Introduction Tadalafil (commercially named Cialis™), a drug for the treatment of male erectile dysfunction, is commonly prepared from L-tryptophan through four steps in which different solvents and reagents are used. As it often happens in drug preparation the overall mass index of the preparation is quite low, causing a great amount of waste to be produced. Results Each step of the published synthesis of Tadalafil was investigated in view of the design of a greener and more afficient process by focussing on solvents and on integrating synthetic steps . Dimethylcarbonate proved to be a good greener alternative to traditional solvents (i.e. nitromethane or ethanenitrile) for the diastereoselective Pictet-Spengler reaction (i.e. the second step of the synthesis). Both its lower toxicity and the water immiscibility contribute to the greenness of the procedure. In addition the last two steps of the preparation could be carried out stepwise in the same reactor by using [C4dmim][NTf2] (an ionic liquid) as the solvent. These findings allowed us to propose two alternative processes named A and B. The principal improvements of processes A and B compared to the published synthesis is that they both do without solvents such as CH3CN, toluene, CH2Cl2, DMF and DMSO, and both combine the final two steps of by using an ionic liquid as solvent. Conclusions In summary processes A and B are high-yielding methods for the preparation of Tadalafil using only [C4dmim][NTf2] (an ionic liquid) and dimethylcarbonate as reaction media. Both have a better mass index than the published process, particularly if the the ionic liquid is recycled.

Greener synthesis of Tadalafil using dimethylcarbonate and ionic liquids

NOE', Marco;PEROSA, Alvise
2012-01-01

Abstract

Introduction Tadalafil (commercially named Cialis™), a drug for the treatment of male erectile dysfunction, is commonly prepared from L-tryptophan through four steps in which different solvents and reagents are used. As it often happens in drug preparation the overall mass index of the preparation is quite low, causing a great amount of waste to be produced. Results Each step of the published synthesis of Tadalafil was investigated in view of the design of a greener and more afficient process by focussing on solvents and on integrating synthetic steps . Dimethylcarbonate proved to be a good greener alternative to traditional solvents (i.e. nitromethane or ethanenitrile) for the diastereoselective Pictet-Spengler reaction (i.e. the second step of the synthesis). Both its lower toxicity and the water immiscibility contribute to the greenness of the procedure. In addition the last two steps of the preparation could be carried out stepwise in the same reactor by using [C4dmim][NTf2] (an ionic liquid) as the solvent. These findings allowed us to propose two alternative processes named A and B. The principal improvements of processes A and B compared to the published synthesis is that they both do without solvents such as CH3CN, toluene, CH2Cl2, DMF and DMSO, and both combine the final two steps of by using an ionic liquid as solvent. Conclusions In summary processes A and B are high-yielding methods for the preparation of Tadalafil using only [C4dmim][NTf2] (an ionic liquid) and dimethylcarbonate as reaction media. Both have a better mass index than the published process, particularly if the the ionic liquid is recycled.
2012
Green Solvents Conference
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10278/33148
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