piperidine-1-carbothioamide

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound 42 was prepared according to the procedure of Example 11 from compound 41 (30 mg, 0.07 mmole) and 1-thiocarbamyl piperidine. Yield: 21 mg, 65.6%. 1H-NMR (CDCl3, 500 MHz) δ 1.19 (d, J=8.5 Hz, 6H), 1.65 (m, 6H), 3.44-3.52 (m, 5H),), 6.48 (d, J=8.4 Hz, 1H), 7.01 (s, 1H), 7.21 (m, 1H), 7.44-7.51 (m, 3H), 7.61 (d, J=8.4 Hz, 1H). MS (DCI/NH3) m/z 463 (M+H)+.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of thiocarbonyldiimidazole (44.9 mmol) in THF (40 mL) at room temperature was added portionwise 2 M Dimethylamine in THF (44 mmol) and a temperature increase was observed. 40 min after final addition the reaction mixture was heated to 55° C. for 1 h, then allowed to reach room temperature again. The reaction was then concentrated in vacuo and the residue purified by flash chromatography (silica gel, Petroleum ether-EtOAc) to give the intermediate imidazole-1-carbothioic acid dimethylamide. This material was treated with freshly prepared sat. ammonia in methanol (40 ml) for 60 h, then concentrated in vacuo and the precipitated residue was suspended in diethyl ether and collected by filtration. The precipitate was washed with diethyl ether and air-dried to give a slight yellow solid (1.71 g, 16.4 mmol) which was used in the subsequent step. 4-(2-bromoacetyl)benzoic acid (1.23 mmol) and 1-piperidinethiocarboxamide (1.23 mmol) were mixed in THF (10 mL), then refluxed for 3 h. The reaction mixture was then allowed to reach room temperature and the obtained precipitate was collected by filtration and washed with 3 portions of diethyl ether. The crude product was crystallized from hot 1:1 EtOH-EtOAc to give a first harvest of colorless needles (0.1 g, 0.40 mmol). 1H NMR (DMSO-d6, 400 MHz) δ 7.94 (4H, m), 7.37 (1H, s), 3.11 (6H, m). refluxed for 3 h to reach room temperature the obtained precipitate was collected by filtration washed with 3 portions of diethyl ether The crude product was crystallized from hot 1:1 EtOH-EtOAc

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of thiocarbonyldiimidazole (44.9 mmol) in THF (40 mL) at room temperature was added portionwise 2 M Dimethylamine in THF (44 mmol) and a temperature increase was observed. 40 min after final addition the reaction mixture was heated to 55° C. for 1 h, then allowed to reach room temperature again. The reaction was then concentrated in vacuo and the residue purified by flash chromatography (silica gel, Petroleum ether-EtOAc) to give the intermediate imidazole-1-carbothioic acid dimethylamide. This material was treated with freshly prepared sat. ammonia in methanol (40 ml) for 60 h, then concentrated in vacuo and the precipitated residue was suspended in diethyl ether and collected by filtration. The precipitate was washed with diethyl ether and air-dried to give a slight yellow solid (1.71 g, 16.4 mmol) which was used in the subsequent step. 4-(2-bromoacetyl)benzoic acid (1.23 mmol) and 1-piperidinethiocarboxamide (1.23 mmol) were mixed in THF (10 mL), then refluxed for 3 h. The reaction mixture was then allowed to reach room temperature and the obtained precipitate was collected by filtration and washed with 3 portions of diethyl ether. The crude product was crystallized from hot 1:1 EtOH-EtOAc to give a first harvest of colorless needles (0.1 g, 0.40 mmol). 1H NMR (DMSO-d6, 400 MHz) δ 7.94 (4H, m), 7.37 (1H, s), 3.11 (6H, m). refluxed for 3 h to reach room temperature the obtained precipitate was collected by filtration washed with 3 portions of diethyl ether The crude product was crystallized from hot 1:1 EtOH-EtOAc

