Halichondrin B Synthesis via C25 Chiral Center Control

Solution Overview

Problem

Current methods for synthesizing halichondrin B analogs, such as B-1939, are inefficient, costly, and require extensive chromatographic purifications, particularly due to challenges in controlling the C25 chiral center during the C14-C26 fragment synthesis.

Innovation Solution

A method is developed that introduces new crystalline intermediates to improve stereochemical quality and reduces chromatographic steps by forming the C25 chiral center at an earlier stage, utilizing alpha-methylated nitrile equilibration and crystallization-induced dynamic resolution to achieve diastereomerically pure compositions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Manufacturing precision

If chromatographic purification is used to control the C25 chiral center, then the stereochemical quality is improved, but the production time and cost increase

Engineering Contradiction:

Improvestereochemical qualityVSAvoidproduction time

Core Design Contradiction:

Manufacturing precisionVSLoss of time

Solution Approach 1:

The invention performs the chiral center formation at an earlier stage in the synthesis pathway, before the problematic C14-C26 fragment assembly. By establishing the C25 chiral center during the synthesis of Compound AA from Compound AG, the method prevents diastereomer formation downstream, eliminating the need for chromatographic purification later in the process.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention changes the reaction parameters and timing of chiral center formation. Instead of forming the C25 chiral center during methyl group addition to Compound AG (which creates diastereomers), the method modifies the synthesis sequence to establish the chiral center at an earlier stage with different reaction conditions, achieving high stereochemical purity without chromatography.

Inventive Principle:

Principle #35Parameter changes

2Manufacturing precision

If chromatographic purification is used to separate diastereomers, then the purity of Compound AH is improved, but the manufacturing complexity and cost increase

Engineering Contradiction:

ImprovepurityVSAvoidmanufacturing complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The invention performs the chiral center formation at an earlier stage in the synthesis pathway, before the problematic C14-C26 fragment assembly. By establishing the C25 chiral center during the synthesis of Compound AA from Compound AG, the method prevents diastereomer formation downstream, eliminating the need for chromatographic purification later in the process.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention extracts or removes the problematic step that generates diastereomers requiring chromatographic separation. By re designing the synthesis route to form the chiral center earlier with different selectivity characteristics, the method eliminates the need for complex purification equipment and procedures.

Inventive Principle:

Principle #2Taking out (Extraction)

3Productivity

If the C25 chiral center is formed by adding a methyl group to Compound AG, then the compound is produced, but a mixture of diastereomers is generated requiring additional purification

Engineering Contradiction:

Improvecompound productionVSAvoidstereoselectivity

Core Design Contradiction:

ProductivityVSManufacturing precision

Solution Approach 1:

The invention performs the chiral center formation at an earlier stage in the synthesis pathway, before the problematic C14-C26 fragment assembly. By establishing the C25 chiral center during the synthesis of Compound AA from Compound AG, the method prevents diastereomer formation downstream, eliminating the need for chromatographic purification later in the process.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention inverts the conventional approach by not forming the C25 chiral center during methyl group addition to Compound AG, but rather establishing it earlier in the synthesis sequence. This reverse strategy transforms a non-selective step into a selective one by changing when and how the chiral center is created.

Inventive Principle:

Principle #13The other way round (Inversion)

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 product yield and reproducibility, decreases production time and costs, and allows for earlier resolution of chiral centers, resulting in a more efficient pharmaceutical manufacturing process for halichondrin B analogs.

Implementation Method 1

a process of equilibrating and selectively crystallizing the desired C25 isomer via an alpha-methylated nitrile

Methodology Applied

Scientific EffectEquilibration:

Implementation Method 2

selectively crystallizing the desired C25 isomer via an alpha-methylated nitrile

Methodology Applied

Scientific EffectCrystallization: Crystallisation

Implementation Method 3

The desired stereochemical configuration at C25 is confirmed by NMR and X-ray crystallographic analysis

Methodology Applied

Scientific EffectNMR spectroscopy:

Implementation Method 4

The desired stereochemical configuration at C25 is confirmed by NMR and X-ray crystallographic analysis

Methodology Applied

Scientific EffectX-ray crystallography: X-Ray

Data Source

PatentUS10717743B2Intermediates and methods for the synthesis of halichondrin B analogs

Publication Date: 2020.07.21 EISAI R&D MANAGEMENT CO LTD

AI summary

Methods of synthesizing intermediates useful for the synthesis of halichondrin B analogs are described.