Diisopropylethylamine → N-(5-((6-methoxy-7-(piperidin-4-ylmethoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-phenylthiazole-2-carboxamide

HRID 1465211Notes

Reaction equation

HRID 1465211 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:36]1([C:42]2[N:43]=[C:44]([C:47](O)=[O:48])[S:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:47]([C:44]2[S:45][CH:46]=[C:42]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:43]=2)=[O:48])=[N:7][CH:6]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 38785394-Phenylthiazole-2-carboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66611940Tert-butyl 4-(((4-((6-aminopyridin-3-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)piperidine-1-carboxylate

Product 1

HCID 66611461N-(5-((6-methoxy-7-(piperidin-4-ylmethoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-phenylthiazole-2-carboxamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
55 °C

Procedure

A mixture of tert-butyl 4-(((4-((6-aminopyridin-3-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)piperidine-1-carboxylate (70 mg, 0.14 mmol), 4-phenylthiazole-2-carboxylic acid (46 mg, 0.21 mmol), DIPEA (56 mg, 0.43 mmol) and HATU (110 mg, 0.29 mmol) in dry DMF (5 mL) was stirred for 72 h at 55° C. The solution was diluted with EtOAc (150 mL) and washed twice with aq.NaHCO3-solution and once with brine. The residue was dissolved in 50% TFA in DCM (5 mL) and stirred for 2 h at RT. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase RP-HPLC (column: C18), using H2O and ACN as eluents. The desired fractions were lyophilized to yield the title compound X14 (25 mg, 30%) as a white powder. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.25 (m, 2H), 1.76 (d, J=12.0 Hz, 2H), 1.95 (m, 1H), 2.55 (t, J=11.0 Hz, 2H), 3.00 (d, J=12.0 Hz, 2H), 3.94 (s, 3H), 3.99 (d, J=6.3 Hz, 2H), 6.58 (d, J=5.2 Hz, 1H), 7.41 (m, 2H), 7.51 (m, 3H), 7.90 (dd, J=2.9 Hz, J=9.0 Hz, 1H), 8.17 (d, J=7.4 Hz, 2H), 8.29 (d, J=9.0 Hz, 1H), 8.48 (d, J=2.9 Hz, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.55 (s, 1H). MS (ES) C3H29N5O4S requires: 567. Found: 568 (M+H)+.

Workup

  1. washwashed twice with aq
  2. dissolutionThe residue was dissolved in 50% TFA in DCM (5 mL)
  3. stirringstirred for 2 h at RT
  4. concentrationThe mixture was concentrated under reduced pressure
  5. customThe residue was purified by reverse phase RP-HPLC (column: C18)

Sources & evidence

ORD record
ord-3d3236e506d74c0e91840f9cc8dadd9e
Source dataset
uspto-grants-2015_04
Patent number
US08999982B2

Reaction notes

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