Hippuric acid/hippurate, synthesis

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... 

Fig. 27 Synthesis of heterocycies via propenoates. Reagents and conditions a Hippuric acid, CsCOs, DMF, 200 °C, 10 min, closed vessel b DMFDEA in DMF, 180 °C, 10 min, closed vessel c HOAc, 180 °C, 10 min, closed vessel...

Erlenmeyer jun., and Halsey, in 1899, synthesised tyrosine by the condensation of hippuric acid with p-oxybenzaldehyde in the presence of acetic anhydride. The reactions are the same as those described by Erlenmeyer for the synthesis of phenylalanine, except that the hydroxyl group of the p-oxybenzaldehyde becomes acetylated in the process —... 

Condensation of A -acylglycines with carbonyl compounds, the Erlenmeyer synthesis, continues to be exploited to prepare of a wide variety of unsaturated-5(47/)-oxazolones. The reaction is performed in the presence of a cyclodehydrating agent and recently bismuth(lll) acetate has been evaluated in this capacity. Alternatively, unsaturated 5(47/)-oxazolones can be obtained from hippuric acid and a carbonyl compound or from the appropriate dehydroamino acid derivative using 3-(aIkoxycarbonyl)benzotriazole-l-oxides as the cyclodehydrating agent. 

The preparation of the first unsaturated azlactone was reported in 1883 by Plochl/40 who condensed benzaldehyde with hippuric acid in presence of acetic anhydride. This approach was later used by Erlenmeyer/41 who extended the procedure to include other aldehydes and also established the usefulness of azlactones as intermediates in the synthesis of DHAs. The method involves the condensation of an A-acylglydne 4 with aldehydes and ketones in the presence of acetic anhydride and anhydrous sodium acetate (Scheme 2)J41 t5l Other catalysts such as copper(II) acetate/46 lead acetate/47,48 potassium carbonate/49 or potassium hydrogen carbonate 50 have also been used. The reaction proceeds via formation of an azlactone 5, which then condenses with the appropriate aldehyde or ketone to give unsaturated azlactone 6. Reaction of 6 with a nucleophile such as OH, OR, or NHR leads to the corresponding A-acyl-DHA derivatives 7. Reaction with the sodium salt of an amino acid gives a DHA containing dipeptide acid. 51 ... 

Selenophene-2-aldehyde takes part in the Hantzsch synthesis [Eq. (I)]108 and reacts readily with ammonia, aromatic amines and diamines,109 hippuric, barbituric, and malonic acids, malononitrile,70 and rhodanine.109 /3-(Selenien-2-yl)acrylic acid has been obtained from selenophene-2-aldehyde by the Perkin reaction and by Knoevenagel condensation with malonic acid.70 Esters of /9-(selenien-2-yl)acrylic acid are easily formed by condensation of the aldehyde... 

Thus both by its synthesis and by its hydrolytic products hippuric acid is proven to be benzoyl glycine. 

Sodium benzoate Sodium benzoate has already been successfully used to treat congenital enzymatic defects of the urea synthesis (M. L. Batshaw et at, 1981). In HE, the administration of sodium benzoate or sodium phenylacetate (each 10 g/day) achieved clinical success equivalent to lactulose therapy in ca. 80% of cases. (122, 144, 159) These substances (which are cheap and practically free of side effects) lead to an increased excretion of nitrogen through the conjugation of glycine and glutamine, whereby ammonium is bound as hippuric acid and excreted renally (bypassing the urea cycle). 

In a manner related to the Erlenmeyer synthesis, hippuric acid (34) is converted to the oxazole (35) by the action of IV-methylformanilide and... 

Azlactone synthesis. Use of the reagent in the azlactone synthesis of amino acids is illustrated by a procedure for the preparation of DL-phenylalanine. - A mixture of 0.5 mole each of benzaldehyde, hippuric acid, and anhydrous sodium acetate is treated with 153 g. of acetic anhydride, and the mixture heated and stirred until the... 

Leucine has been prepared by the hydrolysis of isobutyl-hydantoin with barium hydroxide by reduction and hydrolysis of a-oximinoisocaproate by racemization of /-leucine by the action of ammonia and hydrogen cyanide on isovaleralde-hyde followed by hydrolysis by the action of heat on isobutyl-malonylazidic acid followed by hydrolysis by the action of ammonia on a-bromoisocaproic acid by the condensation of isobutyl halides and sodio aminomalonic ester or sodio benzoyl-aminomalonic ester followed by hydrolysis by the condensation of isobutyraldehyde and hippuric acid followed by reduction and hydrolysis. The method described above is essentially the Fischer method and is undoubtedly the best and cheapest procedure for the synthesis of large amounts of this amino acid. 

Two syntheses of cyclopenin have been fully described. " One involved the preparation of a penultimate intermediate (21) as a mixture of two double bond isomers which were separated and transformed by epoxidation with meta-chloroperbenzoic acid into cyclopenin (18) and isocyclopenin respectively. In the other, the same intermediate (21) was prepared by two stereospecific routes starting with hippuric acid derivatives (23)." The Erlenmeyer synthesis on (23) produced the ester (22) which gave the benzodiazepine (21) in two steps. An extension of this approach led to the synthesis of cyclopenol [(18), m-HOC6H4 for Ph]. 

An important variation of the Perkin reaction is the Erlenmeyer azalactone synthesis exemplified by equation (4), involving condensation of an aldehyde and an N-acylglycine derivative in the presence of acetic anhydride and sodium acetate. Although this reaction, analogous to the classical Perkin condensation, was initially limited to the use of aromatic aldehydes, Baltazzi and Robinson reported that the use of lead acetate and THF allowed the preparation of several azalactones derived from aliphatic aldehydes (equation 15). The results for the condensation of several aldehydes and ketones with hippuric acid (28) under these conditions are shown in Table 2. The reaction proceeds through the intermediate (26) (intramolecular condensation of 25), which reacts with the aldehyde in Perkin fashion to provide the so-called azalactone product (Scheme 8). It is the formation of such oxazolones from acylamino acids which is be-... 

The Erlenmeyer azalactone synthesis generally affords predominantly, and often exclusively, (Z) isomers (32). However, a simple method for the synthesis of ( ) isomers (33), obtained previously by separation of isomeric mixtures or isomerization procedures, has been reported. Aromatic aldehydes condense with hippuric acid when heated in polyphosphoric acid (PPA) to afford (33) in 80-90% yields (equation 17 Table 4). Alternatively, the (Z) isomers may be heated in PPA to afford the corresponding ( ) isomers in excellent yield. The authors note that hippuric acid is not converted to (26) in PPA, the generally accepted intermediate in the Erlenmeyer synthesis. Furthermore, both isomers of 2-(benzamid-oyl)cinnamic acid, (34) and (35), obtained by the alkaline hydrolysis of (32 R = H, Ar = Ph) and (33 R = H, Ar = Ph), respectively are converted to (33 R = H, Ar = Ph) in PPA (Scheme 9). The authors therefore suggest a mechanism involving condensation, first of the aldehyde and hippuric acid followed by... 

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