Structure of 456-14-4
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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. : | 456-14-4 |
Formula : | C7H8ClFN2 |
M.W : | 174.60 |
SMILES Code : | N=C(N)C1=CC=C(F)C=C1.[H]Cl |
MDL No. : | MFCD04114421 |
Boiling Point : | No data available |
InChI Key : | JQDATBKJKUWNGA-UHFFFAOYSA-N |
Pubchem ID : | 12456160 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 44.63 |
TPSA ? Topological Polar Surface Area: Calculated from |
49.87 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.09 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.33 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.36 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.53 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.46 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.95 |
Solubility | 1.97 mg/ml ; 0.0113 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.73 |
Solubility | 3.25 mg/ml ; 0.0186 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.38 |
Solubility | 0.726 mg/ml ; 0.00416 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 |
-6.59 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 |
2.0 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) |
1.19 |
* 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 |
---|---|---|
35.5% | With ammonia; In diethyl ether; ethanol; | EXAMPLE 40 4-Fluorobenzamidine Hydrochloride 4-Fluorobenzonitrile (10 g, 83 mmol) is dissolved in a mixture of anhydrous ethanol (5 mL) and diethyl ether (70 mL). The reaction mixture is cooled to ice-bath temperature and saturated with gaseous hydrogen chloride for 90 minutes. The mixture is allowed to warm to ambient temperature and stirred overnight. The colorless precipitates are filtered off, washed with diethyl ether and dissolved in anhydrous ethanol (20 mL). Diethyl ether (100 mL) saturated with gaseous ammonia is added and the solution is stirred for 3 hours. The resulting suspension is filtered and the solvent of the filtrate is removed in vacuo. The residue is washed with diisopropyl ether. After drying colourless crystals (5.15 g, 35.5percent) of melting point 210° C. are obtained. |
2.9 g (100%) | EXAMPLE 4A 4-Fluorobenzenecarboximidamide Hydrochloride In analogy to the procedure for Example 3A, 2,0 g (16,5 mmol) 4-fluorobenzonitrile and proportionate amounts of the other reagents are used. Yield: 2.9 g (100percent) 1H-NMR (DMSO-d6, 200 MHz): delta=7,5 (m, 2H), 8,0 (m, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.47 g (44%) | EXAMPLE 11A N-{1-[3-(4-Fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl} acetamide In analogy to the procedure for Example 10A, 2,0 g (11,4 mmol) <strong>[456-14-4]4-fluorobenzenecarboximidamide hydrochloride</strong> and proportionate amounts of the other reagents are used. Yield: 1.47 g (44percent) 1H-NMR (DMSO-d6, 300 MHz): delta=0,9 (t, 3H), 1,6 (m, 1H), 1,8 (m, 1H), 1,9 (s, 3H), 4,9 (m, 1H), 7,5 (m, 2H), 8,1 (m, 3H), 14,1 (br. s, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.3% | In sodium hydroxide; ethanol; | Example 38 2-(4-'-Fluorophenyl)-5-methyl-4-pyrimidinone Sodium hydride (0.52 g, 13 mmol) is added to 20 ml of anhydrous ethanol and stirred for 30 minutes at ambient temperature. To this, <strong>[456-14-4]4-fluorobenzamidine hydrochloride</strong> (1.47 g, 8.5 mmol) (from example 1) is added and the mixture is stirred for further 30 minutes. Methyl 2-formylpropionate (1 g, 10.6 mmol) is added dropwise and the reaction mixture is left for 4 days under stirring at ambient temperature. After cooling, the solvent is removed in vacuo and the residue is dissolved in aqueous sodium hydroxide (10 ml, 1M). Then the mixture is brought to pH 5 with 2 molar hydrochloric acid. The precipitate is filtered off and washed with diisopropyl ether. After drying, colorless crystals (0.44 g, 10.3percent) of melting point >250° C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.3% | In sodium hydroxide; ethanol; | EXAMPLE 51 2-(4'Fluorophenyl)-5-methyl-4-pyrimidinone Sodium hydride (0.52 g, 13 mmol) is added to 20 mL of anhydrous ethanol and stirred for 30 minutes at ambient temperature. To this, <strong>[456-14-4]4-fluorobenzamidine