Clopidogrel Base Preparation Without Camphor Sulfonic Acid
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Solution Overview
Problem
Existing processes for preparing Clopidogrel base require expensive camphor sulfonic acid for resolution and chirally enrichment, making them industrially less viable.
Innovation Solution
A process that treats an amide of formula (III) with methanol and suitable acids in solvents to obtain Clopidogrel base without the need for camphor sulfonic acid, using inorganic or organic acids and subsequent basification to achieve chemical and chiral purity, allowing for the formation of pharmaceutically acceptable salts.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If camphor sulfonic acid is used for resolution and chirally enrichment of Clopidogrel base, then chiral purity is improved, but manufacturing cost increases significantly
Solution Approach 1:
The invention extracts and eliminates the need for expensive camphor sulfonic acid from the resolution process. By using alternative acids (inorganic or organic) that form separable salts, the process achieves chiral resolution without relying on the costly chiral resolving agent, thereby reducing manufacturing cost while maintaining chiral purity
Solution Approach 2:
The invention replaces the expensive, reusable camphor sulfonic acid with inexpensive, disposable acids (such as inorganic acids or simple organic acids). These cheaper acids are used in the resolution process and can be easily removed, providing a cost-effective alternative that maintains process efficiency without requiring expensive chiral catalysts
2Manufacturing precision
If multiple purification steps including camphor sulfonic acid treatment are used, then chemical and chiral purity is improved, but process complexity increases
Solution Approach 1:
The invention merges the resolution and purification steps into a single integrated process. By using acids that form salts with differential solubility properties, the process combines chiral resolution and chemical purification in one operation, eliminating the need for separate camphor sulfonic acid treatment and subsequent basification steps, thereby reducing process complexity while maintaining high purity
Solution Approach 2:
The invention employs acids that serve multiple functions simultaneously: they act as resolving agents for chiral separation, purification agents for removing impurities, and solubility-based separation agents. This multi-functionality eliminates the need for multiple specialized reagents and steps, simplifying the overall process while achieving both chemical and chiral purity
3Manufacturing precision
If camphor sulfonic acid resolution process is used, then optically pure Clopidogrel base is obtained, but production time and operational steps increase
Solution Approach 1:
The invention performs preliminary action by selecting acids that naturally provide both resolution and purification in one step. The chosen acids are designed to form salts with the Clopidogrel base that have differential solubility, allowing the resolution process to simultaneously achieve optical purity and chemical purity without requiring subsequent purification steps, thereby reducing total production time
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 eliminates the need for costly camphor sulfonic acid, is operationally simple, and scalable, producing chemically and optically pure Clopidogrel base and its salts with high chiral purity.
Implementation Method 1
an amide of formula (III) in either (±) form or varying mixtures of its optically active (+) and (-) forms, is treated with methanol and suitable acids in suitable solvents to obtain Clopidogrel base (Ia & Ib)
Implementation Method 2
The base is treated with suitable inorganic acids such as hydrochloride acid or hydrobromic acid in suitable solvents to obtain the corresponding salts
Implementation Method 3
The salts are separated based on their differential solubility in the solvent
Implementation Method 4
The salt of the (S)-isomer is subsequently broken using suitable inorganic bases to obtain (S)-Clopidogrel base (Ia) with high chemical and chiral purity
Data Source
AI summary
The present invention relates to an improved processes for the preparation of Methyl (+)-(S)-(2-chlorophenyl)-(6,7dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetate [Clopidogrel base, (I)] and their various pharmaceutically acceptable salts.