(R) - (-) -2- (4-methoxyphenyl) -1-methylethylamine hydrochloride

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

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

Procedure: A solution of 32 g (0.21 mol) of 4'-methoxyacetophenone and 165 g (2.1 mol) of ammonium acetate in 450 ml of methanol is combined with 13.5 g (0.21 mol) of sodium cyanoborohydride, which is added in batches thereto at ambient temperature, with stirring. After a further 20 hours, ice is added and the mixture is acidified with hydrochloric acid (conc. HCl H2O=1/1) until the pH is 2. The acidic solution is extracted with dichloromethane. The aqueous phase is then mixed with conc. ammonia, with cooling, until a clearly alkaline reaction occurs and then extracted exhaustively with dichloromethane. The combined dichloromethane extracts are dried over sodium sulphate and evaporated to dryness in vacuo. The crude 2-(4-methoxyphenyl)-1-methylethylamine thus obtained is purified by column chromatography over silica gel (eluant: dichloro-methane/methanol=20/1) to remove any by-products. A colorless oil is obtained which can be used for reaction without any further purification. is added in batches ice is added The acidic solution is extracted with dichloromethane The aqueous phase is then mixed with conc. ammonia with cooling, until a clearly alkaline reaction extracted exhaustively with dichloromethane The combined dichloromethane extracts are dried over sodium sulphate evaporated to dryness in vacuo

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

Procedure: A solution of 32 g (0.21 mol) of 4'-methoxyacetophenone and 165 g (2.1 mol) of ammonium acetate in 450 ml of methanol is combined with 13.5 g (0.21 mol) of sodium cyanoborohydride, which is added in batches thereto at ambient temperature, with stirring. After a further 20 hours, ice is added and the mixture is acidified with hydrochloric acid (conc. HCl H2O=1/1) until the pH is 2. The acidic solution is extracted with dichloromethane. The aqueous phase is then mixed with conc. ammonia, with cooling, until a clearly alkaline reaction occurs and then extracted exhaustively with dichloromethane. The combined dichloromethane extracts are dried over sodium sulphate and evaporated to dryness in vacuo. The crude 2-(4-methoxyphenyl)-1-methylethylamine thus obtained is purified by column chromatography over silica gel (eluant: dichloro-methane/methanol=20/1) to remove any by-products. A colorless oil is obtained which can be used for reaction without any further purification. is added in batches ice is added The acidic solution is extracted with dichloromethane The aqueous phase is then mixed with conc. ammonia with cooling, until a clearly alkaline reaction extracted exhaustively with dichloromethane The combined dichloromethane extracts are dried over sodium sulphate evaporated to dryness in vacuo

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

Procedure: In 6 ml of pyridine was dissolved 1.5 g of (-)-2-(p-methoxyphenyl)-1-methylethylamine ([α]D23 : -30.1° (c=1.2, methanol)), and after adding thereto 3 ml of acetic anhydride, the mixture was allowed to stand at room temperature for 1 hour. After distilling off the solvent, the residue was extracted with ethyl acetate. The ethyl acetate extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was distilled off and the crude crystals formed were recrystallized from a mixture of n-hexane and benzene to provide 1.8 g of (R)(+)-N-acetyl-2-(p-methoxyphenyl)-1-methylethylamine. after adding After distilling off the solvent the residue was extracted with ethyl acetate The ethyl acetate extract was washed with water dried over anhydrous sodium sulfate the solvent was distilled off the crude crystals formed were recrystallized from a mixture of n-hexane and benzene

