Sodium Bicarbonate → 8-tert-butyl 3-ethyl 2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-2,8-diazaspiro[4.5]decane-3,8-dicarboxylate

HRID 445230Notes

Reaction equation

HRID 445230 reaction equation
[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH2:23]1[C:27]2([CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)[CH2:26][CH:25]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[NH:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.CN(C)C=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:24]2[CH:25]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:26][C:27]3([CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]3)[CH2:23]2)=[CH:21][CH:22]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1

Participants

7

Reactant 4

HCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 497612358-Tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylateHCID 866644634-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzaldehyde

Product 1

HCID 672888618-tert-butyl 3-ethyl 2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-2,8-diazaspiro[4.5]decane-3,8-dicarboxylateYield 60.8%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6228DimethylformamideSolvent

Procedure

Under an argon atmosphere, 4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzaldehyde (International Publication WO 2007/058322 pamphlet, Example 28; 21.0 g) and 8-tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate (JP 2004-002470, Example 21f; 21.2 g) were dissolved in acetic acid (4.5 mL) and anhydrous N,N-dimethylformamide (225 mL), followed by stirring at room temperature for 10 minutes. To this solution, sodium triacetoxyborohydride (17.3 g) was added. The reaction solution was stirred at room temperature for 3 hours. To the reaction solution, an aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (300 mL) and the solution was heated at reflux for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography (CHROMATOREX NH (trade name), manufactured by Fuji Silysia Chemical Ltd.) (n-hexane:ethyl acetate=1:1→1:2→0:1→ethyl acetate:ethanol=19:1→9:1) to obtain the title compound (24.4 g) having the following physical properties.

Workup

  1. stirringThe reaction solution was stirred at room temperature for 3 hours
  2. extractionfollowed by extraction with ethyl acetate
  3. washThe organic layer was washed with saturated brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. dissolutionThe residue was dissolved in ethanol (300 mL)
  7. temperaturethe solution was heated
  8. temperatureat reflux for 2 hours
  9. concentrationThe reaction solution was concentrated under reduced pressure
  10. customthe residue was purified by silica gel chromatography (CHROMATOREX NH (trade name), manufactured by Fuji Silysia Chemical Ltd.) (n-hexane:ethyl acetate=1:1→1:2→0:1→ethyl acetate:ethanol=19:1→9:1)

Sources & evidence

ORD record
ord-bbee2f52b02047d8acb1ca995d33475b
Source dataset
uspto-grants-2013_07
Patent number
US08476290B2

Reaction notes

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