Apremilast Synthesis Using Aprotic Solvents
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Solution Overview
Problem
The existing method for preparing apremilast has a low yield, produces impurities, and requires high-boiling acetic acid distillation, which increases production time and costs, and poses equipment corrosion risks.
Innovation Solution
A new method involving the reaction of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine N-acetyl-L-leucine salt with 3-acetylaminophthalic anhydride in aprotic or organic solvents, such as acetonitrile, with controlled temperature and time, in the presence of organic alkali or alkali metal hydride, to achieve high yield and purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If acetic acid is used as solvent for preparing apremilast, then the reaction can proceed, but the yield is low and deacetylated impurity is produced
Solution Approach 1:
The patent changes the solvent parameter from acetic acid to aprotic solvents (acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, xylene, nitrobenzene, or 1,2-dichlorobenzene). This parameter change eliminates the formation of deacetylated impurity while maintaining high reaction yield above 90%, resolving the contradiction between product purity and reaction yield.
2Loss of energy
If high-boiling acetic acid is distilled at temperature lower than 50°C, then energy consumption is reduced, but production time increases
Solution Approach 1:
The patent extracts and eliminates the need for acetic acid distillation by using aprotic solvents that do not require such processing. The new method removes the problematic distillation step entirely, avoiding both the energy consumption issue and the production time extension, while also eliminating equipment corrosion from high-temperature distillation.
3Loss of time
If acetic acid is not fully distilled, then production time is shortened, but alkaline liquor consumption increases and three wastes increase
Solution Approach 1:
The patent converts the harmful situation of incomplete distillation (which causes waste treatment issues) into a beneficial outcome by eliminating the need for distillation altogether. Using aprotic solvents prevents the formation of residues that would require alkaline neutralization, thereby reducing both production time and alkaline liquor consumption, while also decreasing three wastes treatment burden.
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 high yield and purity of apremilast with reduced by-product formation, simpler post-processing, lower production costs, and improved operational efficiency, making it environmentally friendly and suitable for industrial production.
Implementation Method 1
(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine N-acetyl-L-leucine salt of formula (II) is reacted with 3-acetylaminophthalic anhydride of formula (III) in an aprotic solvent to obtain the compound of formula (I)
Implementation Method 2
the reaction temperature is controlled within the range of 40°C.-150°C., preferably within the range of 40°C.-90°C., and further preferably 75°C.-80°C.
Data Source
AI summary
Provided is a method for preparing apremilast of formula I. Method one: (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine N-acetyl-L-leucine salt of formula II is reacted with 3-acetylaminophthalic anhydride of formula III in an aprotic solvent to produce the compound of formula I; method two: (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine N-acetyl-L-leucine salt of formula II is reacted with 3-acetylaminophthalic anhydride of formula III in an organic solvent in the presence of an organic alkali or an alkali metal hydride to produce the compound of formula I. The method for preparing apremilast requires inexpensive raw materials and reagents, is suitable for industrial production, and has great economic effects.