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Chemistry and Pharmacology of Drug Discovery
The first task was to determine the appropriate functional groups on 38 that would
enable a robust, high-yielding synthesis of this intermediate. After experimentation, the socalled “acid route” was developed commencing with bis-deoxychlorination of
commercially available dihydroxy pyridazine carboxylic ester 39 and subsequent
saponification to yield carboxylic acid 40, which was able to be carried through the S
and Pd-catalyzed amidation steps.
Figure 16. Retrosynthetic analysis of 1
N
Ar
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Chapter 15. Deucravacitinib (Sotyktu)
Scheme 3. First pass proof of concept for “acid route”
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Proof of concept for this route was successfully achieved on the first pass and
ultimately evolved into the commercial process (Scheme
After extensive development and multiple iterations of design and testing, details
hereon in highlight optimization of this first pass process including key reactions and
conditions that were ultimately settled on and employed in the final commercial process.
Chemistry and Pharmacology of Drug Discovery
32
3).
6.2.1. Synthesis of Aniline Fragment 33
Devising an efficient and cost-effective synthesis to aniline 33 was of paramount
importance due to the modest yielding and poorly regioselective triazole methylation step.
The optimized synthesis to aniline 33 commenced with a cyclocondensation reaction
between cheap commercially available 5-chloro-2-methoxybenzonitrile 43 and Nmethylformohydrazide 44, affording the free base which was transformed to the bisulfate
salt 45 (Scheme 4). The nitration reaction to form 46 was extremely clean (>99% inprocess purity). In the final step, a one-pot hydrogenation/hydrogenolysis to reduce both
the nitro group and the aryl chloride moiety was readily achieved using gaseous hydrogen
and palladium on carbon at modest pressure. Selective choices of hydrogen pressure,
catalyst loading, reaction temperature, and reaction concentration (guided by design of
experiment studies) minimized impurity formation to <0.1% (Scheme 4).
Scheme 4. Synthesis of aniline 33
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Chapter 15. Deucravacitinib (Sotyktu)
6.2.2. Synthesis of Pyridazine Core 40-01
The process chemistry synthesis to dihydroxypyridazine 39 was not too dissimilar to the
discovery route and will not be discussed further here (shown in Scheme
deoxychlorination of 39 with POCl3 to the corresponding dichloropyridazine carboxylic
ester 47 was straightforward but required careful quenching with water to ensure
homogeneity of the reaction mixture (Scheme 5). This proved crucial for minimizing the
formation of hydrolytic impurities. Ester 47 was telescoped into the subsequent hydrolysis
step but the resulting free pyridazine carboxylic acid underwent spontaneous
decarboxylation. It was found that addition of lithium bromide and water followed by slow
addition of DIPEA effected the hydrolysis resulting in the stable crystalline lithium
monohydrate salt 40-01. Overall, the chlorination-hydrolysis telescope reproducibly
afforded 40-01 in good yield and high purity on a >200 kg scale (Scheme
1). Double
5).
Scheme 5. Synthesis of dichloropyridazine carboxylic acid salt 40-01
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Chemistry and Pharmacology of Drug Discovery
6.2.3. Nucleophilic Aromatic Substitution Between 33 and
40-01 to Afford 48
Initially, the desired product in its free acid form (presumably a zwitterion) was found to
be both hygroscopic and susceptible to decarboxylation at elevated temperatures. To
circumvent these issues and improve selectivity for the desired product over the undesired
regioisomer and the disubstituted adduct (structures not shown), a screen of Lewis acids
revealed that stoichiometric Zn(OAc)
selectivity. Conveniently, the stable product salt precipitated spontaneously from the
reaction solution as the zinc salt 48. Adding small amounts of isopropanol as co-solvent,
expedited product filtering (due to improved crystal morphology). The zinc salt was
reproducibly isolated in excellent yield and purity on >100 kg scale (Scheme 6).
could mediate the reaction with near-perfect
2
Scheme 6. Synthesis of carboxylic acid zinc salt 48
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Chapter 15. Deucravacitinib (Sotyktu)
6.2.4. Penultimate Step: Palladium-Catalyzed C–N
Coupling of 48 and Cyclopropyl Amide 35 to Afford 49
Scheme 7. Penultimate Step: Synthesis of carboxylic acid zinc salt 49
This was the last step in the discovery synthesis but was switched to a penultimate step in
the process route to minimize cost and avoid the use of a Pd catalyst in the final step. Highthroughput experimentation (HTE) was employed to identify the most suitable
catalyst/ligand/base replacements. From a cost, availability, and stability standpoint,
Pd(OAc)
a significant impact on reaction kinetics and a comprehensive investigation led to the
finding that a combination of DBU and K
zinc carboxylate as well as enhancing the rate of the reaction. Ligand screening with the
was chosen as the catalyst for the commercial process (Scheme 7). The base had
2
was optimal for complete dissolution of the
2CO3
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dual-base combination revealed SL-J009 as the preferred ligand due to lower palladium
catalyst loading requirements. With respect to solvent, an iterative process determined that
an acetonitrile/toluene combination ensured the correct balance between reactivity and
solubility of the zinc carboxylate 48. The product was isolated as zinc salt 49 in excellent
yield and purity, after a seeded crystallization. The robust process was successfully and
reproducibly scaled multiple times to >80 kg/batch (Scheme 7).
