Structure of 72802-25-6
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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. : | 72802-25-6 |
Formula : | C8H6FNO3 |
M.W : | 183.14 |
SMILES Code : | CC(C1=CC=C([N+]([O-])=O)C(F)=C1)=O |
MDL No. : | MFCD13194365 |
InChI Key : | UHAATBAYLFRWMR-UHFFFAOYSA-N |
Pubchem ID : | 20552210 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 45.42 |
TPSA ? Topological Polar Surface Area: Calculated from |
62.89 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.22 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.44 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.36 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.02 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.43 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.29 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.09 |
Solubility | 1.48 mg/ml ; 0.00809 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.37 |
Solubility | 0.788 mg/ml ; 0.0043 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.39 |
Solubility | 0.741 mg/ml ; 0.00405 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 |
-6.39 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) |
1.61 |
* 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 hydrogen bromide; bromine; In ethanol; chloroform; acetic acid; | The 2-guanidino-4-(3-amino-4-fluorophenyl)thiazole used as starting material may be prepared as follows: To a solution of <strong>[72802-25-6]3-fluoro-4-nitroacetophenone</strong> (6 g.) in chloroform (40 ml.) was added 2 drops of hydrogen bromide in acetic acid (45% w/v) followed by bromine (1.75 ml.) added dropwise. After the bromine colour had disappeared the clear yellow solution was evaporated to dryness and the residue, dissolved in hot ethanol (40 ml.), was added to amidinothiourea (4.0 g.) in ethanol (100 ml.) under reflux. The mixture was heated under reflux for 15 minutes and then cooled to room temperature. The crystalline solid was filtered off to give 8.8 g. of 2-guanidino4-(3-fluoro-4-nitrophenyl)thiazole hydrobromide, m.p. 248-252 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With methanol; sodium tetrahydroborate; at 0℃; for 1h; | To a solution of ketone 1 (3.52 g, 19.03 mmol) in MeOH (35 mL) was added NaBH4 (775 mg, 20 mmol) in portions at 00 C.The mixture was stirred at 00 C for 1 h, and then the reaction was quenched with acetone (5 mL).The reaction mixture was concentrated to half of original volume via roto-vapor, the residue was diluted with EtOAc (400 mL), washed with brine (50 mL x 3), dried over Na2SO4.The solvents were removed under reduced pressure and the residue was purified via flash column to afford a clear oil (3.5 g, yield 99%).1HNMR (CDC13, 400 IVIHz) : 8.06 (t, J = 8.4 Hz, 1H), 7.35 (d, J = 11.6 Hz, 1H),7.30 (d, J = 11.6 Hz, 1H), 5.01-4.99 (m, 1H), 1.52 (d, J = 6.4 Hz, 3H). |
75% | With methanol; sodium tetrahydroborate; at -10 - 0℃; for 0.333333h;Reflux; | [0081] To a mixture of Compound 3 (1.9 g, 10.4 mmol) in MeOH (20 mL) at -40 C was added NaBH4 (418 mg, ii mmoi) in portions. The mixture was stirred between -10 C to 0 C for 20 minutes, diluted with EtOAc (300 mL), washed with sat. NH4C1 aqueous solution, brine, dried (Na2SO4). Filtered and concentrated under reduced pressure. The residue was purified via FCC (silica gel, EtOAcfHexane) to afford Compound 4 as a light yellow oil (1.44g. 75% yield).[0082] 1HN?R(CDCl3,400IVllIz)& 8.06(t,J=8.4Hz, IH), 7.35 (d,J 11.6Hz, IH), 730 (d, J 11.6 Hz, 1H), 5.01-4.99 (m, IH), 152 (d, J == 6,4 Hz, 3H). |
