Synthesis of Fostemsavir(BMS 663068)
Synthesis of Fostemsavir
Fostemsavir(alias: BMS 663068) was synthesised in a linear sequence in a two-step reaction using Sulfonyl pyrrole as the starting material.The specific reaction steps are as follows:
Step 1: preparation of Aryl Bromide
Sulfonyl pyrrole 27 underwent a three-step sequence involving a Friedel−Crafts acylation using acetyl chloride and AlCl3, an α- chlorination of the resulting ketone using N-chlorosuccinimide (NCS) and MsOH, and a displacement of the resulting chloroketone with sodium tosylamide 28. This three-step, telescoped sequence rapidly resulted in the delivery of ketopyrrole 29 in 62−75% yield. Protection of the ketone and hydrolysis of the N-formyl group within 29 were performed using H2SO4, ethylene glycol, and trimethyl orthoformate, giving rise to ketal 30 in 90% yield. Next, a Pictet-Spengler cyclization followed by tosyl-deprotection and oxidation using cumene hydroperoxide (CHP) converted ketone 31 to azaindole 32 in 81% and 91% yield, respectively, for the two steps. Next, bromination of the azaindole core was achieved first by oxidation of the pyridine nitrogen and then PyBroPmediated bromination to access aryl bromide 33 in 63% yield.
Bromo-azaindole 33 was reacted with methyl oxalyl chloride, AlCl3, and tetra-n-butylammonium bisulfate to establish the oxalate at the 3-position of the ring system, followed by ester hydrolysis to provide 34 in 87% yield. Amidation of 34 with piperazine 35 was performed using DPPCl in NMP. The addition of water crystallized the coupled product 36（Aryl Bromide）, which was isolated in 94% yield.
Step 2: preparation of Fostemsavir
With aryl bromide 36 in hand, an Ullman coupling with 3-methyl-1H-1,2,4-triazole using CuI and N,N- 1,2-dimethylcyclohexandiamine generated piperazine 37. Residual copper was removed by the addition of pyrrolidinedithiocarbamate ammonium (APDTC), and the target lithium salt 37 was precipitated after treatment of the Ullman coupling product with KOH and then LiI hydrate. Intermediate 37 was isolated in 67% yield.44 Installation of the phosphonooxymethyl prodrug was performed using di-t-butyl (chloromethyl) phosphate 38 with Et4NI and K2CO3. After quenching and extraction with toluene, the crude mixture was treated with brine and NaHSO4 to consume the undesired N-6 isomer byproduct. The penultimate intermediate 39 was isolated in 70% yield. The final step was deprotection of the t-Bu phosphonate ester in 39 to reveal the phosphoric acid moiety in fostemsavir. Hydrolysis was achieved by treatment with acetic acid, and the addition of tris(hydroxymethyl)aminomethane (TRIS) in acetone resulted in precipitation of the TRIS salt of fostemsavir as a white, crystalline solid in 88% yield.