Chemistry and Pharmacology of Drug Discovery
6.2.5. API Step: Amidation with CD3NH2 to Afford 1
The final step in the commercial process to deucravacitinib was amidation between zinc
carboxylate 49 and trideuteromethylamine. Due to handling and commercial availability
concerns, trideuteromethylamine (a gas) was procured as its crystalline hydrochloride salt.
Scheme 8. Commercial API step: synthesis of 1
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Chapter 15. Deucravacitinib (Sotyktu)
Conducting laboratory scale optimization based on HTS data revealed the most effective
coupling reagents to be EDC/HOBt. Polar aprotic solvents worked best (presumably due
to solvation of poorly soluble salt 49), and the nucleophilic sp
2
-hybridized amine base, Nmethylimidazole (NMI), proved superior. The optimal reaction and
crystallization/recrystallization parameters gave suitable impurity purge, excellent yield
and consistently pure deucravacitinib 1 (>99.5% purity) at scales of >100 kg per batch
(Scheme
8).
In summary, an efficient, high-yielding synthesis of 1 in eight steps from
inexpensive commercial materials was developed, enabling production of more than a
metric ton of deucravacitinib for clinical and commercial use (Scheme
9). The convergence
of the synthesis was maximized through development of novel, mild conditions for the
regioselective synthesis of a 1-methyl-3-aryl triazole. Subsequent optimization afforded
protocols that produced intermediates and drug substance of very high purity, while in
32
tandem achieving sustainability goals and a greener synthesis.
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Chemistry and Pharmacology of Drug Discovery
7. Summary
In summary, deucravacitinib (Soyktu) is a first-in-class, oral, selective, allosteric tyrosine
kinase 2 (TYK2) inhibitor that was granted approval by the FDA in September 2022 for
moderate-to-severe plaque psoriasis. The approval was based on results from two pivotal
Phase 3 POETYK PSO-1 and POETYK PSO-2 clinical trials, which demonstrated superior
efficacy of once-daily Sotyktu compared to placebo and twice-daily Otezla in 1684 patients
aged 18 years and older with moderate-to-severe plaque psoriasis.
The approval of deucravacitinib represented a watershed moment for
manufacturer and originator, BMS, with it being the first of its kind in more ways than one:
it is the first approved drug targeting a pseudokinase domain. This unique allosteric
mechanism differentiates deucravacitinib from all other reported JAK/TYK2 inhibitors due
to its exquisite selectivity for TYK2 and its impressive benefit-safety profile that is not
attainable through JAK1/2/3 inhibition. It is also the first approved de novo deuterated
Scheme 9. Commercial process to deucravacitinib (1)
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drug. A “magic methyl” on the amide moiety was found to be responsible for the
remarkable selectivity through binding within a rare “alanine pocket” in the ligand binding
domain of TYK2 JH2. This was protected from N-demethylation via deuteration, thus
preventing formation of the less selective primary amide.
From identification of hits from an HTS campaign to extensive lead optimization,
the discovery of deucravacitinib ran into many issues that are routinely encountered in a
typical drug discovery program, including potency, selectivity, metabolism, permeability,
bioavailability, hERG/cardiotoxicity etc. All of these issues were solved through
innovative structure-based drug design strategies and very clever medicinal chemistry. Of
note was the heterocyclic core modifications (pyridine to pyridazine) to provide optimal
permeability and exposure, replacement of the C6 amino heterocycle with a cyclopropyl
carboxamide to mitigate hERG activity, deuteration to mitigate levels of an undesired
metabolite, and intelligent use of modelling to replace a structural water molecule within
the binding site, leading to significant potency enhancement. These optimizations
culminated in a molecule that had excellent PK properties across species with minimal
profiling liabilities.
Key highlights from the process chemistry route included the development of a
novel cyclocondensation reaction to afford a methylated 1,2,4-triazole with excellent
regioselectivity, and implementation of the amidation with trideuteromethylamine as the
final step, serving to simultaneously reduce costs and control residual metal levels. This
exceptional work led to a highly cost-effective, efficient and sustainable commercial route
that enabled the production of more than a metric ton of deucravacitinib.
The fascinating drug discovery and development story of deucravacitinib provides
the reader with a cornucopia of knowledge in drug design, medicinal chemistry, and
process development. The tour de force of many scientists across several disciplines,
involved in bringing this innovative oral treatment to patients with moderate-to-severe
plaque psoriasis, constitutes a truly heroic effort.
Chapter 15. Deucravacitinib (Sotyktu)
References
1. El-Gabalawy, H.; Guenther, L. C.; Bernstein, C.N. Epidemiology of
2. https://www.psoriasis.org/psoriasis-statistics/
3. See: https://my.clevelandclinic.org/health/diseases/6866-psoriasis
4. Clark, J. D.; Flanagan, M. E.; Telliez, J.-B. Discovery and development
immune-mediated inflammatory diseases: incidence, prevalence, natural
history, and comorbidities. J. Rheumatol. 2010, 37 (Suppl 85), 2–10.
of Janus kinase (JAK) inhibitors for inflammatory diseases. J. Med.
Chem. 2014, 57, 5023−5038.
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