{"id":95,"date":"2026-07-30T23:11:19","date_gmt":"2026-07-30T23:11:19","guid":{"rendered":"https:\/\/astinovabiolabs.com\/blog\/?p=95"},"modified":"2026-07-30T23:11:19","modified_gmt":"2026-07-30T23:11:19","slug":"synthesis-of-zidesamtinib-jideytro-drug-intelligence-dossier","status":"publish","type":"post","link":"https:\/\/astinovabiolabs.com\/blog\/synthesis-of-zidesamtinib-jideytro-drug-intelligence-dossier\/","title":{"rendered":"Synthesis of Zidesamtinib (JIDEYTRO) \u2014 Drug Intelligence Dossier"},"content":{"rendered":"\n

Mechanism:<\/strong>\u00a0Zidesamtinib is a small-molecule inhibitor of the tyrosine kinase ROS1, including ROS1 resistance mutations. In biochemical assays (PI \u00a712.1) it inhibits ROS1 (IC50 = 0.7 nM) with much weaker activity against the tropomyosin receptor kinases \u2014 TRKB (IC50 = 54 nM), TRKC (193 nM), TRKA (258 nM) \u2014 i.e. ~77-fold ROS1-vs-TRKB selectivity; it also inhibits ALK (IC50 = 3 nM). This deliberate TRK(B)-sparing profile is the mechanistic basis for its low CNS\/neurological adverse-event burden versus TRK-inhibiting comparators. In vitro it suppresses viability of cells expressing ROS1 fusions and resistance mutations (G2032R, S1986F, F2004C\/V, L2026M, D2033N, G2101A) and, as a brain-penetrant macrocycle, shows antitumour activity in an intracranial ROS1-fusion NSCLC xenograft. Discovery\/pharmacology: Drilon et al., Cancer Discov 2023;13(3):598-615 (PMID 36511802); resistance-mutation structural biology: Tangpeerachaikul et al., Mol Cancer Ther 2025;24(7):1005-1019 (PMID 40299789).<\/p>\n\n\n\n

Synthesis Route of the Originator<\/h2>\n\n\n\n

Zidesamtinib (NVL-520; JIDEYTRO) is a pentacyclic macrocyclic aryl-ETHER. The disconnection is taken from the Nuvalent composition-of-matter patent US 11,542,278 B1 \/ WO 2021\/226269 A1 (‘Heteroaromatic macrocyclic ether chemotherapeutic agents’), in which zidesamtinib is a labelled example; no dedicated OPRD\/process paper exists (verified on PubMed), and the medicinal-chemistry rationale is described in Drilon et al., Cancer Discov 2023, 13(3), 598-615 (PMID 36511802). The verified patent strategy: (1) the benzylic aryl ether is formed FIRST, on an open-chain precursor, by SNAr of the (R)-1-(5-fluoro-2-iodophenyl)ethanol onto an activated (nitro\/halo) bromopyridine \u2014 this is the structural departure from lorlatinib’s macrolactamization; (2) the ‘west’ pyrazole-CH2-triazole diarylmethane fragment (built by heteroaryl carbinol formation then Et3SiH\/TFA deoxygenation) is joined to the ‘east’ fluorophenyl-ether-aminopyridine unit by an intermolecular Suzuki-Miyaura coupling (via the triazolyl-Bpin), giving an open-chain dibromo precursor (C22H22Br2FN7O); (3) the ~14-membered MACROCYCLE is then closed by an intramolecular Pd-catalysed biaryl coupling \u2014 either one-pot Miyaura borylation\/intramolecular Suzuki or direct C\u2013H arylation (Pd, KOAc or potassium pivalate, high dilution) \u2014 forming the pyrazole(C5)-aminopyridine bond and giving zidesamtinib directly (a final Fe\/NH4Cl reduction unmasks the 2-aminopyridine hinge if a nitropyridine was carried through). Building blocks include 5-bromo-1-ethyl-1H-pyrazole-4-carbaldehyde (CAS 1780579-42-1) and a 4-fluoro-2-iodobenzoic-acid-derived fluorophenyl unit (parent acid CAS 56096-89-0). CONDITIONS ARE REPRESENTATIVE for the named transformations (the exact per-compound conditions\/yields sit on image-only pages of US 11,542,278); the transformation TYPES and the ether-first \/ macrocyclize-last logic are verified from the patent’s General Methods. The full chain is RDKit-validated and the final product canonicalizes exactly to the target C22H22FN7O, (R). Verify against the patent\/process literature before scale-up.<\/p>\n\n\n\n

\"\"<\/figure>\n\n\n\n

a<\/sup>Reagents and conditions: (1) 3-halo-5-bromo-2-nitro(or 2-amino)pyridine (1.0 eq), base (NaH or Cs2CO3, 1.2-2 eq), DMF or NMP, 0 C -> 60 C. Benzylic secondary alkoxide displaces the pyridine C3 halide (nitro-activated). Proceeds with RETENTION at the benzylic centre (O stays CIP #1 in both alcohol and ether -> label stays R). [representative partner\/oxidation state]; (2) West fragment triazolyl-Bpin (from 4-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-5-iodo-2-methyl-2H-1,2,3-triazole via Miyaura borylation, B2pin2\/Pd\/KOAc; 1.1 eq), Pd(dppf)Cl2 (5 mol%), K3PO4 or K2CO3 (2-3 eq), dioxane\/H2O, 80-90 C. Forms the triazole(C5)-fluorophenyl biaryl bond; leaves pyrazole-Br and pyridine-Br as the two macrocyclization handles. [Suzuki\/borylation is the verified patent tactic; which biaryl is intermolecular is representative]; (3) Close the pyrazole(C5)-aminopyridine(C5) bond by either (a) one-pot Miyaura borylation \/ intramolecular Suzuki (B2pin2 then Pd, aqueous base), or (b) direct intramolecular C-H arylation, Pd catalyst with potassium acetate or potassium pivalate as base (the patent states these bases are effective for the macrocyclization). Run at high dilution to suppress oligomerization. Gives zidesamtinib directly (or after a final Fe\/NH4Cl nitro reduction if the 2-nitropyridine was carried through). [transformation type verified from patent General Methods; RDKit-verified to regenerate the exact target].<\/p>\n\n\n\n

Key Intermediates<\/strong><\/p>\n\n\n\n

\"\"<\/figure>\n\n\n\n

Crystal Forms, Salts, and Solid-State Profile<\/h2>\n\n\n\n