1-acetylpiperidin-2-one

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under an inert atmosphere, 0.32 mmol of n-butyllithium (1.6M in hexane) is added over a period of 5 minutes to a solution of 0.32 mmol of diisopropylamine in 750 ml of tetrahydrofuran at 0° C. After stirring the mixture for 15 minutes, 0.32 mmol of tri-n-butyltin hydride is added. After 1 hour 30 minutes at 0° C., the reaction mixture is cooled to −70° C. and 0.26 mmol of N-acetylpiperidone in 225 ml of tetrahydrofuran is added and the reaction mixture is then diluted by adding 380 ml of tetrahydrofuran. After stirring for 2 hours 30 minutes, the reaction mixture is hydrolysed by the addition of 200 ml of an aqueous 10% solution of NaH2PO4, brought to 0° C., and then diluted with 2 litres of ether and 1 litre of water. After decanting and washing with a saturated NaCl solution, the organic phase is dried and filtered and then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane) enables the expected product to be isolated. After 1 hour 30 minutes at 0° C. the reaction mixture is then diluted After stirring for 2 hours 30 minutes brought to 0° C. After decanting washing with a saturated NaCl solution the organic phase is dried filtered concentrated under reduced pressure to be isolated

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under an inert atmosphere, 0.32 mmol of n-butyllithium (1.6M in hexane) is added over a period of 5 minutes to a solution of 0.32 mmol of diisopropylamine in 750 ml of tetrahydrofuran at 0° C. After stirring the mixture for 15 minutes, 0.32 mmol of tri-n-butyltin hydride is added. After 1 hour 30 minutes at 0° C., the reaction mixture is cooled to −70° C. and 0.26 mmol of N-acetylpiperidone in 225 ml of tetrahydrofuran is added and the reaction mixture is then diluted by adding 380 ml of tetrahydrofuran. After stirring for 2 hours 30 minutes, the reaction mixture is hydrolysed by the addition of 200 ml of an aqueous 10% solution of NaH2PO4, brought to 0° C., and then diluted with 2 litres of ether and 1 litre of water. After decanting and washing with a saturated NaCl solution, the organic phase is dried and filtered and then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane) enables the expected product to be isolated. After 1 hour 30 minutes at 0° C. the reaction mixture is then diluted After stirring for 2 hours 30 minutes brought to 0° C. After decanting washing with a saturated NaCl solution the organic phase is dried filtered concentrated under reduced pressure to be isolated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared according to general procedure (I). To a mixture of N-acetyl-piperidone (1.4 g) and cyclopentylamine (0.9 g) and molecular sieves (5 g) in THF (8 mL) and methanol (8 mL) was added sodium cyanoborohydride (2.1 g) and the reaction was stirred overnight at room temperature. Insoluble material was removed by filtration and after removal of solvent in vacuo the crude secondary amine (0.57 g) was isolated. The urea coupling was performed in an similar manner to the synthesis of 1,1-dicyclopentyl-3-thiazol-2-yl-urea using carbonyl imidazole and 2-aminothiazole as starting material. Prepared Insoluble material was removed by filtration after removal of solvent in vacuo the crude secondary amine (0.57 g) was isolated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared according to general procedure (I). To a mixture of N-acetyl-piperidone (1.4 g) and cyclopentylamine (0.9 g) and molecular sieves (5 g) in THF (8 mL) and methanol (8 mL) was added sodium cyanoborohydride (2.1 g) and the reaction was stirred overnight at room temperature. Insoluble material was removed by filtration and after removal of solvent in vacuo the crude secondary amine (0.57 g) was isolated. The urea coupling was performed in an similar manner to the synthesis of 1,1-dicyclopentyl-3-thiazol-2-yl-urea using carbonyl imidazole and 2-aminothiazole as starting material. Prepared Insoluble material was removed by filtration after removal of solvent in vacuo the crude secondary amine (0.57 g) was isolated

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a sodium hydride suspension (40% mineral oil content, 2.77 g) in THF (50 mL) and DMF (200 mL), a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (10 g) obtained in Example 1 and 1-acetylpiperidin-2-one (7.17 g) in THF (50 mL) and DMF (200 mL) were added dropwise over 20 minutes at 5° C. This reaction solution was agitated at 0° C. for 2 hours. The reaction solution was added to iced water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, and concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The deposited solids were separated by filtering and 5.0 g of the title compound was obtained by washing with diethyl ether. The physical properties of the compound are as follows. the reaction solution was extracted with ethyl acetate The obtained organic layer was washed with a saturated sodium chloride solution concentrated under reduced pressure after dried over anhydrous magnesium sulfate The deposited solids were separated by filtering

