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Structure of 446-35-5
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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. : | 446-35-5 |
Formula : | C6H3F2NO2 |
M.W : | 159.09 |
SMILES Code : | FC1=CC=C([N+]([O-])=O)C(F)=C1 |
MDL No. : | MFCD00007050 |
InChI Key : | RJXOVESYJFXCGI-UHFFFAOYSA-N |
Pubchem ID : | 67967 |
GHS Pictogram: |
![]() |
Signal Word: | Danger |
Hazard Statements: | H227-H301-H315-H319-H335 |
Precautionary Statements: | P210-P261-P264-P270-P271-P280-P301+P310+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P370+P378-P403+P233-P403+P235-P405-P501 |
Class: | 6.1 |
UN#: | 2810 |
Packing Group: | Ⅲ |
Num. heavy atoms | 11 |
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 | 35.18 |
TPSA ? Topological Polar Surface Area: Calculated from |
45.82 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.29 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.86 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.71 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.73 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.55 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.63 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.34 |
Solubility | 0.734 mg/ml ; 0.00462 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.44 |
Solubility | 0.573 mg/ml ; 0.0036 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.33 |
Solubility | 0.753 mg/ml ; 0.00473 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 |
-5.95 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) |
1.74 |
* 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 |
---|---|---|
62% | With lithium hydroxide; In water; dimethyl sulfoxide; at 20℃; for 18h; | Add <strong>[138564-58-6]2-amino-5-methyl-thiophene-3-carbonitrile</strong> (10.0 g, 72.4 mmol) and 2,4- [DIFLUORO-1-NITRO-BENZENE] (8.00 mL, 73.0 mmol) to DMSO (130 mL) and stir under nitrogen at ambient temperature. Add lithium hydroxide monohydrate (6.10 g, 145 mmol) in one portion and stir at ambient temperature. After 18 hours, add deionized water (390 mL) dropwise at [10-20 C.] Adjust the pH to 7-8 with concentrated [HC1] (-6 mL) and stir for 4 hours. Filter the crude product and rinse with 3: 1/water : DMSO, then water. Dry at [50 C] to constant weight. Purify by flash chromatography, eluting with methylene chloride to give the title compound 10.3 g (62%) [:'H] NMR (400 MHz, [DMSO-D6)] [5] 9.83 (bs, 1H), 8. 28 (m, [1H),] 7.12 (s, 1H), 6.91 (m, [1H),] 6.73 (m, 1H), 2.53 (s, 3H). HRMS (ES) exact mass M+H calcd for [C12H8FN302S] 300.0219 ; found 300.0219. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tert-butoxide; In tetrahydrofuran; at 0℃; for 0.5h; | To a solution of trifluoroethanol in 4 mL dry THF, was added tert-butoxide (378 mg, 3.37 mmol) at 0 C. The resulting mixture was added dropwise to the solution of 2, 4-difluoro-1-nitro-benzene (536 mg, 3.37 mmol) in 5 mL dry THF at 0C. The mixture was stirred at 0C for 30 minutes, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give 4-fluoro-l-nitro-2- (2, 2,2- trifluoro-ethoxy)-benzene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium ethanolate; In ethanol; | EXAMPLE 26A 2-Ethoxy-4-fluoronitrobenzene To a solution of anhydrous sodium ethoxide (0.55 mole) [prepared by dissolving sodium metal (12.6 g, 0.55 mole) in anhydrous ethanol (300 ml)] at 0 C. is added 2,4-difluoronitrobenzene (79.5 g, 0.50 mole) dropwise over an 8 hour period. Upon completion of addition the reaction mixture is allowed to warm to room temperature and stirred overnight. The solid is removed by filtration, and triturated with toluene and water. The toluene extract is combined with the original filtrate, dried with anhydrous sodium sulfate and the solvent is removed under vacuum to afford 218 g of a yellow oil which was distilled at 0.3 mm, b.p. 95-98 C. to afford substantially pure 2-ethoxy-4-fluoronitrobenzene. STR20 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; | Preparing 2,4-difluoronitrobenzene by Reacting 2,4-dichloronitrobenzene A 1.5 l four-necked flask which is equipped