Atorvastatin Synthesis via Steric-Free 1,4-Dione Cyclization
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for preparing atorvastatin are hindered by long reaction times and low yields due to structural hindrance caused by substituent groups at carbon location 3 of the 1,4-dione compound, leading to inefficient cyclization reactions and increased production of byproducts.
Innovation Solution
A novel intermediate (formula 7a) is synthesized using a 1,4-dione compound without a substituent group at carbon location 3, allowing for easy cyclization with a chiral intermediate, and a method is developed to prepare atorvastatin or its pharmaceutically acceptable salt under mild conditions, involving steps such as reacting formula 7 with formula 8, deprotecting, and hydrolyzing the resulting compound.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If a 1,4-dione compound with a substituent group at carbon location 3 is used in the reaction, then the reaction can proceed, but the cyclization reaction becomes difficult due to steric hindrance, resulting in long reaction time and low yield
Solution Approach 1:
The patent removes the substituent group at carbon location 3 of the 1,4-dione compound (formula A) to eliminate steric hindrance that prevents efficient cyclization. This extraction of the problematic substituent enables the reaction to proceed with high yield and short reaction time, directly resolving the contradiction between ease of manufacture and time loss.
Solution Approach 2:
The patent changes the structural parameter of the 1,4-dione compound by removing the substituent group at carbon location 3. This structural modification fundamentally alters the reaction characteristics, transforming a difficult cyclization into an efficient process that completes quickly with high yield, thereby resolving both the ease of manufacture and time loss issues.
2Productivity
If a 1,4-dione compound with a substituent group at carbon location 3 is used in the reaction, then the reaction can proceed, but the cyclization reaction becomes difficult due to steric hindrance, resulting in low yield
Solution Approach 1:
The patent removes the substituent group at carbon location 3 of the 1,4-dione compound to eliminate steric hindrance that prevents efficient cyclization. This extraction enables the reaction to proceed with high yield and short reaction time, directly resolving the contradiction between ease of manufacture and time loss.
Solution Approach 2:
The patent changes the structural parameter of the 1,4-dione compound by removing the substituent group at carbon location 3. This structural modification fundamentally alters the reaction characteristics, transforming a difficult cyclization into an efficient process that completes quickly with high yield, thereby resolving both the ease of manufacture and time loss issues.
3Productivity
If the reaction is carried out for a very long time to improve yield, then more product can be formed, but side reactions increase and byproduct removal becomes difficult
Solution Approach 1:
The patent removes the substituent group at carbon location 3 of the 1,4-dione compound to eliminate steric hindrance that prevents efficient cyclization. This extraction enables the reaction to proceed with high yield and short reaction time, directly resolving the contradiction between ease of manufacture and time loss.
Solution Approach 2:
The patent accelerates the cyclization reaction by removing the steric hindrance from the 1,4-dione compound structure. This allows the reaction to skip the lengthy reaction time required in conventional methods, completing the transformation quickly with high yield while minimizing side reactions and byproduct formation.
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
This approach enables the production of atorvastatin at high purity and high yield under mild reaction conditions, overcoming the limitations of previous methods by reducing reaction time and byproduct formation.
Implementation Method 1
reacting a compound of formula (7) with a compound of formula (8) to give a compound of formula (9)
Implementation Method 2
deprotecting and hydrolyzing the compound of formula (9)
Data Source
AI summary
The present invention relates to a novel method for preparing atorvastatin. According to the present invention, provided are a novel intermediate of the preparation of atorvastatin and a method of preparing large amounts of atorvastatin in a safe manner using the intermediate.