Iptacopan (Fabhalta) was approved in December 2023 by the US Food and Drug Administration (FDA) as a first-in-class complement factor B inhibitor indicated for the treatment of adults with paroxysmal nocturnal hemoglobinuria. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening blood disorder characterized by complement-driven hemolysis, thrombosis and impaired bone marrow function, resulting in anemia, fatigue, and other debilitating symptoms. Current treatments for patients with PNH include the complement C5 inhibitors eculizumab and ravulizumab which prevent intravascular hemolysis, and the complement C3 inhibitor pegcetacoplan which prevents both intravascular and extravascular hemolysis. Now, patients with PNH have oral alternative to the drugs Soliris and Ultomiris, which are widely used to treat the serious blood disorder.
Novartis has forecast sales of iptacopan reaching beyond $2 billion a year and is developing it for an array of other complement-mediated kidney diseases including C3 glomerulopathy, IgA nephropathy and atypical hemolytic uremic syndrome.
Synthesis of iptacopan hydrochloride starts with the metalation of 4-bromobenzonitrile (1) with i-PrMgCl·LiCl in THF, followed by coupling with 4-methoxypyridine (2). N-protection with CbzCl gives (±)-benzyl 2-(4-cyanophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (3), whose double bond is reduced using Zn in AcOH at 100 °C to afford (±)-benzyl 2-(4-cyanophenyl)-4-oxopiperidine-1-carboxylate (4). Unfortunately, Novartis patent do not present any yield or conversion for the reported steps. Reduction of ketone 4 with LiBH4 in THF, followed by silylation of the resulting alcohol 5 with TBDPSCI and imidazole in DMF generates a diasteomeric mixture of TBDPS-protected alcohols. The desired trans-isomer 6 is separated by means of flash column chromatography and desilylated with TBAF in THF delivering deprotected alcohol 7, which is submitted to optical resolution using chiral supercritical fluid chromatography to provide the desired (2S,4S)-enantiomer 7.
O-Alkylation of this intermediate with EtI in the presence of NaH in DMF produces ethyl ether derivative 8, whose nitrile group is hydrolyzed using Ba(OH)2 in PrOH/H2O at 100 °C to afford carboxylic acid 9. This compound is esterified by means of MeOH and SOCl2 to give methyl ester 10. Cbz is removed from intermediate 10 by means of H2 over Pd/C in MeOH to generate methyl 4-[(2S,4S)-4-ethoxypiperidin-2-yl]benzoate (11). Alternatively to the free base, 11 can be converted into its maleic salt by treatment with maleic acid in i-PrOAc/acetone. Reductive condensation of compound 11 with tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (12) in the presence of NaBH(OAc)3 in DCE gives intermediate 13. Intermediate tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (12) can be synthesized by N-protection of 5-methoxy-7-methyl-1H-indole (14) with Boc2O in the presence of DMAP and Et3N in CH2Cl2, followed by formylation with N-methylformanilide (16). Simultaneous ester hydrolysis and N-deprotection of 13 by means of LiOH in THF/MeOH yields the free base of iptacopan (17), treatment with HCl in H2O/acetonitrile furnishes the desired iptacopan hydrochloride.
REFERENCES AND NOTES
WO2020016749
