Symmetric anhydride phosgene preparation

The loss of half of the carboxylic acid is no cause for concern in acetylation with acetic anhydride, but appeared to be prohibitive when blocked amino acids, obtained sometimes with considerable effort, had to be sacrificed. This situation changed with time. Protected amino acids are now prepared with increasing facility and decreasing cost and their anhydrides are frequently applied. An interesting but not widely practiced approach to symmetrical anhydrides is the use of phosgene ... 

The most secure procedure for the clean preparation of symmetric anhydrides was found in the use of a 10% excess of free carboxylic component over its triethylammonium salt and a 10% excess of this salt over the equivalents of phosgene added at —40 C. 

The coupling method with symmetric anhydrides prepared with phosgene and used in situ with permanent monitoring of the anhydride by flowthrough IR measurement was practized in the synthesis of several linear decapeptide precursors of antamanide. These were obtained in yields between 84% and 96% and in the synthesis of fully protected somatostatin [71], which was built up on polymer with 83% yield as determined by analytically quantified Edman degradation on pol)oner. 

Though the toxicity and vapor pressure of even dilute solutions of phosgene and the necessity for deep-temperature equipment might be considered deficiencies, we have to state that the preparation of symmetric anhydrides with phosgene and their facile and efficient use on polymer phase seem to predestinate this method of activation to the Merrifield synthesis, since all chemical problems depending on dicyclohexylcarbodiimide are circumvented, the wash-out operations (excluding sodium chloride) are simplified, and excess N-protected amino acids are to be recovered pure and in high yield. 

Fig. 45. IR spectra of pure (a) and impure (b) symmetric amino add anhydrides prepared with phosgene...

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