ABT-737 Key Intermediate Synthesis Using Boc Protection
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Solution Overview
Problem
The existing methods for preparing the key intermediate of ABT-737 face challenges due to the poor stability of N-fluorenylmethyloxycarbonyl protective groups, leading to low product yield and difficulty in synthesizing in large quantities, along with the use of toxic reagents and complex purification processes.
Innovation Solution
A method using a tert-butoxycarbonyl protective group is introduced, involving esterification, reduction, vulcanization, hydrolysis, amination, deprotection, and carbonyl reduction reactions, which stabilizes the intermediate and allows for higher yields and simplifies the process by using low-toxicity reagents like thiophenol metal salts and diphenyl disulfide, reducing the complexity of purification and operational costs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If N-fluorenymethyloxycarbonyl protective group is used, then the synthesis method is conventional and well-established, but the intermediate exhibits poor stability and product yield is low
Solution Approach 1:
The patent changes the protective group from N-fluorenymethyloxycarbonyl to tert-butoxycarbonyl, fundamentally altering the chemical parameters of the intermediate. This parameter change results in improved stability of the intermediate and higher product yield, directly resolving the contradiction between reliability and productivity.
2Ease of manufacture
If traditional synthesis route is used, then the method is well-established, but the process is complex and requires toxic reagents
Solution Approach 1:
The patent replaces toxic reagents with low-toxicity alternatives. Specifically, it uses dimethylamine instead of more toxic aminating agents, and employs low-toxicity reducing agents in the carbonyl reduction step. This substitution reduces harmful factors while maintaining ease of manufacture.
Solution Approach 2:
The patent converts potentially harmful reactions into beneficial ones by optimizing reaction conditions and selecting greener reagents. The carbonyl reduction under acidic conditions with low-toxicity reducing agents transforms a potentially hazardous step into a safe and efficient process, reducing environmental impact while maintaining productivity.
3Ease of manufacture
If N-fluorenymethyloxycarbonyl protective group is used, then the synthesis follows conventional protocol, but purification process becomes complex and costly
Solution Approach 1:
The change in protective group from N-fluorenymethyloxycarbonyl to tert-butoxycarbonyl fundamentally alters the physical and chemical properties of intermediates, making them easier to purify. This parameter change simplifies the purification process, reducing both complexity and cost, and directly addresses the contradiction between ease of manufacture and device complexity.
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 yields of the key intermediate with improved stability and reduced toxicity, facilitating easier synthesis and purification, and offers a more cost-effective and industrially viable process compared to traditional methods.
Implementation Method 1
subjecting the active ester and a first reducing agent to a reduction reaction to obtain a compound having a structure represented by formula II
Implementation Method 2
subjecting the compound having a structure represented by formula II, a vulcanizing agent, and an organic phosphine to a vulcanization reaction to obtain a compound having a structure represented by formula III
Implementation Method 3
subjecting the compound having a structure represented by formula III to a hydrolysis reaction under an alkaline condition to obtain a hydrolysate
Implementation Method 4
subjecting the hydrolysate and dimethylamine to an amination reaction to obtain a compound having a structure represented by formula IV
Implementation Method 5
subjecting the compound having a structure represented by formula IV to a deprotection reaction with a deprotection reagent to obtain a deprotected product
Implementation Method 6
subjecting the compound having a structure represented by formula V and a second reducing agent to a carbonyl reduction reaction under an acidic condition to obtain the key intermediate of ABT-737
Data Source
AI summary
The present disclosure relates to the technical field of drug synthesis, and provides a method for preparing a key intermediate of ABT-737 and a method for preparing ABT-737. In the present disclosure, the compound having a structure represented by formula I is used as the starting material. The carboxyl group in the compound having a structure represented by formula I is first reduced to a hydroxyl group, followed by a vulcanization by a vulcanizing agent, and then an amination, a deprotection, a condensation, and a carbonyl group reduction, to obtain the key intermediate of ABT-737 having a structure represented by formula VI. Tert-butoxycarbonyl is used as the protecting group for the compound having a structure represented by formula I, and the subsequent intermediate containing the protecting group of tert-butoxycarbonyl is stable, and easy to be deprotected. This method is suitable for mass synthesis, with high product yield and low production cost, and thus has a good industrialization prospect.