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Structure of 54-96-6 * Storage: {[proInfo.prStorage]}
* 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 the American Chemical Society, 2004, vol. 126, # 31, p. 9532 - 9533
[2] Journal of Natural Products, 2013, vol. 76, # 9, p. 1637 - 1646
[3] Journal of the Chemical Society, 1956, p. 4683
[4] Synlett, 2001, # 1, p. 73 - 74
[5] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 18, p. 5023 - 5026
3
[ 54-96-6 ]
[ 122-51-0 ]
[ 272-97-9 ]
Reference:
[1] ChemMedChem, 2013, vol. 8, # 6, p. 985 - 993
[2] European Journal of Medicinal Chemistry, 2018, vol. 148, p. 384 - 396
4
[ 54-96-6 ]
[ 89792-18-7 ]
[ 272-97-9 ]
Reference:
[1] Patent: EP404797, 1995, B1,
5
[ 54-96-6 ]
[ 68-12-2 ]
[ 272-97-9 ]
Reference:
[1] New Journal of Chemistry, 2016, vol. 40, # 10, p. 8282 - 8287
6
[ 54-96-6 ]
[ 50-00-0 ]
[ 272-97-9 ]
Reference:
[1] Chemische Berichte, 1938, vol. 71, p. 2347,2358
7
[ 54-96-6 ]
[ 2770-01-6 ]
Reference:
[1] ChemMedChem, 2013, vol. 8, # 6, p. 985 - 993
[2] European Journal of Medicinal Chemistry, 2018, vol. 148, p. 384 - 396
8
[ 54-96-6 ]
[ 3243-24-1 ]
Reference:
[1] Journal of the American Chemical Society, 2004, vol. 126, # 31, p. 9532 - 9533
9
[ 1681-37-4 ]
[ 54-96-6 ]
Yield
Reaction Conditions
Operation in experiment
97%
With palladium 10% on activated carbon; hydrogen In tetrahydrofuran at 10℃; for 24 h;
The commercially available 3-nitropyridin-4-amine (50 g, 395 mmol) in the mixture of methanol (500 ml) and THF (500 ml) was hydrogenated with 10 percent Pd/C (5 g) as a catalyst at 10°C (1 atm) for 24 h. After uptake of (3 eq), the catalyst was filtered off and the filtrate was evaporated. 38 g of the title intermediate 8 was obtained, (Yield 97 percent).
Reference:
[1] Journal of Heterocyclic Chemistry, 1999, vol. 36, # 5, p. 1143 - 1145
[2] Patent: WO2014/114776, 2014, A1, . Location in patent: Page/Page column 25
[3] Chemistry of Materials, 2016, vol. 28, # 7, p. 2058 - 2066
[4] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
[5] Chemische Berichte, 1926, vol. 59, p. 1210
[6] Justus Liebigs Annalen der Chemie, 1935, vol. 518, p. 274,287
[7] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 18, p. 5023 - 5026
[8] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6289 - 6304
[9] Patent: WO2017/168333, 2017, A1, . Location in patent: Page/Page column 16
10
[ 33544-42-2 ]
[ 54-96-6 ]
Reference:
[1] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
11
[ 100306-70-5 ]
[ 54-96-6 ]
Reference:
[1] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
12
[ 626-64-2 ]
[ 54-96-6 ]
Reference:
[1] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
[2] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
[3] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
13
[ 94602-04-7 ]
[ 54-96-6 ]
Reference:
[1] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
[2] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
[3] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
14
[ 5435-54-1 ]
[ 54-96-6 ]
Reference:
[1] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
[2] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
[3] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
15
[ 5221-42-1 ]
[ 54-96-6 ]
Reference:
[1] Journal of Heterocyclic Chemistry, 1999, vol. 36, # 5, p. 1143 - 1145
16
[ 79371-42-9 ]
[ 54-96-6 ]
Reference:
[1] Journal of Heterocyclic Chemistry, 1999, vol. 36, # 5, p. 1143 - 1145
17
[ 504-24-5 ]
[ 54-96-6 ]
Reference:
[1] Patent: WO2017/168333, 2017, A1,
18
[ 54-96-6 ]
[ 273-05-2 ]
Yield
Reaction Conditions
Operation in experiment
89%
With hydrogenchloride; sodium nitrite In water at 0℃; for 1 h;
3,4-diaminopyridine (2.0 g, 0.048 mol) was dissolved in a 2N hydrogen chloride aqueous solution (25 mL), cooled to 0 ° C, Sodium nitrite (1.9 g, 0.027 mol) was dissolved in distilled water (3 mL) and added slowly, And stirred for 1 hour. The resulting solid was filtered and washed with distilled water to give the title compound im-7-a (1.96 g, 89percent) as a yellow solid.
Reference:
[1] Bulletin of the Chemical Society of Japan, 1987, vol. 60, p. 1793 - 1800
[2] Phosphorus and Sulfur and the Related Elements, 1988, vol. 38, p. 137 - 148
0613] To the mixture of X-1 (10.0 g, 10 mmol) dissolved in HBr 48percent (200 mL), Br2 (12.5 mL, 13.4 mmol) was added dropwise under ice-water cooling bath, maintaining the temperature below 40° C. After that, the mixture was heated at 110° C. for 5 hrs. The reaction mixture was cooled to rt, filtered and washed with little water. The filter cake is basified to pH 78 with saturated aq. NaHCO3 and extracted with EtOAc (200 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to yield X-2 (17.2 g, 71percent yield). 1H NMR (DMSO-d6, 400 MHz) δ 7.95 (s, 1H), 5.20 (brs, 4H).
71%
With hydrogen bromide; bromine In water at 40 - 110℃; for 5 h; Cooling with ice
To the mixture of X-1 (10.0 g, 10 mmol) dissolved in HBr 48percent (200 mL), Br2 (12.5 mL, 13.4 mmol) was added dropwise under ice-water cooling bath, maintaining the temperature below 40°C. After that, the mixture was heated at 110°C for 5 hrs. The reaction mixture was cooled to rt, filtered and washed with little water. The filter cake is basified to pH 7--8 with saturated aq. NaHCO3 and extracted with EtOAc (200 mLx3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to yield X-2 (17.2 g, 71percent yield). ‘H NMR (DMSO-d6, 400 MHz) 5 7.95 (s, 1H), 5.20 (brs, 4H).
50%
With hydrogen bromide; bromine In water at 100 - 135℃; for 5 h;
The synthesis of 3,4-diamino-2,5-dibromopyridine was improved on the basis of the method reported in a literature [18]. The mixture of pyrido-3,4-diamine(2 g, 18.3 m mol) with an aqueous HBr (48percent, 30 ml) were prepared in a 250 ml three-neck round bottom flask with a magneton inside. After the mixture was heated to 100 deg.C, bromine(2.5 ml) was added dropwise, and the solution was stirred for 5 h at 135 deg.C. After the mixture was cooled to room temperature, an aqueous solution of Na2S2O3, an aqueous solution of Na2CO3, and distilled water were added in this order to get a yellow precipitate. Then the precipitate was separated by filtration and washed with distilled water three times. Recrystallization from the mixture solution of toluene: THF (v:v = 5:1) gave white flocculence solid, yielded: 50percent. 1H NMR (DMSO, 400 MHz, ppm): d=7.53 (s, 1H), 5.99 (s, 2H), 5.03 (s, 2H). 13C NMR (DMSO,101 MHz, ppm): d = 139.93, 139.13, 129.54, 126.67, 106.22 (seeFig. S1 in Supporting Informations)
30%
Stage #1: Reflux Stage #2: at 80℃; for 16 h;
The mixture of 3,4-diaminopyridine (5.45 g, 50 mmol) with 48percent hydrobromic acid (24 mL) in a 50 mL flask was heated to reflux while stirring. After adding bromine (8 mL, 155.7 mmol) dropwise, the reaction mixture was heated for 16 h at 80 °C then cooled down to the room temperature. The mixture was filtered and washed with a saturated solution of Na2S2O3 (150 mL), NaHCO3 (150 mL) and finally water (150 mL). The residue was first purified by flash chromatography using PE (petroleum ether)/EA (ethyl acetate)=1:2 (v/v) as eluent and recrystallized in ethanol to give 4 g orange solid. (Yield: 30percent). 1H NMR (400 MHz, DMSO-d6, ppm): δ=7.53 (s, 1H), 5.99 (s, 2H), 5.05 (s, 2H); 13C NMR (100 MHz, DMSO-d6, ppm): δ=140.66, 140.45, 129.81, 128.30, 106.24.; HRMS (ESI, m/z): [M+H]+ calcd for (C5H5N3Br2), 264.8850; found, 264.8844.
