{"id":135,"date":"2026-09-04T05:19:30","date_gmt":"2026-09-04T05:19:30","guid":{"rendered":"https:\/\/astinovabiolabs.com\/blog\/?p=135"},"modified":"2026-09-04T05:19:30","modified_gmt":"2026-09-04T05:19:30","slug":"synthesis-of-brepocitinib-lisraya-drug-intelligence-dossier","status":"publish","type":"post","link":"https:\/\/astinovabiolabs.com\/blog\/synthesis-of-brepocitinib-lisraya-drug-intelligence-dossier\/","title":{"rendered":"Synthesis of Brepocitinib (LISRAYA) \u2014 Drug Intelligence Dossier"},"content":{"rendered":"\n

Mechanism:<\/strong>\u00a0Brepocitinib is an oral, Type I (ATP-competitive) inhibitor that reversibly binds the catalytic JH1 kinase domain of BOTH tyrosine kinase 2 (TYK2; ChEMBL CHEMBL3553) and Janus kinase 1 (JAK1; CHEMBL2835), with relative JAK2\/JAK3 sparing (enzymatic IC50 ~TYK2 23 nM \/ JAK1 17 nM \/ JAK2 77 nM \/ JAK3 ~6.5 \u00b5M). This dual TYK2+JAK1 blockade suppresses signalling of the type I interferons (IFN-\u03b1\/\u03b2) that drive the dermatomyositis interferon signature, together with IL-12\/IL-23, IL-6 and other JAK1\/TYK2-dependent cytokines implicated in DM. Mechanistically distinct from deucravacitinib (Sotyktu), which is an ALLOSTERIC JH2-pseudokinase-domain, TYK2-selective inhibitor; brepocitinib’s ATP-competitive JH1 mechanism and JAK1 activity are why the Lisraya label carries the JAK-inhibitor class boxed warning whereas deucravacitinib does not. Refs: PMID 30113844 (discovery), PMID 39008325 (TYK2\/JAK1 rationale in DM).<\/p>\n\n\n\n

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

Convergent end-game disclosed in the Pfizer discovery paper (Fensome et al., J. Med. Chem. 2018, 61(19), 8597-8612; PF-06700841). 2,4-Dichloropyrimidine (SM-1) is the regiochemical linchpin: a low-temperature SNAr installs the mono-Boc (1R,5S)-3,8-diazabicyclo[3.2.1]octane (SM-3, Boc on N8, free N3) at the more electrophilic C4 to give INT-1. The weakly nucleophilic 4-amino-1-methylpyrazole (SM-2) is then coupled at the deactivated C2 (Buchwald\u2013Hartwig, or acid-catalysed SNAr) to give the Boc-protected penultimate INT-2. Boc removal frees the hindered N8 bridgehead amine (INT-3), which is acylated LAST with (S)-2,2-difluorocyclopropanecarboxylic acid (SM-4; T3P or HATU, DIPEA) to give brepocitinib, isolated as the tosylate salt. Coupling the resolved acid last minimises material carried through and protects its epimerisable \u03b1-stereocentre. STEREO NOTE: the bicyclic diamine is meso (Cs-symmetric) \u2014 achiral even with different N3\/N8 substituents \u2014 so the only enantiopurity concern is the (S)-difluorocyclopropane. All intermediate SMILES RDKit-validated; the final product matches the API canonical SMILES. Precise operational conditions live in the discovery-paper SI and Pfizer patents (WO2016027195A1, US10980815B2) \u2014 verify before scale-up; conditions shown are representative for the named transformations.<\/p>\n\n\n\n

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a<\/sup>Reagents and conditions: (1) tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (SM-3, 1.0 eq; CAS 149771-44-8), DIPEA or Et3N (1.5-2 eq), EtOH or MeCN (or NMP), 0 \u00b0C \u2192 rt. C4-Cl is the more electrophilic site \u2192 clean mono-substitution; the C2-Cl is retained for the next coupling.; (2) 4-amino-1-methyl-1H-pyrazole (SM-2, 1.1-1.3 eq; CAS 69843-13-6). Either Buchwald\u2013Hartwig (Pd2(dba)3 \/ XantPhos or BrettPhos, Cs2CO3, 1,4-dioxane, 90-110 \u00b0C) or acid-promoted SNAr (cat. TsOH or HCl, n-BuOH\/dioxane, 90-110 \u00b0C) on the deactivated C2 of the electron-rich 4-aminopyrimidine.; (3) HCl (4 M in 1,4-dioxane) or TFA\/CH2Cl2, rt, 1-2 h; isolable as the HCl salt or free-based on workup.; (4) (S)-2,2-difluorocyclopropane-1-carboxylic acid (SM-4, 1.05-1.2 eq; CAS 1883301-82-3), T3P (1.5 eq) or HATU (1.2 eq), DIPEA (2-3 eq), DMF or EtOAc, 0 \u00b0C \u2192 rt, 2-6 h. Coupling the expensive resolved acid LAST minimises material carried through; mild conditions protect the acid \u03b1-stereocentre from epimerisation.; (5) The free base is hygroscopic; the clinical\/commercial drug substance is the tosylate salt (CAS 2140301-96-6) [VERIFY marketed form vs label DESCRIPTION]. Treat free base with p-toluenesulfonic acid (1.0 eq) in a suitable solvent and crystallise. Free base C18H21F2N7O, MW 389.41..<\/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