Transition Metal Catalyzed Synthesis of NEP Inhibitor Intermediates
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Solution Overview
Problem
Current processes for producing NEP inhibitors, such as N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid or its ester, are not economically viable for large-scale manufacture and lack efficient alternative routes for intermediates.
Innovation Solution
A new process involving the conversion of a compound of formula (1) into a compound of formula (3) using a transition metal catalyst, optionally with a base, to produce NEP inhibitors or their prodrugs, specifically utilizing palladium or other transition metals like Ruthenium, Rhodium, or Platinum as catalysts.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional processes are used for producing NEP inhibitors, then the synthesis can be performed with existing methods, but the process is not economically viable for large-scale manufacture and lacks efficiency
Solution Approach 1:
The patent changes the reaction parameters by using transition metal catalysts (palladium, ruthenium, rhodium, or platinum) instead of conventional catalysts, and by optimizing the base selection (carbonates, bicarbonates, hydroxides, or amine bases). These parameter changes improve diastereoselectivity and synthesis efficiency, making the process economically viable for large-scale manufacture while maintaining ease of manufacture through well-established catalytic chemistry
2Manufacturing precision
If alternative routes are developed for preparing intermediates, then synthesis efficiency and diastereoselectivity are improved, but the process complexity increases
Solution Approach 1:
The patent introduces transition metal catalysts as intermediaries to mediate the conversion of compound (1) to compound (3). The catalyst system (palladium, ruthenium, rhodium, or platinum with appropriate ligands) acts as a mediator that enables high diastereoselectivity through controlled catalytic cycles. The base serves as another intermediary to facilitate the reaction. This intermediary approach improves manufacturing precision without requiring complex process equipment, thereby limiting the increase in device complexity
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This process provides an economically advantageous alternative for large-scale production of NEP inhibitors by improving the synthesis efficiency and diastereoselectivity, making it suitable for pharmaceutical manufacturing.
Implementation Method 1
reacting a compound of formula (1) with a transition metal catalyst, optionally in the presence of a base, to obtain the compound of formula (3)
Data Source
AI summary
The invention relates to a new process for producing useful intermediates for the manufacture of NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a y-amino-5-biphenyl-a-methylalkanoic acid, or acid ester, backbone, such as N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester or salt thereof.