic compounds in the reversed-phase mode. Armstrong et al. [29,30,33,34,41,44 46,48,54-63] carried out extensive and remarkable work on the chiral resolution of various racemic compounds using CD-based CSPs. 

Sertraline is an antidepressant that is sold as a single enantiomer and prepared commercially through a resolution of a racemate. The starting material for the resolution step is the hydrochloride salt of racemic sertraline (13.22) (Scheme 13.3). The hydrochloride salts are first neutralized through the addition of NaOH to form the racemic free amine (13.23). The amine is then reacted with 1.0 equivalents of d-(— )-mandelic acid (13.24) in ethanol to form diastereomeric salts. The solution of the salts in ethanol is allowed to stand at room temperature, and a solid consisting of predominantly diastereomer 13.25 precipitates. Filtration of the solid followed by recrystallization from ethanol affords essentially... 

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