Synthesis of a Precursor to Sacubitril Using Enabling Technologies

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Process Chemistry

Background:

• Sacubitril is a crucial neprilysin inhibitor used in treating heart failure.
• Efficient synthesis of sacubitril precursors is vital for pharmaceutical production.
• Existing synthetic routes may have limitations in terms of yield, safety, or scalability.

Purpose of the Study:

• To develop an efficient, safe, and rapid preparation of a key precursor to sacubitril.
• To establish a convergent synthesis incorporating stereoselective steps.
• To integrate machine-assisted methods with traditional batch processes for enhanced production.

Main Methods:

• Convergent synthesis strategy.
• Diastereoselective Reformatsky-type carbethoxyallylation for C-C bond formation.
• Rhodium-catalyzed stereoselective hydrogenation for installing key stereocenters.
• Integration of machine-assisted and batch processing techniques.

Main Results:

• Successful preparation of a sacubitril precursor.
• Installation of two key stereocenters with high stereoselectivity.
• Achieved a 54% overall yield in 7 steps.
• Demonstrated safe and rapid production of key intermediates.

Conclusions:

• The described convergent synthesis is an efficient method for preparing sacubitril precursors.
• The integration of advanced technologies enhances safety and speed in intermediate production.
• This optimized process facilitates the transformation to the target molecule, sacubitril hydrochloride (3·HCl).