3-thiane-2-carboxylic acid (1R,2S,5R)-5-methyl-2-(1-methylethyl)cyclohexyl ester in the following general steps:
1. 6-Amino-5-fluoropyrimidin-2(1H)-one (22.4 g, 0.173 mol, 1.1 mole equivalents), hexamethyldisilazane (HMDS) (100 ml, 0.477 mol, 3.1 mole equivalents), and trimethylmethylsilanedichloro (TMSCL) (11.2 ml) were mixed at 25-30 °C, protected by nitrogen.
2. The reaction mixture was heated to 120-130 °C until a clarified solution was formed, followed by removal of excess solvent by vacuum distillation at 90-100 °C to afford a methylsilylated 6-amino-5-fluoropyrimidin-2(1H)-one residue.
3. The above residue was cooled to room temperature and dissolved by addition of fresh dichloromethane (100 ml) to give Solution A.
4. In another flask, (2R,5R)-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 5-acetoxy-1,3-oxathiolane-2-carboxylate (50 g, 0.151 mol, 1.0 mole equivalent), dichloromethane (250 ml) and zirconium tetrachloride (ZrCl4) (17.6 g, 0.075 mol, 0.5 molar equivalents) were mixed under nitrogen protection to obtain solution B.
5. Solution A was slowly added to solution B at 25-30 °C and the reaction mixture was stirred at the same temperature for 6 h. The reaction process was monitored by HPLC or thin layer chromatography.
6. After completion of the reaction, the reaction mixture was cooled to 10-20 °C and pre-cooled (10-20 °C) water (250 ml) was added under stirring.
7. The pH was adjusted to 8-8.5 using triethylamine and the organic and aqueous layers were separated and the organic layer was washed with 250 ml of water.
8. The organic layer was concentrated under vacuum to obtain a residue, which was dissolved in methanol (200 ml) and n-heptane (100 ml) with stirring.
9. The solution was added to water (200 ml) and the separated solid was filtered and washed sequentially with water and n-heptane.
10. The solid was dried under vacuum at 40-45 °C to give 48.5 g of the target product in 80% yield and 99.94% chiral purity.
