Diiodomethane → 4-(Adamantan-1-ylmethoxy)-2-fluoro-5-(trans-2-(methoxymethyl)cyclopropyl)benzoic acid

Temperature

0 °C

To a mixture of diethylzinc (1.0 M solution in heptane, 6.8 mL, 6.8 mmol) in anhydrous dichloromethane (3 mL) was added a solution of trifluoroacetic acid (0.52 mL, 6.80 mmol) in anhydrous dichloromethane (2 mL) at 0° C. and the reaction mixture was stirred for 15 minutes at 0° C. A solution of diiodomethane (0.55 mL, 6.82 mmol) in anhydrous dichloromethane (2 mL) was added to the reaction mixture at 0° C. and stirring was continued for 15 minutes at 0° C. To the reaction mixture was then added a solution of tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-3-methoxyprop-1-en-1-yl)benzoate (1.17 g) in dichloromethane (3 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. After addition of saturated sodium bicarbonate solution (10 mL), the mixture was diluted with dichloromethane (100 mL). The organic phase was washed with brine (10 mL) dried over sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue which was treated with trifluoroacetic acid (2 mL) in dichloromethane (20 mL) for 1 hour. After evaporation of all volatiles under reduced pressure, the residue was triturated with diethyl ether (5 mL) to afford the title compound as a colorless solid (0.554 g, 63%): 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.4 Hz, 1H), 6.54 (d, J=12.9 Hz, 1H), 3.57 (dd, J=10.3, 6.3 Hz, 1H), 3.55-3.48 (m, 2H), 3.37 (s, 3H), 3.36-3.29 (dd, J=10.3, 7.2 Hz, 1H), 2.07-1.99 (m, 3H), 1.93 (td, J=8.9, 5.1, 5.1 Hz, 1H), 1.82-1.62 (m, 12H), 1.38-1.25 (m, 1H), 1.00 (td, J=8.4, 5.3, 5.3 Hz, 1H), 0.89 (td, J=8.8, 5.2, 5.2 Hz, 1H).

1. stirringstirring
2. waitwas continued for 15 minutes at 0° C
3. temperatureto warm to ambient temperature
4. stirringstirred for 2 hours
5. washThe organic phase was washed with brine (10 mL)
6. dry with materialdried over sodium sulfate
7. filtrationfiltered
8. customConcentration of the filtrate in vacuo gave a residue which
9. customAfter evaporation of all volatiles under reduced pressure
10. customthe residue was triturated with diethyl ether (5 mL)

ORD record

ord-eea0376029304efab61c6607a929d7d0

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08952169B2