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Structure of 1493-27-2
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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. : | 1493-27-2 |
Formula : | C6H4FNO2 |
M.W : | 141.10 |
SMILES Code : | O=[N+](C1=CC=CC=C1F)[O-] |
MDL No. : | MFCD00007048 |
InChI Key : | PWKNBLFSJAVFAB-UHFFFAOYSA-N |
Pubchem ID : | 73895 |
GHS Pictogram: |
![]() ![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H302+H332-H311-H372-H411 |
Precautionary Statements: | P260-P264-P270-P271-P273-P280-P301+P312+P330-P302+P352+P312-P304+P340+P312-P314-P391-P405-P501 |
Class: | 6.1 |
UN#: | 2810 |
Packing Group: | Ⅲ |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 35.22 |
TPSA ? Topological Polar Surface Area: Calculated from |
45.82 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.28 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.69 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.15 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.1 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.11 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.47 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.16 |
Solubility | 0.982 mg/ml ; 0.00696 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.27 |
Solubility | 0.763 mg/ml ; 0.00541 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.03 |
Solubility | 1.31 mg/ml ; 0.00931 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 |
-5.96 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) |
1.57 |
* 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 |
---|---|---|
82.9% | With potassium carbonate In ethanolReflux | 2-fluoronitrobenzene (0.92 g, 6.53 mmol) and ethanolamine (1.19 g, 19.59 mmol) were dissolved in 20 mL ethanol, potassium carbonate (1.08 g, 7.83 mmol) was added and stirred under reflux for 5-6 hours, after the reaction solution was cooled, filtered, the filtrate was concentrated under reduced pressure, to obtain an orange solid, and 20 mL saturated brine was added, extracted with ethyl acetate (3×40 mL), the organic phases were combined, washed with a saturated brine, dried on anhydrous sodium sulfate, rotary evaporated, purified by silica gel column chromatography to obtain 2-nitro-N-(2-hydroxyethyl)aniline (0.98 g, yield 82.9percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.9% | With triethylamine; at 105 - 115℃; for 12h; | 107.6 g of triethylamine, 150 g of o-fluoronitrobenzene,P-chloroaniline (203.4 g), the system was heated to 105-115 C for 12 hours,HPLC showed that the reaction was complete,After cooling to 20-30 C,The filter cake was washed with 150 mL of methanol,Drying, get 248g products. Purity 99.8%Yield 93.9%. |
72.3% | General procedure: To the suspension of NaH (75 mol) in DMF (60 mL), substitutedamines (50 mmol) was added at 0 C. The mixture was stirred for30 min at the same temperature, and then 2-fluoronitrobenzene(60 mmol) diluted in DMF (30 mL) was added slowly. The mixturewas warmed to room temperature and stirred for 16 h. The reactionmixture was carefully poured into stirring saturated NH4Cl(500 mL), then filtered. The filter cake was washed with water,and recrystallized from methanol to afford corresponding N-aryl-2-nitroanilines 15a-15n.6.2.8 N-(4-chlorophenyl)-2-nitroaniline (15h) Orange solid; Yield: 72.3%; M.p.: 135.1-137.0 C; 1H NMR (400 MHz, DMSO-d6) delta 9.31 (s, 1H), 8.12 (d, J = 8.0, 1H), 7.53(t, J = 7.6 Hz, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.4 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H); MS (ESI) m/z (%): 247.2 [M-H]-. | |
72% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 120 - 125℃; for 8h;Inert atmosphere; | In the reaction flask,Put 87 g of o-fluoronitrobenzeneAnd 200 grams of DMAC,94 grams of diisopropylethylamine was added with stirring,After warming to 120 degrees under nitrogen.71 grams of p-chloroaniline was dissolved in 100 grams of DMAC to prepare a solution,After that, the solution was slowly added dropwise to the above reaction system.Dropping temperature will rise during the process,The reaction temperature should be controlled by cooling within 125 degrees.The reaction was continued at 120 to 125 degrees for 8 hours,HPLC monitors the progress of the reaction.When the content of chloroaniline is not declining,At the end of the reaction, about 11% of the chloroaniline remained.Cool to 60 degrees.After the same way with the first embodiment,Finally, 100 g of the condensate intermediate N- (4-chlorophenyl) -2-nitro-1-aniline,Yield 72%HPLC purity> 98%. |
52% | With potassium fluoride; potassium carbonate; In dichloromethane; at 220℃; for 0.466667h;Microwave irradiation; | N-(4-chlorophenyl)-2-nitrobenzenamineA mixture of 2-fluoronitrobenzene (3.5 g, 24.8 mmol), 4-chlorobenzenamine (3.05 g, 24.0 mmol), K2C03 (3.45 g, 25.0 mmol) and KF (1.5 g, 25.8 mmol) was heated at 220 C for 28 min under microwave condition. The solid was dissolved in DCM (150 mL), washed with water (50 mL x 3), dried over Na2S04. The solvent was evaporated in vacuo, and then the mixture was purified by Combi-flash (PE : EA = 20 : 1) to give N-(4-chlorophenyl)-2-nitrobenzenamine (3.2 g, 52%) as a scarlet solid. 1H NMR (300 MHz, CD3OD): delta 6.82-6.87 (m, 1H), 7.27-7.31 (m, 2H), 7.41-7.45 (m, 3H), 7.70-7.73 (m, 1H), 8.15-8.18 (m, 1H). |
In pyridine; water; | Referential Example 16 2-(4-Chlorophenylamino)nitrobenzene 2-Fluoronitrobenzene (3.0 g) and 4-chloroaniline (2.5 g) were dissolved in pyridine (30 ml) and stirred at 80 C. for 18 hours. The resultant solution was allowed to cool, and thereafter, water (100 ml) was added thereto and the mixture was extracted with ethyl acetate (50 ml*3). The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was re-crystallized from ethyl acetate-hexane, to thereby yield the target compound (2.5 g) as pale-brown crystals. 1H-NMR(270 MHz, CDCl3) delta: 9.40 (1H, brs), 8.20 (1H, dd, J=8.58 Hz), 7.37 (2H, d, J=8.90 Hz), 7.35~7.39 (2H, m), 7.21 (2H, d, J=8.90 Hz), 7.15~7.19 (2H, m), 6.80 (1H, t, J=7.26 Hz). | |
With potassium fluoride; at 180℃; for 10h; | A mixture of 2-fluoro-nitrobenzene (33.7 g), 4-chloroanilinc (61.0 g) and anhydrous potassium fluoride (13.9 g) was stirred at 180 C for 10 h. After being cooled to rt, 3 M HC1 was added and the mixture was stirred at 100 C for 30 min. Then cooled to rt, filtered by suction, washed with water to give a brown solid. The solid was dissolved in CH2CI2 and filtered through a thin pad of silica gel, washed with CH2CI2. The filtrate was concentrated to dryness, and the residue was recrystallized with 95% ethanol to give 57.0 g of orange solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃; for 18h;Inert atmosphere; Cooling with ice; | A solution of 1-fluoro-2-nitrobenzene (34.5 g, 244 mmol) and compound 1 (33.1 g, 240 mmol) in dry THF (160 mL) was added dropwise under N2 atmosphere to a vigorously stirred suspension of NaH (13.5 g, 60percent dispersion in oil, 336 mmol) in dry THF (100 mL) in an ice bath. After the reaction mixture was stirred at room temperature (RT) for 10 h, additional NaH (1.53 g, 95percent, 72 mmol) was slowly added to above reaction mixture. The mixture was stirred for another 8 h at rt, and poured into cracked ice, adjusted pH value to 8 with saturated NH4Cl. The resulting precipitate was filtered, and dried; and the crude product was purified by column chromatography (10percent EtOAc/hexanes) on silica gel to obtain 2 (47.9 g, 77percent) as a darkened solid; Rf = 0.62 (25percent EtOAc/hexanes); mp 105?107 °C. 1H NMR (CDCl3): delta 2.47 (d, J = 1.0 Hz, 3H, CH3), 6.78 (q, J = 1.0 Hz, 1H, Ar-H), 6.95 (ddd, J = 1.0, 7.0, 8.5 Hz, 1H, Ph-H), 7.18 (dd, J = 1.0, 8.5 Hz, 1H, Ph-H), 7.50 (ddd, J = 1.5, 7.0, 8.5 Hz, 1H, Ph-H), 8.24 (dd, J = 1.5, 8.5 Hz, 1H, Ph-H), 9.61 (s, 1H, NH). MS (ESI): 258 ([M?H]?, 100percent). |
