Darunavir Solvate Process Segmentation
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Solution Overview
Problem
Current processes for preparing Darunavir are inefficient due to low purity and yield of Diamino alcohol, unwanted reactions, and the need for laborious isolation and special precautions, making them unsuitable for commercial production.
Innovation Solution
A novel process involving the reaction of an epoxide compound with isobutylamine, followed by reaction with p-nitrobenzenesulfonyl halide, deprotection, reduction, and condensation to form Darunavir propylene glycol solvate, which is stable and less hygroscopic, allowing for simpler and more industrially viable production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional processes are used to prepare Diamino alcohol, then the process can be completed, but the purity and yield of the product are low
Solution Approach 1:
The conventional one-pot process is divided into separate steps: (1) epoxide condensation with isobutylamine, (2) isolation of the carbamate intermediate, (3) sulfonamide formation, (4) deprotection, and (5) reduction. This segmentation allows each step to be optimized independently, achieving high purity and yield by controlling conditions at each stage rather than attempting to optimize a single complex one-pot reaction.
Solution Approach 2:
The patent performs preliminary isolation of the carbamate intermediate after epoxide condensation, before proceeding to sulfonamide formation. This preliminary action removes the intermediate from the reaction mixture, preventing unwanted side reactions and enabling better control of subsequent steps, thereby improving overall purity and yield.
2Device complexity
If the process is carried out in one pot, then the process is simpler, but the purity of the obtained product is low
Solution Approach 1:
The one-pot process is segmented into multiple discrete steps with isolation between them. The carbamate intermediate is isolated after epoxide condensation, and the product is isolated after reduction. This segmentation increases process complexity but achieves high purity by allowing controlled conditions at each stage and removing intermediates that could cause side reactions.
3Speed
If sulfonamide reaction is carried out at higher temperature, then the reaction proceeds faster, but the product undergoes degradation and the reaction mass becomes very thick
Solution Approach 1:
The patent optimizes the sulfonamide reaction temperature to a specific range (82-88°C) and controls the reaction time to prevent degradation. By carefully controlling these parameters, the process achieves adequate reaction rate while maintaining product stability and preventing excessive viscosity buildup that would occur at higher temperatures.
4Manufacturing precision
If isolation of Diamino alcohol involves pH adjustment and concentration, then the isolation can be achieved, but the process becomes tedious and laborious
Solution Approach 1:
The patent performs preliminary isolation of the carbamate intermediate and maintains it in a controlled form throughout the process. By isolating and controlling the intermediate at an early stage, subsequent isolation steps are simplified, reducing the need for multiple pH adjustments and concentration steps, thereby reducing laboriousness while maintaining high 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 high purity and yield of Darunavir propylene glycol solvate, which is stable and less hygroscopic compared to ethanolate, facilitating easier large-scale manufacturing and improved pharmaceutical properties.
Implementation Method 1
deprotected by catalytic hydrogenation using palladium on carbon catalyst
Implementation Method 2
reducing the compound of Formula IX or acid addition salt thereof to give Diamino alcohol of Formula II
Data Source
Figure 1
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AI summary
The present invention relates to novel solvates of Darunavir of Formula (I).