异丙醇铝

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A flame-dried 1 L 3-necked flask, fitted with a 30 cm Vigreux column topped with a distillation head, an argon inlet tube and a magnetic stirring bar, was charged with 36.8 g (0.189 mol) of (3E,6R)-6,10-dimethyl-3,9-undecadien-2-one (GC purity 93.6%), 500 mL of iospropanol and 40.0 g (0.196 mol) of aluminum isopropoxide. The reaction mixture was stirred and heated to gentle reflux under argon. Acetone was allowed to distill off at a rate of about 30 drops/min. While maintaining a head temperature of ca. 80° C. After 3.5 hours the reaction was shown by GC to be almost complete with 5% of starting material remaining. The reaction was cooled in an ice bath and the pressure was reduced to ca. 54 mmHg. Isopropanol was distilled off at a head temperature of 30° C.-31° C. until the reaction mixture was concentrated to a volume of about 200 mL. The residual oil was cooled in an ice bath, 200 mL of 2N HCl were carefully added with stirring and the mixture was poured into a separatory funnel containing 200 mL of ether. An additional 200 mL of 2N HCl were added to dissolve some remaining white solid material. The layers were separated and the aqueous phase was extracted with 2×200 mL of ether. The combined organic layers were washed successively with 200 mL of sat. NaHCO3 -solution and 200 mL of brine, dried over MgSO4, filtered and concentrated on the rotovapor. The residue was dried at 0.1 mm for 30 minutes to afford 38.1 g (102.6%) of (2RS,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol as a light yellow liquid. GC analysis indicated a purity of 94.6%. This material was used as is in Example 2. A flame-dried 1 L 3-necked flask, fitted with a 30 cm Vigreux column heated to gentle reflux under argon to distill off at a rate of about 30 drops/min The reaction was cooled in an ice bath Isopropanol was distilled off at a head temperature of 30° C.-31° C. until the reaction mixture was concentrated to a volume of about 200 mL The residual oil was cooled in an ice bath 200 mL of 2N HCl were carefully added with stirring the mixture was poured into a separatory funnel containing 200 mL of ether An additional 200 mL of 2N HCl were added to dissolve some remaining white solid material The layers were separated the aqueous phase was extracted with 2×200 mL of ether The combined organic layers were washed successively with 200 mL of sat. NaHCO3 -solution and 200 mL of brine dried over MgSO4 filtered concentrated on the rotovapor The residue was dried at 0.1 mm for 30 minutes

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of 2.15 g aluminium isopropoxide in 35 ml of isopropanol were added 3.64 g of benzyl [3-chloro-2-oxo-(R)-1-(phenylthiomethyl)-propyl]-carbamate and the mixture was stirred at 50° C./ 400 mbar for 4 hours. The mixture was cooled to 0° C., the pH was adjusted to 1 by adding hydrochloric acid and the isopropanol was evaporated. The residue was partitioned between water and dichloromethane and the organic layer was evaporated. The residue was chromatographed on silica to give 2.9 g (80%) of pure benzyl (1R, 2S)-[3-chloro-2-hydroxy -1-(phenylthiomethyl)-propyl]-carbamate. IR (KBr): 3360 br (NH, OH), 1690 s (C=O), 1540 s (amide II). The mixture was cooled to 0° C. the isopropanol was evaporated The residue was partitioned between water and dichloromethane the organic layer was evaporated The residue was chromatographed on silica

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of 2.15 g aluminium isopropoxide in 35 ml of isopropanol were added 2.88 g of methyl [3-chloro-2-oxo-(R)-1-(phenylthiomethyl)-propyl]-carbamate and the suspension was stirred at 70° C./ 400 mbar for 4 hours. The mixture was cooled to 0° C., the pH was adjusted to 1 by adding hydrochloric acid and the isopropanol was evaporated. The suspension was filtered and the residue was recrystallized from toluene to give 2.18 g (75%) isomerically pure methyl (1R, 2S)-[3-chloro-2-hydroxy-1-(phenylthiomethyl)-propyl]-carbamate, m.p. 113-114° C. IR (KBr): 3389 m and 3327 m (NH, OH), 1695 s (C=O), 1537 s (amide II). MS (EI): 289/35 (M+). The mixture was cooled to 0° C. the isopropanol was evaporated The suspension was filtered the residue was recrystallized from toluene

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

实验步骤: The reaction was carried out in the same manner as in Example 1, except that 2.18 g (10 mmol) of sec-butoxyaluminum diisopropylate was used instead of aluminum isopropylate, and 10.3 g (50 mmol) of 2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-al was used instead of 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-al. After 5 hours, according to GLC analysis, 60% of 2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol was obtained (corresponding to 87% selectivity for conversion of the aldehyde as the starting material).

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

实验步骤: Into a mixture of 150 ml of dried benzene and 100 ml of acetone, was dissolved 1.5 g of 4-hydroxy-5-allyl-2-cyclopentenone. After adding 3 g of freshly distilled aluminum isopropoxide, the mixture was heated under reflux for 12 hours. The reaction mixture was cooled to room temperature, washed twice with 30% sulfuric acid, then with water until the washings had become neutral. After drying over anhydrous sodium sulfate, the mixture was stripped of the solvent by distillation and the residue was distilled in vacuo to obtain 1.2 g (81% yield) of 4-keto-5-allyl-2-cyclopentenone boiling at 53° C./4 mmHg. the mixture was heated under reflux for 12 hours washed twice with 30% sulfuric acid After drying over anhydrous sodium sulfate the mixture was stripped of the solvent by distillation the residue was distilled in vacuo

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

实验步骤: A preferred process for preparing 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one, an especially preferred compound of the present invention, comprises the following steps: (a) pregnenolone (V), an available starting material, is treated by the haloform King reaction with iodine and pyridine to form the 20-pyridinum iodide derivative of the pregnenolone (VI); (b) the pyridinium iodide derivative (VI) is hydrolyzed to the methyl ester of 17-carboxy pregnenolone (VII) with sodium methoxide and methanol, the ester form being preferred for carrying out the following Oppenhauer reaction; (c) the methyl ester of 17-carboxy pregnenolone (VII) is treated with aluminum isopropoxide and cyclohexanone in an appropriate solvent such as toluene to yield methyl-4-androstene-3-one-17-carboxylate (VIII) (d) the methyl-4-androstene-3-one-17-carboxylate (VIII) thus formed is hydrolyzed to the 17-acid (IX) under acid conditions in a methanol: water solvent of approximately 4:1 proportions; (e) the 17 acid (IX) is then treated with an oxalyl chloride: pyridine complex of approximately 1:1 proportions in toluene or other suitable solvent, e.g. xylene, to form the 17-acid chloride (X); (f) the 17-acid chloride (X) is then treated in situ with an excess of diethylamine to form the 17β-N,N-diethylcarbamoyl-4-androstene-3-one (XI); (g) the 4-androstene-3-one (XI) thus formed is oxidized by treatment with sodium periodate and potassium permanganate, using tert-butanol and water as a solvent system, to the corresponding 5-oxo-3,5-secoandrostan-3-oic acid (XII); (h) the secoandrostanoic acid (XII) is then converted to the corresponding 4-aza compound (XIII) by treating it with methylamine in ethylene glycol for a period of about 1 hour over which time the reaction mixture temperature is raised to from 140°-180° C. where it is maintained from 0.5 to 5 minutes; (i) the resulting 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5-androsten-3-one (XIII) is then hydrogenated by treating it with hydrogen at room temperature to 60° C. or higher, using platinum oxide as the catalyst, to form the 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one (XIV) final product, which is then separated and purified. the following Oppenhauer reaction

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

实验步骤: 150 g of 4,8-dimethyl-3,7-nonadien-2-ol, 252.5 g alpha-amylcinnamaldehyde and 16.9 g of aluminum isopropoxide are refluxed for 30 min at 1 mbar. A product/reactant mixture is then distilled over a 15 cm packed column (reflux ratio 1:1). This gives 130 g of the mixture of E- and Z-4,8-dimethyl-3,7-nonadien-2-ol and E- and Z-4,8-dimethyl-3,7-nonadien-2-one . The sum of the two isomers of 4,8-dimethyl-3,7-nonadien-2-ol is 23%, and the sum of the two isomers of 4,8-dimethyl-3,7-nonadien-2-one is 70%. A product/reactant mixture is then distilled over a 15 cm column (reflux ratio 1:1)

