ChEBI: Cabotegravir is a monocarboxylic acid amide obtained by formal condensation of the carboxy group of (3S,11aR)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid with the amino group of 2,4-difluorobenzylamine. Used (as its sodium salt) for treatment of HIV-1. It has a role as a HIV-1 integrase inhibitor. It is a difluorobenzene, a secondary carboxamide, a monocarboxylic acid amide and an organic heterotricyclic compound. It is a conjugate acid of a cabotegravir(1-).
Cabotegravir (GSK744, GSK1265744) is a long-acting HIV integrase inhibitor against a broad range of HIV subtypes, inhibiting HIV-1 integrase-catalyzed strand transfer with IC50 of 3 nM. Phase 2.
Caboggravir is a potent inhibitor of HIV integrase, which prevents the HIV virus from infecting human cells, while rilpivirine prevents the virus from replicating itself.
One-pot four-step synthesis: First, methyl 4-methoxyacetoacetate (9) was condensed with DMF-DMA at room temperature to generate the unpurified vinylamide intermediate (9a). The reaction mixture was concentrated to remove excess reagents, followed by the addition of dimethoxyacetaldehyde (10) in MeOH to generate intermediate (9b). The crude product was treated with dimethyl oxalate (11) and lithium methoxide (LiOMe) in hot MeOH to initiate the cyclization reaction to give the pyridinone intermediate (9c). Selective hydrolysis: 9c was treated with lithium hydroxide (LiOH) at low temperature to selectively hydrolyze the C-5 methyl ester to give a C-5 to C-2 hydrolysis product ratio of approximately 10:1. The crude reaction mixture was treated by acid quenching and the product was precipitated from hot ethyl acetate (EtOAc) to give compound 12 in a total yield of 61% for the four-step reaction. Hydrolysis: First, pyridinone 12 was reacted with methanesulfonic acid (MeSO3H) and acetic acid in hot acetonitrile, resulting in the hydrolysis of the dimethyl ether to generate the desired aldehyde intermediate. Subsequently, (S)-alaninol (13) was slowly added to condense with the transient aldehyde intermediate in the original reaction mixture and react with the adjacent C-2 ester to generate the parent tricyclic structure of cabotegravir in a total yield of 74% for the two-step reaction. The entire process produced 14 in a 34:1 enantiomeric ratio (dr) favoring the desired trans product. The enantiomeric purity of 14 could be further increased by later crystallization. Starting from 14, CDI-mediated activation of the carboxylic acid at 80°C followed by reaction with fluorobenzylamine (15) formed the amide 16 in 95% yield. Multiple conditions were tested to remove the methyl group of the enol ether of 16, and the conditions using lithium bromide in refluxing aqueous tetrahydrofuran (THF) were found to be optimal, generating the free acid of cabotegravir in 93% yield. While the free acid form is desired for intramuscular injection, the sodium salt form (II) of cabotegravir, used to prepare the oral form of the drug, can be generated in high yield (94%) by treating the free acid form with NaOH/EtOH.
