Structure of 34667-88-4
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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. : | 34667-88-4 |
Formula : | C7H3FN2O2 |
M.W : | 166.11 |
SMILES Code : | N#CC1=CC=C([N+]([O-])=O)C=C1F |
MDL No. : | MFCD04038715 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302+H312+H332-H315-H319-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 39.94 |
TPSA ? Topological Polar Surface Area: Calculated from |
69.61 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.09 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.57 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.03 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.69 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.08 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.09 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.16 |
Solubility | 1.14 mg/ml ; 0.00687 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.64 |
Solubility | 0.379 mg/ml ; 0.00228 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.14 |
Solubility | 1.21 mg/ml ; 0.00731 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 |
-6.2 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) |
1.89 |
* 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 |
---|---|---|
100% | Step A. Preparation of 4-amino-2-fluorobenzonitrile [00175] The mixture of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (8.31 g, 50 mmol) and tin (II) chloride dihydrate (56.4 g, 250 mmol) in 250 mL of EtOAc was stirred at 25 °C overnight. LCMS (78109-084) indicated the reaction was completed. 25 mL of sat. K2CO3 was added to the reaction. The resulting mixture was stirred at room temperature for 2h and was followed by addition of lOOg of solid K2CO3. The mixture was stirred at room temperature for 2 hours. Solid was removed by filtration and further washed with EtOAc (50 mLx2). The filtrate was concentrated to yield 6.81 g (100percent) of 4-amino-2-fluorobenzonitrile as an off white solid. 1H NMR (400 MHz, CDCl3) delta ppm 4.30 (s, 2 H) 6.29 - 6.51 (m, 2 H) 7.27 - 7.40 (m, 1 H). MS (ESI) 137 (M+H). | |
96% | With iron; acetic acid; In ethyl acetate; for 2.0h;Heating / reflux; | A mixture of <strong>[34667-88-4]4-nitro-2-fluorobenzonitrile</strong> (1.83 g, 5 mmol) and iron (1.68 g, 6 mmol) in a mixture of acetic acid (40 ml) and ethyl acetate (40 ml) was refluxed for 2 hours. The solid was filtered off and the filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated and chromatographed (dichloromethane:acetone, 95:5) to yield 4- amino-2-fluorobenzonitrile (54a) (0.653 g, 4.8 mmol, 96percent). |
96% | With hydrogen;palladium 10% on activated carbon; In ethanol; ethyl acetate; under 2585.81 Torr; for 1.0h; | To <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (8.5 g, 51.2 mmol) was added 10percent palladium on carbon (0.5 g) and EtOAc (42.5 mL) and EtOH (170 mL) and the reaction was hydrogenated at 50 psi for 1 h. The reaction was filtered through Celite and the reaction mixture was concentrated to afford 6.7 g (96percent yield) as a light brown solid. LCMS m/z 135.1[M + H]+. |
70% | With palladium 10% on activated carbon; hydrogen; In methanol; for 3.0h; | Reference Example 114 4-Amino-2-fluorobenzonitrile To a solution of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (2.51 g) in methanol (125 mL) was added 10percent palladium carbon (50percent containing water, 237 mg), and the mixture was stirred under a hydrogen atmosphere for 3 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow solid (yield 1.43 g, 70percent). 1H-NMR (CDCl3)delta: 4.31 (2H, brs), 6.37-6.45 (2H, m), 7.31-7.36 (1H, m). |
palladium-carbon; In methanol; | Reference Example 114 4-Amino-2-fluorobenzonitrile To a solution of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (2.51 g) in methanol (125 mL) was added 10percent palladium carbon (50percent containing water, 237 mg), and the mixture was stirred under a hydrogen atmosphere for 3 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow solid (yield 1.43 g, 70percent). 1H-NMR (CDCl3)delta: 4.31 (2H, brs), 6.37-6.45 (2H, m), 7.31-7.36 (1H, m). | |
