Abiraterone Synthesis via Crystalline Intermediate Isolation
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Solution Overview
Problem
Current methods for preparing abiraterone and abiraterone acetate suffer from low yields, impurities, and difficulties in purification, making them unsuitable for industrial-scale implementation.
Innovation Solution
A process involving the conversion of prasterone trifluoroacetate to triflate, followed by a Suzuki reaction to obtain abiraterone, which can then be acetylated to abiraterone acetate, with key intermediate isolation as a crystalline solid, optimizing yield and purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If chromatography on silica is used to purify triflate intermediate, then purity is improved, but manufacturing cost and complexity increase
Solution Approach 1:
The patent extracts and removes the chromatography purification step from the synthesis pathway. Instead of using silica chromatography to purify the triflate intermediate, the process directly proceeds to the Suzuki reaction with the crude triflate, eliminating the need for complex purification equipment and operations while maintaining acceptable purity levels through the subsequent reaction steps.
Solution Approach 2:
The patent uses the Suzuki reaction conditions themselves as an intermediary mechanism to handle impurities. The reaction conditions (palladium catalyst, base, solvent system) serve to process both the desired triflate intermediate and the accompanying impurities simultaneously, converting them into separable products that can be removed in later steps, thereby avoiding the need for intermediate purification.
2Manufacturing precision
If multiple purification steps are implemented, then purity is improved, but productivity decreases
Solution Approach 1:
The patent merges multiple operations into fewer integrated steps. The Suzuki reaction step serves dual purposes: it transforms the triflate intermediate into the final abiraterone product while simultaneously facilitating the removal of impurities through the reaction conditions and subsequent workup procedures. This consolidation eliminates separate purification steps and increases overall productivity.
Solution Approach 2:
The patent maintains continuous productive action throughout the synthesis by avoiding interruptions for intermediate purifications. The process flows continuously from triflate formation through Suzuki reaction to final product isolation, with each step designed to handle impurities generated in previous steps, thereby maximizing productivity while maintaining purity standards.
3Productivity
If crude triflate is used directly in Suzuki reaction, then productivity is improved, but harmful factors increase due to impurities
Solution Approach 1:
The patent converts the harmful effect of impurities in crude triflate into a beneficial outcome. The impurities present in the crude material are transformed during the Suzuki reaction into byproducts that are easily removed in the final workup. The reaction conditions are specifically designed to convert potential contaminants into harmless or easily separable substances, thereby allowing direct use of crude material without compromising final product quality.
4Quantity of substance
If acetylation step is added to convert abiraterone to abiraterone acetate, then product value is improved, but device complexity increases
Solution Approach 1:
The patent performs the acetylation reaction as a preliminary action during the Suzuki reaction workup phase. Rather than adding a separate acetylation step after abiraterone isolation, the acetylating agent is introduced during the aqueous workup, allowing simultaneous removal of inorganic salts and formation of the acetylated product. This integration eliminates the need for additional equipment and operational 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 process achieves high yields and purity of abiraterone and abiraterone acetate, facilitating industrial-scale production with reduced impurity formation and improved stability, enabling efficient and cost-effective manufacturing.
Implementation Method 1
conversion of the carbonyl at the 17 position of dehydroepiandrosterone-3-acetate (prasterone acetate, 3) to the corresponding enol triflate (4) by treatment with trifluoromethanesulphonic anhydride
Implementation Method 2
a key element of the process is the isolation of a crystalline intermediate that makes the process particularly suitable for implementation on an industrial scale
Implementation Method 3
The pyridine ring is introduced by Suzuki reaction between said triflate and diethyl(3-pyridyl)borane
Data Source
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AI summary
Disclosed is a process for the preparation of abiraterone and abiraterone acetate with high yields and purity. A key element of the method is the isolation of a crystalline intermediate that makes the process particularly suitable for implementation on an industrial scale.