Lithium hydroxide, monohydrate → N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboxamide

HRID 1992088Notes

Reaction equation

HRID 1992088 reaction equation
[C:1]([N:3]=[C:4]([N:12]1[CH2:17][CH2:16][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[O:5]C1C=CC=CC=1)#[N:2].C1COCC1.O.O.[OH-].[Li+].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([NH:3][C:4]([N:12]1[CH2:13][CH2:14][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][CH2:17]1)=[O:5])#[N:2]

Participants

6

Reactant 4

HCID 168937Lithium hydroxide, monohydrateHCID 516892Sodium BicarbonateHCID 21881883Oxolane--water (1/1)HCID 58728442Phenyl N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboximidoate

Product 1

HCID 58727860N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboxamideYield 85.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a precooled (0° C.) solution of phenyl N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboximidoate (27 mg, 0.047 mmol) in a mixed solvent of THF-H2O (2 mL, 3:1) was added lithium hydroxide monohydrate (7.7 mg, 0.18 mmol). After stirring for 3 hours on an ice-water bath, the reaction mixture was diluted with dichloromethane (20 mL) and buffered with saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (3×10 mL). The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After evaporation of solvents, the residue was purified by flash chromatography on silical gel, eluting with a gradient of 10-30% methanol in ethyl acetate to afford N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboxamide as a white solid (20 mg, 83%). 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=7.1 Hz, 1H), 7.33-7.29 (m, 5H), 7.17-7.14 (m, 1H), 7.11-7.04 (m, 2H), 4.53-4.48 (m, 1H), 4.09 (br, 1H), 3.55-3.51 (m, 2H), 3.21 (br, 2H), 3.06-3.03 (m, 2H), 2.45 (s, 3H), 2.37-2.29 (m, 2H), 1.87-1.64 (m, 10H), 1.59-1.55 (m, 4H). 13C NMR (125 MHz, DMSO-d6) δ 165.0, 152.3, 146.7, 143.7, 134.0, 128.9, 127.3, 126.2, 125.0, 121.8, 121.4, 119.4, 111.6, 57.2, 55.6, 49.3, 48.0, 46.3, 36.3, 35.9, 30.0, 21.8, 14.9. HRMS m/z (M+H)+ calcd: 497.3029, obsd: 497.3026.

Workup

  1. extractionThe aqueous phase was extracted with dichloromethane (3×10 mL)
  2. washThe combined extracts were washed with brine
  3. dry with materialdried over anhydrous sodium sulfate
  4. customAfter evaporation of solvents
  5. customthe residue was purified by flash chromatography on silical gel
  6. washeluting with a gradient of 10-30% methanol in ethyl acetate

Sources & evidence

ORD record
ord-4f9a6f8e1ce0423da10bab941701587f
Source dataset
uspto-grants-2010_01
Patent number
US07645771B2

Reaction notes

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