Structure of 4760-34-3
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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. : | 4760-34-3 |
Formula : | C7H10N2 |
M.W : | 122.17 |
SMILES Code : | NC1=CC=CC=C1NC |
MDL No. : | MFCD00192314 |
InChI Key : | RPKCLSMBVQLWIN-UHFFFAOYSA-N |
Pubchem ID : | 78498 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302+H312+H332-H315-H319 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 0.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 40.15 |
TPSA ? Topological Polar Surface Area: Calculated from |
38.05 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.19 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.23 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.13 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.15 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.81 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.1 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.8 |
Solubility | 1.94 mg/ml ; 0.0159 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.63 |
Solubility | 2.89 mg/ml ; 0.0236 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.43 |
Solubility | 0.454 mg/ml ; 0.00372 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) |
Yes |
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 |
-6.17 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) |
1.0 |
* 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 |
---|---|---|
97% | With sodium metabisulfite; In N,N-dimethyl-formamide;Reflux; | 8.4 g of compound c1, 7 g of benzaldehyde, 13gSodium metabisulfite,200mL dimethylformamide was added to the reaction flask Medium, reflux overnight. After the reaction is finished, cool to room temperature.Pour the reaction solution into 500 mL of ice water with stirring.Solid precipitated, suction filtered, and washed with ethanol, petroleum ether,Drying gave a solid, Compound d1 (11.3 g, yield 97percent). |
94% | With Ag2CO3/celite; In ethanol; at 70℃; for 3h; | General procedure: To a mixture of 1,2-phenylenediamines (1.0 mmol) andaldehydes (1.1 mmol) in ethanol, 25 mol percent of Ag2CO3/Celite (3 mL) was added. The resulting mixture was stirredat 70 °C for 3 h. After this time, the reaction mixture wasdiluted with ethanol (50 mL) and the catalyst was separatedby filtration. Water was then added to the organic layer, andthe products were filtered and washed with water. All of theproducts are known compounds and characterized easily bycomparison with melting point, IR, [1?6] H NMR spectraldata reported in literature. |
90% | In water; N,N-dimethyl-formamide; at 80℃; | General procedure: An ortho-phenylenediamine derivative 3 (1.0 mmol; 1.0 equiv) and an aldehyde 4 (1.0 mmol; 1.0 equiv) were dissolved in wet DMF (DMF 9.0 mL, H2O 1.0 mL). The resulting reaction mixture was stirred at 80°C in an open flask, and the reaction progress was monitored by TLC. On the complete consumption of 3, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product obtained was purified by column chromatography on silica gel to afford the corresponding benzimidazole 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; dicyclohexyl-carbodiimide; In dichloromethane;Heating / reflux; | EXAMPLE 7; ALTERNATE PROCESS FOR PREPARING 2-n-PROPYL-4-METHYL-6- (1- METHYL BENZAMIDAZOLE-2-YL) BENZAMIDAZOLE (FORMULA IV); STEP A; PREPARATION OF 7-METHYL-N-(2-(METHYLAMINO)PHENYL)^-PROPYL-SH-BENZODIIMIDAZOLE-S-CARBOXAMIDE (FORMULA IVA); 15 g of 2-n-propyl-4-methyl-benzimidazole-6-carboxyIic acid of Formula III, obtained in Example 1 , 2.O g of N-methyl o-phenylenediamine, 150 ml of dichloromethane, 7.8 g of dicyclohexyl carbodiimide (DCC), and 2.7 g of dimethylaminopyridine were stirred for about 15 minutes. Heated the reaction mass to reflux and maintained until completion of the reaction, and then cooled to room temperature. Filtered the reaction mass and washed with 75 ml of dichloromethane. Distilled the solvent from the filtrate under vacuum and added 30 ml of acetone to the residue. Stirred at 25-35 C for the separation of the solid, filtered the solid and washed with acetone (15 ml). Dried the solid at 50-55 C to get 6.0 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Example 2; Variant 2; Methanesulphonic acid is heated to about 80 C. At a temperature of 75 C. to 85 C., 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid is added. Then at 85 C. to 95 C. N-methyl-o-phenylene-diamine is added.The mixture is heated to110 C. to 130 C. and phosphorus pentoxide is metered in until an internal temperature of not more than 160 C. is reached. Then the mixture is stirred for 3 hours at a maximum temperature of 145 C. It is cooled to <100 C. and water is metered into the reaction mixture. 50% sodium hydroxide solution is added at <100 C. until a pH of less than 3 is obtained.Finally, treatments with charcoal are carried out at <100 C.At a temperature of <80 C. isopropanol is added and the mixture is adjusted with sodium hydroxide solution to a pH between 4.5 and 7. The aqueous phase is separated off. In order to precipitate dimethyl-2'-propyl-2,5'-bi-1H-benzimidazole water is metered in, the contents of the apparatus are cooled to at least 40 C. for technical reasons and the product is isolated.Yield: 78-90% of theoryHPLC purity: >99.5%. | |
