Fulvestrant Synthesis Using Dess-Martin Periodinane Oxidation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current processes for preparing Fulvestrant suffer from low yields and the use of toxic chromium (VI) reagents, which are carcinogenic and complicate workup procedures, and also produce unwanted 7β epimers during oxidation and alkylation steps.
Innovation Solution
The process employs Dess-Martin Periodinane as an oxidizing agent to improve the yield of Fulvestrant by oxidizing the hydroxy group at position 6, followed by two-step alkylation with 1,9-dibromononane and 4,4,5,5-pentafluoropentane phenyl thioester in the presence of a base, reducing the formation of unwanted epimers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If chromium (VI) reagents are used for oxidation of the hydroxy group at position 6, then the oxidation reaction can be performed, but the yield is low and toxic carcinogenic byproducts are generated requiring complicated workup procedures
Solution Approach 1:
The patent changes the chemical parameters of the oxidation reaction by replacing chromium (VI) reagents with Dess-Martin Periodinane (DMP). This reagent substitution transforms the oxidation process to achieve higher yields (85-95% compared to 73-51% with chromium reagents) while eliminating toxic chromium-containing byproducts that require complicated filtration or chromatographic procedures.
Solution Approach 2:
The patent employs Dess-Martin Periodinane as a disposable oxidizing agent that can be used in stoichiometric amounts and easily removed. The reagent decomposes to non-toxic byproducts (iodobenzene and acetic acid) that do not require complex workup procedures, unlike chromium reagents that generate persistent toxic waste requiring specialized handling and disposal.
2Productivity
If direct alkylation of compound 4 with 1,9-dibromononane is performed in a single step, then the side chain can be added, but the yield is low and unwanted 7β epimer is produced
Solution Approach 1:
The patent segments the alkylation process into two distinct steps: first, alkylation of compound 4 with 1,9-dibromononane to form compound 5; second, conversion of compound 5 to compound 6 with proper stereochemistry. This stepwise approach allows for optimization of each individual reaction condition, achieving higher overall yield and minimizing the formation of unwanted 7β epimer compared to single-step direct alkylation.
Solution Approach 2:
The patent performs preliminary alkylation to form compound 5 before proceeding to the second alkylation step to form compound 6. This preliminary action allows the first alkylation to proceed under optimized conditions to establish the carbon framework, followed by a second controlled alkylation step that ensures proper stereochemistry at the 7-position, thereby minimizing epimer formation.
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 approach significantly increases the yield of Fulvestrant while eliminating the use of toxic chromium reagents and minimizing unwanted 7β epimers, resulting in a more environmentally friendly and efficient pharmaceutical production process.
Implementation Method 1
Oxidation of hydroxy group of FUL- Ia by using oxidizing agent Dess-Martin Periodinane to obtain FUL- I
Data Source
AI summary
The present invention relates to an improved process for the preparation of Fulvestrant (I). Also, provided is novel intermediate of Fulvestrant and a process for the preparation of the same.