索利那新杂质31

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

实验步骤: (Method 1A) To a mixture of 9.3 g (0.1 mol) of aniline and 16.1 g (0.1 mol) of 1-azabicyclo[2.2.2]octan-3-one hydrochloride in 250 mL of dichloroethane (DCE) was added 31.8 g (0.15 mol) of Na(OAc)3BH and the mixture was stirred overnight at room temperature. The reaction was quenched with 3 N NaOH. The layers were separated and the aqueous layer was extracted with an additional portion of CHCl3. The organic layers were combined, dried over NaSO4, and then filtered and the solvent was evaporated in vacuo. Th residue was chromatographed on silica (95/5 CHCl3/10% NH4OH in MeOH) to give N-Phenyl-1-azabicyclo[2.2.2]octan-3-amine (6.0 g 30%) as an off-white solid. MH+=203. 1H NMR (CDCl3) 1.46 (m, 1H), 1.75 (m, 3H), 2.0 (m, 1H), 2.55 (m, 1H), 2.95 (m, 4H), 3.4 (m, 2H), 3.8 (s, 1H), 6.6 (d, 2H), 6.75 (t, 1H), 7.2 (t, 2H). The reaction was quenched with 3 N NaOH The layers were separated the aqueous layer was extracted with an additional portion of CHCl3 dried over NaSO4 filtered the solvent was evaporated in vacuo Th residue was chromatographed on silica (95/5 CHCl3/10% NH4OH in MeOH)

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

实验步骤: A suspension of quinuclidine-3-one hydrochloride (16.2 g, 0.1 mole) in 95% ethanol (25 ml) was treated with 50% sodium hydroxide (8.0 g, 0.1 mole) and stirred until homogeneous. In a separate reactor a cooled (0° C.) solution of pyrrolidine (10.7 g, 0.15 mole) in 95% ethanol (25 ml) was treated dropwise with 37% aqueous formaldehyde (11.5 ml, 0.15 mole), and the solution was stirred at 25° C. for 30 minutes. The two solutions were combined and the mixture was refluxed for 4 hours, cooled, and added to ether (250 ml). Magnesium sulfate was added, and the mixture was stirred for 15 minutes and filtered. The filtrate was concentrated in vacuo, dissolved in methanol (100 ml), and treated with hydroxylamine hydrochloride (7.65 g, 110 mmoles), then with 25% sodium methoxide (2.2 g, 10 mmoles). After 2 hours at room temperature additional 25% sodium methoxide (21.6 g, 100 mmoles) was added and after 15 minutes the solution was filtered. The filtrate was concentrated in vacuo to a residue, which was dissolved in methylene chloride (150 ml) and filtered. The filtrate was concentrated in vacuo, and the residue was triturated from cold ether, then from cold acetonitrile ether to afford 8.09 g (36%) of fine colorless needles, mp 194°-195° C. the solution was stirred at 25° C. for 30 minutes the mixture was refluxed for 4 hours cooled the mixture was stirred for 15 minutes filtered The filtrate was concentrated in vacuo dissolved in methanol (100 ml) was filtered The filtrate was concentrated in vacuo to a residue, which was dissolved in methylene chloride (150 ml) filtered The filtrate was concentrated in vacuo the residue was triturated from cold ether