Stirring blade, a thermometer, three-neck flask 1L fitted with condenser, 4-methyl--2-n-propyl -1H- benzimidazole-6-carboxylic acid 50.0g (229mmol) and polyphosphoric acid added and stirred and 300 g, heated to around 70 C., the reaction solution obtained was stirred for 30 minutes, added in portions over a period N- methyl -O- phenylenediamine 45.0g of (368mmol) 2 hours It was.After adding the entire amount, stirring for 1 hour at around 70 C., and stirred for 5 h warmed to near yet 130. C..After confirming the disappearance of 4-methyl--2-n-propyl -1H- benzimidazole-6-carboxylic acid by HPLC, was cooled to about 70 C., while maintaining the water 600g The temperature of the reaction solution at 70 to 85 C. It was dropped little by little.After the total amount dropwise, 30 C. and cooled to near, pH of the reaction solution with aqueous ammonia was adjusted to be pH 8.3, after stirring for 1 hour warmed to around 50 C., the solid by vacuum filtration It is filtered off and washed the solid was filtered off with water 200g in the vicinity of 50 , to obtain a wet product of light brown crystals.Stirring blade, a thermometer, three-neck flask 1L fitted with condenser, was added and stirred the wet product of the resulting pale brown crystals and water 900 g, after stirring for 1 hour warmed to around 50 C. , vacuum filtered off the solids by filtration, wash the solid was filtered off with 100g of water around 50 C., the resulting wet product was dried for 15 hours under reduced pressure, a pale crude benzimidazole body as brown crystals to obtain a body 60.3g.The crude product of the benzimidazole body was analyzed by HPLC, the purity was 98.20%, the content of methyl benzimidazole body 0.14%, the content of ethyl benzimidazole body with 0.07% there were. stirring blade, a thermometer, three-necked flask 100mL fitted with a condenser, a mixture of a crude product 5.0g of methanol 12g and water 50g benzimidazole body obtained in Production Example 1 was added after stirring on, the addition of hydrochloric acid 2.1g containing hydrogen chloride 0.78 g (21.4 mmol), stirred for 10 minutes at about 25 C., the solid in the reaction solution was confirmed to be dissolved.Then, was added aqueous ammonia 1.1g containing ammonia 0.28 g (16.5 mmol), precipitation of white crystals was confirmed.After stirring for 1 hour at about 25 C., vacuum filtered through the solid was filtered off, the solid was filtered off with water 5g were washed twice and dried for 12 hours at 60 C. under reduced pressure and the resulting wet biomass, to obtain a benzimidazole body 4.2g (13.9mmol) as white crystals.Recovery rate, which is calculated based on the mass of the crude product of the benzimidazole body was 84.4%.As a result of the benzimidazole body obtained was analyzed by HPLC, the purity was 99.56%, the content of methyl benzimidazole body 0.06%, the content of ethyl benzimidazole body 0.02% met. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With acide 2,4,6-trihydroxybenzoique; oxygen; In toluene; at 70℃; under 750.075 Torr; for 24h;Green chemistry; | General procedure: To a two-necked flask, benzylamine derivatives 1 (4.5 mmol), o-phenylenediamine derivatives 2 (3.0 mmol), 4,6-dihydroxysalicylic acid (10 mol%), and distilled toluene (1.0 mL) were added, and then the reaction vessel was connected to an O2 balloon at room temperature. The mixture was stirred at 70 C under an O2 atmosphere for 24 h. The resulting mixture was transferred into a round-bottom flask using methanol (MeOH) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basified with Et3N (25 wt%) (eluent: hexane/EtOAc with 1.0 v/v% Et3N) to give the product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.5% | With sulfur; In dimethyl sulfoxide; at 20 - 60℃; for 2.08333h; | To a solution of <strong>[55589-47-4]3-methylpyridine-2-carbaldehyde</strong> (1 .00 g, 8.26 mmol) in DMSO (16 mL) was added /V-methylbenzene-1 ,2-diamine (1.01 g, 8.26 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and then sulfur was added (8.26 mmol). After being degassed with nitrogen, the reaction mixture