* 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.
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 12, p. 2064 - 2086
[2] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 19, p. 2675 - 2680
[3] Journal of Organic Chemistry, 1958, vol. 23, p. 1944
[4] Dalton Transactions, 2012, vol. 41, # 21, p. 6507 - 6515
2
[ 123-54-6 ]
[ 3694-52-8 ]
[ 76320-88-2 ]
Reference：
[1] Synthesis, 1992, # 12, p. 1283 - 1286
[2] Journal of Medicinal Chemistry, 2001, vol. 44, # 6, p. 851 - 856
[3] Patent: EP1479666, 2004, A1, . Location in patent: Page 183-183
3
[ 64-19-7 ]
[ 3694-52-8 ]
[ 76320-88-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2016, vol. 59, # 3, p. 1140 - 1148
4
[ 3694-52-8 ]
[ 76320-88-2 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1999, vol. 36, # 4, p. 1013 - 1016
5
[ 108-24-7 ]
[ 3694-52-8 ]
[ 76320-88-2 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1911, vol. 379, p. 158[2] Justus Liebigs Annalen der Chemie, 1914, vol. 406, p. 101
[3] Journal of the American Chemical Society, 1951, vol. 73, p. 3030,3035
[4] Justus Liebigs Annalen der Chemie, 1911, vol. 379, p. 158[5] Justus Liebigs Annalen der Chemie, 1914, vol. 406, p. 101
6
[ 131543-46-9 ]
[ 3694-52-8 ]
[ 18514-76-6 ]
Yield
Reaction Conditions
Operation in experiment
97%
at 85℃; for 2 h;
General Procedure 108: 5-Nitroquinoxaline (Intermediate 481)Oxaldehyde (40percent in water; 1.43 ml, 31.3 mmol) was added to a solution of 3-nitro-o-phenylene-diamine (600 mg, 3.9 mmol) in EtOH (15 ml) and the mixture was heated at 85° C. for 2 h. The solvent was removed in vacuo, the residue was diluted in water and the aqueous phase was extracted with DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (99:1) as the eluent to give the title compound (666 mg, 97percent).MW: 175.15HPLCMS: (Method C): [m/z]: 176
97%
at 20℃; Reflux
To a solution of 3-nitro-l,2-benzenediamine (2 g, 13 mmol) in EtOH (30 mL) was added glyoxal (4.4 mL, 40percent in water, 39 mmol). The reaction mixture was heated to reflux for 2 hours before stirring at RT for overnight. The solvent was removed in vacuo, the residue was treated with water and extracted with DCM. The organic extracts were concentrated and purified by recrystallization to afford 5-nitroquinoxaline (2.2 g, 97percent). 1HNMR (CDCI3, 300 MHz) δ: 7.8-7.9 (t, 1 H), 8.2-8.3 (d, 2 H), 8.4-8.5 (d, 1 H), 9.0-0.1 (d, 2 H).
97%
for 6 h; Reflux
6 g of 3-nitro-o-phenylenediamine was dissolved in 50 ml of ethanol, then 14 ml of glyoxal solution was added and refluxed for 6 hours. Ethanol, water and glyoxal were distilled off under reduced pressure to obtain 6.6 g of a yellow solid in a yield of 97percent.
96%
for 1 h; Heating / reflux
To a room temperature solution of 3-nitro-o-phenylenediamine (10 g, 65.3 mmol) in EtOH (50mL) was added glyoxal (40 percent in H2O, 22.47 mL). The reaction mixture was heated at reflux 1 hour, then diluted with H2O (100 mL). The cooled mixture was extracted with CH2Cl2 (2 x 300 mL) and the organic layers were combined and washed again with H2O (500 mL), dried over Na2SO4 and concentrated yielding a bright orange solid which was recrystallized from EtOAc/Hexanes to give 10.96 (96percent) of a tan solid mp 90-92 °C.
96%
With 10 wtpercent sulfated polyborate In neat (no solvent) at 100℃; for 0.05 h; Green chemistry
General procedure: To a mixture of substituted o-phenylenediamines derivative(2.0 mmol) and 1,2-diketone / α-hydroxy ketone (2.0 mmol),was added sulfated polyborate (10 wtpercent). The reaction mixture was stirred at 100 °C in an oil bath. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the mixture was cooled to room temperature and quenched by water. The resultant product was filtered/extracted with EtOAc to get the product. Crude products were either recrystallized from ethanol or purified by column chromatography using silica as the stationary phase and EtOAc: pet. ether as mobile phase. The products obtained were known compounds and were identified by melting point and 1H and 13C NMR spectroscopy. The spectral data were compared with the literature values.
33%
at 20℃; for 72 h; Heating / reflux
Glyoxal (aq, 8.8 M, 2.6 mL, 22.8 mmol) was added to a mixture of 3-nitro- benzene- 1,2-diamine (1.163 g, 7.59 mmol) in EtOH (16 mL). The mixture was heated at reflux for 2 h and stirred at rt for 3 days. Water (50 mL) was added and the resulting mixture was extracted with CH2Cl2 (3x20 mL). The combined extracts were dried (MgSO4) and concentrated to give an orange-red solid which was recrystallised from water to give the sub-title compound (439 mg, 33percent) as pale yellow needles.1H NMR (CDCl3, 400 MHz) δ 9.05 (d, IH), 9.01 (d, IH), 8.38 (dd, IH)5 8.20 (dd, IH), 7.89 (t, IH).
26.22 g
for 2 h; Reflux
A solution of 3-nitrobenzene-1,2-diamine (25 g) and glyoxal solution (40 wtpercent in water, 56.0 ml) in ethanol (96percent, 400 ml) was kept under reflux conditions for 2 hours. The reaction mixture was concentrated in vacuo and water was added. The mixture was extracted with CH2Cl2 (3 x). The combined organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by gravity column chromatography (EtOAc:heptane, 2:3) to yield 26.22 g product.