64% | Step 2; 5-Methyl-2-(2-nitrophenylamino) thiophene-3-carbontrile: At about -10° C. and over a period of 15 minutes, a solution of 2-fluoro-nitro benzene (10.23g, 72.36 mmol), 2-amino -5-methylthiophene-3-carbonitrile (10 g, 72.36 mmol), and tetrahydrofuran (100 mL) was added dropwise to a suspension of sodium hydride (4.35 g, 108.69 mmol) and dry tetrahydrofuran. The resulting mixture was stirred for about 7 hours at ambient temperature and then cooled to about 0° C. Ice-cold water (100 mL) was slowly added, and then 5 N hydrochloric acid was added. Following standard extractive workup with dichloromethane (2.x.100 mL), the resulting residue was triturated with a mixture of n-pentane and diethyl ether (10:1), filtered, and dried to give the title compound as a dark brown color solid (12.0 g, yield=64percent). m.p. 100-103° C. 1H NMR (400 MHz, CDCl3) delta 2.47 (s, 3H), 6.78 (s, 1H), 6.96 (t, J=7.8 Hz, 1H), 7.2 (d, J=8.4 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H) 8.25 (d, J=8.4 Hz, 1H), 9.61 (s, exchangeable with D2O, 1H); IR (KBr) upsilon 3279, 3080, 3027, 2917, 2854, 2226, 1612, 1491, 1402, 1335, 1270, 736 cm-1; MS 258 (M-1). | |
60% | For a general synthesis see He, X.; Griesser, U. J.; Stowell, J. G.; Borchrdt, T. B.; Byrn, S. R. J. Pharm. Sd. 2001, 90, 371.B To NaH (3 equivalents, from 55percent suspension in oil, rendered oil-free by washing with hexane) was added 1 ml of dry THF. 2-amino-5-methyl-3- thiophenecarbonitrile (A, as prepared above, 0.5 g, 3.6 mmol) and 4-fluoro-3- nitotoluene (0.51 g, 3.6 mmol) were dissolved in dry THF (1.5 ml) and added in a dropwise manner to the suspension while the temperature was maintained below 30°C. The reaction mixture was allowed to stir overnight under N2 purge. The mixture was then poured into 11 ml of ice- water mixture, neutralized with concentrated HCl, and extracted with 36 ml of DCM. The DCM solution was dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel (elution with 1 :9 EtOAc/ Hexanes) to give compound B (yield 60percent).1H NMR (200 MHz, CDCl3): delta 9.61 (br s, IH), 8.25 (dd, J = 8.5 Hz, J = 1.5 Hz, IH), 7.52 (dt, J = 7.8 Hz, J = 1.4 Hz, IH), 7.19 (dd, J = 8.5 Hz, J = 1.1 Hz, IH)5 6.97 (dt, J = 7.8 Hz, J = 1.2 Hz5 IH), 6.78 (d, J = 1.1 Hz, IH), 2.48 (s, 3H). |
60% | With potassium hydroxide;N-benzyl-N,N,N-triethylammonium chloride; In DMF (N,N-dimethyl-formamide); at 0 - 25℃; for 5h; | To a stirred mixture of potassium hydroxide (59.1 g), benzyltriethylammonium chloride (1.2 g) and N,N-dimethylformamide (70 mL) in a 250 mL flask was added dropwise a solution of 2-amino-5-methylthiophene-3- carbonitrile (73 g) and 1-fluoro-2-nitrobenzene (74.5 g) in N,N dimethylformamide (175 mL) while maintaining the temperature between at 20-25 °C with an ice/salt bath. After the addition was complete, the mixture was stirred between 20-25°C for 5 hours, then poured onto ice/water (400 mL), and extracted with dichloromethane (480 mL). The organic layer was separated, and the aqueous layer was extracted twice with dichloromethane (240 mLx2). Water (400 mL) was added to the combined organic extracts, and the pH was adjusted between 8-9 with 2N hydrochloric acid. The organic layer was separated and washed with water (400 mL). The solvent was removed under reduced pressure to afford a residue that was crystallized from ethanol (300 mL) to give 2- (2-nitroanilino)-5-methylthiophene-3- carbonitrile (82.2 g). Yield: 60percent |
