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CAS No. : | 2651-55-0 | MDL No. : | MFCD00276591 |
Formula : | C10H12O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DMSAIFTWQMXOBE-UHFFFAOYSA-N |
M.W : | 196.20 | Pubchem ID : | 2822957 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.3 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 51.19 |
TPSA : | 55.76 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.08 cm/s |
Log Po/w (iLOGP) : | 1.92 |
Log Po/w (XLOGP3) : | 2.0 |
Log Po/w (WLOGP) : | 1.79 |
Log Po/w (MLOGP) : | 1.36 |
Log Po/w (SILICOS-IT) : | 1.59 |
Consensus Log Po/w : | 1.73 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.85 |
Log S (ESOL) : | -2.37 |
Solubility : | 0.838 mg/ml ; 0.00427 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.8 |
Solubility : | 0.313 mg/ml ; 0.00159 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.44 |
Solubility : | 0.721 mg/ml ; 0.00367 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.75 |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P330-P362-P403+P233-P501 | UN#: | |
Hazard Statements: | H302-H312-H332 | Packing Group: | |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With alkaline aqueous potassium permanganate solution | ||
4 g | With potassium permanganate; disodium hydrogenphosphate In methanol; water at 20℃; for 0.5h; | 24.2 Step 2 To a purple solution of KMnCL (5.1 g, 32.0 mmol) and Na2HP04 (8.4 g, 32 mmol) in H20 (120 mL) was added a solution of 3-ethoxy-4-methoxybenzaldehyde (5.6 g) in MeOH (120 mL) in a dropwise manner at rt. The reaction mixture was stirred for about 30 min until a brown suspension formed. The resulting suspension was filtered through a pad of Celite, and the filtrate was concentrated via rotovap and was diluted with H20 (100 mL). The diluted filtrate was acidified with IN HC1 until pH reached 3-4. The resulting precipitate was filtered and dried in vacuo at 76 °C overnight to give 3 -ethoxy -4-methoxybenzoic acid (4.0 g, 66%) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride | ||
With thionyl chloride | ||
With thionyl chloride for 0.5h; Heating; |
With oxalyl dichloride In dichloromethane; benzene at 0 - 20℃; for 1.5h; | Synthesis of 3-ethoxy-4-methoxybenzoyl chloride (ZK299); 3-ethoxy-4-methoxybenzoic acid (5 g, 25.5 mmol) was added to a solution of CH2Cl2 (40 mL) and benzene (20 mL) in a flame-dried 150 mL round bottom flask. Anhydrous DMF (9 drops) was added and the solution was cooled on ice. Oxalyl chloride (11 mL, 128 mmol) was added dropwise, and the reaction was then allowed to warm to RT. The reaction was stirred at RT for 90 minutes, then concentrated in vacuo yield an off-white solid. The solid was placed on a high-vacuum line for 2 hours, and then taken onto the next step without further characterization. | |
With thionyl chloride at 90℃; for 3h; | ||
51.6 g | With thionyl chloride In toluene for 2h; Heating; | 4 50 g of 3-ethoxy-4-methoxybenzoic acid and 200 g of toluene were added to the reaction flask, and 31.2 g of sulfoxide was added. The mixture was stirred with heating for 2 h, and then concentrated to dryness under reduced pressure to obtain 51.6 g of 3-ethoxy-4-methoxybenzoyl chloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium permanganate In acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: ClO2-/DMSO / methanol 2: KOH / various solvent(s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: SOCl2 / 0.5 h / Heating 2: Na-ethoxide / ethanol 3: H2SO4 / 8 h / Heating 4: 2.4 g / NaH / benzene / 24 h / Heating 5: 0.6 g / HCl-gas / ethanol / 48 h / Ambient temperature 6: 0.05 g / K2CO3 / acetone / 4 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: SOCl2 / 0.5 h / Heating 2: Na-ethoxide / ethanol 3: H2SO4 / 8 h / Heating 4: 2.4 g / NaH / benzene / 24 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: SOCl2 / 0.5 h / Heating 2: Na-ethoxide / ethanol 3: H2SO4 / 8 h / Heating 4: 2.4 g / NaH / benzene / 24 h / Heating 5: 0.6 g / HCl-gas / ethanol / 48 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: SOCl2 / 0.5 h / Heating 2: Na-ethoxide / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: hydrochloric acid 2: sodium ethylate / 100 °C / im Rohr 3: KOH-solution | ||