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

实验步骤: A slurry of 3-quinuclidinone hydrochloride (16.2 g, 100 mmoles) in ethanol (16.5 ml) and water (7 ml) was treated with sodium hydroxide (4.0 g, 100 mmoles) and stirred for 15 minutes. Separately, a cooled (0° C.) mixture of piperidine (15 ml, 150 mmoles), water (15 ml), and ethanol (10 ml) was treated with 37% aqueous formaldehyde (11.5 ml, 150 mmoles), and the mixture was stirred at room temperature for 15 minutes. The mixtures were combined, refluxed for 45 minutes, cooled, and diluted with petroleum ether (250 ml). The organic layer was separated and the aqueous solution was extracted with petroleum ether (100 ml). The combined organic layers were dried (MgSO4), concentrated in vacuo, and dissolved in methanol (100 ml). Hydroxylamine hydrochloride (7.7 g, 110 mmoles) was added, followed by 25% sodium methoxide/methanol (2.16 g, 10 mmoles), and the mixture was stirred for 18 hours. Additional 25% sodium methoxide (21.6 g, 100 mmoles) was added, and the methanol was removed in vacuo and replaced with water (100 ml). The suspension was filtered, and the solid was collected and dried. The filtrate was saturated with sodium chloride, extracted with methylene chloride (3×100 ml), and the combined extracts were dried (Na2SO4), concentrated in vacuo, and triturated from ether. The combined solids were recrystallized from 2-propanol to yield 4.1 g (17%) of voluminous white needles, mp 196°-198° C. (dec). Separately, a cooled the mixture was stirred at room temperature for 15 minutes refluxed for 45 minutes cooled The organic layer was separated the aqueous solution was extracted with petroleum ether (100 ml) The combined organic layers were dried (MgSO4) concentrated in vacuo dissolved in methanol (100 ml) the mixture was stirred for 18 hours the methanol was removed in vacuo The suspension was filtered the solid was collected dried extracted with methylene chloride (3×100 ml) the combined extracts were dried (Na2SO4) concentrated in vacuo triturated from ether The combined solids were recrystallized from 2-propanol

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

实验步骤: Potassium hydroxide (56 g, 0.54 mole) was dissolved in methanol (420 mL). 3-Quinuclidinone hydrochloride (75 g, 0.49 mole) was added and the mixture was stirred for 30 min at ambient temperature. 3-Pyridinecarboxaldehyde (58 g, 0.54 mole) was added and the mixture stirred for 16 h at ambient temperature. The reaction mixture became yellow during this period, with solids caking on the walls of the flask. The solids were scraped from the walls and the chunks broken up. With rapid stirring, water (390 mL) was added. When the solids dissolved, the mixture was cooled at 4° C. overnight. The crystals were collected by filtration, washed with water, and air dried to obtain 80 g of yellow solid. A second crop (8 g) was obtained by concentration of the filtrate to ˜10% of its former volume and cooling at 4° C. overnight. Both crops were sufficiently pure for further transformation (88 g, 82%). the mixture stirred for 16 h at ambient temperature The reaction mixture became yellow during this period, with solids When the solids dissolved the mixture was cooled at 4° C. overnight The crystals were collected by filtration washed with water, and air dried

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

实验步骤: The manner in which 2-((4-, 5-, and 6-substituted-3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanes can be synthesized can vary. For example, 5-bromopyridine-3-carboxaldehyde and 3-quinuclidinone hydrochloride (commercially available from Aldrich) can be reacted together in the presence of methanolic potassium hydroxide as described in Neilsen and Houlihan, Org. React. 16: 1 (1968). The aldol condensation product, 2-((5-bromo-3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one, can then be treated with sodium borohydride to yield the alcohol, 2-((5-bromo-3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol, as a crystalline solid. This intermediate is reacted with neat thionyl chloride at room temperature to give 3-chloro-2-(5-bromo-3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octane dihydrochloride as a pure crystalline solid. Reductive removal of the chlorine can be accomplished using lithium trimethoxyaluminum hydride and copper iodide as described by Masamune et al., J. Am. Chem. Soc. 95: 6452 (1973) to give the desired product, 2-((5-bromo-3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octane, as a crystalline solid. This methylene intermediate can then be converted to the desired product, 2-((5-bromo-3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane, by hydrogenation in the presence of palladium catalyst. The isomeric compounds, 2-((4-bromo-3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane and 2-((6-bromo-3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane can be prepared in a similar manner by replacing 5-bromopyridine-3-carboxaldehyde with 4-bromopyridine-3-carboxaldehyde or 6-bromopyridine-3-carboxaldehyde, respectively, in the synthetic approach given above. React

