Triethylamine → 2-methyl-1-(8-{2-[4-phenyl-1-(1,3-thiazol-2-ylmethyl)piperidin-4-yl]ethyl}-8-azabicyclo-[3.2.1]oct-3-yl)-1H-benzimidazole

HRID 1992082Notes

Reaction equation

HRID 1992082 reaction equation
Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.C(N(CC)CC)C.[S:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH:47]=O.O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+]>ClCCCl>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([CH2:47][C:43]5[S:42][CH:46]=[CH:45][N:44]=5)[CH2:23][CH2:24]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 27349031,3-Thiazole-2-carbaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 686757782-methyl-1-{8-[2-(4-phenyl piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride

Product 1

HCID 686768082-methyl-1-(8-{2-[4-phenyl-1-(1,3-thiazol-2-ylmethyl)piperidin-4-yl]ethyl}-8-azabicyclo-[3.2.1]oct-3-yl)-1H-benzimidazoleYield 87.5%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) in 1,2-dichloroethane (1 mL) was added triethylamine (14 μL, 0.1 mmol), 2-thiazole-carboxaldehyde (6.6 mg, 0.05 mmol) and sodium triacetoxylborohydride (10.6 mg, 0.05 mmol). The resulting mixture was stirred for 4 hours at ambient temperature before it was quenched with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (2×10 mL). The combined extracts was washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvents, the residue was brought to a flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford 2-methyl-1-(8-{2-[4-phenyl-1-(1,3-thiazol-2-ylmethyl)piperidin-4-yl]ethyl}-8-azabicyclo-[3.2.1]oct-3-yl)-1H-benzimidazole (23 mg, 87%). 1H NMR (300 MHz, CDCl3) δ 7.79-7.65 (m, 2H), 7.46-7.37 (m, 2H), 7.34-7.15 (m, 7H), 5.32 (br, 1H), 3.68 (s, 2H), 3.54 (br, 2H), 2.82-2.80 (m, 2H), 2.67 (s, 3H), 2.63-2.47 (m, 4H), 2.25 (br, 4H), 2.08-1.96 (m, 8H), 1.86 (br, 2H). HRMS m/z (M+H)+ calcd: 526.3004, obsd: 526.3008.

Workup

  1. customwas quenched with saturated sodium bicarbonate solution
  2. extractionThe aqueous phase was extracted with ethyl acetate (2×10 mL)
  3. washThe combined extracts was washed with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. customAfter evaporation of the solvents
  6. washeluting with a gradient of 0-10% methanol in ethyl acetate

Sources & evidence

ORD record
ord-e8f0f8fca72a46fbaa0a2b0d9a1f84d9
Source dataset
uspto-grants-2010_01
Patent number
US07645771B2

Reaction notes

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