New, azide-free transformation of epoxides into 1,2-diamino compounds: synthesis of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu).
A new, azide-free transformation of the key precursor epoxide 6 to the influenza neuraminidase inhibitor prodrug oseltamivir phosphate (1, Tamiflu) is described. This sequence represents a new and efficient transformation of an epoxide into a 1,2-diamino compound devoid of potentially toxic and hazardous azide reagents and intermediates and avoids reduction and hydrogenation conditions. Using catalytic MgBr(2).OEt(2) as a new, inexpensive Lewis acid, the introduction of the first amino function was accomplished by opening of the oxirane ring with allylamine followed by Pd/C-catalyzed deallylation to the amino alcohol 16. The introduction of the second amino group was then accomplished via an efficient reaction cascade involving a domino sequence preferably utilizing a transient imino protection. Selective acetylation of the resulting diamine 17 was achieved under acidic conditions providing the crystalline 4-acetamido-5-N-allylamino-derivative 18, which upon deallylation over Pd/C and phosphate salt formation afforded drug substance 1. The overall yield of this route from 6 of 35-38% exceeds the yield of the azide-based process (27-29%) and does not require any chromatographic purification.
Karpf
M
M
F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Non-Clinical Development, Chemical Process Research, Grenzacherstrasse 124, CH-4070, Basel, Switzerland. martin.karpf@roche.com
Trussardi
R
R
D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D004852:Epoxy Compounds / Q000737:chemistry*; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009975:Orthomyxoviridae / Q000201:enzymology*; D053139:Oseltamivir; D013057:Spectrum Analysis
D000081:Acetamides; D000588:Amines; D000998:Antiviral Agents; D001386:Azides; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D053139:Oseltamivir; D009439:Neuraminidase