p-Bromomandelic acid → HCID 22116897, compound

To a stirred solution of 4-bromomandelic acid (832 mg, 3.6 mmol), 2-phenylpyrrolidine (530 mg, 3.6 mmol), BOP reagent (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphonate, 1.53 g, 3.6 mmol) in 25 mL of anhydrous acetonitrile was added triethylamine (1.06 mL, 7.2 mmol) at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 4 h, concentrated under reduced pressure, then dissolved in methylene chloride (50 mL). The methylene chloride solution was washed with 1N HCl solution, water, saturated sodium bicarbonate solution, water, brine, and dried over anhydrous MgSO4, concentrated under reduced pressure to afford a syrup in a flask. PPA (polyphosphoric acid, 10 g) was added to the flask. The reaction mixture was heated on a rotavap in boiling water bath for 1 h, cooled to room temperature, solublized in ice water, extracted with methylene chloride (4×15 mL). The methylene chloride extract was washed with saturated sodium bicarbonate solution, water, brine, and dried over anhydrous MgSO4, concentrated under reduced pressure to afford a crude product mixture. Flash chromatography (silica gel, 0.5% MeOH, 0.01% Et3N in methylene chloride) to afford 860 mg of 4 (70% yield for two steps) as a mixture of trans and cis isomers with trans to cis ratio 2:1 (estimated by 1H NMR integration). Recrystallization with THF isolated trans isomer as a yellow solid, mp 204-206° C. 1H NMR (CDCl3) δ 1.96-2.22 (m, 3H, C2H2 & C1H), 2.66-2.78 (m, 1H, C1H), 3.48-3.58 (m, 1H, C3H), 3.732 (dd, 1H, J=7.5, 11.7 Hz, C3H), 4.610 (s, 1H, C6H), 4.64-4.70 (m, 1H, C10bH), 6.591 (d, 1H, J=7.8 Hz, aryl), 7.104 (d, 2H, J=8.1 Hz, C6 phenyl aryl), 7.12-7.28 (m, 3H, 8, 9, aryl), 7.520 (d, 2H, J=8.4 Hz, C6 phenyl aryl); 13C NMR (CDCl3) δ 23.06 (C2), 31.21 (C1), 45.07 (C3), 52.99 (C10b), 58.62 (C6), 121.10 (C4'), 123.58 (aromatic), 126.74 (aromatic), 127.38 (aromatic), 131.38 (aromatic), 132.60 (aromatic), 136.15 (aromatic), 136.55 (aromatic), 136.79 (aromatic), 167.36 (C5). HRMS calculated 341.0415 (for C18H16NOBr), measured 341.0427 (relative error 3.4 ppm).

1. concentrationconcentrated under reduced pressure
2. dissolutiondissolved in methylene chloride (50 mL)
3. washThe methylene chloride solution was washed with 1N HCl solution, water, saturated sodium bicarbonate solution, water, brine
4. dry with materialdried over anhydrous MgSO4
5. concentrationconcentrated under reduced pressure
6. customto afford a syrup in a flask
7. temperatureThe reaction mixture was heated on a rotavap
8. customfor 1 h
9. temperaturecooled to room temperature
10. extractionextracted with methylene chloride (4×15 mL)
11. extractionThe methylene chloride extract
12. washwas washed with saturated sodium bicarbonate solution, water, brine
13. dry with materialdried over anhydrous MgSO4
14. concentrationconcentrated under reduced pressure
15. customto afford a crude product mixture

ORD record

ord-9bdc3af77f364c1b98b60cfc096b4b2a

Source dataset

uspto-grants-2000_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06162417