Crystallization Process for High-Purity Furanyl Carbamic Acid Esters
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for preparing furanyl carbamic acid ester compounds of Formula Ia are sensitive to the purity of precursor materials, requiring multiple recrystallizations to achieve high purity, which complicates commercial-scale production and reduces yield and handling properties.
Innovation Solution
A process involving the formation of a saturated solution of Formula I in acetone or 2-methyl-tetrahydrofuran at elevated temperatures, followed by controlled temperature reduction to precipitate a crystalline product with reduced impurity levels, specifically less than 3.0 mole% impurity, and isolating the crystalline product as a solvate form, thereby minimizing the need for recrystallization and ensuring high purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If multiple recrystallizations are performed to achieve high purity, then product purity is improved, but process complexity and time consumption increase
Solution Approach 1:
The patent applies preliminary action by optimizing the initial crystallization conditions (solvent selection, temperature control, addition rate) to achieve high purity in a single step. The process pre-establishes optimal parameters such as using acetone or 2-Me-THF as solvents, controlling temperature between -78°C to room temperature, and adding solution at controlled rates to ensure impurities are excluded from the crystal lattice from the beginning, eliminating the need for subsequent recrystallization steps
Solution Approach 2:
The patent employs parameter changes by systematically optimizing critical process variables including solvent type (acetone, 2-Me-THF), temperature profile (from -78°C to room temperature), addition rate (0.1-1 mL/min), and concentration (0.1-1.0 M). These parameter optimizations enable the crystallization process to achieve >95% purity in a single step by controlling nucleation and crystal growth conditions to favor pure product formation
2Manufacturing precision
If multiple recrystallizations are performed to achieve high purity, then product purity is improved, but production time increases
Solution Approach 1:
The patent applies preliminary action by optimizing the initial crystallization conditions (solvent selection, temperature control, addition rate) to achieve high purity in a single step. The process pre-establishes optimal parameters such as using acetone or 2-Me-THF as solvents, controlling temperature between -78°C to room temperature, and adding solution at controlled rates to ensure impurities are excluded from the crystal lattice from the beginning, eliminating the need for subsequent recrystallization steps
Solution Approach 2:
The patent implements continuity of useful action by designing a streamlined process where the crystallization is performed continuously without interruption for intermediate purification steps. The optimized single-step crystallization maintains continuous product formation and isolation, eliminating downtime associated with multiple recrystallization cycles, filtration, and drying steps that would otherwise be required
3Manufacturing precision
If precursor purity is increased, then product purity is improved, but material cost and availability decrease
Solution Approach 1:
The patent applies the extraction principle by using crystallization to selectively separate and remove impurities from the product. The optimized crystallization process extracts impurities into the mother liquor while pure product crystallizes out, achieving high purity even when starting with impure precursors. This eliminates the need to purchase high-purity precursors at higher cost
Solution Approach 2:
The patent uses the solvent system (acetone or 2-Me-THF) as an intermediary medium that facilitates selective crystallization. The solvent mediates the separation between pure product and impurities by creating conditions where only the desired compound crystallizes in the optimized temperature and concentration range, while impurities remain dissolved in the mother liquor
4Productivity
If recrystallization steps are minimized, then productivity is improved, but product purity may decrease
Solution Approach 1:
The patent employs parameter changes by systematically optimizing critical process variables including solvent type (acetone, 2-Me-THF), temperature profile (from -78°C to room temperature), addition rate (0.1-1 mL/min), and concentration (0.1-1.0 M). These parameter optimizations enable the crystallization process to achieve >95% purity in a single step by controlling nucleation and crystal growth conditions to favor pure product formation
Solution Approach 2:
The patent applies preliminary action by optimizing the initial crystallization conditions (solvent selection, temperature control, addition rate) to achieve high purity in a single step. The process pre-establishes optimal parameters such as using acetone or 2-Me-THF as solvents, controlling temperature between -78°C to room temperature, and adding solution at controlled rates to ensure impurities are excluded from the crystal lattice from the beginning, eliminating the need for subsequent recrystallization steps
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 process consistently produces high-purity compounds of Formula Ia with reduced impurity levels, enhancing yield and handling properties, and is adaptable for commercial-scale preparation, achieving purity levels of less than 2.0 mole% impurity.
Implementation Method 1
providing a saturated solution comprising the compound of Formula I in a solvent comprising substantially acetone or 2-methyl-tetrahydrofuran (2-Me-THF), at a first temperature
Implementation Method 2
forming a suspension comprising crystals of the compound of Formula I
Implementation Method 3
precipitate a crystalline product having less than 3.0 mole% impurity
Data Source
AI summary
This application discloses a novel process to synthesize himbacine analog compounds, and intermediates of formula (I) useful in the synthesis thereof. The subject compounds are useful as Thrombin Receptor Antagonists with useful pharmaceutical properties.