Development of a Scaleable Process for the Synthesis of a Next-Generation Statin

Abstract

This manuscript details the process research and development of a convergent and safe approach to 1 on a multikilo scale. Specific highlights of the process development efforts will be described, including the development of a dehydrogenation method for dihydropyrimidines and a thermochemically safe synthesis of a 1,2,4-aminotriazole fragment. A key feature of the synthesis is the use and optimization of a modified Julia-Kocienski olefination reaction. Specifically, we report an unprecedented dependence of the product olefin geometry on reaction temperature, where an E:Z ratio as high as 200:1 can be obtained. Initial insights into the mechanistic rationale for this observation are also provided. Finally, a purity upgrade sequence via an intermediate crystalline form is highlighted as a method of controlling the final API quality.

Recent Progress in the Synthesis of Super-Statins

“…Therefore, the key process parameters of pH, temperature, and initial substrate and CN -concentration were investigated, to determine their influence on the stability and activity of both of these enzymes when separately expressed in E. coli. These investigations revealed that both Hhe and AtNIT2 were thermally stable up to 30 C and operated best at pH 8.0 (Hhe) and 9.0 (AtNIT2), respectively. Moreover, the inhibitory effects of CN -and 17 on AtNIT2 were quantified.…”

“…As a consequence, several new hepatoselective analogs of atorvastatin were derived, such as 1 [22] [29], and 8 [35]. Similarly, more hepatoselective derivatives of rosuvastatin (e.g., derivative 9) have been investigated [28,30]. Quinoline derivatives analogous to pitavastatin (e.g., derivative 10) have also been identified as interesting targets in this context [25,32,36].…”

“…Interestingly, derivatives 13 are the only examples where the 3,5-dihydroxyheptenoic acid moiety modification has been investigated, through fluorination, in parallel with the introduction of a pyrazole core [34]. Some of these derivatives have already passed into clinical development, and viable processes for their efficient and practical preparation that would meet regulatory requirements have been reported [30,31]. These reports represent masterpieces in heterocyclic process chemistry and are valuable additions to a general heterocyclic chemistry [30,31].…”

“…The optimized reaction conditions (pH 7.5, 30 C, 20 mM of substrate) enabled them to prepare (R)-20 at 46.2% yield and ee > 99%.…”

Highly Stereoselective Formal Synthesis of Rosuvastatin and Pitavastatin Through Julia–Kocienski Olefination Using the Lactonized Statin Side-Chain Precursor

“…This approach provided initial stereoselectivities of 15:1 for E-olefin, which dramatically increased to >100:1 in favor of E-isomer when the reaction mixture was 'aged' after reagents addition at noncryogenic temperatures. 25 Based on the above mentioned shortcomings of other routes to super-statins and our recent success in the first successful assembly of rosuvastatin 26 and pitavastatin 27 via lactonized statin sidechain precursor 1 28 employing the Wittig reaction, we were prompted to consider the assembly of rosuvastatin and pitavastatin via Julia-Kocienski olefination employing lactone 1. This would also enable us to verify, if the suboptimal stereoselectivity of our Wittig approach with lactone 1, where an E/Z ratio between 7:1 and 12:1 was achieved, 26,27 could be improved.…”