was warmed up to 60 °C and stirred for 2 hours. The reaction mixture was cooled to RT and added to a bi- phasic stirred solution of DCM and water (80 mL ea). The resulting emulsion was extracted with DCM (2 x 40 mL) and the combined organics were washed with water (3 x 40 mL), dried over MgS04, filtered and stripped to a red gum. The crude product was purified by flash column chromatography (40 g silica gel, 0-6 percent MeOH/DCM) to provide the title compound (1 .41 g, 76.5 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With sulfur; In 1,1-dimethoxyethane; at 65 - 85℃; for 1.5h; | To a solution of <strong>[118289-17-1]2-bromopyridine-4-carboxaldehyde</strong> (128 mg, 0.688 mmol) in DMA (3 mL) was added /V-methyl-O-phenylenediamine (84 mg, 0.688 mmol) followed by sulfur (22 mg, 0.688 mmol) and the mixture stirred at 65 °C for 1 hour, followed by heating to 85 °C for 30 mins. The reaction was cooled and quenched with water (10 ml_), extracted with EtOAc (25 ml_), dried over MgS04, filtered and stripped to a dark oil. The crude product was purified by Biotage flash chromatography (25 S, eluting with 20- 50 percent EtOAc / heptane over 10 CV, then holding for 2 CV) to afford the title compound (80 mg, 40 percent) as a pale brown solid. 1H NMR (400 MHz, DMSO-d6) d ppm 3.98 (s, 3 H) 7.29 - 7.35 (m, 1 H) 7.35 - 7.44 (m, 1 H) 7.71 (d, J=7.8 Hz, 1 H) 7.76 (d, J=7.6 Hz, 1 H) 7.97 (d, J=5.1 Hz, 1 H) 8.13 (s, 1 H) 8.61 (d, J=5.1 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sulfur; In dimethyl sulfoxide; at 20 - 60℃; for 2.58333h; | To a solution of <strong>[102645-33-0]2,5-dichloropyridine-4-carbaldehyde</strong> (2.75 g, 15.62 mmol) in DMSO (63 mL) was added /V-methyl-O-phenylenediamine (1.91 g, 15.62 mmol) and the mixture stirred at ambient temperature for 5 mins. Sulfur (500 mg, 15.62 mmol) was added and the mixture warmed to 60 C and allowed to stir for 2.5 hrs. The reaction was then cooled to R.T. and added to a bi-phasic stirred solution of DCM and water (200 mL ea). The resulting emulsion was extracted with DCM (3 x 100 mL) and the combined organics were washed with water (3 x 100 mL), dried over MgS04, filtered and stripped to a crude red gum which was purified by Biotage flash chromatography (45 M loaded with DCM, eluting with EtOAc / heptane 5-30 % over 10 CV, then holding for 5 CV) to afford the title compound (3.22 g, 74 %) as a pale orange solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 3.72 (s, 3 H) 7.26 - 7.35 (m, 1 H) 7.35 - 7.44 (m, 1 H) 7.69 (d, J=8.1 Hz, 1 H) 7.74 (d, J=8.1 Hz, 1 H) 7.95 (s, 1 H) 8.78 (s, 1 H). m/z (APCI+) for Ci3H9N3Cl2 278.05 / 280.00 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | at 125℃; for 4h;Inert atmosphere; | Prepared from N-methyl-1,2-phenylenediamine (0.548 g, 4.49 mmol), <strong>[1003-61-8]2-aminothiazole-5-carbaldehyde</strong> (0.512 g, 4.00 mmol), and PEG-400 (0.100 mL) using a reaction temperature of 125 C. The crude mixture was then dissolved in DCM/methanol and adsorbed onto silica gel. The adsorbed material was partially purified by flash column chromatography on silica gel using a gradient mixture of 0 to 10% (2 M ammonia in methanol) in dichloromethane. Chromatography was repeated using the same conditions to provide 22b (0.59 g, 64%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In 1-methyl-pyrrolidin-2-one; water; at 445℃; under 187519.0 Torr; for 0.00277778h;Supercritical conditions; | Under the same conditions as in Example 1-5 except that N-methyl-1,2-phenylenediamine (manufactured by Sigma-Aldrich) and benzoic acid hydride (manufactured by Tokyo Chemical Industry Co., Ltd.) were used at a pressure of 25 MPa, (13) was carried out in supercritical water. As a result, the reaction time was 10 seconds, and the yield was 99percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.3 g | In a three-necked flask equipped with a water separator, a thermometer, a condenser, and a stirring device, 30 g of refined waste oil was added.39 g of N-methyl o-phenylenediamine and 70 ml of xylene were passed through nitrogen and slowly heated at 140 C. for 6.5 h. After evacuation at 190-200 mmHg, vacuum distillation was performed for 2.5-3 h and then at 20-25 mmHg. Distillation for 1 ~ 2h, until no liquid flow out, after cooling, add 110ml of 10% NaCl aqueous solution to the mixture and stir, heat the mixture to 80 C and heat 1h, cooled, let stand 2.0h, separated with a separatory funnel The upper oily substance was washed twice with water and the aqueous layer was separated. The oily phase was dried under vacuum to obtain a creamy oily fat-based inhibitor of N-methylbenzimidazoline, weighing 48.3 g |
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