Triethylamine → Trifluoroacetic acid

HRID 713286Notes

Reaction equation

HRID 713286 reaction equation
[OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1)[C:12]#[N:13].C(N(CC)CC)C.[CH:45]1([C:48](Cl)=[O:49])[CH2:47][CH2:46]1>C(Cl)Cl>[CH:45]1([C:48]([N:31]2[CH2:32][CH2:33][C:27]3[C:28](=[N:29][C:24]([N:21]4[CH2:20][CH2:19][CH:18]([O:17][C:16]5[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=5[F:8])[CH2:23][CH2:22]4)=[C:25]([NH:34][CH:35]([CH3:37])[CH3:36])[N:26]=3)[CH2:30]2)=[O:49])[CH2:47][CH2:46]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 77637Cyclopropanecarbonyl chlorideHCID 118159356HCID 118159356, compound

Product 2

HCID 6422Trifluoroacetic acidYield 75.6%HCID 118159302HCID 118159302, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (98.6 mg, 0.094 mmol) and triethylamine (0.039 mL, 0.283 mmol) in DCM (0.5 mL) was added cyclopropanecarboxylic acid chloride (0.017 mL, 0.188 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (8.1 mg, 15%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 0.69-0.79 (m, 4H), 1.18 (d, J=6.6 Hz, 6H), 1.91 (dd, J=19.5, 5.6 Hz, 2H), 2.13 (dd, J=14.3, 6.2 Hz, 2H), 2.52-2.53 (m, 1H), 2.57-2.64 (m, 0.9H), 2.75 (t, J=6.2 Hz, 1.1H), 2.88-2.99 (m, 2H), 3.22-3.31 (m, 2H), 3.72-3.77 (m, 0.9H), 3.95 (t, J=5.8 Hz, 1H), 4.10-4.16 (m, 1H), 4.42 (br s, 1.1H), 4.67 (br s, 0.9H), 4.80-4.87 (m, 1H), 5.61-5.67 (m, 1H), 7.50 (t, J=8.5 Hz, 1H), 7.65-7.70 (m, 1H), 7.86 (dd, J=11.2, 1.9 Hz, 1H); ESI-MS m/z [M+H]+ 479.5.

Workup

  1. concentrationconcentrated via rotary evaporation
  2. additionThe crude material was diluted with DMSO
  3. filtrationfiltered
  4. washrinsed with DMSO
  5. custompurified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm

Sources & evidence

ORD record
ord-44b6bb35a25644c1900ff772d19cbf5f
Source dataset
uspto-grants-2015_11
Patent number
US09181249B2

Reaction notes

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