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Structure of 2267-23-4
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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. : | 2267-23-4 |
Formula : | C7H5F3N2O3 |
M.W : | 222.12 |
SMILES Code : | NC1=C(C=C(OC(F)(F)F)C=C1)[N+]([O-])=O |
MDL No. : | MFCD00042326 |
InChI Key : | YCGFVAPIBALHRT-UHFFFAOYSA-N |
Pubchem ID : | 2775772 |
GHS Pictogram: |
![]() |
Signal Word: | Danger |
Hazard Statements: | H302+H312-H315-H319-H331-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338-P311 |
Class: | 6.1 |
UN#: | 2811 |
Packing Group: | Ⅲ |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 6.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 46.35 |
TPSA ? Topological Polar Surface Area: Calculated from |
81.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.51 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.07 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.34 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.54 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.38 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.62 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.25 |
Solubility | 0.125 mg/ml ; 0.000563 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.44 |
Solubility | 0.00808 mg/ml ; 0.0000364 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.05 |
Solubility | 1.96 mg/ml ; 0.00883 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 |
No |
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) |
Yes |
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 |
-5.48 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 |
0.0 |
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 |
3.0 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) |
2.3 |
* 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 |
---|---|---|
78% | With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 20℃; for 1 h; | INTERMEDIATE 244-Bromo-3-nitrophenyl trifiuoromethyl ether To a solution of 2-nitro-4-[(trifluoromethyl)oxy]aniline (2.0 g, 9.0 mmol) in acetonitrlle (50 mL) was added tert-butylnitrite (7.4 g, 72 mmol). The solution was stirred 2 min and then Copper(II) bromide (40 g, 180 mmol) was added. The solution stirred for 1 h at rt. The reaction was partitioned between EtOAc (500 mL) and 1N HCl (aq) (100 mL). The layers were separated, and the organics were washed with 1N HCl (aq) (3.x.50 mL), dried over MgSO4, filtered, and the volatiies were evaporated under reduced pressure, and the residue was purified by flash column chromatography (0 to 20percent EtOAc:hexanes) to give 2.0 g (78percent) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J=8.79 Hz, 1H), 7.76 (s, 1H), 7.32 (s, 1H, J=8.79 Hz). |
78% | With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 20℃; for 1 h; | Intermediate 24: 4-Bromo-3-πitrQphenyi..trjflMQ.romet.h.y.J..etherTo a solution of 2-nitro-4-[(tπ^uoromoethyi)oxy]arsHine (2.0 g, 9.0 mrno.) "m acetoπitrile (50 mL) was added te/.pound.butyinitrite (7.4 g, 72 mmol). The solution was stirred 2 min and then Copper(ll) bromide (40 g, 180 mmol) was added. The solution stirred for 1 h at rt The reaction was partitioned between EtOAc (500 rπL) and 1 N HCi (aq) (100 mL). The iayers were separated, and the organics were washed mth 1N HCi (aq) (3 x 50 ml), dried over .VlgS04, filtered, and the volatiles were evaporated under reduced pressure, and the residue was purified by flash column chromatography (0 to 20percent <n="117"/>EiOAc:hexanes) to give 2,0 g (78percent) of the title compound. 1H NMR (400 MHz, CDCI3): δ 7.78 (ds J- 8.79 Hz, 1H), 7,76 (s, IH), 7,32 (s, 1 H, J- 8.79 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methanol; sodium hydroxide; at 20 - 30℃; for 1.08333 - 1.16667h; | Step 2; Hydrolysis; A vessel fitted with a mechanical stirrer, a thermometer probe, water cooling bath and an addition funnel was charged with 4-trifluoromethoxy-2-nitroacetanilide (11.0 Kg) and methanol (42 L) with stirring at ambient temperature. 