* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Heterocyclic Chemistry, 1987, vol. 24, # 3, p. 677 - 682
[2] Collection of Czechoslovak Chemical Communications, 1967, vol. 32, p. 4082 - 4098
5
[ 147219-20-3 ]
[ 25173-76-6 ]
Yield
Reaction Conditions
Operation in experiment
98%
With hydrogen In methanol at 20℃; for 4 h;
A mixture of 3-(3,4-dimethyl-phenyl)-acrylic acid (19.269 g; 109.355 mmol) and 10percent palladium over activated charcoal (1.920 g) was placed under nitrogen before methanol (300 ml) was carefully added. The resulting suspension was placed under vacuum, then under hydrogen (1 atm), and the reaction mixture was vigorously stirred at rt for 4h. The reaction mixture was filtered over a pad of celite, and concentrated under reduced pressure to give the expected product 3- (3,4-dimethyl-phenyl)-propionic acid as a grey solid which was further dried under HV (19.070 g; 98percent). LC-MS: tR = 0.85 min; [M+H]+: no ionisation.
98%
With hydrogen In methanol at 20℃; for 4 h;
A mixture of 3-(3,4-dimethyl-phenyl)-acrylic acid (19.269 g; 109.355 mmol) and 10percent palladium over activated charcoal (1.920 g) was placed under nitrogen before MeOH (300 ml) was carefully added. The resulting suspension was placed under vacuum, then under hydrogen (1 atm), and the reaction mixture was vigorously stirred at rt for 4h. The reaction mixture was filtered over a pad of celite, and concentrated under reduced pressure to give the expected product 3-(3,4-dimethyl-phenyl)-propionic acid as a grey solid which was further dried under HV (19.070 g; 98percent). LC-MS: tR = 0.85 min; [M+H]+: no ionisation.
Reference：
[1] Journal of Heterocyclic Chemistry, 1987, vol. 24, # 3, p. 677 - 682
[2] Monatshefte fur Chemie, 1996, vol. 127, # 2, p. 185 - 200
[3] Patent: WO2008/26149, 2008, A1, . Location in patent: Page/Page column 22
[4] Patent: WO2008/78291, 2008, A1, . Location in patent: Page/Page column 39
[5] Collection of Czechoslovak Chemical Communications, 1967, vol. 32, p. 4082 - 4098
6
[ 102-46-5 ]
[ 105-53-3 ]
[ 25173-76-6 ]
Yield
Reaction Conditions
Operation in experiment
55%
With potassium hydroxide; sulfuric acid In diethyl ether; ethanol; water
Step 1) Synthesis of 3-(3,4-dimethylphenyl)propionic acid To a solution of 70.0 ml of diethyl malonate dissolved in 400 ml of dry ethanol was added 10.0 g of metallic sodium. The reaction mixture was stirred for 30 minutes and cooled to 0° C; and 66.5 g of 3,4-dimethylbenzyl chloride was added thereto. This reaction mixture was stirred at a room temperature for another 1 hour, heated at the boiling temperature for 4 hours and concentrated under a reduced pressure. The residue was dissolved in ethyl ether and the solution was washed with water. After further concentration under a reduced pressure, the organic phase was combined with 500 ml of water and 170 g of KOH; and this mixture was heated at the boiling temperature for 24 hours. The mixture was concentrated under a reduced pressure to about one half volume; then 200 ml of 98percent sulfuric acid was added slowly thereto. The resultant solution was heated at the boiling temperature for 24 hours, extracted twice with 300 ml of ethyl acetate. The organic solvent was distilled off under a reduced pressure and the residue was recrystallized from boiling hexane to obtain 42.1 g of the title compound as a white solid(yield: 55percent). m.p.: 82° C. 1 H-NMR(300 MHz, CDCl3) δ2.22(s, 3H, CH3), 2.24(s, 3H, CH3), 2.66(t, J=8 Hz, 2H, ArCH2), 2.89(t, J=8 Hz, 2H, CH2 CO), 6.93-7.70(m, 3H, ArH)
55%
With potassium hydroxide; sulfuric acid In diethyl ether; ethanol; water
