Acetic Acid → 3-{4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-furan-3-yl]-phenyl}-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester

To a stirred solution of trimethylsilyldiazomethane (2M in diethyl ether, 18.64 mL, 37.289 mmol) in 1,2-dimethoxyethane (DME, 100 mL) was added methyl lithium (1.6M in diethyl ether, 23.32 mL, 37.289 mmol) at −78° C. over period of 10 minutes and stirred reaction mixture for 30 minutes at −78° C. Pre-dissolved 3-{4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-butyryl]-phenyl}-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (Example 1, Intermediate 1) (5 g, 9.322 mmol, 1eq.) in DME (50 mL) was added at −78° C. in drop wise manner over period of 10 minutes. Resulting reaction mixture was stirred for 1 hour at same temperature and then at room temperature for 2 hours. Acetic acid (1.60 mL, 27.967 mmol, 3 eq.) was added at room temperature over period of 5 minutes followed by addition of TBAF (27.92 mL, 27.967 mmol, 3 eq.) at room temperature over period of 10 minutes. After consumption of starting material, reaction mixture was quenched with water (150 mL) and extracted with ethyl acetate (5×150 mL). Combined organic layer was dried over sodium sulphate and concentrated in vacuo to get orange semisolid (6.1 g, crude). Crude was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 10% ethyl acetate in hexane to afford off white semisolid (1.6 g, Impure). The product was again purified by trituration using DCM: pentane (1:5, 2×20 mL) to afford product as off white solid (0.45 g, 9.18%). Yield: −0.45 g (9.18%). 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 9H), 3.20 (d, J=17.24 Hz, 1H), 3.30 (d, J=17.24 Hz, 1H), 4.14-4.21 (m, 2H), 4.33-4.41 (m, 2H), 7.32-7.38 (m, 4H), 7.40 (t, J=1.78 Hz, 1H), 7.52 (d, J=1.36 Hz, 2H). LC-MS (m/z): =529.9 (M−H).

1. customreaction mixture for 30 minutes at −78° C
2. customResulting
3. customreaction mixture
4. stirringwas stirred for 1 hour at same temperature
5. customAfter consumption of starting material, reaction mixture
6. customwas quenched with water (150 mL)
7. extractionextracted with ethyl acetate (5×150 mL)
8. dry with materialCombined organic layer was dried over sodium sulphate
9. concentrationconcentrated in vacuo
10. customto get orange semisolid (6.1 g, crude)
11. customCrude was purified by column chromatography
12. washDesired compound was eluted in 10% ethyl acetate in hexane
13. customto afford off white semisolid (1.6 g, Impure)
14. customThe product was again purified by trituration

ORD record

ord-3e9760786e7a4207aaae24fbdcd7a60d

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09133172B2