Non-Solvate Free Base Crystals for Monophosphate Salt Purity
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Solution Overview
Problem
Existing methods do not provide specific crystalline forms of the (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one free base, leading to impurities in the preparation of its monophosphate salt crystals.
Innovation Solution
The compound is synthesized in a non-solvate crystalline form using a combination of solvents like methanol and ethanol, allowing for accurate determination of phosphoric acid ratio, resulting in stable and reproducible monophosphate salt crystals.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If amorphous form or oil form of Compound A is used, then the compound can be obtained in many solvent systems, but impurities are introduced in the preparation of monophosphate salt crystals
Solution Approach 1:
The invention changes the physical state parameter of Compound A from amorphous/oil form to crystalline free base form. This parameter change enables the compound to be used in specific solvent systems (methanol, ethanol, isopropanol) while eliminating impurities in the monophosphate salt crystal preparation process
Solution Approach 2:
The invention uses readily available alcohols (methanol, ethanol, isopropanol) as solvent systems to crystallize Compound A. These common, inexpensive solvents enable the formation of pure crystalline free base that can be easily processed into monophosphate salt crystals without introducing impurities
2Productivity
If stoichiometric amount of phosphoric acid is precisely controlled, then monophosphate salt crystals can be produced efficiently, but the process requires very well-controlled conditions
Solution Approach 1:
The invention performs preliminary crystallization of Compound A in free base form using alcohol solvents before the salt formation step. This preliminary action purifies the compound and establishes a well-defined starting material that enables straightforward stoichiometric control in the subsequent phosphoric acid reaction, reducing process complexity
Solution Approach 2:
The invention applies different solvent qualities at different stages: alcohol solvents (methanol, ethanol, isopropanol) are used specifically for the crystallization stage to obtain pure free base, while other solvents can be used for the salt formation stage. This localized quality approach optimizes each step independently
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 non-solvate crystalline form minimizes impurities, enabling efficient and consistent production of monophosphate salt crystals with precise stoichiometric control.
Implementation Method 1
the Compound A in such free base crystalline form contains minimum impurities compared to the amorphous form
Implementation Method 2
synthesis of a non-solvate free base crystalline form of Compound A is possible using a combination of solvents previously known to lead to solvate forms of Compound A, e.g., methanol and ethanol
Data Source
AI summary
The present invention relates to crystals of (6aR, 9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrazolo[4,3-e]pyrimidin-4(2H)-one, and methods of making and using such crystals.