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under an inert atmosphere, 0.32 mmol of n-butyllithium (1.6M in hexane) is added over a period of 5 minutes to a solution of 0.32 mmol of diisopropylamine in 750 ml of tetrahydrofuran at 0° C. After stirring the mixture for 15 minutes, 0.32 mmol of tri-n-butyltin hydride is added. After 1 hour 30 minutes at 0° C., the reaction mixture is cooled to −70° C. and 0.26 mmol of N-acetylpiperidone in 225 ml of tetrahydrofuran is added and the reaction mixture is then diluted by adding 380 ml of tetrahydrofuran. After stirring for 2 hours 30 minutes, the reaction mixture is hydrolysed by the addition of 200 ml of an aqueous 10% solution of NaH2PO4, brought to 0° C., and then diluted with 2 litres of ether and 1 litre of water. After decanting and washing with a saturated NaCl solution, the organic phase is dried and filtered and then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane) enables the expected product to be isolated. After 1 hour 30 minutes at 0° C. the reaction mixture is then diluted After stirring for 2 hours 30 minutes brought to 0° C. After decanting washing with a saturated NaCl solution the organic phase is dried filtered concentrated under reduced pressure to be isolated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 0.88 Ammonia (85 ml) was added to a solution of N-acetylpiperidone (15 g, 106 mmol) in methanol (120 ml), followed by palladium hydroxide (2 g) and the mixture hydrogenated at room temperature and 60 psi for 18 hours. The reaction mixture was filtered through Arbocel®, the filtrate concentrated under reduced pressure and the residue azeotroped with toluene to give a yellow oil. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (96:3.5:0.5 to 84:14:2) to afford the title compound as a clear oil, 9.6 g. The reaction mixture was filtered through Arbocel® the filtrate concentrated under reduced pressure the residue azeotroped with toluene to give a yellow oil The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-(pyrimidin-2-ylsulfanyl)-phenylamine (AMR01106, 100 mg, 0.492 mmol), 1-acetylpiperidone (69.5 mg, 0.492 mmol) and acetic acid (0.15 mL, 2.46 mmol) in DCE (2 mL) was treated with NaBH(OAc)3 (261 mg, 1.23 mmol) and stirred under microwave irradiation for 15 min at 100° C. The reaction mixture was diluted with DCM (10 mL) and quenched with saturated NaHCO3 solution. The aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using AcOEt/MeOH 98:2 as eluent gave 1-{4-[2-(pyrimidin-2-ylsulfanyl)-phenylamino]-piperidin-1-yl}-ethanone 36 mg, 22%) as a colorless oil. 1H NMR (270 MHz, CDCl3) δ 1.20-1.40 (2H, m, CH2), 1.90-2.10 (2H, m, CH2), 2.05 (3H, s, CH3), 2.89 (1H, m, ½CH2), 3.18 (1H, m, ½CH2), 3.54-3.74 (2H, m, CH2), 4.26 (1H, m, CH), 4.75 (1H, br s, NH), 6.69-6.75 (2H, m, ArH), 6.97 (1H, t, J=4.7 Hz, Pyrimidine-H), 7.33 (1H, m, ArH), 7.49 (1H, dd, J=7.4, 1.7 Hz, ArH) and 8.47 (2H, d, J=4.7 Hz, Pyrimidine-H), 13C NMR (270 MHz, CDCl3) δ 21.57 (CH3), 31.74, 32.56, 40.14, 45.00 (CH2), 49.63 (CH), 111.45, 111.57, 117.35, 132.12, 138.13, 148.49, 157.88 (ArC and Pyridine-C), and 171.77 (C═O). quenched with saturated NaHCO3 solution The aqueous layer was washed with DCM (2×20 mL) the combined organic layers were dried (MgSO4) filtered evaporated to dryness

