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The pronounced dopaminergic agonist activity reported1,2 for (±)-5,6-dihydroxy- (1a) and 6,7-dihydroxy-2-aminotetralins (1b) and their N-substituted derivatives prompted an investigation of central and peripheral effects in a variety of animal experimental models of an extended series of N-substituted congeners of (±)-alpha-methyldopamine 2 which, like the aminotetralins, bear the amino group on a secondary carbon, rather than on a primary carbon as in dopamine.
Preparation of the compounds based on 2 involved reductive amination of 3,4-dimethoxyphenylacetone and, when appropriate, subsequent N-alkylation of the amine product. The Experimental Section describes representative types of alkylation procedures employed for the target compounds which are listed in Table I.
no. | R | R' | R'' | freebase bp, °C (kPai) |
salt mp, °Ca | Method | Yield |
5 | CH3 | H | H | 148-151@b,c | - |
100% |
|
6 | CH3 | CH3 | H | 117-121@d,e | A |
72% |
|
7 | CH3 | CH3 | CH3 | 157-158@d,f | B |
58% |
|
8 | CH3 | C2H5 | C2H5 | 174-175d | C |
87% |
|
13 | CH3 | n-C3H | n-C3H7 | 130-131@g | C |
54% (free base) |
|
14 | CH3 | n-C4H9 | n-C4H9 | 78-82@g | C |
87% (free base) |
|
15 | CH3 | n-C3H7 | H | 143-146d | Ch |
38% |
|
9 | CH3 | n-C4H9 | H | 147-150@g | D |
89% |
|
16 | CH3 | C2H5 | H | 118-120 (0.026) | 155-159@g | D |
56% |
11 | CH3 | 2-C3H7 | H | 100 (0.0046) | 153-157@g | E |
77% |
12 | CH3 | 2-C3H7 | CH3 | 101 (0.04) | 143-146@g | F |
82% |
1-(3,4-Dimethoxyphenyl)-2-(benzylamino)propane Hydrochloride (3)
Freshly distilled benzylamine (7.28 g, 0.068 mol) in 20 mL of MeOH was treated with 5 N methanolic HCl to pH 7 (pH paper), then 13.2 g (0.068 mol) of 3,4-dimethoxyphenylacetone in 20 mL of MeOH was added, followed by 4.27 g (0.068 mol) of NaCNBH3, and this mixture was stirred under N2 at room temperature for 36 h. The reaction was quenched with excess concentrated HCl, and the volatiles were removed under reduced pressure. The residue was taken up in H2O and washed with Et2O.The aqueous phase was treated with excess KOH and extracted with CHCl3. The extract was dried (MgSO4) and the solvent was removed under reduced pressure. The resulting light-yellow oil was converted to its HCl salt, which was recrystallized twice from MeOH-Et2O to afford 17 g (78%) of white crystals, mp 175-178°C.
1-(3,4-Dimethoxyphenyl)-2-aminopropane Hydrochloride (5)
Compound 3 (6.0 g, 0.0186 mol) was hydrogenated over 1.2g of 5% Pd/C in 80 mL of anhydrous MeOH at an initial pressure of 310 kPa (45 psig). When the calculated amount of H2 was absorbed (18 h), the catalyst was removed by filtration and washed with CHCl3. The combined filtrate and washings were evaporated under reduced pressure and the residue was recrystallized (see Table I).
1-(3,4-Dimethoxyphenyl)-2-aminopropane (4)
Compound 5 was treated with excess 2 N NaOH, and the resulting mixture was extracted with CHCl3. The solvent was removed and the free base was distilled through a "short-path" apparatus to afford a colorless, limpid liquid, bp 100°C (0.053 kPa; 0.4 mmHg), lit.9 bp 104°C (0.039 kPa; 0.3 mmHg).
