GLP-1 RA Synthesis Process for Robust, Scalable Manufacturing
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Solution Overview
Problem
Existing processes for synthesizing GLP-1 receptor agonists like GLPIRA are not robust, efficient, or scalable, necessitating the development of an alternative process that addresses these limitations.
Innovation Solution
A multi-step chemical process involving specific intermediates and reactions, including the use of compounds such as CDI, (R)-4-benyl-2-oxazolidone, and copper-mediated additions, to synthesize GLPIRA, utilizing various solvents and catalysts to optimize yield and scalability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the existing synthetic process for GLPIRA is used, then the compound can be prepared, but the process is not robust, efficient, or scalable
Solution Approach 1:
The synthesis process is divided into multiple discrete steps with specific intermediates (compounds 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100), allowing each step to be optimized independently for robustness and scalability
Solution Approach 2:
The process employs specific reaction conditions including temperature ranges (e.g., -78°C to 0°C for lithiation steps, room temperature for coupling reactions), solvent selections (THF, DMF, DCM), and catalyst amounts (e.g., 0.01-1 equivalent of lithium chloride, 0.01-1 equivalent of copper(I) iodide) to optimize both robustness and scalability at each stage
2Productivity
If the existing synthetic process is used, then GLPIRA can be synthesized, but the yield is lower
Solution Approach 1:
Protecting groups are introduced in advance at strategic positions (e.g., benzyl protection at the indole nitrogen, acetyl protection at the carboxylic acid) to prevent unwanted reactions and enable higher yielding subsequent steps, with these groups removed in final deprotection steps
Solution Approach 2:
Multiple well-defined intermediates are used as mediators to transfer functionality efficiently: compound 4 (acid chloride) mediates the formation of compound 5, compound 6 (alcohol) mediates formation of compound 7, and each intermediate is optimized for the next transformation to maximize overall yield
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 new process enhances the robustness, efficiency, and scalability of GLPIRA synthesis, providing higher yields and improved production capabilities.
Implementation Method 1
a copper mediated addition of 2-methyl allyl magnesium chloride in the presence of lithium chloride to compound 4 to give compound 5
Implementation Method 2
copper mediated addition of 2-methyl allyl magnesium chloride... to compound 4 to give compound 5
Implementation Method 3
The cyclization of compound 6 to compound 7... In one embodiment of the reaction from compound 5 to compound 6, the reaction step comprises reducing compound 5 with lithium borohydride to give compound 6
Implementation Method 4
The cyclization of compound 6 to compound 7 using p-toluenesulfonic acid monohydrate in a solvent such as cyclopentyl methyl ether
Implementation Method 5
A reactor was charged with compound 7 and chloroacetonitrile... Potassium hydroxide and catalytic tetrabutylammonium chloride hydrate were added... to give compound 8
Implementation Method 6
Lithium t-butoxide was added... to give compound 10
Implementation Method 7
The mixture was treated with hydroxylamine... to give compound 10
Implementation Method 8
The mixture was treated with carbon disulfide and a base... to give compound 11
Implementation Method 9
The mixture was treated with carbon disulfide and a base... to give compound 11
Implementation Method 10
The mixture was treated with sodium t-butoxide and water... to give compound 12
Data Source
AI summary
The present invention relates to the synthesis of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl ]-4-methyl-6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carbonyl] indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a salt thereof, and related synthetic intermediate compounds.