Multi-step reaction with 3 steps 1: sulfuric acid / methanol 2: potassium carbonate / <i>N</i>-methyl-acetamide 3: methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In <i>N</i>-methyl-acetamide; dichloromethane | 131.4 PREPARATION 131(4) PREPARATION 131(4) To a mixture of 3-ethoxy-4-methoxybenzoic acid (3.66 g) and oxalyl chloride (2.12 mL) in dichloromethane (40 mL) was added dimethylformamide (5 drops), and the mixture was stirred for 2 hours at ambient temperature. After evaporation of the solvent, the residue was redissolved in dichloromethane (40 mL). The solution was added to a mixture of 28% animonia solution (40 mL) and dichloromethane (40 mL) under ice-water cooling. The mixture was stirred for an hour at ambient temperature. The resulting precipitates were collected by filtration and washed with water and diethyl ether to give 3-ethoxy-4-methoxybenzamide as colorless powders (3.40 g). NMR (DMSO-d6, δ): 1.34 (3H, t, J=7 Hz), 3.80 (3H, s), 4.04 (2H, q, J=7 Hz), 7.00 (1H, d, J=8 Hz), 7.18 (1H, br), 7.39-7.51 (2H, m), 7.83 (1H, br). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
134.2 PREPARATION 134(2) PREPARATION 134(2) 3-Methoxy-4-(2-methoxyethoxy)benzoic acid (4.57 g) was obtained as colorless powders from ethyl 3-methoxy-4-(2-methoxyethoxy)benzoate (5.68 g) in a manner similar to Preparation 131(3). NMR (DMSO-d6, δ): 3.31 (3H, s), 3.68 (2H, t, J=4 Hz), 3.80 (3H, s), 4.15 (2H, t, J=4 Hz), 7.05 (1H, d, J=8 Hz), 7.44 (1H, d, J=4 Hz), 7.53 (1H, dd, J=4, 8 Hz); Mass m/z: 225(M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol | 131.3 PREPARATION 131(3) PREPARATION 131(3) A mixture of methyl 3-ethoxy-4-methoxybenzoate (4.42 g), methanol (160 mL) and IN-sodium hydroxide solution (40 mL) was heated for 2 hours under reflux. The reaction mixture was acidified with 1N-hydrochloric acid to pH 4, and the organic solvent was removed by evaporation. The aqueous layer was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with hexane to give 3-ethoxy-4-methoxybenzoic acid as colorless powders (3.76 g). NMR (CDCl3, δ): 1.50 (3H, t, J=7 Hz), 3.95 (3H, s), 4.17 (2H, q, J=7 Hz), 6.92 (1H, d, J=8 Hz), 7.60 (1H, d, J=4 Hz), 7.76 (1H, dd, J=4, 8 Hz); Mass m/z: 195(M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
133.3 PREPARATION 133(3) PREPARATION 133(3) 4-Ethoxy-3-methoxybenzoic acid (3.46 g) was obtained as colorless powders from methyl 4-ethoxy-3-methoxybenzoate (3.97 g) in a manner similar to Preparation 131(3). NMR (CDCl3, δ): 1.52 (3H, t, J=7 Hz), 3.92 (3H, s), 4.18 (2H, q, J=7 Hz), 6.89 (1H, d, J=8 Hz), 7.58 (1H, s), 7.73 (1H, d, J=8 Hz); Mass m/z: 195(M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
135.2 PREPARATION 135(2) PREPARATION 135(2) 4-Cyclobutylmethoxy-3-methoxybenzoic acid (5.10 g) was obtained as colorless powders from ethyl 4-cyclobutylmethoxy-3-methoxybenzoate (6.20 g) in a manner similar to Preparation 131(3). NMR (DMSO-d6, δ): 1.76-1.98 (4H, m), 2.00-2.17 (2H, m), 2.65-2.83 (1H, m), 3.80 (3H, s), 4.00 (2H, d, J=7 Hz), 7.04 (1H, d, J=8 Hz), 7.43 (1H, d, J=4 Hz), 7.54 (1H, dd, J=4, 8 Hz); Mass m/z: 235(M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PREPARATION 146(2) 3-Benzyloxy-4-methoxybenzoic acid (5.06 g) was obtained as colorless powders from methyl 3-benzyloxy-4-methoxybenzoate (5.60 g) in a manner similar to Preparation 131(3). NMR (DMSO-d6, δ): 3.84 (3H, s), 5.13 (2H, s), 7.07 (1H, d, J=8 Hz), 7.30-7.50 (5H, m), 7.53 (1H, d, J=4 Hz), 7.58 (1H, dd, J=4, 8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.8 g (51%) | With phosphoric acid In 1,2-dimethoxybenzene; dichloromethane | 2.A A. A. 3,4-Dimethoxy-3-ethoxy-4-methoxybenzophenone To an ice bath cooled stirred suspension of 3-ethoxy-4-methoxybenzoic acid (0.98 g, 5.0 mmol) in 20 mL methylene chloride was added oxalyl chloride (0.44 mL, 5.0 mmol) and 2 drop s of N,N dimethylformamide (dimethylformamide). The resulting yellow mixture was stirred at room