Brief Introduction of Synthesis of Amides by Mixed Anhydride Method

Brief Introduction of Synthesis of Amides by Mixed Anhydride Method

The mixed anhydride method was developed in the early 1950s. Beginning with mixed anhydrides of acylamino acids with diphenylphosphoric acid, mixed anhydrides with dibenzylphosphoric acid, and mixed anhydrides with benzoic acid. When the mixed anhydride formed by benzyloxycarbonylamino acid and benzoic acid reacts with the amino component, a by-product of the benzoylation of the amino component will be formed. To suppress this side reaction, mixed anhydrides formed with other carboxylic acids with higher electron density or greater steric hindrance on the carboxyl carbon atom were used later. On the other hand, Wielnad and Boisosnnas developed the reaction of triethylamine salt of acyl amino acid with equivalent ethyl chloroformate to form mixed anhydride, which can obtain a high peptide yield with the amino component. The mixed anhydride formed by the reaction with isobutyl chloroformate can further increase the yield. This is the mixed anhydride method that was later successfully and widely used in peptide synthesis. The mixed anhydride method is introduced as follows:

(1) Chloroformate method: The main application is to react carboxylic acid with ethyl chloroformate or isobutyl ester to form mixed anhydride, and then react with amine to obtain the corresponding amide. In this reaction, if the A-site of the acid is hindered or has an electron-withdrawing group, it will sometimes stop at the mixed anhydride step. But heating can promote its reaction; this reaction can also be used for the synthesis of unsubstituted amides.

(2) Carbonyl diimidazole method: carbonyl diimidazole (CDI) is used to react with carboxylic acid to obtain acyl imidazoles with high activity. Many acyl imidazoles have a certain stability and can sometimes be separated. But generally speaking, it does not need to be separated, and the reaction solution directly reacts with the amine to prepare the corresponding amide; the dimethylated trifluoromethane sulfonate (CBMIT) obtained by the reaction of carbonyldiimidazole and methyl triflate is reported in the literature. ) has a better condensation performance. In this type of reaction, because CDI or CBMIT will react with excess amine to obtain a by-product of urea, the amount must be strictly controlled at 1 equivalent.

(3) Sulfonyl chloride method: Another commonly used method is carboxylic acid and sulfonyl chloride to generate carboxylic acid-sulfonic acid mixed anhydride, which reacts with amine to obtain the corresponding amide. Commonly used sulfonyl chlorides include methane sulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), and nitrobenzene sulfonyl chloride(NaCl). Due to its electron-withdrawing properties, p-nitrobenzene sulfonyl chloride reacts with acids to generate higher activity The mixed acid anhydrides, general secondary amines and tertiary amines, and even amines with large steric hindrance can react smoothly.

(4) Boc anhydride method: the mixed anhydride obtained by reacting acid and Boc anhydride reacts with ammonia to obtain the corresponding primary amide.

(5) Diphenylphosphinyl chloride method: A mixed acid anhydride is obtained by acid and diphenylphosphinyl chloride, and then reacted with ammonia to obtain the corresponding amide. Ph2P(O)Cl can activate carboxylic acids by forming diphenylphosphine anhydride (DPP). The mixed anhydride has more advantages than the mixed anhydride of two carboxylic acids in the synthesis because the nucleophile is more likely to attack the carbonyl group, which solves the position selection problem when the two carboxylic acid mixed anhydrides react. In addition, the mixed anhydride has a stronger electrophilic ability, and the mixed anhydride is formed quickly, shortening the reaction time. DPP can be used to prepare amides of alkyl carboxylic acids, and the yield of primary amines is higher than that of secondary amines.

(6) 2,4,6-TrichlorobenzylAcid chloride method: react with acid and 2,4,6-trichlorobenzoyl chloride to obtain mixed acid anhydride, and then react with ammonia to obtain amide.

The advantages of the mixed acid anhydride method are that the method is simple, the reaction speed is fast, it is relatively easy to obtain high-purity peptides, and the yield is generally good. And the preparation of chloroformate reagents is not difficult and cheap. From an economic point of view, the mixed anhydride method can be said to be the cheapest method for the mass preparation of peptides, so it is also a more commonly used method.