With potassium hydroxide; In acetonitrile; at 0 - 5℃; for 3h; | Potassium hydroxide (101.4 g) in acetonitrile (150 ml) is taken under nitrogen and cooled to 0-5°C. A solution of <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (100 g) and o-fluoronitrobenzene (122.6 g) in acetonitrile (550 ml) is added. The reaction is then stirred for 3 hours and chilled water is added. The solid thus obtained is filtered off and air-dried. The solid is crystallized from water-methanol mixture and the crystallized solid is dried under vacuum at 40-45°C to obtain the title compound (140 g). | |
In tetrahydrofuran; | 2. 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile To a stirred slurry of sodium hydride (14.4 g, 50percent dispersion in oil, 0.3 mol) in dry tetrahydrofuran (50 mL) under nitrogen was added, dropwise, a solution of 2-fluoronitrobenzene (28.2 g, 0.2 mol) and 2-amino-5-methylthiophene3-carbonitrile (27.6 g, 0.2 mol) in dry tetrahydrofuran (250 mL). The mixture was stirred at 25° C. for 24 hours, poured onto cracked ice and extracted into dichloromethane (3*500 mL). The combined extracts were washed with 2N hydrochloric acid (2*200 mL), water (2*200 mL), dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was crystallized from ethanol to give the title compound, (35.2 g), m.p. 99°-102° C. | |
In tetrahydrofuran; | 2. 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile To a stirred slurry of sodium hydride (14.4 g, 50percent dispersion in oil, 0.3 mol) in dry tetrahydrofuran (50 mL) under nitrogen was added, dropwise, a solution of 2-fluoro-nitrobenzene (28.2 g, 0.2 mol) and <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (27.6 g, 0.2 mol) in dry tetrahydrofuran (250 mL). The mixture was stirred at 25° C. for 24 hours, poured onto cracked ice and extracted into dichloromethane (3*500 mL). The combined extracts were washed with 2N hydrochloric acid (2*200 mL), water (2*200 mL), dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was crystallized from ethanol to give the title compound, (35.2 g), m.p. 99°-102° C. | |
In tetrahydrofuran; | 2. 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile To a stirred slurry of sodium hydride (14.4 g, 50percent dispersion in oil, 0.3 mol) in dry tetrahydrofuran (50 mL) under nitrogen was added, dropwise, a solution of 2-fluoro-nitrobenzene (28.2 g, 0.2 mol) and <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (27.6 g, 0.2 mol) in dry tetrahydrofuran (250 mL). The mixture was stirred at 25° C. for 24 hours, poured onto cracked ice and extracted into dichloromethane (3*500 mL). The combined extracts were washed with 2N hydrochloric acid (2*200 mL) water (2*200 mL), dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was crystallized from ethanol to give the title compound, (35.2 g), m.p. 99°-102° C. | |
In tetrahydrofuran; | 2. (2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile To a stirred slurry of sodium hydride (14.4 g, 50percent dispersion in oil, 0.3 mol) in dry tetrahydrofuran (50 mL) under nitrogen was added, dropwise, a solution of 2-fluoro-nitrobenzene (28.2 g, 0.2 mol) and <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (27.6 g, 0.2 mol) in dry tetrahydrofuran (250 mL). The mixture was stirred at 25° C. for 24 hours, poured onto cracked ice and extracted into dichloromethane (3*500 mL). The combined extracts were washed with 2N hydrochloric acid (2*200 mL), water (2*200 mL), dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was crystallized from ethanol to give the title compound, (35.2 g), m.p. 99°-102° C. | |
