Potassium Carbonate → 4-Cyano-2-{5-[4-(6-(2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 71978Notes

Reaction equation

HRID 71978 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37](=[O:68])[NH:38][CH:39]([C:43]([N:45]1[CH:51]([C:52]2[NH:53][C:54]([C:57]3[CH:66]=[CH:65][C:64]4[C:59](=[CH:60][CH:61]=[C:62](Br)[CH:63]=4)[CH:58]=3)=[CH:55][N:56]=2)[CH2:50][C:47]2([CH2:49][CH2:48]2)[CH2:46]1)=[O:44])[CH:40]([CH3:42])[CH3:41].C([O-])([O-])=O.[K+].[K+]>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:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:62]3[CH:61]=[CH:60][C:59]4[C:64](=[CH:65][CH:66]=[C:57]([C:54]5[NH:53][C:52]([CH:51]6[CH2:50][C:47]7([CH2:48][CH2:49]7)[CH2:46][N:45]6[C:43](=[O:44])[CH:39]([NH:38][C:37]([O:36][CH3:35])=[O:68])[CH:40]([CH3:42])[CH3:41])=[N:56][CH:55]=5)[CH:58]=4)[CH:63]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 66620764(1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterHCID 666208224-Cyano-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 666209444-Cyano-2-{5-[4-(6-(2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl esterYield 68.4%

Reagents, catalysts & solvents 1

HCID 178418397HCID 178418397, compoundCatalyst

Procedure

4-Cyano-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.990 g, 2.13 mmol), (1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1.007 g, 1.92 mmol), Pd(PPh3)4 (222 mg, 0.192 mmol) and K2CO3 (2.0 M in H2O, 2.1 mL, 4.2 mmol) were combined in 1,2-dimethoxymethane. The mixture was degassed for 10 min with bubbling N2 then heated to reflux for 4 h then cooled. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine before being dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (EtOAc, then 2% MeOH/DCM, then 4% MeOH/DCM) to provide the title compound (1.028 g, 68%).

Workup

  1. customThe mixture was degassed for 10 min with bubbling N2
  2. temperaturethen heated
  3. temperatureto reflux for 4 h
  4. temperaturethen cooled
  5. additionThe reaction mixture was diluted with EtOAc
  6. washwashed with saturated aqueous NaHCO3 and brine
  7. dry with materialbefore being dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude residue was purified by silica column chromatography (EtOAc

Sources & evidence

ORD record
ord-dd174fb7a627453c8224200bec2df7be
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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