25.5%
for 5 h; Reflux
In a three-neck 100 mL round-bottom flask, was added 3,4-diaminopyridine (1) (5.0 g, 45.2 mmol) with 9.3 mL of 48 percent hydrobromic acid. The resulting mixture was heated to reflux while stirring and bromine (7.6 mL, 148.5 mmol) was added dropwise. The reaction mixture was refluxed for 5 h and cooled to ambient temperature. The mixture was filtered and washed with a saturated solution of Na2S2O3 (100 mL),Na2CO3 (100 mL) and finally water (100 mL). To complete the neutralization process, the crude product was refluxed 30 min in a 10 percent solution of Na2CO3. The mixture was then filtered and washed with water. The brown-dark product wasfirst purified by column chromatography ethyl acetate/hexane(3:2) and by recrystallization from methanol to give compound 2 as an orange powder (3.1 g, 25.5 percent). 1HNMR(Acetone-d6, 300 MHz, δ/ppm): 7.65 (s, 1H), 5.54 (br, 2H),4.66 (br, 2H). 13C NMR (100 MHz, Acetone-d6, δ/ppm):140.66, 140.45, 129.81, 128.30, 106.24. EI-MS m/z: [M +H]+ Cacld for C5H5Br2N3: 264.88, Found: 264.70.
Reference:
[1] Patent: US2014/94456, 2014, A1, . Location in patent: Paragraph 0612-0613; 0635-0636
[2] Patent: WO2015/153683, 2015, A1, . Location in patent: Paragraph 0360
[3] Chemistry of Materials, 2016, vol. 28, # 7, p. 2058 - 2066
[4] Journal of Polymer Science, Part A: Polymer Chemistry, 2016, vol. 54, # 12, p. 1822 - 1833
[5] RSC Advances, 2014, vol. 4, # 106, p. 61537 - 61547
[6] Electrochimica Acta, 2014, vol. 146, p. 231 - 241
[7] Tetrahedron, 2012, vol. 68, # 6, p. 1695 - 1703
[8] Angewandte Chemie - International Edition, 2010, vol. 49, # 43, p. 7992 - 7995
[9] Journal of Materials Chemistry, 2011, vol. 21, # 35, p. 13247 - 13255
[10] Tetrahedron, 2014, vol. 70, # 25, p. 3901 - 3908
[11] Journal of the American Chemical Society, 2008, vol. 130, # 2, p. 732 - 742
[12] Journal of Fluorescence, 2016, vol. 26, # 3, p. 1045 - 1052
[13] Chemical Communications, 2017, vol. 53, # 76, p. 10576 - 10579
24
[ 54-96-6 ]
[ 1007128-70-2 ]
Reference:
[1] Patent: WO2015/153683, 2015, A1,
25
[ 54-96-6 ]
[ 333432-27-2 ]
Reference:
[1] Journal of Materials Chemistry, 2011, vol. 21, # 35, p. 13247 - 13255
[2] RSC Advances, 2014, vol. 4, # 106, p. 61537 - 61547
With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; at 10℃; under 760.051 Torr; for 24h;
The commercially available <strong>[1681-37-4]3-nitropyridin-4-amine</strong> (50 g, 395 mmol) in the mixture of methanol (500 ml) and THF (500 ml) was hydrogenated with 10 % Pd/C (5 g) as a catalyst at 10C (1 atm) for 24 h. After uptake of (3 eq), the catalyst was filtered off and the filtrate was evaporated. 38 g of the title intermediate 8 was obtained, (Yield 97 %).
With sodium sulfide; In methanol; water; at 0 - 65℃;
Methanol (66.7ml) and Water (70.0ml) was charged in to reaction flask containing 4-amino-3- nitro pyridine (46.0g,0.33mol. The reaction mixture was heated to 60-65C under stirring. Sodium sulfide solution (Na2S103.04gm in 114mlD.M. water) was slowly added in to reaction mass at 50-55C for 30 min. Cooled the reaction mass to 0-5C and then stirred the reaction mass for 1 -2 hours. Filtered the material and washed with water (46 ml). Suck dry the material to yield the tilted compound. (0132) Yield: 31.0gm (Wet) (0133) Chromatographic Purity (By HPLC): 94.73%
54 EXAMPLE 54-preparation of [5- [ (4-BROMOPHENYL) METHYL]-2- (2-FLUOROPHENYL)-5H-] imidazo [4,5-c] pyridine (GPJN-52)
A mixture of 3,4-diaminopyridine (1.00 g), 2-fluorobenzoic acid [(1] equivalent) and polyphosphoric acid (25 g) was heated at [190°C] for 3 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was made alkaline by addition of 2N [NAOH] and the resulting precipitate was collected by filtration and dried. The crude product was recrystallized from a mixture of water (100 mL) and ethanol (20 mL) to give 87% of 2- (2-fluorophenyl)-1 (3) H-imidazo [4,5-c] pyridine as an off-white powder. [2- (2-FLUOROPHENYL)-1 (3) H-IMIDAZO] [4,5-c] pyridine (0.355 g) was dissolved in dry DMF (7 [ML)] and the resulting solution was cooled to [0°C.] Aqueous 33% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 4-bromobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (80 mL) was added, the precipitate was collected by filtration and dried to give the crude product.
With PPA; Polyphosphoric acid (PPA) at 200℃; for 3.5h;
Stage #1: 3,4-diaminopyridine; o-fluoro-benzoic acid With methanesulfonic acid at 35 - 50℃;
Stage #2: With phosphorus pentoxide at 90 - 110℃; for 3h;
Stage #3: With ammonia In water at 20℃; for 6h;
1b
Methanesulfonic acid was added to 2-fluorobenzoic acid in a reactor with active cooling keeping T50° C. 3,4-Diaminopyridine was then added portionwise to this cooled slurry, keeping T35° C. The contents of the reactor were then heated to 50° C. Phosphorus pentoxide was added in a single charge. The reaction was then heated at 90-110° C. for at least 3 hours. The reaction was sampled for completion by HPLC analysis. The reaction was cooled to ambient temperature and water was added portionwise slowly to quench the reaction. The reaction was then diluted with water. In solubles were removed by filtration. The pH of the filtrate was adjusted to 5.5-5.8 with ammonium hydroxide. The reaction was allowed to self-seed and granulate for 4 hours at ambient temperature. The pH was then adjusted to 8.0-9.3 with ammonium hydroxide. The slurry was held at ambient temperature for at least 2 hours. The solids were isolated by filtration and washed with water, followed by IPE. The wet cake was dried in vacuo at not more than 60° C. until 1% water remains. The dry product is core (2).
