Structure of 4294-95-5
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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. : | 4294-95-5 |
Formula : | C8H9NO3 |
M.W : | 167.16 |
SMILES Code : | C1=CC(=CC(=C1C(O)=O)N)OC |
MDL No. : | MFCD00667729 |
Boiling Point : | No data available |
InChI Key : | HHNWXQCVWVVVQZ-UHFFFAOYSA-N |
Pubchem ID : | 351010 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 44.3 |
TPSA ? Topological Polar Surface Area: Calculated from |
72.55 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.98 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.34 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.98 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.37 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.5 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.49 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.33 |
Solubility | 7.84 mg/ml ; 0.0469 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.43 |
Solubility | 6.25 mg/ml ; 0.0374 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.53 |
Solubility | 4.91 mg/ml ; 0.0294 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 |
No |
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 |
-7.08 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 |
0.56 |
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) |
1.17 |
* 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 |
---|---|---|
75.92% | With sulfuric acid; for 24h;Reflux; | To a solution of 2-amino-4-methoxybenzoic acid 33 (5.0 g,0.03 mol) in methanol (50 mL) was added strong sulphuricacid (9 mL). The solution was stirred at reflux for 24 h. Itwas cooled to room temperature and the pH of the mixturewas adjusted to 5~6 with saturated sodium carbonatesolution. The solution was extracted with EA (100 mL*2).The combined organic layers were washed with brine(50 mL), dried over Na2SO4, filtered and concentrated,affording white powder 34 (4.11 g, 75.92%). 34: 1H NMR (400 MHz, CDCl3) 7.81 (d, J = 8.9 Hz, 1 H), 6.25 (dd, J =9.0, 2.5 Hz, 1H), 6.13 (d, J = 2.4 Hz, 1H), 5.80 (s, 2H), 3.86(s, 3H), 3.81 (s, 3H). |
37% | With sulfuric acid;Reflux; | Step a): Methyl 2-amino-4-methoxybenzoate 1000 mg (6.0 mmol) of 2-amino-4-methoxybenzoic acid are reacted according to General Method I. Yield: 400 mg (37% of theory) LC-MS (Method 3): Rt=1.96 min; MS (ESIpos): m/z=182 [M+H]+. 5 mmol of the carboxylic acid are dissolved in 50 ml of methanol, and 5 ml of concentrated sulfuric acid are added. The mixture is heated under reflux for 14-24 h. After cooling to room temperature, the solution is poured onto ice and adjusted to pH 6 using sodium bicarbonate. After addition of 100 ml of dichloromethane, the aqueous phase is separated off and reextracted twice with in each case 50 ml of dichloromethane. The combined organic extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | ii. Methyl-4-methoxyanthranilate Esterification of 4-methoxy anthranilic acid as described above afforded methyl-4-methoxyanthranilate, M.P. 77-79 C., in 77% yield. | |
72.6% | In methanol; | c. Methyl 2-amino-4-methoxybenzoate A solution of 2-amino-4-methoxybenzoic acid (11.7 g, 70.0 mM) in methanol (170 mL) was cooled in an ice bath and saturated with hydrogen chloride gas. The resulting solution was refluxed for 18 hr, cooled to room temperature and concentrated. The residue was diluted with saturated agueous bicarbonate and the resulting mixture extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered and concentrated to leave the title amino ester (9.2 g, 72.6%) as a tan crystalline solid; MS(CI): 182 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.0h; | To a solution of 2-amino-4-methoxybenzoic acid (4.00 g, 23.93 mmol) in DMF (120 mL) at 0 C was added NBS (4.68 g, 26.3 mmol). The cooling bath was removedand the reaction mixture was warmed up to room temperature and was stirred at room temperature for 1 h. The mixture was cooled to 0 C and was treated with saturated sodium sulfite solution (25 mL) and was stirred for 5 mm. The pH of the mixture was adjusted to pH = 3 using conc. HC1 (ca. 10-15 mL was added). The reaction mixture was transferred to a separatory funnel containing water (100 mL). Theaqueous layer was extracted with ether (1 x 250 mL then 4 x 100 mL). The combined organic layers were washed with water (3 x 50 mL), brine (50 mL), dried over MgSO4, filtered, and concentrated to afford 2-amino-5-bromo-4- methoxybenzoic acid (5.90 g, 100% yield) as a solid: ?H NMR (400 MHz, DMSOd6) oe 7.78 (s, 1H), 6.43 (s, 1H), 3.81 (s, 3H), 2.90 (s, 1H), 2.74 (s, 1H); MS (ESI) m/e228.0 [(M+H-H2O), calcd for C8H7BrNO2 228.0]. |
77% | With bromine; acetic acid; at 20 - 40℃; for 18.0h; | 2-amino-5-bromo-4-methoxybenzoic acid 2-amino-4-methoxybenzoic acid (5 g, 30 mmol) was suspended in acetic acid (100 mL) and bromine (0.57 mL, 11.25 mmol) added at RT. The mixture was stirred approx. 15 h at RT, then additional bromine (0.2 mL, 3.75 mmol) was added and the reaction mixture held at 40 C. for 3 hours. The reaction course was tracked by thin-film chromatography, the product filtered out and washed with a little water. (Yield: 5.63 g, 77%) |
