alpha,alpha-Dimethyl-1-(phenylmethyl)-4-piperidinemethanol

The produced ethyl 1-benzylpiperidine-4-carboxylate (5.7701 g, 23.3 mmol) was then added to a 500 mL round-bottomed flask in THF at -78 C. Methyllithium (18.7 ml, 46.7 mmol) was added and allowed to stir slowly warming to room temperature overnight. Upon completion, the reaction was concentrated. The residue was diluted with water) and extracted with ethyl acetate. The organic extract was washed with saturated sodium carbonate solution, saturated sodium chloride solution), dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40 M)×2, eluting with a gradient of 1% to 10% methanol in dichloromethane, to provide To a 50 mL round-bottomed flask was added ethyl isonipecotate (5.0 g, 32 mmol) in dimethylformamide at 0 C. Sodium hydroxide (0.86 g, 35 mmol) was added and the reaction mixture was allowed to stir for 15 minutes. 1-(Bromomethyl)benzene (4.2 ml, 35 mmol) was then added and the reaction mixture was allowed to stir slowly warming to room temperature. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, saturated sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. The ethyl 1-benzylpiperidine-4-carboxylate product (5.8 g, 23.3 mmol) was then added to a 500 mL round-bottomed flask in THF at -78 C. Methyllithium (18.7 ml, 46.7 mmol) was added and allowed to stir slowly warming to room temperature overnight. Upon completion, the reaction mixture was concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated sodium carbonate solution, saturated sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M) X2, eluting with a gradient of 1% to 10% methanol in dichloromethane, to provide 138 2-(1-[2-(I H-Indazol-4- ylV4-morpholin-4- yl-thieno[3 , 2-dlp yrimidin-6- ylmethyl-piperidin-4-yl|-propan-2-olVia 2-[l-(2-chloro-4-morpholin-4-yl-thieno[3, 2-d]pyrimidin-6-ylmethyl)- piperidin-4-yl]-propan-2-ol, prepared from 2-piperidin-4-yl-propan-2-ol.Amine preparation: To a solution of piperidine-4-carboxylic acid ethyl ester (3.0g) stirring in dry MeCN (3OmL) was added potassium carbonate (2.9Og) followed by benzyl bromide (2.5mL). The mixture was warmed to 78C. After 3 h the mixture was cooled, poured into water (10OmL) and extracted into ethyl acetate, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to give l-benzyl-piperidine-4-carboxylic acid ethyl ester(2.17g) as a pale yellow oil. EPO To a 50 mL round-bottomed flask was added ethyl isonipecotate (5.0 g, 32 mmol) in dimethylformamide at 0 C. Sodium hydroxide (0.86 g, 35 mmol) was added and the reaction mixture was allowed to stir for 15 minutes. 1-(Bromomethyl)benzene (4.2 ml, 35 mmol) was then added and the reaction mixture was allowed to stir slowly warming to room temperature. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, saturated sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. The ethyl 1-benzylpiperidine-4-carboxylate product (5.8 g, 23.3 mmol) was then added to a 500 mL round-bottomed flask in THF at -78 C. Methyllithium (18.7 ml, 46.7 mmol) was added and allowed to stir slowly warming to room temperature overnight. Upon completion, the reaction mixture was concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated sodium carbonate solution, saturated sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M) X2, eluting with a gradient of 1% to 10% methanol in dichloromethane, to provide The benzyl protecting group was removed with palladium, 10 wt. % on activated carbon and placing the reaction vessel under hydrogen (g) overnight. Upon completion, the reaction mixture was filtered through Celite. The filtrate was concentrated to produce 2-(piperidin-4-yl)propan-2-ol.138 2-(1-[2-(I H-Indazol-4- ylV4-morpholin-4- yl-thieno[3 , 2-dlp yrimidin-6- ylmethyl-piperidin-4-yl|-propan-2-olVia 2-[l-(2-chloro-4-morpholin-4-yl-thieno[3, 2-d]pyrimidin-6-ylmethyl)- piperidin-4-yl]-propan-2-ol, prepared from 2-piperidin-4-yl-propan-2-ol.Amine preparation: To a solution of piperidine-4-carboxylic acid ethyl ester (3.0g) stirring in dry MeCN (3OmL) was added potassium carbonate (2.9Og) followed by benzyl bromide (2.5mL). The mixture was warmed to 78C. After 3 h the mixture was cooled, poured into water (10OmL) and extracted into ethyl acetate, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to give l-benzyl-piperidine-4-carboxylic acid ethyl ester(2.17g) as a pale yellow oil. EPO Reference Example 66 To a mixture of ethyl 1-benzyl-4-piperidinecarboxylate and tetrahydrofuran (50 mL) was added at -78C for 1 hour a 1 M methyl magnesium bromide - tetrahydrofuran solution (1.2 mL). After stirring for 6 hours, the temperature was elevated to room temperature, and the mixture was stirred for 14 hours. The reactant was poured into an ammonium chloride solution and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain

Molecular Weight:233.35
XLogP3:2.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:233.177964357
Monoisotopic Mass:233.177964357
Topological Polar Surface Area:23.5
Heavy Atom Count:17
Complexity:225
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes