3-(Trifluoromethyl)benzeneacetic acid → HCID 66823728, compound

To 5-bromoindoline (5.0 g, 25.2 mmol, 1 equiv) and [3-(trifluoromethyl)phenyl]acetic acid (6.18 g, 30.3 mmol, 1.2 equiv) in 13 mL of DMF was added propylphosphonic anhydride (36.9 mL of a 1.71 M solution in DMF, 63.1 mmol, 2.5 equiv) followed by DIEA (8.82 mL, 50.5 mmol, 2 equiv). The reddish mixture became warm to touch and was cooled at once in an ice bath. After 30 minutes, the cooling bath was removed and the mixture was stirred at ambient temp. After 18 h, the mixture was diluted with 200 mL of EtOAc and washed with 200 mL of water. The aq was extracted with 150 mL of EtOAc. The combined organic was dried over MgSO4, filtered, and concentrated in vacuo to give a paste residue, which was taken up in ether and hexane to provide a suspension. The suspension was filtered. The solids were washed with hexane and then ether and dried under vacuum to afford crude product (6.17 g) a brownish sticky solids. NMR showed presence of some alkyl impurities, so this lot was redissolved in DCM (150 mL) and washed with water (50 mL). The organic was dried over MgSO4, filtered, and conc in vacuo. The residue was triturated in DCM (5 mL) and ether (75 mL). The suspension was filtered, and the cake was washed with ether. The solids were dried under vacuum to afford 5-bromo-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (4.73 g) as light cream solids. The filtrate was concentrated in vacuo, and the residue was dissolved in DCM and absorbed onto a dryload cartridge. Purification was done on an SF40-150 g silica gel cartridge using gardient elution of 1% EtOAc in hexane to 45% EtOAc in hexane. The product peak eluted from 24-33% EtOAc. The product fractions were combined and concentrated in vacuo to afford product (2.80 g) as a brownish sticky solid residue. Both NMR and LCMS showed this lot had some impurities. The residue was triturated in DCM and ether. The suspension was filtered, and the cake was washed with ether. The solids were dried under vacuum to afford additional 5-bromo-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (1.62 g) as off-white solids. Both NMR and LCMS showed this lot was pure. LC-MS (ES) m/z=384 [M+H]+, 386. 1H NMR (400 MHz, DMSO-d6) ppm 3.20 (t, J=8.5 Hz, 2H), 4.00 (s, 2H), 4.23 (t, J=8.6 Hz, 2H), 7.32 (dd, J=8.7, 1.9 Hz, 1H), 7.45 (s, 1H), 7.53-7.70 (m, 4H), 7.96 (d, J=8.6 Hz, 1H).

1. temperatureThe reddish mixture became warm
2. temperaturewas cooled at once in an ice bath
3. customthe cooling bath was removed
4. waitAfter 18 h
5. additionthe mixture was diluted with 200 mL of EtOAc
6. washwashed with 200 mL of water
7. extractionThe aq was extracted with 150 mL of EtOAc
8. dry with materialThe combined organic was dried over MgSO4
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. customto give a paste residue, which
12. filtrationThe suspension was filtered
13. washThe solids were washed with hexane
14. dry with materialether and dried under vacuum
15. customto afford crude product (6.17 g) a brownish sticky solids
16. washwashed with water (50 mL)
17. dry with materialThe organic was dried over MgSO4
18. filtrationfiltered
19. customThe residue was triturated in DCM (5 mL)
20. filtrationThe suspension was filtered
21. washthe cake was washed with ether
22. customThe solids were dried under vacuum

ORD record

ord-6fd3ac008212412a8bfa6f7d51687edd

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08598156B2