R-Configured Spirocyclopropane Synthesis Without Chiral HPLC
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Solution Overview
Problem
There is a need for an efficient process to produce (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl) benzoic acid or its salt on an industrial scale, avoiding expensive and time-consuming enantiomeric separation methods.
Innovation Solution
A process involving the synthesis of (R)-6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid using a Wittig reagent, Makosza reaction, and subsequent steps to convert it into (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl) benzoic acid, with simplified purification suitable for industrial application.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If enantiomeric separation by chiral HPLC is used to prepare (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl) benzoic acid, then enantiomeric purity is improved, but production time and cost increase significantly
Solution Approach 1:
The invention introduces a chiral auxiliary ((R)-6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid) in the preliminary stages of synthesis. This auxiliary establishes the desired (R)-configuration early in the synthetic pathway, allowing subsequent reactions to proceed without requiring enantiomeric separation. The chiral information is built into the molecule structure before the final product formation, eliminating the need for time-consuming chiral HPLC purification steps.
2Manufacturing precision
If chromatographic columns are used for purification, then product purity is improved, but equipment cost and process complexity increase
Solution Approach 1:
The invention extracts and eliminates the need for chromatographic purification equipment by using a chiral synthesis approach. The chiral auxiliary ensures that the desired enantiomer is formed selectively during synthesis, allowing purification to be achieved through simpler methods such as filtration and crystallization, thereby removing the requirement for complex chromatographic columns and associated equipment.
3Ease of manufacture
If racemic mixture synthesis followed by separation is used, then synthesis route simplicity is improved, but loss of time and material increase
Solution Approach 1:
The invention applies local quality by introducing chirality at a specific location in the molecular structure through the chiral auxiliary ((R)-6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid). This localized chiral center directs the stereochemical outcome of subsequent reactions, ensuring that the final product has the desired (R)-configuration without requiring separation of racemic mixtures, thus avoiding time losses associated with enantiomeric resolution.
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 significantly reduces reaction time and eliminates the need for chromatographic columns, providing a cost-effective and efficient method for producing the compound on an industrial scale while avoiding racemization.
Implementation Method 1
converting a compound of formula (VII) into a compound of formula (VIII) using a Wittig reagent in a suitable solvent
Implementation Method 2
reacting through the Makosza reaction the compound of Formula (VIII) using bromoform and a suitable base to obtain cyclopropane compound of Formula (IX)
Implementation Method 3
removing bromine atoms in the presence of a reducing agent and a base in an alcoholic solvent thus obtaining (SM1)
Implementation Method 4
hydrolysing the methyl ester using a suitable inorganic base to obtain compound (IV)
Data Source
AI summary
The present invention provides a process for preparing (R)-6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid (SM1), said process comprising the step of: iv) converting a compound of formula (VII) into a compound of formula (VIII) using a Wittig reagent in a suitable solvent; v) reacting through the Makosza reaction the compound of Formula (VIII) using bromoform and a suitable base to obtain cyclopropane compound of Formula (IX); and vi) removing bromine atoms in the presence of a reducing agent and a base in an alcoholic solvent thus obtaining (SM1). The invention relates also to a process for the conversion of the compound (SM1) for preparing (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl) benzoic acid (IV) or a salt thereof. The salt is preferably the sodium salt, more preferably the polymorphic form A of sodium (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)-cyclopropyl) benzoate characterized by a powder XRD spectrum with peaks at values of the angle 2θ+0.2° of 4.3, 5.0, 5.8, 6.4, 7.1, 8.3, 8.7, 12.8, 15.3, 15.9.