Oseltamivir , preparation

Fukuyama and co-workers constructed the [2.2.2]azabicyclohexane framework enantioselectively via the asymmetric Diels-Alder reaction and MacMillan s catalyst ent-5a and obtained a lactone without purification. Subsequent transformation led to the preparation of (—)-oseltamivir in 22% yield from benzyl chloroformate (Scheme 10.3) [37]. 

The preparation of such dihydropyrans derivatives 21-23 modified at the C-6 position by a hydrophobic substituent (zsopentyl side chain) analogous to the oseltamivir side chain is summarized in Scheme 7. It uses the borono-Mannich Petasis reaction between an amine, ot-hydro)yaldehyde 25 and boronic acid 26. This reaction proceeds with remarkably high stereocontrol, producing 1,2-aminoalcohols with an a tf-configuration. The resulting acyclic aminoalcohol 24 is the key precursor to the functionalized cyclic dihydropyrans 21-23 with the proper functionality and stereochemistry at C4. 

One synthetic advantage of olefin metathesis is that the catalyst tolerates a variety of functional groups in the reactant. In a synthesis of the antiinfluenza drug Tamiflu (oseltamivir), ring-closing metathesis was used to prepare the highly functionalized cyclohexene derivative shown. What was the reactant ... 

Problem 3.2 Oseltamivir (trade name Tamiflu), the most effective antiviral drug against avian influenza currently available, can be prepared in 10 steps from shikimic acid. Identify the functional groups in Tamiflu and shikimic acid. 

CI.ll Tamiflu (Oseltamivir), C16H28N2O4, is a drug that is used to treat influenza. The preparation of Tamiflu begins with the extraction of shikimic add from the seedpods of the Chinese spice, star anise. From 2.6 g of star anise, 0.13 g of shikimic acid can be obtained and used to produce one capsule containing 75 mg of Tamiflu. The usual adult dosage for treatment of influenza is 75 mg of Tamiflu twice daily for 5 days. (2.7, 6.5,7.2,7.3,7.4,7.5)... 

Sample preparation Condition a 3 mL 7 mm Empore Mixed Phase Cation-MPC SPE disc with 1 mL MeOH, three 3 mL portions of MeOH 50 mM ammonium acetate 90 10, and 1 mL 5 mM pH 3.5 ammonium acetate. Mix 100 p,L plasma or urine with 50 xL IS solution and 1 mL 5 mM pH 3.5 ammonium acetate buffer, add to the SPE disc, wash with 1 mL water, wash with 1 mL MeOH, wash with 1 mL MeOHiwater 90 10, dry under vacuum, elute with 1 mL MeOH 50 mM ammonium acetate 90 10. Evaporate the eluate to dryness under a stream of nitrogen at ca. 50°, reconstitute the residue with 150 iiL water, centrifuge at >500 rpm, inject a 100 p,L ahquot. (IS solution contained 50 ng/ml of ds-oseltamivir and 2 fig/ml of d3-GS4071 in water). 

Large-scale Preparation and Usage of Azides 45 Table 2.11 Global sales of Oseltamivir ... 

The heterogeneous, catalytic hydrogenation of substituted aromatic rings is a powerful means for the preparation of cis-substituted cycloalkanes in a highly stereoselective fashion [16]. An elegant example has been reported by researchers at Roche in a synthesis of the anti-influenza drug oseltamivir phosphate (Tamiflu, 20, Scheme 8.4) [35]. Diester 18 was reduced at elevated pressure, exclusively affording the all-cis-substituted meso-cyclohexane 19. 

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