(1R,2R)-N-methyl-2-pyrrolidin-1-ylcyclohexan-1-amine

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

実験手順: To a solution of 4-trifluoromethylphenyl acetic acid (1.45 g, 7.08 mmol) in 10 mL of dry CH2Cl2 under a nitrogen atmosphere was added 1-hydroxybenzotriazole hydrate (HOBT) (0.95 g, 7.08 mmol) and stirred. The reaction mixture was cooled to 0→5oC and added solid EDCI ([1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl])(1.35 g, 7.08 mmol) and stirrat this temperature for 30 min. A solution (±) 3 (1.0 g, 5.48 mmol) in 10 mL of dry CH2Cl2 was added followed by N,N-diisopropylethylamine (Hunig's Base) (0.915 g, 7.08 mmol). The reaction mixture was stirred for 24 h while warming to the room temperature. The reaction mixture was then poured on to excess of ice-cold saturated aqueous NaHCO3 solution and stirred for 30 min. After dilution with CH2Cl2, the organic was separated, washed with saturated salt solution, and dried over anhydrous Na2SO4. Removal of solvent gave a brown oil which was chromatogrphed on a silica gel column [solvent system: CH2Cl2: CH3OH: 28% NH4OH (99:1:2)] to give the desired product as free base. The hydrochloride salt was prepared from 1M etherial HCl and recrystallized from CH2Cl2: Et2O (1:1) to give (±) 5g HCl as a cream colored solid, 0.68 g (30%); 213-215° C.; 1H NMR (200 MHz, CDCl3) δ 1.02-1.47 (m, 4H), 1.52-2.22 (m, 8H), 2.75-2.90 (m, 2H), 2.94 (s, 3H), 3.07 (m, 1H), 3.37 (m, 1H), 3.62 (d, J=15.0 Hz, 1H), 3.77 (m, 1H), 4.17 (d, J=15.0 Hz, 1H), 4.57 (m, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H). Anal. Calcd for C20H27F3N2O.HCl.0.25H2O: C, 58.68; H, 7.02; N, 6.84. Found: C, 58.68; H, 6.84; N, 6.69. The reaction mixture was cooled to 0→5oC The reaction mixture was stirred for 24 h The reaction mixture was then poured on to excess of ice-cold saturated aqueous NaHCO3 solution stirred for 30 min After dilution with CH2Cl2, the organic was separated washed with saturated salt solution dried over anhydrous Na2SO4 Removal of solvent gave a brown oil which

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-trifluoromethylphenyl acetic acid (1.45 g, 7.08 mmol) in 10 mL of dry CH2Cl2 under a nitrogen atmosphere was added 1-hydroxybenzotriazole hydrate (HOBT) (0.95 g, 7.08 mmol) and stirred. The reaction mixture was cooled to 0→5° C. and added solid EDCI ([1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl]) (1.35 g, 7.08 mmol) and stirrat this temperature for 30 min. A solution (±) 3 (1.0 g, 5.48 mmol) in 10 mL of dry CH2Cl2 was added followed by N,N-diisopropylethylamine (Hunig's Base) (0.915 g, 7.08 mmol). The reaction mixture was stirred for 24 h while warming to the room temperature. The reaction mixture was then poured on to excess of ice-cold saturated aqueous NaHCO3 solution and stirred for 30 min. After dilution with CH2Cl2, the organic was separated, washed with saturated salt solution, and dried over anhydrous Na2SO4. Removal of solvent gave a brown oil which was chromatographed on a silica gel column [solvent system: CH2Cl2:CH3OH:28% NH4OH (99:1:2)] to give the desired product as free base. The hydrochloride salt was prepared from 1M etherial HCl and recrystallized from CH2Cl2:Et2O (1:1) to give (±) 5 g HCl as a cream colored solid, 0.68 g (30%); 213-215° C.; 1H NMR (200 MHz, CDCl3) δ1.02-1.47 (m, 4H), 1.52-2.22 (m, 8H), 2.75-2.90 (m, 2H), 2.94 (s, 3H), 3.07 (m, 1H), 3.37 (m, 1H), 3.62 (d, J=15.0 Hz, 1H), 3.77 (m, 1H), 4.17 (d, J=15.0 Hz, 1H), 4.57 (m, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H). Anal. Calcd for C20H27F3N2O.HCl.0.25H2O: C, 58.68; H, 7.02; N, 6.84. Found: C, 58.68; H, 6.84; N, 6.69. The reaction mixture was stirred for 24 h while warming to the room temperature The reaction mixture was then poured on to excess of ice-cold saturated aqueous NaHCO3 solution stirred for 30 min After dilution with CH2Cl2, the organic was separated washed with saturated salt solution dried over anhydrous Na2SO4 Removal of solvent gave a brown oil which was chromatographed on a silica gel column [solvent system: CH2Cl2:CH3OH:28% NH4OH (99:1:2)]