Stage #1: 3,4-diaminopyridine; o-fluoro-benzoic acid With methanesulfonic acid; phosphorus pentoxide at 20 - 100℃;
Stage #2: With ammonia In water at 22 - 30℃; for 1h;
Stage #3: With ammonia In water at 22℃; for 2h;
1.3
To a reactor was charged methanesulfonic acid, followed by phosphorus pentoxide (1.00 eq) in portions while maintaining the content at 23° C. 3,4-Diaminopyridine (1.00 eq) was charged in portions while maintaining the content at 20 to a maximum of 50° C. 2-Fluorobenzoic acid (1.09 eq) was then charged. The mixture was heated to 100° C. and the reaction was monitored by HPLC until completion.The content was adjusted to 10° C. and water was charged while maintaining the content at a maximum of 25° C. After agitating the mixture at this temperature for 1 h, it was filtered into a second reactor.To the filtrate in the second reactor was charged 27% ammonium hydroxide until the pH was in between 6.0-6.5. The content temperature was kept at a maximum of 30° C. The resultant thin slurry was agitated at 22° C. for a minimum of 1 h and 27% ammonium hydroxide was further charged, until the pH was between 8.0-9.3. The slurry was further agitated at 22° C. for a minimum of 2 h.The product was filtered, washed with water twice, and dried at a maximum of 60° C. under vacuum, until the water content is not more than 1%. If necessary, the product is milled to remove large lumps. w/w Mole v/w Materials M.W. Ratio Ratio Ratio Ammonium hydroxide, 27% 35.05 - - - 3,4-Diaminopyridine 109.13 1.00 1.00 - Drinking water 18.02 24.00 - 24.00 2-Fluorobenzoic acid 140.11 1.40 1.09 - Methanesulfonic acid 96.10 7.00 - 4.70 Phosphorous pentoxide 141.94 1.30 1.00 -
With zirconium oxide salicylaldehyde-(3-aminopropyl)trimethoxysilane imine complex modified SBA-15 In water for 3h; Reflux;
97%
With Cu(II)-Schiff base/SBA-15 In water for 2h; Reflux;
General procedure for the synthesis of pyrido[2,3-b]pyrazines, pyrido[3,4-b]pyrazines and 2,3-disubstituted quinoxalines in water
General procedure: A round-bottomed flask equipped with a magnet and condenser was charged with desired 1,2-diamine (1.0 mmol), 1,2-diketone (1.0 mmol), water (2 mL) and catalyst Cu/SBA-15 (0.01 g (0.0014 mmol)). The resulting mixture was stirred at reflux temperature for the appropriate times, and the course of the reaction was monitored using TLC on silica gel. For separation of the catalyst, the reaction mixture (at the end of reaction) was filtered and the precipitates on the filter were dissolved in ethanol or ethyl acetate. These solvents can dissolve the products (and also organic starting materials), but the catalyst was remained insoluble. After filtration of the later solution, the catalyst was recovered
96%
With SBA-15 mesoporous silica supported Fe(III)-Schiff base In water for 2h; Reflux;
94%
In ethanol at 70℃; for 6h;
94%
In ethanol at 70℃; for 6h;
13
5.51 g (0.026 mmol) of benzil were added to a suspension of 2.86 g (0.026 mol) of 3,4-diaminopyridine in 50 ml of ethanol and the reaction mixture was heated at an oil bath temperature of 70° C. for 6 hours. After cooling to room temperature, the precipitated yellow solid was filtered off (cooling by means of an ice water bath may be useful). Recrystallization from ethanol gave 6.91 g (0.024 mol, 94%) of a pale yellow solid. 1H NMR: (400 MHz, CDCl3): δ=7.32-7.42 (m, 6H, 3,4,5-phenyl-H), 7.54-7.51 (m, 4H, 2,6-phenyl-H), 7.98 (dd, 3J=6 Hz, 4J=0.8 Hz, 1H, 7-H), 8.82 (d, 3J=6 Hz, 1H, 8-H), 9.59 (d, 4J=0.8 Hz, 1H, 5-H) ppm. 13C NMR (100 MHz, CDCl3): δ=121.3 (C-7), 128.4, 129.4-129.9 (phenyl-C), 136.3 (Cq, C-4a), 143.5 (Cq, C-8a), 147.3 (C-8), 154.5 (C-5), 155.3, 157.9 (Cq, phenyl-C) ppm. GC-MS (EI): RT 12.34 min, m/e (%) 285 (3), 284 (M++H, 22), 283 (M+, 100), 282 (46), 206 (2), 181 (3), 180 (25), 179 (17), 154 (3), 153 (5), 152 (3) 142 (1), 141 (8), 140 (4), 127 (2), 104 (3), 103 (14), 102 (3), 78 (2), 77 (5), 76 (4), 51 (2), 50 (9); IR (neat): ν=3061 (w), 1589 (m), 1577 (w), 1538 (w), 1492 (w), 1443 (m), 1419 (w), 1379 (s), 1346 (w), 1326 (m), 1315 (m), 1288 (w), 1211 (m), 1244 (w), 1227 (m), 1212 (w), 1180 (w), 1075 (m), 1058 (m), 1020 (m), 1001 (w), 976 (s), 921 (w), 892 (m), 892 (m), 830 (m), 819 (w), 811 (m), 763 (s), 735 (m), 708 (vs), 629 (s), 615 (m) cm-1.
91%
With ziconium(IV) oxychloride octahydrate In water at 100℃; for 2.5h; Green chemistry;
7 4.2. General procedure for the synthesis of compounds 3a-3p
For the synthesis of entitled heterocycles, a roundbottom flask equipped with a stir bar was chargedwith 1,2-phenylenediamine (1.0 mmol), 1,2-diketones(1.0 mmol), water (2 mL) and zirconium(IV) oxide chloride(25 mol%). The resulting mixture was heated in an oil bathat 100 8C for the appropriate time, and the course of the reaction was monitored using TLC on silica gel. Finally, thereaction mixture was cooled and the crude mixture waspurified by column chromatography or crystallization togive the desired product. The authenticity of the productswas established by comparing their melting points withdata of the literature and by analyzing the spectroscopicdata of 1H and 13C NMR and IR [9-16,26,27].
87%
With 1-methyl-3-(3-trimethoxysilylpropyl)imidazolium hydrogen sulfate immobilized on cellulose In water at 20℃; for 0.0166667h; Green chemistry;
General procedure for the preparation of pyrazine,benzoxazine and quinoxaline derivatives
General procedure: A vial containing a solution of 1,2-diketone (1 mmol) ando-diamine (1 mmol) and Cell-[pmim]HSO4 (300 mg) in water (3 mL) was stirred at room temperature for the time as shown in Table 2. The progress of the reaction was monitored by TLC. After completion of the reaction, ethyl acetate was added to the reaction mixture and the insoluble catalyst was separated by filtration. The organic medium was removed with a rotary evaporator under reduced pressure.The crude product was purified by recrystallization from EtOH/H2O or by flash chromatography using ethyl acetate/n-hexane as eluent.
86%
In ethanol for 3h; Heating;
85%
With Tween 40 In water at 20℃; for 2h; Green chemistry;
82%
In 1,4-dioxane for 120h; Reflux;
79%
With mesoporous silica SBA-15 functionalized with Cu(II)-DiAmSar complex In neat (no solvent) at 100℃; for 1h;
2.3. General procedure for the synthesis of pyrazine-basedheterocycles under solvent-free conditions
General procedure: A round-bottomed flask equipped with a magnet and condenserwas charged with the desired 1,2-diamine (1.0 mmol),1,2-diketone (1.0 mmol), and catalyst (Cu(II)DiAmSar/SBA-15,0.005 g). The resulting mixture was heated at 100 °C for theappropriate time. The course of the reaction was monitoredusing TLC on silica gel. Finally, the reaction mixture was cooled,and the crude mixture was purified by column chromatographyor crystallization to get the desired product. Spectral and physicaldata for all heterocycles were compared with referencesamples and were in accord with previously reported data.
43%
With zeolite HY In ethanol at 20℃; for 10h; Green chemistry;
General procedure for the synthesis of quinoxalines in the presence of Zeolite HY
General procedure: A mixture of 1,2-dicarbonyl (1 mmol) and aromatic 1,2-diamine (1 mmol) in ethanol (5 ml) was stirred at room temperature in presence of Zeolite HY as a catalyst (5 wt. %). The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered to recover the catalyst. The further purified products were obtained by recrystalization from ethanol/water (3:1).
