Lurasidone Hydrochloride Synthesis via Safer Reduction
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Solution Overview
Problem
Existing processes for preparing lurasidone hydrochloride are not suitable for large-scale commercial production due to the use of pyrophoric reagents, costly phase transfer catalysts, high residual solvent levels, and complex purification steps, which increase costs and reduce yield.
Innovation Solution
A novel process involving the conversion of (R,R)-cyclohexane-1,2-diyl)bis((1H-imidazol-1-yl)methanone) to trans(R,R)-1,2-bis(hydroxymethyl)cyclohexane, followed by reduction and subsequent steps to produce lurasidone hydrochloride, which is substantially free of residual solvents and uses cost-effective methods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If lithium aluminium hydride is used for reduction, then the reduction reaction proceeds effectively, but the reagent is highly pyrophoric and causes handling problems on commercial scale
Solution Approach 1:
The patent replaces the expensive and hazardous lithium aluminium hydride with cheaper, safer reducing agents such as sodium borohydride or calcium borohydride. These reagents are less pyrophoric and can be handled more safely on commercial scale while still achieving the required reduction of the imidazole compound to the cyclohexane diol.
Solution Approach 2:
The patent changes the reaction parameters by using different solvents and conditions. Instead of requiring strictly anhydrous conditions with lithium aluminium hydride, the invention uses solvents like ethanol, methanol, or THF with sodium borohydride, which are less sensitive to moisture and easier to handle commercially.
2Manufacturing precision
If column chromatography is used for purification, then pure lurasidone is obtained, but the process is not viable on commercial scale
Solution Approach 1:
The patent eliminates the column chromatography step by using alternative purification methods such as filtration, washing with solvents, and recrystallization. These methods remove impurities effectively while being scalable to commercial production, replacing the laboratory-scale column chromatography with industrial-appropriate techniques.
Solution Approach 2:
The invention uses filtration and washing steps where impurities are discarded as solids or soluble contaminants, and the desired product is recovered in high purity form. This approach replaces the gradual purification of chromatography with a more efficient solid-liquid separation process suitable for large-scale manufacturing.
3Productivity
If dibenzo-18-crown-6-ether is used as phase transfer catalyst, then the reaction proceeds efficiently, but the catalyst is costly and increases production cost
Solution Approach 1:
The patent replaces the expensive dibenzo-18-crown-6-ether phase transfer catalyst with cheaper alternatives such as tetrabutylammonium bromide, tetraheptylammonium bromide, or even simple inorganic bases like potassium carbonate or sodium bicarbonate. These substitutes maintain adequate reaction efficiency while dramatically reducing catalyst cost.
Solution Approach 2:
The invention uses different intermediary substances to facilitate the reaction between organic and aqueous phases. Instead of the crown ether complexing with metal ions, the patent employs quaternary ammonium salts or simple carbonate/bicarbonate buffers that mediate the reaction through different mechanisms, achieving the same practical result at lower cost.
4Manufacturing precision
If resolution is carried out in the last stage, then the enantiopure product is obtained, but the process affects overall yield and is not suitable for industrial scale
Solution Approach 1:
The patent performs resolution at an earlier stage in the synthesis pathway, resolving the racemic mixture before subsequent reaction steps. This preliminary resolution ensures that only the desired enantiomer proceeds through the remaining synthesis steps, avoiding yield losses that would occur if resolution were performed after all transformations are complete.
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 cost-effective and industrially viable production of lurasidone hydrochloride with reduced residual solvent content, making it suitable for commercial use as a drug, while avoiding the limitations of previous methods.
Implementation Method 1
converting ((R,R)-cyclohexane-1,2-diyl)bis((1H-imidazol-1-yl)methanone) to trans(R,R)-1,2-bis(hydroxymethyl)cyclohexane
Data Source
AI summary
Disclosed herein is an improved process for the preparation of Lurasidone and its pharmaceutically acceptable salts via novel intermediate and use thereof for the preparation of an antipsychotic agent useful for the treatment of schizophrenia and bipolar disorder. Further, present invention provides a cost effective and eco-friendly process for producing Lurasidone hydrochloride of formula (I) substantially free of residual solvent(s) at industrial scale.