Indacaterol Free Base Solid Form Preparation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for preparing Indacaterol and its pharmaceutically acceptable salts suffer from low yields and the presence of impurities such as dimers and regioisomers, requiring high energy conditions and resulting in instability of the free base in organic solvents.
Innovation Solution
A process involving the reaction of 2-amino-5,6-diethylindan with a compound to form Indacaterol or its salt, using mild alkaline conditions and avoiding the use of epoxy compounds, which allows for higher yields (>70%) and reduced impurities, enabling the isolation of Indacaterol in solid form and its conversion to stable pharmaceutically acceptable salts like maleate.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If the condensation between indanolamine and quinolone epoxide is performed using high energy conditions (temperatures of 110°C or more for several hours), then the reaction can proceed to form Indacaterol, but the appearance of impurities (dimers and regioisomers) is favoured
Solution Approach 1:
The patent changes the reaction parameters by using a different approach: instead of high temperature conditions, it employs a two-step process with (1) formation of an intermediate salt with chiral catalyst, and (2) conversion to the final product. This parameter change avoids the formation of dimer and regioisomer impurities while maintaining productivity.
Solution Approach 2:
The patent introduces an intermediary compound (intermediate salt formed with chiral catalyst) between the starting materials and the final product. This intermediary approach allows the reaction to proceed through a controlled pathway that avoids direct formation of impurities, achieving both high purity and acceptable productivity.
2Manufacturing precision
If the purification process involves initial formation of salt with acid, hydrogenation and final formation of maleate salt, then Indacaterol can be purified, but the overall yield is only 49%
Solution Approach 1:
The patent extracts the chiral catalyst from the reaction mixture and uses it to form an intermediate salt that can be easily separated. This extraction approach allows for high purity product while avoiding the loss of material through multiple transformation steps, thereby improving overall yield compared to the conventional three-step process.
Solution Approach 2:
The patent segments the purification process into two main steps: (1) formation of intermediate salt with chiral catalyst, and (2) conversion to final maleate salt. This segmentation reduces the number of transformation steps and avoids the yield losses associated with multiple hydrogenation and salt formation steps in the conventional process.
3Productivity
If the process proceeds via the free base of Indacaterol, then the product can be obtained, but the free base is unstable in organic solvents
Solution Approach 1:
The patent uses the chiral catalyst as an intermediary that forms a stable intermediate salt with the indanolamine. This intermediary complex is stable in organic solvents and can be easily converted to the final maleate salt product. This approach avoids the instability problem of the free base while maintaining product obtainability and purity.
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 achieves higher yields and purer products with reduced impurities, stabilizing Indacaterol in solid form and facilitating the production of pharmaceutically acceptable salts, thereby improving the efficiency and stability of the manufacturing process.
Implementation Method 1
reacting the compound of formula I with 2-amino-5,6-diethylindan of formula II, preferably in the presence of a base, to the compound of formula III
Implementation Method 2
converting the compound of formula III to Indacaterol or a pharmaceutically acceptable salt thereof
Data Source
AI summary
The present invention relates to the Indacaterol free base in solid form. The Indacataterol free base may be in a crystalline form or in an amorphous form. The present invention also discloses an improved preparation of the Idacaterol maleate salt using the isolated Indacaterol free base in solid form as an intermediate. Indacataterol (5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-(1H)-quinolin-2-one) is a beta-selective adrenoceptor agonists with a potent bronchodilating activity. Indacaterol is especially useful for the treatment of asthma and chronic obstructive pulmonary disease (COPD) and is sold commercially as the maleate salt.