temperature for 35 minutes at which time a solution had formed. The solution was cooled in an ice bath and veratrole (0.64 mL, 5.0 mmol) was added followed by aluminum chloride (0.73 g, 5.5 mmol). The ice bath was removed and the mixture was stirred at room temperature. The reaction was monitored by HPLC (Waters Nova-Pak/C,8 column 3.9*150 mm, 4 micron, 1 mL/min, 35/65 acrylonitrile/0.1% aqueous phosphoric acid and after 37 hours the reaction was complete. The reaction mixture was poured into 30 mL of ice, stirred for 30 minutes and was then extracted with methylene chloride (3*20 mL). The methylene chloride extracts were washed successively with aqueous sodium bicarbonate (30 mL), water (2*50 mL) and brine (50 nlL). The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo to afford 1.05 g of a brown solid. The crude product was purified by flash column chromatography (silica gel, 5% ethyl acetate/methylene chloride) and the resulting product was then dried in vacuo (60° C., <1 mmHg) to afford 0.8 g (51%) of the product: mp 122-124.5° C.; 1 H NMR (CDCl3) δ 7.48-7.34 (m, 4H),6.98-6.86 (m, 2H), 4.16 (q, J=7 Hz, 2H), 3.96 (s, 3H), 3.96 (s, 3H), 3.94 (s, 3H), 1.49 (t,J=7 Hz, 3H); 13 C NMR (CDCl3) δ 194.4, 152.8, 152.5, 148.8, 148.0, 130.7, 130.6, 124.6, 124.5, 113.5, 112.2, 109.9, 109.7, 64.3, 55.9, 55.9, 14.6; HPLC (Waters Nova-Pak/C,8 column, 3.9*150 mm, 4 micron, 1 mL/min, 35/65 acrylonitrile/0.1% aqueous phosphoric acid 8 min, 99%; Anal. Calcd for C18 H20 O5. Theoretical: C, 68.34; H, 6.37. Found: C, 68.56; H, 6.51. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: thionyl chloride / 3 h / 90 °C 2.1: sodium hydride / tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere 2.2: 24 h / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-ethoxy-4-methoxybenzoic acid; 2-amino-N-(2-(dimethylamino)ethyl)-3-(3′-(trifluoromethyl)biphenyl-4-yl)propanamide hydrochloride With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 18 - 30℃; for 2h; Stage #2: trifluoroacetic acid In water; acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 4.5 h / 60 °C / Sealed tube 2: water; sodium hydroxide / ethanol / 1.5 h / 60 °C | ||
Multi-step reaction with 2 steps 1: potassium carbonate / <i>N</i>-methyl-acetamide 2: methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.5% | With water; sodium hydroxide In ethanol at 60℃; for 1.5h; | 5.2 Step 2: 3-Ethoxy-4-methoxybenzoic acid Step 2: 3-Ethoxy-4-methoxybenzoic acid[0579]To a mixed solvent of ethanol (20 mL) and water (10 mL) was added methyl 3-ethoxy-4-methoxybenzoate (11.66 g, 55.5 mmol) , and sodium hydroxide (11.1g, 277.5 mmol) was added to the solution. The mixture was stirred at 60 for 1.5 hours, then ethanol was removed and the residue was dissolved in water (20 mL) . To the mixture was added hydrochloric acid (1 M) to adjust the pH of the mixture to 1. The mixture was extracted with ethyl acetate (25 mL × 3) . The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed to give the title compound as a white solid (10.25 g, 94.5) .[0580]MS-ESI: m/z 197.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 20 °C 1.2: 20 °C / Cooling with ice 2.1: Lawessons reagent / tetrahydrofuran / 2 h / 75 °C 3.1: dichloromethane / 3 h / -78 - 0 °C 4.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 5.1: water; lithium hydroxide monohydrate / tetrahydrofuran / 3 h / 40 °C 6.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 0 °C 6.2: 22 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 20 °C 1.2: 20 °C / Cooling with ice 2.1: Lawessons reagent / tetrahydrofuran / 2 h / 75 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 20 °C 1.2: 20 °C / Cooling with ice 2.1: Lawessons reagent / tetrahydrofuran / 2 h / 75 °C 3.1: dichloromethane / 3 h / -78 - 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 20 °C 1.2: 20 °C / Cooling with ice 2.1: Lawessons reagent / tetrahydrofuran / 2 h / 75 °C 3.1: dichloromethane / 3 h / -78 - 0 °C 4.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 20 °C 1.2: 20 °C / Cooling with ice 2.1: Lawessons reagent / tetrahydrofuran / 2 h / 75 °C 3.1: dichloromethane / 3 h / -78 - 0 °C 4.