Prasugrel Synthesis Using Low-Boiling Solvents
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Solution Overview
Problem
Existing methods for preparing prasugrel and its hydrochloride salts face challenges such as the use of toxic and high-boiling solvents, thermal instability of intermediates, and the presence of polymorphic forms that affect purity, bioavailability, and stability, leading to unsuitable pharmaceutical products.
Innovation Solution
A method involving acetylation of a compound with an acetylating agent in a solvent with a boiling point less than 80°C and low toxicity, followed by recrystallization with acetone and water, to produce highly pure prasugrel hydrochloride in novel crystalline forms (H1 and H3) with improved stability and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high boiling solvents such as dimethylformamide or toluene are used for acetylation reaction, then the reaction can proceed effectively, but the solvents require high temperature for removal which causes thermal degradation of prasugrel and reduces product purity
Solution Approach 1:
The patent changes the boiling point parameter of the solvent from high (dimethylformamide, toluene) to low (ethyl acetate, boiling point 77°C). This parameter change allows the solvent to be removed at lower temperatures, preventing thermal degradation of prasugrel while maintaining effective acetylation reaction conditions
Solution Approach 2:
The patent employs ethyl acetate as a disposable solvent that can be easily removed by evaporation at low temperature. The solvent serves its purpose during the reaction and is then discarded through simple evaporation, avoiding the need for high-temperature removal processes that would degrade the thermally unstable prasugrel product
2Reliability
If high boiling solvents such as dimethylformamide or toluene are used for acetylation reaction, then the reaction can proceed effectively, but recycling these solvents is energy consuming and costly
Solution Approach 1:
The patent changes the boiling point parameter of the solvent from high (dimethylformamide, toluene) to low (ethyl acetate, boiling point 77°C). This parameter change reduces the energy required for solvent removal and recycling, making the process more energy-efficient while still achieving effective acetylation
Solution Approach 2:
The patent uses ethyl acetate as a disposable solvent that requires minimal energy for removal through evaporation. The low boiling point of ethyl acetate means less energy is consumed during the removal process compared to high boiling solvents, reducing both energy costs and environmental impact
3Ease of manufacture
If prasugrel hydrochloride is prepared by mixing hydrochloric acid with prasugrel free base, then the salt form is obtained, but the product exists in mixture of unknown polymorphic forms with significant differences in properties
Solution Approach 1:
The patent performs preliminary action by conducting the acetylation reaction in ethyl acetate solvent before salt formation. This preliminary step in a controlled low-boiling solvent creates a more uniform intermediate that subsequently forms a single polymorphic form when converted to hydrochloride salt, rather than a mixture of polymorphs
Solution Approach 2:
The patent changes the solvent parameter from conventional high-boiling solvents to low-boiling ethyl acetate. This parameter change in the reaction medium influences the crystal lattice formation during subsequent salt preparation, leading to a single polymorphic form with consistent properties rather than a mixture of polymorphs
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 method enhances the yield and purity of prasugrel, reduces thermal instability, and produces crystalline forms with low toxicity and high bioavailability, suitable for pharmaceutical applications, addressing the issues of polymorphism and solvent toxicity.
Implementation Method 1
acetylating a compound of formula (III) with an acetylating agent
Implementation Method 2
acetylating a compound of formula (III) with an acetylating agent in a solvent
Implementation Method 3
acetylating a compound of formula (III) with an acetylating agent in a solvent and in the presence of a base
Implementation Method 4
purifying the product; wherein the purifying step is recrystallizing the compound of Formula (III) with a mixture of acetone and water
Data Source
AI summary
Disclosed herein are a process or method for the preparation of prasugrel and several novel crystalline forms of prasugrel hydrochloride. The process comprises preparation of prasugrel by acetylation in solvents which have low boiling point and/or low toxicity, and the process not only avoids using solvents which have high boiling point and/or high toxicity such as toluene, acetonitrile and so on, but also resolves the problem about thermal instability of prasugrel, and the loss of prasugrel is reduced, as well as the yield is raised. The yield of prasugrel is higher than 85% and the purity is higher than 99.5%. The process can prepare prasugrel and its pharmaceutically acceptable salts. The novel crystalline forms of prasugrel hydrochloride are crystalline form H1, H2 and H3, and their performance in oral absorbability, activating metabolism and inhibiting platelet aggregation is excellent. They have a low toxicity and good thermal stability, and are applicable to the preparation of a drug for preventing or treating diseases caused by thrombosis or embolism.