Substituted Phenyl Compounds Synthetic Route
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Solution Overview
Problem
Current synthetic routes for preparing 6-substituted-1-(2H)-isoquinolinone derivatives, which act as Rho-Kinase inhibitors, are costly and inefficient, particularly when scaling up, due to the use of expensive and poorly characterized reagents like tert-Butyloxy-bis-(dimethylamino)methane.
Innovation Solution
A new synthetic route involving the reaction of a compound (IV) with a reagent (R2O)2HC-N(CH3) and pyrrolidine in excess molar equivalents, along with optional DMF addition, allows for the preparation of compound (VI) in high yield using readily available starting materials and reagents, facilitating the production of 6-substituted-1-(2H)-isoquinolinone derivatives.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If expensive reagents like tert-Butyloxy-bis-(dimethylamino)methane are used in the synthesis route described in WO 2009/080335, then the preparation of compound (I) can be achieved, but the manufacturing cost increases significantly and the reagent characterization is poor
Solution Approach 1:
The patent replaces expensive, poorly characterized reagents (tert-Butyloxy-bis-(dimethylamino)methane) with cheaper, readily available alternatives (reagent of formula (V) with R2 = (C1-C6)alkyl). This substitution maintains synthesis effectiveness while significantly reducing manufacturing costs and improving reagent availability for large-scale production.
Solution Approach 2:
The patent modifies the reagent structure by changing the R2 group from dimethylamino to (C1-C6)alkyl, creating a new class of reagents with improved properties. This parameter change in the reagent molecular structure leads to better cost-effectiveness and availability while maintaining the desired synthetic function.
2Productivity
If the existing synthetic route is used for large-scale production, then compound (I) can be prepared, but the process becomes less economical and more complex
Solution Approach 1:
The patent employs inexpensive, commercially available reagents that are suitable for large-scale production. The use of readily available starting materials and reagents (formula V with R2 = (C1-C6)alkyl) eliminates the need for expensive, specialized reagents, making the process economically viable for industrial-scale manufacturing.
Solution Approach 2:
The patent extracts and eliminates the problematic expensive reagent (tert-Butyloxy-bis-(dimethylamino)methane) from the synthetic route, replacing it with a simplified, cost-effective alternative. This extraction of the problematic component resolves the economic issues associated with large-scale production.
3Manufacturing precision
If excess molar equivalents of reagent (V) and pyrrolidine are used, then compound (VI) is obtained in high yield, but the quantity of reagents consumed increases
Solution Approach 1:
The patent applies partial or excessive action by using excess molar equivalents (1.5 or more for reagent V, 4.0 or more for pyrrolidine) to ensure high conversion and yield of compound (VI). The excess reagents drive the reaction to completion, compensating for any side reactions or equilibrium limitations, thereby achieving high manufacturing precision.
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 route provides a more economical and efficient method for producing 6-substituted-1-(2H)-isoquinolinone derivatives, achieving high yields and purity, and can be used as intermediates for further Rho-Kinase inhibitors or modified to introduce additional substituents, thereby addressing the limitations of existing methods.
Implementation Method 1
reacting a compound of formula (IV) with a reagent of the formula (R2O)2HC-N(CH3) and pyrrolidine
Implementation Method 2
reacting a compound of formula (IV) with a reagent of the formula (R2O)2HC-N(CH3) and pyrrolidine, wherein reagent (V) is used in a molar excess of 1.5 or more equivalents and pyrrolidine is used in a molar excess of 4.0 or more equivalents over a compound of formula (IV)
Data Source
AI summary
The present invention relates to novel substituted phenyl compounds of the formula (VI) and to a process for making them. The compounds can be used as intermediates for making 6-substituted-1-(2H)-isoquinolinone derivatives.