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Acid Azide Method for Peptide Synthesis

As early in 1902, Theodor Curtius introduced acid azide to peptide chemistry, so it was one of the oldest condensation methods. In alkaline aqueous solutions, amino acid esters can be used in organic solvents besides the free amino acids and peptides that are condensated with acyl azide. It is different from many other methods of condensation, and it does not need to increase the auxiliary alkali or other equivalent amino components to capture the hydrazonic acid.

For a long time, it has been considered that the method of azote is the only method of condensation that does not occur racemization. With the introduction of the amino acid protection base of selective cracking, this method has undergone a major renaissance. The initial raw materials by this method are crystalline amino acid hydrazide and peptide hydrazide 64, the corresponding ester is easy to obtain by hydrazide. In - 10 ℃ by using sodium nitrite of equivalent hydrazide nitrosation, hydrochloric acid is produced for transforming into acid azide 65, in turn, washing, drying, and then react with the corresponding amino component. Some of the acid azide is diluted with ice water and precipitated.

Diphenylphosphoryl azide nitride (DPPA) can also be used for synthesis of acyl azide. The Honzl-Rudinger method uses tert butyl nitrite as a nitrosification reagent, and the condensation reaction of azo can be prepared in organic solvents. Because of the thermal instability of the acyl azide, the condensation reaction should be prepared at a low temperature. When the temperature is high, the Curtius is rearranged, the reaction of transforming acyl azide into isocyanate is a major sub-reaction, resulting in the production of the by-product urea. Because the low temperature (4 ℃) causes the reaction rate is fairly slow, making the peptide condensation reaction usually take a few days to be completed.

For long peptide chains of N-terminal protection, the hydrazinolysis of ester is generally difficult, therefore, it is an option to use the orthogonal N to protect hydrazine derivatives. After the selective removal of hydrazide, the peptide fragments of the backing-off strategy components can be used for azide condensation.

As mentioned above, although the azide method is always considered to be the smallest condensation method, but in the reaction, too much alkali can induce a considerable amount of racemization. Therefore, It should be avoided to contact with alkali during condensation reaction, for example, the ammonium salt of amino component should be neutralized by N, N-diisopropylamine or N-alkyl morpholine instead of triethylamine.

Despite these limitations, this method is still very important, especially for the fragment condensation. Because this method has lower tendency of isomerization, and it is suitable for hydroxyl that did not protect the serine or threonine components. At the same time, the N ˊ protection hydrazide also has various purposes.