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

実験手順: To a solution of 4-trifluoromethylphenyl acetic acid (1.45 g, 7.08 mmol) in 10 mL of dry CH2Cl2 under a nitrogen atmosphere was added 1-hydroxybenzotriazole hydrate (HOBT) (0.95 g, 7.08 mmol) and stirred. The reaction mixture was cooled to 0→45° C. and solid EDCI ([1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl]) (1.35 g, 7.08 mmol) was added and stirred at this temperature for 30 mm. A solution of (±) 3 (1.0 g, 5.48 mmol) in 10 mL of dry CH2Cl2 was added followed by N,N-diisopropylethylamine (Hunig's Base) (0.915 g, 7.08 mmol). The reaction mixture was stirred for 24 h while warming to room temperature. The reaction mixture was then poured onto excess of ice-cold saturated aqueous NaHCO3 solution and stirred for 30 min. After dilution with CH2Cl2, the organic layer was separated, washed with saturated salt solution, and dried over anhydrous Na2SO4. Removal of solvent gave a brown oil which was chromatographed on a silica gel column [solvent system: CH2Cl2:CH3OH:28% NH4OH (99:1:2)] to give the desired product as free base. The hydrochloride salt was prepared from 1M etherial HCl and recrystallized from CH2Cl2:Et2O (1:1) to give (±) 5g HCl as a cream colored solid. 0.68 g (30%); 213-215° C.; 1H NMR (200 MHz, CDCl3) δ 1.02-1.47 (m, 4H), 1.52-2.22 (m, 8H), 2.75-2.90 (m, 2H), 2.94 (s, 3H), 3.07 (m, 1H), 3.37 (m, 1H), 3.62 (d, J=15.0 Hz, 1H), 3.77 (m, 1H), 4.17 (d, J=15.0 Hz, 1H), 4.57 (m, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H). Anal. Calcd for C20H27F3N2O.HCl.0.25H2O: C, 58.68; H, 7.02; N, 6.84. Found: C, 58.68; H, 6.84; N, 6.69. was added stirred at this temperature for 30 mm The reaction mixture was stirred for 24 h The reaction mixture was then poured onto excess of ice-cold saturated aqueous NaHCO3 solution stirred for 30 min After dilution with CH2Cl2, the organic layer was separated washed with saturated salt solution dried over anhydrous Na2SO4 Removal of solvent gave a brown oil which was chromatographed on a silica gel column [solvent system: CH2Cl2:CH3OH:28% NH4OH (99:1:2)]

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

実験手順: 7-Methyl-7-azabicyclo[4.1.0]heptane (7.0 g, 0.063 mol) from the previous step, 17.92 g (0.25 mol) of pyrrolidine, 0.16 g of ammonium chloride, and 10 ml of water were stirred and heated under reflux for 21 hours. The solution was then cooled and solid sodium hydroxide was added and the mixture was extracted three times with 50-ml portions of ether. The combined extracts were dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield a residual brown oil. This residue was distilled under high vacuum to yield 6.0 g of colorless trans-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine, bp 95° C. (high vacuum). heated under reflux for 21 hours The solution was then cooled the mixture was extracted three times with 50-ml portions of ether The combined extracts were dried over anhydrous magnesium sulfate evaporated under reduced pressure to yield a residual brown oil This residue was distilled under high vacuum

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

実験手順: 7-Methyl-7-azabicyclo[4.1.0]heptane (7.0 g, 0.063 mol) from the previous step, 17.92 g (0.25 mol) of pyrrolidine, 0.16 g of ammonium chloride, and 10 ml of water were stirred and heated under reflux for 21 hours. The solution was then cooled and solid sodium hydroxide was added and the mixture was extracted three times with 50-ml portions of ether. The combined extracts were dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield a residual brown oil. This residue was distilled under high vacuum to yield 6.0 g of colorless trans-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine, bp 95° C. (high vacuum). heated under reflux for 21 hours The solution was then cooled the mixture was extracted three times with 50-ml portions of ether The combined extracts were dried over anhydrous magnesium sulfate evaporated under reduced pressure to yield a residual brown oil This residue was distilled under high vacuum

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

実験手順: Trans-N-Methyl-2-(1-pyrrolidinyl]cyclohexanamine (0.182 g) was dissolved in methylene chloride (10 ml) and stirred at room temperature. The acid chloride of 4-chlorophenoxyacetic acid (0.205 g) dissolved in methylene chloride (10 ml) was added and let stand for 12 hours. Ether was added to rapidly stirred solution until no more precipitate appeared. After further rapid stirring for one hour, the precipitate was filtered and dried in a vacuum oven at 90° C. for one hour, and stored in a predried bottle. The product was in the form of white needles (360 mg) mp 184°-186° C. was added After further rapid stirring for one hour the precipitate was filtered dried in a vacuum oven at 90° C. for one hour

