Lurasidone Synthesis Using Protic Solvent Mixture
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing processes for synthesizing Lurasidone and its intermediates rely on toxic and costly solvents like acetonitrile, requiring high temperatures and complex workup procedures, making them industrially inefficient and environmentally unfriendly.
Innovation Solution
A process using a mixture of protic solvents, specifically an alcoholic solvent and water, in the presence of a base to react compounds III and IV, achieving high yield and purity of (3aR,7aR)-4′-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1′-piperazin]-1′-ium methanesulfonate, which is then converted into Lurasidone, eliminating the need for toxic solvents and harsh purification steps.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If acetonitrile is used as solvent in the synthesis process, then the reaction can proceed, but the process becomes toxic and environmentally unfriendly
Solution Approach 1:
The patent changes the solvent parameter from acetonitrile to a mixture of protic solvents (alcoholic solvent and water). This parameter change eliminates toxicity while maintaining the reaction's manufacturability, as the protic solvent mixture allows the quaternary ammonium salt formation to proceed effectively without harmful substances.
2Ease of manufacture
If acetonitrile is used as solvent, then the synthesis can be performed, but the cost increases
Solution Approach 1:
The patent replaces expensive acetonitrile with a cost-effective mixture of protic solvents (alcoholic solvent and water). These cheaper solvents maintain the necessary reaction conditions for synthesizing the quaternary ammonium salt, significantly reducing material costs while preserving manufacturability.
3Productivity
If high temperature is used for the reaction, then the reaction rate increases, but the workup procedure becomes complex
Solution Approach 1:
The patent changes the solvent system parameter to a mixture of protic solvents, which enables the reaction to proceed at moderate temperatures with improved reaction rates. This parameter change simultaneously simplifies the workup procedure by improving product solubility and facilitating easier separation, thus resolving the contradiction between reaction rate and workup complexity.
4Ease of manufacture
If conventional solvents are used, then the synthesis process is established, but the purity of the product decreases
Solution Approach 1:
The patent changes the solvent parameter from conventional acetonitrile to a mixture of protic solvents (alcoholic solvent and water). This parameter change enhances product purity by improving solubility characteristics and facilitating better separation during workup, while the process remains manufacturable using these alternative solvents.
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 yield of 85-90% with ≥99% purity, reducing impurities to less than 0.06% and eliminating the use of toxic solvents, making it environmentally friendly and cost-effective for large-scale production.
Implementation Method 1
reacting the compound-III with the compound-IV in a mixture of protic solvents; in the presence of a base to obtain the compound II
Implementation Method 2
reacting the compound-III with the compound-IV in a mixture of protic solvents consisting of an alcoholic solvent and water
Data Source
AI summary
The present invention provides an improved process for preparation of the substantially pure (3aR,7aR)-4′-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1′-piperazin]-1′-ium methanesulfonate (referred to as compound-II), which is useful as a key intermediate for the synthesis of lurasidone ((3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione). The process comprises reaction of the compound-III (as described herein) with the compound-IV (as described herein) in the presence of a solvent mixture selected from an alcohol and water; and a base The improved process for the preparation of compound II provides the product with total amount of unreacted compound-IV as impurity in less than 0.06% and the product with HPLC purity as ≥99.8%. The process further refers purification of Lurasidone hydrochloride, wherein the product contains the residual acetone <5000 ppm.