* 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 Organic Chemistry, 1955, vol. 20, p. 1729,1731
2
[ 21901-40-6 ]
[ 3430-27-1 ]
Reference：
[1] Russian Journal of Organic Chemistry, 2009, vol. 45, # 1, p. 115 - 118
[2] Journal of Organic Chemistry, 1955, vol. 20, p. 1729,1731
3
[ 21901-40-6 ]
[ 23056-33-9 ]
Yield
Reaction Conditions
Operation in experiment
20%
With copper dichloride In N,N-dimethyl-formamide at 60 - 110℃; for 16.5 h;
Copper (II) chloride (10.01 g, 74.5 mmol) was dissolved in N, N-dimethylformamide (75 mL) and tine solution was warmed to 60°C. A solution of 2-amino-4-methyl-5-nitropyridine (9.50 g, 62.0 mmol) in N, N-dimethylformamide (145 mL) was added with addition funnel over 0.5 h. The reaction mixture was heated at 110°C for 16 h. The reaction mixture was cooled to room temperature and poured into 3 N aqueous hydrochloric acid (300 mL), followed by extraction with diethyl ether. The organic extract was dried over sodium sulfate and adsorbed onto silica gel for purification by column chromatography (Si02, 20: 3 t(at)(at)h(at)'(at)(at)ries'percent"(at)(at)tfY(at)'(at)'(at).''(at)a'(at)(at)'(at)'(at)(at)(at)(at)e(at)9(at)(at)i(w 2-Chloro-4-methyl -5-nitropyridine was obtained as a yellow solid (2.10 g, 20percent) : 1H NMR (300 MHz, CD30D) 62.63 (3H, s), 7.60 (lH, s), 8.96 (1H, s) ; ESI MS m/z 173 [C6HsClN2O2 + H]+.
Reference：
[1] Patent: WO2005/97129, 2005, A2, . Location in patent: Page/Page column 176-177
[2] Journal of Organic Chemistry, 1955, vol. 20, p. 1729,1731
[3] Journal of the Chemical Society, 1954, p. 2448,2455
[4] Patent: EP2366691, 2011, A1,
[5] European Journal of Medicinal Chemistry, 2016, vol. 121, p. 143 - 157
[6] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 21, p. 5229 - 5233
[7] Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 1, p. 66 - 81
4
[ 21901-40-6 ]
[ 21901-41-7 ]
Yield
Reaction Conditions
Operation in experiment
67.2%
at -5 - 0℃; for 3.16667 h;
Weigh the starting material 2-amino-4-methyl-5-nitropyridine 23 (10 g) in a 250 ml round bottom flask and 70 ml of concentrated H2SO4Stirring dissolved, until the raw material is completely dissolved, the reaction flask placed in -5 low temperature cold bath, from the constant pressure low liquid funnel slowly dropping pre-configured NaNO2(6.76g) solution, resulting in a large number of bubbles, to avoid the temperature rise too fast to keep the whole process does not exceed the temperature of 0 , with the reaction, the reaction bottle gradually precipitated solid, drop Bi, stirring 10min reaction liquid into orange The solution was clarified and the reaction was continued at 0 ° C.TLC monitoring showed complete response after 3 h, stop the reaction.The reaction solution was poured into a beaker containing about 300 ml of water to precipitate a large amount of a yellow solid. After crystallization at room temperature for 3 hours, the solid was collected by filtration and dried under an infrared lamp to give 6.72 g of a yellow solid in 67.2percent yield.
63.7%
at 0 - 20℃; for 2 h;
Synthesis of the compound 31 The compound 30 (17.4 g, 0.114 mol) was added into 300 mL of water, a concentrated sulphuric acid (30 mL) was slowly added with agitation and cooled to 0°C in an ice bath. Sodium nitrite (17.5 g, 0.254 mol) was dissolved in 35 mL of water and added slowly beneath the reaction liquid surface of the reaction system via a long stem funnel. The reaction was run at room temperature for 2 h and boiled up until the reaction ends which was marked by no further brown gas was emitted. The reaction liquid was poured into broken ice, filtered, and dried to obtain 11.15g of the compound 31 with a yield of 63.7percent. The melting point is 187.3-188.9°C (ethanol) (M.P. 186°C was reported in the reference)[J. Chem. Soc.. 1954, 2248 -2451].
