CFTR Modulator Synthesis Processes for Higher Yield and Purity

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Solution Overview

Problem

Current treatments for cystic fibrosis (CF) are inadequate, and there is a need for therapeutics that can modulate the cystic fibrosis transmembrane conductance regulator (CFTR) to address ion and fluid transport imbalances, as well as efficient methods for synthesizing CFTR modulators with higher yield, selectivity, and purity.

Innovation Solution

The development of processes for synthesizing compounds such as N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide and N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4(S))-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which are designed to modulate CFTR function and improve anion and fluid transport.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments for cystic fibrosis are used, then patients receive standard care, but the treatments are inadequate and do not effectively address ion and fluid transport imbalances

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidability to modulate CFTR

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent develops new chemical compounds with modified molecular structures and properties designed to specifically modulate CFTR function. By changing the chemical parameters of the therapeutic agents, the invention achieves effective CFTR modulation and corrects ion transport defects that current treatments cannot address

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces CFTR modulator compounds as intermediary substances that mediate between the administered therapy and the CFTR protein. These compounds act as molecular intermediaries that bind to CFTR and restore its proper function, enabling effective treatment of the underlying transport defects

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If conventional synthesis methods are used for CFTR modulators, then compounds can be produced, but the yield, selectivity, and purity are insufficient

Engineering Contradiction:

Improvesynthesis yieldVSAvoidcompound purity

Core Design Contradiction:

ProductivityVSManufacturing precision

Solution Approach 1:

The patent divides the synthesis of complex CFTR modulator compounds into separate modular stages, with independent optimization of each step. This segmentation allows for improved control over reaction conditions, higher yields at each stage, and better overall purity of the final product

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent replaces conventional mechanical mixing and heating methods with catalytic systems and optimized reaction conditions. By using catalysts and controlled chemical environments instead of brute-force mechanical approaches, the synthesis achieves higher selectivity, yield, and purity

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Data Source

PatentUS12415798B2Processes for making modulators of cystic fibrosis transmembrane conductance regulator

Publication Date: 2025.09.16 VERTEX PHARMACEUTICALS INC

AI summary

The disclosure provides processes for preparing a compound of Formula (I):