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With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 72h; |
1-(1,1-Dimethylethyl) 4-(4-carboxy-2-thiazolyl)-l-piperidinecarboxylate (i.e. the product of Example 1, Step B) (6.86 g, 21.96 mmol) was suspended in 30 mL of dry acetonitrile and treated with triethylamine (6.12 mL, 43.92 mmol) to give a homogeneous solution. To this was added O-benzotriazol-l-yl-N,/V,N',N'-tetramethyluronium hexafluorophosphate (9.16 g, 24.16 mmol) followed by methanamine (3.19 mL, 21.96 mmol). The reaction mixture was stirred at ambient temperature for 3 days, concentrated under reduced pressure, diluted with ethyl acetate, washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark oil. Purification by silica gel chromatography using 25-100 % ethyl acetate in hexanes as eluant gave 9.12 g of the title compound as an oil.1H NMR (CDCl3) delta 1.46 (s, 9H), 1.6-1.8 (m, 5H), 2.0-2.2 (m, 2H), 2.7-3.0 (m, 5H), 3.15 (m, IH), 4.15 (m, 2H), 5.7-6.2 (m, IH), 7.25-7.45 (m, 5H), 7.81 (s, IH). |
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With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 72h; |
EXAMPLE 5 Preparation of N-methyl-2- [1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1-phenylethyl]-4-thiazolecarboxamide (Compound 70) Step A: Preparation of 1,1-dimethylethyl 4-[4-[[methyl [(1R)-1-phenylethyl]arrno]-carbonyl]-2-thiazolyl]-1-piperidinecarboxylate. 1-(1,1-Dimethylethyl)4-(4-carboxy-2-thiazolyl)-1-piperidinecarboxylate (i.e. the product of Example 1, Step B) (6.86 g, 21.96 mmol) was suspended in 30 mL of dry acetonitrile and treated with triethylamine (6.12 mL, 43.92 mmol) to give a homogeneous solution. To this was added O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (9.16 g, 24.16 mmol) followed by (alphaR)-N-alpha-dimethylbenzene-methanamine (3.19 mL, 21.96 mmol). The reaction mixture was stirred at ambient temperature for 3 days, concentrated under reduced pressure, diluted with ethyl acetate, washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark oil. Purification by silica gel chromatography using 25-100 % ethyl acetate in hexanes as eluant gave 9.12 g of the title compound as an oil.1H NMR (CDCl3) delta 1.46 (s, 9H), 1.6-1.8 (m, 5H), 2.0-2.2 (m, 2H), 2.7-3.0 (m, 5H), 3.15 (m, IH), 4.15 (m, 2H), 5.7-6.2 (m, IH), 7.25-7.45 (m, 5H), 7.81 (s, IH). |
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