Reference：
[1] Patent: CN105906621, 2016, A, . Location in patent: Paragraph 0045
[2] Patent: EP2366691, 2011, A1, . Location in patent: Page/Page column 13
[3] Journal of the Chemical Society, 1954, p. 2448,2455
[4] Journal of Organic Chemistry, 1955, vol. 20, p. 1729,1731
[5] Patent: WO2007/53394, 2007, A1, . Location in patent: Page/Page column 12
[6] European Journal of Medicinal Chemistry, 2016, vol. 121, p. 143 - 157
[7] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 21, p. 5229 - 5233
[8] Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 1, p. 66 - 81
5
[ 695-34-1 ]
[ 21901-40-6 ]
Yield
Reaction Conditions
Operation in experiment
46.6%
Stage #1: at 0 - 50℃; for 24 h; Stage #2: Cooling with ice
Example 9: Synthesis of the 2-(1-ethyleneimine)-4-carbamoyl-5-nitropyridine (compound VI) [Show Image][Show Image] The reagents used was ( i ) HNO3/H2SO4; ( ii ) NaNO2; (iii) POCl3; (iv) Na2Cr2O7; (v) SOCl2/DMF, followed by NH4OH; (vi) aziridine.Synthesis of the compound 30 A concentrated sulphuric acid (240mL) was cooled in an ice bath, the starting material compound 29 (50g, 0.462 mol) was slowly added and cooled to 0°C, 55 mL of an mixture in volumetric ratio of 1:1 of a concentrated sulphuric acid (98percent) and a concentrated nitric acid (72percent) was slowly added and heated slowly to 50°C, and the reaction was completed after 24 hours. The reaction solution was introduced into 2 L of ice-water, followed by adjusting pH to 7 by adding strong aqua, and filtered. The filter cake was dried, yielding 54g of the crude product. The above mixture was subject to wet distillation to remove 4-methyl-3-nitro-2-aminopyridine, then filtered and recrystallized in ethanol (95percent) to obtain 33 g of the compound 30 with a melting point of 220-222°C(M.P. 220-222°C was reported in the reference [J.O.C. , 1955, 20, 1729-1731]). The yield was 46.6percent.
37.08%
at -5 - 50℃; for 24 h;
A solution of 150 ml of concentrated H2SO4 was charged into a 500 ml round bottom flask and placed in a low temperature cold bath at -5 ° C. After 20 minutes, 50 g of raw material 22 (2-amino-4-methylpyridine) was added in portions and the solution was gradually purified from the colorless clear solution Into a yellow viscous solution, the whole process to keep the internal temperature does not exceed 0 .Preparation of 34ml concentrated H2SO4With 34ml concentrated HNO3Of the mixed acid in -5 in the pre-cooling, through the constant pressure dropping funnel slowly added to the reaction solution, keep the temperature does not exceed 0 , drop Bi, the reaction at room temperature for 20min, transferred to the oil bath slowly heated Heated to 50 , resulting in a large number of bubbles, the reaction liquid color gradually deepened into brown.After the bubble was no longer produced, the reaction was continued at 50 ° C.TLC monitoring reaction, 24 hours after the reaction is complete, stop the reaction.The reaction solution was slowly added to the beaker with ice-water stirring to avoid exotherm. The pH was adjusted to pH (about 8) with NaOH solution. A large amount of mud-yellow solid was precipitated, washed and washed with water to neutral, To the culture dish, dried under an infrared lamp, and dried at 50 ° C under reduced pressure for 3 hours to obtain 41.61 g of a crude yellow solid.After recrystallization with EA, the insoluble impurities were removed by hot filtration, and a portion of the solvent was removed by spin-spinning and then recrystallized from EA. The crystals were crystallized at room temperature and filtered to give an orange solid of 18.54 g and a yield of 37.08percent.