Reductive Amination of 3,4-Dimethoxyphenylacetone with NaBH4
1-(3,4-Dimethoxyphenyl)-2-(methylamino)propane Hydrochloride (6)
A chilled (0-5°C) solution of 3.75 g (0.019 mol) of 3,4-dimethoxyphenylacetone in 25 mL of MeOH was treated with 7.5 mL of a 36% aqueous solution of methylamine. Maintaining the temperature of this mixture at 0-10 °C, 0.75 g (0.019 mol) of NaBH4 was added in small portions over 20 min and then the mixture was stirred at room temperature for 1 h. MeOH (10 mL) and 2.5 g of K2CO3 were added, and the mixture was evaporated under reduced pressure. H2O (10 mL) was added to the residue, and this mixture was extracted with six 40-mL portions of Et2O. The combined extracts were dried (K2CO3), and the solution was treated with ethereal HCl to yield a heavy gum, which upon washing with Et2O yielded a white solid which was recrystallized (see Table I).
Reductive Amination of 3,4-Dimethoxyphenylacetone with NaCNBH3
1-(3,4-Dimethoxyphenyl)-2-(dimethylamino)propane Hydrochloride (7)
A mixture of 5.82 g (0.03 mol) of 3,4-dimethoxyphenylacetone, 2.45 g (0.03 mol) of dimethylamine hydrochloride (previously dried by refluxing it for 3 h with toluene in a Dean-Stark apparatus), and 1.89 g (0.03 mol) of NaCNBH3 in 75 mL of MeOH were stirred at room temperature for 72 h. The MeOH was removed under reduced pressure, the brown semisolid residue was taken up in 30 mL of 2 N HCl, and this solution was extracted three times with Et2O. The H2O layer was basified with KOH and the resulting mixture was extracted repeatedly with Et2O. The combined extracts were dried (Na2SO4), and the volatiles were evaporated to leave a golden-yellow syrup, which was converted to its HCl salt with ethereal HCl (see Table I).
N-Alkylation of 1-(3,4-Dimethoxyphenyl)-2-aminopropane with NaBH4-Carboxylic Acid
1-(3,4-Dimethoxyphenyl)-2-(diethylamino)propane Hydrochloride (8)
Method "B" of Marchini et al.30 was used. To 16.82 g (0.279 mol) of AcOH in 70 mL of benzene (distilled from Na) maintained at 10-15 °C under N2 was added in small portions 3.17 g (0.084 mol) of NaBH4. When evolution of H2 ceased, 1.09 g (0.0056 mol) of 4 in 10 mL of dry benzene was added, and the resulting mixture was heated under reflux for 16 h. The reaction mixture was treated with excess 2 N NaOH and then was extracted repeatedly with Et2O. The pooled extracts were dried (Na2SO4), and the volatiles were removed under reduced pressure to leave a yellow oil. This was treated with 3 mL of phenyl isocyanate and was permitted to stand at room temperature overnight. MeOH (25 mL) was added and the resulting solution was heated on a steam bath for 20 min; then volatiles were removed under reduced pressure. The residue was azeotroped with benzene, then fresh benzene was added, and the resulting solution was extracted repeatedly with 2.5 N HCl. The combined HCl extracts were extracted with Et2O and the aqueous phase was treated with excess KOH. The resulting emulsion was extracted repeatedly with Et2O. Evaporation of the pooled ethereal extracts left a light-yellow oil, which was treated with ethereal HCl (see Table I).
N-[1-(3,4-Dimethoxyphenyl)-2-propyl]acetamide (10)
A mixture of 2 g (0.01 mol) of 4 and 8 mL of Ac2O was refluxed for 2 h. The resulting brown solution was treated with 80 mL of H2O, and this mixture was extracted several times with benzene. The pooled extracts were washed with saturated NaHCO3 and then with H2O, dried (MgSO4), and evaporated, to leave a yellow oil. This was chromatographed on 50 g of silica gel and eluted with EtOAc-MeOH (5:1). Evaporation of the eluate left a solid, which was crystallized from EtOH-petroleum ether to afford 1.52 g (63%) of white crystals, mp 89-91 °C.
