Hippuric acids

This procedure was also used in building up polypeptides of high pioleoular weight. 

Amino-acids in solution are quantitatively determined as follows  

Method of van Slyke. The nitrogen, evolved when nitrite is added to an acid solution of the amino-acid, is measured. 

Sorensen s method. The amino-acid is condensed with formal dehyde and the substance produced is now a sufficiently strong acid to be titrated. 

Method of Willstatter and Waldschmidt-Leitz. Direct titration in alcoholic solution with 0-1 A-alkali using phenolphthalein as indicator. 

The residual solution is then transferred to a 2-1. beaker, a solution of 50 g. (1.25 moles) of sodium hydroxide in 100 cc. of water and a little decolorizing carbon are added, and the mixture is boiled until the odor of ammonia is ompleteIy absent (Note 4). The solution is filtered by suction, diluted to 500 cc. 

An equivalent amount of recovered ammonium hydroxide (sp. gr. 0.93 or less) was used in a number of runs without reducing the yield. 

Eastman s Practical grade reagents were used. 

The yield was slightly less after two days and no greater after a week. 

Ammonia must be completely removed to avoid the formation of benzamide. 

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Thiazolecarboxaldehydes exhibit many reactions typical of aldehydes. However, they give no aldolization reaction (no a-hydrogen), but they do react with different compounds such as acetic anhydride, hippuric acid, acetylglycine, and so for (37, 101, 102). Thus 2-phenyl-4-fonnylthiazole (31) mixed with hippuric acid and treated with AcOa and anhydrous NaOAc gives the azalactone (32) (Scheme 32). 

Benzoic acid in the free state, or in the form of simple derivatives such as salts, esters, and amides, is widely distributed in nature. Gum benzoin (from styrax ben in) may contain as much as 20% benzoic acid in the free state or in combinations easily broken up by heating. Acaroid resin (from anthorrhoca haslilis) contains from 4.5 to 7%. Smaller amounts of the free acid are found in natural products including the scent glands of the beaver, the bark of the black cherry tree, cranberries, pmnes, ripe cloves, and oil of anise seed. Pern and Tolu balsams contain benzyl benzoate the latter contains free benzoic acid as well. The urine of herbivorous animals contains a small proportion of the glycine derivative of benzoic acid, hippuric acid [495-69-2] (CgH CONHCH2COOH). So-called natural benzoic acid is not known to be available as an item of commerce. 

Human sensitization studies were negative at 10% solution (47). Undiluted benzyl alcohol produces moderate dermal irritation in guinea pigs and mild dermal irritation in rabbits (48,49). Severe eye irritation was noted in a rabbit study (50). Acute oral rat LD q values were reported between 1.23 and 3.10 g/kg (50—52). A dermal rabbit LD q value of 2.0 g/kg has been reported (49). Rats died after 2 h when exposed to a 200-ppm vapor concentration (53). Benzyl alcohol is readily oxidized in animals and humans to benzoic acid [65-85-0] which is then conjugated with glycine [56-40-6], and rapidly eliminated in the urine as hippuric acid [495-69-2] (54). 

This azlactone is prepared readily from benzaldehyde according to the procedure given for the azlactone of a-ben-zoylamino-/3-(3,4-dimethoxyphenyl)-acrylic acid (Org. Syn. 13, 8). From 53 g. (0.5 mole) of benzaldehyde, 89.5 g. (0.5 mole) of hippuric acid, 41 g. of fused sodium acetate, and 153 g. of acetic anhydride there is obtained 78-80 g. (62-64 per cent yield) of an almost pure product melting at 165-166° (corr.). This material is sufficiently pure for use in the preparation of phenylalanine. By crystallization from 150 cc. of benzene a product melting at 167-168° (corr.) is obtained. 

Erlenmeyer reaction is the condensation of aromatic aldehydes with hippuric acid to form aziactones (important intermediates in the preparation of amino- and keto-acids)... 

By the action of an acid chloiide on the amino-acid, the hydrogen of the amino-group may be replaced by an acid radical. Hippuric acid has been synthesised in this way. 

