Hydrochloric Acid → 4-(adamantan-2-yloxy)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluorobenzamide

Temperature

110 °C

To a solution of tert-butyl 4-(adamantan-2-yloxy)-5-chloro-2-fluorobenzoate in toluene-water (v/v 20:1, 20 mL) was added cyclopropylboronic acid (0.57 g, 6.65 mmol) and tribasic potassium phosphate (4.10 g, 19.31 mmol). The mixture was then sparged with argon for 5 minutes and was then charged with tricyclohexylphosphine tetrafluoroborate (0.33 g, 0.90 mmol) and palladium acetate (0.11 g, 0.47 mmol) and the reaction mixture was heated at 110° C. for 16 hours. The reaction mixture was cooled to ambient temperature, filtered through a pad of diatomaceous earth and washed with ethyl acetate, concentrated in vacuo. to give the crude product: 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J=8.5 Hz, 1H), 6.49 (d, J=12.9 Hz, 1H), 4.45 (br s, 1H), 2.18-2.04 (m, 6H), 1.94-1.81 (m, 9H), 1.56 (s, 9H), 0.92-0.86 (m, 2H), 0.67-0.62 (m, 2H). The crude product was dissolved in anhydrous dichloromethane (6 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred for 2 hours at ambient temperature; concentrated in vacuo to give the crude carboxylic acid (1.02 g, 72%): 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=8.6 Hz, 1H), 6.56 (d, J=13.2 Hz, 1H), 4.49 (br s, 1H), 2.20-1.70 (m, 12H), 1.62-1.53 (m, 1H), 1.34-1.17 (m, 2H), 0.96-0.90 (m, 2H), 0.69-0.64 (m, 2H). The crude carboxylic acid (0.34 g, 1.03 mmol) was dissolved in anhydrous dichloromethane (27 mL) and added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.30 g, 1.56 mmol) and 4-dimethylaminopyridine (0.30 g, 2.42 mmol), after stirring for 5 minutes, azetidine-1-sulfonamide (0.23 g, 1.69 mmol) was added and stirring was continued for 16 hours at ambient temperature. The mixture was then poured into a 5% aqueous solution of hydrochloric acid, the layers separated and the aqueous layer extracted with dichloromethane (3×20 mL). The combined organic layers were then washed with distilled water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (0% to 30% ethyl acetate in hexanes) to afford the title compound (0.11 g, 24%): 1H NMR (300 MHz, CDCl3) δ 8.65 (d, J=16.5 Hz, 1H), 7.63 (d, J=9.3 Hz, 1H), 6.56 (d, J=14.8 Hz, 1H), 4.53-4.48 (m, 1H), 4.25 (t, J=7.74 Hz, 4H), 2.32-2.07 (m, 7H), 2.01-1.79 (m, 8H), 1.62-1.58 (m, 2H), 0.97-0.90 (m, 2H), 0.71-0.65 (m, 2H); MS (ES−) m/z 447.2 (M−1).

1. customThe mixture was then sparged with argon for 5 minutes
2. temperatureThe reaction mixture was cooled to ambient temperature
3. filtrationfiltered through a pad of diatomaceous earth
4. washwashed with ethyl acetate
5. concentrationconcentrated in vacuo
6. customto give the crude product
7. concentrationconcentrated in vacuo
8. customto give the crude carboxylic acid (1.02 g, 72%)
9. stirringafter stirring for 5 minutes
10. stirringstirring
11. waitwas continued for 16 hours at ambient temperature
12. customthe layers separated
13. extractionthe aqueous layer extracted with dichloromethane (3×20 mL)
14. washThe combined organic layers were then washed with distilled water (20 mL) and brine (20 mL)
15. dry with materialdried over anhydrous sodium sulfate
16. filtrationfiltered
17. concentrationconcentrated in vacuo
18. customThe residue was purified by column chromatography (0% to 30% ethyl acetate in hexanes)

ORD record

ord-2a0f050803834102844b0eb9a198dd80

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08952169B2