3-Aminoquinoline → (R)-2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid quinolin-3-ylamide

HRID 1697475Notes

Reaction equation

HRID 1697475 reaction equation
[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[CH:2]=1.[F:12][C:13]([F:31])([F:30])[C:14]([C:17]1[CH:26]=[CH:25][C:24]2[CH2:23][C@H:22]([C:27](O)=[O:28])[CH2:21][CH2:20][C:19]=2[N:18]=1)([CH3:16])[CH3:15].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1C=NC2N(O)N=NC=2C=1>CN1CCCC1=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:27]([C@@H:22]2[CH2:21][CH2:20][C:19]3[N:18]=[C:17]([C:14]([CH3:16])([CH3:15])[C:13]([F:31])([F:30])[F:12])[CH:26]=[CH:25][C:24]=3[CH2:23]2)=[O:28])[CH:2]=1

Participants

7

Reactant 5

HCID 113753-AminoquinolineHCID 81531DiisopropylethylamineHCID 181649HOAtHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58118632(R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid

Product 1

HCID 44194674(R)-2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid quinolin-3-ylamideYield 75%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
60 °C

Procedure

To a mixture of 3-quinolinamine (26 mg, 0.18 mmol), (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (40 mg, 0.14) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (79 mg, 0.21 mmol) in N-methylpyrrolidinone (0.7 mL), followed by N,N-diisopropylethylamine (73 μL, 0.42 mmol) was added. Aliquot after 2 min: LCMS showed formation of the HOAt and Me ester, and some amide. After 1.3 h, the reaction was heated at 60° C. Aliquot after 25 h: LCMS showed the reaction was complete—all HOAt ester had been consumed. The material was filtered and purified by reverse-phase HPLC (20-80% ACN in 10 mM Et2NH/H2O; 3 injections of 400 μL, each) to afford the amide (43 mg, 75%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.95 (d, J=2.4 Hz, 1H), 8.76 (d, J=2.4 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.92 (dd, J=1.1, 8.0 Hz, 1H), 7.68-7.54 (m, 3H), 7.40 (d, J=8.0 Hz, 1H), 3.08-3.00 (m, 2H), 2.99-2.87 (m, 3H), 2.29-2.20 (m, 1H), 2.03-1.91 (m, 1H), 1.56 (s, 6H); m/z=414.1 (M+1)+.

Workup

  1. additionwas added
  2. waitAfter 1.3 h
  3. waitAliquot after 25 h
  4. customhad been consumed
  5. filtrationThe material was filtered
  6. custompurified by reverse-phase HPLC (20-80% ACN in 10 mM Et2NH/H2O

Sources & evidence

ORD record
ord-515dbeeb03ec45c29bb3537ec492671e
Source dataset
uspto-grants-2012_04
Patent number
US08163901B2

Reaction notes

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