Nitrogen → 3-{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]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

HRID 417749Notes

Reaction equation

HRID 417749 reaction equation
[CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28](Br)[CH:29]=4)[CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:35]([O:39][C:40]([N:42]1[CH:47]([C:48]2[NH:49][C:50]([C:53]3[CH:58]=[CH:57][C:56](B4OC(C)(C)C(C)(C)O4)=[CH:55][CH:54]=3)=[CH:51][N:52]=2)[CH:46]2[CH2:68][CH:43]1[CH2:44][CH2:45]2)=[O:41])([CH3:38])([CH3:37])[CH3:36].C([O-])(O)=O.[Na+].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:35]([O:39][C:40]([N:42]1[CH:47]([C:48]2[NH:49][C:50]([C:53]3[CH:58]=[CH:57][C:56]([C:28]4[CH:27]=[CH:26][C:25]5[C:30](=[CH:31][CH:32]=[C:23]([C:20]6[NH:19][C:18]([CH:17]7[CH2:16][C:13]8([CH2:15][CH2:14]8)[CH2:12][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:34])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=6)[CH:24]=5)[CH:29]=4)=[CH:55][CH:54]=3)=[CH:51][N:52]=2)[CH:46]2[CH2:68][CH:43]1[CH2:44][CH2:45]2)=[O:41])([CH3:38])([CH3:36])[CH3:37]

Participants

7

Reactant 4

HCID 947NitrogenHCID 516892Sodium BicarbonateHCID 666205563-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterHCID 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 ester

Product 1

HCID 666207943-{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]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterYield 56.3%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

A solution of (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 (1.00 g, 1.9 mmol), 3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.31 g, 2.8 mmol) and aq NaHCO3 (7.6 mL of a 1M solution, 7.6 mmol) in DME (20 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (110 mg, 0.095 mmol) and then the reaction was heated to 80° C. overnight. After cooling to room temperature, the solvent was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate. The organic phase was washed with H2O and then brine then dried over sodium sulfate. After filtration the solvent was removed from the filtrate under reduced pressure. The crude material was purified by silica gel chromatography (70-100% EtOAc/Hexanes) to afford 3-{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}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (835 mg, 1.07 mmol, 56% yield).

Workup

  1. temperatureAfter cooling to room temperature
  2. customthe solvent was removed under reduced pressure
  3. dissolutionthe resulting residue was dissolved in ethyl acetate
  4. washThe organic phase was washed with H2O
  5. dry with materialbrine then dried over sodium sulfate
  6. filtrationAfter filtration the solvent
  7. customwas removed from the filtrate under reduced pressure
  8. customThe crude material was purified by silica gel chromatography (70-100% EtOAc/Hexanes)

Sources & evidence

ORD record
ord-0f05e3a174914edc9fc28bf12bcb092b
Source dataset
uspto-grants-2012_01
Patent number
US08088368B2

Reaction notes

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