15-Oxosteroid Synthesis via Hypervalent Iodine Oxidation

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Solution Overview

Problem

Current methods for introducing an oxo group at the 15-position of a steroid skeleton are complex and result in low yields, requiring multiple steps and introducing unwanted bromine atoms, making it difficult to produce steroid compounds with high pharmacological activity efficiently.

Innovation Solution

A 15-oxosteroid compound is produced by oxidizing a compound with a specific substituent at the 7-position of the steroid skeleton using a hypervalent iodine compound and a co-oxidant, such as peroxide, in the presence of an acid, allowing for a single-step introduction of an oxo group with high yield and maintaining optical activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Manufacturing precision

If multiple steps (dehydration, oxidation, addition) are used to introduce an oxo group at the 15-position, then the oxo group can be introduced, but the yield significantly decreases and the process becomes complex

Engineering Contradiction:

Improveintroduction of oxo group at 15-positionVSAvoidyield of pregnane compound

Core Design Contradiction:

Manufacturing precisionVSProductivity

Solution Approach 1:

The invention segments the complex multi-step process into a single selective oxidation step by using a catalyst system that specifically targets the 15-position methylene group, avoiding the need for sequential dehydration, oxidation, and addition steps

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention changes the reaction parameters by introducing a specific catalyst system (metal complex with ligand) that enables selective oxidation at the 15-position under mild conditions, transforming an unreactive methylene group into a reactive site for oxo group introduction

Inventive Principle:

Principle #35Parameter changes

2Ease of manufacture

If N-bromoacetamide addition reaction is used, then the addition step can be performed, but a bromine atom is introduced at the 16-position requiring additional debromination steps

Engineering Contradiction:

Improveaddition reaction stepVSAvoidnumber of steps to obtain 15-oxo compound

Core Design Contradiction:

Ease of manufactureVSDevice complexity

Solution Approach 1:

The invention extracts the harmful bromine atom introduction step from the synthesis pathway by using a different chemical approach (direct oxidation) that achieves the same goal (15-oxo group) without introducing unwanted substituents that require removal

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention converts the previously harmful side effect (bromine atom introduction requiring debromination) into a benefit by using a clean oxidation method that directly produces the desired 15-oxo compound without unwanted byproducts

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Manufacturing precision

If three-step process (dehydration, oxidation, addition) is used to introduce acetoxy group at 15-position, then the functional group can be introduced, but the process complexity increases and yield decreases

Engineering Contradiction:

Improveintroduction of acetoxy group at 15-positionVSAvoidnumber of steps in synthesis process

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The invention merges multiple sequential steps (dehydration, oxidation, addition) into a single oxidation step that directly introduces the oxo group, which can then be converted to acetoxy group in a separate step, thereby reducing overall process complexity

Inventive Principle:

Principle #5Merging (Combining)

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 method simplifies the production of steroid compounds with high pharmacological activity, such as antiandrogenic activity, by efficiently introducing an oxo group at the 15-position with a high yield and reduced steps, while maintaining optical activity and selectivity.

Implementation Method 1

oxidizing a compound with a specific substituent at the 7-position of the steroid skeleton using a hypervalent iodine compound and a co-oxidant

Methodology Applied

Scientific EffectOxidation: Oxidation

Implementation Method 2

co-oxidant, such as peroxide

Methodology Applied

Scientific EffectPeroxide oxidation: Hydrogen Peroxide

Data Source

PatentEP3581577B115-oxosteroid compound and method for producing same

Publication Date: 2023.10.11 ASKA PHARMACEUTICAL CO LTD

AI summary

Provided is a process for producing a compound, which has an oxo group specifically introduced on the 15-position of a steroid skeleton and which is useful as an intermediate, with a high yield without complicated steps. A compound represented by the formula (2) is allowed to react with an oxidant (e.g., a hypervalent iodine compound) and a co-oxidant (e.g., a peroxide) to produce a 15-oxosteroid compound represented by the formula (1), which is useful as an intermediate: wherein R1 to R3 are the same or different and each represent a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, or a haloalkoxy group, R4 represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an acyl group, or an alkoxycarbonyl group, R5 represents a hydrogen atom, an alkyl group, or an acyl group, R6 represents a hydrogen atom, an alkyl group, an acyl group, or a sulfonyl group, X represents an oxygen atom (O) or a methylene group (CH2).