Triethylamine → (4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)(phenyl)acetic acid

HRID 1992083Notes

Reaction equation

HRID 1992083 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.O.[C:43]([OH:47])(=[O:46])[CH:44]=O.[C:48]1(B(O)O)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1COCC1>[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]([CH:44]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)[C:43]([OH:47])=[O:46])[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 66827Phenylboronic AcidHCID 15620607Glyoxylic acid, monohydrateHCID 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 56674000(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)(phenyl)acetic acidYield 78.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

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 THF (3 mL) was added triethyl amine (14 μL), glyoxylic acid monohydrate (4.6 mg, 0.05 mmol) and phenyl boronic acid (6.1 mg, 0.05 mmol). The resulting mixture was then purged with nitrogen and sealed. After being heated to 60° C. for 3 hours, the solvent was evaporated and the residue was purified by flash chromatography on silical gel, eluting with a gradient of 10-80% methanol in ethyl acetate to afford (4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)(phenyl)acetic acid (22 mg, 76%). 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.53-7.48 (m, 3H), 7.36-7.34 (m, 8H), 7.24-7.23 (m, 1H), 7.17-7.09 (m, 2H), 4.58-4.45 (m, 1H), 4.20 (s, 1H), 3.24-3.21 (m, 2H), 3.08 (br, 1H), 2.82-2.65 (m, 2H), 2.82-2.65 (m, 2H), 2.44 (s, 3H), 2.39-2.05 (m, 7H), 1.83-1.68 (m, 8H), 1.59 (d, J=7.6 Hz, 2H). HRMS m/z (M+H)+ calcd: 563.3386, obsd: 563.3390.

Workup

  1. customThe resulting mixture was then purged with nitrogen
  2. customsealed
  3. customthe solvent was evaporated
  4. customthe residue was purified by flash chromatography on silical gel
  5. washeluting with a gradient of 10-80% methanol in ethyl acetate

Sources & evidence

ORD record
ord-0808093534524e9db466ac2bc8da1190
Source dataset
uspto-grants-2010_01
Patent number
US07645771B2

Reaction notes

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