In ethanol at 70℃; for 2h;
1 Step 1 : 2,3-Diphenylpyrido[3,4-b]pyrazine
To a suspension of pyridine-3,4-diamine (1.038 g, 9.51 mmol) in EtOH (30 ml) was added benzil (2g, 9.51 mmol). The reaction mixture was stirred at 70°C for 2 hours and then cooled to RT overnight. The resulting precipitate was collected by filtration and washed with EtOH (10 ml) to afford the titled compound as an off-white solid; LCMS; Rt 1.07mins MS m/z 284.2[M+H]+; Method 2minl_C_v003
With hydrogenchloride; In water; for 20.0h;Heating / reflux;
To a suspension of 3,4-diaminopyridine (10 g, 0.068 mol) in 4N aqueous HCl (100 ml) is added oxalic acid (10.4 g, 0.082 mol) and the reaction mixture is refiuxed for 2Oh. The reaction mixture is cooled down and the solid precipitated is filtered, washed with water then dried under vacuum to afford 9 g (80 %) of the title compound as a solid. HPLC (max plot) 98%. LC/MS: (ES+): 164.3.
With hydrogenchloride; sodium nitrite; In water; at 0℃; for 1h;
3,4-diaminopyridine (2.0 g, 0.048 mol) was dissolved in a 2N hydrogen chloride aqueous solution (25 mL), cooled to 0 C, Sodium nitrite (1.9 g, 0.027 mol) was dissolved in distilled water (3 mL) and added slowly, And stirred for 1 hour. The resulting solid was filtered and washed with distilled water to give the title compound im-7-a (1.96 g, 89%) as a yellow solid.
2,3-bis(p-methoxyphenyl)pyrido<3,4-b>pyrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With zirconium oxide salicylaldehyde-(3-aminopropyl)trimethoxysilane imine complex modified SBA-15 In water for 5h; Reflux;
95%
With SBA-15 mesoporous silica supported Fe(III)-Schiff base In water for 2h; Reflux;
94%
With Cu(II)-Schiff base/SBA-15 In water for 2h; Reflux;
General procedure for the synthesis of pyrido[2,3-b]pyrazines, pyrido[3,4-b]pyrazines and 2,3-disubstituted quinoxalines in water
General procedure: A round-bottomed flask equipped with a magnet and condenser was charged with desired 1,2-diamine (1.0 mmol), 1,2-diketone (1.0 mmol), water (2 mL) and catalyst Cu/SBA-15 (0.01 g (0.0014 mmol)). The resulting mixture was stirred at reflux temperature for the appropriate times, and the course of the reaction was monitored using TLC on silica gel. For separation of the catalyst, the reaction mixture (at the end of reaction) was filtered and the precipitates on the filter were dissolved in ethanol or ethyl acetate. These solvents can dissolve the products (and also organic starting materials), but the catalyst was remained insoluble. After filtration of the later solution, the catalyst was recovered
86%
With ziconium(IV) oxychloride octahydrate In water at 100℃; for 3h; Green chemistry;
5 4.2. General procedure for the synthesis of compounds 3a-3p
For the synthesis of entitled heterocycles, a roundbottom flask equipped with a stir bar was chargedwith 1,2-phenylenediamine (1.0 mmol), 1,2-diketones(1.0 mmol), water (2 mL) and zirconium(IV) oxide chloride(25 mol%). The resulting mixture was heated in an oil bathat 100 8C for the appropriate time, and the course of the reaction was monitored using TLC on silica gel. Finally, thereaction mixture was cooled and the crude mixture waspurified by column chromatography or crystallization togive the desired product. The authenticity of the productswas established by comparing their melting points withdata of the literature and by analyzing the spectroscopicdata of 1H and 13C NMR and IR [9-16,26,27].
75%
In 1,4-dioxane Reflux;
74%
With mesoporous silica SBA-15 functionalized with Cu(II)-DiAmSar complex In neat (no solvent) at 100℃; for 1.5h;
2.3. General procedure for the synthesis of pyrazine-basedheterocycles under solvent-free conditions
General procedure: A round-bottomed flask equipped with a magnet and condenserwas charged with the desired 1,2-diamine (1.0 mmol),1,2-diketone (1.0 mmol), and catalyst (Cu(II)DiAmSar/SBA-15,0.005 g). The resulting mixture was heated at 100 °C for theappropriate time. The course of the reaction was monitoredusing TLC on silica gel. Finally, the reaction mixture was cooled,and the crude mixture was purified by column chromatographyor crystallization to get the desired product. Spectral and physicaldata for all heterocycles were compared with referencesamples and were in accord with previously reported data.
In ethanol at 110℃; for 1h; Microwave irradiation;
71%
In ethanol at 70℃; for 5h;
6
1,2-Cyclohexanedione (1.52 g, 13.93 mmol) was added to a suspension of 1.56 g (13.93 mmol) of 3,4-diaminopyridine in 50 ml of ethanol. The reaction mixture was subsequently heated at an oil bath temperature of 70° C. for 5 hours, then cooled to room temperature and the solvent was then distilled off on a rotary evaporator. The product obtained was purified by flash chromatography using ethyl acetate as eluent. This gave 1.84 g (71%) of a white solid which was stored in a refrigerator and processed further after 1-2 days. Allowing the solid to stand in an open flask in sunlight resulted in the color changing to greyish green. Rf=0.25 (EtOAc/hexane, 20:1). 1H NMR:(200 MHz, CDCl3): δ=2.05 (m, 4H, H-7,8), 3.18 (m, 4H, H-6,9), 7.79 (d, 3J=5.8 Hz, 1H), 8.72 (d, 3J=5.8 Hz, 1H), 9.38 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ=22.8 (CH2, C-7,8), 33.7 (CH2, C-6,9), 121.2 (CH), 136.9 (Cq), 144.1 (Cq), 146.8 (CH), 153.9 (CH), 156.8 (Cq) 159.9 (Cq) ppm. GC-MS (EI): RT 8.44 min, m/e (%) 186 (11), 185 (M+, 100), 184 (39), 183 (3), 182 (3), 171 (2), 170 (21), 169 (4), 158 (2), 157 (5), 156 (5) 131 (2), 104 (2), 103 (4), 78 (3), 76 (4), 67 (2), 64 (2), 51 (2), 50 (6); IR (KBr): ν=3435 (vs), 2947 (s), 2864 (m), 1594 (s), 1557 (w), 1461 (w), 1421 (m), 1385 (s), 1365 (w), 1330 (w), 1297 (m), 1211 (m), 1140 (w), 979 (m), 949 (w), 901 (m), 849 (m), 679 (w), 629 (w), 570 (w), 412 (w) cm-1. HRMS (EI): calculated for C11H11N3 185.0953 [M+], found: 185.0935
Preparation of imidazo[4,5-c]pyridine (IV) An example of a specific method for preparation of the imidazo[4,5-c]pyridine intermediate, from which the general preparation of intermediate (IV), above, may be derived, is as follows: A stirred mixture of 3,4-diaminopyridine (10.0 g, 0.092 mol) and formic acid (20 ml) was heated under reflux for 2.5 hours. The resulting mixture was cooled and the formic acid was evaporated off under reduced pressure to yield a residue. The residue was dissolved in ethanol (30 ml) at 80C and the resulting solution was treated with calcium carbonate (10 g) and neutralized by stirring under reflux for 1 hour. The hot mixture was filtered and the residue was washed with hot ethanol (3 x 300 ml). The filtrate and washings were combined and the ethanol was evaporated off under reduced pressure to yield 3,4-diformylaminopyridine as a colorless solid. The 3,4-diformylaminopyridine was heated at 200-220C and 66.5 Pa (0.5 mm Hg) pressure in a Kugelrohr bulb-to-bulb distillation apparatus to yield a crude product as a distillate which solidified on cooling. The crude product was recrystallized from ethyl acetate to yield imidazo[4,5-c]pyridine as a colorless crystalline solid, having a melting point of 174-176C and the following physical characteristics: 1H-NMR (delta, DMSO-d6: 6.60 (broad s,1H), 7.66 (dd,1H), 8.37 (d,1H), 8.44 (s,1H) and 9.00 (d,1H).
