methyl (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Grignard reagent was made in a three necked reaction flask equipped with mechanical stirring, an intensive condenser and a pressure equilibrated funnel, using 4-bromo-fluorobenzene (55 ml, 500 mmol) and magnesium turnings (12.6 g, 520 mmol) in 500 ml absolute diethyl ether. The solution of grignard reagent was cooled to -20° C. and a solution of (-)-anhydroecgonine methyl ester (43 g, 233 mmol) in 200 ml absolute diethyl ether was added over 1/2 hour. The reaction was first stirred one hour at -20° C. and then 16 hours at room temperature and was finally quenched by addition of water (50 ml). The mixture was acidified by addition of hydrochloric acid (4M, 50 ml) and the aqueous phase was washed twice with diethyl ether. To the aqueous phase was added ammonium hydroxide (25%) to basic reaction and the resulting mixture was finally extracted three times with diethyl ether. After drying and concentration of the combined organic phase in vacuo. the crude product was subjected to column chromatography using diethyl ether+triethyl amine (5%) as eluent, yielding (1R,2S,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, white crystals m.p. 178°-180° C. and (1R,2R,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, white crystals m.p. 124°-140° C. equipped with mechanical stirring, an intensive condenser 16 hours at room temperature and was finally quenched by addition of water (50 ml) The mixture was acidified by addition of hydrochloric acid (4M, 50 ml) the aqueous phase was washed twice with diethyl ether To the aqueous phase was added ammonium hydroxide (25%) to basic reaction the resulting mixture was finally extracted three times with diethyl ether After drying

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The anhydroecgonine methyl ester 1 (leq.) is dissolved in 25 ml of anhydrous ether and then added to 5 eq. of (methylphenyl) magnesium bromide at −40° C. After 3 hours of mechanical stirring, the mixture is cooled to −78° C. and treated drop by drop with a solution of 5 ml of trifluoroacetic acid diluted in 25 ml of anhydrous ether. After one hour's stirring, the mixture is brought to 0° C. and then treated with 70 ml of water and 26 ml of concentrated HCl. The aqueous phase is then treated with NH4OH and extracted with ether (3×40 ml). The different organic phases are collected, washed in brine, dried on Na2SO4 and evaporated to produce compound 2 with a yield of 30%. is brought to 0° C. extracted with ether (3×40 ml) The different organic phases are collected washed in brine dried on Na2SO4 evaporated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The anhydroecgonine methyl ester 1 (leq.) is dissolved in 25 ml of anhydrous ether and then added to 5 eq. of (methylphenyl) magnesium bromide at −40° C. After 3 hours of mechanical stirring, the mixture is cooled to −78° C. and treated drop by drop with a solution of 5 ml of trifluoroacetic acid diluted in 25 ml of anhydrous ether. After one hour's stirring, the mixture is brought to 0° C. and then treated with 70 ml of water and 26 ml of concentrated HCl. The aqueous phase is then treated with NH4OH and extracted with ether (3×40 ml). The different organic phases are collected, washed in brine, dried on Na2SO4 and evaporated to produce compound 2 with a yield of 30%. is brought to 0° C. extracted with ether (3×40 ml) The different organic phases are collected washed in brine dried on Na2SO4 evaporated

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Grignard reagent was made in a three necked reaction flask equipped with mechanical stirring, an intensive condenser and a pressure equilibrated funnel, using 4-bromo-fluorobenzene (55 ml, 500 mmol) and magnesium turnings (12.6 g, 520 mmol) in 500 ml absolute diethyl ether. The solution of grignard reagent was cooled to -20° C. and a solution of (-)-anhydroecgonine methyl ester (43 g, 233 mmol) in 200 ml absolute diethyl ether was added over 1/2 hour. The reaction was first stirred one hour at -20° C. and then 16 hours at room temperature and was finally quenched by addition of water (50 ml). The mixture was acidified by addition of hydrochloric acid (4M, 50 ml) and the aqueous phase was washed twice with diethyl ether. To the aqueous phase was added ammonium hydroxide (25%) to basic reaction and the resulting mixture was finally extracted three times with diethyl ether. After drying and concentration of the combined organic phase in vacuo, the crude product was subjected to column chromatography using diethyl ether+triethyl amine (5%) as eluent, yielding (1R,2S,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, white crystals m.p. 178°-180° C. and (1R,2R,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, white crystals m.p. 124°-140° C. equipped with mechanical stirring, an intensive condenser 16 hours at room temperature and was finally quenched by addition of water (50 ml) The mixture was acidified by addition of hydrochloric acid (4M, 50 ml) the aqueous phase was washed twice with diethyl ether To the aqueous phase was added ammonium hydroxide (25%) to basic reaction the resulting mixture was finally extracted three times with diethyl ether After drying