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

Procedure: A solution of 32 g (0.21 mol) of 4'-methoxyacetophenone and 165 g (2.1 mol) of ammonium acetate in 450 ml of methanol is combined with 13.5 g (0.21 mol) of sodium cyanoborohydride, which is added in batches thereto at ambient temperature, with stirring. After a further 20 hours, ice is added and the mixture is acidified with hydrochloric acid (conc. HCl H2O=1/1) until the pH is 2. The acidic solution is extracted with dichloromethane. The aqueous phase is then mixed with conc. ammonia, with cooling, until a clearly alkaline reaction occurs and then extracted exhaustively with dichloromethane. The combined dichloromethane extracts are dried over sodium sulphate and evaporated to dryness in vacuo. The crude 2-(4-methoxyphenyl)-1-methylethylamine thus obtained is purified by column chromatography over silica gel (eluant: dichloro-methane/methanol=20/1) to remove any by-products. A colorless oil is obtained which can be used for reaction without any further purification. is added in batches ice is added The acidic solution is extracted with dichloromethane The aqueous phase is then mixed with conc. ammonia with cooling, until a clearly alkaline reaction extracted exhaustively with dichloromethane The combined dichloromethane extracts are dried over sodium sulphate evaporated to dryness in vacuo

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

Procedure: 2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2-(4-methoxyphenyl)-1-methylethylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-[2-(4-methoxyphenyl)-1-methylethyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.41 min, MH+ 442. The DMF was evaporated under vacuum the residue partitioned between DCM (0.4 ml) and water (0.4 ml) The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) the DCM evaporated under vacuum The residue was purified by mass

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

Procedure: In 6 ml of pyridine was dissolved 1.5 g of (-)-2-(p-methoxyphenyl)-1-methylethylamine ([α]D23 : -30.1° (c=1.2, methanol)), and after adding thereto 3 ml of acetic anhydride, the mixture was allowed to stand at room temperature for 1 hour. After distilling off the solvent, the residue was extracted with ethyl acetate. The ethyl acetate extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was distilled off and the crude crystals formed were recrystallized from a mixture of n-hexane and benzene to provide 1.8 g of (R)(+)-N-acetyl-2-(p-methoxyphenyl)-1-methylethylamine. after adding After distilling off the solvent the residue was extracted with ethyl acetate The ethyl acetate extract was washed with water dried over anhydrous sodium sulfate the solvent was distilled off the crude crystals formed were recrystallized from a mixture of n-hexane and benzene

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

Procedure: 7-Methoxy-1,2,3,4-tetrahydro-isoquinoline and 1,2,3,4-tetrahydro-isoquinolin-7-ol were prepared by a literature procedure (J. Med. Chem. 1987, 30, 2208–2216). 2-(4-Methoxy-phenyl)-1-methyl-ethylamine required for the preparation of 3-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ol was obtained from 1-(4-methoxy-phenyl)-propan-2-one by Procedure X and was subsequently converted to the tetrahydroisoquinoline by the same literature method.

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

Procedure: 2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2-(4-methoxyphenyl)-1-methylethylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-[2-(4-methoxyphenyl)-1-methylethyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.41 min, MH+ 442. The DMF was evaporated under vacuum the residue partitioned between DCM (0.4 ml) and water (0.4 ml) The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) the DCM evaporated under vacuum The residue was purified by mass

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

Procedure: In 6 ml of pyridine was dissolved 1.5 g of (-)-2-(p-methoxyphenyl)-1-methylethylamine ([α]D23 : -30.1° (c=1.2, methanol)), and after adding thereto 3 ml of acetic anhydride, the mixture was allowed to stand at room temperature for 1 hour. After distilling off the solvent, the residue was extracted with ethyl acetate. The ethyl acetate extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was distilled off and the crude crystals formed were recrystallized from a mixture of n-hexane and benzene to provide 1.8 g of (R)(+)-N-acetyl-2-(p-methoxyphenyl)-1-methylethylamine. after adding After distilling off the solvent the residue was extracted with ethyl acetate The ethyl acetate extract was washed with water dried over anhydrous sodium sulfate the solvent was distilled off the crude crystals formed were recrystallized from a mixture of n-hexane and benzene

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

Procedure: 7-Methoxy-1,2,3,4-tetrahydro-isoquinoline and 1,2,3,4-tetrahydro-isoquinolin-7-ol were prepared by a literature procedure (J. Med. Chem. 1987, 30, 2208–2216). 2-(4-Methoxy-phenyl)-1-methyl-ethylamine required for the preparation of 3-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ol was obtained from 1-(4-methoxy-phenyl)-propan-2-one by Procedure X and was subsequently converted to the tetrahydroisoquinoline by the same literature method.