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 5.1: water; lithium hydroxide monohydrate / tetrahydrofuran / 3 h / 40 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 20 °C 1.2: 20 °C / Cooling with ice 2.1: Lawessons reagent / tetrahydrofuran / 2 h / 75 °C 3.1: dichloromethane / 3 h / -78 - 0 °C 4.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 5.1: water; lithium hydroxide monohydrate / tetrahydrofuran / 3 h / 40 °C 6.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 0 °C 6.2: 12 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 20 °C 1.2: 20 °C / Cooling with ice 2.1: Lawessons reagent / tetrahydrofuran / 2 h / 75 °C 3.1: dichloromethane / 3 h / -78 - 0 °C 4.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 5.1: lithium hexamethyldisilazane / tetrahydrofuran / 2.5 h / 20 °C 6.1: hydrogenchloride / dichloromethane; ethyl acetate / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 20 °C 1.2: 20 °C / Cooling with ice 2.1: Lawessons reagent / tetrahydrofuran / 2 h / 75 °C 3.1: dichloromethane / 3 h / -78 - 0 °C 4.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 5.1: lithium hexamethyldisilazane / tetrahydrofuran / 2.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 20 °C 1.2: 20 °C / Cooling with ice 2.1: Lawessons reagent / tetrahydrofuran / 2 h / 75 °C 3.1: dichloromethane / 3 h / -78 - 0 °C 4.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 5.1: water; lithium hydroxide monohydrate / tetrahydrofuran / 3 h / 40 °C 6.1: triethylamine; trifluoro-[1,3,5]triazine / dichloromethane / 2 h / -40 - -10 °C 7.1: sodium hydride / tetrahydrofuran / 1 h / 20 °C 7.2: 14 h / 0 - 20 °C 8.1: hydrogenchloride / dichloromethane; ethyl acetate / 2.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 20 °C 1.2: 20 °C / Cooling with ice 2.1: Lawessons reagent / tetrahydrofuran / 2 h / 75 °C 3.1: dichloromethane / 3 h / -78 - 0 °C 4.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 5.1: water; lithium hydroxide monohydrate / tetrahydrofuran / 3 h / 40 °C 6.1: triethylamine; trifluoro-[1,3,5]triazine / dichloromethane / 2 h / -40 - -10 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 20 °C 1.2: 20 °C / Cooling with ice 2.1: Lawessons reagent / tetrahydrofuran / 2 h / 75 °C 3.1: dichloromethane / 3 h / -78 - 0 °C 4.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 5.1: water; lithium hydroxide monohydrate / tetrahydrofuran / 3 h / 40 °C 6.1: triethylamine; trifluoro-[1,3,5]triazine / dichloromethane / 2 h / -40 - -10 °C 7.1: sodium hydride / tetrahydrofuran / 1 h / 20 °C 7.2: 14 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 20 °C 1.2: 20 °C / Cooling with ice 2.1: Lawessons reagent / tetrahydrofuran / 2 h / 75 °C 3.1: dichloromethane / 3 h / -78 - 0 °C 4.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 5.1: water; lithium hydroxide monohydrate / tetrahydrofuran / 3 h / 40 °C 6.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 0 °C 6.2: 12 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 20 °C 1.2: 20 °C / Cooling with ice 2.1: Lawessons reagent / tetrahydrofuran / 2 h / 75 °C 3.1: dichloromethane / 3 h / -78 - 0 °C 4.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 5.1: water; lithium hydroxide monohydrate / tetrahydrofuran / 3 h / 40 °C 6.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.5 h / 0 °C 6.2: 22 h / 20 °C 7.1: hydrogenchloride / dichloromethane; ethyl acetate / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.7% | Stage #1: 3-ethoxy-4-methoxybenzoic acid With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Stage #2: glycine ethyl ester hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Cooling with ice; | 5.3 Step 3: Methyl 2- (3-ethoxy-4-methoxybenzamido) acetate Step 3: Methyl 2- (3-ethoxy-4-methoxybenzamido) acetate[0582]To 50 mL of dichloromethane were added 3-ethoxy-4-methoxybenzoic acid (11.86 g, 60.5 mmol) , 1-hydroxy-7-azabenzotriazole (HOAT) (8.229 g, 60.51 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (17.336 g, 90.76 mmol) . The mixture