Acylation isosorbide

The molecular structures of the two diastereoisomers of the 5-0-acyl substituted isosorbide derivative 5-[l,4-dihydro-3-(methoxycarbonyl)-2,6-... 

In connection with the elaboration of specific procedures for the manufacture of both of the isosorbide mononitrates, methods were developed to shift, with high regioselectivity, the course of the acylation reaction either towards the 5 (endo) or the 2 (exo) position, depending on the conditions applied.104-106 Thus, isosorbide 5-acylates are obtained in 70-85% yield when 3 is treated with the appropriate acid anhydride in the presence of lead(II) oxide or acetate for 20 to 40 h at room temperature. To avoid transesterifications to the appropriate 2-acylate, the workup procedures, especially during the distillation, have to be conducted under strictly neutral conditions. The contrary effect, a remarkable enrichment by the isosorbide 2-acylate (up to 90%) is realized by a transesterification process mediated by a small proportion of sodium or potassium carbonate, hydroxide, or meth-oxide, which are added to the acylation mixture from isosorbide at HOMO0, and subsequent removal of the 2-acylate by vacuum distillation.104 These two regioselective acylation methods may be used for aliphatic, as well as for aromatic, carboxylic acid anhydrides. 

Isosorbide 2-acetate may also be prepared by transesterification of equimolar amounts of isosorbide 2,5-diacetate and isosorbide in the presence of acidic or basic catalysts (KOH or p-toluenesulfonic acid, for 1 hat 140°, and distillation104,107 of the 2-acetate at 100° at 27 kPa 89%). Subsequent esterification of the resulting isosorbide mononitrates with acyl and aroyl halides... 

Isosorbide 2- and 5-nitrates substituted at the second hydroxyl group by a number of aliphatic, aromatic, and cinnamic acids (78, R = various acyl groups) have been claimed to be useful in vasodilating therapy.111 However, it was confirmed by the authors that there seems to be no direct correlation between lipophilicity and therapeutic activity, and that structure-activity relationships in the isosorbide nitrate area are more complex than that. 

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