{"id":161,"date":"2026-09-29T02:47:13","date_gmt":"2026-09-29T02:47:13","guid":{"rendered":"https:\/\/astinovabiolabs.com\/blog\/?p=161"},"modified":"2026-09-29T02:47:13","modified_gmt":"2026-09-29T02:47:13","slug":"synthesis-of-lirafugratinib-lyrfigtu-drug-intelligence-dossier","status":"publish","type":"post","link":"https:\/\/astinovabiolabs.com\/blog\/synthesis-of-lirafugratinib-lyrfigtu-drug-intelligence-dossier\/","title":{"rendered":"Synthesis of Lirafugratinib (LYRFIGTU) \u2014 Drug Intelligence Dossier"},"content":{"rendered":"\n

Mechanism:<\/strong>\u00a0Lirafugratinib (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\u00a0<\/p>\n\n\n\n

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

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 \u2014 no SNAr amination is required. N7-methylation (MeI, Cs\u2082CO\u2083) then C6 iodination (NIS, TFA) build the pivotal 5-bromo-6-iodo dihalide hub. The more reactive C6-iodide undergoes Suzuki\u2013Miyaura coupling FIRST (Pd(PPh\u2083)\u2084, K\u2083PO\u2084, DMF\/H\u2082O, 50 \u00b0C) with N-(4-pinacolboronate-phenyl)methacrylamide, installing the covalent-warhead arm. The remaining C5-bromide then couples LAST (Pd(dppf)Cl\u2082 or Pd(DtBPF)Cl\u2082\/CsF, 90 \u00b0C) 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 \u2014 Boc-aniline coupling \u2192 TFA \u2192 methacryloyl chloride \u2192 then C5 Suzuki \u2014 is also demonstrated in patent Ex.2). Conditions are quoted from WO2020231990A1 Examples 1\u20132 on this scaffold; verify against the process literature before scale-up.<\/p>\n\n\n\n

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a<\/sup>Reagents and conditions: (1) Iodomethane (1.0 eq), Cs\u2082CO\u2083 (2 eq), DMF, 0 \u00b0C, 3 h (~70%). [VERIFIED: WO2020231990A1, Ex.1 Step 1]; (2) N-iodosuccinimide (NIS, 1.0 eq), TFA (5 eq), CH\u2082Cl\u2082, 0 \u00b0C \u2192 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(PPh\u2083)\u2084 (10 mol%) [or Pd(PPh\u2083)\u2082Cl\u2082], K\u2083PO\u2084 (3 eq), DMF\/H\u2082O, 50 \u00b0C, 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 \u00b0C \u2192 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)Cl\u2082 (10 mol%) [or Pd(DtBPF)Cl\u2082\/CsF], K\u2083PO\u2084 (3 eq), DMF\/H\u2082O (16:1), 90 \u00b0C, 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].<\/p>\n\n\n\n

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

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