Daprodustat API synthesis route and production process

Daprodustat (Daprodustat) is an oral small molecule HIF-PHD inhibitor that mainly works by inhibiting prolyl hydroxylase isoenzymes (PHD1, PHD2, PHD3), thereby stabilizing HIF transcription factors, promoting erythropoiesis, and improving chronic kidney disease-related anemia. Due to its unique molecular structure and complex synthesis route, the production process of APIs has always been the focus of the pharmaceutical industry.

From a chemical point of view, the systematic chemical name of daprostat is N-(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl)glycine, the molecular formula is C19H27N3O6, and the molecular weight is 393.43. The structure contains multiple chiral carbon atoms as well as key functional groups such as urea group and pyrimidinone ring, which makes the synthesis process extremely demanding on stereochemical control and impurity removal.

In terms of synthetic strategy, multiple data show that the synthesis of daporostat is mainly divided into three key steps: the first is the construction of the hexahydropyrimidinetrione skeleton, which is often completed by a cyclization reaction; the second is the introduction of urea groups and glycine fragments, which are achieved through condensation or acylation reactions; the third is chiral selectivity and purity control, which usually requires the use of asymmetric synthesis or chiral resolution technology. To increase yields and reduce process impurities, pharmaceutical companies use multi-step purification processes, including crystallization, chromatography, and solvent optimization.

In terms of industrial production, the synthesis of daprostat API emphasizes the concept of green chemistry. Due to the large clinical usage, the use of traditional solvents or heavy metal catalysts needs to be strictly controlled to avoid residual risks and comply with international ICH standards. In recent years, some process improvements have attempted to introduce recyclable solvent systems and catalysts to improve the sustainability and economy of the process.

In addition, the preparation process also places strict requirements on the purity of raw materials. The oral tablet specifications of Jesduvroq are 1mg, 2mg, 4mg, 6mg and 8mg. The quality of each tablet depends on the stable supply and consistent production of raw materials. Efficient and stable synthesis routes are not only related to production capacity, but also determine the accessibility and price trends of drugs in the global market.

Reference materials:https://en.wikipedia.org/wiki/Daprodustat