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

实验步骤: A solution of potassium cyanide (10.15 g, 0.156 mol) in water (31.25 ml) was added dropwise to a solution of 1-azabicyclo[2.2.2]-octan-3-one hydrochloride (25.0 g, 0.155 mol) in water (31.25 ml) at 0°-5°. Following the addition, the reaction mixture was stirred for 3 h and then filtered. The solid was washed with ice-cold water (2×15 ml) and was then dried over phosphorus pentoxide overnight, m.p. 155°-156°. Recrystallisation of a 1 g sample from dioxane gave pure 3-cyano-3-hydroxy-1-azabicyclo[2.2.2]octane, m.p. 172°-173°. the addition filtered The solid was washed with ice-cold water (2×15 ml) was then dried over phosphorus pentoxide overnight, m.p. 155°-156° Recrystallisation of a 1 g sample from dioxane

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

实验步骤: A solution of potassium cyanide (10.15 g, 0.156 mol) in water (31.25 ml) was added dropwise to a solution of 1-azabicyclo[2.2.2]-octan-3-one hydrochloride (25.0 g, 0.155 mol) in water (31.25 ml) at 0°-5°. Following the addition, the reaction mixture was stirred for 3 h and then filtered. The solid was washed with ice-cold water (2×15 ml) and was then dried over phosphorus pentoxide overnight, m.p. 155°-156°. Recrystallisation of a 1 g sample from dioxane gave pure 3-cyano-3-hydroxy-1-azabicyclo[2.2.2]octane, m.p. 172°-173°. the addition filtered The solid was washed with ice-cold water (2×15 ml) was then dried over phosphorus pentoxide overnight, m.p. 155°-156° Recrystallisation of a 1 g sample from dioxane

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

实验步骤: 3-Quinuclidinone hydrochloride (8.25 kg, 51.0 mol) and methanol (49.5 L) were added to a 100 L glass reaction flask, under an nitrogen atmosphere, equipped with a mechanical stirrer, temperature probe, and condenser. Potassium hydroxide (5.55 kg, 99.0 mol) was added via a powder funnel over an approximately 30 min period, resulting in a rise in reaction temperature from 50° C. to 56° C. Over an approximately 2 h period, 3-pyridinecarboxaldehyde (4.80 kg, 44.9 mol) was added to the reaction mixture. The resulting mixture was stirred at 20° C.±5° C. for a minimum of 12 h, as the reaction was monitored by thin layer chromatography (TLC). Upon completion of the reaction, the reaction mixture was filtered through a sintered glass funnel and the filter cake was washed with methanol (74.2 L). The filtrate was concentrated, transferred to a reaction flask, and water (66.0 L) was added. The suspension was stirred for a minimum of 30 min, filtered, and the filter cake was washed with water (90.0 L) until the pH of the rinse was 7-9. The solid was dried under vacuum at 50° C.±5° C. for a minimum of 12 h to give 8.58 kg (89.3%) of 2-((3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one. equipped with a mechanical stirrer resulting in a rise in reaction temperature from 50° C. to 56° C Upon completion of the reaction the reaction mixture was filtered through a sintered glass funnel the filter cake was washed with methanol (74.2 L) The filtrate was concentrated transferred to a reaction flask water (66.0 L) was added The suspension was stirred for a minimum of 30 min filtered the filter cake was washed with water (90.0 L) until the pH of the rinse The solid was dried under vacuum at 50° C.±5° C. for a minimum of 12 h

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

实验步骤: Potassium hydroxide (56 g, 0.54 mole) was dissolved in methanol (420 mL). 3-Quinuclidinone hydrochloride (75 g, 0.49 mole) was added and the mixture was stirred for 30 min at ambient temperature. 3-Pyridinecarboxaldehyde (58 g, 0.54 mole) was added and the mixture stirred for 16 h at ambient temperature. The reaction mixture became yellow during this period, with solids caking on the walls of the flask. The solids were scraped from the walls and the chunks broken up. With rapid stirring, water (390 mL) was added. When the solids dissolved, the mixture was cooled at 4° C. overnight. The crystals were collected by filtration, washed with water, and air dried to obtain 80 g of yellow solid. A second crop (8 g) was obtained by concentration of the filtrate to ˜10% of its former volume and cooling at 4° C. overnight. Both crops were sufficiently pure for further transformation (88 g, 82% yield). the mixture stirred for 16 h at ambient temperature The reaction mixture became yellow during this period, with solids When the solids dissolved the mixture was cooled at 4° C. overnight The crystals were collected by filtration washed with water, and air dried

