[O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.[CH3:36][CH:37]1[CH:42]([NH2:43])[CH:41]2[CH2:44][CH2:45][N:38]1[CH2:39][CH2:40]2.[OH-].[Na+]>C1COCC1>[CH3:36][CH:37]1[CH:42]([NH:43][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)[CH:41]2[CH2:44][CH2:45][N:38]1[CH2:39][CH2:40]2TEA (0.32 mL, 2.3 mmol, 1 eq) is added to a solution of 4-phenoxybenzoic acid 0.50 g, 2.3 mmol, 1 eq) in 15 mL THF. Diphenylchlorophosphate (0.44 mL, 2.3 mmol, 1 eq) is added and the mixture is stirred at room temperature. After 0.5 h, a suspension of 2-methylquinuclidin-3-amine dihydrochloride from Step N (0.49 g, 2.3 mmol, 1 eq) and TEA (1.30 mL, 9.2 mmol, 4 eq) in THF is added and the resulting mixture is stirred overnight at room temperature. 1N NaOH is added and the aqueous layer is extracted with CHCl3. The combined organic layers are dried over MgSO4, filtered and concentrated to provide 0.64 g (82%) of N-(2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-4-phenoxybenzamide. MS (ESI) for C21H24N2O2 m/z 337.3 (M+H)+. The fumaric acid salt of the product is made and crystallized from IPA to give the product as a white solid. Reverse phase HPLC (ZORBAX Eclipse XDB-C8, 4.6 mm×15 cm, 75:5:20 H2O/CH3CN/IPA) reveals an 85:15 trans/cis mixture of isomers.
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