Monoacylglycerol Lipase Inhibitor Manufacturing via Controlled Crystallization
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Solution Overview
Problem
Current manufacturing processes for 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate are not optimal for industrial-scale production and pharmaceutical development due to issues with processability and reproducibility.
Innovation Solution
A new process involving the reaction of tert-butyl piperazine-1-carboxylate with hexafluoropropan-2-ol in the presence of an acyl transfer agent, followed by reaction with a strong acid and subsequent reductive amination with 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde, using less toxic solvents and specific solvents like ethyl acetate to achieve high yields and controlled crystallization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If the current manufacturing process from WO 2013/103973 is used, then the compound can be prepared, but the process is not optimal for industrial scale applicability
Solution Approach 1:
The patent changes key process parameters including solvent selection (using ethyl acetate and isopropanol instead of traditional solvents), reaction temperature (38-70°C dissolution, 70-76°C salt formation), and pH control during salt formation to optimize the manufacturing process for industrial scale while maintaining product quality
Solution Approach 2:
The patent utilizes controlled crystallization through phase transition, dissolving the compound at elevated temperature (38-70°C) and then cooling the solution to induce controlled crystal formation during salt formation (cooling to 10-40°C), which improves processability and enables scalable production
2Reliability
If the process from WO 2018/093953 is used, then the mono-hydrochloride salt form can be manufactured, but it is not optimal for pharmaceutical development regarding processability and industrial production
Solution Approach 1:
The patent optimizes parameters for salt formation including using isopropanol as solvent, controlling HCl addition rate and temperature (70-76°C), and maintaining specific pH ranges to achieve reproducible crystallization of the mono-hydrochloride salt form with improved processability for pharmaceutical development
Solution Approach 2:
The patent implements feedback control through monitoring pH during salt formation and adjusting HCl addition accordingly, and through controlled cooling rates during crystallization to ensure reproducible product quality and enable scalable industrial production
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 enables scalable, high-yield production of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate with improved particle size distribution suitable for pharmaceutical applications, such as tablet formulation, and reduces environmental impact and costs.
Implementation Method 1
reacting tert-butyl piperazine-1-carboxylate with hexafluoropropan-2-ol in the presence of an acyl transfer agent to form 1-(tert-butyl) 4-(1,1,1,3,3,3-hexafluoropropan-2-yl) piperazine-1,4-dicarboxylate
Implementation Method 2
reacting 1-(tert-butyl) 4-(1,1,1,3,3,3-hexafluoropropan-2-yl) piperazine-1,4-dicarboxylate obtained in step a) with a strong acid to form 1,1,1,3,3,3-hexafluoropropan-2-yl piperazine-1-carboxylate
Implementation Method 3
reacting 1,1,1,3,3,3-hexafluoropropan-2-yl piperazine-1-carboxylate obtained in step b) with 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde in the presence of a reducing agent and an organic base to form a reaction mixture comprising 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate
Implementation Method 4
dissolving 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate in a sixth solvent at a temperature of 38-70° C., optionally under stirring
Implementation Method 5
cooling the suspension from 63-69° C. to a temperature of 10-40° C., preferably at a temperature of 16-23° C. during a period between 12-20 hours under stirring
Data Source
AI summary
Described herein is the manufacture of MAGL inhibitor 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate including salts thereof.