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Grignard reagent was made in a three necked reaction flask equipped with mechanical stirring, an intensive condenser and a pressure equilibrated funnel, using 4-bromo-fluorobenzene (55 ml, 500 mmol) and magnesium turnings (12.6 g, 520 mmol) in 500 ml absolute diethyl ether. The solution of grignard reagent was cooled to -20° C. and a solution of (-)-anhydroecgonine methyl ester (43 g, 233 mmol) in 200 ml absolute diethyl ether was added over 1/2 hour. The reaction was first stirred one hour at -20° C. and then 16 hours at room temperature and was finally quenched by addition of water (50 ml). The mixture was acidified by addition of hydrochloric acid (4M, 50 ml) and the aqueous phase was washed twice with diethyl ether. To the aqueous phase was added ammonium hydroxide (25%) to basic reaction and the resulting mixture was finally extracted three times with diethyl ether. After drying and concentration of the combined organic phase in vacuo, the crude product was subjected to column chromatography using diethyl ether+triethyl amine (5%) as eluent, yielding (1R,2S,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, white crystals m.p. 178°-180° C. and (1R,2R,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, white crystals m.p. 124°-140° C. equipped with mechanical stirring, an intensive condenser 16 hours at room temperature and was finally quenched by addition of water (50 ml) The mixture was acidified by addition of hydrochloric acid (4M, 50 ml) the aqueous phase was washed twice with diethyl ether To the aqueous phase was added ammonium hydroxide (25%) to basic reaction the resulting mixture was finally extracted three times with diethyl ether After drying

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Grignard reagent was made in a three necked reaction flask equipped with mechanical stirring, an intensive condenser and a pressure equilibrated funnel, using 4-bromo-fluorobenzene (55 ml, 500 mmol) and magnesium turnings (12.6 g, 520 mmol) in 500 ml absolute diethyl ether. The solution of grignard reagent was cooled to -20° C. and a solution of (-)-anhydroecgonine methyl ester (43 g, 233 mmol) in 200 ml absolute diethyl ether was added over 1/2 hour. The reaction was first stirred one hour at -20° C. and then 16 hours at room temperature and was finally quenched by addition of water (50 ml). The mixture was acidified by addition of hydrochloric acid (4M, 50 ml) and the aqueous phase was washed twice with diethyl ether. To the aqueous phase was added ammonium hydroxide (25%) to basic reaction and the resulting mixture was finally extracted three times with diethyl ether. After drying and concentration of the combined organic phase in vacuo, the crude product was subjected to column chromatography using diethyl ether+triethyl amine (5%) as eluent, yielding (1R,2S,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, white crystals m.p. 178°-180° C. and (1R,2R,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, white crystals m.p. 124°-140° C. equipped with mechanical stirring, an intensive condenser 16 hours at room temperature and was finally quenched by addition of water (50 ml) The mixture was acidified by addition of hydrochloric acid (4M, 50 ml) the aqueous phase was washed twice with diethyl ether To the aqueous phase was added ammonium hydroxide (25%) to basic reaction the resulting mixture was finally extracted three times with diethyl ether After drying

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

Procedure: The title compound was prepared by modification of a reported procedure used to prepare other similar compounds.refThus, using anhydroecgonine methyl ester (500 mg, 2.76 mmol) and 3-methyl-4-fluorophenyl magnesium bromide (prepared from 200 mg of magnesium metal and 1 mL of 3-methyl-4-fluoro-1-bromobenzene) yielded 234 mg (29%) of the title compound. The hydrochloride salt had mp 163°-165° C.; [α]D25 -103.8° (c 0.08, MeOH); 1H NMR of free base of 41 (250 MHz, CDCl3) δ1.67 (m, 3), 2.15 (m, 2), 2.19 is, 3, CH3), 2.20 is, 3, NCH3), 2.55 (m, 2), 2.87 (m, 1, H-2), 2.93 (m, 1, H-3), 3.35 (m, 1, H-5), 3.49 (s, 3, OCH3), 3.55 (m, 1, H-1), 6.85, 6.97 (m, 3, C6H3). The title compound was prepared by modification of a reported procedure to prepare other similar compounds.refThus

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

Procedure: Acetamide oxime (500 mg, 6.75 mmol) suspended in THF (50 mL) under nitrogen was heated at 60° C. with NaH (132 mg, 5.5 mmol in oil dispersion) for 1 h. Anhydroecgonine methyl ester (2.76 mmol) and 4 Å° molecular sieves (2 g) were added and the reaction mixture heated under reflux for 3 h. After cooling, the reaction mixture was filtered and the solvent removed in vacuo. The residue was chromatographed on a silica gel column eluting with CHCl3 --CH3OH (95:5) to give the free base. the reaction mixture heated under reflux for 3 h After cooling the reaction mixture was filtered the solvent removed in vacuo The residue was chromatographed on a silica gel column eluting with CHCl3 --CH3OH (95:5) to give the free base

