Diisopropylethylamine → 1-[5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(4-triisopropylsilanyloxymethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

HRID 711159Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 711159
[CH:1]([Si:4]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:17]3[CH:18]=[C:19]([O:22][C@H:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C@@H:26]([NH2:33])[CH2:25][CH2:24]4)[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH2:9][CH2:8]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:43][C:44](=O)[NH:45][C:46]1[N:47]([C:55]2[CH:60]=[CH:59][C:58]([O:61][Si:62]([CH:69]([CH3:71])[CH3:70])([CH:66]([CH3:68])[CH3:67])[CH:63]([CH3:65])[CH3:64])=[C:57]([Cl:72])[CH:56]=2)[N:48]=[C:49]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:50]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:51]([C:49]1[CH:50]=[C:46]([NH:45][C:44]([NH:33][C@@H:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:23]([O:22][C:19]3[CH:20]=[CH:21][C:16]4[N:17]([C:13]([N:10]5[CH2:11][CH2:12][CH:7]([CH2:6][O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:34]([CH3:36])[CH3:35])[CH:37]([CH3:39])[CH3:38])[CH2:8][CH2:9]5)=[N:14][N:15]=4)[CH:18]=3)[CH2:24][CH2:25]2)=[O:43])[N:47]([C:55]2[CH:60]=[CH:59][C:58]([O:61][Si:62]([CH:66]([CH3:68])[CH3:67])([CH:69]([CH3:70])[CH3:71])[CH:63]([CH3:65])[CH3:64])=[C:57]([Cl:72])[CH:56]=2)[N:48]=1)([CH3:54])([CH3:53])[CH3:52]

Komponenten

5

Edukt 3

HCID 81531DiisopropylethylamineHCID 86687046(1S,4R)-4-[3-(4-Triisopropylsilanyloxymethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamineHCID 123455231[5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester

Produkt 1

HCID 1317339801-[5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(4-triisopropylsilanyloxymethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 312751,4-DioxaneLösungsmittel

Versuchsvorschrift

A solution of Intermediate G (153 mg, 0.28 mmol) and [5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (WO2011/154734A1, which is incorporated herein by reference, 167 mg, 0.28 mmol) in 1,4-dioxane (4 mL) and DIPEA (87 μL, 0.50 mmol) was stirred at 95° C. for 4 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-7.5% MeOH in DCM, to give 1-[5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(4-triisopropylsilanyloxymethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea (193 mg). This was dissolved in THF (3 mL) and treated with TBAF (1M in THF, 0.47 mL, 0.47 mmol). The solution was stirred at RT for 1.75 h, then diluted with water and extracted with DCM (3×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-25% [2M NH3 in MeOH] in DCM, to give the product. This was further purified by HPLC (C18 X-select column, 30-98% MeCN in H2O, 0.1% HCO2H) to give the title compound (72 mg, 56%). LCMS (Method 5): Rt 3.99 min, m/z 685 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.38-1.52 (2H, m), 1.55-1.66 (1H, m), 1.73-1.96 (4H, m), 1.98-2.17 (2H, m), 2.85-2.97 (2H, m), 3.3-3.5 (4H, m, under water signal), 4.52 (1H, br s), 4.77-4.85 (1H, m), 5.55 (1H, br t, J=4.4 Hz), 6.28 (1H, s), 7.05 (1H, s), 7.08 (1H, s), 7.15 (1H, dd, J=2.0, 9.8 Hz), 7.23-7.40 (5H, m), 7.44 (1H, d, J=2.5 Hz), 7.61 (1H, d, J=9.9 Hz), 7.64 (1H, br d, J=1.5 Hz), 8.02 (1H, br s), 10.55 (1H, br s).

Aufarbeitung

  1. concentrationThe cooled mixture was concentrated in vacuo
  2. customThe residue was purified by FCC

Quellen und Nachweise

ORD-Eintrag
ord-974f90daf4984ad6ad5039cb62da063f
Quelldatensatz
uspto-grants-2015_11
Patentnummer
US09181242B2

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