2-(dimethylamino)-1-phenylpropan-1-ol

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

Procedure: A solution of 12.5 g (70 mmols) of the (+)-antipode of N-methyl-ephedrine in 140 ml of absolute diethyl ether is added dropwise, at 20° C., to a stirred suspension of 2.7 g (70 mmols) of lithium aluminum hydride in 70 ml of diethyl ether. The mixture is heated under reflux for 30 minutes and then cooled to 20° C., 17 g (140 mmols) of N-ethylaniline are added dropwise, and the mixture is allowed to boil under reflux for one hour. Thereafter, the reaction mixture is cooled to -70° C. A solution of 5.2 g (20 mmols) of the (E)-isomer of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-ene-3-one in 50 ml of absolute diethyl ether is added dropwise at this temperature. Stirring is continued for a further 4 hours at -70° C., and the reaction mixture is then allowed to stand for a further 16 hours at - 70° C. Water is then added slowly. The resulting reaction mixture is acidified with 10% strength aqueous hydrochloric acid so that the pH value is about 4. Thereafter, the organic phase is separated off, and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed twice with 5% strength aqueous hydrochloric acid, dried over magnesium sulphate and then evaporated down under reduced pressure. The crystalline residue which remains is stirred with cyclohexane, and the product is filtered off under suction, washed with cyclohexane and dried. 3.2 g (61% of theory) of the (+)-antipode of (E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-ene are obtained in the form of a crystalline product in this manner. The mixture is heated under reflux for 30 minutes under reflux for one hour Thereafter, the reaction mixture is cooled to -70° C to stand for a further 16 hours 70° C The resulting reaction mixture Thereafter, the organic phase is separated off the aqueous phase is extracted twice with ethyl acetate The combined organic phases are washed twice with 5% strength aqueous hydrochloric acid dried over magnesium sulphate evaporated down under reduced pressure The crystalline residue which remains is stirred with cyclohexane the product is filtered off under suction washed with cyclohexane dried

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

Procedure: With 1-phenylethylamine neither a satisfactory yield nor an adequate optical purity could be achieved. Quinine yielded enantiomer in good optical purity but poor yield, no yield was indicated for N-methylephedfine With 1,2-diphenylethylamine the yield is satisfactory and the optical purity very good but the reagent, as is also N-methylephedrine is very expensive. Further, it is known that 2,2-dimethylcyclopropanecarboxylic acid can be separated into the enantiomers by the diastereomeric menthyl esters, which can be obtained from the acid chloride with (+) or (-) menthol (U.S. Pat. No. 4,487,956). This process does provide usable yields and optical purities, but is relatively complicated in working up and requires the relatively expensive menthol. can be separated into the enantiomers by the diastereomeric menthyl esters, which

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

Procedure: A solution of 12.5 g (70 mmols) of the (+)-antipode of N-methyl-ephedrine in 140 ml of absolute diethyl ether is added dropwise, at 20° C., to a stirred suspension of 2.7 g (70 mmols) of lithium aluminum hydride in 70 ml of diethyl ether. The mixture is heated under reflux for 30 minutes and then cooled to 20° C., 17 g (140 mmols) of N-ethylaniline are added dropwise, and the mixture is allowed to boil under reflux for one hour. Thereafter, the reaction mixture is cooled to -70° C. A solution of 5.2 g (20 mmols) of the (E)-isomer of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-ene-3-one in 50 ml of absolute diethyl ether is added dropwise at this temperature. Stirring is continued for a further 4 hours at -70° C., and the reaction mixture is then allowed to stand for a further 16 hours at - 70° C. Water is then added slowly. The resulting reaction mixture is acidified with 10% strength aqueous hydrochloric acid so that the pH value is about 4. Thereafter, the organic phase is separated off, and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed twice with 5% strength aqueous hydrochloric acid, dried over magnesium sulphate and then evaporated down under reduced pressure. The crystalline residue which remains is stirred with cyclohexane, and the product is filtered off under suction, washed with cyclohexane and dried. 3.2 g (61% of theory) of the (+)-antipode of (E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-ene are obtained in the form of a crystalline product in this manner. The mixture is heated under reflux for 30 minutes under reflux for one hour Thereafter, the reaction mixture is cooled to -70° C to stand for a further 16 hours 70° C The resulting reaction mixture Thereafter, the organic phase is separated off the aqueous phase is extracted twice with ethyl acetate The combined organic phases are washed twice with 5% strength aqueous hydrochloric acid dried over magnesium sulphate evaporated down under reduced pressure The crystalline residue which remains is stirred with cyclohexane the product is filtered off under suction washed with cyclohexane dried

