Nitrogen → [1-(2-{[(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester

HRID 79676Notes

Reaction equation

HRID 79676 reaction equation
[CH3:1][O:2][C:3](=[O:27])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][NH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:28][O:29][C:30](=[O:63])[NH:31][CH:32]([C:36]([N:38]1[CH2:42][CH2:41][CH2:40][CH:39]1[C:43]1[NH:44][C:45]([C:48]2[CH:53]=[CH:52][C:51](B3OC(C)(C)C(C)(C)O3)=[CH:50][CH:49]=2)=[CH:46][N:47]=1)=[O:37])[CH:33]([CH3:35])[CH3:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>COCCOC.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>[CH3:1][O:2][C:3](=[O:27])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][NH:17][C:18]([C:19]1[CH:24]=[CH:23][C:22]([C:51]2[CH:52]=[CH:53][C:48]([C:45]3[NH:44][C:43]([CH:39]4[CH2:40][CH2:41][CH2:42][N:38]4[C:36](=[O:37])[CH:32]([NH:31][C:30]([O:29][CH3:28])=[O:63])[CH:33]([CH3:35])[CH3:34])=[N:47][CH:46]=3)=[CH:49][CH:50]=2)=[CH:21][CH:20]=1)=[O:26])=[O:10])[CH:6]([CH3:8])[CH3:7]

Participants

7

Reactant 4

HCID 947NitrogenHCID 62657Potassium Phosphate, TribasicHCID 66619939[2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl esterHCID 66620367(1-{2-[(4-Bromo-benzoylamino)-methyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

Product 1

HCID 66620842[1-(2-{[(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl esterYield 15%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

A solution of (1-{2-[(4-bromo-benzoylamino)-methyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (104 mg, 0.24 mmol), [2-methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (117 mg, 0.24 mmol) and aq K3PO4 (480 μl of a 2M solution, 0.96 mmol) in DME (3 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (13.9 mg, 0.012 mmol) then the reaction was heated to 80° C. overnight. After cooling to room temperature, the reaction was concentrated and purified by reverse phase preparative HPLC (15-60% MeCN—H2O; 0.1% formic acid modifier) to afford [1-(2-{[(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (26 mg, 0.036 mmol, 15% yield). 1H-NMR: 400 MHz, (DMSO-d6) δ: 11.8 (s, 1H), 8.61 (m, 1H), 7.94-7.73 (m, 9H), 7.34 (d, 1H), 7.29 (d, 1H), 5.08 (m, 1H), 4.23 (t, 1H), 4.30 (m, 1H), 4.07 (t, 1H), 4.01 (t, 1H), 4.07-4.01 (m, 1H), 3.18 (m, 2H), 3.73-3.70 (m, 1H), 3.61 (m, 1H), 3.63 (s, 3H), 3.61 (s, 3H), 2.16-1.81 (m, 10H), 0.90-0.84 (m, 12H). LCMS-ESI+: calc'd for C39H52N7O7: 730.4 (M+H+). Found: 730.1 (M+H+).

Workup

  1. temperatureAfter cooling to room temperature
  2. concentrationthe reaction was concentrated
  3. custompurified by reverse phase preparative HPLC (15-60% MeCN—H2O; 0.1% formic acid modifier)

Sources & evidence

ORD record
ord-4e296030662d415eaf6eb23cee69bcba
Source dataset
uspto-grants-2014_09
Patent number
US08841278B2

Reaction notes

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