hydrochloride</strong> (1.47 g, 8.5 mmol) (from example 40) is added and the mixture is stirred for further 30 minutes. Methyl 2-formylpropionate (1 g, 10.6 mmol) is added dropwise and the reaction mixture is left for 4 days under stirring at ambient temperature. After cooling, the solvent is removed in vacuo and the residue is dissolved in aqueous sodium hydroxide (10 mL, 1M). Then the mixture is brought to pH 5 with 2 molar hydrochloric acid. The precipitate is filtered off and washed with diisopropyl ether. After drying, colorless crystals (0.44 g, 10.3percent) of melting point >250° C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium methylate; In methanol; ethanol; toluene; | EXAMPLE 1 Preparation of 5-propyl-2-(4-fluorophenyl)pyrimidine To a sodium methylate solution under agitation obtained by dissolving Na (2.8 g, 0.12 mol) in anhydrous methanol (20 c.c.) was added <strong>[456-14-4]4-fluorobenzamidine hydrochloride</strong> (10.5 g, 0.06 mol), followed by adding alpha-propyl-beta-dimethylaminoacrolein (9.2 g, 0.06 mol), thereafter refluxing on heating for 3 hours with stirring, distilling off methanol under the atmospheric pressure after completion of the reaction, adding toluene (20cc) to the reaction residue to extract the resulting product, washing the extraction liquid with water, drying with anhydrous sodium sulfate, distilling off toluene and recrystallizing the remaining oily substance from ethanol (20 c.c.) to obtain the objective 5-propyl-2-(4-fluorophenyl)pyrimidine (7.0 g). Yield: 55%. M.P. 52.7 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydroxide; In dichloromethane; water; at 0 - 20℃; for 2h; | General procedure: To a stirred solution of 2-fluorobenzenecarboximidamide (1.38 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 mL, 10.0 mmol) in CH2Cl2 (10 mL) was added a solution of NaOH (1.60 g, 40.0 mmol) in H2O (4.0 mL) dropwise at 0 C. The mixture was stirred at 0 C for 1.0 h and at room temperature for 1.0 h. The organic layer was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane?EtOAc) to give 9 |
With sodium hydroxide; In dichloromethane; water; at 0℃; for 0.5h; | Intermediate 13; 5-Chloro-3-(4-fluoro-phenyl)-[1,2,4]thiadiazole; To a suspension of <strong>[456-14-4]4-fluorobenzamidine hydrochloride</strong> (0.385 g) in DCM (5 mL) was added perchloromethyl mercaptan (0.219 mL). The resulting mixture was cooled to 0° C., treated with 6 N NaOH (2 mL) and stirred for 30 min. The resulting mixture was diluted with water (10 mL) and extracted with DCM (20 mL). The organic layer was dried (MgSO4) and concentrated. Chromatography of the residue (0-20percent EtOAc-hexanes) gave the title compound as a yellow-orange solid (0.43 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ethanol; potassium tert-butylate; for 8h;Heating / reflux; | Example 132 3-[2-(4-Fluoro-phenyl)-pyrimidin-5-yl]-N-(thiazol-2-yl)-acrylamide [Show Image] (a) 2-(4-Fluoro-phenyl)-pyrimidine-5-carbaldehyde; 2 g (11.45 mmol) of <strong>[456-14-4]4-fluorobenzamidine hydrochloride</strong>, 4.09 g (11.45 mmol) of 2-dimethylaminomethylene-1,3-bis(dimethylimmonio)propane-bis(tetrafluoroborate) and 3.86 g (34.36 mmol) of potassium tert-butylate in 70 ml of ethanol were heated under reflux for 8 h. After concentration, water and ethyl acetate were added. The organic phase was washed with a potassium hydrogensulfate solution and water, dried and evaporated. Yield: 1.87 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Example 42; 2-f4-Difluorophenyl)-4-methylpyrimidine-5-carboxylic acid-3-methylsulfamoyl-benzylamide; Step 1; <strong>[456-14-4]4-Fluorobenzamidine hydrochlorid</strong>e (1.25 g, 7.16 mmol) is added to a solution of sodium metal (0.17 g, 7.39 mmol) in dry ethanol (25 mL) and stirred at room temperature for 20 min. Ethyl-2- acetyl-3-(dimethylamino)acrylate (1.35 g, 7.16 mmol) is added. The mixture is heated to reflux for 3 hours. The solvent is removed in vacuo. The residue is dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo to afford ethyl-2-(4-fluorophenyl)-4-methyl- pyrirnidine-5-carboxylate (1.65 g, 87percent) as a solid. MS: 261 (M+H) |
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