26 g
for 8 h; Reflux
Add 35 g of 3-nitro-o-phenylenediamine to 120 ml of toluene, add 50 g of glyoxal, stir at reflux for 8 hours, concentrate, add ethyl acetate and water, separate, dry, and concentrate. The residue is separated on the column to obtain 26 g. 5-Nitrobenzopyrazine.
Reference：
[1] Patent: US2012/214803, 2012, A1, . Location in patent: Page/Page column 174
[2] Patent: WO2016/77240, 2016, A2, . Location in patent: Page/Page column 68
[3] Patent: CN107805223, 2018, A, . Location in patent: Paragraph 0019
[4] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 14, p. 6707 - 6723
[5] Patent: EP1147083, 2004, B1, . Location in patent: Page 38
[6] Journal of Chemical Sciences, 2017, vol. 129, # 2, p. 141 - 148
[7] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 4, p. 803 - 806
[8] Patent: WO2006/32851, 2006, A1, . Location in patent: Page/Page column 50
[9] Organic Magnetic Resonance, 1980, vol. 14, # 4, p. 300 - 304
[10] Journal of Medicinal Chemistry, 2005, vol. 48, # 3, p. 744 - 752
[11] Patent: WO2014/184355, 2014, A1, . Location in patent: Page/Page column 26; 63
[12] Patent: CN107793370, 2018, A, . Location in patent: Paragraph 0018; 0019; 0020
7
[ 517-21-5 ]
[ 3694-52-8 ]
[ 18514-76-6 ]
Reference：
[1] Journal of the American Chemical Society, 1950, vol. 72, p. 3824
8
[ 3694-52-8 ]
[ 6299-39-4 ]
Yield
Reaction Conditions
Operation in experiment
83.6%
at 20 - 60℃; for 2.25 h;
Example 1 Synthesis of (4-Hydroxy-piperidin-1-yl)-(4-{4-[4-(4-(4-methylthiophen-3-yl)-benzotriazol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (Compound 1) To a mixture of 3-nitrobenzene-1,2-diamine (15.0 g) in AcOH (100 mL) was added NaNO2 (7.0 g). The reaction mixture was stirred for 15 min at RT, then heated at 60° C. for about 2 h, over which time the reaction mixture turned red. The mixture was cooled to RT, diluted with ice water, and the resulting precipitate filtered off and washed with ice water, then dried under vacuum to yield 4-nitro-1H-benzotriazole (13.45 g, 83.6percent yield) as a light brown solid. The product was used without further purification.
Reference：
[1] Justus Liebigs Annalen der Chemie, 1911, vol. 379, p. 158[2] Justus Liebigs Annalen der Chemie, 1914, vol. 406, p. 101
10
[ 50-00-0 ]
[ 3694-52-8 ]
[ 31493-66-0 ]
Reference：
[1] Nucleosides, Nucleotides and Nucleic Acids, 2010, vol. 29, # 1, p. 27 - 38
11
[ 606-22-4 ]
[ 3694-52-8 ]
Yield
Reaction Conditions
Operation in experiment
66.5%
With sodium sulfide; water; sodium hydrogencarbonate In methanol at 60℃; for 1 h;
14 g of commercially available 1-amino-2,5-dinitrobenzene was dissolved in 225 ml of methanol, to which a solution of 60 g of sodium sulfide and 21 g of sodium hydrogen carbonate dissolved in 240 g of water was added by use of a dropping funnel while keeping the reaction temperature at 60°C. After completion of the addition, agitation was continued at 60°C for 1 hour. After completion of the reaction, the mixture was cooled down to room temperature and filtered. m/z: (FD+) 153 (calculated 153. 1396) 1H-NMR: 7.7228, 7.7203, 7.7026, 7.2433, 6.9245, 6.6209, 6.6063, 6.6038, 6.5886, 5.9210, 3.3978 ppm Yield: 7.79 g (66.5percent) Reddish brown fine crystals Melting point: 140° C
Reference：
[1] Synthetic Communications, 1995, vol. 25, # 5, p. 711 - 718
[2] Journal of Medicinal Chemistry, 1999, vol. 42, # 12, p. 2064 - 2086
[3] Nucleosides, Nucleotides and Nucleic Acids, 2010, vol. 29, # 1, p. 27 - 38
[4] Chemistry - A European Journal, 2011, vol. 17, # 23, p. 6533 - 6544
[5] Organic Preparations and Procedures International, 1999, vol. 31, # 3, p. 347 - 348
[6] Patent: EP1705178, 2006, A1, . Location in patent: Page/Page column 21
[7] Justus Liebigs Annalen der Chemie, 1911, vol. 379, p. 158[8] Justus Liebigs Annalen der Chemie, 1914, vol. 406, p. 101
[9] Recueil des Travaux Chimiques des Pays-Bas, 1948, vol. 67, p. 45,48,51
[10] Gazzetta Chimica Italiana, 1967, vol. 97, p. 750 - 757
[11] Chemistry Letters, 2003, vol. 32, # 12, p. 1142 - 1143
[12] Green Chemistry, 2014, vol. 16, # 9, p. 4162 - 4169
[13] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5433 - 5440
[14] Angewandte Chemie - International Edition, 2017, vol. 56, # 50, p. 15954 - 15958[15] Angew. Chem., 2017, vol. 129, # 50, p. 16170 - 16174,5
12
[ 20718-41-6 ]
[ 3694-52-8 ]
Yield
Reaction Conditions
Operation in experiment
54%
With hydrogenchloride; hydrogen iodide In water at 20℃; for 3 h;