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Grignard reagent was made in a three necked reaction flask equipped with mechanical stirring, an intensive condenser and a pressure equilibrated funnel, using 4-bromo-fluorobenzene (55 ml, 500 mmol) and magnesium turnings (12.6 g, 520 mmol) in 500 ml absolute diethyl ether. The solution of grignard reagent was cooled to -20° C. and a solution of (-)-anhydroecgonine methyl ester (43 g, 233 mmol) in 200 ml absolute diethyl ether was added over 1/2 hour. The reaction was first stirred one hour at -20° C. and then 16 hours at room temperature and was finally quenched by addition of water (50 ml). The mixture was acidified by addition of hydrochloric acid (4M, 50 ml) and the aqueous phase was washed twice with diethyl ether. To the aqueous phase was added ammonium hydroxide (25%) to basic reaction and the resulting mixture was finally extracted three times with diethyl ether. After drying and concentration of the combined organic phase in vacuo, the crude product was subjected to column chromatography using diethyl ether+triethyl amine (5%) as eluent, yielding (1R,2S,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, white crystals m.p. 178°-180° C. and (1R,2R,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, white crystals m.p. 124°-140° C. equipped with mechanical stirring, an intensive condenser 16 hours at room temperature and was finally quenched by addition of water (50 ml) The mixture was acidified by addition of hydrochloric acid (4M, 50 ml) the aqueous phase was washed twice with diethyl ether To the aqueous phase was added ammonium hydroxide (25%) to basic reaction the resulting mixture was finally extracted three times with diethyl ether After drying

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a three-neck, round-bottomed flask containing freshly distilled ether (125 mL) and magnesium turnings (268 mg, 11.0 mmol),was added 3,4-dichloroiodobenzene (2.26 g, 8.27 mmol). After 2 h, the reaction flask was equipped with a mechanical stirrer, and the Grignard reagent was cooled to -55° C. before adding anhydroecgonine methyl ester (500 mg, 2.75 mmol). The resulting solution was stirred for an additional 2.5 h before being cooled to -78° C. After 1 h, 2 mL of trifluoroacetic acid was added to the solution followed by 2 h of stirring. The quenched reaction mixture was then diluted with 1N HCl (100 mL) and extracted with ether (3×100 mL). The ethereal layers were discarded, and the aqueous layer was basified with conc. ammonium hydride and then extracted with chloroform (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield the crude product as a colorless oil. Flash chromatography (ether triethylamine, 9:1) yielded 71 mg (9.0%) of pure product: 1H NMR (250 MHz, CDCl3) δ1.52-1.76 (m, 2), 1.81-1.95 (m, 2), 1.96-2.22 (m, 2), 2.38 (s, 3), 3.07-3.15 (br s, 2), 3.21-3.32 (br s, 1), 3.45-3.65 (m, 1), 3.50 (s, 3), 7.10-7.38 (m, 3). the reaction flask was equipped with a mechanical stirrer After 1 h followed by 2 h of stirring The quenched reaction mixture extracted with ether (3×100 mL) extracted with chloroform (3×50 mL) The combined organic layers were dried (MgSO4) concentrated under reduced pressure to yield the crude product as a colorless oil

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

Procedure: Acetamide oxime (500 mg, 6.75 mol) suspended in THF (50 mL) under nitrogen was heated at 60° C. with NaH (132 mg, 5.5 mmol in oil dispersion) for 1 h. Anhydroecgonine methyl ester (2.76 ml) and 4 A° molecular sieves (2 g) were added and the reaction mixture heated under reflux for 3 h. After cooling, the reaction mixture was filtered and the solvent removed in vacuo. The residue was chromatographed on a silica gel column eluting with CHCl3 --CH3OH (95:5) to give the free base. the reaction mixture heated under reflux for 3 h After cooling the reaction mixture was filtered the solvent removed in vacuo The residue was chromatographed on a silica gel column eluting with CHCl3 --CH3OH (95:5) to give the free base

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Grignard reagent was made in a three necked reaction flask equipped with mechanical stirring, an intensive condenser and a pressure equilibrated funnel, using 4-bromo-fluorobenzene (55 ml, 500 mmol) and magnesium turnings (12.6 g, 520 mmol) in 500 ml absolute diethyl ether. The solution of grignard reagent was cooled to -20° C. and a solution of (-)-anhydroecgonine methyl ester (43 g, 233 mmol) in 200 ml absolute diethyl ether was added over 1/2 hour. The reaction was first stirred one hour at -20° C. and then 16 hours at room temperature and was finally quenched by addition of water (50 ml). The mixture was acidified by addition of hydrochloric acid (4M, 50 ml) and the aqueous phase was washed twice with diethyl ether. To the aqueous phase was added ammonium hydroxide (25%) to basic reaction and the resulting mixture was finally extracted three times with diethyl ether. After drying and concentration of the combined organic phase in vacuo the crude product was subjected to column chromatography using diethyl ether+triethyl amine (5%) as eluent, yielding (1R,2S,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, white crystals m.p. 178°-180° C. and (1R,2R,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, white crystals m.p. 124°-140° C. equipped with mechanical stirring, an intensive condenser 16 hours at room temperature and was finally quenched by addition of water (50 ml) The mixture was acidified by addition of hydrochloric acid (4M, 50 ml) the aqueous phase was washed twice with diethyl ether To the aqueous phase was added ammonium hydroxide (25%) to basic reaction the resulting mixture was finally extracted three times with diethyl ether After drying