SIK3 Inhibitor E9 Synthesis for Large-Scale Manufacturing
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Solution Overview
Problem
Existing methods for preparing the SIK3 inhibiting compound E9 are not suitable for large-scale production, requiring improved procedures to reduce costs, time, and improve yield and purity for clinical trials and potential commercial availability.
Innovation Solution
A method involving the reaction of a carboxylic acid intermediate with an amino intermediate under coupling conditions, using specific coupling agents and bases in polar aprotic solvents, to produce compound E9 in bulk quantities, including intermediates such as ester intermediates and amino intermediates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If existing methods for preparing compound E9 are used, then the compound can be produced, but the production is not suitable for large-scale manufacturing due to high costs, long time, and low yield/purity
Solution Approach 1:
The synthesis route is divided into distinct modular stages: (i) preparation of carboxylic acid intermediate I through hydrolysis of ester Ia using sodium hydroxide in water/methanol, (ii) separate preparation of amino intermediate II from nitrile IV via reduction with triethylphosphite and diisobutylaluminum hydride, and (iii) final coupling of I and II. Each module can be independently optimized and scaled, enabling large-scale production while maintaining control over cost and complexity.
Solution Approach 2:
The carboxylic acid intermediate I and amino intermediate II are prepared in advance as separate modules before the final coupling step. The ester intermediate Ia is hydrolyzed to I, and nitrile IV is reduced to II, both completed prior to the amide bond formation. This preliminary preparation allows for optimized conditions at each stage and facilitates scale-up by decoupling the synthesis steps.
2Manufacturing precision
If existing synthesis procedures are used, then compound E9 can be obtained, but the yield and purity are insufficient for clinical trials and commercial use
Solution Approach 1:
The synthesis parameters are optimized at each stage: hydrolysis uses controlled molar ratios of sodium hydroxide (2-5 equivalents) and specific solvent compositions (water/methanol), reduction uses precise molar ratios of triethylphosphite (1.05-1.2 equivalents) and diisobutylaluminum hydride (1.1-1.3 equivalents), and coupling uses optimized amounts of HATU (1.1-1.3 equivalents) and DIPEA (2-5 equivalents). These parameter optimizations ensure high purity while maintaining efficient production.
3Productivity
If existing methods are used, then compound E9 can be synthesized, but the time required is too long for efficient production
Solution Approach 1:
The synthesis procedure maintains continuous productive action through sequential reactions without unnecessary interruptions. The hydrolysis of ester Ia to carboxylic acid I proceeds continuously with stirring at controlled temperatures, followed by direct isolation and subsequent coupling with pre-prepared amino intermediate II. The reduction of nitrile IV to amine II also proceeds continuously with controlled addition of reagents. This continuous operation minimizes downtime and maximizes production efficiency.
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
Enables the production of high-purity compound E9 in larger quantities, suitable for clinical trials and commercial use, with improved efficiency and cost-effectiveness.
Implementation Method 1
A method of preparing the compound E9, especially a method of preparing greater than about 125 g of the compound E9 wherein the method comprises a step of reacting under coupling conditions a carboxylic acid intermediate having the formula I with an amino intermediate having the formula II
Implementation Method 2
wherein the method further comprises a step of preparing the carboxylic acid intermediate having formula I by hydrolysis of an ester intermediate having the formula Ia
Data Source
AI summary
The present invention relates to a new scheme and process for the preparation of one specific SIK3 inhibiting compound known as (and described herein as) “E9”. Compound E9 has previously been described by the present applicant to show surprisingly superior drug-like properties, such as in respect of target-potency/specificity and ADMET/PK properties, compared to other prior art SIK3 inhibiting compound. The present invention also relates to novel intermediates used in such process of preparing compound E9, as well as to a new methodology used within the process of producing a characteristic key thiophene-based amino intermediate that is used to produce compound E9, and other related aspects as disclosed herein.