27%
Stage #1: at 0 - 100℃; for 22 h; Stage #2: With sodium hydroxide In water at 20℃;
Concentrated sulfuric acid (120 mL) was cooled in an ice bath at 0°C. 2-Amino-4-methylpyridine (25.0 g, 230 mmol) was added portionwise. A mixture of concentrated sulfuric acid (18 mL) and concentrated nitric acid (17.5 mL) was added with addition funnel over 1 h, maintaining the temperature at 0°C. The reaction mixture was then warmed to room temperature over 4 h. After 15 h, the reaction mixture was heated at 60°C for 1 h, and then at 100°C for 1 h. The reaction mixture was poured over ice and adjusted to pH 4-5 with 6 N aqueous sodium hydroxide. The 3-regioisomer was removed by steam distillation (9.11 g, 26percent). The remaining residue was extracted with methylene chloride and dried over sodium sulfate, and the solvent was evaporated. The dark yellow solid was crystallized from acetonitrile and methanol to give 2-amino-4-methyl-5- nitropyridine (9.53 g, 27percent) as a dark yellow solid: 1H NMR (300 MHz, CD30D) 82.53 (3H, s), 6.39 (lH, s), 8.76 (lH, s).
18%
Stage #1: at 20 - 50℃; for 7.75 h;
Ste 1: 4-methyl-5-nitropyridin-2-amineTo the solution of 4-methylpyridin-2-amine (5.80 g, 53.6 mmol) in COW.H2SO4 (8 mL), the mixture of sulfuric acid (4.00 mL, 75 mmol) and nitric acid (4.05 mL, 91 mmol) was added at 5-20 °C during 15 minutes. The mixture was stirred at room temperature for 30 minutes, and then heated to 35-40 °C for 2 hours, 50 °C for 5 hours. The mixture was poured onto ice, adjusted pH to 9 with con. NH4OH. The precipitates were collected and purified with Column Chromatography (EtOAc : petrol ether = 1:3) to give the desired product (1.5 g, 18percent).1H NMR (DMSO- ): δ 8.75 (1H, s), 7.27 (2H, s), 6.31 (1H, s), 2.49 (3H, s).
Reference：
[1] Patent: EP2366691, 2011, A1, . Location in patent: Page/Page column 12-13
[2] Patent: CN105906621, 2016, A, . Location in patent: Paragraph 0044
[3] Patent: WO2005/97129, 2005, A2, . Location in patent: Page/Page column 176
[4] Patent: WO2012/103806, 2012, A1, . Location in patent: Page/Page column 43
6
[ 695-34-1 ]
[ 21901-40-6 ]
[ 6635-86-5 ]
Yield
Reaction Conditions
Operation in experiment
27%
at 0 - 70℃; for 4 h;
The syntheses of several 2-aminonitropyridines were described previously by Talik and Talik [29]. Their methods were applied in the syntheses of I–III compounds using commercially available 2-amino-4-methylpyridine (Fluka, >99percent). These compounds were obtained as follows: 25 g of appropriate 2-amino-4-methylpyridine were dissolved in 125 cm3 of concentrated H2SO4 (Fluka, 96percent). The reaction mixture was cooled under intensive stirring to 0 °C by adding ice mixed with NaCl. Subsequently, 37.5 cm3 of HNO3 (Chempur, 65percent, d = 1.4 g/cm3) were added in small portions keeping the temperature below 10 °C. Then the mixture was stirred for 1.5 h with continuous cooling, and kept at ambient temperature for 1 h. Next, the reaction mixture was heated in a water bath for half an hour at 40 °C, 1 h in the temperature range 60–70 °C and half an hour in a boiling water bath. Then, the whole reaction mixture was cooled to ambient temperature, poured on ice and neutralized with ammonia to a slightly alkaline pH. The solid reaction product was filtered off under vacuum. Two nitro isomers (3 and 5) were separated by steam distillation. More volatile 3- nitro isomer (I) was distilled off and condensed as a pure compound (obtained after drying 10 g), while residual 5-nitro isomer (III) was filtered off and crystallized from water (with H2SO4 and active carbon added initially for dissolving the compound and removing impurities). After neutralization, filtering off and drying, about 15 g of 5-nitro isomer (III) was obtained. The 2-amino-4-methyl-3,5-dinitropyridine (II) was obtained from 2-amino-4-methyl-5-nitropyridine (III) by a similar procedure (nitration and rearrangement to dinitropyridines). The residues were purified by crystallization from water to give 2-amino-4-methyl-3-nitropyridine, I (Yield: (27percent (10 g), m.p. 134(1) °C), 2-amino-4-methyl-3,5-dinitropyridine, II (Yield: 80percent (10.4 g), m.p. 197(1) °C) and 2-amino-4-methyl-5-nitropyridine, III (Yield: 40percent (15 g), m.p. 218(1) °C), respectively. Melting points were determined using a Köfler apparatus. The chemical composition of the obtained compounds was checked using the Carlo Erba Analyser, Model 1104.
