Synthesizing 17α-Ethynyl-Androstane Steroids Without Receptor Impurities
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Solution Overview
Problem
Existing methods for preparing 17α-ethynyl-10R,13S-dimethyl 2,3,4,7,8R,9S,10,11,12,13,14S,15,16,17-hexadecahydro-1H-cyclopenta[a]phenanthrene-3R,7R,17S-triol (Compound 1) often result in undesired steroid impurities with sex steroid receptor activity, leading to unwanted side effects and increased production costs due to the need for purification.
Innovation Solution
A series of reaction sequences are developed to introduce an alkynyl group at position 17 and a hydroxy group at position 7 in androst-5-ene derivatives, avoiding the formation of impurities with sex steroid receptor activity, including the use of dehydroepiandrosterone as a starting material and specific oxidation and reduction steps to ensure the absence of oxygen substituents at position 7, thereby preventing undesired binding activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If existing methods are used to prepare Compound 1, then the compound can be produced, but undesired steroid impurities with sex steroid receptor activity are formed
Solution Approach 1:
The patent applies preliminary action by performing oxidation at position 7 before introducing the alkynyl group at position 17. This sequence ensures that the oxygen substituent is already in place at position 7 before the alkynyl addition, preventing the formation of impurities that would otherwise lack the position 7 oxygen and exhibit unwanted sex steroid receptor activity.
Solution Approach 2:
The patent changes the sequence of chemical transformations and the parameters of the reaction conditions. Specifically, it oxidizes the androst-5-ene derivative at position 7 first, then introduces the alkynyl group at position 17 under controlled conditions. This parameter change in reaction sequence and conditions prevents the formation of harmful impurities while maintaining production efficiency.
2Manufacturing precision
If purification steps are added to remove steroid impurities, then the purity of Compound 1 increases, but production costs increase
Solution Approach 1:
The patent converts the potential harm of impurity formation into a benefit by designing a reaction sequence where the oxidation at position 7 occurs before alkynyl introduction. This prevents the formation of harmful impurities in the first place, turning what would have been a purification problem into an inherent advantage of the synthetic route, eliminating the need for additional purification steps and reducing production costs.
3Ease of manufacture
If the reaction sequence introduces alkynyl group first then oxygen functionality, then the synthesis follows conventional sequence, but impurities with undesired binding activity are produced
Solution Approach 1:
The patent applies inversion by reversing the conventional synthesis sequence. Instead of introducing the alkynyl group at position 17 first and then oxidizing at position 7, it performs the oxidation at position 7 first and then introduces the alkynyl group. This inverted sequence prevents the formation of harmful impurities that would otherwise be produced by the conventional sequence.
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 proposed method effectively produces Compound 1 that is essentially free of sex steroid receptor binding activity, reducing the need for purification and minimizing side effects, while maintaining the compound's pharmaceutical efficacy.
Implementation Method 1
a prior step of oxidizing an appropriately protected androst-5-ene having a first and second oxygen linked group at positions 3 and 17 such that a third oxygen linked group is introduced at position 7
Implementation Method 2
a subsequent step of reacting an intermediate wherein the second oxygen linked group at position 17 is ═O with an anion derived from an alkyne
Data Source
AI summary
The invention relates to processes for preparing 17-alkynyl-7-hydroxy-steroids, such as 17-Ethynyl-10R,13S-dimethyl 2,3,4,7,8R,9S,10,11,12,13,14S,15,16,17-hexadecahydro-1H-cyclopenta[a]phenanthrene-3R,7R,17S-triol (also referred to as 17α-ethynyl-androst-5-ene-3β,7β,17β-triol), that are essentially free of process impurities having binding activity at nuclear estrogen receptors.