N-[1-(3,4-Dimethoxyphenyl)-2-propyl]butyramide (17)
A mixture of 1 g (0.0051 mol) of 4 and 7 mL of butyric anhydride was refluxed for 2 h. The resulting brown solution was treated with 40 mL of H2O, and this mixture was extracted several times with benzene. The pooled extracts were washed with saturated NaHCO3 and then with H2O, dried (MgSO4), and evaporated to leave a yellow oil, which was distilled through a "short path" apparatus, bp 175-177 °C (0.01 kPa; 0.1 mmHg), to afford 0.90 g (66%) of product. This was chromatographed on 50 g of silica gel and eluted with EtOAc-MeOH (5:1). Evaporation of the eluate left a crystalline solid, mp 80-83 °C.
Reduction of Amides with LiAlH4
1-(3,4-Dimethoxyphenyl)-2-(n-butylamino)propane Hydrochloride (9)
To 0.429 g (0.01 mol) of LiAlH4 in 50 mL of dry Et2O was added dropwise under N2 and with stirring 2.47 g (0.0093 mol) of the amide 10 in 20 mL of Na-dried benzene, and the reaction mixture was kept immersed in an ice bath. After addition of the amide, the reaction mixture was heated under reflux for 6 h. Excess LiAlH4 was destroyed by the cautious addition of H2O, and the reaction mixture was filtered. The filter cake was washed with benzene, and the filtrate and washings were evaporated under reduced pressure to afford 2.09 g of a yellow oil. This was treated with ethereal HCl, and the resulting salt was recrystallized (see Table I).
Reductive Alkylation of 1-(3,4-Dimethoxyphenyl)-2-aminopropane with Acetone and PtO2
1-(3,4-Dimethoxyphenyl)-2-(isopropylamino)propane Hydrochloride (11)
Compound 4 (1.075 g, 0.0054 mol), 0.99 g (0.017 mol) of acetone, and 0.116 g of PtO2 in 80 mL of EtOH were hydrogenated at room temperature at an initial pressure of 310 kPa (45 psig). When the calculated amount of H2 was absorbed, the reduction mixture was filtered and the solvent was removed from the filtrate under reduced pressure. The residue was distilled through a short-path apparatus, bp 100°C (0.004 kPa; 0.03 mmHg), to yield 0.75 g (63%) of an oil. This was converted to its HCl salt with ethereal HCl and was recrystallized (see Table I).
Reductive Alkylation of a Secondary Amine with Formaldehyde and Pd/C
1-(3,4-Dimethoxyphenyl)-2-(N-methyl-N-isopropylamino)propane Hydrochloride (12)
The free base of 11 (1.47 g, 0.0062 mol) and 3 mL of 37% aqueous formaldehyde were hydrogenated in the presence of 0.2 g of 10% Pd/C in 80 mL of anhydrous EtOH at an initial pressure of 248 kPa (36 psig). After 1 h, the calculated amount of H2 was absorbed; the reduction mixture was filtered and volatiles were removed from the filtrate under reduced pressure. The oily residue was treated with excess 5 % KOH and this mixture was extracted with Et2O. The volatiles were removed from this extract; the oily residue was taken up in 10% HCl and this solution was extracted with Et2O, which was discarded. The aqueous phase was treated with excess KOH and was extracted with Et2O. The extract was dried (MgSO4) and the Et2O was removed under reduced pressure to leave an oil: bp 101°C (0.004 kPa; 0.03 mmHg); yield 1.40 g (90%); This material was converted to its HCl salt with ethereal HCl, and the salt was recrystallized (see Table I).
Ether Cleavage Reactions.
The amine or its HCl salt (0.001 mol) was heated under N2 with 6 mL of 48% HBr at 110-120°C for 3 h. Volatiles were removed under reduced pressure, and the residue was recrystallized (see Table I).