5 N NaOH (10.41 L) was added to the slurry at 20-30 0C with water bath over 5-10 min to give a homogeneous dark amber solution. The reaction mixture was stirred at 25- 30 0C for Ih. After the reaction was complete, water (63 L) was added at 15-25 0C over 40-50 min with ice water bath. After addition of water, the batch was transferred to a 200 L vessel with mechanical stirring. The slurry was stirred at ambient temperature for another 2-3 h before filtration. The yellow solid product was isolated by filtration, and the wet cake was washed with 3:2 water/methanol (2 x 12.5 L) and dried under nitrogen with vacuum suction to give 2-nitro-4-trifluoromethoxyaniline 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20℃; for 1h; | INTERMEDIATE 244-Bromo-3-nitrophenyl trifiuoromethyl ether To a solution of <strong>[2267-23-4]2-nitro-4-[(trifluoromethyl)oxy]aniline</strong> (2.0 g, 9.0 mmol) in acetonitrlle (50 mL) was added tert-butylnitrite (7.4 g, 72 mmol). The solution was stirred 2 min and then Copper(II) bromide (40 g, 180 mmol) was added. The solution stirred for 1 h at rt. The reaction was partitioned between EtOAc (500 mL) and 1N HCl (aq) (100 mL). The layers were separated, and the organics were washed with 1N HCl (aq) (3×50 mL), dried over MgSO4, filtered, and the volatiies were evaporated under reduced pressure, and the residue was purified by flash column chromatography (0 to 20% EtOAc:hexanes) to give 2.0 g (78%) of the title compound. 1H NMR (400 MHz, CDCl3): delta 7.78 (d, J=8.79 Hz, 1H), 7.76 (s, 1H), 7.32 (s, 1H, J=8.79 Hz). |
78% | With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20℃; for 1h; | Intermediate 24: 4-Bromo-3-?itrQphenyi..trjflMQ.romet.h.y.J..etherTo a solution of 2-nitro-4-[(t?^uorom°thyi)oxy]arsHine (2.0 g, 9.0 mrno.) "m aceto?itrile (50 mL) was added te/£butyinitrite (7.4 g, 72 mmol). The solution was stirred 2 min and then Copper(ll) bromide (40 g, 180 mmol) was added. The solution stirred for 1 h at rt The reaction was partitioned between EtOAc (500 r?L) and 1 N HCi (aq) (100 mL). The iayers were separated, and the organics were washed mth 1N HCi (aq) (3 x 50 ml), dried over .VlgS04, filtered, and the volatiles were evaporated under reduced pressure, and the residue was purified by flash column chromatography (0 to 20% <n="117"/>EiOAc:hexanes) to give 2,0 g (78%) of the title compound. 1H NMR (400 MHz, CDCI3): delta 7.78 (ds J- 8.79 Hz, 1H), 7,76 (s, IH), 7,32 (s, 1 H, J- 8.79 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; water; In methanol; at 0 - 20℃; for 1h; | To a solution of 2-nitro-4-trifluoromethoxyacetylaniline (45 g, 170 mmol) in methanol (200 mL) at 0 to 100C, was added sodium hydroxide solution (NaOH, 8.5g, 220 mmol, in 45 mL water). The reaction mixture was stirred at room temperature for one hour and diluted with 300 mL of water. The slurry was stirred in an ice bath for two hours and filtered. The yellow solid was washed with 50 mL methanol: water (1:2) and dried under vacuum to obtain a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitrous acid isobutyl ester;copper dichloride; at 18 - 50℃; for 1 - 2h;Product distribution / selectivity; | Step 3; Meerwein arylationlsopropenyl acetate CuCI2, i-butylnitrite A vessel was charged with isopropenyl acetate (30 L) followed by copper(II)chloride (2.93 Kg) in one portion at 18-25 0C with stirring. The temperature of the solution was adjusted to 40-45 0C. A solution of aniline 4 (4.05 Kg) in isopropenyl acetate (5 L) was added to the reaction mixture via an addition funnel over 1-2 h concomitantly with the addition of isobutyl nitrite (2.84 L) in a separate addition funnel over the same amount of time by keeping the reaction temperature at 40-50 0C.The reaction mixture was cooled to 18-22 0C, diluted with toluene (21.5 L) and quenched by addition of 1.0 N HCl (21.5 L). The reaction mixture was stirred for 15 min. The organic layer was washed with water (21.5 L)5 NaHCO3 aq sat (21.5 L) and water (2.5 L). The organic layer was concentrated under partial vacuum (max temp 20 0C) and the solvent switched to toluene. The volume was adjusted to 10.75 L and the homogeneous amber solution is