Triethylamine → HCID 178502196, compound

HRID 2039061Notes

Reaction equation

[CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:13][CH:12]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=2)[N:26]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:35][O:36][C:37](=[O:63])[NH:38][CH:39]([C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:51][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[CH:62])=[CH:57][CH:56]=2)=[CH:53][N:54]=1)=[O:44])[CH:40]([CH3:42])[CH3:41].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C>[CH3:35][O:36][C:37](=[O:63])[NH:38][CH:39]([C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:51][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:30]3[CH:31]=[CH:32][C:27]([C:25]4[N:26]=[C:22]([CH:12]5[CH2:13][N:14]([CH2:17][C:18]([F:21])([F:19])[F:20])[CH2:15][CH2:16][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:34])[CH:6]([CH3:8])[CH3:7])[NH:23][CH:24]=4)=[CH:28][CH:29]=3)=[CH:57][CH:56]=2)=[CH:53][N:54]=1)=[O:44])[CH:40]([CH3:42])[CH3:41]

Participants

Conditions

Temperature: 80 °C

Procedure

{1-[2-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2,2,2-trifluoro-ethyl)-piperazine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (98.7 mg, 0.181 mmol) was combined with (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (71.2 mg, 0.181 mmol) and Pd(PPh3)4 (21.5 mg, 0.018 mmol) under an argon atmosphere. DMF (degassed with Argon) was added followed by triethylamine (181 mg, 1.8 mmol) and copper(I) iodide (3.5 mg, 0.018 mmol). The mixture was heated at 80° C. After 20 minutes, volatiles were removed in vacuo and the crude material was semi-purified via chromatography on silica gel (eluent EtOAc w MeOH 10%/hexanes) and further purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product [1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-(2,2,2-trifluoro-ethyl)-piperazin-2-yl]-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (12.4 mg): LCMS-ESI+: calc'd for C44H52F3N9O6: 859.9 (M+); Found: 860.5 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.91-7.68 (m, 10H), 6.06 (m, 2H), 5.24 (m, 1H), 4.43 (m, 1H), 4.23 (d, J=7.8 Hz, 1H), 4.11 (m, 1H), 3.85 (m, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.49-3.45 (m, 2H), 3.15-3.02 (m, 3H), 2.77 (m, 1H), 2.58 (m, 1H), 2.29-2.01 (m, 5H), 1.07-0.83 (m, 12H).

Workup

customvolatiles were removed in vacuo
customfurther purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA)

Sources & evidence

ORD record: ord-d397a58a002949308cc82830be15507f
Source dataset: uspto-grants-2013_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08575118B2

Reaction notes

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