was stirred at rt for 30 minutes, then glycine methyl ester hydrochloride (9.076 g, 72.61 mmol) was added. The mixture was placed in an ice-bath, and N, N-diisoproylethylamine (42.2 mL, 242.0 mmol) was added dropwise. The resulting mixture was stirred overnight at rt. To the reaction mixture was added water (30 mL) and the mixture was extracted with dichloromethane (25 mL × 3) . The organic layers were combined and dried over anhydrous sodium sulfate. The organic solvent was removed, then the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) 1/1) to give the title compound as a white solid (12.88 g, 79.7) .[0583]1H NMR (400 MHz, CDCl3) : δ ppm 7.42 (s, 1H) , 7.33 (d, J 8.3 Hz, 1H) , 6.87 (d, J 8.4 Hz, 1H ) , 6.60 (s, 1H) , 4.23 (d, J 5.0 Hz, 2H) , 4.12-4.17 (m, 2H) , 3.91 (s, 3H) , 3.80 (s, 3H) , 1.47 (t, J 7.0 Hz, 3H) and MS-ESI: m/z 268.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 2: potassium carbonate / <i>N</i>-methyl-acetamide 3: methanol | ||
Multi-step reaction with 3 steps 3: methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: <i>N</i>-methyl-acetamide; dichloromethane 2: trichlorophosphate / pyridine 3: tetrahydrofuran; ethyl acetate 5: <i>tert</i>-butylamine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: <i>N</i>-methyl-acetamide; dichloromethane 2: trichlorophosphate / pyridine 3: tetrahydrofuran; ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: <i>N</i>-methyl-acetamide; dichloromethane 2: trichlorophosphate / pyridine 3: tetrahydrofuran; ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: <i>N</i>-methyl-acetamide; dichloromethane 2: trichlorophosphate / pyridine 3: tetrahydrofuran; ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: <i>N</i>-methyl-acetamide; dichloromethane 2: trichlorophosphate / pyridine 3: tetrahydrofuran; ethyl acetate 6: trifluoroacetic acid / dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: <i>N</i>-methyl-acetamide; dichloromethane 2: trichlorophosphate / pyridine 3: tetrahydrofuran; ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: <i>N</i>-methyl-acetamide; dichloromethane 2: trichlorophosphate / pyridine 3: tetrahydrofuran; ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: <i>N</i>-methyl-acetamide; dichloromethane 2: trichlorophosphate / pyridine 3: tetrahydrofuran; ethyl acetate 6: triphenylphosphine / 1,2-dichloro-ethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: <i>N</i>-methyl-acetamide; dichloromethane 2: trichlorophosphate / pyridine 3: tetrahydrofuran; ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: <i>N</i>-methyl-acetamide; dichloromethane 2: trichlorophosphate / pyridine 3: tetrahydrofuran; ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: <i>N</i>-methyl-acetamide; dichloromethane 2: trichlorophosphate / pyridine 3: tetrahydrofuran; ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: <i>N</i>-methyl-acetamide; dichloromethane 2: trichlorophosphate / pyridine 3: tetrahydrofuran; ethyl acetate 5: pyridine 6: silica gel / dichloromethane; acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 24.3 Step 3 To a solution of 3-ethoxy-4-methoxybenzoic acid (0.59 g, 3.0 mmol) and (2R)-2-amino-3- phenyl-l-(6-(pyridin-3-yl)-5,6-dihydropyridin-l(2H)-yl)propan-l-one (0.92 g, 3.0 mmol) was added EDC hydrochloride (0.72 g, 3.8 mmol) and z-Pr2NEt (0.70 mL, 3.9 mmol) in DCM (10 mL). The reaction mixture was stirred at rt overnight and quenched with H20 (10 mL). Layers were separated and the organic layer was washed with brine, dried and concentrated to give 3- ethoxy-4-methoxy-N-((2R)-l-oxo-3-phenyl-l-(6-(pyridin-3-yl)-5,6-dihydropyridin-l(2H)- yl)propan-2-yl)benzamide as a film in the flask, existing as a mixture of two diastereomers after purification with CombiFlash using HP Cl 8 Aq GOLD column with MeCN/buffered H20 as an eluting mobile phase. MS (ESI, pos. ion) m/z: 486.2 (M+l). |
Tags: 2651-55-0 synthesis path| 2651-55-0 SDS| 2651-55-0 COA| 2651-55-0 purity| 2651-55-0 application| 2651-55-0 NMR| 2651-55-0 COA| 2651-55-0 structure
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