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

実験手順: A mixture of 7-methyl-7-azabicyclo[4.1.0]heptane (7.0 g, 0.063M), pyrrolidine (17.92 g, 0.25M), water (10 ml) and ammonium chloride (0.16 g) was stirred and refluxed for 21 hours. The solution was cooled and solid sodium hydroxide added and extracted with ether (3×50 ml). The extracts were dried over magnesium sulphate and evaporated under reduced pressure to a brown oil. This was distilled under high vacuum to yield a colorless oil. refluxed for 21 hours The solution was cooled extracted with ether (3×50 ml) The extracts were dried over magnesium sulphate evaporated under reduced pressure to a brown oil This was distilled under high vacuum to yield a colorless oil

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

実験手順: A mixture of 7-methyl-7-azabicyclo[4.1.0]heptane (7.0 g, 0.063M), pyrrolidine (17.92 g, 0.25M), water (10 ml) and ammonium chloride (0.16 g) was stirred and refluxed for 21 hours. The solution was cooled and solid sodium hydroxide added and extracted with ether (3×50 ml). The extracts were dried over magnesium sulphate and evaporated under reduced pressure to a brown oil. This was distilled under high vacuum to yield a colorless oil. refluxed for 21 hours The solution was cooled extracted with ether (3×50 ml) The extracts were dried over magnesium sulphate evaporated under reduced pressure to a brown oil This was distilled under high vacuum to yield a colorless oil

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

実験手順: Trans-N-Methyl-2-(1-pyrrolidinyl]cyclohexanamine (0.182 g) was dissolved in methylene chloride (10 ml) and stirred at room temperature. The acid chloride of 4-chlorophenoxyacetic acid (0.205 g) dissolved in methylene chloride (10 ml) was added and let stand for 12 hours. Ether was added to rapidly stirred solution until no more precipitate appeared. After further rapid stirring for one hour, the precipitate was filtered and dried in a vacuum oven at 90° C. for one hour, and stored in a predried bottle. The product was in the form of white needles (360 mg) mp 184°-186° C. was added After further rapid stirring for one hour the precipitate was filtered dried in a vacuum oven at 90° C. for one hour

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

実験手順: Trans-N-Methyl-2-(1-pyrrolidinyl]cyclohexanamine (0.182 g) was dissolved in methylene chloride (10 ml) and stirred at room temperature. The acid chloride of 4-chlorophenoxyacetic acid (0.205 g) dissolved in methylene chloride (10 ml) was added and let stand for 12 hours. Ether was added to rapidly stirred solution until no more precipitate appeared. After further rapid stirring for one hour, the precipitate was filtered and dried in a vacuum oven at 90° C. for one hour, and stored in a predried bottle. The product was in the form of white needles (360 mg) mp 184°-186° C. was added After further rapid stirring for one hour the precipitate was filtered dried in a vacuum oven at 90° C. for one hour

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

実験手順: A mixture of 7-methyl-7-azabicyclo[4.1.0] heptane (7.0 g, 0.063 M), pyrrolidine (17.92 g, 0.25 M), water (10 ml) and ammonium chloride (0.16 g) was stirred and refluxed for 21 hours. The solution was cooled and solid sodium hydroxide added and extracted with ether (3×50 ml). The extracts were dried over magnesium sulphate and evaporated under reduced pressure to a brown oil. This was distilled under high vacuum to yield a colorless oil. refluxed for 21 hours The solution was cooled extracted with ether (3×50 ml) The extracts were dried over magnesium sulphate evaporated under reduced pressure to a brown oil This was distilled under high vacuum to yield a colorless oil

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

実験手順: Triethylamine (139 μl, 1 mmol) was added to a solution of 1H-indole-1-acetic acid (175 mg, 1 mmol) in tetrahydrofuran (10 ml) at -15° C. with vigorous stirring. Ethyl chloroformate (96 μl, 1 mmol) was added, and the mixture stirred for five minutes. A solution of trans-(±)-N-methyl-2-(1-pyrrolidinyl)-cyclohexanamine (182 mg, 1 mmol) in tetrahydrofuran (2 ml) was added, and stirring continued for 30 minutes at -15° C., then 30 minutes at room temperature. The reaction was evaporated to small volume, the residue dissolved in ethyl acetate (50 ml), and washed with saturated sodium biocarbonate solution (3×50 ml). The organic extract was drige (MgSO4), evaporated under reduced pressure, and recrystallized from diethyl ether/methylene chloride to yield the amide (100 mg, 32%); Vmax C=0 1635 cm-1. stirring continued for 30 minutes at -15° C. 30 minutes at room temperature The reaction was evaporated to small volume the residue dissolved in ethyl acetate (50 ml) washed with saturated sodium biocarbonate solution (3×50 ml) The organic extract evaporated under reduced pressure recrystallized from diethyl ether/methylene chloride