To a suspension of 8 (18 g, 79 mmol) in concd hydrochloric acid (225 mL), 70 mL of aqueous hydroiodic acid (57percent w/v, 70 mL) was added dropwise at room temperature with vigorous stirring. The reaction mixture was stirred further at room temperature for 3 h. A 5percent aqueous sodium hydrogen sulfide solution (400 mL) was added to the dark-red reaction mixture. This was then warmed to 80 °C and filtered hot and afterwards cooled to 4 °C. The needle like salt of the diamine crystallized out. The product was neutralized with 30percent NaOH to pH 8 and extracted with ethyl acetate (6 * 100 mL). The ethyl acetate layer was collected, dried over Na2SO4, filtered off and evaporated to yield 6.5 g (42.44 mmol, 54percent) of the title compound 9 as a red solid: 1H NMR (300 MHz, CD3OD) δ 6.47-6.56 (dd, 1H, J = 7.5 Hz and 8.7 Hz, Ar), 6.87-6.92 (dd, 1H, J = 1.2 Hz and 7.5 Hz, Ar), 7.48-7.53 (dd, 1H, J = 1.2 Hz and 8.7 Hz, Ar). 13C NMR (75 MHz, CD3OD) δ 116.4, 117.0, 120.6 (quaternary carbon not detected). HRMS for C6H7N3O2Na ([M+Na]+) calcd: 176.0431 found 176.1058.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 10, p. 2875 - 2886
13
[ 619-18-1 ]
[ 3694-52-8 ]
Yield
Reaction Conditions
Operation in experiment
66.5%
With sodium sulfide; sodium bicarbonate In methanol; water
Synthesis Example 1 Synthesis of 1-nitro-2,3-diaminobenzene In 225 ml of methanol was dissolved 14 g of commercial 1-amino-2,5-dinitrobenzene. To the solution was added dropwise through a dropping funnel a solution of sodium sulfide (60 g) and sodium hydrogen carbonate (21 g) dissolved in water (240 g), with the reaction temperature kept at 60°C. The reaction solution was stirred at 60°C for one hour. After the completion of reaction, the reaction solution was cooled to room temperature and filtered. M/z (FD+) 153 (calculated: 153.1396) 1H-NMR (CDCl3, δppm) 7.72, 7.70, 7.24, 6.92, 6.62, 6.60, 6.59, 5.92, 3.40 Yield: 7.79 g (yield ratio:66.5percent)
With sodiumsulfide nonahydrate; sodium hydrogencarbonate; In water; at 60 - 75℃; for 1h;
3-Nitro-1,2-phenylenediamine (9i) 4 (0.90 g, 4.9 mmol) was suspended in water (18 ml) and heated at 60 C for 10 min. Then, a solution of sodium sulfide nonahydrate (3.8 g, 16.0 mmol) and sodium hydrogen carbonate (1.3 g, 14.9 mmol) in water (27 ml) was added and the reaction mixture was heated at 75 C for 1 h. The resulting precipitate was filtered, washed with ice water and purified by column chromatography (DCM/MeOH, 95:5). Dark red solid, yield: 90%. 1H-NMR (400 MHz, DMSO-d6): delta 7.30 (dd, 1H, 3J = 8.8 Hz, 4J = 1.4 Hz), 6.91 (br s, 2H), 6.77 (d, 1H, 3J = 7.4 Hz), 6.51-6.40 (m, 1H), 5.23 (br s, 2H).
66.5%
With sodium sulfide; water; sodium hydrogencarbonate; In methanol; at 60℃; for 1h;
14 g of commercially available 1-amino-2,5-dinitrobenzene was dissolved in 225 ml of methanol, to which a solution of 60 g of sodium sulfide and 21 g of sodium hydrogen carbonate dissolved in 240 g of water was added by use of a dropping funnel while keeping the reaction temperature at 60C. After completion of the addition, agitation was continued at 60C for 1 hour. After completion of the reaction, the mixture was cooled down to room temperature and filtered. m/z: (FD+) 153 (calculated 153. 1396) 1H-NMR: 7.7228, 7.7203, 7.7026, 7.2433, 6.9245, 6.6209, 6.6063, 6.6038, 6.5886, 5.9210, 3.3978 ppm Yield: 7.79 g (66.5%) Reddish brown fine crystals Melting point: 140 C
With 5% active carbon-supported ruthenium; hydrazine hydrate; In ethanol; for 3.5h;Reflux;
To a stirred solution of <strong>[606-22-4]2,6-dinitroaniline</strong> (10.0 g, 54.6 mmol) in 250 mL of EtOH was added 0.5 g of 5% Ru/C. To this suspension was then added hydrazine monohydrate (5.0 mL 82.8 mmol) dropwise via syringe pump over 30 minutes. The solution was heated to reflux for 3 h before being cooled to rt. The solution was filtered through Celite and concentrated in vacuo to afford the desired di-aniline product 33 as an orange solid. The solid was taken onto the next step with no further purification.
Step A: Preparation of 4-nitro-1H-benzo[d]imidazole: A solution of 3-nitrobenzene-1,2-diamine (1.0 g, 6.5 mmol) in formic acid (10 mL) was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature and concentrated. The resulting solids were suspended in water and treated with saturated aqueous NaHCO3 until the pH was about 7 to about 8. The solids were collected by filtration and dried in vacuo to give the desired product (1.0 g, 94%). MS (APCI-neg) M-1=162.2.
8.51 g
for 18h;Reflux;
The unpurified 33 was dissolved in 150 mL of formic acid and was then heated to reflux for 18 h. The solution was then cooled to rt and concentrated in vacuo to afford a brown solid. The solid was cooled to 0 C before 100 mL of 30% NH4OH was added slowly over a period of 30 minutes. The solution was then allowed to warm to rt and stirred at rt for 1 h during which time a tan precipitate formed. The precipitate was collected by filtration to afford benzimidazole 34 as a tan solid (8.51 g, 95% over 2 steps).