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

实验步骤: 3-Quinuclidinone hydrochloride (Aldrich, 1.61 g, 10 mmol) in acetic acid (25 mL) was treated with biphenyl-4,4′-diamine (Aldrich, 0.92 g, 5.0 mmol), Na2SO4 (anhydrous, Aldrich, 7.40 g, 50 mmol) and NaBH(OAc)3 (Aldrich, 3.16 g, 15 mmol) at ambient temperature for 15 hours. The reaction mixture was slowly poured into a flask containing 75 mL of saturated NaHCO3, stirred for 20 minutes, and extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with brine (2×20 mL). The organic phase was concentrated under reduced pressure and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 80:20:4, Rf. 0.10) as a solid (0.98 g, yield, 67%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40-1.52 (m, 1H), 1.64-1.84 (m, 2H), 1.89-2.04 (m, 2H), 2.57 (ddd, J=13.9, 5.2, 2.1 Hz, 1H) 2.75-3.00 (m, 4H), 3.27-3.35 (m, 1H), 3.50-3.60 (m, 1H), 6.61-6.69 (m, 2H), 6.80-6.86 (m, 2H), 6.92-6.97 (m, 2H), 7.06-7.13 (m, 2H) ppm. MS (DCl/NH3) m/z 294 (M+H)+. The reaction mixture was slowly poured into a flask extracted with ethyl acetate (3×100 mL) washed with brine (2×20 mL) The organic phase was concentrated under reduced pressure the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 80:20:4, Rf. 0.10) as a solid (0.98 g, yield, 67%)

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

实验步骤: 3-Quinuclidinone hydrochloride (Aldrich, 1.61 g, 10 mmol) in acetic acid (25 mL) was treated with biphenyl-4,4′-diamine (Aldrich, 0.92 g, 5.0 mmol), Na2SO4 (anhydrous, Aldrich, 7.40 g, 50 mmol) and NaBH(OAc)3 (Aldrich, 3.16 g, 15 mmol) at ambient temperature for 15 hours. The reaction mixture was slowly poured into a flask containing 75 mL of saturated NaHCO3, stirred for 20 minutes, and extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with brine (2×20 mL). The organic phase was concentrated under reduced pressure and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 80:20:4, Rf. 0.10) as a solid (0.98 g, yield, 67%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40-1.52 (m, 1H), 1.64-1.84 (m, 2H), 1.89-2.04 (m, 2H), 2.57 (ddd, J=13.9, 5.2, 2.1 Hz, 1H) 2.75-3.00 (m, 4H), 3.27-3.35 (m, 1H), 3.50-3.60 (m, 1H), 6.61-6.69 (m, 2H), 6.80-6.86 (m, 2H), 6.92-6.97 (m, 2H), 7.06-7.13 (m, 2H) ppm. MS (DCl/NH3) m/z 294 (M+H)+. The reaction mixture was slowly poured into a flask extracted with ethyl acetate (3×100 mL) washed with brine (2×20 mL) The organic phase was concentrated under reduced pressure the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 80:20:4, Rf. 0.10) as a solid (0.98 g, yield, 67%)

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

实验步骤: Potassium hydroxide (56 g, 0.54 mole) was dissolved in methanol (420 mL). 3-Quinuclidinone hydrochloride (75 g, 0.49 mole) was added and the mixture was stirred for 30 min at ambient temperature. 3-Pyridinecarboxaldehyde (58 g, 0.54 mole) was added and the mixture stirred for 16 h at ambient temperature. The reaction mixture became yellow during this period, with solids caking on the walls of the flask. The solids were scraped from the walls and the chunks broken up. With rapid stirring, water (390 mL) was added. When the solids dissolved, the mixture was cooled at 4° C. overnight. The crystals were collected by filtration, washed with water, and air dried to obtain 80 g of yellow solid. A second crop (8 g) was obtained by concentration of the filtrate to ˜10% of its former volume and cooling at 4° C. overnight. Both crops were sufficiently pure for further transformation (88 g, 82%). the mixture stirred for 16 h at ambient temperature The reaction mixture became yellow during this period, with solids When the solids dissolved the mixture was cooled at 4° C. overnight The crystals were collected by filtration washed with water, and air dried