with thermometer, anchor stirrer and reflux condenser with bubble counter is charged with 192 g (1 mol) of 2,4-dichloronitrobenzene, 550 ml of tetramethylene sulfone (TMS), 136.8 g (2.4 mol) of potassium fluoride and 5.99 g (0.015 mol) of tetrakis(diethylamino)phosphonium bromide (Example 7) or, respectively, 3.63 g (0.015 mol) of tetrakis(dimethylamino)phosphonium chloride (Example 8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; | Comparison Example 6 Preparing 2,4-difluoronitrobenzene by Reacting 2,4-dichloronitrobenzene Using tetraphenylphosphonium bromide as Catalyst 192 g (1 mol) of 2,4-dichloronitrobenzene, 550 ml of tetramethylene sulfone, 136.8 g (2.4 mol) of potassium fluoride and 6.29 g (0.015 mol) of tetraphenylphosphonium bromide are employed and the procedure described in Example 7 and 8 is followed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; | STARTING MATERIAL SYNTHESIS EXAMPLE 5 Ethyl 2-aminobenzo[b]thiophene-3-carboxylate (69.3 g) and 2,4-difluoronitrobenzene (50 g) were dissolved in dimethyl sulfoxide (550 ml) and heated to 50 C. Thereto was added potassium carbonate (63 g) and the mixture was stirred at 100 C. for 70 min. After cooling, the reaction mixture was allowed to cool to 70 C. and poured into water (2.5 L). The reaction mixture was allowed to stand still, and filtered. The filtrated orange crystals were washed with ethyl acetate to give ethyl 2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate (50.7 g). melting point 137-140 C. 1H-NMR (400 MHz, CDCl3) δ: 12.40(br.s, 1H), 8.33-8.29(m, 2H), 7.79(dd, J=7.8, 2.9 Hz, 1H), 7.65(d, J=8.3 Hz, 1H), 7.42(dd, J=8.3, 8.2 Hz, 1H), 7.29(dd, J=6.9, 8.3 Hz, 1H), 6.80-6.77(m, 1H), 4.54(q, J=6.8 Hz, 2H), 1.49(t, J=6.8 Hz, 3H). IR (KBr): 3085, 2993, 1624, 1582, 1553, 1510, 1274, 1206, 1035 cm-1. MS: m/e 360. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Synthesis of 1,3-difluoro-2-iodo-4-nitrobenzene (17c): 2,4-Difluoro-1-nitrobenzene 15 (159 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25 C. and the reaction mixture was then stirred at this temperature for 45 min according to TP 2. 12 (381 mg, 1.5 mmol) dissolved in dry THF (2 mL) was then dropwise added and the resulting mixture was stirred for 0.5 h. The reaction mixture was quenched with a sat. aq. Na2S2O3 solution (10 mL) and with a sat. aq. NH4CI solution (20 mL), extracted with diethyl ether (3×50 mL) and driedanhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:1) furnished compound 17c (256 mg, 90%) as a colourless solid. m.p.: 46.1-47.5 C.1H NMR (300 MHz, CDCl3) δ: 8.12-8.17 (m, 1 H), 7.04-7.08 (m, 1 H).13C NMR (75 MHz, CDCl3) δ: 165.6 (dd, J=5.0 Hz, J=252.6 Hz), 156.4 (dd, J=6.9 Hz, J=264.1 Hz), 127.7 (dd, J=2.3 Hz, J=10.3 Hz), 111.6 (dd, J=4.2 Hz, J=26.1 Hz), 74.3 (dd, J=29.2 Hz, J=1.9 Hz).MS (70 eV, El) m/z (%): 285 (100) [M+], 258 (17), 239 (19), 227 (17), 167 (25), 149 (66), 112 (58), 71 (11), 57 (12), 44 (12).IR (ATR) v (cm-1): 3098, 2926, 2855, 2359, 1916, 1739, 1602, 1584, 1529, 1463, 1425, 1336, 1301, 1277, 1218, 1147, 1105, 1011, 860, 827, 751, 698, 669, 621, 616.HRMS (El) for C6H2F2INO2 (284.9098): 284.9094. | |
74% | With (TMP)2Zn.MgCl2; iodine; In tetrahydrofuran; at 25℃;Inert atmosphere; | A dry, argon-filled Schlenk tube with a magnetic stirrer bar and septum is initially charged with 2,4- difluoro-1 -nitrobenzene (159 mg, 1 mmol) in anhydrous THF (2 ml). After adding (TMP^Zn.MgCh (3.00 ml, 1.2 mmol) at 25 C, the mixture is stirred for 30 min, then a solution of iodine (381 mg, 1.5 mmol) in anhydrous THF (2 ml) is added dropwise and the mixture is stirred at 25 C overnight. For workup, the mixture is diluted with aqueous sat. NH4CI solution (30 ml) and aqueous sat. Na2S203 solution (30 ml) and extracted with ethyl acetate (3 x 30 ml). After the combined organic phases have been dried over Na2S04, the solvent has been distilled off and purification has been effected by column chromatography on silica gel (heptane : ethyl acetate), the desired compound (210 mg, 74% of theory) was obtained as a colourless crystalline product. ¾ NMR (400 MHz, CDC13): δ in ppm = 8.15 (m, 1 H), 7.06 (m, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 130℃; for 92h; | Step D1. Synthesis of D-2. A mixture of D-1 (16.02 mmol) and substituted aniline (16.02 mmol) was stirred at 130 C. After 92 h, the mixture was cooled to rt and a black solid was formed. The mixture containing the black solid was dissolved in DCM (50 mL) and washed with satd. aq. NaHCO3 solution (30 mL×1). