C(NC(C)C)(C)C.C([Li])CCC.C([N:15]([CH2:26][CH3:27])[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C.[CH3:28][CH:29]1[CH2:33][CH:32]([CH3:34])[N:31]([CH2:35]CC#N)[CH:30]1[CH2:39][OH:40].Cl>O1CCCC1>[CH3:28][CH:29]1[CH2:33][CH:32]([CH3:34])[N:31]([CH2:35][CH2:27][C:26]2[NH:15][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[CH:30]1[CH2:39][OH:40]
Diisopropylamine (3.3 g) was dissolved in tetrahydrofuran (20 mL) and n-butyllithium (1.58M, hexane solution, 19 mL) was added dropwise under a nitrogen stream at −78° C. After the completion of the dropwise addition, a solution (20 mL) of N,N-diethyl-2,3-dimethylbenzamide (5.2 g) in tetrahydrofuran was added dropwise and the mixture was stirred for 1 hr. A solution (20 mL) of 3-(3,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl)propionitrile (2.3 g) in tetrahydrofuran was added dropwise to the reaction mixture and the temperature of the reaction mixture was raised to room temperature. After the completion of the reaction, the reaction mixture was acidified by adding conc. hydrochloric acid. The reaction mixture was concentrated and washed with hexane. The aqueous layer was basified by adding potassium carbonate and extracted with chloroform. The organic layer was dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography. The fraction eluted with chloroform:methanol=30:1 was concentrated and the obtained residue was again purified by silica gel column chromatography (NH silica gel, Fuji Silysia Chemical). The fraction eluted with chloroform was concentrated and ether was added to the obtained residue. The precipitated crystals were collected by filtration to give 3-[2-(3,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (0.5 g).
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