cyclohexylmethanesulfonyl chloride

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Triethylamine (22.15 ml) was added to a solution of (2S)-2-(methoxycarbonyl)piperidine hydrochloride (10 g) [see Preparation 24] and cyclohexylmethanesulfonyl chloride (16.42 g) [King. J. F. et al,. J. Am. Chem. Soc., 1992, 114(5), 1743-9] in dichloromethane (100 ml). The reaction mixture was stirred for 18 hours after which time the solvent was removed under reduced pressure and the residue diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 95:5 changing to 80:20, by volume, hexane:ethyl acetate to afford methyl (2S)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidinecarboxylate (11.9 g) as a white solid. was removed under reduced pressure the residue diluted with ethyl acetate The organic layer was washed with water, brine dried over magnesium sulphate the solvent was removed under reduced pressure The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 95:5 changing to 80:20, by volume, hexane

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

Procedure: Cyclohexylmethanesulfonyl chloride (359 mg) [King. J. F. et al., J. Am. Chem. Soc., 1992, 114(5), 1743-9] was added to a solution of 2-[4-(3-[(2S)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzyl]-1,3-isoindolinedione hydrochloride (627 mg) [see Preparation 153 and triethylamine (0.4 ml) in dichloromethane (2 ml). The reaction mixture was stirred at room temperature for 18 hours after which time it was heated to 30° C. and stirred for a further 56 hours. The mixture was diluted with dichloromethane and washed with dilute aqueous hydrochloric acid solution, the organic layer dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 75:25, by volume, hexane:ethyl acetate to afford 2-[4-(3-[(2S)-1-cyclohexylmethylsulfonyl-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzyl]-1,3-isoindolinedione (192 mg). was heated to 30° C. stirred for a further 56 hours washed with dilute aqueous hydrochloric acid solution the organic layer dried over magnesium sulphate the solvent removed under reduced pressure The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 75:25, by volume, hexane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the compound of Example 12 (4.0 g, 20 mmole) was added POCl3 (15 mL) and the mixture heated at 100° C. for 48 hours. Upon cooling to room temperature the mixture was poured onto crushed ice and then the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic extracts were then washed with saturated aqueous sodium bicarbonate (2×50 mL), brine and then dried over MgSO4, filtered and the solvent was evaporated under vacuum to provide 3.46 g of the title compound as a light yellow oil. Thin layer chromatography analysis of the title compound showed a single spot with Rf =0.53 (silica, 4:1 hexanes/ethyl acetate). Upon cooling to room temperature the mixture was poured onto crushed ice the aqueous phase was extracted with ethyl acetate (2×100 mL) The combined organic extracts were then washed with saturated aqueous sodium bicarbonate (2×50 mL), brine dried over MgSO4 filtered the solvent was evaporated under vacuum

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the compound of Example 12 (4.0 g, 20 mmole) was added POCl3 (15 mL) and the mixture heated at 100° C. for 48 hours. Upon cooling to room temperature the mixture was poured onto crushed ice and then the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic extracts were then washed with saturated aqueous sodium bicarbonate (2×50 mL), brine and then dried over MgSO4, filtered and the solvent was evaporated under vacuum to provide 3.46 g of the title compound as a light yellow oil. Thin layer chromatography analysis of the title compound showed a single spot with Rf =0.53 (silica, 4:1 hexanes/ethyl acetate). Upon cooling to room temperature the mixture was poured onto crushed ice the aqueous phase was extracted with ethyl acetate (2×100 mL) The combined organic extracts were then washed with saturated aqueous sodium bicarbonate (2×50 mL), brine dried over MgSO4 filtered the solvent was evaporated under vacuum

