Edoxaban Synthesis Without HOBT for High-Purity Scale-Up
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Solution Overview
Problem
Existing processes for the preparation of Edoxaban and its intermediates face issues such as lower yield, purity, longer reaction times, use of potentially genotoxic impurities like 1-hydroxybenzotriazole (HOBT), and tedious work-up procedures, making them unsuitable for industrial scale production.
Innovation Solution
A process involving the reaction of compounds in the absence of bases for intermediates and the use of 2-Hydroxy pyridine-1-oxide (HOPO) as an additive with a condensing agent to enhance the preparation of Edoxaban, achieving high purity and yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If 1-hydroxybenzotriazole (HOBT) is used as a catalyst for condensation reaction, then the reaction can proceed, but it introduces potential genotoxic impurities and requires longer reaction time
Solution Approach 1:
The patent removes HOBT from the reaction system entirely and replaces it with EDC·HCl as the sole condensing agent. This extraction of the harmful substance (HOBT) eliminates the source of genotoxic impurities while maintaining the condensation reaction functionality through the alternative mechanism provided by EDC·HCl
Solution Approach 2:
The patent employs EDC·HCl as a disposable condensing agent that converts to water-soluble byproducts (urea derivatives) that can be easily removed during aqueous workup. This replaces the persistent HOBT catalyst with a consumable reagent that leaves no harmful residues
2Productivity
If base is used in the reaction of Formula-Ia with Formula-Ib, then the reaction proceeds, but it requires additional purification steps and reduces yield
Solution Approach 1:
The patent removes the base component from the reaction system by using EDC·HCl as a self-sufficient condensing agent that does not require base catalysis. This extraction eliminates the need for base addition and subsequent base removal purification steps, directly addressing the complexity issue
Solution Approach 2:
EDC·HCl acts as an intermediary that facilitates the coupling reaction between carboxylic acid and amine groups without requiring base. It forms an active O-acylisourea intermediate that reacts directly with the amine, bypassing the need for base-mediated deprotonation steps
3Manufacturing precision
If column chromatography is used for purification, then pure intermediate is obtained, but the process becomes tedious and yield is reduced
Solution Approach 1:
The patent removes column chromatography from the purification process by designing a reaction system where EDC·HCl byproducts and unreacted materials are water-soluble and can be removed through simple aqueous washing. This extraction of the complex purification step replaces it with a straightforward liquid-liquid extraction protocol
Solution Approach 2:
The patent changes the solubility parameters of reaction byproducts by using EDC·HCl, which produces water-soluble urea derivatives. This parameter change enables purification through aqueous extraction rather than requiring chromatographic separation, dramatically simplifying the process
4Reliability
If excess HOBT is used for condensation reaction, then reaction completeness is improved, but genotoxic impurity control becomes difficult and additional purification is required
Solution Approach 1:
The patent extracts HOBT entirely from the reaction system and replaces it with EDC·HCl. This eliminates the source of genotoxic impurities at the outset, making impurity control unnecessary rather than requiring additional purification steps to remove excess HOBT
Solution Approach 2:
The patent converts the potential harm of excess reagent use into a benefit by designing EDC·HCl to produce water-soluble byproducts. Even when used in excess, EDC·HCl byproducts can be easily removed with water, transforming what would be a purification challenge into a simple washing step
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 process achieves high purity and yield of Edoxaban and its intermediates, suitable for industrial scale production with reduced effluents and simpler procedures.
Implementation Method 1
reacting compound of Formula-II with compound of Formula-III in presence of base and condensing agent EDC.HCl to obtain compound of Formula-IV
Implementation Method 2
reacting compound of Formula-II with compound of Formula-III in presence of base and condensing agent EDC.HCl
Implementation Method 3
reacting compound of Formula-V with compound of Formula-VI in presence of base, condensing agent and 2-Hydroxy pyridine-1-oxide (HOPO) as an additive to obtain Edoxaban compound of Formula-I
Implementation Method 4
The resulting compound is then reacted with lithium hydroxide in presence of water to obtain compound of Formula-IIb
Data Source
AI summary
The present invention relates to an efficient and industrially advantageous process for the preparation of Edoxaban of Formula-I or salt thereof. The present invention also relates to a process for preparation of Edoxaban intermediates namely methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride of Formula-II, tert-Butyl [(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylaminocarbonyl)cyclohexyl]carbamate of Formula-IV, and their use for the preparation of Edoxaban or salt thereof.