Hippuric acid synthesis and

Azlactones 22 are intermediates in the Erlenmeyer synthesis (1893) of cr-amino acids. They are made by the action of acetic anhydride/sodium acetate upon a mixture of A-benzoylglycine (hippuric acid) 21 and benzaldehyde via 2-phenyloxazol-5(4//)-one 20 ... 

Coenzyme A has recently been implicated in the activation and transfer of acyl groups other than acetate. For example, CoA is required for the oxidative decarboxylation of a-ketoglutarate to form succinate (Kaufman, 1951 Sanadi and Littlefield, 1951). Succinyl-CoA was proposed as an intermediate in this reaction. Hippuric acid synthesis also requires CoA (Chantrenne, 1951). The postulated intermediate in this case was benzoyl-CoA. The formation of acyl-CoA complexes from acetyl-CoA and free fatty acids may also occur (Stadtman, 1950, 1951). 

Chantrenne (59) and Schachter and Taggert (60) have demonstrated that hippuric-acid synthesis is the result of a similar reaction between benzoyl-SCoA and glycine. Finally, extracts of C. kluyveri contain an enzyme system that catalyzes the acylation of various amino acids and amines (61, 62). Again acyl-SCoA derivatives are the acyl donors. The latter reactions are, however, unique in that they do not occur in the absence of relatively high concentrations of HCN. As yet the role of HCN is undetermined. 

The key to the mechanism of the reaction came from Chantrenne s discovery that Coenzyme A as well as ATP is needed for hippuric acid synthesis.He also found that benzoylphosphate was unable to replace benzoic acid plus ATP, thus excluding benzoylphosphate as an intermediate. On the basis of known reactions and interactions of ATP, Co A, and acyl groups it appears that the reaction mechanism is... 

The substance represented by formula (IV), viz., 4-hydroxy-8-allyl-3 4-dihydroquinazoline, m.p. 180°, was synthesised by Reynolds and Robinson, and proved to be different from vasicine. Spath and Kufhier established the identity of the degradation product (V), upon which formula (IV) for vasicine was chiefly based by synthesis from isatoic anhydride, which, on treatment with glycine ester hydrochloride and sodium meth-oxide, gave the substituted hippuric acid (VI), and this, on heating with... 

Substituted-2-oxazoline-5-ones are extremely useful for the synthesis of a-aminoacids and peptides. A report on their formation using a water-soluble carbodi-imide for the dehydration-cyclization step has now appeared (Scheme 49). Previous methods for cyclization of hippuric acid (356) and its derivatives include use of AC2O, PX3, and DCC. The water-soluble carbodi-imide method gave a good yield and made work-up simpler. 

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 ... 

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... 

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