Step 1) Synthesis of 3-(3,4-dimethylphenyl)propionic acid To a solution of 70.0ml of diethyl malonate dissolved in 400ml of dry ethanol was added 10.0g of metallic sodium. The reaction mixture was stirred for 30 minutes and cooled to 0°C; and 66.5g of 3,4-dimethylbenzyl chloride was added thereto. This reaction mixture was stirred at a room temperature for another 1 hour, heated at the boiling temperature for 4 hours and concentrated under a reduced pressure. The residue was dissolved in ethyl ether and the solution was washed with water. After further concentration under a reduced pressure, the organic phase was combined with 500ml of water and 170g of KOH; and this mixture was heated at the boiling temperature for 24 hours. The mixture was concentrated under a reduced pressure to about one half volume; then 200ml of 98percent sulfuric acid was added slowly thereto. The resultant solution was heated at the boiling temperature for 24 hours, extracted twice with 300ml of ethyl acetate. The organic solvent was distilled off under a reduced pressure and the residue was recrystallized from boiling hexane to obtain 42.lg of the title compound as a white solid(yield: 55percent). m.p.: 82°C 1H NMR(300MHz, CDCl3) δ 2.22(s, 3H, CH3), 2.24(s, 3H, CH3), 2.66(t, J=8Hz, 2H, ArCH2), 2.89(t, J=8Hz, 2H, CH2CO), 6.93-7.70(m, 3H, ArH)
With potassium hydroxide; sulfuric acid In diethyl ether; ethanol; water
PREPARATION EXAMPLE 1 Synthesis of 3-(3,4-dimethylphenyl)propylamine To a solution of 70.0 ml of diethyl malonate dissolved in 400 ml of dry ethanol was added 10.0 g of metalic sodium. The reaction mixture was stirred for 30 minutes and cooled to 0° C; and 66.5 g of 3,4-dimethylbenzyl chloride was added thereto. This reaction mixture was stirred for 1 hour at room temperature, heated at the boiling temperature for 4 hours and concentrated under reduced pressure to produce residues, which were dissolved in ethyl ether. This ethereal solution was washed with water. To the residues obtained after a further concentration of the organic phase were added 500 ml of water and 170 g of KOH; and this mixture was heated at the boiling temperature for 24 hours. This mixture was concentrated under reduced pressure until about a half of the amount remained, and 200 ml of sulfuric acid was then slowly added thereto. The resultant solution was heated at the boiling temperature for 24 hours, extracted twice with 300 ml of ethyl ether and evaporated under reduced pressure to obtain solids, which were recrystallized from boiling hexane to provide 42.1 g of 3-(3,4-dimethylphenyl)propanoic acid as a white solid (yield 55percent), having the characteristics of: m.p. 82° C.; NMR(CDCl3, 300 MHz) δ2.22(s, 3H, CH3), 2.24(s, 3H, CH3), 2.66(t, J=8 Hz, 2H, ArCH2), 2.89(t, J=8 Hz, 2H, CH2 CO), 6.93~7.70(m, 3H, ArH).
55%
With potassium hydroxide; sulfuric acid In diethyl ether; ethanol
Preparation Example 1: Synthesis of 3-(3,4-dimethylphenyl)propylamine To a solution of 70.0m of diethyl malonate dissolved in 400m of dry ethanol was added 10.0g of metalic sodium. The reaction mixture was stirred for 30 minutes and cooled to 0°C; and 66.5g of 3,4-dimethylbenzyl chloride was added thereto. This reaction mixture was stirred for 1 hour at room temperature, heated at the boiling temperature for 4 hours and concentrated under reduced pressure to produce residues, which were dissolved in ethyl ether. This ethereal solution was washed with water. To the residues obtained after a further concentration of the organic phase were added 500m of water and 170g of KOH; and this mixture was heated at the boiling temperature for 24 hours. This mixture was concentrated under reduced pressure until about a half of the amount remained, and 200m of sulfuric acid was then slowly added thereto. The resultant solution was heated at the boiling temperature for 24 hours, extracted twice with 300m of ethyl ether and evaporated under reduced pressure to obtain solids, which were recrystallized from boiling hexane to provide 42.1g of 3-(3,4-dimethylphenyl)propanoic acid as a white solid(yield 55percent), having the characteristics of: m.p. 82°C; NMR(CDCl3, 300MHz)δ 2.22(s, 3H, CH3), 2.24(s, 3H, CH3), 2.66(t, J=8Hz, 2H, ArCH2), 2.89(t, J=8Hz, 2H, CH2CO), 6.93~7.70(m, 3H, ArH).
