Chiral Benzodiazepinone Preparation via Pyroglutamic Acid Resolution
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for preparing chiral benzodiazepinone compounds, such as (2R,3S)-N-[(3S)-5-(3-Fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)succinimide, are inefficient and costly, with chiral chromatographic methods like SFC and HPLC having low yields and being time-consuming.
Innovation Solution
A method involving the reaction of benzodiazepinone compounds with L-pyroglutamic acid or D-pyroglutamic acid, followed by base treatment and reaction with S(+)-camphor sulfonic acid, to produce chiral benzodiazepinone derivatives with high chiral purity and improved yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If chiral chromatographic methods (SFC or HPLC) are used to prepare chiral benzodiazepinone compounds, then chiral purity can be achieved, but the manufacturing cost increases and productivity decreases
Solution Approach 1:
The patent introduces a chiral resolving agent as an intermediary substance that forms diastereomeric salts with the racemic benzodiazepinone compound. This mediator enables chiral separation through simple filtration and crystallization processes, replacing the need for complex chiral chromatographic methods while achieving high chiral purity (>99%).
Solution Approach 2:
The patent changes the physical and chemical parameters of the system by introducing a chiral resolving agent that alters the solubility characteristics of the enantiomers. By controlling pH, temperature, and solvent composition during the resolution process, the patent achieves efficient chiral separation with high yield and purity, overcoming the limitations of conventional chromatographic methods.
2Manufacturing precision
If chiral chromatographic methods (SFC or HPLC) are used to prepare chiral benzodiazepinone compounds, then chiral purity can be achieved, but the manufacturing cost increases
Solution Approach 1:
The patent employs inexpensive chiral resolving agents that can be used in stoichiometric or catalytic amounts to achieve chiral separation. These resolving agents form transient diastereomeric salts that are easily separated by filtration, eliminating the need for expensive chiral stationary phases and specialized chromatographic equipment, thereby significantly reducing manufacturing costs.
Solution Approach 2:
The chiral resolving agent serves as a cost-effective intermediary that enables chiral separation through simple chemical interactions. By forming diastereomeric salts with distinct solubility properties, the resolving agent facilitates purification through conventional techniques rather than expensive chromatography, achieving high chiral purity at low manufacturing cost.
3Manufacturing precision
If chiral chromatographic methods are used, then chiral compounds can be produced, but the process becomes time-consuming and tedious
Solution Approach 1:
The patent skips the time-consuming chromatographic separation step by using a chemical resolution method. The rapid formation of diastereomeric salts followed by simple filtration and crystallization allows the process to rush through the chiral separation in a matter of hours rather than days, significantly reducing process time while maintaining high chiral purity.
Solution Approach 2:
The resolution process maintains continuous useful action through a streamlined sequence of steps: mixing the racemic compound with the chiral resolving agent, allowing diastereomeric salt formation, filtering the precipitated salt, and regenerating the free base. This continuous process eliminates idle time between operations and achieves high chiral purity efficiently without the interruptions inherent in chromatographic methods.
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 method achieves chiral purities above 99% and yields greater than 50%, providing a more efficient and cost-effective process for producing chiral benzodiazepinone compounds.
Implementation Method 1
reacting the compound of Formula (Ia) with L-pyroglutamic acid (L-PGA) to provide a compound of Formula (Ib)
Implementation Method 2
reacting the compound of Formula (Ib) with a base and solvent to provide a compound of Formula (I)
Data Source
AI summary
The present invention provides methods of preparing compound of Formula (I), wherein the compounds are represented by the structure of Formula (I):wherein:R1 each is independently F, Cl, Br, I, OCH3, CN or NO2;R2 each is independently identical or different C1-C5 alkyl;n1 is an integer between 1 and 5; andn2 is an integer between 1 and 4.In addition, the present invention provides a compound represented by the following structures:wherein X comprises:chloride, acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydroiodide, maleate, 2-hydroxyethanesulfonate, lactate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, sulfonate, tartrate, thiocyanate, toluenesulfonate, or undecanoate salt, or any combination thereof.