The Intermediate Too Unstable to Bottle A Manufacturing Route to Evenamide

This application does not claim a drug. It claims the way one is made. The compound at the centre of it is 2-[2-(3-butoxyphenyl)ethylamino]-N,N-dimethylacetamide, better known as evenamide, a sodium channel blocker that Newron Pharmaceuticals is developing as an add-on treatment for schizophrenia. The published route to it was too dirty, too low yielding and too dangerous to run at scale, and the obvious alternative depended on an intermediate that falls apart before you can use it.

The Problem

The compound class here, substituted 2-[2-(phenyl)ethylamino]alkaneamide derivatives, was disclosed in WO 2008/151702. These molecules modulate sodium and calcium channels and are described as substantially free of monoamine oxidase inhibitory activity, which separates them from Newron’s earlier and structurally related work on safinamide. They are of interest across neurological, psychiatric, inflammatory, urogenital and gastrointestinal conditions.

The synthesis published in that earlier document is a laboratory route, and the specification is unusually candid about why it cannot be industrialised. The starting material, 3-methoxyphenylethylamine, is not commercially available and takes several steps to make. The intermediates are oils and therefore awkward to purify. It uses large excesses of 1-bromobutane and 2-chloro-N,N-dimethylacetamide, the latter potentially genotoxic. It calls for sodium hydride in dimethylformamide, a combination that generates hydrogen and has a documented history of thermal runaway. The final hydrochloride is made in ethereal solvents that form peroxides on standing in air. Overall yield is about 13 per cent, and the purity of the final product is simply not known.

The same 2008 document suggested a cleaner alternative in passing: take 3-butoxyphenyl-acetaldehyde and run a reductive amination with an alpha-aminoalkaneamide. It gave no conditions, no yield, and no method for making the aldehyde. The present inventors established why. That aldehyde is highly unstable, which makes isolating it, storing it and charging it into a large reactor impractical.

So the problem is narrow and specific. The good reaction is known. The molecule it needs cannot survive the journey to the reaction.

What This Invention Does

The process builds the unstable aldehyde in a masked form, then unmasks it inside the vessel where it will immediately be consumed. Step a is a Wittig reaction between the substituted benzaldehyde and an (alkoxymethyl)phosphonium halide under a strong base. That extends the chain by one carbon and delivers an enol ether. The enol ether is stable, isolable and easy to handle, and it is chemically one hydrolysis away from the aldehyde nobody wants to store.

Step b hydrolyses that enol ether under aqueous acidic conditions to release the arylacetaldehyde. Step c adds the alpha-aminoalkaneamide to the same aqueous mixture, forming a condensation product that the specification describes as a Schiff base, or the related alpha-hydroxyamine, or an unsaturated amine, or a mixture of all three in equilibrium. Step d adds a reducing agent to that same mixture and delivers the target amine. Step e, optional, converts it to a pharmaceutically acceptable salt.

The claimed advantage sits in how those steps are joined. Steps b, c and d are run as a telescoped sequence, meaning no extraction, no work-up and no crystallisation between them. Reagents are added to the reactor in turn and the product is only isolated at the end of step d. The specification calls this unusual for a three step sequence, and it is the reason the unstable aldehyde is never a problem: it exists only as a transient species in a pot that already contains the amine waiting to react with it. A further variant, step c prime, skips the hydrolysis as a separate operation and reacts the enol ether directly with the aminoalkaneamide before reduction.

The final salt step is chosen for the same practical reason. Salification with hydrochloric acid in methyl tert-butyl ether or methyl isobutyl ketone at 0 to 25 degrees Celsius produces a salt with low solubility in those solvents, so the pure product is recovered by filtration rather than by crystallisation from a carefully tuned solvent system. Worked examples in the specification run at plant scale, including a batch producing 18.7 kilograms of the hydrochloride in 82 per cent yield from the free base.

Key Features

• Masked aldehyde by Wittig olefination. An (alkoxymethyl)phosphonium salt converts the benzaldehyde into a stable enol ether that carries the extra carbon atom the target molecule needs.
• Hydrolysis in the reaction vessel. The enol ether is opened to the unstable arylacetaldehyde under aqueous acid, in the same pot where it will be consumed.
• Reductive amination without isolation. The aminoalkaneamide is added directly to that aqueous mixture and the resulting condensation product is reduced in place.
• Telescoped three step sequence. Steps b, c and d proceed without any extraction, work-up or crystallisation, with a single work-up at the end of the third step.
• Filtration based purification. The hydrochloride salt is poorly soluble in the chosen ethers and ketones, so isolation is a filtration rather than a controlled crystallisation.
• Standard equipment and reagents. The route avoids the sodium hydride in dimethylformamide, the large excess of genotoxic alkylating agent and the peroxide forming ethereal solvents that made the earlier synthesis unscalable.

Who Is Behind It

Newron Pharmaceuticals S.p.A. is an Italian biopharmaceutical company founded in 1999 and based at Bresso, near Milan, with shares listed on the SIX Swiss Exchange. It works on diseases of the central and peripheral nervous system. Its best known output is safinamide, marketed for Parkinson’s disease, and its lead clinical asset is evenamide, also known as NW-3509, which has moved into Phase III trials as an add-on therapy for treatment resistant schizophrenia.

The named inventors are William Leong, Dongxiao Lan, Weifang Zhang, Xiang Fang and Sizhong Wu. None of them appear on the earlier compound patents in this family, which is what you would expect: this is process development work, the discipline that takes a molecule someone else discovered and works out how to make tonnes of it safely, and it is routinely carried out with a contract development and manufacturing partner rather than in the originating research group.

The Australian filing is a divisional of application 2020259813, which was the national phase entry of PCT/EP2020/060470, published as WO 2020/212352 and filed on 14 April 2020. That in turn claims priority from European application 19169715, filed on 17 April 2019.

Why It Matters

Process patents are the quieter half of pharmaceutical intellectual property. A compound patent tells competitors what they cannot sell; a process patent tells them what they cannot easily make. For a company with a single lead asset in late stage trials, protecting the only economically viable manufacturing route matters roughly as much as protecting the molecule, and it matters for longer, because process filings made a decade after the original discovery outlive the compound patent.

Technically, this is a good illustration of where fine chemical manufacturing has been heading. Telescoping, sometimes called through-processing, removes the isolation steps that dominate cost, cycle time and solvent consumption in a multi-step synthesis. It also solves stability problems by construction: an intermediate that cannot be stored does not need to be, if it is generated and consumed in the same vessel. The parallel move away from genotoxic alkylating agents and from reagent combinations with known runaway risk reflects both regulatory pressure on impurity control and plain occupational safety.

The filing strategy is straightforward to read. A 2019 European priority, a 2020 international filing, and an Australian divisional taken out in 2026 while the drug is still in Phase III. Divisionals kept in play this late usually mean the applicant wants claim scope options open until the commercial route is locked down and the product’s approval path is clearer.

Related Concepts

• Evenamide – the specific compound this manufacturing route is designed to produce at scale.
• Wittig reaction – the olefination that creates the stable enol ether standing in for the unstable aldehyde.
• Reductive amination – the bond forming step that joins the aldehyde fragment to the amide fragment.
• Schiff base – the condensation intermediate formed and reduced without ever being isolated.
• One-pot synthesis – the general principle behind the telescoped three step sequence.
• Voltage-gated sodium channel – the target that makes this class of molecules therapeutically interesting.

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AU 2026202091 was published in the Australian Official Journal of Patents on 9 April 2026 and is open for public inspection. Patent applications represent inventions that are sought to be protected and do not necessarily reflect commercially available products.