Phase Separation Macrocyclization in a Complex Pharmaceutical Setting: Application toward the Synthesis of Vaniprevir

Area of Science:

• Organic Chemistry
• Chemical Engineering
• Medicinal Chemistry

Background:

• Traditional synthesis of macrocyclic compounds often requires slow addition and high dilution techniques, leading to long reaction times and low concentrations.
• The macrocyclic core of complex pharmaceuticals, such as vaniprevir, presents synthetic challenges due to these limitations.

Purpose of the Study:

• To develop a more efficient synthetic strategy for macrocyclic compounds.
• To apply a phase separation/continuous flow approach for the synthesis of the vaniprevir macrocyclic core.
• To investigate the use of dendritic polyethylene glycol (PEG) cosolvents in this strategy.

Main Methods:

• Utilized an oxidative Glaser-Hay coupling of alkynes within a phase separation/continuous flow system.
• Compared the efficiency of this strategy against conventional slow addition/high dilution methods.
• Incorporated dendritic PEG cosolvents to facilitate macrocyclization at higher concentrations.

Main Results:

• The phase separation/continuous flow strategy yielded comparable results to traditional methods but at 100-500 times higher concentrations and with significantly shorter reaction times.
• Dendritic PEG cosolvents were successfully employed for the first time in this phase separation strategy.
• Productive macrocyclization was achieved at concentrations up to 200 mM using dendritic PEG cosolvents.

Conclusions:

• The phase separation/continuous flow strategy offers a more concentrated and faster alternative for synthesizing macrocyclic compounds.
• The use of dendritic PEG cosolvents enhances the efficiency of macrocyclization under concentrated conditions.
• This approach holds promise for the scalable synthesis of complex pharmaceutical intermediates like vaniprevir.