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

实验步骤: According to the same procedure of Example 1, using 19.5 g (200 mmol) of furfural, and 642 mg (3 mmol) of aluminum isopropoxide, 18.2 g (100 mmol) of geranyl formate was oxidized to obtain citral at a yield of 86%.

反应条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 500 mL three-necked, round-bottomed flask equipped with a magnetic stirrer, dropping funnel, condenser, thermometer, and a nitrogen atmosphere are charged 5.00 g (14.7 mmol) of 2-(2,4-dihydroxyphenyl)-4,6-bis-phenyl-s-triazine and 300 mg of aluminum isopropoxide. The mixture is heated to 160° C. and 17.3 g of α-methylstyrene are added all at once. After stirring at this temperature for 26 hours the mixture is allowed to cool and a portion of heptane is added. Vacuum filtration affords 4.45 g of the title compound as a yellow solid. To a 500 mL three-necked, round-bottomed flask equipped with a magnetic stirrer to cool Vacuum filtration

反应条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 500 mL three-necked, round-bottomed flask equipped with a magnetic stirrer, dropping funnel, condenser, thermometer, and a nitrogen atmosphere are charged 5.00 g (14.7 mmol) of 2-(2,4-dihydroxyphenyl)-4,6-bis-phenyl-s-triazine and 300 mg of aluminum isopropoxide. The mixture is heated to 160° C. and 17.3 g of α-methylstyrene are added all at once. After stirring at this temperature for 26 hours the mixture is allowed to cool and a portion of heptane is added. Vacuum filtration affords 4.45 g of the title compound as a yellow solid. To a 500 mL three-necked, round-bottomed flask equipped with a magnetic stirrer to cool Vacuum filtration

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

实验步骤: A mixture of methyl 2-methoxy-4-acetamido-5-chlorobenzoate (25.7 g; 0.1 moles), xylene (80 ml), 1-cyclohexylmethyl-4-aminopiperidine (21.6 g; 0.11 moles) and aluminium isopropoxide (5 g) was heated to the boiling point whilst methanol was distilled off as it was formed. When the theoretical quantity of methanol was removed, the xylene was distilled off and the residue was dissolved in 2 N hydrochloric acid (200 ml). The aqueous solution was made alkaline with sodium hydroxide solution, extracted with chloroform and the chloroformic layer evaporated to dryness to give N-(1-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide (27 g). Its hydrochloride monohydrate was prepared by the procedure described in Example 2, m.p. 219°-221° C. was distilled off as it was formed When the theoretical quantity of methanol was removed the xylene was distilled off the residue was dissolved in 2 N hydrochloric acid (200 ml) extracted with chloroform the chloroformic layer evaporated to dryness

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

实验步骤: A mixture of methyl 2-methoxy-4-acetamido-5-chlorobenzoate (25.7 g; 0.1 moles), xylene (80 ml), 1-cyclohexylmethyl-4-aminopiperidine (21.6 g; 0.11 moles) and aluminium isopropoxide (5 g) was heated to the boiling point whilst methanol was distilled off as it was formed. When the theoretical quantity of methanol was removed, the xylene was distilled off and the residue was dissolved in 2 N hydrochloric acid (200 ml). The aqueous solution was made alkaline with sodium hydroxide solution, extracted with chloroform and the chloroformic layer evaporated to dryness to give N-(1-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide (27 g). Its hydrochloride monohydrate was prepared by the procedure described in Example 2, m.p. 219°-221° C. was distilled off as it was formed When the theoretical quantity of methanol was removed the xylene was distilled off the residue was dissolved in 2 N hydrochloric acid (200 ml) extracted with chloroform the chloroformic layer evaporated to dryness