Structure of 3,4,5-Trimethoxyaniline
CAS No.: 24313-88-0
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 24313-88-0 |
Formula : | C9H13NO3 |
M.W : | 183.20 |
SMILES Code : | COC1=CC(N)=CC(OC)=C1OC |
MDL No. : | MFCD00008393 |
InChI Key : | XEFRNCLPPFDWAC-UHFFFAOYSA-N |
Pubchem ID : | 32285 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H335 |
Precautionary Statements: | P261 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 50.32 |
TPSA ? Topological Polar Surface Area: Calculated from |
53.71 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.93 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.25 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.3 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.6 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.12 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.24 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.91 |
Solubility | 2.27 mg/ml ; 0.0124 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.98 |
Solubility | 1.94 mg/ml ; 0.0106 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.42 |
Solubility | 0.693 mg/ml ; 0.00378 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.53 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.72 |
* 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 |
---|---|---|
88% | In ethanol; for 3h;Reflux; | General procedure: The appropriate amine (10 mmol) was heated at reflux with the appropriate aldehyde (10 mmol) in ethanol (50 mL) for 3 h. The reaction mixture was reduced in vacuo and the resulting solution was left to stand until solid product crystallised. The resulting imine was recrystallised from ethanol. |
In ethanol; at 80℃; for 6h; | General procedure: A solution of various aromatic aldehydes A1-A10 (1.0 mmol, 1.0 eq) and 3,4,5-trimethoxyaniline (1.0 mmol, 1.0 eq) were added into EtOH (20 ml) at 80 C for 6 h. When the reactions were complete, organic phases were collected to give crude the products C1-C10 without further purified with column chromatography. A solution of compounds C1-C10 (1.0 mmol,1.0 eq), benzoic acid (1.0 mmol, 1.0 eq) and NaBH4 (1.0 mmol, 1.0 eq) were added into DCM (20 ml) at 25 C for 8 h. When the reactions were complete, organic phases were collected to obtain crude products and then were purified by column chromatography to obtain compounds D1-D10. A solution of compounds D1-D10 (1.0 mmol, 1.0 eq) and acyl chloride derivatives (1.0 mmol, 1.0 eq) were added into DMF (8 ml) at 25 C for 6-8 h. Then using EA (20 ml) extracted aqueous layers for three times. Collected organic layers were washed by saturated salt water, dried over magnesium sulfate anhydrous and evaporated to get crude products. Crude products were purified by column chromatography to obtain compounds E1-E11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | In diethyl ether; ethanol; dichloromethane; | EXAMPLE 2 1-Methyl-4-[N-(3,4,5-trimethoxyphenyl)-carbamoyl]piperazine (hydrochloride) A solution of 10 g (0.061 mole) 1-methyl-4-chloroformyl-piperazine in 100 ml dry methylene chloride is added to a solution of 11.2 g (0.061 mole) 3,4,5-trimethoxy-aniline in a 100 ml methylenechloride. After stirring at ambient temperature for 24 hours, the solvent is evaporated off in vacuo; the residue is dissolved in the minimum of ethanol and then the crude hydrochloride precipated by the addition of diethyl ether, and dried. Purification by recrystallisation from an acetone 3-ethanol 1 mixture gives the pure product (9.4 g; 44% yield) which melts at 184-86 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | Example 106 N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-3,4,5-trimethoxyaniline 3,4,5-Trimethoxyaniline (0.216 g, 1.18 mmol), triethylamine (0.119 g, 1.18 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.199 g, 1.18 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform: methanol = 10:1) to obtain the titled compound (0.109 g, 0.202 mmol, 38percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | Example 128 N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoyl]-3,4,5-trimethoxyaniline 3,4,5-Trimethoxyaniline (0.260 g, 1.42 mmol), triethylamine (0.144 g, 1.42 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.240 g, 1.42 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.200 g, 0.473 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform: methanol = 10:1) and then recrystallized from ether to obtain the titled compound (0.050 g, 0.085 mmol, 18percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With acetic acid; for 12h;Reflux; | General procedure: A solution of 3,4,5-trimethoxyaniline (1.83 g, 10 mmol) and acid anhydride (10 mmol) in glacial acetic acid (15 mL) was heated under reflux for 12 h. After the evaporation of the reaction mixture to dryness under reduced pressure, the residue was neutralized by a solution of sodium bicarbonate (4%) until effervescence ceased. The precipitate obtained was washed with water, dried (P2O5) and recrystallized from an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.6% | 2) 200 mg (0.8 mmol) of the product from step 1) is mixed with 120 mg (0.9 mmol) HOBT and 0.06 ml (0.6 mmol) DIC in dry DMF under ice-water bath condition. The mixture is stirred for 30 min. under N2 protection, then 160 mg (0.9 mmol) 3,4,5-trimethoxyaniline is subsequently added, the mixture is let to naturally resume room temperature and stirred overnight. The resulted reactant is evaporated to dryness under reduced pressure, the residue is dissolved in ethyl acetate and subsequently filtered, the filtrate is evaporated to dryness, separated using preparatory thin layer silica plate to obtain 180 mg product, yield: 55.