General Procedure 108: 5-Nitroquinoxaline (Intermediate 481)Oxaldehyde (40% in water; 1.43 ml, 31.3 mmol) was added to a solution of 3-nitro-o-phenylene-diamine (600 mg, 3.9 mmol) in EtOH (15 ml) and the mixture was heated at 85 C. for 2 h. The solvent was removed in vacuo, the residue was diluted in water and the aqueous phase was extracted with DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (99:1) as the eluent to give the title compound (666 mg, 97%).MW: 175.15HPLCMS: (Method C): [m/z]: 176
97%
In ethanol; water; at 20℃;Reflux;
To a solution of 3-nitro-l,2-benzenediamine (2 g, 13 mmol) in EtOH (30 mL) was added glyoxal (4.4 mL, 40% in water, 39 mmol). The reaction mixture was heated to reflux for 2 hours before stirring at RT for overnight. The solvent was removed in vacuo, the residue was treated with water and extracted with DCM. The organic extracts were concentrated and purified by recrystallization to afford 5-nitroquinoxaline (2.2 g, 97%). 1HNMR (CDCI3, 300 MHz) delta: 7.8-7.9 (t, 1 H), 8.2-8.3 (d, 2 H), 8.4-8.5 (d, 1 H), 9.0-0.1 (d, 2 H).
97%
In ethanol; for 6.0h;Reflux;
6 g of 3-nitro-o-phenylenediamine was dissolved in 50 ml of ethanol, then 14 ml of glyoxal solution was added and refluxed for 6 hours. Ethanol, water and glyoxal were distilled off under reduced pressure to obtain 6.6 g of a yellow solid in a yield of 97%.
96%
In ethanol; water; for 1.0h;Heating / reflux;
To a room temperature solution of 3-nitro-o-phenylenediamine (10 g, 65.3 mmol) in EtOH (50mL) was added glyoxal (40 % in H2O, 22.47 mL). The reaction mixture was heated at reflux 1 hour, then diluted with H2O (100 mL). The cooled mixture was extracted with CH2Cl2 (2 x 300 mL) and the organic layers were combined and washed again with H2O (500 mL), dried over Na2SO4 and concentrated yielding a bright orange solid which was recrystallized from EtOAc/Hexanes to give 10.96 (96%) of a tan solid mp 90-92 C.
96%
With 10 wtpercent sulfated polyborate; In neat (no solvent); at 100℃; for 0.05h;Green chemistry;
General procedure: To a mixture of substituted o-phenylenediamines derivative(2.0 mmol) and 1,2-diketone / alpha-hydroxy ketone (2.0 mmol),was added sulfated polyborate (10 wt%). The reaction mixture was stirred at 100 C in an oil bath. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the mixture was cooled to room temperature and quenched by water. The resultant product was filtered/extracted with EtOAc to get the product. Crude products were either recrystallized from ethanol or purified by column chromatography using silica as the stationary phase and EtOAc: pet. ether as mobile phase. The products obtained were known compounds and were identified by melting point and 1H and 13C NMR spectroscopy. The spectral data were compared with the literature values.
33%
In ethanol; at 20℃; for 72.0h;Heating / reflux;
Glyoxal (aq, 8.8 M, 2.6 mL, 22.8 mmol) was added to a mixture of 3-nitro- benzene- 1,2-diamine (1.163 g, 7.59 mmol) in EtOH (16 mL). The mixture was heated at reflux for 2 h and stirred at rt for 3 days. Water (50 mL) was added and the resulting mixture was extracted with CH2Cl2 (3x20 mL). The combined extracts were dried (MgSO4) and concentrated to give an orange-red solid which was recrystallised from water to give the sub-title compound (439 mg, 33%) as pale yellow needles.1H NMR (CDCl3, 400 MHz) delta 9.05 (d, IH), 9.01 (d, IH), 8.38 (dd, IH)5 8.20 (dd, IH), 7.89 (t, IH).
26.22 g
In ethanol; water; for 2.0h;Reflux;
A solution of 3-nitrobenzene-1,2-diamine (25 g) and glyoxal solution (40 wt% in water, 56.0 ml) in ethanol (96%, 400 ml) was kept under reflux conditions for 2 hours. The reaction mixture was concentrated in vacuo and water was added. The mixture was extracted with CH2Cl2 (3 x). The combined organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by gravity column chromatography (EtOAc:heptane, 2:3) to yield 26.22 g product.
26 g
In toluene; for 8.0h;Reflux;
Add 35 g of 3-nitro-o-phenylenediamine to 120 ml of toluene, add 50 g of glyoxal, stir at reflux for 8 hours, concentrate, add ethyl acetate and water, separate, dry, and concentrate. The residue is separated on the column to obtain 26 g. 5-Nitrobenzopyrazine.
With pyridinium p-toluenesulfonate; In toluene; for 1.5h;Heating / reflux;
A 500-mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with compound 3a (4.70 g, 30.6 mmol), toluene (200 mL), triethyl orthoformate (13.6 g, 92.0 mmol) and p-toluenesulfonic acid (386 mg, 1.5 mmol) and the mixture then heated to reflux under nitrogen. After 1.5 h the reaction was cooled to 0 C. and the resulting precipitate filtered, washed with ether (3*50 mL) and dried in the vacuum oven to afford compound 3b as a tan powder.
A stirred solution of 7.53 g (50.0 mmol) of in 100 mL of 98% formic acid was set to reflux under argon for 3 hours. The reaction mixture was cooled and evaporated. The resulting solid residue was stirred with 100 mL of concentrated ammonium hydroxide for 30 min. The solids were collected, washed with 20 mL of water and dried in vacuo at 40C to give title compound as a white solid, 7.76 g, 95%, mp 238-240C.