cooled to 5 to -10 0C. Heptane (3.6 L) was added and the mixture aged for Ih. Heptane (37 L) was slowly added keeping the temperature at -5 to -10 0C. The slurry was cooled to -25 to -20 0C, aged 1 h at -25 to -20 0C and filtered.. The dark yellow cake was washed with toluene/heptane (1:6 v/v, 1 IL ) at -25 to -20 0C, and heptane (4 L) at -25 to -20 0C and dried at ambient temperature under partial vacuum with a flow of nitrogen to afford the ketone 5.; EXAMPLE 9; The conversion of Compound 4 of the synthetic procedure in Example 1 to Compound 6 can also be carried out by the following procedure: Meerwein Reaction and Ketalization; A solution of nitroaniline 4 (22.2Ig) in isopropenyl acetate (22mL) and a solution of iBuONO (94%, 13.7Ig) are each added from separate addition funnels at ca the same rate (+/- 10%) over Ih to a suspension of CuC12 (2.0Ig) in 20OmL isopropenyl acetate maintained at 40-50 C. The mixture is aged for Ih at 40-50 0C and cooled to 25 C. Toluene (10OmL) is added and the mixture is washed with IM HCl (2x15mL); most of the copper is concentrated in these two small aq. washes) and then with water (2x10OmL). The organic phase is concentrated to 50 mL and at constant volume solvent switched to toluene using 10OmL toluene at 200 Torr. The mixture is then constant volume solvent switched to EtOH using 15OmL EtOH at 200 Torr. The solution containing nitroketone 5 in 5OmL EtOH was mixed with EPO <DP n="24"/>ethylene glycol (9.3 Ig), (EtO)3CH (21.03 g), and p-TsOH (0.5Og), and the solution was heated to 45 C for 16h or 80 0C for l-2h and was then cooled to 25C. Conversion of the nitroketone 5 was monitored by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | A solution of <strong>[2267-23-4]2-nitro-4-trifluoromethoxy-phenylamine</strong> 1 (25.0 g, 0.112 mol) in EtOH (200 ml) was added to solution of stannous chloride dihydrate (82.0 g, 0.363 mol) in cone HCl (330 ml) . The resulting suspension was stirred for 0.5 h at 70-80C, cooled at 0-5C, and basified to pH=ll-12 by 40% NaOH solution, and the product extracted with ether (2x200 ml) . The organic solution was washed with water, dried over Na2Stheta4 and evaporated to dryness under reduced pressure to give the title compound as a brown oil (21.1 g, 98%). | |
92% | With hydrogen;palladium; In ethanol; for 48h; | EXAMPLE 61; 1 -(7H-Pyrro lor2,3-dlpyrimidin-4-yl)-4-(5-(trifluoromethoxy)-lH-benzordlimidazo 1-2- vDpiperidin-4-amine6 IA. 4-(trifluoromethoxy)benzene- 1 ,2-diamine 2-Nitro-4-(trifluoromethoxy)aniline (2.000 g, 9.00 mmol) and palladium (0.096 g, 0.90 mmol) were dissolved in ethanol (25 mL) and stirred under a balloon of hydrogen for 48 hours. The reaction was filtered and evaporated to dryness to afford 4-(trifluoromethoxy)- benzene-l,2-diamine (1.392 g, 7.24 mmol, 92 %) as a black oil; m/z (ESI+) (M+H)+ = ; HPLC tR = 1.53 min. IH NMR (400.132 MHz, CDC13) delta 3.41 (4H, vbrs), 6.60 - 6.58 (2H, m), 6.67 (IH, d). |
86% | With hydrogen;nickel; In ethanol; at 20℃; under 2585.81 Torr; | <strong>[2267-23-4]2-nitro-4-trifluoromethoxy-phenylamine</strong> Compound 16a (0.5 g, 2.25 mmol) was dissolved into EtOH (30 mL) and Raney Ni (~ 0.5 g, prewashed with EtOH) was added. The mixture was shaken in a Parr shaker under H2 (50 psi) at room temperature overnight, filtered through Celite and the solvent was evaporated to dryness to provide 4-trifluoromethoxy-benzene-l,2-diamine Compound 16b (0.373 g, yield 86%) as. a red- brown semi-solid. |
With hydrogen;palladium 10% on activated carbon; In methanol; under 2327.23 Torr; for 4h; | To a solution of 2-Nitro-4-trifluoromethoxyaniline (4Og, 180 mmol) in methanol (250 ml), was added 10% palladium on carbon (Pd/C, 10% wt/wt, 500 mg). The suspension was shaken in a Parr bottle under 45 psi of hydrogen for 4 hours, and then filtered through celite. The filtrate was concentrated to dryness to obtain a light gray solid. | |