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

Procedure: To a stirred solution of 0.71 g of tert-butyl [3-amino-6-methyl-2-oxo-1,2-dihydropyridinyl]-acetate (WO 97/01338) at 0° C. under a nitrogen atmosphere was added 0.60 mL cyclohexylmethanesulfonyl chloride (J. F. King et al J. Am. Chem. Soc. 114, 1743 (1992)). After stirring at room temperature for 3 hours the reaction mixture-was concentrated. The residue was dissolved in ethyl acetate, washed successively with 0.1 N hydrochloric acid, water and brine, dried over sodium sulphate and concentrated. The residue was dissolved in a mixture of 0.2 mL water and 1.8 mL trifluoroacetic acid. After stirring at room temperature for 4 h, water and ethyl acetate were added. The organic layer was separated, washed twice with 0.1 N hydrochloric acid, dried over sodium sulphate and concentrated. The solid residue was washed with a cold dichloromethane/diethyl ether mixture to give 0.72 g of the title compound. concentrated The residue was dissolved in ethyl acetate washed successively with 0.1 N hydrochloric acid, water and brine dried over sodium sulphate concentrated The residue was dissolved in a mixture of 0.2 mL water and 1.8 mL trifluoroacetic acid After stirring at room temperature for 4 h water and ethyl acetate were added The organic layer was separated washed twice with 0.1 N hydrochloric acid dried over sodium sulphate concentrated The solid residue was washed with a cold dichloromethane/diethyl ether mixture

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

Procedure: Reaction of {3-[4-(4-amino-butyl)-piperazin-1-yl]-phenyl}-dimethyl-amine and cyclohexyl-methanesulfonyl chloride as described in Preparation 8 gave desired compound, C-Cyclohexyl-N-{4-[4-(3-dimethylamino-phenyl)-piperazin-1-yl]-butyl}-methanesulfonamide. as described in Preparation 8

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

Procedure: Reaction of {3-[4-(4-amino-butyl)-piperazin-1-yl]-phenyl}-dimethyl-amine and cyclohexyl-methanesulfonyl chloride as described in Preparation 8 gave desired compound, C-Cyclohexyl-N-{4-[4-(3-dimethylamino-phenyl)-piperazin-1-yl]-butyl}-methanesulfonamide. as described in Preparation 8

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

Procedure: 5-[4-(2-Aminoethyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one TFA salt (Example 67, step A) (0.49 g, 0.96 mmol) is dissolved in 5 mL of CH2Cl2 and triethylamine (0.27 mL, 1.92 mmol) is added. Cyclohexylmethyl sulfonyl chloride (0.19 g, 0.96 mmol) is then added and the reaction stirred for 1 h. The reaction mixture is concentrated and the residue is partitioned between EtOAc and 1N HCl and extracted with EtOAc. The combined organic layers are washed with sat. sodium bicarbonate and brine, dried over MgSO4 and concentrated to a yellow oil. The oil is purified by chromatography over silica (hexane/EtOAc gradient) to afford the title compound as an oil. The reaction mixture is concentrated the residue is partitioned between EtOAc and 1N HCl extracted with EtOAc The combined organic layers are washed with sat. sodium bicarbonate and brine dried over MgSO4 concentrated to a yellow oil The oil is purified by chromatography over silica (hexane/EtOAc gradient)

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

Procedure: 5-[4-(2-Aminoethyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one TFA salt (Example 67, step A) (0.49 g, 0.96 mmol) is dissolved in 5 mL of CH2Cl2 and triethylamine (0.27 mL, 1.92 mmol) is added. Cyclohexylmethyl sulfonyl chloride (0.19 g, 0.96 mmol) is then added and the reaction stirred for 1 h. The reaction mixture is concentrated and the residue is partitioned between EtOAc and 1N HCl and extracted with EtOAc. The combined organic layers are washed with sat. sodium bicarbonate and brine, dried over MgSO4 and concentrated to a yellow oil. The oil is purified by chromatography over silica (hexane/EtOAc gradient) to afford the title compound as an oil. The reaction mixture is concentrated the residue is partitioned between EtOAc and 1N HCl extracted with EtOAc The combined organic layers are washed with sat. sodium bicarbonate and brine dried over MgSO4 concentrated to a yellow oil The oil is purified by chromatography over silica (hexane/EtOAc gradient)