With hydrogen;palladium 10% on activated carbon; In methanol; at 20.0℃; under 760.051 Torr; for 4.0h;
A mixture of 3-(3,4-dimethyl-phenyl)-acrylic acid (19.269 g; 109.355 mmol) and 10% palladium over activated charcoal (1.920 g) was placed under nitrogen before methanol (300 ml) was carefully added. The resulting suspension was placed under vacuum, then under hydrogen (1 atm), and the reaction mixture was vigorously stirred at rt for 4h. The reaction mixture was filtered over a pad of celite, and concentrated under reduced pressure to give the expected product 3- (3,4-dimethyl-phenyl)-propionic acid as a grey solid which was further dried under HV (19.070 g; 98%). LC-MS: tR = 0.85 min; [M+H]+: no ionisation.
98%
With hydrogen;palladium 10% on activated carbon; In methanol; at 20.0℃; under 760.051 Torr; for 4.0h;
A mixture of 3-(3,4-dimethyl-phenyl)-acrylic acid (19.269 g; 109.355 mmol) and 10% palladium over activated charcoal (1.920 g) was placed under nitrogen before MeOH (300 ml) was carefully added. The resulting suspension was placed under vacuum, then under hydrogen (1 atm), and the reaction mixture was vigorously stirred at rt for 4h. The reaction mixture was filtered over a pad of celite, and concentrated under reduced pressure to give the expected product 3-(3,4-dimethyl-phenyl)-propionic acid as a grey solid which was further dried under HV (19.070 g; 98%). LC-MS: tR = 0.85 min; [M+H]+: no ionisation.
With thionyl chloride; nitrogen; In dichloromethane;
3-(3,4-Dimethylphenyl)propionyl Chloride A 1 L three-neck round bottom flask equipped with a condenser, magnetic stir bar, thermometer, and a nitrogen inlet was charged with 3-(3,4-dimethylphenyl) propionic acid (64.0 g, 0.359 mol), dichloromethane (500 mL), and thionyl chloride (110 mL, 1.5 mol). The reaction mixture was stirred at reflux for 7 hours. Dichloromethane and excess thionyl chloride were removed by rotary evaporation under reduced pressure to yield 3-(3,4-dimethylphenyl)propionyl chloride as an amber oil (70.6 g, 100% conversion by GC).
3-(3,4-dimethylphenyl)-N-[3-(2-ethyl-5-methyl-2H-pyrazol-3-yl)propyl]propionamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20.0℃; for 1.0h;
To a solution of <strong>[25173-76-6]3-(3,4-dimethyl-phenyl)-propionic acid</strong> (0.796 g; 4.470 mmol) in anhydrous DMF (15 ml) were added successively PyBOP (2.558 g; 4.917 mmol), a solution of 3-(2-ethyl-5-methyl-2/-/-pyrazol-3-yl)-propylamine (0.747 g; 4.470 mmol) in anhydrous DMF (10 ml), and finally lambda/-ethyldiisopropylamine (1.91 ml; 11.175 mmol). The resulting solution was further stirred at rt, under nitrogen, for 1 h. Ethyl acetate (100 ml) was added, and the resulting solution was washed with a 1/1 mixture of brine and water (3 x 30 ml), and with water (30 ml). The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude was purified by flash <n="29"/>chromatography (silicagel; DCM / MeOH = 15 / 1 ) to give the pure product 3-(3,4- dimethyl-phenyl)-lambda/-[3-(2-ethyl-5-methyl-2/-/-pyrazol-3-yl)-propyl]-propionamide as a beige solid which was further dried under HV (1.250 g; 85%). LC-MS: tR = 0.82 min.; [M+H]+ = 328.24 g/mol.
