Trifluoroacetic acid → (R)-2-(2-(piperidin-3-yloxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate

HRID 1055912Notes

Reaction equation

HRID 1055912 reaction equation
[O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[C:18]([O:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[CH:17]=[CH:16]4)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:24]1[CH2:25][CH2:26][CH2:27][C@@H:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[C:11]([C:9]4[NH:10][C:6]5[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=5[CH:8]=4)[CH:12]=[CH:13][CH:14]=3)[N:19]=2)[CH2:23]1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 89784696(R)-tert-butyl 3-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)oxy)piperidine-1-carboxylate

Product 1

HCID 118511975(R)-2-(2-(piperidin-3-yloxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetateYield 13.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (R)-tert-butyl 3-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)oxy)piperidine-1-carboxylate (117 mg, 0.25 mmol) in DCM (3.0 mL) at 0° C. was added TFA (0.5 mL, 6.73 mmol). The reaction was stirred at RT for 20 min. The solution was concentrated, the residue was dissolved in DCM and washed with a saturated aq. solution of NaHCO3. The aq. layer was extracted with DCM (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was dissolved in DMSO (3.0 mL). Purification by rpHPLC (Silicycle Silichrome XT C18 column; 30×150 mm, 5 μm, 5-95% 0.1% TFA/ACN in 0.1% TFA/water by volume over 10 min.), followed by drying in a Genevac Series II Evaporator afforded (R)-2-(2-(piperidin-3-yloxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (15.7 mg, 0.033 mmol, 13.0% yield) as an amorphous yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.63 (br. s., 1H), 8.76 (s, 1H), 8.80 (s, 1H), 8.34 (d, J=8.8 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.03 (br. s., 1H), 5.52 (br. s., 1H), 3.39-3.55 (m, 4H), 3.15 (br. s., 2H), 2.89 (t, J=6.7 Hz, 2H), 2.13-2.24 (m, 1H), 1.93-2.07 (m, 2H), 1.82-1.92 (m, 1 H). 19F NMR (376 MHz, DMSO-d6) δ ppm −74.47 (s, 3F). m/z (ESI, +ve ion) 363.0 (M+H)+.

Workup

  1. concentrationThe solution was concentrated
  2. dissolutionthe residue was dissolved in DCM
  3. washwashed with a saturated aq. solution of NaHCO3
  4. extractionThe aq. layer was extracted with DCM (2×)
  5. dry with materialThe combined organic layers were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. dissolutionThe residue was dissolved in DMSO (3.0 mL)
  9. customPurification by rpHPLC (Silicycle Silichrome XT C18 column; 30×150 mm, 5 μm, 5-95% 0.1% TFA/ACN in 0.1% TFA/water by volume over 10 min.)
  10. dry with materialby drying in a Genevac Series II Evaporator

Sources & evidence

ORD record
ord-fe7c68fa62624a43b63f8a1ec76eab59
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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