Benzyl mandelate

Figure 10.12 Chromatogram of tranquillizers (reproduced with permission of Hewlett-Packard). Conditions column, 25cm x 4mm i.d. stationary phase, LiChrosorb RP-8,10pm mobile phase, gradient elution, 30% acetonitrile in water up to 90% acetonitrile in water, 16 min UV detector, 254 nm. Peaks 1 = bromural 2 —carbromal 3 —acetocarbromal 4- — benzyl mandelate.

Fig. 79. Detection with iodine, of a mixed pharmaceutical preparation after thin-layer chromatographic separation [215]. I caffeine II aminopyrine III phena-cetin /F benzyl mandelate. 15 cm run using cyclohexane-acetone (40 -h 50) on silica gel G...

Generally at least 5 ml solvent is used for extracting a spot, so as to be able to work with the normal 1 cm cuvettes. A 50 jig amount applied to the layer thus yields a concentration of 10 [xg/ml after extraction. If such a procedure is used for example for the four pharmaceuticals aminopyrine, caffeine, benzyl mandelate and phenacetin, which absorb in the UV, the extinctions at the maxima are, respectively, 0.36,... 

Several authors have worked on TLC of the more frequently occurring mixed pharmaceutical preparations such as, the analgesic-antipyretic mixture of caflFeine, phenacetin, acetylsalicylic acid and salicylamide (Table 121/1) or the anti-rheumatic preparation in Table 121/4. In this connection, one may mention here also the separations and quantitative evaluations of the analgesic mixtures, caffeine-benzyl mandelate-aminopyrine-phenacetin and caffeine-propylphenazone-phenacetin-pyrithyldione [66, 72, 96] (cf. p. 147). Other TLC separation procedures which have been described are of the components of an analgesic powder on ion exchange layers [135] an anti-influenza elixir, with semi-quantitative evaluation [114] the water-soluble vitamins in a commercial vitamin preparation [67] and the fat-soluble vitamins in such preparations [21]. Further extensive information about the analysis of commercial preparations is to be found elsewhere [19, 63, 65 and 75]. 

The phenylacetic acid derivative 469 is produced by the carbonylation of the aromatic aldehyde 468 having electron-donating groups[jl26]. The reaction proceeds at 110 C under 50-100 atm of CO with the catalytic system Pd-Ph3P-HCl. The reaction is explained by the successive dicarbonylation of the benzylic chlorides 470 and 471 formed in situ by the addition of HCl to aldehyde to form the malonate 472, followed by decarboxylation. As supporting evidence, mandelic acid is converted into phenylacetic acid under the same reaction conditions[327]. 

The (ZZ-ephedrine was resolved into its components by the use of d-and Z-mandelic acids. In 1921 Neuberg and Hirsch showed that benz-aldehyde was reduced by yeast, fermenting in suerose or glueose solution to benzyl aleohol and a phenylpropanolone, which proved to be Z-Ph. CHOH. CO. CH3. This ean be simultaneously, or consecutively, eondensed with methylamine and then eonverted to Z-ephedrine by reduction, e.g., with aluminium amalgam in moist ether, or by hydrogen in presenee of platinic oxide as catalyst (Knoll, Hildebrant and Klavehn ). 

The secondary benzylic alcohol l-phenylethan-l,2-diol requires 20 hours of treatment at room temperature to produce a 64% yield of 2-phenylethanol (Eq. 43).137 Under the same conditions, methyl mandelate fails to undergo reduction, presumably because of the greater carbocation-destabilizing effect of a neighboring carboalkoxy compared to a hydroxymethyl group (Eq. 43).137... 

Although the reaction could proceed via intermediate 14 or 15, the authors favour a mechanism where the formation of 14 is rate-determining because the displacement of the acetate at Pb by carboxylate anions is known to be rapid. The large negative AS (—34 e.u./mol) observed for the oxidation reaction is consistent with formation of the pseudo-cyclic intermediate 14. Also, the small Hammett p value of 0.4 determined for a series of meta- and para-substituted mandelic acids indicates that there is very little charge development on the benzyl carbon in the transition state of the rate-determining step. This is also consistent with the proposed mechanism. 

Certain classes of compounds are too reactive for the present method. Ethyl mandelate produced a racemic, protected phenyl glycine derivative. Benzylic alcohols with two methoxy groups (directly conjugating in the 2 and 4 positions) gave azide of 50% e.e. 

