1-(二溴甲基)-2-甲基苯

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred mixture of 1-(3-amino-2-hydroxypropyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.24 g, 7.6 mmol), K2CO3 (1.61 g, 11.7 mmol) in acetonitrile (100 was added α,α-dibromo-o-xylene (1.54 g, 6.1 mmol). The mixture was heated at reflux for 4 hours then cooled. The insolubles were filtered. The dark red solution was concentrated down. The residue was purified by flash chromatography over s silica gel column (SiO2, 30 g; eluted with 1% CH3OH in dichloromethane). The product so obtained weighed 940 mg as an oil. This oil was dissolved in ethanol and was treated with a solution of HCl in ethanol (188 mg of AcCl in ethanol). The dark solids were collected and recrystallized again in ethanol to yield off-white crystals (1.01 g), m.p. 240°-243° C. The mixture was heated at reflux for 4 hours then cooled The insolubles were filtered The dark red solution was concentrated down The residue was purified by flash chromatography over s silica gel column (SiO2, 30 g; eluted with 1% CH3OH in dichloromethane) The product so obtained The dark solids were collected recrystallized again in ethanol

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46 g, 12.5 mmol), K2CO3 (4 g, 29 mmol) and α,α-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the insolubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206°-209° C. was heated at reflux for 3.5 hours The mixture was cooled the insolubles were filtered The dark red solution was concentrated down to a dark oil This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane) The product thus obtained The resulting crystals were collected as an off white solid

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium (3.7 g) was dissolved in 80 ml of ethyl alcohol, followed by the addition of 150 ml of diethyl ether. Diethyl malonate (12.5 ml) was added followed by 20 g of α, α-dibromo-o-xylene in 150 ml of diethyl ether with overhead stirring. The reaction was heated to reflux for 5 hours. The reaction was cooled, filtered, and the solvent was removed under vacuum. The residue was treated with a potassium hydroxide solution (20 g in 125 ml of water) and heated to reflux for 15 hours. The reaction was then cooled and rinsed with 200 ml of diethyl ether. The aqueous phase was acidified with 30% hydrochloric acid. The precipitate was collected and dried under vacuum over Drieruite for 5 hours to yield 8.86 g of indan-2,2-dicarboxylic acid. The reaction was heated to reflux for 5 hours The reaction was cooled filtered the solvent was removed under vacuum The residue was treated with a potassium hydroxide solution (20 g in 125 ml of water) heated to reflux for 15 hours The reaction was then cooled rinsed with 200 ml of diethyl ether The precipitate was collected dried under vacuum over Drieruite for 5 hours

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A process for the preparation of the compounds of the present invention which are substituted by alkyl substituents, e.g., methyl substituents in the 8 and/or 11 positions, begins with the treatment of an α,α-dihaloxylene with an alkylated or dialkylated derivative of the appropriate cycloalkanone-enamine. Thus, for example, α,α-dibromoxylene is treated with the pyrrolidine enamine of 2,5-dimethylcyclopentanone to produce the corresponding 6,9-dimethyl-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene-11-one, followed by thallation as described hereinabove, to introduce the corresponding 2'-hydroxy compound and subsequent conversion to the oxime, followed by catalytic reduction to the desired d,1-11-endo-amino-6,9-dimethyl-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene. A process for the preparation of the compounds of the present invention which

反应条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetamide (2.56 g, 9.2 mmol) in DMF (40 ml) was chipped in sodium hydride (770 mg, 60% in oil, 20.1 mmol) at room temperature under N2. The mixture was heated to 65° C. for 3 hours. α,α-dibromoxylene (2.43 g, 9.2 mmol) was added and the resulting mixture was heated at 70° C. for 4 hours, then left standing overnight for 16 hours. The DMF mixture was poured into H2O (400 ml) and the organics were extracted into ethyl acetate (250 ml). The ethyl acetate solution was washed with brine and dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography over a silica gel column (SiO2, 45 gm; eluted with 1%CH3OH: 99% DCM). The product thus purified as a white solid weighed 1.73 g. Recrystallization from a small amount of ethanol yielded white crystals: 1.65 g, m.p. 184°-185° C. the resulting mixture was heated at 70° C. for 4 hours left the organics were extracted into ethyl acetate (250 ml) The ethyl acetate solution was washed with brine dried over MgSO4 The solvent was removed the residue was purified by flash chromatography over a silica gel column (SiO2, 45 gm; eluted with 1%CH3OH: 99% DCM) The product thus purified as a white solid Recrystallization from a small amount of ethanol yielded white crystals

