Methyl iodide → 6-Methyl-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid

A solution of LDA in THF (0.64 M, 4 mL, 2.56 mmol), prepared from N,N-diisopropylamine (358 μL, 2.56 mmol), 1.47 M of butyllithium in hexane (1.74 mL, 2.56 mmol) and THF (2 mL) was added dropwise to a 0° C. solution of (S)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (294 mg, 1.02 mmol) in dry THF (4 mL). After 2 min at 0° C., the dark red mixture was warmed to room temperature, and aged for 1 h, before recooling to 0° C. Neat methyl iodide (159 μL, 2.56 mmol) was added, and the mixture rapidly lightened to pale red. After 2 min at 0° C., the mixture was warmed to room temperature. After 1 h, the reaction was quenched by addition of water (5 mL), then partitioned between 1M KH2PO4 (30 mL) and DCM (40 mL). The aqueous layer was extracted with DCM (2×20 mL), the combined organic layers were dried (Na2SO4), filtered and concentrated to a yellow semi-solid, which was purified by reverse-phase HPLC (40-75% ACN in 0.1% HCO2H/H2O). The combined purified fractions were concentrated to remove ACN, and the mixture buffered with 1M pH 6 phosphate buffer (30 mL), and extracted with DCM (3×20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to afford the acid as a solid (104 mg, 34%). 1H NMR (400 MHz, CDCl3) δ 10.76 (br s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 3.25 (d, J=16.6 Hz, 1H), 2.99 (br s with fine str, 2H), 2.66 (d, J=16.6 Hz, 1H), 2.27 (app dt, J=12.7, 5.9 Hz, 1H), 1.90 (app dt, J=13.8, 7.1 Hz, 1H), 1.58 (s, 6JH), 1.36 (s, 3H); m/z=302.1 (M+H)+.

1. waitaged for 1 h
2. custombefore recooling to 0° C
3. waitAfter 2 min at 0° C.
4. temperaturethe mixture was warmed to room temperature
5. waitAfter 1 h
6. customthe reaction was quenched by addition of water (5 mL)
7. custompartitioned between 1M KH2PO4 (30 mL) and DCM (40 mL)
8. extractionThe aqueous layer was extracted with DCM (2×20 mL)
9. dry with materialthe combined organic layers were dried (Na2SO4)
10. filtrationfiltered
11. concentrationconcentrated to a yellow semi-solid, which
12. customwas purified by reverse-phase HPLC (40-75% ACN in 0.1% HCO2H/H2O)
13. customThe combined purified fractions
14. concentrationwere concentrated
15. customto remove ACN
16. extractionextracted with DCM (3×20 mL)
17. dry with materialThe combined organic layers were dried (Na2SO4)
18. filtrationfiltered
19. concentrationconcentrated

ORD record

ord-d1198e0608d7490d9ce456895390b340

Source dataset

uspto-grants-2012_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08163901B2