With bromine; In acetic acid; at 0 - 20℃; for 8.0h; | Step 1: 2-Amino-5-bromo-4-methoxybenzoic acidTo a stirred suspension of 2-amino-4-methoxybenzoic acid (5 g, 0.029 mol) in acetic acid (100 mL) was added bromine (1.23 mL, 0.023 mol) dropwise at 0C. The reaction mixture was stirred at room temperature for 8 h. The separated solid was filtered, washed with water (30 mL) and dried under vacuum to afford the product as white solid (6.3 g, 86 %). As per the LC-MS data this solid contains 14% of starting material, 22% of dibromo byproduct and 61% of desired compound.1H NMR (400 MHz, DMSO-de) : delta 7.76 (s, 1H), 6.42 (s, 1H), 3.72 (s, 3H); ESI-MS: Calculated mass: 244.97; Observed mass LC-MS: 246.0 [M + H]+RT: 2.07 min. |
1.3 g | With N-Bromosuccinimide; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 4.0h; | To a mixture of 4-methoxyanthranilic acid (0.67 g, 4.0 mmol) in DCM (10 mL) and DMF (3 mL) was added NBS (0.71 g, 4.0 mmol) at 0 C. The mixture was stirred at room temperature for 4 h, then concentrated and subjected to silica gel chromatography (5-100% EtOAc/Heptane) to provide 2-amino-5-bromo-4-methoxybenzoic acid as a beige solid (1 .30 g, containing 1 equivalent succinamide). MS (M-1 ) = 244.3/246.3. 1H NMR (DMSO-d6) delta 7.76 (s, 1 H), 6.42 (s, 1 H), 3.79 (s, 3H). This material was used without further purification. |
With bromine; acetic acid; In acetonitrile; at 0 - 20℃; for 1.0h;Inert atmosphere; | 2-Amino-4-methoxybenzoic acid (5.00 g, 29.91 mmol) was dissolved in acetic acid (10 mL) and acetonitrile (100 mL), slowly added dropwise with liquid bromine (4.78 g, 29.91 mmol) at 0 C and under nitrogen protection,, and stirred at 20 C for 1 hour. TLC showed that the reaction was complete. After the reaction solution was concentrated, water (100 ml) and petroleum ether (100 ml) were successively used for making a slurry, which was vaccum dried to obtain compound 1A. 1H NMR (400MHz, DMSO-d6) delta= 7.76 (s, 1H), 6.41 (s, 1H), 3.79 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In tetrahydrofuran; methanol; diethyl ether; at 0 - 20℃; for 16h; | To a solution of 4-methoxyanthranilic acid (5.0 g, 30.0 mmol) in a mixtue of 10% methanol in tetrahydrofuran (100 mL) was added dropwise (trimethylsilyl)diazomethane (2.0 M solution in diethyl ether, 18.0 mL, 36.0 mmol) at 0 C. The reaction mixture was stirred for 16 hours at room temperature then quenched by the addition of glacial acetic acid (0.1 mL). The reaction mixture was concentrated and the residue was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (250 mL). The organic layer was separated and washed with water (50 mL), saturated sodium bicarbonate (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to give methyl 2-amino-4-methoxybenzoate as an oil (5.4 g, quantitative). MS (EI) for C9HnNO3: 182 (MH+). |
74% | In methanol; toluene; at 0 - 20℃; for 1h; | To a solution of 2-amino-4-(methyloxy) benzoic acid (5 g, 30 mmol) in MeOH (30 mL) and toluene (60 mL) wasadded trimethylsilyldiazomethane (30 mL, 60 mmol). The reaction mixture was stirred atooc for 1 h. The reaction mixture was allowed to warm to rt and solvent was removed in5 vacuo. The crude material was purified by column chromatography (0 to 15%EtOAC/hexanes) to provide 4.2 g of the title compound (74%). MS: m/z: 182 [M+H+] |
74% | In methanol; toluene; at 0℃; for 1h; | Step 1. Methyl 2-amino-4-methoxybenzoate: To a solution of 2-amino-4- (methyloxy) benzoic acid (5 g, 30 mmol) in MeOH (30 mL) and toluene (60 mL) was added trimethylsilyldiazomethane (30 mL, 60 mmol). The reaction mixture was stirred at 0C for 1 h. The reaction mixture was allowed to warm to rt and solvent was removed in vacuo. The crude material was purified by column chromatography (0 to 15% EtOAc/hexanes) to provide 4.2 g of the title compound (74%). MS: m/z: 182 [M+H]+. |
74% | In methanol; toluene; at 0℃; for 1h; | To a solution of 2-amino-4-(methyloxy) benzoic acid (5 g, 30 mmol) in MeOH (30 mL) and toluene (60 mL) was added trimethylsilyldiazomethane (30 mL, 60 mmol). The reaction mixture was stirred at 0C for 1 h. The reaction mixture was allowed to warm to rt and solvent was removed in vacuo. The crude material was purified by column chromatography (0 to 15% EtOAC/hexanes) to provide 4.2 g of the title compound (74%). MS: m/z: 182 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium carbonate; In acetone; at 20℃; for 3h;Inert atmosphere; | To a suspension of compound 2-amino-4-methoxybenzoic acid (10 g, 59.8 mmol) in acetone (110 ml) was added K2003 (12.3 g, 89.7 mmol) followed by dimethyl sulfide (7.1 ml, 71.7 mmol) under argon atmosphere. The reaction mixture was stirred at room temperature for 3h. It was diluted with H20 then extracted with ethyl acetate (2 x 200 ml). The combined organic layer was dried over Na2SO4 then concentrated under reduced pressure. The crude compound was purified by column chromatography using silica gel (100-200 mesh), (eluent 0-30% EtOAc in petroleum ether) to afford the title compound If-I as a pale brown solid (7 g, 68% yield). LCMS [M+H] 182. |
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