9-cis-retinoic acid production via Wittig reaction and solvent merging
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Solution Overview
Problem
Current methods for producing 9-cis-retinoic acid result in low yields, with existing processes achieving only around 25% to 16% yield, and involve a two-stage process with solvent changes.
Innovation Solution
A method involving the Wittig reaction of β-formyl-crotonic acid esters with isolated 9-(Z)-C 15 -triarylphosphonium salt in the presence of a base, followed by saponification and protonation, using a solvent mixture of alcohols and non-polar solvents, to directly obtain 9-(Z)-retinoic acid with enhanced yield and purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Device complexity
If the Wittig reaction is performed using mother liquor containing enriched 9-(Z)-C15-triarylphosphonium salt without complete isolation, then the process complexity is reduced, but the yield of 9-(Z)-retinoic acid decreases to approximately 25%
Solution Approach 1:
The 9-(Z)-C15-triarylphosphonium salt is isolated and purified before the Wittig reaction to ensure high stereochemical purity and maximize yield. This preliminary isolation step, involving extraction with methylene chloride, concentration, and recrystallization from ethyl acetate, prevents side reactions and ensures optimal reaction conditions, resolving the contradiction between process simplicity and yield.
2Manufacturing precision
If a two-stage process with solvent change is used for saponification, then the purification is more effective, but the process complexity and time increase
Solution Approach 1:
The saponification step is performed in the same solvent system (methylene chloride/alcohol mixture) used for the Wittig reaction, eliminating the need for solvent changes. The base (sodium hydroxide or potassium hydroxide) is added directly to the reaction mixture, and the saponification proceeds under the existing conditions, thereby combining multiple operations into one continuous process while maintaining effective purification.
3Loss of time
If the Wittig reaction is performed without isolating the 9-(Z)-C15-triarylphosphonium salt, then the production time is reduced, but the yield decreases to about 16%
Solution Approach 1:
The 9-(Z)-C15-triarylphosphonium salt is isolated and purified before the Wittig reaction to ensure high stereochemical purity and maximize yield. This preliminary isolation step, involving extraction with methylene chloride, concentration, and recrystallization from ethyl acetate, prevents side reactions and ensures optimal reaction conditions, resolving the contradiction between process simplicity and yield.
4Device complexity
If mother liquor is used directly without enrichment and isolation, then the process steps are reduced, but the yield and purity of 9-(Z)-retinoic acid decrease
Solution Approach 1:
The 9-(Z)-C15-triarylphosphonium salt is isolated and purified before the Wittig reaction to ensure high stereochemical purity and maximize yield. This preliminary isolation step, involving extraction with methylene chloride, concentration, and recrystallization from ethyl acetate, prevents side reactions and ensures optimal reaction conditions, resolving the contradiction between process simplicity and yield.
Solution Approach 2:
The patent replaces mechanical separation methods with chemical enrichment through selective crystallization. By utilizing the differential solubility of the 9-(Z) and all-(E) isomers in ethyl acetate at low temperatures, the desired 9-(Z) isomer is selectively crystallized and isolated, achieving high purity without complex mechanical separation equipment.
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 yields of over 45% with purities greater than 98%, significantly improving upon previous methods by optimizing the isolation and purification steps to enhance the production efficiency.
Implementation Method 1
β-formyl-crotonic acid-C1-C10 linear, branched or cyclic alkyl or phenyl ester is reacted by the Wittig reaction with a 9-(Z)-C15-triarylphosphonium salt in isolated form in the presence of a base to the corresponding 9-(Z)-retinoic acid ester
Implementation Method 2
after the end of the Wittig reaction the reaction mixture is then saponified with a base to the corresponding 9-(Z)-retinoic acid carboxylate
Implementation Method 3
following protonation with an acid, the desired 9-(Z)-retinoic acid is obtained
Data Source
AI summary
Improved method of production of 9-(Z)-retinoic acid, in which: a) a ß-formyl-crotonic acid C1-C10 alkyl or phenyl ester is reacted with an isolated 9-(Z)-C15-triarylphosphonium salt by the Wittig reaction in the presence of a base to the corresponding 9-(Z)-retinoic acid ester, which b) is then saponified with a base to the corresponding 9-(Z)-retinoic acid carboxylate and then, following protonation with an acid, the desired 9-(Z)-retinoic acid is obtained, and improved method for the enrichment and isolation of the 9-(Z)-C15-triarylphosphonium salt.