The Synthesis of Abrocitinib (Cibinqo)

The commercial route to Abrocitinib started from isopropyl ester 2 (Scheme 1). Several designed library of mutant wide-type SpRedAm from Streptomyces purpureus was screen for reductive amination of 2. The resulted enzyme delivered succinate salt 3 in 74% yield with >99:1 diastereomeric ratio. Pyrrolopyrimidine 4 was incorporated with 3 to provide 5 in 81% isolated yield. The ester in 5 was converted into hydroxamic acid in 6 with preinstalled oxidation state by the treatment of hydroxylamine hydrochloride supplemented with NaOMe in MeOH. 1,1′-carbonyldiimidazole (CDI) promoted Lossen rearrangement showed the best outcome. Phosphoric acid mediated hydrolysis had a crucial role to avoid urea formation and delivered amine phosphate salt 7. A judicious evaluation of several sulfonylation reagents uncovered 1,2,4-triazole derivative 8 (Figure 1) as the lead sulfonylating agent based on the standard of stability, reaction kinetics and safety profile. A generated solution of 8 in THF was used to react with neutralized 7 to form 1, which crystallized upon addition of water to the reaction mixture.

 

 

Step 1: Biocatalytic reductive amination (SpRedAm, MeNH3Cl, succinic acid).

Step 2: SNAr reaction (IPA, DIPEA).

Step 3: Hydroxamic acid synthesis (HONH3Cl, NaOMe/MeOH).

Step 4: Lossen rearrangement (CDI, MeTHF; Then aq. H3PO4).

Step 5: Sulfonylation (THF, H2O, NaOH).

A preheated solution of commercially available carboxylic acid 9 (Scheme 2) was treated with diphenylphosphoryl azide (DPPA) and triethylamine to result in an acyl azide intermediate 16 (Scheme 3). The acyl intermediate was heated to promote the Curtius rearrangement to give an isocyanate 17. The reactive isocyanate 17 was trapped with benzyl alcohol to afford benzyl carbamate 10. A cryogenic reductive amination was used to convert ketone in 10 to secondary amine in 11 with 4:1 ratio of cis and trans diastereomers. The successive crystallization of hydrochloride salt 11 improved the diastereomeric ratio to >99:1. The connection of cyclobutyldiamine 11 and pyrrolopyrimidine 12 to form 13 was achieved in isopropyl alcohol (IPA) with diisopropylethylamine (DIPEA). Deprotection of benzyl carbamate with hydrobromic acid in ethyl acetate afforded amine dihydrobromide salt 14. Releasing the free amine in 14 with triethylamine in MeTHF, followed by adding sulfonyl chloride 15 to give Ts-protected 1. The tosyl group was removed by hydrolysis using sodium hydroxide to provide crystallized 1 upon pH adjustment.

 

 

Step 1: Curtius rearrangement (DPPA, Et3N, BnOH, 50 °C, 50-62%).

Step 2: Reductive amination (MeNH2, LiBH4, AcOH/EtOH, HCl, 44-51%).

Step 3: SNAr reaction (DIPEA, IPA, 92-95%).

Step 4: Cbz deprotection (HBr, EtOAc, 76-81%).

Step 5: Sulfonylation (15, MeTHF, NEt3; then NaOH, 75-76%).

The Hofmann rearrangement was also applied to synthesize amine 14 (Scheme 4) on multikilogram scale. The tosyl protected pyrrole was critical to success, otherwise the starting material 21 was consumed rapidly by the oxidant.





cheme 5 summarized the named  nitrene-involved degenerate rearrangement reactions to synthesize primary amine. 

References

  1. Connor, C. G.; DeForest, J. C.; Dietrich, P.; Do, N. M.; Doyle, K. M.; Eisenbeis, S.; Greenberg, E.; Griffin, S. H.; Jones, B. P.; Jones, K. N.; Karmilowicz, M.; Kumar, R.; Lewis, C. A.; McInturff, E. L.; McWilliams, J. C.; Mehta, R.; Nguyen, B. D.; Rane, A. M.; Samas, B.; Sitter, B. J.; Ward, H. W.; Webster, M. E. Development of a Nitrene-Type Rearrangement for the Commercial Route of the JAK1 Inhibitor Abrocitinib. Org. Process Res. Dev. 2021, 25, 608–615,  DOI: 10.1021/acs.oprd.0c00366.
  2.  Arora, K. K.; Deforest, J. C.; Hills, A. K.; Jones, B. P.; Jones, K. N.; Lewis, C. A.; Rane, A. M. Manufacturing process and intermediates for a pyrrolo[2,3-d]pyrimidine compound and use thereof. WO 2020008391 A1, 2020.
  3. Bhirud, S. B.; Kadam, S. M.; Gavhane, S. B.; Peddy, V.; Bhadane, S. N.; Bhujade, V. K. Process for preparation of abrocitinib. WO 2020261041 A1, 2020.