反应条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetamide (2.56 g, 9.2 mmol) in DMF (40 ml) was chipped in sodium hydride (770 mg, 60% in oil, 20.1 mmol) at room temperature under N2. The mixture was heated to 65° C. for 3 hours. α,α-dibromoxylene (2.43 g, 9.2 mmol) was added and the resulting mixture was heated at 70° C. for 4 hours, then left standing overnight for 16 hours. The DMF mixture was poured into H2O (400 ml) and the organics were extracted into ethyl acetate (250 ml). The ethyl acetate solution was washed with brine and dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography over a silica gel column (SiO2, 45 gm; eluted with 1%CH3OH: 99% DCM). The product thus purified as a white solid weighed 1.73 g. Recrystallization from a small amount of ethanol yielded white crystals: 1.65 g, m.p. 184°-185° C. the resulting mixture was heated at 70° C. for 4 hours left the organics were extracted into ethyl acetate (250 ml) The ethyl acetate solution was washed with brine dried over MgSO4 The solvent was removed the residue was purified by flash chromatography over a silica gel column (SiO2, 45 gm; eluted with 1%CH3OH: 99% DCM) The product thus purified as a white solid Recrystallization from a small amount of ethanol yielded white crystals

反应条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetamide (2.56 g, 9.2 mmol) in DMF (40 ml) was chipped in sodium hydride (770 mg, 60% in oil, 20.1 mmol) at room temperature under N2. The mixture was heated to 65° C. for 3 hours. α,α-dibromoxylene (2.43 g, 9.2 mmol) was added and the resulting mixture was heated at 70° C. for 4 hours, then left standing overnight for 16 hours. The DMF mixture was poured into H2O (400 ml) and the organics were extracted into ethyl acetate (250 ml). The ethyl acetate solution was washed with brine and dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography over a silica gel column (SiO2, 45 gm; eluted with 1% CH3OH: 99% DCM). The product thus purified as a white solid weighed 1.73 g. Recrystallization from a small amount of ethanol yielded white crystals: 1.65 g, m.p. 184°-185° C. the resulting mixture was heated at 70° C. for 4 hours left the organics were extracted into ethyl acetate (250 ml) The ethyl acetate solution was washed with brine dried over MgSO4 The solvent was removed the residue was purified by flash chromatography over a silica gel column (SiO2, 45 gm; eluted with 1% CH3OH: 99% DCM) The product thus purified as a white solid Recrystallization from a small amount of ethanol yielded white crystals

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred mixture of 1-(3-amino-2-hydroxypropyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.24 g, 7.6 mmol), K2CO3 (1.61 g, 11.7 mmol) in acetonitrile (100 ml) was added α,α-dibromo-o-xylene (1.54 g, 6.1 mmol). The mixture was heated at reflux for 4 hours then cooled. The insolubles were filtered. The dark red solution was concentrated down. The residue was purified by flash chromatography over s silica gel column (SiO2, 30 g; eluted with 1% CH3OH in dichloromethane). The product so obtained weighed 940 mg as an oil. This oil was dissolved in ethanol and was treated with a solution of HCl in ethanol (188 mg of AcCl in ethanol). The dark solids were collected and recrystallized again in ethanol to yield off-white crystals (1.01 g), m.p. 240°-243° C. The mixture was heated at reflux for 4 hours then cooled The insolubles were filtered The dark red solution was concentrated down The residue was purified by flash chromatography over s silica gel column (SiO2, 30 g; eluted with 1% CH3OH in dichloromethane) The product so obtained The dark solids were collected recrystallized again in ethanol

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46 g, 12.5 mmol), K2CO3 (4 g, 29 mmol) and α,α-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the insolubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206°-209° C. was heated at reflux for 3.5 hours The mixture was cooled the insolubles were filtered The dark red solution was concentrated down to a dark oil This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane) The product thus obtained The resulting crystals were collected as an off white solid

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46 g, 12.5 mmol), K2CO3 (4 g, 29 mmol) and α,α-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the insolubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206°-209° C. was heated at reflux for 3.5 hours The mixture was cooled the insolubles were filtered The dark red solution was concentrated down to a dark oil This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane) The product thus obtained The resulting crystals were collected as an off white solid

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46 g, 12.5 mmol), K2CO3 (4 g, 29 mmol) and α,α-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the insolubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206°-209° C. was heated at reflux for 3.5 hours The mixture was cooled the insolubles were filtered The dark red solution was concentrated down to a dark oil This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane) The product thus obtained The resulting crystals were collected as an off white solid

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46 g, 12.5 mmol), K2CO3 (4 g, 29 mmol) and α,α-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the insolubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206°-209° C. was heated at reflux for 3.5 hours The mixture was cooled the insolubles were filtered The dark red solution was concentrated down to a dark oil This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane) The product thus obtained The resulting crystals were collected as an off white solid