Development of a Scalable Synthetic Process for DG-051B, A First-in-Class Inhibitior of LTA4H

Abstract

DG-051B is a first-in-class small molecule inhibitor of leukotriene A4 hydrolase (LTA4H), currently in Phase II clinical development for the prevention of heart attack. Process optimization led from a linear seven-step synthetic procedure to a convergent four-step manufacturing sequence that has been used to manufacture at 100-kg scale. The entire process can be telescoped due to high conversion reactions, low impurity levels, efficient separations, and a very effective final purification. Two key aspects of the process are: (a) bypassing the isolation of a reactive electrophile by using its aqueous-washed reaction mixture directly into a coupling reaction with a phenoxide nucleophile and (b) modulating the properties of the final product solutions for optimal extraction, purification, and crystallization.

CuI/Oxalamide Catalyzed Couplings of (Hetero)aryl Chlorides and Phenols for Diaryl Ether Formation

“…These three products are important building blocks for assembling bioactive molecules that have been prepared on large scale by employing different coupling methods. [9][10][11][12] Fore xample,d iaryl ether 3k is the key intermediate for synthesizing DG-051B,w hich has entered phase II clinical evaluation for the treatment of myocardial infarction and stroke. [1e, 9] Diaryl ether 3q has been used for manufacturing the insecticide diafenthiuron, [10] and diaryl ether 3y is ac ommon building block for manufacturing insecticidal pyrethroids,s uch as permethrin, cypermethrin, and deltamethrin.…”

“…[1e, 9] Diaryl ether 3q has been used for manufacturing the insecticide diafenthiuron, [10] and diaryl ether 3y is ac ommon building block for manufacturing insecticidal pyrethroids,s uch as permethrin, cypermethrin, and deltamethrin. [1e, 11] Thec urrently adopted synthetic approaches require the use of more expensive aryl bromides as the coupling partners (for 3k [9] and 3q), [10] or higher reaction temperatures (150-170 8 8Cf or 3y). [11] Our coupling method has clear advantages over previously reported ones and will probably find practical usage for preparing these diaryl ethers.…”

CuI/Oxalamide Catalyzed Couplings of (Hetero)aryl Chlorides and Phenols for Diaryl Ether Formation

“…For an electron‐rich aryl chloride, a catalyst loading of 5 mol % (for both CuI and L9 ) was still necessary to obtain coupling product 3 q in good yield. These three products are important building blocks for assembling bioactive molecules that have been prepared on large scale by employing different coupling methods . For example, diaryl ether 3 k is the key intermediate for synthesizing DG‐051B, which has entered phase II clinical evaluation for the treatment of myocardial infarction and stroke .…”

“…These three products are important building blocks for assembling bioactive molecules that have been prepared on large scale by employing different coupling methods . For example, diaryl ether 3 k is the key intermediate for synthesizing DG‐051B, which has entered phase II clinical evaluation for the treatment of myocardial infarction and stroke . Diaryl ether 3 q has been used for manufacturing the insecticide diafenthiuron, and diaryl ether 3 y is a common building block for manufacturing insecticidal pyrethroids, such as permethrin, cypermethrin, and deltamethrin .…”

Efficient synthesis of unnatural dipeptides based on cis-2,5-disubstituted pyrrolidine

“…The unnatural peptides play a key role in peptidomimetics (Sun et al 2008;Hanessian and Auzzas 2008;IsidroLlobet et al 2011;Ung and Winkler 2011), among them peptides containing 2,5-disubstituted pyrrolidine moiety have drawn much attention of chemists and pharmaceutists by their unique physiological activities (Wang et al 2001;Enache et al 2009;Davis et al 2008;Draper and Britton 2010). Due to non-planar nature of pyrrolidine, peptides containing pyrrolidine motif can have flexible conformation which is responsible for their biological activities (Madis 1977;Giordano et al 2010;Warren et al 2010).…”