With ammonium chloride; zinc; In ethanol; water; at 60℃; for 1h; | To a mixture of <strong>[2267-23-4]2-nitro-4-(trifluoromethoxy)aniline</strong> (1.17 g) and EtOH (20 mL) were added ammonium chloride (565 mg) and water (5 mL), followed by further adding zinc powder (1.73 g) at 60 C., and heating and stirring at 60 C. for 1 hour. The reaction mixture was cooled to room temperature, filtered over Celite, and washed with EtOAc. This filtrate was washed with a saturated aqueous NaHCO3 solution and brine in this order, dried over MgSO4, and then concentrated under reduced pressure to obtain 4-(trifluoromethoxy)benzene-1,2-diamine. | |
With ethanol; water; iron; ammonium chloride; at 70℃; for 4h; | 4-(Trifluoromethoxy)-1 ,2-benzenediamine is commercially available, alternatively it can be prepared according to the following procedure. <n="45"/>To a stirred mixture of iron (2.011 g, 36.0 mmol), ammonium chloride (2.408 g, 45.0 mmol) and water (5 ml) was added dropwise a solution of 2-nitro-4- (trifluoromethoxy)aniline (commercially available from e.g. Fluorochem. Ltd., 2 g, 9.0 mmol) in ethanol (10 ml). The mixture was heated to 70 0C and stirred for 4 hours. By TLC the reaction was complete. The mixture was cooled to room temperature and filtered through celite, washing with ethanol. The filtrate was concentrated under vacuum; the residue was partitioned between dichloromethane and water. The organic phase was filtered through a hydrophobic membrane (Phase Sep) and concentrated under vacuum to give the title compound (1.51 g) as a dark brown oil. 1 H-NMR (400 MHz, CDCI3): delta 6.66 (1 H, d, J 8 Hz), 6.60-6.55 (2H, m), 3.84-2.89 (4H, m); UPLC-MS: 0.50 min, mz 193 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In ethanol; at 30 - 35℃; under 1520.1 - 2280.15 Torr; for 1h; | 2-Nitro-4-trifluoromethoxy-phenylamine 1 (25.0 g, 0.112 mol) was dissolved in EtOH (300 ml), and cone HCl (29 ml) and 10% Pd/C (2.5 g) was added, and the mixture was reacted for 1 h with H2 at 2-3 atm at 30-350C. The suspension was filtered and the filtrate was evaporated to dryness under reduced pressure. The solid was collected, washed with cold EtOH (20-30 ml) and dried to give 25.8 g (80 %) of the HCl salt of the title compound, mp 255-26O0C (decomp.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With N-chloro-succinimide; In acetonitrile; at 70℃; for 4h; | [00348] A solution of <strong>[2267-23-4]2-nitro-4-trifluoromethoxy-aniline</strong> 21 (40.0 g, 0.180 mol) and N- chlorosuccinimide (30.0 g, 0.225 mol) in ACN (300 mL) was heated at 70 C for 4 hrs. The mixture was then cooled down to room temperature and diluted with saturated NH4C1 solution (600 mL) and ethyl acetate (600 mL). The organic layer was washed with water (200 mL) and dried over Na2S04. Evaporation of solvent under reduced pressure gave a dark orange solid, which on trituration with hexane gave 2-chloro-6-nitro-4-(trifluoromethoxy)- aniline 22 as an orange solid in 50% yield (23.0 g). 1H NMR (400 MHz, chloroform-* ) delta 8.03 (dq, J= 2.7, 0.9 Hz, IH), 7.52 - 7.46 (m, IH), 6.60 (s, 2H). |
50% | With N-chloro-succinimide; In acetonitrile; at 70℃; for 4h; | A solution of <strong>[2267-23-4]2-nitro-4-trifluoromethoxy-aniline</strong> 21 (40.0 g, 0.180 mol) and Nchlorosuccinimide (30.0 g, 0.225 mol) in ACN (300 mL) was heated at 70 C for 4 hrs. The mixture was then cooled down to room temperature and diluted with saturated NH4C1 solution (600 mL) and ethyl acetate (600 mL). The organic layer was washed with water (200 mL) and dried over Na2 SO4. Evaporation of solvent under reduced pressure gave a dark orange solid, which on trituration with hexane gave 2-chloro-6-nitro-4-(trifluoromethoxy)- aniline 22 as an orange solid in 50% yield (23.0 g). ?HNMR (400 IVIFIz, chloroform-cl) 5 8.03 (dq, J= 2.7, 0.9 Hz, 1H), 7.52 - 7.46 (m, 1H), 6.60 (s, 2H). |