With formic acid; In water;
EXAMPLE 10 2-[4-[2-(2H-Tetrazol-5-yl)benzamido]-1H-benzimidazol-1-yl]octanoic acid 3-Nitro-1,2-phenylenediamine (0.065 moles, 10.2 g) was added to 200 ml formic acid and heated to reflux for 3 hours. The solution was cooled and then concentrated under vacuum. The residue was dissolved in water. The pH was adjusted to 8.3 using 5N sodium hydroxide. The intermediate was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated to yield 7.0 g of 4-nitrobenzimidazole. (MS) M. Pt.: 248-249 C. Calculated for C7 H5 N3 O2: C, 51.54; H, 3.09; N, 25.76. Found: C, 51.60; H, 3,17; N, 25.57.
EXAMPLE 19 4-Nitrobenzimidazole was prepared from 3-nitro-1,2-phenylendiamine as described in Example 1. Mp 242-245 C.
With phosgene; triethylamine In tetrahydrofuran; toluene at 0 - 20℃;
424. A A.
To a solution of 3-nitro-1,2-benzenediamine (5.36 g, 35 mmol) in 300 mL of dry THF cooled at 0°C was added Et3N (10.95 mL), followed by dropwise addition of phosgene/toluene (1.93 M, 20 mL, 38.5 mmol). After addition, the resulting suspension was stirred at room temperature overnight, then filtered. The collected solid was washed with H2O (4X), dried over P2O5 in vacuo for 2 days to give 3.98 g (63% yield) of title compound as a brown solid.
With triethylamine In bis(trichloromethyl) carbonate
2 a)Preparation of 4-nitro-benzimidazolin-2-one
a)Preparation of 4-nitro-benzimidazolin-2-one To a solution of 3-nitro-phenylenediamine(10 g, 6.53 mmol) in dimethylforamide(20 ml) was added triphosgene(0.775 g, 2.60 mmol)and triethylamine(1 ml, 7.80 mmol). The mixture was then heated to 80° C. for about 1 hour. The solvents were then evaporated and the product was precipitated out of solution with methylene chloride/hexane(1equiv./20equiv.). (700 mg, 64%). 1H NMR (CD3SO2CD3): δ11.61 (s, 1H), 11.35 (s, 1H), 7.85 (d, 1H), 7.34 (d,bH), 7.15 (t, 3H).
With bis(trichloromethyl) carbonate In acetonitrile at 0 - 20℃; for 0.75h;
26.A
Triphosgene (56 g, 188.8 mol) was added portionwise over 15 min to a solution of 3- nitro-l,2-phenylenediamine (25.5 g, 167 mol) in CH3CN (400 mL) at 0 0C and the mixture was allowed to warm to ambient temperature after 30 min. The reaction was concentrated in vacuo, diluted with toluene (100 mL) and the solid precipitate was collected by filtration to give the title compound. MS: tnlz = ISO (M + 1).
With acetic acid; sodium nitrite; at 20 - 60℃; for 2.25h;
Example 1 Synthesis of (4-Hydroxy-piperidin-1-yl)-(4-{4-[4-(4-(4-methylthiophen-3-yl)-benzotriazol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (Compound 1) To a mixture of 3-nitrobenzene-1,2-diamine (15.0 g) in AcOH (100 mL) was added NaNO2 (7.0 g). The reaction mixture was stirred for 15 min at RT, then heated at 60 C. for about 2 h, over which time the reaction mixture turned red. The mixture was cooled to RT, diluted with ice water, and the resulting precipitate filtered off and washed with ice water, then dried under vacuum to yield 4-nitro-1H-benzotriazole (13.45 g, 83.6% yield) as a light brown solid. The product was used without further purification.
With acetic acid; sodium nitrite; at 60℃;
3-Nitro-1, 2-phenylenediamine (10 g), sodium nitrite (5.4 G) and acetic acid (20 mL) were heated at 60C overnight, then concentrated in vacuo, diluted with water and extracted with EtOAc. The product precipitated from the organic phase (5.7 g) as a solid and used directly in step B.
With acetic acid; sodium nitrite; at 60℃;
3-Nitro-l,2-phenylenediamine (10 g), sodium nitrite (5.4 g) and acetic acid (20 mL) were heated at 60 C. overnight, then concentrated in vacuo, diluted with water and extracted with EtOAc. The product precipitated from the organic phase (5.7 g) as a solid and used directly in step B.
With sodium nitrite; In water; acetic acid;
a)Preparation of 4-nitrobenzotriazole To a solution of 3-nitro-phenylenediamine(15.3 g, 100 millimole (hereinafter mmol)) in acetic acid (50 milliliter (hereinafter"ml")) was stirred with sodium nitrite(6.9 g, 100 mmol). The mixture was then heated to 60 C. for 1 hour (hereinafter "hr"). The reaction was then cooled to room temperature and water was added, the desired product precipitated out of solution and the mixture was filtered to give the desired product(10.7 grams (hereinafter"g"), 65%). 1H NMR (CD3SOCD3): delta8.58 (d, 1H), 8.44 (d, 1H), 7.61 (t, 1H).
With acetic acid; sodium nitrite; at 60℃;
PREPARATIVE EXAMPLE 14; Step A; 3-Nitro-1, 2-phenylenediamine (10 g), sodium nitrite (5.4 g) and acetic acid (20 mL) were heated at 60C overnight, then concentrated in vacuo, diluted with water and extracted with EtOAc. The product precipitated from the organic phase (5.7 g) as a solid and used directly in step B.
With acetic acid; sodium nitrite; at 60℃;
3-Nitro-1, 2-phenylenediamine (10 g), sodium nitrite (5.4 g) and acetic acid (20 mL) were heated at 60C overnight, then concentrated in vacuo, diluted with water and extracted with EtOAc. The product precipitated from the organic phase (5.7 g) as a solid and used directly in step B.