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-(4-chlorophenoxy)benzylamine (AMR01073, 100 mg, 0.428 mmol), 1-acetylpiperidone (121 mg, 0.856 mmol) and acetic acid (0.13 mL, 2.14 mmol) in DCE (2 mL) was treated with NaBH(OAc)3 (227 mg, 1.07 mmol) and stirred under microwave irradiation for 15 min at 100° C. The reaction mixture was diluted with DCM (10 mL) and quenched with saturated NaHCO3 solution. The aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using AcOEt to AcOEt/MeOH 9:1 gradient as eluent gave 1-{4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}ethanone (124 mg, 81%) as a colorless oil. Rf: 0.14 (AcOEt/MeOH 9:1) LC/MS (APCI) tr=4.79 min, m/z 361.46 (35), 359.51 (M++H, 100). HPLC tr=3.04 min (97.37%) 1H NMR (270 MHz, CDCl3) δ 1.25 (2H, m, CH2), 1.68 (br s, NH), 1.79 (2H, m, CH2), 2.05 (3H, S, CH3), 2.67 (2H, m, CH2), 3.02 (1H, m, CH), 3.70 (1H, m, ½CH2), 3.82 (2H, s, CH2), 4.33 (1H, m, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.86 (1H, m, ArH), 7.11 (1H, m, ArH), 7.21 (1H, m, ArH), 7.24 (2H, AA′BB′, ArH) and 7.38 (1H, dd, J=7.2, 1.5 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 21.10 (CH3), 31.49, 32.32, 39.64, 44.47, 45.05 (CH2), 53.21 (CH), 118.49, 119.04, 124.04, 127.51, 128.30, 129.36, 130.14, 131.02, 153.89, 155.80 (ArC), and 168.42 (C═O). quenched with saturated NaHCO3 solution The aqueous layer was washed with DCM (2×20 mL) the combined organic layers were dried (MgSO4) filtered evaporated to dryness

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a sodium hydride suspension (40% mineral oil content, 2.77 g) in THF (50 mL) and DMF (200 mL), a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (10 g) obtained in Example 1 and 1-acetylpiperidin-2-one (7.17 g) in THF (50 mL) and DMF (200 mL) were added dropwise over 20 minutes at 5° C. This reaction solution was agitated at 0° C. for 2 hours. The reaction solution was added to iced water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, and concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The deposited solids were separated by filtering and 5.0 g of the title compound was obtained by washing with diethyl ether. The physical properties of the compound are as follows. the reaction solution was extracted with ethyl acetate The obtained organic layer was washed with a saturated sodium chloride solution concentrated under reduced pressure after dried over anhydrous magnesium sulfate The deposited solids were separated by filtering

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a sodium hydride suspension (40% mineral oil content, 2.77 g) in THF (50 mL) and DMF (200 mL), a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (10 g) obtained in Example 1 and 1-acetylpiperidin-2-one (7.17 g) in THF (50 mL) and DMF (200 mL) were added dropwise over 20 minutes at 5° C. This reaction solution was agitated at 0° C. for 2 hours. The reaction solution was added to iced water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, and concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The deposited solids were separated by filtering and 5.0 g of the title compound was obtained by washing with diethyl ether. The physical properties of the compound are as follows. the reaction solution was extracted with ethyl acetate The obtained organic layer was washed with a saturated sodium chloride solution concentrated under reduced pressure after dried over anhydrous magnesium sulfate The deposited solids were separated by filtering

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under an inert atmosphere, 0.32 mmol of n-butyllithium (1.6M in hexane) is added over a period of 5 minutes to a solution of 0.32 mmol of diisopropylamine in 750 ml of tetrahydrofuran at 0° C. After stirring the mixture for 15 minutes, 0.32 mmol of tri-n-butyltin hydride is added. After 1 hour 30 minutes at 0° C., the reaction mixture is cooled to −70° C. and 0.26 mmol of N-acetylpiperidone in 225 ml of tetrahydrofuran is added and the reaction mixture is then diluted by adding 380 ml of tetrahydrofuran. After stirring for 2 hours 30 minutes, the reaction mixture is hydrolysed by the addition of 200 ml of an aqueous 10% solution of NaH2PO4, brought to 0° C., and then diluted with 2 litres of ether and 1 litre of water. After decanting and washing with a saturated NaCl solution, the organic phase is dried and filtered and then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane) enables the expected product to be isolated. After 1 hour 30 minutes at 0° C. the reaction mixture is then diluted After stirring for 2 hours 30 minutes brought to 0° C. After decanting washing with a saturated NaCl solution the organic phase is dried filtered concentrated under reduced pressure to be isolated