Concept and synthetic approach for a kilogram scale synthesis of octa-d-arginine amide nonahydrochloride salt

Oligomers of arginine, such as octa-d-arginine amide, are excellent transporters for active drugs through cell membranes and tissue. The synthesis of octa-d-arginine amide, as the nonahydrochloride salt, was approached via a solution phase synthetic route involving the preparation of an octa-d-ornithine intermediate, which was then converted into the desired octa-d-arginine compound through a guanidinylation step. The multi-step synthesis was carried out at pilot scale, resulting in the preparation of 700 g of the target molecule. No chromatographic purification was needed at any step of the process.     

Solvent-free synthesis of azole carboximidamides

A one-pot procedure is described for the preparation of 1H-pyrazole-carboximidamides 2, 1H-benzotriazole-carboximidamides 3 and guanidinylation of amines with 3. The X-ray crystal structure of N,N-dimethyl-1H-benzotriazole-1-carboximidamide 3b, has been determined.     

Concise total synthesis of phidianidine A and B

The shortest total synthesis of cytotoxic indole alkaloids phidianidine A and B is described. Rapid assembly of the 1,2,4-oxadiazole core from a novel N-hydroxyguanidine and the corresponding indole-3-acetic acid chloride led to formal syntheses of phidianidine A and B in only three steps from known compounds. Deprotection under standard conditions provided the trifluoroacetate salts of phidianidine A and B in quantitative yield.     

The utilization of ball milling in synthesis of aryl guanidines through guanidinylation and N-Boc-deprotection sequence

Solid state ball milling was used in guanidinylation reactions of aromatic amines with N,N′-Di-Boc-1H-pyrazole-1-carboxamidine reagent. Reaction conditions are advantageous, and in general reactions proceed in significantly shorter reaction times and in higher yields than under the conventional solution conditions. Mechanochemical conditions were also successfully applied to the cleavage of N-Boc protecting group.