The azlactones of a-benzoylaminocinnamic acids have traditionally been prepared by the action of hippuric acid (1, Ri = Ph) and acetic anhydride upon aromatic aldehydes, usually in the presence of sodium acetate. The formation of the oxazolone (2) in Erlenmeyer-Plochl synthesis is supported by good evidence. The method is a way to important intermediate products used in the synthesis of a-amino acids, peptides and related compounds. The aldol condensation reaction of azlactones (2) with carbonyl compounds is often followed by hydrolysis to provide unsaturated a-acylamino acid (4). Reduction yields the corresponding amino acid (6), while drastic hydrolysis gives the a-0X0 acid (5). ... 

In 1959, Crawford and Little reported superior yields of 3 in reactions of aromatic aldehydes by using isolated, crystalline 2-phenyloxazol-5-one (2, Ri = Ph) compared to direct reaction with hippuric acid (1, Ri = Ph). An early report by Boekelheide and Schramm on the use of ketones in the Erlenmeyer azlactone synthesis includes treatment... 

Another approach to the l-oxo-l,2-dihydro-j8-carboline system is that due to King and Stiller. When 2-ethoxy carbonyl-3-formyl-indole is condensed with hippuric acid the azlactone 162 is formed, which, with 10% methanolic potassium hydroxide, gives a mixture of the orthoester 163 and the potassium salt 164. 

Several improved methods for the preparation of known unsaturated azlactones as well as some interesting new compounds of this type have been reported. Crawford and Little observed that the direct use of 2-phenyl-5-oxazolone (1) in the Erlenmeyer reaction gave much improved yields (35-74%) of unsaturated azlactones with aliphatic aldehydes and with ketones such as acetone and cyclohexanone [Eq, (1)], The usual procedure of mixing a carbonyl compound, hippuric acid, acetic anhydride, and sodium (or lead) acetate affords poor yields in the aliphatic series. 

Aromatic aldehydes react rapidly with hippuric acid in the presence of a sulfur trioxide-dimethylformamide complex to form azlactones... 

The reaction of hippuric acid with a three-fold excess of trifluoro-acetic anhydride gives a 90% yield of 2-phenyl-4-(2, 2, 2 -trifluoro-l -hydroxyethylidene)-5-oxazolone (2). This compound is also obtained... 

This compound is prepared from ethyl orthoformate and hippuric acid by a convenient three-step procedure, c/. ref. 1. 

The isolation of several pairs of geometric isomers of 4-unsaturated-5-oxazolones has been described. Generally, only one isomer is obtained when an aldehyde reacts with hippuric acid in the presence of acetic anhydride. Occasionally, mixtures have been separated in base-catalyzed reactions. In acetic anhydride-sulfuric acid or in 100% sulfuric acid, a mixture is obtained, and it has been suggested that sulfuric acid inhibits mutarotation of the intermediate addition product 53, which is a mixture of diastereomers (see, e.g., compound... 

A mixture of 537 g (3 moles) of hippuric acid (Note 1) and 16 1 (17 moles) of acetic anhydride is prepared in a 3 1. threenecked, round-bottomed flask fitted with a sealed stirrer, a reflux condenser with a drying tube, a thermometer, and a nitrogen inlet tube (Note 2)... 

Acetic anhydride, condensation with and acetylation of glycine, 46, 1 in cyclization of c-formylphenoxy-acetic acid to coumarone, 46, 28 in cyclization of hippuric acid to 2-phenyl-5-oxazolone, 47, 101 reaction with N-nitroso-N-phenyl-glycine to yield 3-phenylsydnone, 46,96... 

Hippuric acid, cyclization to 2 phenyl-5 oxazolone with acetic anhydride, 47,101 Holarrhimine, 46, 61 Hydrazine, reaction with cinnamalde-hyde, 47, 99... 

Condensation of 1,3-diphenyl[ 1,2,4]triazin-6-one 360, obtained from reaction of hippuric acid and phenylhydrazine, with aromatic aldehydes... 

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