In tetrahydrofuran; | 2. 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile To a stirred slurry of sodium hydride (14.4 g, 50percent dispersion in oil, 0.3 mol) in dry tetrahydrofuran (50 mL) under nitrogen was added, dropwise, a solution of 2-fluoro-nitrobenzene (28.2 g, 0.2 mol) and 2-amino-5- methylthiophene-3-carbonitrile (27.6 g, 0.2 mol) in dry tetrahydrofuran (250 mL). The mixture was stirred at 25° C. for 24 hours, poured onto cracked ice and extracted into dichloromethane (3*500 mL). The combined extracts were washed with 2N hydrochloric acid (2 *200 mL), water (2*200 mL), dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was crystallized from ethanol to give the title compound, (35.2 g), m.p. 99°-102° C. | |
With potassium hydroxide; In isopropyl alcohol; | 2-fIuoronitrobenzene is condensed with 5-Amino-4-Cyano-2-Methyl Thiophene in Isopropyl alcohol and Potassium Hydroxide powder give 4-cyano-2-methyl-1-(2-nitrophenyl amino) Thiophene | |
With potassium hydroxide; In acetonitrile; at 0 - 5℃; for 3h; | EXAMPLE 2; Preparation of 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrilePotassium hydroxide (101.4 g) in acetonitrile (150 ml) is taken under nitrogen and cooled to 0-5° C. A solution of <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (100 g) and o-fluoronitrobenzene (122.6 g) in acetonitrile (550 ml) is added. The reaction is then stirred for 3 hours and chilled water is added. The solid thus obtained is filtered off and air-dried. The solid is crystallized from water-methanol mixture and the crystallized solid is dried under vacuum at 40-45° C. to obtain the title compound (140 g). | |
With potassium hydroxide; In acetonitrile; at 0 - 5℃;Inert atmosphere; | Example 2; Preparation of 2-(2-nitroanilino)-5-methylthiophene-3-carbonitrilePotassium hydroxide (101 g) in acetonitrile (150 ml) was taken under nitrogen and cooled to 0-5° C. A solution of <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (100 g) and ortho-fluoronitrobenzene (122 g) in acetonitrile (550 ml) was added. The reaction mixture was then stirred for 3 hours and chilled water was added into the reaction mixture. The solid was separated out. The solid thus obtained was filtered off and air-dried. The solid was crystallized from water-methanol mixture and the crystallized solid was dried under vacuum at 40-45° C. to obtain the title compound (140 g). | |
With potassium hydroxide; In dimethyl sulfoxide; | Step E 5-Methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile To a solution of <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (13.8 g, 100 mmol) and 1-fluoro-2-nitrobenzene (16.92 g, 120 mmol) in dimethylsulfoxide was added potassium hydroxide (11.2 g, 200 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water, and the resulting suspension was filtered. The filtered cake was dried to give 5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile as a red solid used without further purification. 1H NMR: (400 MHz, CDCl3) delta 9.69 (s, 1H), 8.27-8.25 (m, 1H), 7.56-7.52 (m, 1H), 7.23-7.20 (m, 1H), 7.0-6.96 (m, 1H), 6.80 (s, 1H), 2.49 (s, 3H). | |
With potassium hydroxide; In dimethyl sulfoxide; at 20℃; | To a solution of <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (13.8 g, 100mmol) and 1-fluoro-2-nitrobenzene (16.92 g, 120 mmol) in dirnethylsulfoxide wasadded potassium hydroxide (11.2 g, 200 mmol). The reaction mixture was stirred atroom temperature overnight The mixture was diluted with water, and the resultingsuspension was filtered. The filtered cake was dried to give 5-methyl-2-((2-nitropllenyl)amino)thiophene-3-carbonitrile as a red solid used without furtherpurification. 1H NMR: (400 MHz, CDCb) o 9.69 (s, 1 H), 8.27-8.25 (m, 1 H), 7.56-7.52(m, 1 H), 7.23-7.20 (m, 1 H), 7.0-6.96 (m, 1 H), 6.80 (s, 1 H), 2.49(s, 3H). | |
