Potassium Carbonate → {1-[2-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-[1,1'; 4',1'']terphenyl-3''-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester

HRID 71852Notes

Reaction equation

HRID 71852 reaction equation
[CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:39])[NH:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:41][O:42][C:43](=[O:68])[NH:44][CH:45]([C:49]([N:51]1[CH2:55][CH2:54][CH2:53][CH:52]1[C:56]1[NH:57][C:58]([C:61]2[CH:66]=[CH:65][C:64](Br)=[CH:63][CH:62]=2)=[CH:59][N:60]=1)=[O:50])[CH:46]([CH3:48])[CH3:47].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>[CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:39])[NH:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]=[CH:26][C:27]([C:64]3[CH:65]=[CH:66][C:61]([C:58]4[NH:57][C:56]([CH:52]5[CH2:53][CH2:54][CH2:55][N:51]5[C:49](=[O:50])[CH:45]([NH:44][C:43]([O:42][CH3:41])=[O:68])[CH:46]([CH3:48])[CH3:47])=[N:60][CH:59]=4)=[CH:62][CH:63]=3)=[CH:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 66620141Methyl (1-(2-(4-(4-bromophenyl)-1H-imidazol-2-YL)pyrrolidin-1-YL)-3-methyl-1-oxobutan-2-YL)carbamateHCID 66620539HCID 66620539, compound

Product 1

HCID 66620360{1-[2-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-[1,1'; 4',1'']terphenyl-3''-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl esterYield 5.1%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

(2-Methyl-1-{2-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-3-ylcarbamoyl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (135 mg, 0.246 mmol), (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (110 mg, 0.246 mmol), Pd(PPh3)4 (14 mg, 0.0123 mmol) and a 2 M aqueous solution of potassium carbonate (0.246 mL, 0.492 mmol) were degassed in 1,2-dimethoxyethane (2.5 mL) for 13 min. The stirred suspension was heated to 85° C. for 3 hours then concentrated, brought up in DMF/water and purified by reverse phase preparative HPLC to provide {1-[2-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-[1,1′;4′,1″]terphenyl-3″-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (10 mg, 5%). (MeOH-d4, 400 MHz) 7.90 (s, 1H), 7.82-7.66 (m, 8H), 7.54-7.51 (m, 1H), 7.40-7.37 (m, 2H), 4.59 (m, 1H), 4.24 (m, 1H), 4.02-3.73 (m, 4H), 3.66 (s, 3H), 3.65 (s, 3H), 2.36-2.02 (m, 10H), 1.15-0.88 (m, 12H); MS (ESI) m/z 792 [M+H]+.

Workup

  1. concentrationthen concentrated
  2. custompurified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-d1dfce6d278d43729dbe2f796a239275
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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