1,2-Dimethoxyethane → 6-[5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester

HRID 71742Notes

Reaction equation

[CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]3[NH:16][C:17]([C:20]4[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=4)=[CH:18][N:19]=3)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4].[CH3:27][O:28][C:29](=[O:62])[NH:30][CH:31]([C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42]1[NH:43][C:44]([C:47]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][CH:48]=2)=[CH:45][N:46]=1)=[O:36])[CH:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].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.O>[CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]3[NH:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:50]5[CH:51]=[CH:52][C:47]([C:44]6[NH:43][C:42]([CH:38]7[CH2:39][CH2:40][CH2:41][N:37]7[C:35](=[O:36])[CH:31]([NH:30][C:29]([O:28][CH3:27])=[O:62])[CH:32]([CH3:34])[CH3:33])=[N:46][CH:45]=6)=[CH:48][CH:49]=5)=[CH:22][CH:21]=4)=[CH:18][N:19]=3)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4]

Participants

Conditions

Temperature: 120 °C

Procedure

A mixture of 6-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (65 mg, 0.15 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 (77 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol), potassium carbonate (42.8 mg, 0.31 mmol), 1,2-dimethoxyethane (4 mL) and water (1 mL) was heated in a microwave reactor at 120° C. for 20 minutes. The mixture was cooled and all volatiles were removed under reduced pressure. The resulting residue was taken up in dimethylformamide (2 mL) and subjected to reverse phase chromatography with an eluent of 0.1% TFA in water and 0.1% TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization to provide 6-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (16.8 mg, 0.024 mmol, 15%). C38H44BrN8O6 calculated 708.3 observed [M+1]+ 709.4; rt=1.39 min. 1H (DMSO-d6): δ=8.10 (s, 2H), 7.89 (m, 7H), 7.33 (d, J=9 Hz, 1H), 5.03 (t, J=7.8 Hz, 1H), 5.12 (m, 1H), 4.30 (m, 1H), 4.23 (m, 1H), 4.11 (t, J=8.1 Hz, 1H), 3.99 (m, 2H), 3.83 (m, 1H), 3.67 (s, 3H), 3.54 (m, 3H), 2.90 (m, 1H), 2.41 (m, 1H), 2.18 (m, 2H), 2.01 (m, 4H), 1.67 (m, 1H), 0.82 (m, 6H).

Workup

temperatureThe mixture was cooled
customall volatiles were removed under reduced pressure
customthe solvent was removed by lyophilization

Sources & evidence

ORD record: ord-fce84a0c3ca34409bd110d642fbb075a
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08822430B2

Reaction notes

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