1-Methylpiperazine → 1-{5-tert-Butyl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4] triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

HRID 630889Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 630889
[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16]Cl)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:61]3[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]3)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]

Komponenten

5

Edukt 3

HCID 531671-MethylpiperazineHCID 81531DiisopropylethylamineHCID 866871731-[5-tert-Butyl-2-(4-chloromethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

Produkt 1

HCID 716038501-{5-tert-Butyl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4] triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureaAusbeute 7,3 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
50 °C

Versuchsvorschrift

To a solution of Intermediate 106b (0.25 mmol) in THF (2.5 mL) was added DIPEA (130 μL, 0.75 mmol) followed by N-methylpiperazine (83 μL, 0.75 mmol). The reaction mixture was heated at 50° C. for 18 h in a sealed tube, then cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM followed by HPLC (C, 18 X-select column, 10-98% gradient MeCN in H2O, 0.1% HCO2H), to give the title compound (13 mg, 7%). LCMS (Method 5): Rt 3.44 min, m/z 717 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.57-1.66 (2H, m), 1.68-1.77 (4H, m), 1.79-1.95 (2H, m), 1.98-2.19 (5H, m), 2.22-2.46 (8H, m), 3.14 (4H, t, J=5.3 Hz), 3.49 (2H, s), 4.76-4.85 (1H, m), 5.54 (1H, t, J=4.4 Hz), 6.33 (1H, s), 7.09 (1H, d, J=8.6 Hz), 7.17 (1H, dd, J=9.8, 2.2 Hz), 7.25-7.47 (8H, m), 7.59-7.65 (2H, m), 8.11 (1H, s).

Aufarbeitung

  1. temperaturecooled
  2. custompartitioned between EtOAc and water
  3. extractionThe aqueous phase was extracted with EtOAc (×3)
  4. washthe combined organic layers were washed with brine
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customThe resultant residue was purified by FCC on silica

Quellen und Nachweise

ORD-Eintrag
ord-2b881bf9e21647b3b4bb472912051982
Quelldatensatz
uspto-grants-2016_04
Patentnummer
US09315503B2

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