Triethylamine → [1-(4-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-5,5-dimethyl-thiazolidine-3-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester

HRID 71888Notes

Reaction equation

HRID 71888 reaction equation
[CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[C:14]([CH3:29])([CH3:28])[S:13][CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:31][O:32][C:33](=[O:59])[NH:34][CH:35]([C:39]([N:41]1[CH2:45][CH2:44][CH2:43][CH:42]1[C:46]1[NH:47][C:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57]#[CH:58])=[CH:53][CH:52]=2)=[CH:49][N:50]=1)=[O:40])[CH:36]([CH3:38])[CH3:37].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:58]#[C:57][C:54]4[CH:55]=[CH:56][C:51]([C:48]5[NH:47][C:46]([CH:42]6[CH2:43][CH2:44][CH2:45][N:41]6[C:39](=[O:40])[CH:35]([NH:34][C:33]([O:32][CH3:31])=[O:59])[CH:36]([CH3:38])[CH3:37])=[N:50][CH:49]=5)=[CH:52][CH:53]=4)=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[C:14]([CH3:29])([CH3:28])[S:13][CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]

Participants

7

Reactant 3

HCID 8471TriethylamineHCID 66621028(1-{4-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5,5-dimethyl-thiazolidine-3-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterHCID 72338228(1-{2-[4-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

Product 1

HCID 66621121[1-(4-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-5,5-dimethyl-thiazolidine-3-carbonyl)-2-methyl-propyl]-carbamic acid methyl esterYield 23.8%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

(1-{4-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5,5-dimethyl-thiazolidine-3-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (83 mg, 0.167 mmol) was combined with (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (66.0 mg, 0.167 mmol) and PdCl2(PPh3)2 (11.7 mg, 0.017 mmol) under an argon atmosphere. DMF (2.0 mL degassed with Argon) was added followed by triethylamine (168 mg, 1.67 mmol) and copper(I) iodide (3.2 mg, 0.017 mmol). The mixture was heated at 80° C. After 20 hours, 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-(4-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-5,5-dimethyl-thiazolidine-3-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (32.1 mg) as a TFA salt.

Workup

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

Sources & evidence

ORD record
ord-bba0f4f7efd04a16af6ae62c25d3b268
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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