A.1 [PART A]; EXAMPLE 1 - preparation of 2-(2,6-Difluorophenyl)-1 (3) H-imidazo [4,5-c] pyridine
A mixture of 3, 4-diaminopyridine (2.00 g), 2,6-difluorobenzoic acid [(1] equivalent) and polyphosphoric acid [(50] g) was heated at [180°C] for 4 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was neutralized by addition of solid [NA2C03.] The crude product was collected by filtration, washed with water and dried. It was used in the next step without further purification.
A mixture of 3, 4-diaminopyridine (2.00 g), <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> (1 equivalent) and polyphosphoric acid (50 g) was heated at 180 C for 4 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was neutralized by addition of solid NaOH. The crude 2- (2, 3- difluorophenyl)-1 (3) H-imidazo [4,5-c] pyridine was collected by filtration, washed with water and dried. It was used in the next step without further purification. Yield: 88%.
With phosphorus pentoxide; In methanesulfonic acid; at 50 - 190℃; for 3h;
Phosphorous pentoxide (24.56g) was dissolved in methanesulfonic acid (165. 8mL) at 50 C with stirring. To the solution, 3,4-diaminopyridine (12.3g, 0 lmoles) and <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> (19.4g, 0.12moles) were added. The reaction mixture was heated to 190 C for 3 hours. The reaction was done three times. The reaction mixtures was cooled to 50 C and poured into ice with stirring. At this stage, all three batches were combined. The reaction mixture was neutralized by the addition of NaOH with stirring until the pH is 8. Solid material precipitated out of solution, was collected by filtration and air-dried. The final product was re-crystallized from ethanol/water twice to yield 36g of 2- (2, 3-difluorophenyl) -3H-imidazo [4,5- c] pyridine. 1H 300Mhz (CD30D) sigma 7.3-7. 42 (m, lp) ; 7.43-7. 58 (m, lp) ; 7.70 (d, lp) ; 8.0 (m, lp) ; 8.34 (d, lp) ; and 8.95 (s, lp). LC/MS data M/z = 232.
A combination of pyridine-3,4-diamine (1.0 g, 9.16 mmol) and urea (3.3 g, 54.9 mmol) were stirred as a melt at 165 0C for 4 h, then cooled and H2O (100 mL) was added. The aqueous mixture was heated at reflux until all solid dissolved and the solution was allowed to cool and aged for 18 h. The precipitate was isolated by filtration to give the title compound. MS: m/z = 136 (M + 1).
at 165℃; for 4h;
A combination of pyridine-3,4-diamine (1.0 g, 9.16 mmol) and urea (3.3 g, 54.9 mmol) were stirred as a melt at 165 0C for 4 h, then cooled and eta2O (100 mL) was added. The aqueous mixture was heated at reflux until all solid dissolved and the solution was allowed to cool and aged for 18 h. The precipitate was isolated by filtration to give the title compound. MS: m/z = 136 (M + 1).
A combination of pyridine-3,4-diamine (1.0 g, 9.16 mmol) and urea (3.3 g, 54.9 mmol) were stirred as a melt at 165 0C for 4 h, then cooled and H2O (100 mL) was added. The aqueous mixture was heated at reflux until all solid dissolved and the solution was allowed to cool and aged for 18 h. The precipitate was isolated by filtration to give the title compound. MS: m/z = 136 (M + 1).
at 165℃; for 4h;
Step A. 1.3-Dihydro-2H-imidazo[4.5-c]pyridin-2-oneA combination of pyridine-3,4-diamine (1.0 g, 9.16 mmol) and urea (3.3 g, 54.9 mmol) were stirred as a melt at 165 C for 4 h, then cooled and H2O (100 mL) was added. The aqueous mixture was heated at reflux until all solid dissolved and the solution was allowed to cool and aged for 18 h. The precipitate was isolated by filtration to give the title compound. MS: m/z = 136 (M + 1).
PREPARATION 1 Preparation of 2,3(1H,4H)-dioxo-pyrazino[5,6-c]-pyridine To a solution of 4 g of 3,4-diaminopyridine in 120 ml of methanol, 4.36 g of sodium methoxide was added, and the mixture was stirred at room temperature for 30 minutes. A solution of 4.3 g of dimethyloxalate in 40 ml of methanol was added dropwise to the mixture over 30 minutes and the resulting mixture heated to reflux for 7 hours. The mixture was concentrated under reduced pressure, diluted with 240 ml of water, and then cooled in an ice bath. The reaction mixture was adjusted to pH 6.5 with 10 % hydrochloric acid. The precipitated solids were collected by filtration, washed with water, and dried to give 4.5 g of the title compound as a white solid. IR (KBr, cm-1): 3230; 1709; 1383. NMR (DMSO-d6) 12.1(2H,s); 8.4(1H,s); 8.2(1H,d); 7.05 (1H,d).
Example 4 Preparation of 6-Aza-1,4-dihydroquinoxaline-2,3-dione (11) A solution of 1.64 g (15.0 mmol) of 3,4-diaminopyridine (10) and 1.45 g (16.1 mmol) of oxalic acid in 10 mL of 2N HCl was refluxed for 3 h and cooled to room temperature. The mixture was filtered, washed with water, and dried to leave a white solid (2.40 g, 98%), mp >250 C. 1 H NMR (DMSO-d6), 7.448 (d, 1, J=6.32), 8.391 (d, 1, J=6.11), 8.452 (s,1), 12.511 (s,1), 12.885 (sb, 1). MS, 163 (M+, 60), 135 (40), 107 (20), 38 (100). HRMS calcd for C7 H5 N3 O2, 163.0378, found 163.0383.
2-(3-Methylthio-4-methoxyphenyl)-1H-imidazo-[4,5-c]pyridine dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With thionyl chloride; triethylamine; In pyridine; methanol; ethylene glycol; toluene;
EXAMPLE 34 2-(3-Methylthio-4-methoxyphenyl)-1H-imidazo-[4,5-c]pyridine dihydrochloride 3-Methylthio-4-methoxybenzoic acid (obtained by diazotization of <strong>[2840-26-8]3-amino-4-methoxybenzoic acid</strong>, followed by treatment with methylmercaptan) was suspended in dry toluene and thionyl chloride (1.1 eq) was added slowly to it. The mixture was refluxed for 3.5 hours. T.l.c. indicated reaction to be complete. The solvent was removed in vacuo to leave a dark brown residue. The acid chloride obtained above was suspended in the minimum quantity of dry ether and added portionwise to a suspension of 3,4-diaminopyridine (1 eq) in dry pyridine and triethylamine. The resulting mixture was refluxed for 5 hours. T.l.c. indicated the reaction to be complete. The cooled reaction mixture was filtered through hyflo and the filtrate evaporated in vacuo. The residue was triturated with ether and then dissolved in methanol. The solid that separated was filtered off and the methanol filtrate was evaporated under reduced pressure to give a viscous oil. NMR indicated this to consist mainly of the intermediate amide. This oil was dissolved in ethylene glycol and the solution obtained heated at 200 for 4 hours. T.l.c. indicated reaction to be complete. The cooled reaction mixture was poured into water. A white solid precipitated and was filtered and dried. The solid was triturated into ethyl acetate/ether to give a solid which was converted to the title dihydrochloride, m.p. 275-277 C.
