873055-54-0

Usage

Uses

Used in Pharmaceutical Industry:
Carbonic acid, 2,4-bis(1,1-dimethylethyl)phenyl methyl ester is used as a key intermediate in the synthesis of triazoles as amide biosters. These compounds have potential applications as modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), a protein involved in the regulation of chloride ion transport across cell membranes. The modulation of CFTR activity is crucial for the treatment of cystic fibrosis, a genetic disorder characterized by the buildup of thick, sticky mucus in the lungs and other organs.
In the synthesis of triazoles as amide biosters, the carbonate ester group of bis(2,4-di-tert-butylphenyl) carbonate can be used to react with appropriate amines or other nucleophiles to form the desired triazole structures. The bulky 2,4-di-tert-butylphenyl groups provide steric hindrance, which can influence the reactivity and selectivity of the reaction, leading to the formation of the desired products with improved properties.
Overall, Carbonic acid, 2,4-bis(1,1-dimethylethyl)phenyl methyl ester plays a significant role in the development of new therapeutic agents for the treatment of cystic fibrosis and other related disorders. Its unique structural features and reactivity make it a valuable building block in the synthesis of bioactive compounds with potential pharmaceutical applications.

Upstream product

• 96-76-4 2,4-di-tert-Butylphenol 
• 79-22-1 methyl chloroformate 

Downstream Products

• 873055-55-1 carbonic acid 2,4-di(tert-butyl)-5-nitrophenyl ester methyl ester 
• 873055-56-2 carbonic acid 2,4-di(tert-butyl)-6-nitrophenyl ester methyl ester 
• 1236060-10-8 N-(2,4-di-tert-butyl-5-hydroxyphenyl)-6-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide 
• 1236058-06-2 N-(2,4-di-tert-butyl-5-hydroxyphenyl)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide 
• 873051-19-5 N-(2,4-di-tert-butyl-5-hydroxyphenyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide 
• 1236058-25-5 N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide 
• 1085-21-8 2,4-di-tert-butyl-6-(N-methylamino)phenol 
• 1643-39-6 2-amino-4,6-di-tertbutylphenol 
• 873055-58-4 5-amino-2-4-di-tert-butyl-phenol 
• 873055-57-3 2,4-di-tert-butyl-5-nitro-phenol 
• 1246213-45-5 2,4-di-tert-butyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate 
• 873054-44-5 ivacaftor 

Relevant academic research and scientific papers

COMPOUND FOR TREATING CYSTIC FIBROSIS

Provided herein is a compound represented by Formula I: or a pharmaceutically acceptable salt, hydrate, solvate or complex thereof. Also provided are pharmaceutical compositions comprising the compound noted above, in combination with a pharmaceutically acceptable excipient.

Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases

The present invention features compositions comprising a plurality of therapeutic agents wherein the presence of one therapeutic agent enhances the properties of at least one other therapeutic agent. In one embodiment, the therapeutic agents are cystic fibrosis transmembrane conductance regulators (CFTR) such as a CFTR corrector or CFTR potentiator for the treatment of CFTR mediated diseases such as cystic fibrosis. Methods and kits thereof are also disclosed.

METHODS OF TREATMENT FOR CYSTIC FIBROSIS

This application describes methods of treating cystic fibrosis or a CFTR mediated disease comprising administering Compound I or a pharmaceutically acceptable salt thereof. (I) The application also describes pharmaceutical compositions comprising Compound I or a pharmaceutically acceptable salt thereof and optionally comprising one or more additional CFTR modulating agents.

METHODS OF TREATMENT FOR CYSTIC FIBROSIS

This application describes methods of treating cystic fibrosis comprising administering Compound I:, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing.

Utilizing o-Quinone Methide Chemistry: Synthesis of d9-Ivacaftor

Lead time and cost are important factors for any pharmaceutical API. However, these issues become even more important when the drug substance contains an isotope such as deuterium, which has a natural abundance of only ～0.016% of all hydrogen. Fewer suppliers and logistical barriers both play a role in driving up the cost. These factors can challenge the supply route used to manufacture d9-ivacaftor (17), requiring investigation into alternative routes. By adapting the work from Pettus et al., a synthetic approach utilizing a transient o-quinone methide allowed access to the deuterium-labeled o-tert-butylphenol moiety. This was developed and proven on pilot scale to significantly reduce the number of deuterated reagents used, leading to an overall reduction in cost by a factor of 10, while also providing the substantial benefit of applying prior process knowledge from the parent, nonisotopically enriched API ivacaftor (7).

COMPOSITIONS AND METHODS FOR TREATMENT OF CYSTIC FIBROSIS

Compositions comprising Compound I of the formula (I) and methods of treating cystic fibrosis comprising administering Compound I. Compositions comprising a pharmaceutically acceptable salt of Compound I and methods of treating cystic fibrosis comprising administering a pharmaceutically acceptable salt of Compound I.

METHODS OF TREATMENT FOR CYSTIC FIBROSIS

Methods of treating cystic fibrosis comprising administering at least Compound (I) of the formula. Pharmaceutical compositions containing a pharmaceutically acceptable salt of at least Compound I and methods of treating cystic fibrosis comprising administering a pharmaceutically acceptable salt of at least Compound (I).

METHODS OF TREATMENT FOR CYSTIC FIBROSIS

Compound I of the formula (I) and/or pharmaceutically acceptable salt(s) of Compound I comprised in a pharmaceutical composition and methods of using the same to treat cystic fibrosis.

Evaluation of 1,2,3-Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX-770 and VX-809

The 1,2,3-triazole has been successfully utilized as an amide bioisostere in multiple therapeutic contexts. Based on this precedent, triazole analogues derived from VX-809 and VX-770, prominent amide-containing modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), were synthesized and evaluated for CFTR modulation. Triazole 11, derived from VX-809, displayed markedly reduced efficacy in F508del-CFTR correction in cellular TECC assays in comparison to VX-809. Surprisingly, triazole analogues derived from potentiator VX-770 displayed no potentiation of F508del, G551D, or WT-CFTR in cellular Ussing chamber assays. However, patch clamp analysis revealed that triazole 60 potentiates WT-CFTR similarly to VX-770. The efficacy of 60 in the cell-free patch clamp experiment suggests that the loss of activity in the cellular assay could be due to the inability of VX-770 triazole derivatives to reach the CFTR binding site. Moreover, in addition to the negative impact on biological activity, triazoles in both structural classes displayed decreased metabolic stability in human microsomes relative to the analogous amides. In contrast to the many studies that demonstrate the advantages of using the 1,2,3-triazole, these findings highlight the negative impacts that can arise from replacement of the amide with the triazole and suggest that caution is warranted when considering use of the 1,2,3-triazole as an amide bioisostere.

COMPOSITIONS FOR TREATING CYSTIC FIBROSIS

A single tablet comprising Compound I:. Methods of treating cystic fibrosis comprising administering one or more of such single tablets to a patient.