Mandelic acid derivatives, resolution

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. 

Nitrilase l-Catalyzed Production of Mandelic Acid Derivatives Under Dynamic Kinetic Resolution Conditions (Scheme 20.1)... 

Blixt, H.J., et al, June 2011. Process for the preparation and resolution of mandelic acid derivatives. US patent 7960582. 

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>. 

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. 

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... 

Biphenyl-bridged bis-Cp titanocene dichloride and dimethyl complexes have been synthesized, and the kinetic resolution of the racemic final mixture of the products has been carried out. A mixture of diastereomers is obtained by treatment of the dimethyl compound with O-acetyl-mandelic acid, while enantiomerically pure products result in the reaction of the dichloro derivative with (i )-binaphthol and 1 equiv. of LiBun (Scheme 661).1050... 

As shown in Table 5.4, the resolution efficiencies for the p-substituted 1-phenyl-efhylamine derivatives were greatly improved, as was expected, when p-methyl-and p-methoxymandelic acids were used in the place of mandelic acid. These results strongly support our explanation that two factors, hydrogen-bonding interaction to form a supramolecular sheet consisting of 2i-columns and van der Waals interaction between the sheets, govern the stability of diastereomeric salts [11]. The same factors were also found in the diastereomeric salts of racemic arylalka-noic acids with enantiopure amino alcohols [12]. 

Blaschke, G. Chromatographic resolutions of racemates. III. Chromatography of racemic mandelic acid on polyacrylic esters and amides of optically active ephedrine derivatives, Chem. Ber., 1974, 107, 237-252. 

Separation of the syn and anti diastereoisomers by crystallisation of the HC1 salt revealed that it was the syn diastereoisomer that was active and the reductive animation of 44 could be controlled to give 70%. vvn-45. The diastereoisomers of 45 were separated before the resolution. There is no point in resolving any earlier compound in the synthesis as even more material would be wasted in the reductive amination step. Natural ()-(/ )-mandelic acid 46 was a good resolving agent for 45 and 50% of the material derived from 44 could be isolated as the active (I )-vyn-(TS, 4S )-45. 

An enantioselective nitrilase has also been shown to be applicable in the dynamic kinetic resolution of mandelonitrile. Using the nitrilase produced by Alcaligenes faecalis ATCC 8750 Yamamoto et al. showed that they could derive (Rj-(-)-mandelic acid from mandelonitrile in 91% yield with an ee of 100%. Under the reaction conditions used non-reacting (S) -mandelonitrile undergoes spontaneous racemiza-tion leading to the high yield (see Scheme 12.1-8)[48]. Currently (R)-mandelic acid and (R)-chloromandelic acid are produced using nitrilases on an industrial scale by the Mitsubishi Rayon Corp. 

Unlike lactic acid, mandelic acid (7) occurs in nature only in small amounts and is therefore more expensive. Formerly, it was obtained by resolution of the racemate with a chiral base, such as l-phenylethylamines or ephedrine6, but enantioselective reductions of a-oxo-a-phenylacetic acid by chemical or biochemical methods have become feasible (Section D.2.3.I.). Esters of mandelic acid, e.g.. 8. can be prepared by any convenient esterification technique (see. for example, refs 7 and 46) and have been used for enantioselective protonation reactions (Sections C. and D.2.I.). Similar to the corresponding lactic esters, fumaric acid derivatives 9 are obtained from the mandelic esters and used as chiral dienophiles in diastereoselective Diels Alder reactions (Section D. 1.6.1.1.1.2.2.1.). 

The monoaminomonophosphonic acids, either in the free state or, very often, as their diethyl esters, have been resolved by the usual techniques of repeated crystallization of appropriate salts those of L-(+)-tartaric acid (2,3-dihydroxybutanedioic acid) or its mono-or di-benzoyl derivativesor of D-(-)-mandelic acid, have been widely employed the use of di-O-benzoylated L-tartaric anhydride, which is based on the separation of diastereoisomeric amides (111), has also been employed to a limited extent. In selected cases, such as the monoaminomonophosphonocarboxylic acids or A -acylated (aminoalkyl)phosphonic acids, resolution following salt formation with organic bases has also been carried out ephedrine, quinine and both enantiomers of l-phenylethylamine have all been used. In many cases, only one enantiomer of the (aminoalkyl)phosphonic acid (or diester) has been isolated in optically pure form. Sometimes, the acidity of the substrate, and hence choice of base for resolution, can be modified by using a mono- (as opposed to di-) ester or (or even in addition to) protection of the amino group as, for example, the phthalimido, benzyloxycarbonyl (cbz) or r r -butyloxycarbonyl (boc) derivative. Resolved di- and mono-esters can be hydrolysed to the free acids under acidic conditions, and A -protection can also be removed through the customary procedures. 

