Tezacaftor Synthesis Route for High-Yield, High-Purity Production
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Solution Overview
Problem
Existing processes for the preparation of Tezacaftor do not achieve high yields and high purity suitable for industrial scale production.
Innovation Solution
A novel process involving specific reactions and purifications steps, including reacting compounds of Formula II with alkyne of Formula III, treating with compounds of Formula V, cyclizing, reducing, and coupling to obtain Tezacaftor, with optional deprotection steps, using suitable protecting groups and solvents for purification.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If existing processes for preparation of Tezacaftor are used, then the drug can be produced, but the yield and purity are not high enough for industrial scale production
Solution Approach 1:
The synthesis process is divided into multiple discrete steps with intermediate purification stages. The process segments the overall transformation into: (1) formation of intermediate compound (II) with purification, (2) reaction to form compound (IV), (3) cyclization to form compound (VI), (4) reduction to form compound (VIII), and (5) final coupling to produce Tezacaftor. Each segment is optimized independently to maintain high purity while achieving good yields.
Solution Approach 2:
Protecting groups are introduced in preliminary steps to prevent unwanted side reactions before the main transformations occur. The hydroxyl groups are protected as ethers or esters before the key coupling reactions, ensuring high purity of intermediates and final product. This preliminary protection strategy prevents contamination and reduces the need for extensive purification later.
2Manufacturing precision
If existing processes are used, then Tezacaftor can be obtained, but multiple purification steps are required which reduce productivity
Solution Approach 1:
The process design allows intermediates to crystallize in high purity forms directly from reaction mixtures without requiring extensive additional purification. Compound (II), (IV), (VI), and (VIII) are designed to precipitate or crystallize in high purity forms that can be isolated by simple filtration, making the purification process self-service rather than requiring multiple complex chromatographic or recrystallization steps.
3Manufacturing precision
If existing synthesis routes are followed, then Tezacaftor is produced but the process is complex and not suitable for industrial scale
Solution Approach 1:
The process employs specific parameter optimizations including temperature control during each reaction step, controlled addition rates of reagents, and specific solvent systems that favor high purity product formation. These parameter changes simplify the overall process by reducing side reactions and eliminating the need for complex purification equipment, making the process suitable for industrial scaling.
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 yields and high purity of Tezacaftor suitable for industrial scale production, enhancing the efficiency and quality of the drug used in treating cystic fibrosis.
Implementation Method 1
reacting a compound of Formula II with an alkyne of Formula III to obtain a compound of Formula IV
Implementation Method 2
treating the compound of Formula IV with a compound of Formula V to obtain a compound of formula VI
Implementation Method 3
cyclizing the compound of Formula VI to obtain a compound of Formula VII
Implementation Method 4
reduction with a suitable reducing agent to obtain an amine compound of Formula VIII
Implementation Method 5
coupling the amine compound of formula VIII or a salt thereof with an acid compound of Formula IX or its reactive derivative thereof to obtain a compound of Formula X
Implementation Method 6
optionally deprotecting the compound of Formula X with a suitable deprotecting agent to obtain Tezacaftor of Formula I
Implementation Method 7
with optional deprotection steps, using suitable protecting groups and solvents for purification
Data Source
AI summary
The present invention generally relates to processes for preparation of Tezacaftor and pharmaceutical composition comprising the same. The present invention also encompasses novel intermediates of tezacaftor, processes for its preparation and use of said intermediates in the preparation of tezacaftor.