Production-Scale Synthesis of gem-Dimethylcyclopropylproline
The gem-dimethylcyclopropyl group is a key element in drugs, candidates, and agrochemicals, with a recent example being nirmatrelvir, the active ingredient in the Pfizer COVID-19 drug, Paxlovid. Here, we review synthetic strategies used to produce the key gem-dimethylcyclopropylproline intermediate, which may now be required in hundred-ton quantities to support nirmatrelvir manufacturing.
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Synthesis Spotlight: The gem-Dimethylcyclopropyl Group in Commercial Molecules
The gem-dimethylcyclopropyl group is a powerful group in drug discovery, offering a way to introduce lipophilicity in a tight spot while maintaining three-dimensionality and minimizing rotatable bonds. In this way it can contribute to drug potency while preserving solubility and oral bioavailability. While it has been applied commercially in agrochemicals as early as the 50’s (in cypermethrin, an active ingredient in the insecticide Raid), it was made famous in drug discovery by the Schering-Plough HCV protease inhibitor, boceprevir.
It's regained fame now as a key element of nirmatrelvir, our 2021 Molecule of the Year and the active ingredient in COVID-19 drug, Paxlovid. In late 2021, Pfizer signed an agreement with The Medicine Patent Pool to allow 35 generic manufacturers to help supply Paxlovid to the world, but worldwide demand for Paxlovid in 2022 is estimated to be 250 million courses. With each course made up of 2 x 150 mg tablets, twice a day, over 5 days, 750 metric tons of nirmatrelvir are going to be needed until Covid subsides, which means an unprecedented amount of this complex gem-dimethylcyclopropylproline building block is needed!
Indeed, BirdoTech analyzed the landscape for various routes to nirmatrelvir and determined that this gem-dimethylcyclopropylproline methyl ester is a key limiting reagent (needed in 600 ton quantities) without an existing commercial supply chain.
In this Synthesis Spotlight, we highlight the recent history of gem-dimethylcyclopropylproline syntheses, including:
The Schering medicinal chemistry routes to gem-dimethylcyclopropylproline (2006/2009)
The Schering process syntheses applying C-H oxidation (2005/2007 patents), starting from caronic anhydride
The Schering/Codexis enzymatic synthesis (2012 JACS + 2013 Codexis patent)
A modified Simmons-Smith direct catalytic cyclopropanation breakthrough (2018 ACIE)
And in case anyone’s looking for tons of this thing, BirdoTech has a route to 99%+ ee AC020251 on production scale… you can get in touch with the BirdoTech team here.
Original Schering Research Routes
The original route to this isomerically pure dimethylcyclopropylproline methyl ester was developed by Schering to support the discovery of boceprevir, and started from protected pyroglutaminol. Oxidation, diastereoselective cyclopropanation with a phosphorous ylide, and reduction resulted in the gem-dimethylcyclopropylprolinol. This medicinal chemistry route was reported on milligram scales.
A later published (2009) route from Schering-Plough/Merck used the naturally occurring terpene, (+)-3-carene, as the source of the dimethylcyclopropyl group. This route was applied on multi-gram scale.
Schering’s initially patented synthesis (WO2007/075790A1) of gem-dimethylcyclopropylproline methyl ester leveraged carene as a starting point (via caronic anhydride and ethyl crystanthemate), though not as a source of asymmetry. Interesting, this route leveraged what could be called a silver-mediated C-H oxidation on scale, using Ag(I) nitrate as the oxidant. The oxidation resulted in racemic material that was later resolved by classical resolution.
The Schering-Plough/Codexis Enzymatic Route
The next major synthetic breakthrough was made by the Schering-Plough (Merck) and Codexis teams, reported in JACS in 2012 and in a 2013 patent (US10066250B2), which employed an engineered monoamine oxidase and molecular oxygen to carry out the key desymmetrizing C-H oxidation, generating an imine which was trapped as a sulfonate. This could be trapped by sodium cyanide resulting in a net asymmetric Strecker reaction, with highly enantiopure resulting material.
This process was used on scale until boceprevir was discontinued in 2015 for commercial reasons. With no commercial impetus to supply gem-dimethylcyclopropylproline, the intermediate virtually disappeared from the global supply chain. The enzymatic route would be difficult to scale to support the 600-ton scale required for nirmatrelvir, requiring unprecedented enzyme reactor volumes, on top of the 6 steps needed to prepare the feedstock amine and another 4 steps to complete the synthesis.
A Direct, Catalytic, Modified Simmons-Smith Reaction
Recently, a more direct gem-dimethylcyclopropanation reaction was reported by the Uyeda group in 2018 using a cobalt catalyst and simple reagents. This type of direct transformation will be applicable to the synthesis of gem-dimethylcyclopropane-containing molecules in medicinal chemistry in the future, and works on the multi-kilo scale. However, this does not address the need for isomerically pure final product.
To support the manufacture of molecules like nirmatrelvir, BirdoTech independently developed a proprietary chemical process to prepare enantiomerically pure AC020251 that can be scaled to production levels. While we hope this process can be publicly disclosed someday, for now interested parties can contact BirdoTech for partnering opportunities for this particular intermediate or other complex projects.
Cost of Goods Sold: Final Thoughts
Cost of goods sold is often underappreciated in drug discovery. One key question that remains is whether the nirmatrelvir can be manufactured economically to support the global demand. The US has so far only been willing to pay ~$500 per course of treatment of Paxlovid, putting an upper limit on the cost of goods for nirmatrelvir at ~$260 per gram. Accounting for distribution, overhead, and other components likely puts the budget for nirmatrelvir and its corresponding building blocks at a far lower price. Can chemists do it?
We hope this Synthesis Spotlight helped satisfy your curiosity about this building block, and gave you ideas for what kinds of building blocks might be easily accessible in the future thanks to new chemistry. Happy hunting!
