Abrocitinib

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Following the idea to discuss the synthesis of recently approved APIs, in this issue we will present synthetic strategies towards the synthesis of abrocitinib, a Janus kinase inhibitor (JAK1) used for the treatment of adults living with refractory, moderate-to-severe atopic dermatitis (AD), developed by Pfizer. Abrocitinib sold under the brand name Cibinqo was approved on 14th of January 2022 (already approved in UK, Japan and Europe in 2021) with an oral, once-daily dose, after five large scale clinical trials (1, 2).

 

Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, where inappropriate tyrosine kinase activity (JAK1, JAK2, JAK3, and Tyk2) can lead to a variety of biological cellular responses related to already known autoimmune and hematological disorders (3).

 

 

Synthetic strategies towards abrocitinib are focused on the construction of the diaminecyclobutane ring 3, starting in most cases from 3-oxocyclobutanecarboxylic acid (1), to deliver the common intermediate 5 (4).

 

First strategy starts with a tandem azidation and Curtius rearrangement by treatment of 3-oxocyclobutanecarboxylic acid (1) with DPPA in the presence of Et3N or DIEA in toluene at 60 °C, followed by reaction of the resultant isocyanate with benzyl alcohol affording benzyl 3-oxocyclobutylcarbamate (2) in 55% yield. Reductive amination between ketone (2) and methylamine in the presence of AcOH in EtOH, generates a mixture of cis- and trans-isomers of benzyl [3-(methylamino)cyclobutyl]carbamate (3) in 46% yield, which upon treatment with HCl and recrystallization provides a diastereomeric ratio >99:1. Coupling of secondary amine 3 with 2,4-dichloropyrrolo[2,3-d]pyrimidine leads to the formation of intermediate 4 in 95% yield, which undergoes debenzylation by means of HBr in EtOAc/AcOH to afford dihydrobromide salt of free amine 5, in 79% yield. Coupling of cyclobutanamine derivative 5 with 1-propanesulfonyl chloride using Et3N in 2-MeTHF and subsequent removal of tosyl group by means of aqueous NaOH furnishes the target abrocitinib in 75% and 14% overall yield. (5, 6).

 

The second approach is known as the commercial route to abrocitinib. It starts with the esterification of 3-oxocyclobutanecarboxylic acid (1) with i-PrOH in the presence of TsOH at 80 °C arriving at the corresponding isopropyl ester 6 in 95% yield. Reductive amination mediated by an imine reductase (SpRedAm) yields succinic acid isopropyl cis-3-(methylamino)cyclobutane-1-carboxylate (7) in 74% yield and 99:1 diastereomeric ratio. Coupling of intermediate 7 with 4-chloropyrrolo[2,3-d]pyrimidine in the presence of DIEA in i-PrOH at 80 °C leads to intermediate 8, which is condensed with hydroxylamine hydrochloride in the presence of NaOMe in MeOH to provide hydroxamic acid 9 in 94% yield. Lossen rearrangement produces primary amine 5 which undergoes the same synthetic route presented previously, arriving at the desired abrocitinid skeleton with an overall yield of 32% (7, 8).

 

Finally, the third approach rely on the Hoffman rearrangement but incompatibility of the IIII oxidant with the electron-rich pyrrolopyrimidine required the use of a different route. Coupling of 3-(methylamino)cyclobutanecarboxamide hydrochloride (10) with 2,4-dichloropyrrolo[2,3-d]pyrimidine in the presence of DBU in i-PrOH yields amide 11 in 78% yield, which upon Hofmann rearrangement by means of PhI(OAc)2 in DMF/acetonitrile/H2O, followed by treatment with HBr in AcOH affords dihydrobromide salt of free amine 5 in 58% isolated yield. The corresponding amine 5 can then be transformed into abrocitinib by coupling with 1-propanesulfonyl chloride and removal of tosyl group.

 

REFERENCES AND NOTES

1. Peeva, E.; Hodge, M. R.; Kieras, E.; Vazquez, M. L.; Goteti, K.; Tarabar, S. G.; Alvey, C. W.; Banfield, C. British Journal of Clinical Pharmacology 2018 84 (8): 1776–1788.
2. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2022
3. Connor, C. G.; DeForest, J. C.; Dietrich, P.; Do, M. N.; Doyle, K. M. et al Organic Process Research And Development 2021, 25, 608-615.
4. Pesu, M.; Laurence, A.; Kishore, N.; Zwillich, S. H.; Chan, G.; O’Shea, J. J. Immunological Reviews 2008, 223: 132–42.
5. Aubé, J.; Fehl, C.; Liu, R.; McLeod, M. C.; Motiwala, H. F. Comprehensive Organic Synthesis II, 2nd ed.; Knochel, P., Ed.; Elsevier: Amsterdam, 2014; pp 598−635.
6. Sun, X.; Rai, R.; Deschamps, J. R.; MacKerell, A. D., Jr.; Faden, A. I.; Xue, F. Tetrahedron Lett. 2014, 55 (4), 842−844.
7. Strotman, N. A.; Ortiz, A.; Savage, S. A.; Wilbert, C. R.; Ayers, S.; Kiau, S. J. Org. Chem. 2017, 82 (8), 4044−4049.
8. Arora, K. K.; Deforest, J. C.; Hills, A. K.; Jones, B. P.; Jones, K. N.; Lewis, C. A.; Rane, A. M. WO 2020008391 A1, 2020.