Fig. 11.12. Metabolic scheme for reaction of benzyl cyanide (11.80) to mandelonitrile (11.81) as a crossroads to benzoic acid (11.83) via oxidative denitrilation, and to mandelic acid (11.82) as a minor metabolite produced by hydrolysis of the CN group [118][122]...

There are a few data in the literature to suggest that the hydrolysis of aliphatic nitriles occurs in mammals, but only as a minor or even undetectable pathway in competition with oxidative denitrilation. For example, benzyl cyanide (11.80, Fig. 11.12) undergoes cytochrome P450 catalyzed hydroxy-lation to mandelonitrile (11.81), from which cyanide and benzaldehyde are produced, the latter being oxidized to benzoic acid (11.83) [118]. However, a careful metabolic study of mandelonitrile has shown that, in the rat, this pathway accounts for ca. 90% and not 100% of the dose [122], Only ca. 10% of orally administered benzyl cyanide was converted to mandelic acid (11.82, Fig. 11.12) by hydrolysis of the CN group. 

Oeavage of esters to acids and hydrocarbons mentioned above was achieved not only with hydrides but also by catalytic hydrogenation and reduction with metals. For example the acetate of mandelic acid was converted to mandelic acid and acetic acid by hydrogenation at 20° and 1 atm over palladium on barium sulfate in ethanol in the presence of triethylamine in 10 minutes [1035], and a,a-diphenylphthalide was reduced by refluxing for 5 hours with zinc in formic acid to a,a-diphenyl-o-toluic acid in 92% yield [1036]. Such reductions are of immense importance in esters of benzyl-type alcohols where the yields of the acids are almost quantitative. 

R)- and (S)-Mandelic acid can also be used to resolve the benzyl esters 39t77 8°l of racemic Tic (Scheme 16).[79] Both isomers of Tic are released by hydrolysis of their respective benzyl esters. This also constitutes a valuable synthetic route. 

Benzyl (S)-l,2,3,4-Tetrahydroisoquinoline-3-carboxylate (S)-Mandelic Add Salt (40A) and Benzyl (R)-l,2,3,4-Tetrahydroisot uinoline-3-carboxylate (f )-Mandelic Acid Salt (40B) [791... 

This compound was prepared in the same manner as (R)-Tic, using benzyl (S)-1,2,3,4-tetra-hydroisoquinoline-3-carboxylate (S)-mandelic add salt (40A) as starting material yield of (S)-33 920 mg (81%) mp 322-327 °C. 

Various dehydrating agents—concentrated sulphuric acid, zinc chloride, phosphorus pentoxide—can be used. Sulphuric acid, although perhaps the most convenient, has the disadvantage that it tends to sulphonate the aromatic substances employed. At a low temperature, however, diphenylmethane can be obtained from benzyl alcohol and benzene. At 140° phosphorus pentoxide condenses benzene and diphenylcarbinol to triphenylmethane (see B., 7,1204). Not only substituted benzyl alcohols, but even mandelic acid can be brought within the scope of the reaction, while in place of benzefte its nitro, amino or phenolic derivatives may be used. 

Mandelic acid, (S)-,(+)-Lithium aluminum hydride m-Chloroperbenzoic acid Benzyl bromide Cyclohexene... 

In contrast to benzyl alcohol, a-substituted benzyl alcohols, benzyl ethers, and aryl ketones may be successfully hydrogenated over rhodium and rhodium-platinum catalysts to give the corresponding saturated products in high yields, as shown in eqs. 11.38-11.41. In the hydrogenations shown in eqs. 11.38 and 11.39, no racemization took place D-mandelic acid afforded D-hexahydromandelic acid in 94% yield and meso- and dl-2,3-dicyclohexyl-2,3-butanediol were obtained in 93 and 94% yields, respectively, by hydrogenation of the corresponding diphenyl compounds. 

Pedro et al. reported the enantioselective synthesis of (,S )-3-hydroxy-3-phenyl-3,4-d i hydroquinol i n - 2 (1 /f)-o n c through an extension of their methodology for the diastereoselective benzylation of (.S )-mandelic acid <07S108>. The reaction commences with the benzylation of dioxolane 90 with substituted o-nitrobenzyl bromides 91 followed by the cyclization of adduct 92 resulting in enantiomerically pure dihydroquinolines 93 in good to high yields. 

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