With potassium hydroxide; sulfuric acid; In diethyl ether; ethanol; water;
PREPARATION EXAMPLE 1 Synthesis of 3-(3,4-dimethylphenyl)propylamine To a solution of 70.0 ml of diethyl malonate dissolved in 400 ml of dry ethanol was added 10.0 g of metalic sodium. The reaction mixture was stirred for 30 minutes and cooled to 0 C; and 66.5 g of 3,4-dimethylbenzyl chloride was added thereto. This reaction mixture was stirred for 1 hour at room temperature, heated at the boiling temperature for 4 hours and concentrated under reduced pressure to produce residues, which were dissolved in ethyl ether. This ethereal solution was washed with water. To the residues obtained after a further concentration of the organic phase were added 500 ml of water and 170 g of KOH; and this mixture was heated at the boiling temperature for 24 hours. This mixture was concentrated under reduced pressure until about a half of the amount remained, and 200 ml of sulfuric acid was then slowly added thereto. The resultant solution was heated at the boiling temperature for 24 hours, extracted twice with 300 ml of ethyl ether and evaporated under reduced pressure to obtain solids, which were recrystallized from boiling hexane to provide 42.1 g of 3-(3,4-dimethylphenyl)propanoic acid as a white solid (yield 55%), having the characteristics of: m.p. 82 C.; NMR(CDCl3, 300 MHz) delta2.22(s, 3H, CH3), 2.24(s, 3H, CH3), 2.66(t, J=8 Hz, 2H, ArCH2), 2.89(t, J=8 Hz, 2H, CH2 CO), 6.93~7.70(m, 3H, ArH).
55%
With potassium hydroxide; sulfuric acid; In diethyl ether; ethanol;
Preparation Example 1: Synthesis of 3-(3,4-dimethylphenyl)propylamine To a solution of 70.0ml of diethyl malonate dissolved in 400ml of dry ethanol was added 10.0g of metalic sodium. The reaction mixture was stirred for 30 minutes and cooled to 0C; and 66.5g of 3,4-dimethylbenzyl chloride was added thereto. This reaction mixture was stirred for 1 hour at room temperature, heated at the boiling temperature for 4 hours and concentrated under reduced pressure to produce residues, which were dissolved in ethyl ether. This ethereal solution was washed with water. To the residues obtained after a further concentration of the organic phase were added 500ml of water and 170g of KOH; and this mixture was heated at the boiling temperature for 24 hours. This mixture was concentrated under reduced pressure until about a half of the amount remained, and 200ml of sulfuric acid was then slowly added thereto. The resultant solution was heated at the boiling temperature for 24 hours, extracted twice with 300ml of ethyl ether and evaporated under reduced pressure to obtain solids, which were recrystallized from boiling hexane to provide 42.1g of 3-(3,4-dimethylphenyl)propanoic acid as a white solid(yield 55%), having the characteristics of: m.p. 82C; NMR(CDCl3, 300MHz)delta 2.22(s, 3H, CH3), 2.24(s, 3H, CH3), 2.66(t, J=8Hz, 2H, ArCH2), 2.89(t, J=8Hz, 2H, CH2CO), 6.93~7.70(m, 3H, ArH).
With ammonium hydroxide; sodium hydroxide; thionyl chloride; LiAlH4; In tetrahydrofuran; diethyl ether; water;
A mixture of 18.5 g of <strong>[25173-76-6]3-(3,4-dimethylphenyl)propanoic acid</strong> obtained above and 50 ml of thionyl chloride was heated to reflux for 2 hours and concentrated under reduced pressure to give residues, which were dissolved in 100 ml of ethyl ether. The ethereal solution was added to a mixture of 200 ml of ethyl ether, 150 ml of water and 50 ml of 30% aqueous ammonia solution with stirring. The organic layer was separated and the remaining aqueous layer was extracted twice with 150 ml of dichloromethane. The organic layers were combined and concentrated under reduced pressure to give residues, which were dissolved in 150 ml of tetrahydrofuran. The solution was added to a mixture of 8.0 g of LiAlH4 and 200 ml of tetrahydrofuran; and the resultant solution was heated at the boiling temperature for 6 hours. To this reaction mixture were slowly added 30 ml of 30% NaOH aqueous solution and 20 ml of water. The tetrahydrofuran layer was separated from the mixture and the remaining solids were dissolved in 300 ml of water. The aqueous solution was extracted twice with 200 ml of ethyl ether. The previously separated tetrahydrofuran solution and the ethyl ether solution were combined and then concentrated. The residues so obtained were distilled under reduced pressure to obtain 13.4 g of 3-(3,4-dimethylphenyl)propylamine (yield 70%), having the characteristics of: b.p. 140-150 C./0.5 mmHg; NMR(CDCl3, 300 MHz) delta1.32 (br s, 2H, NH2), 1.74(quint, J=7 Hz, 2H, CH2), 2.23(s, 3H, CH3), 2.24(s, 3H, CH3), 2.59(t, J=7 Hz, 2H, ArCH2), 2.72(t, J=7 Hz, 2H, CH2 N), 6.91-7.06(m, 3H, ArH).
