Neramexane Synthesis via Direct Conversion and Purification Removal
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Solution Overview
Problem
Current methods for preparing 1-amino-1,3,3,5,5-pentamethylcyclohexane (Neramexane) are inefficient, resulting in low yields and significant waste production, making large-scale industrial production economically unfeasible.
Innovation Solution
A method involving specific steps such as converting isophorone to 3,3,5,5-tetramethylcyclohexanone with methylmagnesium chloride, followed by conversion to 1-hydroxy-1,3,3,5,5-pentamethylcyclohexane and then to 1-chloroacetamido-1,3,3,5,5-pentamethylcyclohexane, without the need for intermediate purification, allowing for the direct production of Neramexane with improved yield and reduced waste.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If traditional five-step reaction sequence with intermediate purification is used, then product purity is maintained, but manufacturing complexity and time increase
Solution Approach 1:
The patent removes the intermediate purification steps (distillation and chromatography) from the traditional five-step reaction sequence, extracting only the essential reaction steps while eliminating redundant purification operations. This reduces process complexity from five steps to three steps, while maintaining acceptable product purity through direct conversion of intermediates.
Solution Approach 2:
The patent merges multiple operations into fewer steps by performing direct conversions without isolation. The crude intermediates from step (i) are directly used in step (ii), and the crude product from step (ii) is directly used in step (iii), combining what were previously separate reaction and purification cycles into a continuous process.
2Manufacturing precision
If traditional five-step reaction sequence with intermediate purification is used, then product purity is maintained, but production time increases
Solution Approach 1:
The patent establishes continuous useful action by eliminating idle time associated with purification operations. The reaction mixture from step (i) is directly subjected to step (ii) without purification interruption, and the product from step (ii) is directly used in step (iii), creating an uninterrupted synthetic sequence that reduces total production time.
Solution Approach 2:
The patent skips the time-consuming purification steps (distillation and chromatography) that were traditionally performed between reactions. By rushing through directly from one reaction to the next using crude intermediates, the overall production time is significantly reduced while still achieving acceptable product quality.
3Reliability
If traditional five-step reaction sequence is used, then complete reaction pathway is covered, but overall yield decreases
Solution Approach 1:
The patent extracts and eliminates the purification steps that caused material loss in the traditional sequence. By removing distillation and chromatography operations, the material that would have been lost during these purification processes is retained in the final product, improving overall yield from approximately 50% to at least 60%.
4Loss of substance
If traditional five-step reaction sequence with purification steps is used, then waste is minimized through proper separation, but manufacturing cost increases
Solution Approach 1:
The patent applies self-service by allowing the reaction system to handle its own by-products and impurities without requiring separate purification operations. The crude intermediates are directly used in subsequent reactions, and the final purification is achieved through a single recrystallization step, reducing both waste and manufacturing cost.
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 method achieves a yield of at least 60% of Neramexane, enabling economical industrial-scale production by omitting complex purification steps and minimizing waste, while maintaining sufficient product purity for medicinal applications.
Implementation Method 1
converting isophorone to 3,3,5,5-tetramethylcyclohexanone in the presence of methylmagnesium chloride
Implementation Method 2
converting 3,3,5,5-tetramethylcyclohexanone to 1-hydroxy-1,3,3,5,5-pentamethylcyclohexane in the presence of methylmagnesium chloride
Implementation Method 3
converting 1-hydroxy-1,3,3,5,5-pentamethylcyclohexane to 1-chloroacetamido-1,3,3,5,5-pentamethylcyclohexane in the presence of chloroacetonitrile in acidic solution
Implementation Method 4
converting 1-chloroacetamido-1,3,3,5,5-pentamethylcyclohexane to 1-amino-1,3,3,5,5-pentamethylcyclohexane in the presence of thiourea in water
Data Source
Figure 1~2
Figure 3
Figure 4~5
AI summary
Method of preparing 1-amino-1,3,3,5,5-pentamethylcyclohexane or a pharmaceutically acceptable salt thereof, comprising at least two steps selected from the following steps (i) to (iv): (i) converting isophorone to 3,3,5,5-tetramethylcyclohexanone in the presence of methylmagnesium chloride; (N) converting 3,3,5,5-tetramethylcyclohexanone to 1-hydroxy-1,3,3,5,5- pentamethylcyclohexane in the presence of methylmagnesium chloride; (iii) converting 1-hydroxy-1,3,3,5,5-pentamethylcyclohexane to 1-chloroacetamido- 1,3,3,5,5-pentamethylcyclohexane in the presence of chloroacetonitrile in acidic solution; (iv) converting 1-chloroacetamido-1,3,3,5,5-pentamethylcyclohexane to 1-amino- 1,3,3,5,5-pentamethylcyclohexane in the presence of thiourea in water.