Ethyl mandelate acetate

Chloro-2-phenylacetic acid 945 Ethyl mandelate (0.75 mole from mandelic acid and ethanol-HCl) is dissolved in SOCl2 (0.82 mole), and the solution is set aside at room temperature for 16 h, heated on a water-bath for 30 min, and poured into ice-water. The ethyl 2-chloro-2-phenylacetate formed (81-85 % yield) is extracted with ether and, after isolation, is hydrolysed by a boiling mixture of glacial acetic acid and concentrated hydrochloric acid. 

R)-2-hydroxy-2-phenylacetate (mandelate) in 59% yield, ethyl 2-keto-2-(a-thienyl)acetate to ethyl (—)-(R)-2-hydroxy-2-(a-thienyl)acetate in 49% yield, and ethyl benzoylacetate to ethyl (—)(S)-3-hydroxy-3-phenylpropa-noate in 70% yield. Ethyl acetoacetate gave also optically pure ethyl (+)-(S)-3-hydroxybutanoate (yield 80%) whereas the optical yield of ethyl (+)-lactate from ethyl pyruvate was only 92% [1089],... 

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. 

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... 

Borane-methyl sulfide complex (68 ml, 0.71 mol) was added dropwise to a solution of (S)-(+)-mandelic acid (98.5 g, 0.65 mol) in THF (900 ml) at room temperature (RT) under a flow of argon over 3 h. The reaction was stirred for 6 h. Then methanol was added dropwise and stirring continued for a further 13 h. The volatiles were then removed in vacuum, the residue stirred in methanol, and the process repeated 3 times. Column chromatography (MeOH-ethyl acetate-petrol, gradient elution) of the residue afforded the diol (57.3 g, 64%). p-Toluenesulphonyl chloride (80 g, 98% 0.41 mol) was then added portionwise to a solution of the diol in pyridine (700 ml) at 0°C over 8 h. The reaction was stirred at RT for 13 h, then the volatiles removed in vacuum. 

The mandelate esters serve yet an additional role in chiral synthesis - facilitation of resolution by hplc. The diastereo-mers in entries 1,2, and 4 of Chart 1 are all readily resolved on a Waters Prep 500 column utilizing 2-105S ethyl acetate in hexane (7,8,10,13). The diastereomer labelled S of entry 2,... 

Form, prulaurasin. Slightly bitter needles from ethyl acetate + ether, mp 123-125". [a]D —54 (water). Soluble in water, alcohol practically insol in etheT. On hydrolysis yields d(-mandelic acid. 

Form, samhunfgrfn. Bitter needles from hot ethyl acetate, mp 151-152°. [ ](f —75.1. Soluhle in water, alcohol, ethyl acetate. On hydrolysis yields /-mandelic acid. 

C2-homologizati on of sugars with, 264-265 Acetamide, JV-bromo- (AcNHBr, NBA) bromohydrination with, 275-276, 287 Acetaminophen (= paracetamol), 301 Acetate, piperidinium cat. for aldol add., 82 —, sodium a-epimerization of ketones, 277 opening of oxiranes, 282 Acetic acid, anhydride (AcfO) protection with. See Protection Pummerer rearr. with, 51, 265 —, esters (See also Protection of hydroxy groups) C-H acidity, 10 1-methylethenyi ester pr., 174 transenolization, 58 —, bromo-, esters pr., 179 a2-synthon, 19, 65, 309 d2-synthon, 19, 301 —, chloro-, esters pr., 179 hydantoins from, 308 —, cyano-, esters pr., 177 pyrrolines from, 298 —, (dialkoxyphosphinyl)-, esters pr 188 Wittig-Horner olefinations, 267, 282 —, diazo-, ethyl ester pr, 176, 178 cyclopropanes from, 74—75 —, dichloro- deblocking of pixyl ethers, 342 —, hydroxy-, esters pr., 176 —, hydroxyphenyl-, (S)- (l-mandelic acid) ... 

Thus from the sodium salt of glycolic acid (CH,OH. COOH), ethyl-glycolic acid (CH,OC,Hj.COOH), and a-lactic acid (CH3.CH(OH)COOH) the chief product obtained is acetic aldehyde, and it is quite possible that the production of hydrobenzoin and isohydrobenzoin from mandelic acid is due to the electrolytic reduction of the benzaldehyde originally formed. 

In addition to the compounds listed in Table I, corresponding basic derivatives of the following acids have been reported crotonic isocrotonic levulinic succinic cyano-acetic mono-, di-, and trichloroacetic monobromoacetic monochloro- and monobromopropionic lactic glycolic ethyl- and phenylglycolic (a-hydroxybutyric and mandelic, respectively) and salicylic. Confirmatory evidence for the identities of most of these is completely lacking. 

GW597599 is a novel NK-1 antagonist used for the treatment of central nervous system disorders and emesis. The initial synthetic route to this important product involved a classical resolution step of a ketopiperazine obtained in 38% yield through a classical fractional crystallisation using (-F)-mandelic acid (0.8 equivalent) in ethyl acetate. To avoid wasting the... 

The Pd-catalyzed reaction of allylic carbonates with the lithio derivatives of diox-olanone prepared by the treatment of mandelic acid with acetone dimethyl acetal gives the desired a-allylation products in good yields. Upon treatment with HCl in ethanol the corresponding a-hydroxy ethyl esters can be obtained " (Scheme 11). 

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