Zavegepant (zavzpret) is a calcitonin gene-related peptide (CGRP) receptor antagonist nasal spray for the acute treatment of migraine sold by Pfizer and approved by the FDA on march 2023. Migraine is a severe pulsating headache of moderate to severe pain intensity, often associated with nausea or vomiting, phonophobia, and photophobia. Attacks can last from four to 72 hours. Zavegepant belongs to the class of drugs called CGRP receptor antagonists. CGRP receptor antagonists work to treat migraine by reversibly blocking CGRP receptors, thereby inhibiting the biologic activity of the CGRP neuropeptide which is thought to play a causal role in migraine. Zavegepant may provide an important alternative for patients who need a quick onset of action or those who cannot take oral treatments due to nausea and vomiting at the time of migraine onset. This molecule was a key part of a recent acquisition by Pfizer (BioHaven, 11.6Bi USD) where they were looking to the future growth on company’s portfolio of migraine medicines. The deal handed Pfizer rights to rimegepant, a pill for migraine prevention and treatment, as well as zavegepant and other preclinical studies. In January, the company predicted the two medicines will achieve more than $6 billion in combined peak yearly sales.
Synthetic strategy towards zavegepant begins with Horner-Emmons reaction of trimethylphosphonoacetate (1) with N-Boc-4-piperidone (2) in the presence of NaH in DMF gives enoate 3 in 92% yield after 3h, which is then hydrogenated (55psi) over Pd/C 10% in EtOAc/MeOH to yield saturated ester 4 (97%, 16h). Aldol reaction between ester 4 and o-nitrobenzaldehyde (5) using LDA in THF affords alcohol 6 (94%, 4h), which upon reductive cyclocondensation by means of Fe in AcOH at 80 °C furnishes quinoline derivative 7 (30min, 77%). Dehydration of 7 with HCl in dioxane/EtOAc provides enone 8, which is condensed with indazole derivative 9 in the presence of Et3N in DMF to produce urea derivative 10 (24h, 78%). Saponification of methyl ester 10 with LiOH in THF gives the corresponding carboxylic acid 11 (4h, 94%), which is finally coupled with 1-(1-methyl-4-piperidyl)piperazine (12) in the presence of TBTU and Et3N in DMF (18h, 77%) to afford the target zavegepant in an overall yield of 27%.
Intermediate 9 can be synthesized accordingly to the following strategy, starting with iodination of 2,6-xylidine (13) with ICl in the presence of NaHCO3 (4h, 89%), followed by treatment with HCl gives 4-iodo-2,6-dimethylaniline hydrochloride (14), which upon Heck coupling with methyl 2-(benzyloxycarbonylamino)acrylate (15) in the presence of Bu4NCl, Pd(OAc)2 and Et3N in THF yields enoate 16 after 4h with 65% yield. Asymmetric hydrogenation (65psi, 16h) of alkene 16 over chiral catalyst, ((2R,5R)-EtDuPhosRh(COD))BF4 in CH2Cl2/MeOH affords the desired (R)-isomer 17 (98%), which is submitted to cyclocondensation with isoamyl nitrite in the presence of KOAc and AcOH in toluene to furnish indazole derivative 18 (16h, 76%). N-Deprotection of compound (XX) with H2 (15psi) over Pd/C 10% in MeOH gives intermediate 9 (18h, 99%).
REFERENCES AND NOTES
- CGRP receptor antagonista, Bristol-Myers Squibb Co, WO2011123232.
