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 60640Notes

Reaction equation

HRID 60640 reaction equation
[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]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 86687046HCID 86687046, compoundHCID 123455231[5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester

Product 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

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

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).

Workup

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

Sources & evidence

ORD record
ord-caebdb249af74a05bde500337d96699d
Source dataset
uspto-grants-2016_09
Patent number
US09440974B2

Reaction notes

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