Blog › FDA approved small molecules

Synthesis of Lirafugratinib (LYRFIGTU) — Drug Intelligence Dossier

astinovabiolabs · · 4 min read

Mechanism: Lirafugratinib (RLY-4008) is a highly selective, IRREVERSIBLE (covalent) small-molecule inhibitor of fibroblast growth factor receptor 2 (FGFR2). A methacrylamide (2-methylprop-2-enamide) Michael-acceptor warhead covalently engages Cys491 at the tip of the FGFR2 phosphate-binding (P)-loop (homologous Cys488 in FGFR1). Selectivity was engineered using long-timescale molecular-dynamics simulations (Relay Therapeutics + D. E. Shaw Research) that revealed differential P-loop flexibility between FGFR1 and FGFR2; FGFR1’s P-loop is stabilised in a rigid extended conformation that disfavours covalent engagement, giving lirafugratinib ~250-fold selectivity over FGFR1, >80-fold over FGFR3, and ~5,000-fold over FGFR4 in vitro. Sparing FGFR1 avoids the class-defining hyperphosphatemia and sparing FGFR4 avoids diarrhea, allowing dosing to efficacious exposures without the dose-limiting toxicities that force interruption of pan-FGFR inhibitors. Lirafugratinib also retains activity against on-target FGFR2 kinase-domain resistance mutations 

Synthesis Route of the Originator

Convergent route disclosed in origin patent WO2020231990A1 (D. E. Shaw Research & Relay Therapeutics; US family US11,780,845B2). The discovery paper (Schoenherr et al., PNAS 2024) reports the synthesis was performed at Pharmaron with detail in the SI Appendix; the patent Examples are the authoritative synthetic source. Lirafugratinib is achiral, so no stereochemistry is set. The C4-amino group is PRE-INSTALLED in the commercial starting material 5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-amine — no SNAr amination is required. N7-methylation (MeI, Cs₂CO₃) then C6 iodination (NIS, TFA) build the pivotal 5-bromo-6-iodo dihalide hub. The more reactive C6-iodide undergoes Suzuki–Miyaura coupling FIRST (Pd(PPh₃)₄, K₃PO₄, DMF/H₂O, 50 °C) with N-(4-pinacolboronate-phenyl)methacrylamide, installing the covalent-warhead arm. The remaining C5-bromide then couples LAST (Pd(dppf)Cl₂ or Pd(DtBPF)Cl₂/CsF, 90 °C) with 2-(2-fluoro-4-pinacolboronate-phenoxy)-4-methylpyrimidine, forming the biaryl ether and completing lirafugratinib. The Michael-acceptor methacrylamide is carried through and survives the final hot coupling (a warhead-late variant — Boc-aniline coupling → TFA → methacryloyl chloride → then C5 Suzuki — is also demonstrated in patent Ex.2). Conditions are quoted from WO2020231990A1 Examples 1–2 on this scaffold; verify against the process literature before scale-up.

aReagents and conditions: (1) Iodomethane (1.0 eq), Cs₂CO₃ (2 eq), DMF, 0 °C, 3 h (~70%). [VERIFIED: WO2020231990A1, Ex.1 Step 1]; (2) N-iodosuccinimide (NIS, 1.0 eq), TFA (5 eq), CH₂Cl₂, 0 °C → rt, 2 h (~80%). [VERIFIED: WO2020231990A1, Ex.1 Step 2]; (3) N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1.2 eq), Pd(PPh₃)₄ (10 mol%) [or Pd(PPh₃)₂Cl₂], K₃PO₄ (3 eq), DMF/H₂O, 50 °C, 1 h (~54%). C6-iodide is more reactive and couples selectively over the C5-bromide. [VERIFIED: WO2020231990A1, Ex.1 Step 3. Variant B (Ex.2): couple the Boc-4-aminophenyl boronate, TFA-deprotect, then acylate the free aniline with methacryloyl chloride / pyridine, DMF, 0 °C → rt.]; (4) 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (1.2 eq), Pd(dppf)Cl₂ (10 mol%) [or Pd(DtBPF)Cl₂/CsF], K₃PO₄ (3 eq), DMF/H₂O (16:1), 90 °C, 2 h. The methacrylamide Michael acceptor survives this hot coupling. Crystallise to the drug substance. [VERIFIED: WO2020231990A1 final Suzuki on this scaffold; the fluoro/methylpyrimidinyl C5 boronate is a patent-named building block].

Key intermediates

Crystal Forms, Salts, and Solid-State Profile

  • API in approved drug product: Lirafugratinib free base, C₂₈H₂₄FN₇O₂, MW 509.55; achiral. XLogP ~4.3, TPSA ~121 Ų, HBD 2 / HBA 8. Solid-state form (polymorph/salt) of the marketed drug substance [VERIFY vs label §11 DESCRIPTION].
  • Strengths approved: Oral tablet; 70 mg total daily dose [tablet strength(s) VERIFY vs PI]
  • Third-party polymorph activity: No third-party US polymorph activity identified as of 2026-09-26 (expected, given the long-dated COM). Monitor SureChEMBL/Espacenet.
  • Originator polymorph filing: Relay/Elevar drug-substance solid form is the marketed form; form/polymorph claims expected within the secondary estate [VERIFY exact patent no.]

Available experimental protein structures (RCSB PDB)

PDB IDTargetTitleResolution (Å)MethodReleased
32OAFibroblast growth factor receptor 2The ultra-high-resolution hyaluronan-binding…0.775X-RAY DIFFRACTION2026-08-12
1ET1Fibroblast growth factor receptor 2CRYSTAL STRUCTURE OF HUMAN PARATHYROID HORMONE…0.9X-RAY DIFFRACTION2000-09-06
7G1FFibroblast growth factor receptor 2Crystal Structure of human FABP4 in complex…0.91X-RAY DIFFRACTION2023-06-14

For SAR / docking and ligand-bound forms relevant to polymorph analysis.

Key peer-reviewed literature