{"id":59,"date":"2026-06-17T03:08:04","date_gmt":"2026-06-17T03:08:04","guid":{"rendered":"https:\/\/astinovabiolabs.com\/blog\/?p=59"},"modified":"2026-06-17T03:08:04","modified_gmt":"2026-06-17T03:08:04","slug":"synthesis-of-remibrutinib-rhapsido","status":"publish","type":"post","link":"https:\/\/astinovabiolabs.com\/blog\/synthesis-of-remibrutinib-rhapsido\/","title":{"rendered":"Synthesis of Remibrutinib (RHAPSIDO)"},"content":{"rendered":"\n

Compiled:<\/strong> 2026-06-17 \u00b7 Trigger event:<\/strong> FDA approval, 2025-09-30 Innovator:<\/strong> Novartis Pharmaceuticals Corporation Status:<\/strong> Approved NME<\/p>\n\n\n\n

INN:<\/strong> remibrutinibBrand (US):<\/strong> RHAPSIDOCAS:<\/strong> 1787294-07-8ChEMBL:<\/strong> CHEMBL4483575MW:<\/strong> 507.5 g\/molNDA #:<\/strong> NDA 218436Approval:<\/strong> 2025-09-30<\/p>\n\n\n\n

Mechanism:<\/strong>\u00a0Remibrutinib is an oral, small-molecule covalent (irreversible) inhibitor of Bruton’s tyrosine kinase (BTK), engaging the catalytic Cys481 via its acrylamide warhead and binding an inactive BTK conformation \u2014 the basis of its high kinome selectivity (reported biochemical IC\u2085\u2080 ~1 nM). BTK is expressed in mast cells, basophils, B cells, macrophages, and platelets and signals downstream of the high-affinity IgE receptor (Fc\u03b5R1), Fc\u03b3 receptors, and the B-cell antigen receptor (BCR). Remibrutinib also inhibits the BTK-related TEC-family kinases TEC and BMX. By blocking Fc\u03b5R1\/Fc\u03b3R signalling it inhibits mast-cell and basophil degranulation \u2014 release of histamine and other proinflammatory mediators driven by pathogenic IgE or IgG \u2014 the mechanism relevant to CSU. ChEMBL CHEMBL4483575; target BTK (CHEMBL5251). Ref: Angst et al., J. Med. Chem. 2020, PMID 32083858.<\/p>\n\n\n\n

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

Convergent route disclosed in the Novartis discovery paper (Angst et al., J. Med. Chem. 2020, 63, 5102-5118; remibrutinib = compound 25) and optimised in the process patent (WO2024069507A1 \/ EP4594306A1). Fragment B (central aniline) is built by acylating 3-bromo-5-fluoro-2-methylaniline with 4-cyclopropyl-2-fluorobenzoyl chloride (INT-1), then borylated to the arylboronate (INT-2). Fragment A is a 6-amino-4-chloropyrimidine bearing the N-Boc-N-methyl-aminoethoxy side chain (built from 4,6-dichloro-5-methoxypyrimidine by mono-amination, O-demethylation to the 5-ol, and Mitsunobu with N-Boc-N-methylethanolamine). Suzuki\u2013Miyaura coupling of INT-2 with Fragment A forms the Boc-protected biaryl (INT-3); Boc removal frees the secondary amine (INT-4); acryloylation installs the acrylamide warhead to give remibrutinib, crystallised as anhydrous Form A. The warhead is installed last \u2014 the standard covalent-kinase-inhibitor strategy. The improved process deliberately carries the aniline as an aryl bromide and borylates late to avoid a genotoxic boronate-aniline. Conditions are representative for the named transformations (corroborated by the process patent and a 2023 Molecules review); verify per-step loadings\/temperatures against the discovery-paper SI before scale-up.<\/p>\n\n\n\n

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a<\/sup>Reagents and conditions: (1) 4-cyclopropyl-2-fluorobenzoic acid (CAS 1247927-81-6) \u2192 acyl chloride (SOCl\u2082, cat. pyridine, toluene, 50 \u00b0C); then SM-1 aniline, DIPEA, iPrOAc\/toluene; ~87\u201393% (process route, EP4594306A1); (2) B\u2082pin\u2082 (or bis-boronic acid), Pd(MeCN)\u2082Cl\u2082 (0.25\u20130.5 mol%), tBuPPh\u2082, KOAc, 2-MeTHF, 50\u201360 \u00b0C (process route, EP4594306A1). The process route deliberately borylates late to avoid isolating the Ames-positive boronate-aniline of the original route.; (3) Fragment A pyrimidinyl chloride (1.0 eq), Pd(MeCN)\u2082Cl\u2082 + tBuPPh\u2082 (or XPhos-Pd-G2), K\u2083PO\u2084, 2-MeTHF\/H\u2082O ~10:3, 60 \u00b0C, ~24 h, ~92% (process route). Discovery route used PdCl\u2082(PPh\u2083)\u2082.; (4) HCl (process route) or TFA\/CH\u2082Cl\u2082 (discovery route), rt; free-base on workup; (5) Acryloyl chloride (1.05 eq), Na\u2082CO\u2083 (1.2 eq), EtOAc, 50\u219265 \u00b0C (process route); discovery route used acrylic acid + T3P\/base. Warhead installed last to avoid Michael side-reactions\/oligomerisation upstream. Crystallise to anhydrous Form A (free base)..<\/p>\n\n\n\n

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atent Landscape & Exclusivity<\/h2>\n\n\n\n

2.1 Key patent filings<\/h3>\n\n\n\n
Patent \/ Application<\/th>Type<\/th>Assignee<\/th>Filed<\/th>Expiry (~)<\/th><\/th><\/tr><\/thead>
WO2015079417A1 \u2014 ‘Novel amino pyrimidine derivatives’ (composition of matter)<\/strong><\/td>Composition of matter (originator)<\/td>Novartis AG (inventors incl. D. Angst et al.)<\/td>PCT published 2015-06-04; priority ~2013 (the BTK-inhibitor amino-pyrimidine benzamide series described in Angst et al., J. Med. Chem. 2020) [VERIFY exact priority date on Espacenet]<\/td>~2034\u20132035 nominal (20 yr from PCT filing), before any PTE [VERIFY exact date]<\/td><\/td><\/tr>
WO2024069507A1 \/ EP4594306A1 \u2014 ‘Synthesis methods and intermediates for the production of remibrutinib’ (process)<\/strong><\/td>Process<\/td>Novartis<\/td>~2023 (published 2024)<\/td>~2043\u20132044 nominal<\/td><\/td><\/tr>
WO2023161887A1 \u2014 ‘Remibrutinib for use in the treatment of hidradenitis suppurativa’ (method of use)<\/strong><\/td>Method of use<\/td>Novartis<\/td>~2022 (published 2023)<\/td>~2042\u20132043 nominal<\/td><\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n

Structural class & SAR background:<\/strong> Convergent route disclosed in the Novartis discovery paper (Angst et al., J. Med. Chem. 2020, 63, 5102-5118; remibrutinib = compound 25) and optimised in the process patent (WO2024069507A1 \/ EP4594306A1). Fragment B (central aniline) is built by acylating 3-bromo-5-fluoro-2-methylaniline with 4-cyclopropyl-2-fluorobenzoyl chloride (INT-1), then borylated to the arylboronate (INT-2). Fragment A…<\/p>\n\n\n\n

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