4- Hydroxy phenyl acetic acid

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. 

Mandellic Acid.—Mandellic acid is phenyl glycolic acid, CeHs— CH(OH)—COOH, phenyl hydroxy acetic acid. This constitution is proven by its synthesis from benzaldehyde by condensation with hydrogen cyanide and the hydrolysis of the resulting nitrile. 

Di-oxindole.— Similarly a di-hydroxy compound known as di-oxin-dole is obtained as a lactam anhydride from ortho-amino mandellic acid, ortho-amino phenyl hydroxy acetic acid. 

From Phenyl Vinyl Acetic Acid.—A second synthesis very closely analogous to the preceding is from phenyl vinyl acetic acid (p. 700), which has the constitution CeHs—CH = CH—CH2—COOH. When this is heated it loses water and yields a hydroxy naphthalene or naph-thol in which the hydroxyl is linked to the carbon next to the ortho carbon of the ring. 

The nitro substitution products of naphthalene are easily prepared by the action of nitric acid on the hydrocarbon. By such direct nitration the product obtained is alpha-nitro naphthalene. This is proven by the following series of reactions. Nitro-naphfhalene by reduction yields amino naphthalene, naphthylamine, which by the diazo reaction yields hydroxy naphthalene, naphthol. Now the naphthol so obtained is identical with the one resulting from the phenyl vinyl acetic acid synthesis (p. 768) and this must be the alpha compound. 

Hydroxy-l-naphthalenyl)azo] phenyl thio acetic acid, 9CI... 

Monoxime, in H-00292 [[2-[(2-Hydroxy-5-methylphenyl)azo]phenyl] thio]acetic acid, H-00303 A-Hydroxy-7/ -methyl-A-phenylthiourea, in T-00175... 

Hydroxy-1 -naphthalenyl)azo]phenyl] thio]acetic acid, H-00352... 

Hydroxy-5-methylphenyl)azo]phenyl] thio]acetic acid, H-00303 2-[[5-Hydroxy-3-methyl-l-(phenylmethyl)-1 //-pyrazol-4-yl]azo]-5-nitrobenzenesulfonic acid, H-00312 4-[3-Hydroxy-6-methyl-4-(4-sulfophenylazo)phenylazo] benzenesulfonic acid, H-00327 4-[(2-Hydroxy-1 -naphthalenyl)azo] benzenesulfonic acid Na salt, in H-00348... 

The principal coloring matter in turmeric and its oleoresin is curcumin [458-37-7] (l,6-heptadiene-3,5-dione, l,7-bis[4-hydroxy-3-methoxy-phenyl] (45), an orange-yeUow, crystalline powder, insoluble in water and ether but soluble in ethanol and glacial acetic acid. It has a reported melting point of 180-183°C. 

A mixture of 3-hydroxy-4-phenylfurazan and 1,2,4-oxadiazole 243 was prepared from a-phenyl-a-hydroximino hydroxamic acid by acylation and subsequent treatment with 15% aqueous NaOH (Scheme 164) (25G201). The reaction of tetraacetate 244 with sodium acetate hydrate in glacial acetic acid at 70°C gives 3,4-dihydroxyfurazan (9%) (92URP1752734). a-Hydroximino ester 245 reacts with hydroxylamine to form furazan 246 in 25% yield (Scheme 164) (79JHC689). 

Diketones 1 can be converted into the salt of an a-hydroxy carboxylic acid upon treatment with alkali hydroxide after acidic workup the free a-hydroxy carboxylic acid 2 is obtained. A well-known example is the rearrangement of benzil (R, R = phenyl) into benzilic acid (2-hydroxy-2,2-diphenyl acetic acid). The substituents should not bear hydrogens a to the carbonyl group, in order to avoid competitive reactions, e.g. the aldol reaction. 

The pure dimethylaminoethanol salt was dissolved in 400 ml of 50% acetic acid at 90°C and then cooled to 5°C. The solid which precipitated was collected by filtration, washed with water, cold 50% acetic acid and finally with low-boiling petroleum ether. After drying in vacuo there was obtained 24 g of hydrated dextro-/3-(3,5-diiodo-4-hydroxy)-a-phenyl-propionic acid, MP 80° to 85°C. 

B) Add to a suspension of 34 g of 3-acetoxy-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzo-diazepin-2-one in 80 ml of alcohol, 6 ml of 4N sodium hydroxide. Allow to stand after complete solution takes place to precipitate a solid. Redissolve the solid by the addition of 80 ml of water. Acidify the solution with acetic acid to give white crystals. Recrystallize from ethanol to obtain 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1 4-benzodiazepin-2-one, melting point 203°Cto 204°C. 

C20H2JNO3 3608-67-/) see Propiverine (-)-(lS,2S)-/V-(2-hydroxy-l-phenyl-3-butenyl)benzamide (C17H17NO2 136693-02-2) see Paclitaxel [hydroxy(4-phenylbutyl)phosphinyl]acetic acid phenylmc-thyl ester... 

On the other hand, refluxing 9 in formic acid for 5 h afforded the N-formyl derivative 11 in high yield. Acetylation of 9 by refluxing in acetic acid, afforded acetic acid N -(2-(7-hydroxy-2-oxo-2H-chromen-4-yl)-acetyl)-hydrazide 12 in good yield. Compound 13 was also obtained by refluxing 9 with 3-(2-bromoacetyl)-4-hydroxy-2H-chromen-2-one in ethanol. Reaction of compound 9 with phenyl isothiocyanate in ethanol at room temperature gave 4-phenyl-1 - (7-hydroxy-2-oxo-2 H-chromen-4-acetyl- )thiosemicarbazide 14. 

Amino-6-phenyl-7-hydroxy-l,8-naphthyridine reacted with an excess of diethyl alkoxymethylenemalonates in the presence of concentrated hydrochloric acid or in acetic acid to afford JV-(l,8-naphthyridin-2-yl)aminomethylenemalonate (78) in 44-63% yields (69G677). 

Steric effects dominate in the oxidation of dialkyl, alkyl phenyl and benzal methyl phenyl sulfides to their sulfoxides by quinolinium fluorochromate (QFC) in aqueous acetic acid. QFC oxidation of phenoxyacetic acids has been smdied. Imidazolium dichromate oxidations of a-hydroxy acids have been smdied. ... 

Ring transformation involving the intramolecular reaction of a hydrazone or in situ formed hydrazone also appeared. The transformation of 6-methyl-2//-pyran-2,3,4-trione 3-arylhydrazones 332 into l-aryl-6-methyl-4-oxo-l,4-dihydropyridazine-3-carboxylic acids 333 is an example of the former (Scheme 82). Compound 332 are formed via reaction of 4-hydroxy-6-methyl-27/-pyran-2-one 331 with substituted benzenediazonium chlorides. These are normally not isolated and immediately used further <2005EJM1325>. An example where a hydrazone is formed in situ is the reaction of 2-amino-5-aryldiazenyl-4-oxo-6-phenyl-4//-pyran-3-carbonitriles 334 with H2SO4 in glacial acetic acid, yielding 2-aryl-6-benzoyl-3-hydroxy-5-oxo-2,5-dihydropyridazine -carbonitriles 335 (Scheme 83) <2001T6787>. 

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