Continuous Flow Pridopidine Synthesis Reducing Energy and Impurities
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Solution Overview
Problem
The existing process for synthesizing pridopidine hydrochloride requires harsh conditions, including extreme temperatures, distillation, and extractions, which are energy-intensive and inefficient, leading to low assay purity and residual impurities.
Innovation Solution
A modified process involving a continuous flow reactor for halogen-lithium exchange and coupling reactions at higher temperatures, followed by optimized work-ups to isolate pridopidine base and subsequent conversion to hydrochloride, reducing the need for cryogenic systems and improving chemical purity and yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If harsh conditions including extreme temperatures, distillation, and extractions are used in the existing process, then pridopidine hydrochloride can be synthesized, but energy consumption increases and assay purity decreases
Solution Approach 1:
The patent changes the temperature parameter from extreme/cryogenic conditions to higher temperatures (20-50°C for lithiation, 60-80°C for coupling reactions). This parameter change eliminates the need for cryogenic systems while improving assay purity to >98% and reducing energy consumption significantly.
Solution Approach 2:
The patent eliminates the distillation and extraction steps from the synthesis process. The continuous flow reactor design allows direct conversion of reactants to product without requiring separate purification steps through distillation or liquid-liquid extraction, thereby reducing energy consumption and improving overall process efficiency.
2Ease of manufacture
If cryogenic systems are used for halogen-lithium exchange and coupling reactions, then reactions can proceed, but device complexity and energy consumption increase
Solution Approach 1:
The patent changes the temperature parameter from cryogenic (-78°C or lower) to higher temperatures (20-50°C for lithiation, 60-80°C for coupling). This eliminates the need for complex cryogenic systems including liquid nitrogen tanks, cooling coils, and temperature control mechanisms, significantly simplifying the device while maintaining reaction efficiency.
Solution Approach 2:
The patent employs a continuous flow reactor design where reactants flow continuously through the reaction zones at controlled temperatures. This continuous process eliminates the need for batch-wise cryogenic cooling and heating, reducing device complexity and enabling easier manufacturing scale-up.
3Productivity
If traditional batch processing with multiple steps is used, then pridopidine can be synthesized, but productivity decreases and time consumption increases
Solution Approach 1:
The patent merges the halogen-lithium exchange and coupling reactions into a single continuous flow reactor system. Multiple reaction steps that traditionally required separate batch operations are combined into one continuous process, eliminating intermediate handling, filtration, and solvent exchange steps, thereby increasing productivity and reducing process time.
Solution Approach 2:
The continuous flow reactor enables uninterrupted synthesis where reactants are continuously converted to product. This eliminates the downtime between batch operations, including setup, heating/cooling cycles, and manual intervention, significantly improving synthesis efficiency and reducing overall process time.
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 higher assay purity and yield of pridopidine hydrochloride with reduced energy consumption and minimal residual impurities, addressing the inefficiencies of the traditional method.
Implementation Method 1
A modified process involving a continuous flow reactor for halogen-lithium exchange and coupling reactions
Implementation Method 2
the catalytic reduction of the compound of Compound 8 at a predetermined reduction temperature and with an amount of a reduction catalyst to form pridopidine base
Implementation Method 3
precipitating pridopidine base from the solution with a volume of one or more alkanes to form solid pridopidine base
Implementation Method 4
removing an amount of the organic solvent under vacuum distillation to obtain a mixture comprising a volume of the organic solvent
Implementation Method 5
the process comprises adding a strong base to the solution, wherein the strong base is added until the pH of the solution is pH 8- 14, pH 11-14 or pH 13
Data Source
AI summary
This invention provides a pridopidine base in a solid form, a method of preparing the solid pridopidine base, and a composition comprising the pridopidine base including a pharmaceutical composition.