With hydrogen bromide; bromine; at 40 - 110℃; for 5.0h;
0613] To the mixture of X-1 (10.0 g, 10 mmol) dissolved in HBr 48% (200 mL), Br2 (12.5 mL, 13.4 mmol) was added dropwise under ice-water cooling bath, maintaining the temperature below 40 C. After that, the mixture was heated at 110 C. for 5 hrs. The reaction mixture was cooled to rt, filtered and washed with little water. The filter cake is basified to pH 78 with saturated aq. NaHCO3 and extracted with EtOAc (200 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to yield X-2 (17.2 g, 71% yield). 1H NMR (DMSO-d6, 400 MHz) delta 7.95 (s, 1H), 5.20 (brs, 4H).
71%
With hydrogen bromide; bromine; In water; at 40 - 110℃; for 5.0h;Cooling with ice;
To the mixture of X-1 (10.0 g, 10 mmol) dissolved in HBr 48% (200 mL), Br2 (12.5 mL, 13.4 mmol) was added dropwise under ice-water cooling bath, maintaining the temperature below 40C. After that, the mixture was heated at 110C for 5 hrs. The reaction mixture was cooled to rt, filtered and washed with little water. The filter cake is basified to pH 7--8 with saturated aq. NaHCO3 and extracted with EtOAc (200 mLx3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to yield X-2 (17.2 g, 71% yield). ?H NMR (DMSO-d6, 400 MHz) 5 7.95 (s, 1H), 5.20 (brs, 4H).
67.5%
With hydrogen bromide; bromine; at 110℃; for 5.0h;
B3-a (4.0 g, 36.7 mmol) and 48% hydrobromic acid (80 mL) were added to a dry 250 mL three-necked flask in this order. Liquid bromine (7.0 g, 44 mmol) was added dropwise with stirring at normal temperature.The reaction solution was stirred at 110 C for 5 hours. After the reaction is completed, it is cooled to room temperature.A brown solid was obtained by filtration and washed with a small amount of cold water. The solid was dissolved in ethyl acetate (200 mL), and washed with saturated sodium bicarbonate (100 mL) and saturated brine (100 mL).The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a brown solid.B3-b (6.6 g, 67.5% yield).
50%
With hydrogen bromide; bromine; In water; at 100 - 135℃; for 5.0h;
The synthesis of 3,4-diamino-2,5-dibromopyridine was improved on the basis of the method reported in a literature [18]. The mixture of pyrido-3,4-diamine(2 g, 18.3 m mol) with an aqueous HBr (48%, 30 ml) were prepared in a 250 ml three-neck round bottom flask with a magneton inside. After the mixture was heated to 100 deg.C, bromine(2.5 ml) was added dropwise, and the solution was stirred for 5 h at 135 deg.C. After the mixture was cooled to room temperature, an aqueous solution of Na2S2O3, an aqueous solution of Na2CO3, and distilled water were added in this order to get a yellow precipitate. Then the precipitate was separated by filtration and washed with distilled water three times. Recrystallization from the mixture solution of toluene: THF (v:v = 5:1) gave white flocculence solid, yielded: 50%. 1H NMR (DMSO, 400 MHz, ppm): d=7.53 (s, 1H), 5.99 (s, 2H), 5.03 (s, 2H). 13C NMR (DMSO,101 MHz, ppm): d = 139.93, 139.13, 129.54, 126.67, 106.22 (seeFig. S1 in Supporting Informations)
30%
The mixture of 3,4-diaminopyridine (5.45 g, 50 mmol) with 48% hydrobromic acid (24 mL) in a 50 mL flask was heated to reflux while stirring. After adding bromine (8 mL, 155.7 mmol) dropwise, the reaction mixture was heated for 16 h at 80 C then cooled down to the room temperature. The mixture was filtered and washed with a saturated solution of Na2S2O3 (150 mL), NaHCO3 (150 mL) and finally water (150 mL). The residue was first purified by flash chromatography using PE (petroleum ether)/EA (ethyl acetate)=1:2 (v/v) as eluent and recrystallized in ethanol to give 4 g orange solid. (Yield: 30%). 1H NMR (400 MHz, DMSO-d6, ppm): delta=7.53 (s, 1H), 5.99 (s, 2H), 5.05 (s, 2H); 13C NMR (100 MHz, DMSO-d6, ppm): delta=140.66, 140.45, 129.81, 128.30, 106.24.; HRMS (ESI, m/z): [M+H]+ calcd for (C5H5N3Br2), 264.8850; found, 264.8844.
25.5%
With hydrogen bromide; bromine; for 5.0h;Reflux;
In a three-neck 100 mL round-bottom flask, was added 3,4-diaminopyridine (1) (5.0 g, 45.2 mmol) with 9.3 mL of 48 % hydrobromic acid. The resulting mixture was heated to reflux while stirring and bromine (7.6 mL, 148.5 mmol) was added dropwise. The reaction mixture was refluxed for 5 h and cooled to ambient temperature. The mixture was filtered and washed with a saturated solution of Na2S2O3 (100 mL),Na2CO3 (100 mL) and finally water (100 mL). To complete the neutralization process, the crude product was refluxed 30 min in a 10 % solution of Na2CO3. The mixture was then filtered and washed with water. The brown-dark product wasfirst purified by column chromatography ethyl acetate/hexane(3:2) and by recrystallization from methanol to give compound 2 as an orange powder (3.1 g, 25.5 %). 1HNMR(Acetone-d6, 300 MHz, delta/ppm): 7.65 (s, 1H), 5.54 (br, 2H),4.66 (br, 2H). 13C NMR (100 MHz, Acetone-d6, delta/ppm):140.66, 140.45, 129.81, 128.30, 106.24. EI-MS m/z: [M +H]+ Cacld for C5H5Br2N3: 264.88, Found: 264.70.
5.A
Example 5; Preparation of 2-(3,4-dichlorophenyl)-5-methyl-5H-imidazor4,5-c1pyridine; (Compound 10); A. 2-(3,4-Dichlorophenyl)-5H-imidazo[4,5-c]pyridine[00195] A mixture of 3,4-diaminopyridine (2.5 g, 22.94 mmol), 3,4-dichlorobenzoic acid (4.374 g, 22.90 mmol) and polyphosphoric acid (60 g) was heated at 1900C for 3 hours with stirring. The reaction mixture was allowed to cool to 25°C and poured into ice/water and the mixture neutralised by the addition of solid Na2CO3. The crude product was collected by filtration and washed with water to give the desired product (3.994 g, 15.12 mmol, 66% yield). 1H NMR (DMSO) 8.96 (IH, d, J=LOHz), 8.44 (IH, d, J=2.0Hz), 8.30 (IH, d, 7=5.6Hz), 8.20 (IH, dd, 7=8.4, 2.1Hz), 7.86 (IH, d, 7=8.4Hz), 7.62 (IH, dd, 7=5.6, 1.1Hz).
Example 2; Preparation of 2-(2,3-dichlorophenyr)-5-isopropyl-5H-imidazo[4,5- dpyridine; (Compound 13); A. 2-(2,3-Dichlorophenyl)-5H-imidazo[4,5-c]pyridine[00191] A mixture of 3,4-diaminopyridine (2.0 g, 18.35 mmol), 2,3-<strong>[50-45-3]dichlorobenzoic acid</strong> (3.505 g, 18.35 mmol) and polyphosphoric acid (48 g) was heated at 190°C for 3 hours with stirring. The reaction mixture was allowed to cool to 25°C and poured into ice/water and the mixture neutralised by the addition of solid Na2CO3. The crude product was collected by filtration and washed with water to give the title compound (3.317 g, 12.56 mmol, 70percent yield). 1H NMR (DMSO) 13.32 (IH, s), 9.01 (IH, s), 8.36 (IH, d, J=5.5Hz), 8.74-8.79 (2H, m), 7.64 (IH, s), 7.57 (IH, t, /=7.8Hz).
