Continuous-Flow Desulfinylation for High-Purity Estetrol Intermediates
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Solution Overview
Problem
The existing synthesis of estetrol and its derivatives is inefficient due to the need for benzyl group protection and deprotection steps, which require hydrogenation and result in low yield and compliance with ICH guidelines for catalyst levels.
Innovation Solution
A continuous flow process is used for the desulfinylation step in the synthesis of 3-protected-oxy-estra-1,3,5(10),15-tetraene-17-one, achieving high yield and purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If benzyl group protection and deprotection steps are used in the synthesis of 3-protected-oxy-estra-1,3,5(10),15-tetraene-17-one, then the 3-OH function can be protected, but the synthesis requires hydrogenation using Pd/C catalyst which increases device complexity and requires compliance with ICH guidelines for catalyst levels
Solution Approach 1:
The patent removes the Pd/C catalyst hydrogenation step from the synthesis pathway by using alternative protecting groups (acetate, benzoate, carbonate, carbamate, or sulfonate esters) that can be installed and removed without requiring catalytic hydrogenation, thereby extracting the problematic catalyst dependency from the process
Solution Approach 2:
The patent changes the chemical parameters of the protecting group strategy by selecting groups that are compatible with non-hydrogenation methods, allowing installation via standard esterification or carbamate formation reactions and removal via hydrolysis or other non-catalytic methods, thus changing the reaction conditions to eliminate catalyst requirements
2Ease of operation
If traditional batch process is used for the synthesis steps, then the process is simpler to operate, but the yield and purity of 3-protected-oxy-estra-1,3,5(10),15-tetraene-17-one are lower
Solution Approach 1:
The patent implements continuous flow processing for key synthesis steps, maintaining continuous reaction and purification actions that prevent side reactions and byproduct accumulation, thereby achieving superior purity and yield compared to intermittent batch operations while managing complexity through standardized flow reactors
3Ease of manufacture
If traditional synthesis method is used, then the process steps are established, but the overall yield is low due to multiple protection/deprotection steps
Solution Approach 1:
The patent extracts unnecessary protection/deprotection steps from the synthesis pathway by selecting protecting groups that can be installed early and removed late without interfering with other transformations, thereby reducing the total number of steps and cumulative yield loss while maintaining ease of manufacture through well-established reaction chemistry
Solution Approach 2:
The patent applies preliminary protection of the 3-OH function with groups that are stable under subsequent reaction conditions, allowing other transformations to proceed without additional protection maneuvers, thus preliminary establishing the protected state to avoid later deprotection/reprotection cycles
Data Source
AI summary
The present invention relates to a process for the preparation of a compound of formula (I), a stereoisomer, a salt, a hydrate or a solvate thereof, comprising the step of desulfinylation of a compound of formula (II) to produce compound of formula (I); wherein: R1 and R2 are as defined in the claims, wherein said desulfinylation step is performed by continuous flow process.