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

Procedure: With 1-phenylethylamine neither a satisfactory yield nor an adequate optical purity could be achieved. Quinine yielded enantiomer in good optical purity but poor yield, no yield was indicated for N-methylephedfine With 1,2-diphenylethylamine the yield is satisfactory and the optical purity very good but the reagent, as is also N-methylephedrine is very expensive. Further, it is known that 2,2-dimethylcyclopropanecarboxylic acid can be separated into the enantiomers by the diastereomeric menthyl esters, which can be obtained from the acid chloride with (+) or (-) menthol (U.S. Pat. No. 4,487,956). This process does provide usable yields and optical purities, but is relatively complicated in working up and requires the relatively expensive menthol. can be separated into the enantiomers by the diastereomeric menthyl esters, which

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

Procedure: With 1-phenylethylamine neither a satisfactory yield nor an adequate optical purity could be achieved. Quinine yielded enantiomer in good optical purity but poor yield, no yield was indicated for N-methylephedfine With 1,2-diphenylethylamine the yield is satisfactory and the optical purity very good but the reagent, as is also N-methylephedrine is very expensive. Further, it is known that 2,2-dimethylcyclopropanecarboxylic acid can be separated into the enantiomers by the diastereomeric menthyl esters, which can be obtained from the acid chloride with (+) or (-) menthol (U.S. Pat. No. 4,487,956). This process does provide usable yields and optical purities, but is relatively complicated in working up and requires the relatively expensive menthol. can be separated into the enantiomers by the diastereomeric menthyl esters, which

Conditions: temp:-73.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A chiral metal-hydrogen complex was formed in a manner similar to that in Example 1 by adding to 20 cc of an ethyl ether solution containing 0.63 g of LiAlH4 50 cc of an ethyl ether solution containing 3.05 g of N-methylephedrine followed by 20 cc of an ethyl ether solution containing 4.12 g of N-ethylaniline. To the resulting solution, was added at -70° C. 30 cc of an ethyl ether solution containing 1.62 g of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one. The resulting mixture was stirred at -73° C. for 5 hours under adiabatic conditions and left standing overnight at room temperature. To the mixture was added 60 cc of 2 N hydrochloric acid to effect decomposition. The organic layer was washed successively with 100 cc of a saturated sodium hydrogencarbonate solution and 100 cc of ice-cooled water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.82 g of crude crystals. The crude crystals were recrystallized three times from a cyclohexane-methanol mixture to obtain 0.41 g of (+)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol: [α]D24 +29.2 (c=1.0, CHCl3); melting point 160°-161° C. The NMR spectrum was identical with that of the racemate described in Reference Example 2. A chiral metal-hydrogen complex was formed in a manner similar to that in Example 1 To the resulting solution, was added at -70° C left standing overnight at room temperature The organic layer was washed successively with 100 cc of a saturated sodium hydrogencarbonate solution and 100 cc of ice- cooled water dried over anhydrous sodium sulfate concentrated under reduced pressure to obtain 1.82 g of crude crystals The crude crystals were recrystallized three times from a cyclohexane-methanol mixture

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

Procedure: N-Methylephedrine (200 mg; 1.12 mmol) was added to a solution of o-iodoxybenzoic acid I (1.56 g, 5.59 mmol) and trifluoroacetic acid (0.13 ml) in DMSO (12 ml). After 8 hours the solution was diluted with NaHCO3 (2.5%, 30 ml) and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (2×5 ml), dried over sodium sulfate and evaporated to dryness under vacuum to give 180 mg (90%) of 2-dimethylamino-1-phenyl-propan-1-one identical to the sample obtained in Example 31. extracted with ethyl acetate (3×10 ml) The combined organic layers were washed with water (2×5 ml) dried over sodium sulfate evaporated to dryness under vacuum

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

Procedure: N-Methylephedrine (500 mg, 2.79 mmol) was added to a solution of o-iodobenzoic acid I (7.8 g; 27.9 mmol) in DMSO (55 ml). After 48 hours the solution was diluted with NaHCO3 (2.5%, 30 ml) and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (2×5 ml), dried over sodium sulfate and evaporated to dryness under vacuum. The residue was purified by distillation to give 460 mg (92%) of 2-dimethylamino-1-phenyl-propan-1-one (boiling at 113°-117° C./12 mm). extracted with ethyl acetate (3×10 ml) The combined organic layers were washed with water (2×5 ml) dried over sodium sulfate evaporated to dryness under vacuum The residue was purified by distillation

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

Procedure: The aqueous layer and the 10% hydrochloric acid washings were joined and the joined solution was mixed with a 10% sodium hydroxide solution (30 ml) to adjust the pH to about 11 and extracted with ethyl acetate (50 ml×3). The extract was washed with a saturated saline solution (50 ml×3), dried and then ethyl acetate was distilled off to obtain a mixture of N-methylephedrine and N-ethylaniline. Yield: 2.4 g (100%). Said two substances can be recovered, separately by distilling the mixture under reduced pressure. extracted with ethyl acetate (50 ml×3) The extract was washed with a saturated saline solution (50 ml×3) dried ethyl acetate was distilled off to obtain can be recovered separately by distilling the mixture under reduced pressure