In tetrachloromethane; Petroleum ether; | PREPARATION 22 This description illustrates the preparation of 2-chloro-6-nitro-4-trifluoromethoxy-aniline. Chlorine gas was passed through a solution of <strong>[2267-23-4]2-nitro-4-trifluoromethoxy-aniline</strong> (14.5g) in carbon tetrachloride (175ml). The stirred mixture became solid, and more carbon tetrachloride (50ml) was added. Chlorine gas was passed through the reaction mixture until thin layer chromatography on silica gel, using petroleum ether (boiling range 60-80 C.) containing ethyl acetate (30% by volume) as eluent, demonstrated the absence of starting material. Evaporation of the solvent under reduced pressure gave a dark orange solid, which on trituration with petroleum ether (boiling range 60-80 C.) gave 2-chloro-4-trifluoromethoxy-6-nitroaniline as an orange solid. 1 H NMR delta(CDCl3): 8.04 (1H,d); 7.49 (1H,d); 6.60 (2H, broad s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 60℃; for 16h; | Step A-Methyl 3-[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-({2-nitro-4-[(trlfluoromethyl)oxy]phenyl}amino)-2-thiophenecarboxylate 4-Bromo-3-nitrophenyl trifluoromethyl ether (2.0 g, 7.0 mmol) and methyl 5-amino-3-[(1R)-1-(2-chlorophenyI)ethyl]oxy}-2-thiophenecarboxylate (2.2 g, 7.0 mmol) were dissolved in 1,4-dioxane (80 mL) with stirring in a flask equipped with a stir bar, reflux condenser, and thermometer. The solution was degassed for 15 min by bubbling N2 through the stirring solution. 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.18 g, 0.31 mmol), cesium carbonate (11 g, 35 mmol), and tris(dibenzylideneacetone) dipaliadium(0) (0.13 g, 0.14 mmol) were added. The reaction was heated to 60 C. and stirred for 16 h. The reaction was cooled to rt and filtered through Celite. The solid was washed with 20% MeOH in DCM. The volatiies were evaporated under reduced pressure and the residue was purified by flash column chromatography (0 to 50% EtOAc:DCM) to give 3.5 g (97%) of the title compound as a solid. MS (ESI): 516 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | [Example 734] Compound q12 1-Iodo-2-nitro-4-(trifluoromethoxy)benzene [1549] sodium nitrite (378 mg, 5.48 mmol) were added to a mixture of <strong>[2267-23-4]2-nitro-4-(trifluoromethoxy)aniline</strong> (1.11 g, 4.98 mmol), a 35% aqueous hydrochloric acid solution (7.2 ml) and water (7.2 ml) under ice-cooling. After 20 minutes of stirring, acetic acid (5 ml) was added, and the mixture was stirred at room temperature for 20 minutes. Sodium nitrite (80.7 mg, 1.17 mmol) was added, and the mixture was stirred for 20 minutes under ice-cooling, after which potassium iodide (1.22 g, 7.38 mmol) dissolved in water (1.5 ml) was added, followed by 30 minutes of stirring. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was then washed with a saturated aqueous sodium thiosulfate solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to yield the title compound (1.07 g, 65%) as an orange oily substance. LCMS: m/z 334 [M+H]+ HPLC retention time: 0.90 min (analysis condition F) | |
65% | The mixture of 2-nitro-4- (trifluoromethoxy) aniline (l.llg, 4.98mmol), 35% aqueous hydrochloric acid (7.2ml) and water (7.2ml) of, and under ice-cooling was added ice (8G ) and sodium nitrite (378mg, 5.48mmol), stirring for 20 minutes, acetic acid (5ml), stirred at room temperature for 20 minutes. Under ice-cooling, sodium nitrite (80.7mg, l_17mmol), stirred for 20 min, dissolved in water (1.5ml) of potassium iodide (1.22g, 7.38mmol), stirred for 30 minutes. The reaction mixture was added water, extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium thiosulfate solution, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off and concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to obtain the title compound (1.07g, 65%) of an orange oily substance. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | a. A mixture of 2-nitro-4-trifluoromethylaniline (12 g) and activated palladium on charcoal (0.6 g) in methanol was hydrogenated with one atmosphere of hydrogen under stirring at room temperature for one hour. