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0 °C

3-Chloro-2-fluoroiodobenzene (Tokyo Chemical Industry CO., LTD., 3.1 g) was dissolved in tetrahydrofuran (20 ml) and the mixture was cooled to 0° C. An isopropylmagnesium chloride-tetrahydrofuran solution (2M, 18 ml) was added, and the mixture was stirred for 3 hr. Then, 1-(tert-butoxycarbonyl)-4-piperidone (2 g) was added and the mixture was stirred for 3 hr. After completion of the reaction, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (5:1-2:1)). Then, the residue was dissolved in 1,4-dioxane (30 ml) and 10% aqueous sulfuric acid (5 ml) was added thereto. The mixture was stirred with heating at 70° C. for 2 hr. After completion of the reaction, the reaction system was basified (pH=9) with a 1N aqueous sodium hydroxide solution and extracted three times with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-(3-chloro-2-fluorophenyl)piperidin-4-ol (1.0 g, yield 44%).

1. stirringthe mixture was stirred for 3 hr
2. customAfter completion of the reaction
3. extractionthe mixture was extracted three times with ethyl acetate
4. customThe organic layer was dried
5. customthe solvent was evaporated under reduced pressure
6. customThe obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (5:1-2:1))
7. dissolutionThen, the residue was dissolved in 1,4-dioxane (30 ml)
8. addition10% aqueous sulfuric acid (5 ml) was added
9. stirringThe mixture was stirred
10. temperaturewith heating at 70° C. for 2 hr
11. customAfter completion of the reaction
12. extractionextracted three times with chloroform
13. customThe organic layer was dried
14. customthe solvent was evaporated under reduced pressure