With potassium hydroxide; In dimethyl sulfoxide; at 20℃; | To a solution of <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (13.8 g, 100 mmol) and 1-fluoro-2-nitrobenzene (16.92 g, 120 mmol) in dimethylsulfoxide was added potassium hydroxide (11.2 g, 200 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water, and the resulting suspension was filtered. The filtered cake was dried to give 5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile as a red solid used without further purification. 1H NMR (400 MHz, CDCl3) delta 9.69 (s, 1H), 8.27-8.25 (m, 1H), 7. 56-7.52 (m, 1H), 7.23-7.20 (m, 1H), 7.0-6 .96 (m,1H), 6. 80 (s, 1H) , 2 .49 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With lithium hydroxide; In water; dimethyl sulfoxide; at 50℃; for 3h; | Add a solution of <strong>[31785-05-4]ethyl 5-amino-2-methylthiazole-4-carboxylate</strong> (120g; 645 mmol) and 2-fluoronitrobenzene (68 mL; 645 mmol) in dimethylsulphoxide [(1L)] to a 2L 3-necked RB flask equipped with reflux condenser, thermometer, mechanical stirrer. Add lithium hydroxide monohydrate (54 g; 1290 mmol) to the solution and heat at [50C] for 3 hours under nitrogen. Cool the purple solution and pour onto ice/water, allow to stir for one hour, filter and wash with water, dry at [50C] under reduced pressure to give 190 g (96%) as an orange solid: mass spectrum (m/e): 308 (M+1) [; 1HNMR (300MHZ, DMSO-D6,] ppm): [8] 1.25 (tr, 3H), 2.56 (s, 3H), 4.25 (q, 2H), 7.20 (m, [1H),] 7.78 (m, 2H), 8.20 (d, 1H), 11.42 (s, 1H, NH). [13CNMR] (75MHz, DMSO, ppm): [5] 24.4, 29.2, 71.2, 127.8, 132.5, 132.8, 137.8, 146.5, 147.0, 147.5, 160.2, 161.5, 173.7. Formula : C13H13N3O4S. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 180℃; for 0.333333h;Microwave irradiation; | Step A. (+/-)-N-(2-Nitrophenyl)tetrahvdrofuran-3 -amineA solution of N, jV-diisopropylethylamine (3.20 mL, 18.4mmol), l-fluoro-2- nitrobenzene (0.484 mL, 4.59 mmol), and (+/-)-tetrahydrofuran-3 -amine (400 mg, 4.59 mmol) in rc-butanol (10 mL) was heated to 180 0C in a microwave reactor. After 20 min, the reaction was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography, eluting with a gradient of hexane: EtOAc - 100:0 to 0:100, gave the title compound. MS: mlz = 209 (M + 1). | |
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 180℃; for 0.333333h;microwave reactor; | A solution of N, N-diisopropylethylamine (3.20 mL, 18.4mmol), l-fluoro-2-nitrobenzene (0.484 mL, 4.59 mmol), and (+)-tetrahydrofuran-3 -amine (400 nig, 4.59 mmol) in 7z-butanol (10 mL) was heated to 180 0C in a microwave reactor. After 20 min, the reaction was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography, eluting with a gradient of hexane:EtOAc - 100:0 to 0:100, gave the title compound. MS: mlz = 209 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(3) 2-[[4-[2-(methoxycarbonyl)ethyl]phenyl]amino]-aniline The starting material 2-[[4-[2-(methoxycarbonyl)-ethyl]phenyl]-amino]-nitrobenzene (melting point: 68-70 C.) is obtained by reacting 2-fluoro-nitrobenzene with <strong>[35418-07-6]methyl 3-(4-aminophenyl)propionate</strong>. Rf value: 0.25 (Silica gel; methylene chloride/ethyl acetate=100:1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In acetonitrile; for 5h;Heating / reflux; | A mixture of 1 ,1-dimethylethyl (3R)-3-(aminomethyl)-1-piperidinecarboxylate (3.50 g, 16.3 mmol, Ennova MedChem Group, Inc.), 1-fluoro-2-nitrobenzene (3.46 g, 24.5 mmol, Avocado Research Chemicals Ltd.), and K2CO3 (11.3 g, 81.5 mmol) in 40 mL of anhydrous acetonitrile was heated to reflux with stirring. After 5 hours the mixture was cooled to RT and filtered through a medium fritted funnel to remove solids. The EPO <DP n="88"/>filter cake was rinsed with an additional 40 mL portion of acetonitrile and the filtrate concentrated to dryness at reduced pressure. The crude oil was subjected to flash chromatography (silica gel, gradient elution of hexane to 6:4 hexane/EtOAc) to afford 1 ,1-dimethylethyl (3R)-3-[(2-nitrophenyl)amino]methyl}-1-piperidinecarboxylate as a viscous, yellow oil in quantitative yield. 