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | General procedure: To a solution of the acid derivative (1mmol) in CH2Cl2 were added triethylamine (2mmol) and ethyl chloroformate (1mmol), followed by stirring at 0C for 30min. After addition of the appropriate amine derivative (1.2mmol), the mixture was stirred for an additional 1h at 0C. Then, the reaction mixture was warmed to room temperature and stirred overnight. After the solvent was evaporated under reduced pressure, acetone was added, filtered, and evaporated. The residue was dissolved in CH2Cl2, and the organic phase was washed with a 1% NaHCO3 solution and brine, dried over Na2SO4, and evaporated under vacuum. The final residue was purified by flash column chromatography (Combiflash Rf) using CH2Cl2-MeOH (0-5%) as eluents. 4.3.5 (E)-3-(1H-Indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acrylamide 3e Yield 53%, mp 246-248 C; IR (FTIR/FTNIR-ATR): 1733 cm-1 (C=O), 3304 cm-1 (N-H). 1H NMR (DMSO-d6) delta: 11.68 (1H, s), 9.96 (1H, s), 7.95 (1H, m), 7.83 (1H, s), 7.74 (1H, d, J = 15.6 Hz), 7.48 (1H, m), 7.23 (2H, m), 7.10 (2H, s), 6.79 (1H, d, J = 15.6 Hz), 3.77 (6H, s), 3.63 (3H, s). 13C NMR (DMSO-d6) delta: 165.5, 153.4, 138.1, 136.6, 135.2, 133.7, 131.8, 125.5, 123.0, 121.1, 120.6, 116.7, 113.1, 112.8, 97.1, 60.8, 56.3; HRMS C20H21N2O4 [M+H]+ Calcd 353.1501, Found m/z 353.1503. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | General procedure: Similar to the reported method [19], a mixture of the appropriate indole (0.6 mmol), 1,2-bis-(3,4,5-trimethoxyphenyl)diselenide(0.35 mmol, 0.45 g mixture of 1,2-bis-(3,4,5-trimethoxyphenyl)diselenide with 1,10-selenobis(3,4,5-trimethoxybenzene)), FeCl3 (20 mol%) and I2 (1 mol%, 0.0001 g/mL in CH3CN) was placed into the microwave cavity (closed vessel mode). Microwave irradiation at 150 W was used, the temperature being ramped from 25 C to 80 C. Once 80 C was reached, takingabout 1 min, the reaction mixture was held at this temperature for 30 min while stirring, until complete consumption of the starting material, as monitored by TLC. After the evaporation of the solvent,the residual crude product was purified by column chromatography on silica gel (200-300 mesh) with petroleumether/AcOEt (v/v 5:1) or pure CH2Cl2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | General procedure: Similar to the reported method [19], a mixture of the appropriate indole (0.6 mmol), 1,2-bis-(3,4,5-trimethoxyphenyl)diselenide(0.35 mmol, 0.45 g mixture of 1,2-bis-(3,4,5-trimethoxyphenyl)diselenide with 1,10-selenobis(3,4,5-trimethoxybenzene)), FeCl3 (20 molpercent) and I2 (1 molpercent, 0.0001 g/mL in CH3CN) was placed into the microwave cavity (closed vessel mode). Microwave irradiation at 150 W was used, the temperature being ramped from 25 °C to 80 °C. Once 80 °C was reached, takingabout 1 min, the reaction mixture was held at this temperature for 30 min while stirring, until complete consumption of the starting material, as monitored by TLC. After the evaporation of the solvent,the residual crude product was purified by column chromatography on silica gel (200-300 mesh) with petroleumether/AcOEt (v/v 5:1) or pure CH2Cl2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 60℃; | General procedure: A solution of <strong>[848398-41-4]2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine</strong> (4, 1.89g, 10mmol) in DMSO (10mL) was added commercially available 3,4-dimethoxyaniline (1.53g, 10mmol) and DIPEA (2.58g, 20mmol). The solution was heated to 60C and stirred overnight. Then the solution was poured into water and extracted with EtOAc, the organic layer was washed by brine, dried with anhydrous Na2SO4, and filtered and concentrated under reduced pressure. The crude product was further purified by flash chromatography on silica gel (EtOAc/hexane=1:1) to afford 8 compound 5 (2.00g, yield 65%) as an off-white solid. 1H NMR (400MHz, CDCl3) delta: 6.90-6.81 (m, 3H), 4.88 (s, 2H), 4.42 (s, 2H), 3.92 (s, 3H), 3.89 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | at 90℃; for 0.0666667h;Microwave irradiation; | General procedure: Equimolar quantities of <strong>[3012-80-4]1-methyl-1H-benzo[d]imidazole-2-carbaldehyde</strong> and the respective aniline derivative were placed in microwave vial, and the reaction mixture was irradiated at 90 C during 4 min. After cooling to room temperature, the resulting residue was then purified by recrystallization in ethanol to give the pure Schiff base. N-(4-methoxyphenyl)-1-(1-methyl-1H-benzo[d]imidazol-2-yl)methanimine (L1). |
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