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 60640ノート

反応式

HRID 60640 の反応式
[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]

参加物

5

反応物 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

生成物 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

試薬・触媒・溶媒 1

HCID 312751,4-Dioxane溶媒

実験手順

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 (11H, 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).

後処理

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

出典と根拠

ORDレコード
ord-caebdb249af74a05bde500337d96699d
出典データセット
uspto-grants-2016_09
特許番号
US09440974B2

反応ノート

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