Stage #1: di(1H-imidazol-2-yl)methanethione; tert-butyl 4-(aminomethyl)piperidine-1-carboxylate With 1H-imidazole In acetonitrile at 0 - 20℃; for 2.5h;
Stage #2: 2,3-diamino-nitrobenzene In acetonitrile at 50℃; for 12h;
Stage #3: With diisopropyl-carbodiimide In acetonitrile for 3.5h; Heating / reflux;
1.3.1 Reference Example 1-3-1; Synthesis of 4-[(4-nitro-1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester
After dissolving 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (2 g) in acetonitrile (100 ml), thiocarbonyldiimidazole (2 g) and imidazole (0.2 g) were added at 0°C. The mixture was stirred at room temperature for 2 hours and 30 minutes, 3-nitro-1,2-phenylenediamine (2.1 g) was added, the temperature was raised to 50°C, and the mixture was stirred for 12 hours. Diisopropylcarbodiimide (2.4 g) was added, the mixture was refluxed for 3 hours and 30 minutes, and then the solvent was removed under reduced pressure and the obtained residue was purified by silica gel chromatography (dichloromethane/hexane = 7/3 → 1/0) to obtain 4-[(4-nitro-1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester. The compound was identified by LC-MS. Yield: 3.5 g (100%), Purity: 95%, Found: ESI/MS m/e 376.4(M+1).
With triethylamine In N,N-dimethyl-formamide at 75℃; for 1h;
Q4 Q4. Preparation of 4-nitro-1H-benzo[d]imidazole-2(3H)-one
In a 1L flask, dissolve 153g of 3-nitro-o-phenylenediamine in 500ml of N,N-dimethylformamide, then slowly add 118.6g of triphosgene and 70ml of triethylamine to the solution,The mixture was heated to 75°C and reacted for 1 hour. After the reaction, the residual solvent was evaporated.Then column chromatography (dichloromethane: n-hexane=1:20),145.2 g of 4-nitro-1H-benzo[d]imidazole-2(3H)-one was obtained with a yield of 81.1%.
In acetonitrile at 0 - 20℃; for 0.5h;
A
Triphosgene (56 g, 188.8 mol) was added portionwise over 15 min to a solution of 3-nitro-l,2-phenylenediamine (25.5 g, 167 mol) in CH3CN (400 mL) at 0 °C and the mixture was allowed to warm to ambient temperature after 30 min. The reaction was concentrated in vacuo, diluted with toluene (100 mL) and the solid precipitate was collected by filtration to give the title compound. MS: mlz = 180 (M + 1).
In acetonitrile at 0℃; for 0.75h;
31.A
Triphosgene (56 g, 188.8 mol) was added portionwise over 15 min to a solution of 3- nitro-l,2-phenylenediamine (25.5 g, 167 mol) in CH3CN (400 mL) at 0 0C and the mixture was allowed to warm to ambient temperature after 30 min. The reaction was concentrated in vacuo, diluted with toluene (100 mL) and the solid precipitate was collected by filtration to give the title compound. MS: m/z = 180 (M + 1).
In acetonitrile at 0 - 20℃; for 0.75h;
9.A
Triphosgene (56 g, 188.8 mol) was added portionwise over 15 min to a solution of 3- nitro-l,2-phenylenediamine (25.5 g, 167 mol) in CΗ3CN (400 mL) at 0 0C and the mixture was allowed to warm to ambient temperature after 30 min. The reaction was concentrated in vacuo, diluted with toluene (100 mL) and the solid precipitate was collected by filtration to give the title compound. MS: w/-r = 180 (M + l).
In acetonitrile at 0 - 20℃;
9.A
Step A. 4-Nitro- 1.3 -dihvdro-2//-benzimidazol-2-oneTriphosgene (56 g, 188.8 mol) was added portionwise over 15 min to a solution of 3-nitro-l,2-phenylenediamine (25.5 g, 167 mol) in CH3CN (400 mL) at 0 °C and the mixture was allowed to warm to ambient temperature after 30 min. The reaction was concentrated in vacuo, diluted with toluene (100 mL) and the solid precipitate was collected by filtration to give the title compound. MS: mlz - 180 (M + 1).
1.53 g (10 mmol) of 2,3-diaminonitrobenzene and 3.68 g (10 mmol) of 4,4'-dibromobenzyl were dissolved in 80 g of a mixed solvent of acetic acid and methanol (1:1) and reacted at a reaction temperature of 70C for 30 hours. After completion of the reaction, the solvent was removed and a reaction product was extracted by means of a silica gel column. Yield: 1.89 g Yellow fine crystals m/z: 485 (calculated: 485.12) 13C-NMR: 153.4453, 153.3613, 147.0065, 140.7945, 136.8116, 136.3766, 133.7824, 133.2635, 132.0504, 131.8749, 131.8215, 131.3789, 128.5787, 124.9849, 124.8780, 124.7102 ppm
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 96h;
To a solution of 9 g of 4-(terf-butoxycarbonyl-methyl-amino)-butyric acid (prepared from 4- (methylamino)butyric acid and BOC anhydride) in 159 mL DCM were added 14.2 mL of DIPEA, 8 g of HOBt and 9.1 g of EDC. After stirring for 5 min 6.1 g of 3-nitro-benzene-1 ,2-diamine were added and the mixture was stirred for 4 days at rt. Saturated aq. NaHCO3 solution was added, the phases were separated and the organic phase washed with brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. Purification by CC using EtOAc/heptane 1/4 to 3/1 yielded 5.2 g of [3-(2-Amino-3-nitro-phenylcarbamoyl)-propyl]-methyl-carbamic acid tert-butyl ester as orange foam.LC-MS: tR = 0.94 min; [M+H]+: 352.48.