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-(2-bromoacetyl)benzoic acid (1.23 mmol) and 1-piperidinethiocarboxamide (1.23 mmol) were mixed in THF (10 mL), then refluxed for 3 h. The reaction mixture was then allowed to reach room temperature and the obtained precipitate was collected by filtration and washed with 3 portions of diethyl ether. The crude product was crystallized from hot 1:1 EtOH-EtOAc to give a first harvest of colorless needles (0.28 g, 0.95 mmol). 1H NMR (DMSO-d6, 400 MHz,) δ 7.93 (4H, m), 7.40 (1H, s), 3.48 (4H, m), 1.60 (6H, m). refluxed for 3 h to reach room temperature the obtained precipitate was collected by filtration washed with 3 portions of diethyl ether The crude product was crystallized from hot 1:1 EtOH-EtOAc

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-(2-bromoacetyl)benzoic acid (1.23 mmol) and 1-piperidinethiocarboxamide (1.23 mmol) were mixed in THF (10 mL), then refluxed for 3 h. The reaction mixture was then allowed to reach room temperature and the obtained precipitate was collected by filtration and washed with 3 portions of diethyl ether. The crude product was crystallized from hot 1:1 EtOH-EtOAc to give a first harvest of colorless needles (0.28 g, 0.95 mmol). 1H NMR (DMSO-d6, 400 MHz,) δ 7.93 (4H, m), 7.40 (1H, s), 3.48 (4H, m), 1.60 (6H, m). refluxed for 3 h to reach room temperature the obtained precipitate was collected by filtration washed with 3 portions of diethyl ether The crude product was crystallized from hot 1:1 EtOH-EtOAc

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of piperidine-1-carbothioamide (3.00 g), 3-chloro-2-butanone (4.43 g) and 2-propanol (30 mL) was heated under reflux for 15 hrs. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 1-(4,5-dimethyl-1,3-thiazol-2-yl)piperidine as a colorless oil (4.05 g, yield 99%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v). was heated under reflux for 15 hrs the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of piperidine-1-carbothioamide (3.00 g), 3-chloro-2-butanone (4.43 g) and 2-propanol (30 mL) was heated under reflux for 15 hrs. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 1-(4,5-dimethyl-1,3-thiazol-2-yl)piperidine as a colorless oil (4.05 g, yield 99%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v). was heated under reflux for 15 hrs the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of piperidine-1-carbothioamide (3.00 g), 3-chloro-2-butanone (4.43 g) and 2-propanol (30 mL) was heated under reflux for 15 hrs. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 1-(4,5-dimethyl-1,3-thiazol-2-yl)piperidine as a colorless oil (4.05 g, yield 99%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v). was heated under reflux for 15 hrs the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of piperidine-1-carbothioamide (1.0 g), 1,3-dichloro-2-propanone (0.91 g) and ethanol (30 mL) was heated under reflux for 1 hr. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 1-(4-chloromethyl-1,3-thiazol-2-yl)piperidine as a colorless oil (1.00 g, yield 67%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v). was heated under reflux for 1 hr the mixture was extracted with ethyl acetate The ethyl acetate layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of piperidine-1-carbothioamide (1.0 g), 1,3-dichloro-2-propanone (0.91 g) and ethanol (30 mL) was heated under reflux for 1 hr. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 1-(4-chloromethyl-1,3-thiazol-2-yl)piperidine as a colorless oil (1.00 g, yield 67%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v). was heated under reflux for 1 hr the mixture was extracted with ethyl acetate The ethyl acetate layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of piperidine-1-carbothioamide (1.0 g), 1,3-dichloro-2-propanone (0.91 g) and ethanol (30 mL) was heated under reflux for 1 hr. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 1-(4-chloromethyl-1,3-thiazol-2-yl)piperidine as a colorless oil (1.00 g, yield 67%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v). was heated under reflux for 1 hr the mixture was extracted with ethyl acetate The ethyl acetate layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.250 g, 0.632 mmol; Preparation #A.2) and piperidine-1-carbothioamide (Oakwood Products Inc., 0.082 g, 0.57 mmol) in EtOH (3 mL) was heated to reflux for about 3 h. After cooling to ambient temperature, the crude mixture was partitioned between DCM and water. The organics were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using heptane/EtOAc (linear gradient, 50:50 to 0:100) to give the title compound (0.098 g, 35%): LC/MS (Table 1, Method a) Rt=4.18 min; MS m/z: 441.8 (M+H)+. was heated to reflux for about 3 h the crude mixture was partitioned between DCM and water The organics were dried over MgSO4 filtered concentrated under reduced pressure purified by silica gel chromatography