229975-97-7

Atazanavir (BMS-232632, III), an azapeptide HIV protease inhibitor, has been developed and launched by Bristol-Myers Squibb (BMS), under worldwide license from Novartis, for the treatment of HIV infection. Atazanavir was launched in the US as Reyataz™ in July 2003.

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Atazanavir is a HIV protease inhibitor with Ki of 2.66 nM

Atazanavir is a novel azapeptide HIV protease inhibitor (PI). Antiviral.

Reyataz (Bristol-Myers Squibb).

The synthesis of atazanavir (III) appeared in several reports. The synthetic route depicted in the scheme was one of the best routes which was suitable for large scale production. The commercially available chiral diol 25 was converted to its silyl mesylate 26 in one pot via selective silylation and subsequent mesylation. This oily intermediate 26 was carried into the next step without further purification. The desilylation of 26 was achieved by using inexpensive ammonium fluoride. The resulting solid product 27 was readily isolated and further purified through recrystallization from IPA/H2O in 80% yield. The epoxide formation from 27 was affected by KO^tBu in THF/IPA to provide enantiomerically pure epoxide 28 in 88% yield. Suzuki coupling of boronic acid 29 with bromopyridine (30) provided pyridyl benzaldehyde 31 in 80% yield after crystallization. The subsequent condensation of aldehyde 31 with t-butylcarbamate was carried out by refluxing in toluene/IPA and Shiff base 32 was collected by filtration upon cooling. Reduction of hydrazone 32 to hydrazine 33 was accomplished by employing a catalytic phase-transfer hydrogenation protocol (Pd/C, HCOONa) to furnish hydrazine 33 in 78% yield after crystallization. Coupling of the hydrazinocarbamate 33 with epoxide 28 was performed in refluxing IPA, followed by the addition of water to precipitate the crude product. Subsequent recrystallization from MeCN/H2O furnished 34 in 85% yield. Treatment of 34 with concentrated HCl in THF at 50oC removed the two Boc groups in 34 to give the product as an oil, which was then dissolved in a mixture of DCM/DIPEA and slowly transferred into a premixed solution of N-methoxycarbonyl- L-tert-leucine (35), HOBT, and WSC in DCM. After removal of the solvent the crude product was crystallized from IPA/EtOH to furnish the freebase 36 in 82% yield. The sulfate III was obtained by stirring the free base 36 with concentrated H2SO4 in EtOH at ambient temperature. Direct crystallization by addition of n-heptane provided the sulfate salt III as an easily filterable solid in 85% yield.

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