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate concentrated under reduced pressure to give a residue. This residue was then dissolved in acetic acid (100 mL) and water (15 mL) and cooled to 0 C. prior to adding hydrochloric acid (4 mL) and a solution of sodium nitrite (4.4 g) in water (10 mL). The mixture was stirred at room temperature for two hours and then diluted with water. The resulting solid was filtered, washed with water and dried to obtain an off-white solid (8.0 g, 73%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Reference Production Example 206; To a mixture of 2.22 g of 2-nitro-4- trifluoromethoxyaniline and 20 ml of DMF was added 0.44 g of sodium hydride (60% oily), and the mixture was stirred for 10 minutes under ice cool. To this mixture was added 1.42 g of methyl iodide, then, the mixture was stirred for 1 hour at room temperature. Into the reaction mixture, a saturated ammonium chloride aqueous solution was poured, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.80 g of N-methyl-2- nitro-4-trifluoromethoxyaniline.1H-NMR (CDCl3) delta: 8.10-8.01 (m, 2H), 7.3 7 (dtd, J=9.3, 1.8, 1.0Hz, IH), 6.87 (d, J=9.3Hz, IH), 3.05 (d, J=5.1Hz, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In water; toluene; at 80 - 100℃; for 19.91h;Inert atmosphere; | 18.32 g (80.0 mmol) of <strong>[2267-23-4]2-nitro-4-(trifluoromethoxy)aniline</strong>, and 15.1 g (95.7 mmol) of bromobenzene, in 320 ml of toluene and 4.3 g of water, are heated at 80C under nitrogen during 15 minutes. 8.72 g (90.7 mmol) of sodium feri-butylate are added and the yellow-red suspension stirred at 80C for 40 minutes. 0.73 g (0.8 mmol) of tris(dibenzylideneacetone)dipalladium(0), and 1 .43 g of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene are added and the resulting suspension heated at 100C during 19 hours, cooled down to room temperature and filtered. The yellow-red solution is concentrated under vacuum and the resulting dark yellow oil further purified by chromatography (silica gel, cyclohexane/dichloromethane 3:1 ) giving the title product as yellow solid (yield: 18.8 g (79%)). 1H-NMR (400 MHz, CD2Cl2): delta = 7.29-7.36 (m, 5 H), 7.46-7.54 (m, 2 H), 8.13 (d, 1 H), 9.50 (br. s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With sulfuric acid; arsenic pentoxide pentahydrate; In water; at 80 - 120℃; for 4.5h; | General procedure: The reaction was performed according to a literature knownprocedure [20]. Aniline 1b (5.0 g, 29 mmol) and arsenic pentoxidehydrate (4.5 g, 5.8 mmol) were dissolved in a mixture of sulfuricacid (70%, 15 mL) and water (9 mL). This solution was heated upto 80 C, and at constant temperature ADEA (6.2 mL, 41 mmol) wasadded dropwise during 3 h with a syringe pump. After completionof addition the solution was heated up to 120 C for 90 min withvigorous stirring. The mixture was allowed to cool down, waspoured onto an ice/water mixture (100 mL) and the resultingsuspension wasfiltered. Aqueous ammonia was added dropwise tothefiltrate until reaching pH6. The crude mixture was extractedwith dichloromethane (350 mL). The organic phase was washedwith brine and dried over anhydrous Na2SO4. 2b was obtained as ayellow solid after sublimation (70 C/2*102mbar) of the crudeproduct in 33% yield (2.0 g, 9.5 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.1% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In toluene; at 110℃; for 4h;Inert atmosphere; | A solution of 3- (2,6-dichloro-3,5-dimethoxyphenyl) -7-chloro-2H-pyrano [3,2-c] -pyridin-2-one (200 mg, 0.517 mmol ) And 2-nitro(Trifluoromethoxy) aniline (344 mg, 1.55 mmol) was dissolved in 12 mL of toluene and the reaction was bubbled with nitrogen for 15 min followed byPd2 (dba) 3 (48 mg, 0.052 mmol), Xphos (49 mg, 0.103 mmol) and cesium carbonate (505 mg, 1.55 mmol) Under heating under heating to 110 C for 4 h. The reaction solution was cooled to room temperature, and the reaction solution was filtered, washed with a mixed solvent of dichloromethane and methanol (5: 1) And the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 500: 1) to give the title compound as a yellow solid3- (2,6-dichloro-3,5-dimethoxyphenyl) -7 - ((2-nitro-4- (trifluoromethoxy) phenyl) amino) -2H-pyran And [3,2-c] pyridin-2-one (157 mg, Yield 53.1%). |
Tags: 2267-23-4 synthesis path| 2267-23-4 SDS| 2267-23-4 COA| 2267-23-4 purity| 2267-23-4 application| 2267-23-4 NMR| 2267-23-4 COA| 2267-23-4 structure
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