1H NMR (DMSOd6): delta 8.19 (br s, I H), 8.05(d, 1H), 7.52 (t, 1 H), 7.06 (d, 1 H), 6.68 (t, 1 H), 3.93-3.58 (m, 2H), 3.29-3.20 (m, 2H), 2.89-2.48 (m, 2H), 1.85-1.68 (m, 2H), 1.60 (m, 1H), 1.50-1.10 (br s, 11 H). MS m/z 358 (M+Na). |
100% | With potassium carbonate; In acetonitrile; for 5h;Heating / reflux; | A mixture of 1,1-dimethylethy. (3R)-3-(aminomethyl)-1-piperidinecarboxylate (3.50 g, 16.3 mmol, Ennova MedChem Group, Inc.), 1-fluoro-2-nitrobenzene (3.46 g, 24.5 mmol, Avocado Research Chemicals Ltd.), and K2C03 (11.3 g, 81.5 mmol) in 40 mL of anhydrous acetonitrile was heated to reflux with stirring. After 5 hours the mixture was cooled to RT and filtered through a medium fritted funnel to remove solids. The filter cake was rinsed with an additional 40 mL portion of acetonitrile and the filtrate concentrated to dryness at reduced pressure. The crude oil was subjected to flash chromatography (silica gel, gradient elution of hexane to 6:4 hexane/EtOAc) to afford 1,1-dimethylethyl (3ft)-3-[(2-nitrophenyl)amino]methyl}-1-piperidinecarboxylate as a viscous, yellow oil in quantitative yield. 1H NMR (DMSO-cfe): 5 8.19 (br s, 1H), 8.05 (d, 1H), 7.52 (t, 1H), 7.06 (d, 1H), 6.68 (t, 1H), 3.93-3.58 (m, 2H), 3.29-3.20 (m, 2H), 2.89-2.48 (m, 2H), 1.85-1.68 (m, 2H), 1.60 (m, 1H), 1.50-1.10 (brs, 11H). MS m/z 358 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 15 Replacing of dimethylformamide by 75 g tetramethylene sulphone in the reaction of Example 14 which uses KF-CsF-silica and carrying out the reaction at ca. 220 C. for 16 h. (reagent quantities being identical to those used before) gives ca. 100% conversion of 2-chloronitrobenzene to 2-fluoronitrobenzene (by chloride analysis). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; dimethyl sulfoxide; | Preparing 2-nitrofluorobenzene by Reacting 2-nitrochlorobenzene Using tetrakis(diethylamino)phosphonium bromide as Catalyst A 1.5 l four-necked flask which is equipped with thermometer, anchor stirrer and reflux condenser with bubble counter is charged with 157 g (1 mol) of 2-nitrochlorobenzene, 400 ml of dimethyl sulfoxide (DMSO) (Example 4) or, respectively, 480 ml of tetramethylene sulfone (TMS) (Example 5), 68.4 g (1.2 mol) of potassium fluoride and 3.99 g (0.01 mol) of tetrakis(diethylamino)phosphonium bromide. The reaction mixture is then heated with stirring to the predetermined reaction temperature and is allowed to react for the time indicated. Subsequent workup is as described in Examples 1 and 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In N,N-dimethyl-formamide; at 100℃; for 2.5h;Microwave irradiation; | Example 114: Preparation of Compound 114.Me Step 1.; Aminoproline (5g, 17.8 mmol) and fluoronitrobenzene (1.9mL, 17.8 mmol) were taken up in DMF (5mL) and placed in a sealed tube which was then heated via microwave to 1000C for 2.5h. The reaction was cooled and ethyl acetate and brine were added. The organic layer was separated, dried, concentrated and purified via flash chromatography to provide the nitrobenzyl compound (5.63g, 87percent). The nitrobenzyl species (2.86g, 7.85 mmol) was taken up in ethanol (70 mL). Palladium on carbon (10percent) was added and the flask