Benzoate Salt Preparation via Solvent Exchange
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Solution Overview
Problem
Existing processes for synthesizing the LSD1 inhibitor Compound (A) and its benzoate salt result in high impurity levels and are not scalable or reproducible.
Innovation Solution
A process involving solvent exchange from 2-methyl tetrahydrofuran (2-Me THF) to isopropyl alcohol (IPA) is used to prepare the benzoate salt of Compound (A), avoiding the isolation of Compound (A) as a dry solid and reducing impurities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If multi-step synthetic routes are used to prepare Compound (A) and its benzoate salt, then the compound can be synthesized, but impurities from various steps are carried into the final product
Solution Approach 1:
The patent extracts and removes impurities from the reaction mixture through selective extraction steps. The process extracts Compound (A) into 2-Me THF from the reaction mixture, then performs a second extraction to remove impurities, effectively separating the desired product from contaminants without requiring multiple synthesis steps
Solution Approach 2:
The patent changes the physical-chemical parameters of the system by introducing specific solvents (2-Me THF, IPA, benzoic acid) to alter the solubility and extraction efficiency. The solvent exchange from 2-Me THF to IPA, followed by benzoic acid addition, changes the chemical environment to facilitate pure product formation and salt conversion
2Productivity
If traditional synthesis processes are used, then Compound (A) can be produced, but the process is not scalable or reproducible
Solution Approach 1:
The patent implements a continuous process where Compound (A) is extracted directly from the reaction mixture into 2-Me THF, then undergoes solvent exchange to IPA, and finally converts to benzoate salt in sequence without isolation steps. This continuous flow of useful actions ensures scalability and reproducibility while maintaining high purity
Solution Approach 2:
The patent systematically changes solvent parameters (from reaction mixture to 2-Me THF, then to IPA, and finally adding benzoic acid) to control the chemical environment throughout the process. These parameter changes ensure consistent and reproducible results that can be scaled up while achieving high purity products
3Ease of manufacture
If Compound (A) is isolated as a dry solid intermediate, then the synthesis can proceed in traditional steps, but a solvent removal step is required which adds complexity
Solution Approach 1:
The patent performs preliminary solvent exchange from 2-Me THF to IPA before the final benzoate salt formation step. This preliminary action prepares the system in advance for the salt conversion, eliminating the need for subsequent solvent removal steps and streamlining the manufacturing process
Solution Approach 2:
The patent merges the solvent exchange step with the benzoate salt formation step by performing both operations in the same reaction medium (IPA). This combines what would traditionally be separate steps into one continuous operation, reducing overall process time and 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
The process achieves a high-purity benzoate salt of Compound (A) with reduced impurities, is scalable, and reproducible, improving the morphology and purity of the final product.
Implementation Method 1
extracting Compound (A) into 2-methyl tetrahydrofuran (2-Me THF) from a reaction mixture comprising Compound (A) to obtain a solution of Compound (A) in 2-Me THF
Implementation Method 2
conducting a solvent exchange from 2-Me THF to isopropyl alcohol (IPA) to obtain a solution of Compound (A) in IPA
Implementation Method 3
adding benzoic acid to the solution of Compound (A) in IPA under conditions sufficient to obtain benzoate salt of Compound (A)
Data Source
AI summary
A process for preparation of benzoate salt of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile, designated herein as Compound (A), and methods of using Compound (A) are provided. (I)