Larotrectinib Sulfate Synthesis Solvent Switch
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The existing synthesis process for Larotrectinib often results in high levels of 3-O-sulfonylated impurities, making it difficult to achieve the required purity standards for industrial-scale production, particularly during the precipitation step where ethanol is used, leading to a rubbery precipitate that is hard to manage and high ethanol absorption.
Innovation Solution
Replacing ethanol with dichloromethane in the conversion from hydrochloride salt to sulphate salt, followed by a series of reactions and filtrations, significantly reduces the 3-O-sulfonylated impurity content to less than 0.10% by weight, and using HPLC analysis with S-Larotrectinib as a reference standard for purity evaluation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If ethanol is used in the precipitation step to convert hydrochloride salt to sulphate salt, then the conversion can be achieved, but the precipitate becomes rubbery and difficult to manage, and ethanol absorption increases
Solution Approach 1:
The patent changes the solvent parameter from ethanol to dichloromethane in the precipitation step. This parameter change transforms the nature of the precipitate from rubbery (ethanol-based) to crystalline (dichloromethane-based), making it much easier to filter and handle while maintaining the conversion efficiency from hydrochloride salt to sulphate salt.
2Productivity
If ethanol is used in the synthesis process, then the conversion from hydrochloride salt to sulphate salt is achieved, but the 3-O-sulfonylated impurity content increases
Solution Approach 1:
The patent changes the solvent parameter from ethanol to dichloromethane, which fundamentally alters the reaction environment. This parameter change suppresses the formation of 3-O-sulfonylated impurities while maintaining high conversion efficiency from hydrochloride salt to sulphate salt, achieving both productivity and manufacturing precision improvements.
Solution Approach 2:
The patent converts the harmful effect of ethanol (which causes impurity formation and rubbery precipitate) into a beneficial effect by using dichloromethane instead. The new solvent not only eliminates the harmful impurity formation but also produces a crystalline precipitate that is easier to handle, turning a problematic process into an optimized one.
3Productivity
If ethanol is used in the synthesis process, then the conversion is achieved, but the residual solvent content must be reduced to 0.5% by weight, increasing process complexity
Solution Approach 1:
The patent changes the solvent from ethanol to dichloromethane, which has different solubility and evaporation characteristics. This parameter change reduces the residual solvent content requirement from 0.5% by weight, simplifying the drying and purification steps while maintaining high conversion rate, thus reducing overall process complexity.
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 approach allows for the production of Larotrectinib sulfate with improved purity and reduced residual solvents, meeting international quality standards and simplifying the filtration process by avoiding the challenges associated with ethanol use, thereby enhancing the safety and quality of the final product.
Implementation Method 1
the unblocking reaction of Larotrectinib hydrochloride in dichloromethane, in the presence of bases
Implementation Method 2
the treatment of Larotrectinib obtained in step a) with sulfuric acid in methyl ethyl ketone, and water
Implementation Method 3
the filtration of Larotrectinib sulfate
Implementation Method 4
an HPLC analysis, which uses S-Larotrectinib compound as a reference standard
Data Source
AI summary
The present invention relates to a Larotrectinib synthesis process with a 3-O- sulfonylated impurity content lower than 0.10% by weight. A further object of the invention is the compound 3-O-sulfo-Larotrectinib ((3S)-N-[5-[(2R)-2- (2, 5 -Difluorophenyl)- 1- pyrrolidinyl] pyrazole [1,5- a] pyrimidine-3-yl]-3 -hydroxy sulphonyloxy-1- pyrrolidinecarboxamide), hereinafter referred to as S-Larotrectinib, useful as an analytical standard to evaluate the purity of Larotrectinib.