CyDs have been used as major chiral mobile phase additives (CMPAs) for enantio-separations in HPLC. The first application of 8-CyD as a CMPA in combination with an achiral reversed-phase material for HPLC enantioseparations was reported by Sybilska and co-workers in 1982 [27]. These authors could achieve partial resolution of the enantiomers of mandelic acid and derivatives. The CMPA method played an important role in HPLC enantioseparations before the development of effective chiral stationary phases (CSPs) but is now rarely used. The major disadvantage of this technique, together with difficulties associated with the isolation of resolved enantiomers, is the rather large consumption of chiral selector. 

Epichlorohydrin-cross-linked cyclohexa- and cyclohepta-amylose gels have been used for the chromatographic resolution of racemic mandelic acid and its derivatives. Modified cyclohepta-amylose bound the L-(- -)-isomers preferentially, and resolved D,L-methyl mandelate to give the D-(—)-isomer of 100% optical purity in the first fraction. Cross-linked cyclohexa-amylose bound D-(—)-isomers more strongly than L-(-t-)-isomers, resolving D,L-methyl mandelate to a smaller extent than cross-linked cyclohepta-amylose. Binding was studied quantitatively by the equilibrium method. 

CDs are produced from starch by the action of Bacillus macerans amylase or the eitzyme cyclodextrin transglycosylate (CTG) [16-19]. The latter enzyme can be used to produce CDs of specific sizes by controlling the reaction conditions. In the past few years, enantiomers have been resolved using peralkylated a-, and y-CDs dissolved in polysiloxanes and coated within glass or fused silica capillary tubing [20, 21]. Subsequently, the CDs were linked to the solid supports. In 1979, Harada etal. [22] polymerized and crosslinked a CD with a gel support, and the CSP developed was tested for the chiral resolution of mandelic acid and its derivatives. Various workers have subsequently bonded all three CDs with different solid supports [23-33]. Of course, these CDs bonded to gel support have been used for the chiral resolution of different racemates, but they suffer from certain drawbacks because of their poor mechanical strength and efficiency in both GC and HPLC. An improvement to these... 

A new diphosphine ligand, Norphos , catalyses the reduction of Z-a-(acetyl-amino)cinnamic acids to the expected dihydrocinnamic acids with optical yields of ca. 96%. ° The ligand is prepared from trans-vinylidenebis(diphenylphosphine oxide) by a Diels-Alder reaction with cyclopentadiene, classical resolution using (L)-(-)-dibenzoyltartaric acid, and finally reduction. The same substrates can also be reduced in ca. 80% optical yields using diphosphine ligands derived from enantiomerically pure menthoP or mandelic acid. ... 

Two details in the above scheme are worth mentioning. Initial attempts at nitrosa-tion of 1,4-BZD ring at C(3) with isoamyl nitrite, the most frequently used agent, failed, due to concomitant attack by isoamyl alkoxide on the oxime. Indeed, when the sterically more crowded t-butyl nitrite (t-BuONO) was substituted for isoamylnitrite oxime, 15 was obtained reproducibly in 85% isolated yield. Second, the effective resolution of racemic 16 was completed with (/ )-(—)-mandelic acid. For complete conversion of the racemate to the mandelate of (3/ )-16, however, 1-2 mol equivalents of water in iso-propylacetate were required, in additimi to the salicaldehyde derivative, whose function is explained in Scheme 6.2. On isolation and structural determination, it became clear that the mandelate of (3/ )-16 crystallizes as the hydrate. 

The preparation of myo-inositol 1,4,5-triphosphate by a process involving selective formation of diastereomeric menthyl esters in a similar way to that described in Vol. 25, p. 209, ref. 59 or by resolution of racemic derivatives with R-mandelic acid or l-/-menthoxyacetyl chloride (which involves the use of a new phosphitylating agent, o-xylene AT,lV-diethylphosphoramidite) have been reported. 

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