949908-51-4

Upstream product

• 1196490-68-2 ethyl (3aR,4R,6S,7R,7aS)-7-(acetylamino)-6-azido-2,2-dimethylhexahydro-1,3-benzodioxole-4-carboxylate 
• 1173701-23-9 (1R,2S,6S,7S)-9-acetyl-4,4-dimethyl-3,5,8-trioxa-9-aza-tricyclo[5.2.2.0.2.6]undec-10-ene-7-carboxylic acid ethyl ester 
• 1185040-54-3 (+)-ethyl (3aR,7aS)-2,2-dimethyl-3a,7a-dihydrobenzo[d][1,3]dioxole-4-carboxylate 
• 1173701-22-8 (+)-ethyl (5S,6R)-5,6-dihydroxycyclohexa-1,3-dienecarboxylate 
• 1196490-63-7 ethyl (3aR,4R,6R,7S,7aS)-7-(acetylamino)-2,2-dimethyl-6-[(methylsulfonyl)oxy]hexahydro-1,3-benzodioxole-4-carboxylate 
• 1196490-59-1 ethyl (3aR,4R,6R,7R,7aS)-7-(acetylamino)-6-hydroxy-2,2-dimethylhexahydro-1,3-benzodioxole-4-carboxylate 
• 1173701-27-3 ethyl (3aR,6R,7R,7aS)-7-(acetylamino)-6-hydroxy-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole-4-carboxylate 
• 1173701-25-1 ethyl (3aR,5aR,8aR,8bS)-2,2,7-trimethyl-3a,5a,8a,8b-tetrahydro[1,3]dioxolo[4,5-e][1,3]benzoxazole-4-carboxylate 
• 1173701-24-0 ethyl (3aS,4S,7R,7aS)-7-(acetylamino)-4-hydroxy-2,2-dimethyl-3a,4,7,7a-tetrahydro-1,3-benzodioxole-4-carboxylate 
• 108-24-7 acetic anhydride 

Downstream Products

• 204255-06-1 oseltamivir 

Relevant academic research and scientific papers

Several generations of chemoenzymatic synthesis of oseltamivir (Tamiflu): Evolution of strategy, quest for a process-quality synthesis, and evaluation of efficiency metrics

Four generations of chemoenzymatic approaches to oseltamivir are presented. The first two generations relied on the use of cyclohexadiene-cis-diol derived enzymatically from bromobenzene. The third and fourth generation used the corresponding diol obtaine

Sugar-based synthesis of tamiflu and its inhibitory effects on cell secretion

Tamiflu is currently the most effective drug for the treatment of influenza, but the insufficient supply and side-effects of this drug demand urgent solutions. We present a practical synthesis of Tamiflu by using novel synthetic routes, cheap reagents, and the abundantly available starting material D-glucal. The strategy features a Claisen rearrangement of hexose to obtain the cyclohexene backbone and introduction of diamino groups through tandem intramolecular aziridination and ring opening. In addition, this synthetic protocol allows late-stage functionalization for the flexible synthesis of Tamiflu analogues. By using the synthesized Tamiflu and its active metabolite (oseltamivir carboxylate), we inves-tigated their influences on neuroendocrine PC12 cells in various aspects. It was discovered that oseltamivir carboxylate significantly inhibits the vesicular exocytosis (regulated secretion) of PC 12 cells, and suggests a mechanism underlying the Tamiflu side-effects, in particular its possible adverse influences on neurotransmitter release in the central nervous system.

PROCESSES AND INTERMEDIATES FOR THE PREPARATION OF OSELTAMIVIR AND ANALOGS THEREOF

The present application relates to processes for the preparation of oseltamivir and the H3PO4 salt of oseltamivir, Tamiflu. The application further relates to novel intermediate compounds and to pharmaceutical compositions containing said compounds. The application further relates to a method of using the novel intermediates to treat or prevent influenza.

SYNTHESIS OF OSELTAMIVIR CONTAINING PHOSPHONATE CONGENERS WITH ANTI-INFLUENZA ACTIVITY

Novel phosphonate compounds are described. The compounds have activity as neuraminidase inhibitors against wild-type and H274Y mutant of H1N1 and H5N1 viruses. The present disclosure also provides an enantioselective synthetic route to known neuraminidase inhibitors oseltamivir and the anti-flu drug Tamiflu, as well as novel phosphonate compounds, via D-xylose. Another efficient and flexible synthesis of Tamiflu and the highly potent neuraminidase inhibitor Tamiphosphor was also achieved in 11 steps and > 20% overall yields from the readily available fermentation product (1S-cis)-3-bromo-3,5- cyclohexadiene-1,2-diol. Most of the reaction intermediates were obtained as crystals without tedious purification procedures. The key transformations include an initial regio- and stereoselective bromoamidation of a bromoarene cis- dihydrodiol, as well as the final palladium-catalyzed carbonylation and phosphonylation.

METHOD OF FORMING OSELTAMIVIR AND DERIVATIVES THEREOF

A process is provided for the synthesis of 4,5-diamino cyclohexene carboxylate ester (1): or a pharmaceutically acceptable salt thereof. R1 - R3 are a silyl-, an aliphatic, alicyclic, aromatic, arylaliphatic, or an arylalicyclic group. R4, R11 and R12 are H, a silyl-group, an aliphatic, alicyclic, aromatic, arylaliphatic, or an arylalicyclic group. 3,4-Dihydropyran compound (9): with R5 and R6 being suitable protecting groups, is reacted to form aldehyde (4): which is oxidized and converted to N-substituted carbamate (3): with R7 being a suitable protecting group. (3) is, via oxazolinidone (13): converted to azido carboxylate ester (2): and then to 4,5-diamino cyclohexene carboxylate ester (1).

Synthesis of tamiflu and its phosphonate congeners possessing potent anti-influenza activity

Using d-xylose as an appropriate chiral precursor, we have synthesized active neuraminidase inhibitor oseltamivir, antiflu drug Tamiflu, and novel phosphonate congeners that exhibit even stronger antiflu activities by inhibiting the neuraminidases of the wild-type and H274Y mutant of H1N1 and H5N1 viruses. Molecular modeling of the neuraminidase-phosphonate complex indicates a pertinent binding mode of the phosphonate with three arginine residues in the active site. Discovery of such potent neuraminidase inhibitors will offer an opportunity to the development of new anti-influenza drugs. Copyright