With hydrogen;5%-palladium/activated carbon; In methanol; at 20℃; under 1500.15 Torr; for 2.0h; | A solution of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (5 g, 30 mmol) in 300 mL methanol is stirred in a hydrogenation reactor with palladium (5percent on activated charcoal, 400 mg) for 2 h at RT and 2 bar hydrogen pressure. The reaction mixture is filtered and evaporated down. Yield: 4 g. | |
With iron; ammonium chloride; In ethanol; water; acetic acid; for 5.0h;Heating / reflux; | Preparation 15: 4-Amino-2-fluorobenzonitrile: Saturated aqueous ammonium chloride (50 mL) and acetic acid (3 mL) were added to a stirred solution of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (50.0 g, 301 mmol) in EtOH (600 mL) followed by iron powder (2 g, 35.7 mmol). The mixture was heated under reflux and more iron powder (123 g, 2.20 mol) added portionwise over a 4 h period. The reaction heated for a further 1 h then allowed to cool to rt before being filtered through a celite plug. The filtrate was evaporated to dryness and the residual material partitioned between EtOAc (500 mL) and water (200 mL). The organic phase was washed with water (50 mL) and brine (100 mL), then dried (MgSO4) and evaporated to afford the title compound: deltaH (ddelta-DMSO) 6.41-6.46 (2H, m), 6.52 (2H, br s), 7.37- 7.41 (IH, m). | |
With palladium 10% on activated carbon; hydrogen; In ethanol; acetonitrile; under 2585.81 Torr; for 1.0h; | <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (0.125 g, 0.751 mmol) was hydrogenated at 50 psi in the presence of 10percent Pd/C (40 mg) in EtOH/EtOAc (15mL) for 1 h. Filtered through Celite® and concentrated to an orange solid that was carried onto next step. MS (ESI) m/z: 137 (M+H)+. | |
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 12.0h; | A solution of 66 6 (10.0g, 60.24mmol) in 69 methanol (100mL) was hydrogenated with 10percent 70 Pd/C (1.0g) under hydrogen atmosphere at room temperature for 12h. After filtration, the filtrate was evaporated to give the corresponding product. It was obtained as a gray 16 solid in 88percent yield. 7 was ready for the next step without the further purification. HRMS (ESI): m/z, calculated for C7H5FN2 137.0487 (M+H)+, found 137.0452. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With Hexamethyldisiloxane; phosphorus pentoxide; In 1,2-dichloro-ethane; at 100℃; for 4.0h;Heating / reflux; | A mixture of 2-fluoro-4-nitrobenzamide (0.83 g, 4.6 mmol) and phosphorus pentoxide/hexamethyl disiloxane in 1,2-dichloroethane (20 mL) was heated under nitrogen at 100° C. for 4 hours. Upon cooling, the solution was poured onto a plug of silica gel and washed with hexane (200 mL) followed by 5percent methanol/chloroform (400 mL). The methanol/chloroform washes were collected and concentrated under reduced pressure to give 2-fluoro-4-nitrobenzonitrile (0.71 g, 95percent) as a beige solid. 1H NMR (DMSO-d6): delta 8.46 (dd, J=9.5, 2.0 Hz, 1H), 8.37-8.22 (m, 2H). |
86.73% | With trichlorophosphate; In water; N,N-dimethyl-formamide; at 25℃; for 12.0h; | To a solution of 15 5 (10g, 54.35mmol) in 63 DMF (100mL) was added 64 phosphorus oxychloride (35mL) dropwisely. And the mixture was stirred at 25°C for 12h. This mixture was treated with 65 ice water (300mL) for 30min. Then the mixture was extracted with EA, and the organic layer was washed with sat, dried with Na2SO4, filtered, and concentrated under reduced pressure to afford 66 product 6 (7.82g, 86.73percent) as a yellow solid. HRMS (ESI): m/z, calculated for C7H3FN2O2 167.0261 (M+H)+, found 167.0283. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With triethylamine; In acetonitrile; at 25℃; for 19.0h; | Methyl 3-amino-6-nitrobenzothiophene-2-carboxylate: Methyl thioglycolate (0.08 mL, 0.85 mmol) was added to a solution of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (145 mg, 0.87 mmol), and triethylamine (0.14 mL, 1.0 mmol) in acetonitrile (20 mL) stirred under nitrogen at 25° C. After 3 hours further triethylamine (0.28 mL, 2.0 mmol) was added to the solution, which was stirred at 25° C. for a further 16 hours. The solvent was removed under reduced pressure to give a brown residue, which upon trituration with chloroform precipitated methyl 3-amino-6-nitrobenzothiophene-2-carboxylate (103 mg, 54percent) as a red brown solid, mp 228.5-229.5° C. 1H NMR (DMSO-d6): delta 8.87 (d, J=2.0 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 8.15 (dd, J=8.8, 2.0 Hz, 1H), 7.26 (brs, 2H), 3.77 (s, 3H). Mass Spectrum (CI): 253 (100, MH+), 252 (52, M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In methanol; under 2844.39 Torr; for 22.0h; | [00293] A solution of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (0.541 g, 2.43 mmol) in methanol (20 mL) and 6N hydrochloric acid (3 mL) was hydrogenated (55 psi) over 10percent palladium on carbon (164 mg) for 22 li. The reaction mixture was filtered and concentrated in vacuo to afford 77A (0.65 g, 100percent). 1H NMR (400 MHz, CD3OD) delta 4.23 (s, 2 H), 7.29 (d, J=8.79 Hz, 2 H), 7.68 (t, J=I.91 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; In methanol; acetonitrile; | Production Example 6-1 2-(6-bromo-2-naphthyloxy)-4-nitrobenzonitrile After heating to reflux <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (1 g), 6-bromo-2-naphthol (1.41 g), potassium fluoride/alumina (0.7 g) and 18-crown-6 (0.16 g) in acetonitrile, the mixture was reacted for 12 hours. It was then cooled to room temperature, the insoluble portion was filtered using celite, the ethyl acetate layer was washed with water and saturated saline and then dried over magnesium sulfate, and the solvent was distilled off. Methanol was added to the residue for crystallization to obtain 1.43 g of 2-(6-bromo-2-naphthyloxy)-4-nitrobenzonitrile. 1H-NMR (CDCl3) delta:7.31 (1H, dd, J=2.4, 8.8 Hz), 7.54 (1H, d, J=2.0 Hz), 7.62-7.70 (3H, m), 7.88 (1H, s), 7.90 (1H, s), 8.01 (1H, dd, J=2.0, 8.4 Hz), 8.08 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With hydrazine hydrate; In ethanol; at 80℃; for 12.0h; | To a solution of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong>, 273 (5 g, 30.1 mmols) in ethanol (50 ml) was added hydrazine hydrate (15 ml). The resulting solution was heated at 80 C for 12 h. The reaction mixture was poured into water. The solid formed, consistent with the title compound was filtered and dried. Yield 2.1 g (39 %). 1 H NMR (400 MHz, DMSO) d 8.13 (d, J = 1.9 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.8, 2.0 Hz, 1H). |
With hydrazine; In water; isopropyl alcohol; at 80℃; for 12.0h; | Example 69; Synthesis of 2-(pyridin-2-ylamino)-lH-benzimidazole-5-carboxylic acid (3 -amino- IH- indazol-6-yl)-amideTo a solution of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (10 mmol) in isopropanol (30 mL) was added aqueous hydrazine (4 mL). The resulting solution was heated at 800C for 12 h. The reaction mixture was then concentrated, water (30 mL) was added, and the solution was extracted with ethyl acetate (2x25 mL). The combined organics were washed with water (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The volatiles were removed in vacuo yielding 3-amino-6-nitroindazole as an orange solid, which was utilized for further transformation without further purification.The nitro compound from above was hydrogenated, following general procedure F, to yield 3,6-diaminoindazole.2-Isothiocyanatopyridine (4 mmol), prepared from 2-aminopyridine employing general procedure A, was reacted with methyl 3,4-diaminobenzoate as described in general procedure B to afford 2-(pyridin-2-ylamino)-lH-benzirnidazole-S-carboxylic acid methyl ester. This ester was hydrolyzed, following general procedure C, to obtain 2-(pyridin-2- ylamino)-lH-benzimidazole-5-carboxylic acid.The cafboxylic acid (0.5 mmol) from above was coupled with aforementioned 3,6- diaminoindazole (0.5 mmol) using HBTU as described in general procedure D to afford 2- <n="60"/>(pyridin-2-ylamino)-lH-benzimidazole-5-carboxylic acid (3-amino-lH-indazol-6-yl)-amide. MS: m/z 385 (M+H)+. |
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