Anhydrides, mixed procedure/method

Active esters can be prepared via the mixed anhydrides, but the method has not been popular probably due to its unreliability and the moderate yields obtained. A better understanding of the chemistry of mixed anhydrides has led to a simple general procedure that gives good yields in most cases (see Table 12). Mixed anhydride 51 is generated from acid 23 in dichloromethane at room temperature by the addition of ethyl chloroformate in the presence of A-methylmorpholine (Scheme 11). Reaction of 51 with a 50% excess of the hydroxy compound in the presence of an equal amount of Af-methylmorpholine or a catalytic amount of triethylamine generates active ester 24. 

The procedures as outlined are applicable to both the aliphatic and aromatic series. They are superior to the common interchange method in that they avoid the fractional distillation which is very troublesome in the aliphatic series. They have been used in numerous instances and can be adapted to give mixed anli3"drides. Benzoic anhydride has been obtained, by closely related procedures, from benzoic acid and benzoyl chloride by heating under reduced pressure or in the presence of zinc chloride. 

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. 

A more elaborate but general procedure for esterification involves reaction of the A-alkoxycarbonylamino acid with the alkyl chloroformate of the alcohol to be esterified in the presence of triethylamine and a catalytic amount of 4-dimethylami-nopyridine (see Section 4.19) (Figure 3.21). The product probably arises by acylation of the alcohol by the acylpyridinum ion, both originating from decomposition of the mixed anhydride. The method can be used also to prepare activated esters (see Section 2.09), though the latter are usually obtained using the common coupling techniques (see Section 7.7).47 57... 

A convenient procedure for synthesis of pyrophosphates by this method was developed by Michelson.317,318 It employs mixed anhydrides (72) formed from nucleoside 5 -phosphates and diphenyl... 

Nucleoside 5 -phosphorothioates have also been employed as activated nucleotide derivatives for synthesis of pyrophosphates.321 The interaction of tributylammonium 2, 3 -di-0-benzoyluridine 5 -phosphorothioate (73) with silver a-D-glucopyranosyl and a-D-galac-topyranosyl phosphates in pyridine solution, with subsequent de-benzoylation, gave the corresponding glycosyl esters in 60-70% yield. This procedure can probably be classified as a variant of the mixed-anhydride method, the driving force of the reaction being the formation of insoluble silver sulfide. 

Antisera to cloxacillin/oxacillin/dicloxacillin and cefuroxime were also produced by similar procedures and successfully utilized in methods for the detection of these antibiotics in milk (34). Unfortunately, a number of other -lactams including aminopenicillins and some cephalosporins were not amenable to this mixed anhydride procedure. Thus, a carrier protein derivatization procedure was used to allow cross-linking of cephalosporins, such as cephataxime that has an acetoxy side chain, to ovalbumin. Because acetoxy groups react readily with the heterocyclic nitrogen atoms, the latter were introduced into ovalbumin through the carbodiimide-mediated derivatization of protein carboxyl groups with amino-methylpyridine (34). 

This procedure describes the use of pseudoephedrine as a chiral auxiliary for the asymmetric alkylation of carboxylic acid amides. In addition to the low cost and availability in bulk of both enantiomeric forms of the chiral auxiliary, pseudoephedrine, a particular advantage of the method is the facility with which the pseudoephedrine amides are formed. In the case of carboxylic acid anhydrides, the acylation reaction occurs rapidly upon mixing with pseudoephedrine. Because pseudoephedrine amides are frequently crystalline materials, the acylation products are often isolated directly by crystallization, as illustrated in the procedure above. 

As mentioned above, thiazolidine-4-carboxylic acid is characterized by an anomalously low basicity and thus difficult acylation in peptide synthesis. 189 Therefore, the incorporation of this amino acid residue into a growing peptide chain is preferentially preformed via dipeptide derivatives. 139 Suitably N-protected amino acids are coupled directly to the thiazolidine-4-carboxylic acid by the acid fluoride 139 or iV-carboxyan hydride 1392111 methods. The resulting dipeptides are used as building blocks without risk of racemization 139 and standard coupling procedures are applied as pentachlorophenyl esters prepared by the mixed anhydride procedure 121 or PyBOP. 171 ... 

The Z-protected derivative, again prepared by standard methods using benzyl chloroformate,t208 may serve in the case of racemic pipecolic acid for resolution into the pure enantiomers by fractional crystallization with L-tyrosine hydrazide/208 Acylation with N-protected pipecolic acid or of pipecolyl peptides is performed by standard procedures via the active ester methods, e.g. A-hydroxysuccinimide ester/121 by the mixed anhydride method, e.g. with isobutyl chloro-formate 95-114 or pivalic acid chloride/121 as well as by DCC/HOBt/118 In the synthesis on solid support, longer coupling times are required when compared to N-protected proline.1[235 ... 

Since depsipeptides, in contrast to classical peptides, contain units constructed from amino and hydroxy acid residues, the various methods for their preparation are generally pathways involving the formation of ester bonds. The novel achievements in this area discussed (vide infra) are associated with further developments in the mixed anhydride technique, the application of effective catalysts in the carbodiimide procedure, and adaptation of the known Mitsunobu reaction to the depsipeptide case. A number of significant and efficient esterification procedures utilized for the preparation of depsipeptides are considered. 

The diazomethyl ketone Z-L-Ile-CHN2 (1, R = sBu) was prepared from CH2N2 and Z-L-Ile-OH using the mixed anhydride method. A detailed procedure for the preparation of diazomethyl ketones is given in Section 15.1.2. To a cold (0-5 °C) stirred soln of Z-L-Ile-CHN2 (1, R = sBu 0.8g, 2.8mmol) in dry... 

Scheme 4 General Coupling Procedure for l-Aminoalkylphosphonic Acids by the Mixed Anhydride Method...

Synthesis of Z-Gly-DL-Alap from Alap by the Mixed Anhydride Method Typical Procedure 171... 

Synthesis of Peptides 17 with C-Terminal Phosphonate by the Mixed Anhydride Method General Procedure 1251... 

Various methods can be used to determine the amounts of monoethylaniline and diethylaniline in a given tra xture. One method depends on the determination of the temperature increase occurring when a prescribed amount of the base mixture is mixed with an accurately measured amount of pure acetic anhydride. More reliable and accurate results are obtained, however, by determining the specific gravity of the mixture. From the table below, the composition of the mixture can be determined directly, and with great accuracy, from the density at 15 . It is necessary, of course, that no unchanged aniline be present. This condition is fulfilled in the procedures described above. 

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