75% | With methanol; sodium tetrahydroborate; at -10 - 0℃; for 0.333333h; | To a mixture of Compound 3 (1.9 g, 10.4 mmol) in MeOH (20 mL) at -10 C was added NaBH4(418 mg, 11 mmol) in portions. The mixture was stirred between -10 C to 0 C for 20 minutes, diluted with EtOAc (300 mL), washed with sat. NH4Cl aqueous solution, brine, dried (Na2SO4). Filtered and concentrated under reduced pressure. The residue was purified via FCC (silica gel, EtOAc/Hexane) to afford Compound 4 as a light yellow oil (1.44g, 75% yield).[0065]1H NMR (CDCl3, 400 MHz) delta: 8.06 (t, J = 8.4 Hz, 1H), 7.35 (d, J = 11.6 Hz, 1H), 7.30 (d, J = 11.6 Hz, 1H), 5.01-4.99 (m, 1H), 1.52 (d, J = 6.4 Hz, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | [0077] A mixture of MgCI2 (930 mg, 9.8 mmol), TEA (4.7 mL, 33.4 mmol) and dimethyl malonate (1.9 mL, 16.6 mmoi) was stirred at RT for 1.5 Ii before the above mentioned toluene solution of Compound 2 was added. The resulting mixture was stirred at RT for another 1 5 Ii before conc, HC1 (4 mE) was added and stirred for 5 minutes. The mixture was extracted with EtOAc (30 mL x 3), dried Na2SO4), filtered and concentrated under reduced pressure.[0078] To the residue was added 6N HC1 (30 ml. and the mixture was refiuxed overnight.[0079] The mixture was extracted with EtOAc (30 mL x 3), dried (Na2 SO4), filtered and concentrated under reduced pressure. The residue was purified via FCC (silica gel, EtOAc/Hexane) to afford Compound 3 as a light yellow solid (1.9 g, 63% yield). | |
1.9 g | Compound 1 (3 g, 16.2 mmol) was refluxed in SOCl2(10 mL) with DMF (3 drops) for 3 h and then SOCl2was removed under vacuum. The residue was diluted with toluene (5mL) and was used in the following step without further purification.[0062] A mixture of MgCl2(930 mg, 9.8 mmol), TEA (4.7 mL, 33.4 mmol) and dimethyl malonate (1.9 mL, 16.6 mmol) was stirred at RT for 1.5 h followed by addition of the above mentioned toluene solution of Compound 2. The resulting mixture was stirred at RT for another 1.5 h then conc. HCl (4 mL) was added and stirred for 5 minutes. The mixture was extracted with EtOAc (30 mL x 3), dried (Na2SO4), filtered and concentrated under reduced pressure. To the residue was added 6N HCl (30 mL and the mixture was refluxed overnight. The mixture was extracted with EtOAc (30 mL x 3), dried (Na2SO4), filtered andconcentrated under reduced pressure. The residue was purified via FCC (silica gel,EtOAc/Hexane) to afford Compound 3 as a light yellow solid (1.9 g, 63% yield).[0063]1H NMR (CDCl3, 400 MHz) delta: 8.16 (d, J = 8.0 Hz, 1H), 7.86 (t, d = 9.2 Hz, 2H), 2.68 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.6 g | With borane-THF; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; In tetrahydrofuran; toluene; at -40℃; for 6h;Inert atmosphere; | Under argon, BH3.THF(1M, 11mL) was added to a solution of compound 4 in 1M toluene (3mL, 3 mmol) at 0oC. The solution was stirred for 30 min. then cooled down to - 40oC. A solution of compound 3 (1.83g, 10mmol) in THF(40mL) was added slowly during 4 hrs at -40oC. The system was stirred at -40oC for 2 hrs (TLC showed SM disappeared). MeOH (20ml) was added to about solution at -40oC and the solution was stirred for 30 min. After the solvents were removed at rt and the residue was purification by column(Hex/AcOEt = 3/1 (V/V)) to get compound 5 (1.6 g) .[0091]1HNMR (CDCl3, 400 MHz) delta: 8.05 (t, 1H), 7.34 (d, 1H), 7.27 (d, 1H), 4.99 (m,1H), 1.51 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.8 g | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere; | (2) Dissolve 3-hydroxy-N, N-dimethylbenzamide (2g) and <strong>[72802-25-6]3-fluoro-4-nitroacetophenone</strong> (3g) in anhydrous DMF (20mL), add under nitrogen protection Anhydrous potassium carbonate powder (3g);The reaction was performed at 100 C for 2 hours, cooled to room temperature, extracted with dichloromethane, the organic phase was dried, concentrated, and methyl tert-butyl ether was crystallized to obtain compound 3-(5-acetyl-2-nitrophenoxy)-N,N-dimethylbenzamide(1.8 g, white solid); |