2-(4-Iodo-2-methoxy-pyridin-3-yl)-7-nitro-lH-benzoimidazole3-Nitro-benzene-l,2-diamine (0.153 g, 1.0 mmol), 4-Iodo-2-methoxy-pyridine-3- carbaldehyde (0,263 g, 1.0 mmol) and sulfur (0.032 g, 1.0 mmol) were heated at160 for 60 min. The resulting slurry was purred on ice water (100 ml). Precipitates were collected by filtration and dried in vacuum to yield the desired product (0.40 g, quant.) which was used without any further purification.
2.i; 1
To 3-nitro- l ,2-phenylenediamine 3a (2g, 13.06mmol) dissolved in THF (50 ml) was added in one portion DCI (1.5equiv., 19.6mmol, 3.176g) and the reaction was refluxed for 2 hours. (TLC AcOEt 1 / petroleum ether 1). The reaction was filtrated and the yellow solid material was washed with THF and diethyl ether obtaining 2g of the product that was used for the following step without further purification. Yield = 88% *HNMR (DMSO, 200 MHz) δ 7.1 1 (1H, t, J = 7.6 Hz), 7.31 (1H, dd, J = 7.8 Hz, J' = 1.2 Hz), 7.74 (1H, dd, J = 8.6 Hz, J' = 1 Hz), 1 1.45 (2H, bs)
88%
In tetrahydrofuran for 2h; Reflux;
1
Example 1: 1-(4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea (scheme 1) Preparation of 4-nitro-1H-benzo[d]imidazol-2(3H)-one 4a (scheme 2) To 3-nitro-1,2-phenylenediamine 3a (2g, 13.06mmol) dissolved in THF (50 ml) was added in one portion DCI (1.5equiv., 19.6mmol, 3.176g) and the reaction was refluxed for 2 hours. (TLC AcOEt 1 / petroleum ether 1). The reaction was filtrated and the yellow solid material was washed with THF and diethyl ether obtaining 2g of the product that was used for the following step without further purification. Yield = 88% 1HNMR (DMSO, 200 MHz) δ 7.11 (1H, t, J = 7.6 Hz), 7.31 (1H, dd, J = 7.8 Hz, J' = 1.2 Hz), 7.74 (1H, dd, J = 8.6 Hz, J' = 1 Hz), 11.45 (2H, bs)
In tetrahydrofuran at 20℃; for 2h;
10
The title compound was prepared by the general method described in J. Med. Chem. 2006, 49(12), 3719-3742: 1,1'-carbonyldiimidazole (0.574 g, 3.75 mmol) was added to a solution of 3-nitro-1,2-phenylenediamine (0.729 g, 4.50 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 2 hours, then was concentrated. The residue was stirred in water and the yellow solid precipitate was collected by vacuum filtration, washed with water, and dried to afford the title compound.
In tetrahydrofuran at 0 - 20℃;
A.A; 1.A; 1
Example 1 /V-[2-({1 -[3-(Trifluoromethyl)phenvnethyl)a The title compound is prepared in five steps as described in Procedure A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)acetamide (MS(ES+) m/z 210 ([M+1 ]+, 100)) and commercially 10 available 1 -[3-(trifluoromethyl)phenyl]ethanamine) by column chromatography as the parent compound. HR-MS: 363.1447 ([M+1 ]+, Ci8Hi8N4OF3; calc. 363.14327). Subsequently, the two enantiomers of the title compound can be isolated by separation of the above racemate by preparative chiral chromatography. Enantiomer A: HR-MS: 363.14383 ([M+1 ]+, Ci8Hi8N4OF3; calc. 15 363.142725. Enantiomer B: HR-MS: 363.14382 ([M+1 ]+, Ci8Hi8N4OF3; calc. 363.142725. Procedure A Step A: Commercially available 3-nitrobenzene-1 ,2-diamine is dissolved in THF, cooled to 0°C, W,/V-carbonyldiimidazole (3 eq) is added, and the mixture stirred at rt until complete conversion of the starting material. The reaction mixture is concentrated to dryness and the residue is diluted with ice-cold water. The yellow precipitate is isolated by filtration, washed with EtOAc and dried under vacuum to give crude 4-nitro-1 ,3-dihydrobenzimidazol-2-one for use in Step B.
Multi-step reaction with 3 steps
1: methanol / 48 h / 80 °C
2: acetic acid / 3 h / 80 °C
3: ammonium chloride; iron / water; tetrahydrofuran; methanol / 1 h / 60 °C
With acetic acid; In water; at 50℃; for 0.5h;Green chemistry;
General procedure: The 4-nitro-1,2-phenylenediamine (50.0mg, 0.30mmol), p-chlorobenzaldehyde (45.9mg, 0.30mmol), and SPB (55.3mg, 0.33 mmol) were added to a solution of H2O/ HOAc=1:2 (v/v, 3mL) at 50C for 0.5h (Table 3). The progress of the reaction was monitored by TLC (eluent: 2/1, v/v, n-hexane/ethyl acetate). After completion of the reaction, the solution was poured into a beaker containing 20mL of water. Many solid precipitated. It was filtered, washed with water (10mL×2), and then purified by quick column chromatography (eluent: 4/1, v/v, n-hexane/ethyl acetate). Yellow solid; yield: 83.1mg, 93%; mp 304.7-304.9C. 1H NMR (400MHz, DMSO-d6) delta 7.67 (d, J=8.0Hz, 2H), 7.75 (d, J=8.8Hz, 2H), 8.12 (d, J=8.8Hz, 1H), 8.20 (d, J=8.0Hz, 1H), 8.45 (s, 1H); HRMS (ESI): calcdfor C13H9ClN3O2 [M+H]+ 274.0383, found 274.0378.