charged with hydrogen gas. The mixture was stirred at room temp for Ih and then filtered through a fritted funnel. The filtrate was concentrated and purified via flash chromatography to provide the diamine (2g, 76percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1 : <strong>[443-86-7]3-Fluoro-2-methylaniline</strong> (1.7 ml, 15 mmol) was dissolved in DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL, 10 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH4CI and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via lsco chromatography (Redisep, silica, gradient 5-30percent ethyl acetate in hexane) to afford 1.2 g (3-fluoro-2-methyl-phenyl)-(2-nitro- phenyl)-amine that was carried on directly to the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; In ethanol;Reflux; | 3-methyl-3-(2-nitrophenylamino)butanoic acid (Step 1). A round bottomed flask was charged with <strong>[625-05-8]3-amino-3-methylbutanoic acid</strong> (1.452 g, 12.39 mmol), potassium carbonate (2.57 g, 18.59 mmol), and a stirbar. EtOH (20 mL, 0.5 M) was added, followed by l-fluoro-2- nitrobenzene (2.84 ml, 15.49 mmol), and the solution was stirred at reflux overnight. The mixture was cooled, concentrated with celite, and purified by silica gel chromatography (eluting with methylene chloride/methanol/ammonium hydroxide) to yield 3-methyl-3-(2- nitrophenylamino)butanoic acid as a red solid (2.32 g, 9.73 mmol, 79percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 4.0h; | 2.00 g of 1 (8.395 mmol), 2.49 g of 2-fluoronitrobenzene (17.63 mmol) and 2.90 g of K2C03 (20.99 mmol) are stirred together in 15 mL of DMSO at 100C for 4h. The mixture is then poured into 100 mL of water and the beige powder is washed with 2x50 mL of water and 2x50 mL of methanol. It is purified by chromatography (silica gel, heptane/dichloromethane) to yield 3.3g of the desired product (yield = 81 %). 1H NMR (400 MHz, CDCI3); delta = 7.22 (dd, 1.5 Hz, 2H); 7.36 (m, 6H); 7.52 (m, (0659) 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.03% | With potassium carbonate; In N,N-dimethyl-formamide; for 6h;Reflux; | 1-(4-Chlorophenyl)-3-hydroxy-1H-pyrazole (5.85 g, 30.00 mmol) was added to the reaction flask in that order.2-fluoronitrobenzene (4.23 g, 30.00 mmol), DMF (60 mL) and potassium carbonate (4.55 g, 33.00 mmol),The reaction solution was heated to reflux. After refluxing for 6 hours, the reaction mixture was cooled to room temperature, and water (100 ml) was evaporated.The organic layer was washed with brine (50 ml) and dried over anhydrous magnesium sulfate.Was concentrated under reduced pressure, the residue was purified by column chromatography (as eluent PE: EA = 20: 1), to give a white solid 7.5 g, yield 79.03percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h; | To a stirred solution of l-fluoro-2-nitrobenzene (0.1 g, 0.52 mmol) in N,N-dimethyformamide (5 mL) at room temperature was added potassium carbonate (0.14 g, 1.04 mmol) and tert-butyl 3-(aminomethyl)piperidine-l-carboxylate (0.13 g, 0.62 mmol), the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash column chromatography by using combiflash purifier with 20 % ethyl acetate in hexane as eluent to give the title compound as yellow solid m/z = 392.1 [M + H] ; Yield (0.15 g, 73 %). |
Tags: 1493-27-2 synthesis path| 1493-27-2 SDS| 1493-27-2 COA| 1493-27-2 purity| 1493-27-2 application| 1493-27-2 NMR| 1493-27-2 COA| 1493-27-2 structure
A112850 [113269-06-0]
4-Fluoro-5-nitrobenzene-1,2-diamine
Similarity: 0.92
A112850 [113269-06-0]
4-Fluoro-5-nitrobenzene-1,2-diamine
Similarity: 0.92
A112850 [113269-06-0]
4-Fluoro-5-nitrobenzene-1,2-diamine
Similarity: 0.92
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