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1,1'-Carbonyldiimidazole → Urea 4-{2-[4-(3-tert-butyl-5-{3-[4-(pyridin-3-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester

HRID 1174862
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[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27]([NH2:28])=[CH:26][C:25]([C:29]([CH3:32])([CH3:31])[CH3:30])=[N:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH:34]=1.C1N=C[N:49]([C:52]([N:54]2C=NC=C2)=[O:53])C=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[C:27]([NH:28][C:52]([NH:46][C:43]4[CH:44]=[CH:45][C:40]([O:39][C:35]5[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=5)=[CH:41][CH:42]=4)=[O:53])=[CH:26][C:25]([C:29]([CH3:32])([CH3:31])[CH3:30])=[N:24]3)=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2].[NH2:49][C:52]([NH2:54])=[O:53]
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4

Edukt 3

HCID 682631,1'-CarbonyldiimidazoleHCID 31596314-(Pyridin-3-Yloxy)AnilineHCID 536301924-{2-[4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester

Produkt 1

HCID 67022306Urea 4-{2-[4-(3-tert-butyl-5-{3-[4-(pyridin-3-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester

Versuchsvorschrift

4-{2-[4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester was coupled with 4-(pyridin-3-yloxy)phenylamine by reaction with CDI in a similar manner to that described above, to provide the urea 4-{2-[4-(3-tert-butyl-5-{3-[4-(pyridin-3-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (LC-MS [M+H]+=655, RT=3.51 min). Step 2. To a solution of 4-{2-[4-(3-tert-butyl-5-{3-[4-(pyridin-3-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (210 mg, 0.32 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.3 mL). The reaction mixture was stirred at room temperature for 16 h, concentrated at reduced pressure, re-dissolved in methanol and purified by preparative HPLC. The HPLC fraction containing the desired product was basified by addition of saturated aq Na2CO3 and then extracted with EtOAc. Evaporation of the solvent at reduced pressure gave the desired product 1-{5-tert-butyl-2-[4-(2-piperidin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-3-yloxy)-phenyl]-urea (46.6 mg, 26%). 1H-NMR (DMSO-d6) δ 9.20 (s, 1H), 8.30 (m, 3H), 7.45-7.35 (m, 5H), 7.00 (m, 3H), 6.30 (s, 1H), 4.0 (m, 4H), 2.40 (m, 2H), 1.70-1.60 (m, 6H), 1.40 (s, 9H), 1.05 (m, 1H); MS LC-MS [M+H]+=555.3, RT=2.73 min.

Quellen und Nachweise

ORD-Eintrag
ord-b4bbc4e4a63a4963a425d2c3d5817796
Quelldatensatz
uspto-grants-2010_11
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US07838524B2

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