With K10-montmorillonite clay In acetonitrile at 50℃; for 3h;
2-(3-bromophenyl)-5-nitroquinoxaline
General procedure: Substituted 1,2-phenylenediamines (1 mmol) and substituted phenacyl bromides (1 mmol) were dissolved in acetonitrile (5 ml). To this solution, K10-Mont. clay (50 mg) was added and heated at 50 °C for 3 h. After completion, the reaction mixture was filtered to remove the catalyst and washed with ethyl acetate (10 mL). The filtrate was concentrated and the residue was purified by column chromatography using hexane:ethyl acetate (15 % ethyl acetate in hexane) as an eluent to afford quinoxaline derivatives in high yields. The recovered catalyst was thoroughly washed with ethyl acetate, air dried, activated at 80 °C for 3 h and reused for successive runs. The purified products are characterized by their 1H, 13C NMR as well as by mass spectral data
With hydrogenchloride; hydrogen iodide In water at 20℃; for 3h;
3 3-Nitro-1,2-phenylenediamine (9)
To a suspension of 8 (18 g, 79 mmol) in concd hydrochloric acid (225 mL), 70 mL of aqueous hydroiodic acid (57% w/v, 70 mL) was added dropwise at room temperature with vigorous stirring. The reaction mixture was stirred further at room temperature for 3 h. A 5% aqueous sodium hydrogen sulfide solution (400 mL) was added to the dark-red reaction mixture. This was then warmed to 80 °C and filtered hot and afterwards cooled to 4 °C. The needle like salt of the diamine crystallized out. The product was neutralized with 30% NaOH to pH 8 and extracted with ethyl acetate (6 * 100 mL). The ethyl acetate layer was collected, dried over Na2SO4, filtered off and evaporated to yield 6.5 g (42.44 mmol, 54%) of the title compound 9 as a red solid: 1H NMR (300 MHz, CD3OD) δ 6.47-6.56 (dd, 1H, J = 7.5 Hz and 8.7 Hz, Ar), 6.87-6.92 (dd, 1H, J = 1.2 Hz and 7.5 Hz, Ar), 7.48-7.53 (dd, 1H, J = 1.2 Hz and 8.7 Hz, Ar). 13C NMR (75 MHz, CD3OD) δ 116.4, 117.0, 120.6 (quaternary carbon not detected). HRMS for C6H7N3O2Na ([M+Na]+) calcd: 176.0431 found 176.1058.
With palladium on activated charcoal; hydrogen; In methanol; for 1.5h;
Step 1 Benzene-1,2,3-triamine A solution of 3-nitrobenzene-1,2-diamine at 0.05 mol/1 in methanol was passed through an H-Cube reactor on a cartridge of palladium on carbon with a flow rate of 1 ml/min. After one and a half hours, the product was completely hydrogenated. The solvent was concentrated. 450.7 g of benzene-1,2,3-triamine were obtained in the form of a green oil. Yield>100percent.
N-mesityl-7-nitro-1H-benzimidazole-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
Stage #1: 2,4,6-trimethylphenyl isothiocyanate; 2,3-diamino-nitrobenzene With sodium carbonate In ethanol for 12h; Reflux;
Stage #2: With diisopropyl-carbodiimide In ethanol for 48h; Reflux;
With 10 wtpercent sulfated polyborate; air In neat (no solvent) at 100℃; for 0.5h; Green chemistry;
2.3 General procedure for the synthesis of quinoxaline derivatives
General procedure: To a mixture of substituted o-phenylenediamines derivative(2.0 mmol) and 1,2-diketone / α-hydroxy ketone (2.0 mmol),was added sulfated polyborate (10 wt%). The reaction mixture was stirred at 100 °C in an oil bath. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the mixture was cooled to room temperature and quenched by water. The resultant product was filtered/extracted with EtOAc to get the product. Crude products were either recrystallized from ethanol or purified by column chromatography using silica as the stationary phase and EtOAc: pet. ether as mobile phase. The products obtained were known compounds and were identified by melting point and 1H and 13C NMR spectroscopy. The spectral data were compared with the literature values.
4-nitro-2-trichloromethyl-1H-benzoimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With trifluoroacetic acid; In diethyl ether; dichloromethane; at 20℃; for 1h;
3-Nitro-o-phenylenediamine (500 mg, 3.27 mmol) Dissolved in ether (12 mL) And DCM (8 mL) Was added methyl trichloroacetimidate (720 mg, 4.08 mmol) After mixing, Trifluoroacetic acid (1.79 g, 15.67 mmol) was added, Room temperature reaction lh, the basic disappearance of raw materials. The solvent was evaporated, EpsilonAlpha (20 mL) was added, washed with water (20 mL X), column chromatography (P / E = 20: 1) A yellowish powdery solid 834 mg, yield 91%
N-isopropyl-7-nitro-1H-benzo[d]imidazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With diisopropyl-carbodiimide In pyridine at 80℃; for 16h;
4.1.2.1 Procedure A
General procedure: A mixture of the corresponding substituted-phenylenediamine (limiting reagent), isothiocyanate (1.2 equiv.) and dialkylcarbodiimide (1.2 equiv.) was stirred in pyridine or acetonitrile (3mL) at 80°C for 16h. After, the reaction mixture was evaporated to remove volatiles. The residue was either purified by flash column chromatography on silica gel (CH2Cl2/CH3OH : 95/5) or filtrated and washed with a 1/1 mixture of Et2O and acetonitrile (3×10 mL).
With diisopropyl-carbodiimide In pyridine at 80℃; for 16h;
4.1.2.1 Procedure A
General procedure: A mixture of the corresponding substituted-phenylenediamine (limiting reagent), isothiocyanate (1.2 equiv.) and dialkylcarbodiimide (1.2 equiv.) was stirred in pyridine or acetonitrile (3mL) at 80°C for 16h. After, the reaction mixture was evaporated to remove volatiles. The residue was either purified by flash column chromatography on silica gel (CH2Cl2/CH3OH : 95/5) or filtrated and washed with a 1/1 mixture of Et2O and acetonitrile (3×10 mL).
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