(1S-4R)-4-[[(1,1-diMethylethoxy)carbonyl]aMino]- 2-Cyclopentene-1-carboxylic acid Methyl ester

Uses

(3aR,4R,6S,6aS)-4-[[(1,1-Dimethylethoxy)carbonyl]amino]-3-(1-ethylpropyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]isoxazole-6-carboxylic Acid Methyl Ester is an intermediate used in the synthesis of peramivir (P285500), a neuraminidase inhibitor developed as an antiviral agent for the treatment of influenza.

Synthesis

1. (3aR,4R,6S,6aS)-4-((tert-butoxycarbonyl)amino)-3-(pentan-3-yl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazole-6-carboxylic acid 2-methylpropan-2-ammonium salt (3210 g, 7.8 mol) was suspended in acetone (4000 g). 2. potassium carbonate (53.8 g) and 30% aqueous sodium hydroxide (containing 312 g sodium hydroxide) were added to the suspension. 3. 3000 ml of solvent was removed by evaporation, 3000 ml of acetone was added and 3000 ml of solvent was again removed by evaporation. This operation was repeated once, and finally 4000 ml of acetone was removed by evaporation to obtain a reaction solution essentially free of tert-butylamine odor. 4. Cool the reaction solution to 30-35°C and slowly add 1060 ml of dimethyl sulfate dropwise, controlling the rate of dropwise acceleration in order to keep the reaction temperature from exceeding 45°C. After the dropwise acceleration is completed, the reaction solution is added to the reaction solution. 5. After the dropwise addition, the reaction mixture was stirred at 40-45°C for 1.5 hours. 6. The reaction mixture was cooled to 15-20 °C, 1500 ml of 25% ammonia was added and stirred for 30 minutes. 7. After addition of 1500 ml of methanol, the reaction mixture was cooled to 0-5 °C. 8. 2240 ml of 25% ammonia was slowly added to the reaction mixture over 45 minutes. 9. The product was collected by filtration, washed with 3000 ml of water and dried under vacuum at 45-50 °C. 10. 2686.2 g of the target product was finally obtained in 97.13% yield.

References

[1] Patent: EP2186795, 2010, A1. Location in patent: Page/Page column 6; 11-12