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 20℃;
To a lOOmL RBF was added pyridine-3,4-diamine (327 mg, 3.00 mmol) in DMF (30 mL) along with 1- <strong>[84677-06-5](benzyloxycarbonylamino)cyclopropanecarboxylic acid</strong> (706 mg, 3.00 mmol), triethylamine. (1.20 mL, 8.40 mmol), and TBTU, 2-(lH-benzo[d][l,2,3]triazol-l-yl)- 1, 1,3,3-tetramethylisouronium tetrafluoroborate (1.20 mg, 3.75 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with 50mL of DCM and extracted; the organics were washed with lOmL of water, lOmL of brine, dried over magnesium sulfate, decanted and evaporated to dryness to give 949mgs of a mixture of benzyl l-(4-aminopyridin-3- ylcarbamoyl)cyclopropylcarbamate and benzyl l-(3-aminopyridin-4- ylcarbamoyl)cyclopropylcarbamate as a yellow solid (68% yield). XH NMR (400 MHz, CD3OD) delta ppm 1.12 - 1.19 (m, 2 H), 1.52 - 1.60 (m, 2 H), 5.13 (s, 2 H), 7.23 - 7.43 (m, 6 H), 7.82 (d, J=5.5 Hz, 1 H), 8.06 (s, 1 H). LCMS rt = 1.880min., m/z 327.1(M + H), 71% purity.
To a lOOmL RBF was added pyridine-3,4-diamine (327 mg, 3.00 mmol) in DMF (30 mL) along with 1- <strong>[84677-06-5](benzyloxycarbonylamino)cyclopropanecarboxylic acid</strong> (706 mg, 3.00 mmol), triethylamine. (1.20 mL, 8.40 mmol), and TBTU, 2-(lH-benzo[d][l,2,3]triazol-l-yl)- 1, 1,3,3-tetramethylisouronium tetrafluoroborate (1.20 mg, 3.75 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with 50mL of DCM and extracted; the organics were washed with lOmL of water, lOmL of brine, dried over magnesium sulfate, decanted and evaporated to dryness to give 949mgs of a mixture of benzyl l-(4-aminopyridin-3- ylcarbamoyl)cyclopropylcarbamate and benzyl l-(3-aminopyridin-4- ylcarbamoyl)cyclopropylcarbamate as a yellow solid (68% yield). XH NMR (400 MHz, CD3OD) delta ppm 1.12 - 1.19 (m, 2 H), 1.52 - 1.60 (m, 2 H), 5.13 (s, 2 H), 7.23 - 7.43 (m, 6 H), 7.82 (d, J=5.5 Hz, 1 H), 8.06 (s, 1 H). LCMS rt = 1.880min., m/z 327.1(M + H), 71% purity. To a medium size microwave vial was added 5mL of acetic acid and 850mgs of the crude reaction mixture prepared in the previous step (benzyl l-(4-aminopyridin-3- lcarbamoyl)cyclopropylcarbamate and benzyl l-(3-aminopyridin-4- ylcarbamoyl)cyclopropylcarbamate). The vial was sealed and the mixture heated at 120C for 70minutes in the microwave. The vessel was cooled to near 0C and 50mL of cold saturated sodium carbonate was added along with lOOmL of 10: 1 DCM/methanol. The product was extracted; the organics washed with brine, dried over magnesium sulfate and evaporated. The product mixture was taken up in 15 mL of methanol and purified using a Shimadzu preparative HPLC employing methanol/water/ trifluoroacetic acid where solvent A was 10% methanol / 90% water / 0.1% trifluoroacetic acid and solvent B was 10% water / 90% methanol / 0.1% trifluoroacetic acid with a Phenomenex-Luna IotaOmicronmuiotaeta CI 8 30x100mm column at a gradient of 0-100% B and a flow rate of 40 mL/min. over 15 minutes with a 10 minute hold. Solvent was removed giving a 70% yield of benzyl l-(lH-imidazo[4,5-1c]pyridin-2-yl)cyclopropylcarbamate as a light yellow solid. H NMR (400 MHz, CD3OD) delta ppm 1.44 - 1.59 (m, 2 H), 1.68 - 1.83 (m, 2 H), 5.05 - 5.14 (m, 2 H), 6.99- 7.14 (m, 1 H), 7.19 - 7.41 (m, 4 H), 7.88 - 7.97 (m, 1 H), 8.40 (d, J=6.5 Hz, 1 H), 8.97 (s, 1 H). LCMS rt = 1.483min., m/z 309.2(M + H), 94.5% purity.
INTERMEDIATE 77 2-Chloro-6-{lH-imidazo[4,5-c]pyridin-2-yl}pyridine 6-Chloropyridine-2-carboxylic acid (2.00 g, 12.7 mmol), 3,4-diaminopyridine (1.52 g, 14.0 mmol) and DIPEA (2.43 mL, 14.0 mmol) were dissolved in DMF (20 mL) and HBTU (5.29 g, 14.0 mmol) was added. The reaction mixture was stirred for 48 h and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with 1 M aq Na2C03 (2 x 100 mL), water (100 mL), dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography, dissolved in AcOH and heated at 120 C for 50 min. The solvent was removed in vacuo and the residue was suspended in 1 M aq Na2C(¾ (50 mL) and extracted with EtOAc (5 x 50 mL). The combined organic fractions were dried (MgSC^) and concentrated in vacuo. The residue was purified by column chromatography and recrystallisation from MeOH to give the title compound (534 mg, 37%) as a white solid.
With N,N?-bis(2,6-diisopropylphenyl)imidazol-2-ylidene hydrochloride; phenylsilane; In tetrahydrofuran; at 70℃; under 750.075 - 2250.23 Torr; for 24h;Schlenk technique; Inert atmosphere; Glovebox;
General procedure: A-Synthesis of Benzimidazole and Derivatives from Aromatic 1,2-DiaminesThe first results presented describe the synthesis of benzimidazole rings and derivatives from aromatic 1,2-diamines. In this case, the amine R1NH2 and the nitrogenous nucleophilic agent R5R6NH are two reactive functional groups of one and the same molecule (diamine) and are thus connected via a covalent bond. This bond is preferably an aromatic ring of benzene, pyridine or pyrimidine type and the ring formed during the reaction is a nitrogenous heterocycle comprising 5 atoms of imidazole type. In the case where the nucleophile is oxygen-based (R7OH), the rings obtained are benzoxazoles. The results presented were produced by preferably using two sources of different reducing agents, polymethylhydrosiloxane (PMHS), sold by Aldrich under the reference 176206, and phenylsilane (PhSiH3), sold by Aldrich. In the case of the PMHS, as a silane is a polymer, the number of equivalents introduced is given with respect to the number of hydrides introduced and thus the number of monomers introduced with respect to the amine. Thus, the introduction of 3 equivalents of PMHS corresponds to the introduction of 3 equivalents of hydride and thus 3 equivalents of monomers of the PMHS with respect to the amine. Different (pre)catalysts were tested for the reaction.
A mixture of pyridine-3,4-diamine (2?g, 18.3?mmol) and triethyl orthoformate (50?mL) was refluxed for about 3?h?at 145?C. After completion of the reaction monitored by TLC, 2?mL of formic acid was added and the mixture was refluxed at the same temperature for another 2?h. The solution was evaporated to dryness at reduced pressure, and the residue was dissolved in methanol and stirred at room temperature overnight in presence of charcoal. Following removal of the charcoal by vacuum filtration through celite-545, the filtrate was evaporated to give the title compound 2 as an off-white solid in quantitative yield without further purification. 1H NMR (300?MHz, DMSO-d6) delta 8.97 (d, J?=?1.1?Hz, 1H), 8.32 (d, J?=?5.6?Hz, 1H), 7.61 (dd, J?=?5.6, 1.1?Hz, 1H); 13C NMR (75?MHz, DMSO) delta 144.35, 141.18 (2?*?C, overlapped), 139.72, 137.73, 109.46. HRMS (ESI): m/z calcd. for C6H6N3 [M+H]+: 120.0556; found, 120.0556.