With potassium hydroxide; sulfuric acid; In diethyl ether; ethanol; water;
Step 1) Synthesis of 3-(3,4-dimethylphenyl)propionic acid To a solution of 70.0 ml of diethyl malonate dissolved in 400 ml of dry ethanol was added 10.0 g of metallic sodium. The reaction mixture was stirred for 30 minutes and cooled to 0 C; and 66.5 g of 3,4-dimethylbenzyl chloride was added thereto. This reaction mixture was stirred at a room temperature for another 1 hour, heated at the boiling temperature for 4 hours and concentrated under a reduced pressure. The residue was dissolved in ethyl ether and the solution was washed with water. After further concentration under a reduced pressure, the organic phase was combined with 500 ml of water and 170 g of KOH; and this mixture was heated at the boiling temperature for 24 hours. The mixture was concentrated under a reduced pressure to about one half volume; then 200 ml of 98% sulfuric acid was added slowly thereto. The resultant solution was heated at the boiling temperature for 24 hours, extracted twice with 300 ml of ethyl acetate. The organic solvent was distilled off under a reduced pressure and the residue was recrystallized from boiling hexane to obtain 42.1 g of the title compound as a white solid(yield: 55%). m.p.: 82 C. 1 H-NMR(300 MHz, CDCl3) delta2.22(s, 3H, CH3), 2.24(s, 3H, CH3), 2.66(t, J=8 Hz, 2H, ArCH2), 2.89(t, J=8 Hz, 2H, CH2 CO), 6.93-7.70(m, 3H, ArH)
55%
With potassium hydroxide; sulfuric acid; In diethyl ether; ethanol; water;
Step 1) Synthesis of 3-(3,4-dimethylphenyl)propionic acid To a solution of 70.0ml of diethyl malonate dissolved in 400ml of dry ethanol was added 10.0g of metallic sodium. The reaction mixture was stirred for 30 minutes and cooled to 0C; and 66.5g of 3,4-dimethylbenzyl chloride was added thereto. This reaction mixture was stirred at a room temperature for another 1 hour, heated at the boiling temperature for 4 hours and concentrated under a reduced pressure. The residue was dissolved in ethyl ether and the solution was washed with water. After further concentration under a reduced pressure, the organic phase was combined with 500ml of water and 170g of KOH; and this mixture was heated at the boiling temperature for 24 hours. The mixture was concentrated under a reduced pressure to about one half volume; then 200ml of 98% sulfuric acid was added slowly thereto. The resultant solution was heated at the boiling temperature for 24 hours, extracted twice with 300ml of ethyl acetate. The organic solvent was distilled off under a reduced pressure and the residue was recrystallized from boiling hexane to obtain 42.lg of the title compound as a white solid(yield: 55%). m.p.: 82C 1H NMR(300MHz, CDCl3) delta 2.22(s, 3H, CH3), 2.24(s, 3H, CH3), 2.66(t, J=8Hz, 2H, ArCH2), 2.89(t, J=8Hz, 2H, CH2CO), 6.93-7.70(m, 3H, ArH)
With hydrogen;palladium; In tetrahydrofuran; ethanol;
3-(3,4-Dimethylphenyl)propionic Acid A titanium 3 L stirred autoclave was charged with a solution of trans-3,4-dimethylcinnamic acid (64.0g, 0.363 mol) in tetrahydrofuran (500 mL), ethanol (1 L), and 5% palladium on carbon (15 g, 50 wt% water). The reactor was sealed, purged with nitrogen, pressurized to 80 psi (550 kPa) with hydrogen and stirred at room temperature for 4 hours. The reaction mixture was transferred from the reactor, filtered, and evaporated to dryness to give 3-(3,4-dimethyl)propionic acid (64.1 g, 97+% purity by GC). 1H-NMR (CD2Cl2) delta 7.04 (d, JAB=7.5 Hz, 1H); 6.98 (s, 1H); 6.92 (d, JAB=7.5 Hz, 1H); 2.87 (t, J=8 Hz, 2H); 2.64 (t, J=8 Hz, 2H); 2.23 (s, 3H); 2.22 (s, 3H).
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