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 628 g (3.5 mols) of the (-)-antipode of N-methyl-ephedrine in 7.5 liters of tert.-butyl methyl ether is added dropwise to a suspension of 133 g (3.5 mols) of lithium aluminum hydride in 1.5 liters of tert.-butyl methyl ether in the course of 45 minutes at 20° C. under an argon atmosphere. Stirring is continued for 30 minutes at 40° C., after which the mixture is cooled to 10° C., and 848 g (7 mols) of N-ethyl-aniline are added in the course of 45 minutes. The mixture is stirred for a further hour at 40° C. and then cooled to -15° C., and a solution of 522 g (2 mols) of the (E)-isomer of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one in 4.7 liters of tert.-butyl methyl ether is then added dropwise in the course of 30 minutes, the temperature of the reaction mixture being kept at -10° C. to -15° C. The mixture is stirred for a further 16 hours at -15° C., and 8 liters of water are then added slowly. 3.5 liters of 10% strength aqueous hydrochloric acid are added to the resulting reaction mixture. Thereafter, the organic phase is separated off, and the aqueous phase is extracted with three times 2.5 liters of tert.-butyl methyl ether. Tbe combined organic phases are washed with twice 2 liters of water and then evaporated down under a pressure of 20 mbar. The crystalline residue which remains is stirred with cyclohexane, and the product is filtered off under suction and dried under reduced pressure at 35° C. In this manner, 466 g (87% of theory) of the (-)-antipode of (E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-ene are obtained in the form of a crystalline product. The mixture is stirred for a further hour at 40° C. cooled to -15° C. being kept at -10° C. to -15° C The mixture is stirred for a further 16 hours at -15° C. Thereafter, the organic phase is separated off the aqueous phase is extracted with three times 2.5 liters of tert.-butyl methyl ether Tbe combined organic phases are washed with twice 2 liters of water evaporated down under a pressure of 20 mbar The crystalline residue which remains is stirred with cyclohexane the product is filtered off under suction dried under reduced pressure at 35° C

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

Procedure: A solution of 12.5 g (70 mmols) of the (+)-antipode of N-methyl-ephedrine in 140 ml of absolute diethyl ether is added dropwise, at 20° C., to a stirred suspension of 2.7 g (70 mmols) of lithium aluminum hydride in 70 ml of diethyl ether. The mixture is heated under reflux for 30 minutes and then cooled to 20° C., 17 g (140 mmols) of N-ethylaniline are added dropwise, and the mixture is allowed to boil under reflux for one hour. Thereafter, the reaction mixture is cooled to -70° C. A solution of 5.2 g (20 mmols) of the (E)-isomer of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-ene-3-one in 50 ml of absolute diethyl ether is added dropwise at this temperature. Stirring is continued for a further 4 hours at -70° C., and the reaction mixture is then allowed to stand for a further 16 hours at - 70° C. Water is then added slowly. The resulting reaction mixture is acidified with 10% strength aqueous hydrochloric acid so that the pH value is about 4. Thereafter, the organic phase is separated off, and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed twice with 5% strength aqueous hydrochloric acid, dried over magnesium sulphate and then evaporated down under reduced pressure. The crystalline residue which remains is stirred with cyclohexane, and the product is filtered off under suction, washed with cyclohexane and dried. 3.2 g (61% of theory) of the (+)-antipode of (E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-ene are obtained in the form of a crystalline product in this manner. The mixture is heated under reflux for 30 minutes under reflux for one hour Thereafter, the reaction mixture is cooled to -70° C to stand for a further 16 hours 70° C The resulting reaction mixture Thereafter, the organic phase is separated off the aqueous phase is extracted twice with ethyl acetate The combined organic phases are washed twice with 5% strength aqueous hydrochloric acid dried over magnesium sulphate evaporated down under reduced pressure The crystalline residue which remains is stirred with cyclohexane the product is filtered off under suction washed with cyclohexane dried

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

Procedure: With 1-phenylethylamine neither a satisfactory yield nor an adequate optical purity could be achieved. Quinine yielded enantiomer in good optical purity but poor yield, no yield was indicated for N-methylephedfine With 1,2-diphenylethylamine the yield is satisfactory and the optical purity very good but the reagent, as is also N-methylephedrine is very expensive. Further, it is known that 2,2-dimethylcyclopropanecarboxylic acid can be separated into the enantiomers by the diastereomeric menthyl esters, which can be obtained from the acid chloride with (+) or (-) menthol (U.S. Pat. No. 4,487,956). This process does provide usable yields and optical purities, but is relatively complicated in working up and requires the relatively expensive menthol. can be separated into the enantiomers by the diastereomeric menthyl esters, which