2-Hydroxyisobutyric acid → 2-methyl-1-(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1-piperidinyl)-1-oxo-2-propanol

HRID 1992062Notes

Reaction equation

HRID 1992062 reaction equation
[OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:20][C:21]1[N:25]([CH:26]2[CH2:32][CH:31]3[N:33]([CH2:34][CH2:35][C:36]4([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH:28]([CH2:29][CH2:30]3)[CH2:27]2)[C:24]2[CH:48]=[CH:49][CH:50]=[CH:51][C:23]=2[N:22]=1.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:6][C:2]([OH:1])([CH3:7])[C:3]([N:39]1[CH2:38][CH2:37][C:36]([CH2:35][CH2:34][N:33]2[CH:28]3[CH2:29][CH2:30][CH:31]2[CH2:32][CH:26]([N:25]2[C:24]4[CH:48]=[CH:49][CH:50]=[CH:51][C:23]=4[N:22]=[C:21]2[CH3:20])[CH2:27]3)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:41][CH2:40]1)=[O:4]

Participants

6

Reactant 4

HCID 116712-Hydroxyisobutyric acidHCID 682631,1'-CarbonyldiimidazoleHCID 516892Sodium BicarbonateHCID 587278272-Methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole

Product 1

HCID 686780722-methyl-1-(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1-piperidinyl)-1-oxo-2-propanolYield 38.4%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

2-hydroxy-2-methylpropanoic acid (36 mg, 0.35 mmole) was dissolved in 0.92 ml of 1,2-dichloroethane. To this was added 1,1′-carbonyldiimidazole (37 mg, 0.23 mmole) and shaken for 30 min. 2-Methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole (50 mg, 0.12 mmole) was added as a dry powder and shaking was resumed overnight. 1 ml of NaHCO3 sat. was added to the reaction mixture and shaken, followed by filtration through a hydrophobic frit and concentrated to an oil. The oil was separated on silica using gradient flash chromatography (0-8% MeOH in CHCl3) to afford 2-methyl-1-(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1-piperidinyl)-1-oxo-2-propanol 20 23.7 mg (38%) as a white glassy solid. 1H NMR (300 MHz, CDCl3) δ 7.7-7.6 (m, 1H), 7.1-7.4 (m, 8H), 4.7 (s, 1H), 4.0 (s, 2H), 3.2-3.4 (m, 4H), 2.6 (s, 3H), 2.2-2.5 (m, 5H), 2.1-1.7 (m, 11H), 1.7-1.5 (m, 2H).

Workup

  1. stirringshaking
  2. waitwas resumed overnight
  3. stirringshaken
  4. filtrationfollowed by filtration through a hydrophobic frit
  5. concentrationconcentrated to an oil
  6. customThe oil was separated on silica using gradient flash chromatography (0-8% MeOH in CHCl3)

Sources & evidence

ORD record
ord-d93eaa2e94504327834b76e7abbce81a
Source dataset
uspto-grants-2010_01
Patent number
US07645771B2

Reaction notes

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