Synthesis of Pemigatinib

Pemigatinib is synthesised using pyrrolopyridine as a raw material, firstly by synthesis of Pemigatinib Morpholine Intermediate and then by reduction, cyclisation and other reactions. The specific synthesis steps are as follows:

Step 1: Preparation of Pemigatinib Morpholine Intermediate

Pyrrolopyridine 276 was converted to N-oxide followed by treatment with mesyl chloride in warm DMF to furnish the 4- chloroazaindole 278 (which is also widely commercially available). Protection of the N-1 position with TIPS strategically allowed for subsequent lithiation directed by the chlorine atom. Quenching with DMF and an aqueous acid workup afforded the unprotected aldehyde 280 in excellent yield. Sulfonylation of N- 1 and acetal protection of the aldehyde allowed for lithiation at the more activated C2-position of the azaindole ring, and this was followed by quenching with formamide 283. This provided an intermediate aldehyde, which underwent a reductive amination with morpholine to prepare azaindole 284 in good yield.

Step 2: Preparation of Pemigatinib

Acidic removal of the acetal within 284 revealed aldehyde 285, which underwent reductive amination with aniline 286 to give benzylamine 287. The reaction with isocyanate 288 gave the expected urea 289. Upon exposure to LHMDS, this compound underwent an intramolecular cyclization to displace the proximal chloride and furnish azatricycle 290. Basic hydrolysis removed the phenylsulfonyl group, finishing the construction of pemigatinib in good yield.