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on a 120 g of Redi-Sep column using 0 to 50% gradient of EtOAc in hexane over 27 min and then 50% isocratic of EtOAc in hexane for 27 min as eluent to give D-2.; Prepared according to Step D1 in General Procedure D using 2,4-difluoronitro-benzene (0.571 mL, 5.20 mmol) and <strong>[35216-39-8]3-(methylsulfonyl)aniline</strong> (0.891 g, 5.20 mmol) to give 5-fluoro-N-(3-(methylsulfonyl)phenyl)-2-nitroaniline as a bright yellow solid: 1H NMR (400 MHz, DMSO-d6) delta ppm 9.65 (1H, s), 8.25 (1H, dd, J=9.6, 6.1 Hz), 7.85-7.89 (1H, m), 7.64-7.75 (3H, m), 6.98 (1H, dd, J=11.4, 2.6 Hz), 6.79-6.87 (1H, m), 3.24 (3H, s); LC-MS (ESI) m/z 311.0 [M+H] 5-Fluoro-N1-(3-(methylsulfonyl)phenyl)benzene-1,2-diamine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 1h; | a) To a solution of 2,4-difluoro-nitrobenzene (2.0 g, 12.6 mmol) and (lR)-l-(2,4- dichlorophenyl)ethanamine (prepared from Example 1, 2.4 g, 12.6 mmol) in anhydrous DMSO (20 mL) was added K2CO3 (3.5 g, 25.2 mmol). The reaction mixture was heated at 120 C for 1 h. After cooling to room temperature, the mixture was diluted with deionized water (100 mL), and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried (Na2S04), filtered, and concentrated in vacuo. The crude product was used without further purification (0.65 g, 2.0 mmol, 16%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With caesium carbonate;Heating; | To ethanol (70 mL) was added compound 68 2,4-difluoro-1-nitrobenzene (5.0 g, 31.44 mmol), and cesium carbonate (30.66 g, 94.34 mmol). The mixture was heated and stirred overnight. After TLC indicated the reaction was completed, the mixture was evaporated to dryness, diluted with water, and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to remove solvent, thus obtaining a crude product. The crude product was further isolated and purified by column chromatography to obtain a white solid (5.5g, yield 95%). |
92% | (aox-4-fluoro-1-nitro-benzeneTo a cold (0 C) mixture of ethanol (0.735 mL, 12.6 mmol) in THE (15 mL)was added sodium hydride (60% dispersion in mineral oil, 553 mg, 13.83 mmol). The reaction mixture wasstirred at 0C for 15 mm, after which a solution of 2,4-difluoro-1-nitrobenzene (1.38 mL, 12.6 mmol) in THE (25 mL) was added dropwise. After stirring for an additional 90 mm at room temperature the reaction was quenched with water the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacua. The residue was purified by column chromatography (heptane/ethylacetate = 100/0 to 85/15 v/v%) to afford 2-ethoxy-4-fluoro-1-nitro-benzene (2.15 g, 92 %). | |
Ethanol (83mg, 1.82mmol) Soluble in toluene (8ml), Cool to 0 - 5 C in an ice bath, Slowly add potassium tert-butoxide (205mg, 1.82mmol), Keep the temperature at 0 - 5 C, Stir for 15 minutes, Slowly add 2,4-difluoronitrobenzene (290mg, 1.82mmol), React in ice bath for 2 hours, Diluted with water and extracted with ethyl acetate, Dry over anhydrous sodium sulfate and filter, Concentrate under reduced pressure to give a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 80 - 90℃; for 6h; | In the 250 mL three-necked flask,16 g of 2,4-difluoronitrobenzene was added,15g4-hydroxypyridylformamide,15 g of potassium carbonate, 100 mL of N, N-dimethylformamide,Temperature control 80-90 C for 6 hours. The reaction solution was lowered to room temperature,The reaction solution was poured into 300 mL of water and extracted with ethyl acetate 70 mL x 3 to combine the organic phases,Water 50 mL x 2 The organic phase was washed, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure,To give 26.3 g of a yellow solid,Yield 91.0%, purity 92.6%. |
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