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 48h;
6-Chloropyridine-2-carboxylic acid (2.00 g, 12.7 mmol), 3,4-diaminopyridine (1.52 g, 14.0 mmol) and DIPEA (2.43 mL, 14.0 mmol) were dissolved in DMF (20 mL) and HBTU (5.29 g, 14.0 mmol) was added. The reaction mixture was stirred for 48 h and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with 1 M aq Na2CO3 (2*100 mL), water (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography, dissolved in AcOH and heated at 120 C. for 50 min. The solvent was removed in vacuo and the residue was suspended in 1 M aq Na2CO3 (50 mL) and extracted with EtOAc (5*50 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography and recrystallisation from MeOH to give the title compound (534 mg, 37%) as a white solid.
Preparation of the solid 1:1 complexes 2,3-DAP-CHA and 2,3-DAPDHBQ
The solid CT-complexes (1:1) between 2,3-DAP and CHA and between 2,3-DAP and DHBQ were prepared by mixing equimolar amounts of 2,3-DAP with CHA and 2,3-DAP with DHBQ in EtOH.The resulting complexes solutions were allowed to evaporate slowly at room temperature where the complexes were isolated as reddish purple and reddish-brown crystals for 2,3-DAP-CHA and 2,3-DAP-DHBQ complexes respectively. The separated complexes were filtered off, washed well with EtOH and dried over calcium chloride for 24 h.
Preparation of the solid 1:1 complexes 2,3-DAP-CHA and 2,3-DAPDHBQ
The solid CT-complexes (1:1) between 2,3-DAP and CHA and between 2,3-DAP and DHBQ were prepared by mixing equimolar amounts of 2,3-DAP with CHA and 2,3-DAP with DHBQ in EtOH.The resulting complexes solutions were allowed to evaporate slowly at room temperature where the complexes were isolated as reddish purple and reddish-brown crystals for 2,3-DAP-CHA and 2,3-DAP-DHBQ complexes respectively. The separated complexes were filtered off, washed well with EtOH and dried over calcium chloride for 24 h.
In methanol for 2h;
2.3. Synthesis of solid complexes
General procedure: The solid complexes of AMFP with the studied acceptors were synthesizedby adding acceptor solution (1.0 mmol in 20 mL MeOH) toAMFP solution (1.0 mmol in 20 mL MeOH). The mixed solutions werestirred for 2 h and then allowed to evaporate at room temperature.The resulting colored products were collected, washed with a small amount of MeOH, and dried over anhydrous calcium chloride in adesiccator.
tert-butyl (R)-(1-(3H-imidazo[4,5-c]pyridin-2-yl)-2-(4-methoxyphenyl)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
iert-Butyl (K)-(1-(3H-imidazo[4,5-c]pyridin-2-yl)-2-(4- methoxyphenyl)ethyl)carbamate: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (ft)-2-((te/f-butoxycarbonyl)amino)-3-(4- methoxyphenyl)propanoic acid (1028 mg, 3.48 mmol) in DMF (34.5 mL) was treated at rt with DIPEA (2.38 mL, 13.9 mmol), HATU (1324 mg, 3.48 mmol) and pyridine-3,4-diamine (380 mg, 3.48 mmol). The reaction mixture was stirred at rt until completion. The reaction mixture was diluted with EA and water. The org. phase was dried over MgS04, filtered, and the solvent was removed under reduced pressure. The residue was purified by combiflash using acetone as eluent to give 400 mg of material as white foam that was dissolved in glacial acetic acid (9.7 mL) and the reaction mixture was stirred at 100 C until completion. The mixture was cooled to rt and the solvent was removed under reduced pressure. The residue was partitioned between EA (25 mL) and sat. aq. NaHC03 (25 mL). The org. layer was washed with sat. aq. NaHC03 (twice 25 mL), dried over MgS04, filtered, and the solvent was removed under reduced pressure to give the title compound as yellow foam: LC-MS-conditions 07: tR = 0.63 min; [M+H]+ = 369.08.
With sodium metabisulfite; In N,N-dimethyl-formamide; at 120℃;
General procedure: A solution of substituted o-phenyldiamine (1.0 equiv), thiazole-4-aldehyde or pyridine-2-aldehyde (1.0 equiv) with sodium pyrosulfite in DMF was stirred at 120° C overnight. On completion of the reaction monitored by TLC, the solvent was evaporated and the residue was purified by silica gel chromatography by DCM/MeOH system to afford the final product. If necessary, the crudeproduct could be recrystallized in DCM or dichloroethane to afford pure sample.
With cesium hydroxide In dimethyl sulfoxide at 90℃; for 24h;
17 Example 17: 2- hydroxyacetophenone and 3,4-pyridine-3-phenyl-pyrido [3,4-b] pyrazine
Reaction tubes are sequentially added CsOH (0.0126g, 15mol %), 3,4-diaminopyridine (0.75mmol, 1 . 5equiv.) and 2-hydroxy acetophenone (0.068g, 0 . 5mmol,), then adding DMSO (1.0 ml) as the solvent, plus atmospheric air ball, heating to 90oC reaction 24h.TLC monitoring after the reaction is complete, post chromatographic separation and purification of product, separation yield 70%.
With oxygen In ethanol at 70℃; for 6h; Schlenk technique; Sealed tube; Green chemistry;
With triton X-100; In water; at 80℃; for 4h;Green chemistry;
General procedure: A mixture of beta-lapachone 2 (1.0 mmol), 2,3-diaminopyridine (1.0 mmol), triton X-100 (15 mol%), and distilled water (5.0 ml) were taken in a round-bottom flask. The reaction mixture was allowed to stir magnetically at 80 C for 2 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the crude mass was obtained. The residue was purified over a column of silica gel (100-200 mesh) eluting with a mixture of hexane and ethyl acetate in different ratio, to yield regioisomers (4a and 4b).
With C24H29IrN2O5(2+)*2CF3O3S(1-); caesium carbonate In 5,5-dimethyl-1,3-cyclohexadiene at 150℃; for 48h; Schlenk technique; Inert atmosphere;
General procedure for the synthesis of 3a.
General procedure: The catalyst A (5% mmol, 0.05 mmol), 1,2-phenylenediamine (1 mmol, 1.0 equiv), 1,2-propanediol (1 mmol, 1.0 equiv), Cs2CO3 (3.0 equiv) and xylene (4 mL) were added to a Schlenk tube under the atmosphere of nitrogen. The mixture was heated for 48 h at 150 °C and then cooled down to room temperature. The volatile solvent was evaporated. The residue was purified by column chromatography to give the corresponding product 3a.
2-(2-methylbiphenyl-3-yl)-1H-imidazo[4,5-c]pyridine trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of pyridine-3,4-diamine (15 mg, 0.14 mmol) and <strong>[89951-60-0]2-methylbiphenyl-3-carbaldehyde</strong> (30 mg, 0.15 mmol) in methanol (0.69 mL) was added catalytic amount of zinc triflate (5 mg), then heated at 70° C. for 36 h. The resulting mixture was filtered and purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C19H16N3(M+H)+: m/z=286.2; found 286.2.
N-ethyl-1H-imidazo[4,5-c]pyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
In isopropyl alcohol; at 80℃; for 0.25h;Microwave irradiation;
General procedure: A mixture of o-phenylenediamine (1.0 mmol) and EDC.HCl (1.1 mmol) in 2-propanol (10 mL) was irradiated in microwave apparatus at 200 W (80 C) for 15 min. The reaction was monitored by TLC (eluent CH2Cl2 / MeOH 95:5). After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure and the obtained crude product was purified by flash column chromatography using silica gel (100-200 mesh) with 1-5% MeOH/CH2Cl2 as eluent. The fractions containing product were collected and concentrated under reduced pressure to afford N-ethyl-1Hbenzo[d]imidazol-2-amine (1a, 90% yield) as an off white solid.