Nitrogen → 3-{5-[4-(6-[2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

HRID 79871Notes

Reaction equation

HRID 79871 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]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26](B4OC(C)(C)C(C)(C)O4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:41]([O:45][C:46]([N:48]1[CH:53]([C:54]2[NH:55][C:56]([C:59]3[CH:64]=[CH:63][C:62](Br)=[CH:61][CH:60]=3)=[CH:57][N:58]=2)[CH:52]2[CH2:66][CH:49]1[CH2:50][CH2:51]2)=[O:47])([CH3:44])([CH3:43])[CH3:42].C([O-])([O-])=O.[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>[C:41]([O:45][C:46]([N:48]1[CH:53]([C:54]2[NH:55][C:56]([C:59]3[CH:64]=[CH:63][C:62]([C:26]4[CH:25]=[CH:24][C:23]5[C:28](=[CH:29][CH:30]=[C:21]([C:18]6[NH:17][C:16]([CH:12]7[CH2:13][CH2:14][CH2:15][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:40])[CH:6]([CH3:7])[CH3:8])=[N:20][CH:19]=6)[CH:22]=5)[CH:27]=4)=[CH:61][CH:60]=3)=[CH:57][N:58]=2)[CH:52]2[CH2:66][CH:49]1[CH2:50][CH2:51]2)=[O:47])([CH3:44])([CH3:42])[CH3:43]

Participants

7

Reactant 4

HCID 947NitrogenHCID 11430Potassium CarbonateHCID 596109073-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterHCID 66620765[2-Methyl-1-(2-{4-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester

Product 1

HCID 666214363-{5-[4-(6-[2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterYield 16.3%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

A solution of [2-Methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (500 mg, 0.92 mmol), 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (383 mg, 0.92 mmol) and aq K2CO3 (920 μl of a 2M solution, 1.84 mmol) in DME (9 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (106 mg, 0.092 mmol) and PdCl2dppf (75 mg, 0.092 mmol) and then the reaction was heated to 80° C. overnight. After cooling to room temperature, the reaction was quenched with acetic acid, filtered, and then concentrated. The crude product was purified by reverse phase preparative HPLC (5-50% MeCN—H2O; 0.1% formic acid modifier) to afford 3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (112 mg, 0.15 mmol, 16% yield). LCMS-ESI+: calc'd for C44H52N7O5: 758.4 (M+H+). Found: 758.0 (M+H+).

Workup

  1. temperatureAfter cooling to room temperature
  2. customthe reaction was quenched with acetic acid
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe crude product was purified by reverse phase preparative HPLC (5-50% MeCN—H2O; 0.1% formic acid modifier)

Sources & evidence

ORD record
ord-7c2f5b5bfaa14485b48300bfdec313e1
Source dataset
uspto-grants-2014_09
Patent number
US08841278B2

Reaction notes

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