Uses
Tetrahydropyranyl-4-acetic acid is mainly used as a protecting agent in organic synthesis, especially in the multi-step complex synthesis of organic molecules to protect functional groups such as hydroxyl or amino groups.
Synthesis
General procedure for the synthesis of tetrahydropyran-4-acetic acid from ethyl tetrahydropyran-4-yl-acetate:
1. a solution of sodium hydroxide (15.9 g, 44.06 mmol) in water (150 ml) was added dropwise to a methanolic solution of ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate (15 g, 8.81 mmol) at 0 °C or lower.
2. The mixture was stirred at room temperature for 15 hours.
3. The solvent was removed from the reaction mixture by depressurized distillation.
4. The aqueous layer was adjusted to pH 3 by adding 1 M hydrochloric acid and extracted with ethyl acetate.
5. Wash the organic layer with saturated brine and dry with anhydrous sodium sulfate.
6. The filtrate was concentrated under pressure to give tetrahydropyran-4-acetic acid as a colorless solid (12.0 g, 94%). This compound can be used in the next step without further purification.
7. Benzyl bromide (14.3 g, 83.33 mmol) was added dropwise to a suspension of tetrahydropyran-4-acetic acid (10.0 g, 69.44 mmol) and anhydrous potassium carbonate (28.8 g, 208.3 mmol) in acetonitrile (100 ml) at room temperature.
8. The mixture was refluxed for 48 hours.
9. The solvent was removed from the mixture by decompression distillation and the residue was diluted with water and extracted with dichloromethane.
10. The organic layer was dried over anhydrous sodium sulfate.
11. The filtrate was concentrated under pressure and the residue was chromatographed on a silica gel column (hexane: ethyl acetate = 9:1) to afford benzyl tetrahydropyran-4-acetate as an oil (12.0 g, 75% yield). 12.
12. Product characterization data: 1H-NMR (400 MHz, CDCl3): δ (ppm) 7.39-7.34 (m, 5H), 5.12 (s, 2H), 3.95-3.92 (m, 2H), 3.42-3.36 (m, 2H), 2.30 (d, J = 7.2 Hz, 2H), 2.09-1.99 (m, 1H) 1.64-1.61 (m, 2H), 1.39-1.29 (m, 2H); MS (ESI): m/z 234 (M+).
References
[1] Patent: EP2737900, 2014, A1. Location in patent: Paragraph 0114; 0117-0118
[2] Journal of Medicinal Chemistry, 1993, vol. 36, # 16, p. 2300 - 2310
[3] Patent: US5221671, 1993, A
[4] Patent: EP1019398, 2004, B1. Location in patent: Page 51
