New, efficient synthesis of oseltamivir phosphate (Tamiflu) via enzymatic desymmetrization of a meso-1,3-cyclohexanedicarboxylic acid diester

Journal of Organic Chemistry

Volumn 73, Issue 13, 2008, Pages 4895-4902

  Zutter, Ulrich ^a   Iding, Hans ^a   Spurr, Paul ^a   Wirz, Beat ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

AMINES; CHEMICAL REACTIONS; ESTERS; FUNCTION EVALUATION; HYDROLYSIS; ORGANIC COMPOUNDS; SULFATE MINERALS;

CHEMICAL EQUATIONS; CURTIUS DEGRADATION; DESYMMETRIZATION; DIETHYL ESTER; DIMETHOXY PHENOL; EFFICIENT SYNTHESIS; ENANTIO SELECTIVE SYNTHESIS; ENZYMATIC DESYMMETRIZATION; ENZYMATIC HYDROLYSIS; ISO-PHTHALIC ACID (IPA); MESO DIESTERS; NEURAMINIDASE; OSELTAMIVIR; OXAZOLIDINONE; PIG LIVER ESTERASE (PLE); PRODRUG; TAMIFLU;

SYNTHESIS (CHEMICAL);

5 (1 ETHYLPROPOXY) 4,6 DIMETHOXYISOPHTHALIC ACID DIETHYL ESTER; CARBOXYLIC ACID DERIVATIVE; CYCLOHEXENOL; ESTERASE; MESO 1,3 CYCLOHEXANEDICARBOXYLIC ACID DIESTER; OSELTAMIVIR; PHTHALIC ACID; SIALIDASE INHIBITOR; SYRINGOL; VIRUS SIALIDASE;

ARTICLE; DECARBOXYLATION; DRUG BINDING; DRUG SYNTHESIS; ELIMINATION REACTION; ENANTIOMER; ENZYME ANALYSIS; HYDROLYSIS; INFLUENZA; NONHUMAN; SWINE;

ANTIVIRAL AGENTS; DICARBOXYLIC ACIDS; MOLECULAR STRUCTURE; OSELTAMIVIR;

EID: 46849084792     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo800264d     Document Type: Article

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25. In fact, as the absolute configuration of ent-8a was unknown and ent-8a was obtained as the first product of desymmetrization, ent-1 was synthesized before 1.
26. The desymmetrization concept discussed at the beginning included a synthesis of 1 via both enantiomeric monoacids 8b and ent-8b (Scheme 2). Alternatively, the desired oxazolidinone 13 should be accessible using the (R)-monoacid ent-8b via ammonolysis (or hydrazinolysis) and Hofmann (or Curtius) degradation of the resultant amide (or hydrazide) followed by esterification: (Chemical Equation Presented)
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28. An independent synthesis of the carbonate intermediate 19 was accomplished as follows: (Chemical Equation Presented)