Reference：
[1] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2012, vol. 96, p. 952 - 962
[2] Journal of the Chemical Society, 1954, p. 2448,2455
[3] Journal of the American Chemical Society, 1955, vol. 77, p. 3154
[4] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[5] Journal of Molecular Structure, 2013, vol. 1043, p. 15 - 27
[6] Organic Process Research and Development, 2007, vol. 11, # 5, p. 885 - 888
7
[ 19346-47-5 ]
[ 21901-40-6 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 41, p. 7564 - 7567
8
[ 5832-44-0 ]
[ 21901-40-6 ]
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 4, p. 376 - 378
9
[ 33245-30-6 ]
[ 21901-40-6 ]
[ 6635-86-5 ]
Reference：
[1] Acta Chimica Hungarica, 1986, vol. 121, # 4, p. 333 - 338
[2] Acta Chimica Hungarica, 1986, vol. 121, # 4, p. 333 - 338
[3] Australian Journal of Chemistry, 1982, vol. 35, # 10, p. 2035 - 2040
[4] Organic Process Research and Development, 2007, vol. 11, # 5, p. 885 - 888
10
[ 33245-30-6 ]
[ 13466-41-6 ]
[ 21901-40-6 ]
[ 6635-86-5 ]
Reference：
[1] Australian Journal of Chemistry, 1983, vol. 36, # 6, p. 1159 - 1166
11
[ 33245-30-6 ]
[ 7664-93-9 ]
[ 21901-40-6 ]
[ 6635-86-5 ]
Reference：
[1] Chemische Berichte, 1924, vol. 57, p. 794
12
[ 695-34-1 ]
[ 21901-40-6 ]
[ 6635-86-5 ]
Yield
Reaction Conditions
Operation in experiment
27%
at 0 - 70℃; for 4 h;
The syntheses of several 2-aminonitropyridines were described previously by Talik and Talik [29]. Their methods were applied in the syntheses of I–III compounds using commercially available 2-amino-4-methylpyridine (Fluka, >99percent). These compounds were obtained as follows: 25 g of appropriate 2-amino-4-methylpyridine were dissolved in 125 cm3 of concentrated H2SO4 (Fluka, 96percent). The reaction mixture was cooled under intensive stirring to 0 °C by adding ice mixed with NaCl. Subsequently, 37.5 cm3 of HNO3 (Chempur, 65percent, d = 1.4 g/cm3) were added in small portions keeping the temperature below 10 °C. Then the mixture was stirred for 1.5 h with continuous cooling, and kept at ambient temperature for 1 h. Next, the reaction mixture was heated in a water bath for half an hour at 40 °C, 1 h in the temperature range 60–70 °C and half an hour in a boiling water bath. Then, the whole reaction mixture was cooled to ambient temperature, poured on ice and neutralized with ammonia to a slightly alkaline pH. The solid reaction product was filtered off under vacuum. Two nitro isomers (3 and 5) were separated by steam distillation. More volatile 3- nitro isomer (I) was distilled off and condensed as a pure compound (obtained after drying 10 g), while residual 5-nitro isomer (III) was filtered off and crystallized from water (with H2SO4 and active carbon added initially for dissolving the compound and removing impurities). After neutralization, filtering off and drying, about 15 g of 5-nitro isomer (III) was obtained. The 2-amino-4-methyl-3,5-dinitropyridine (II) was obtained from 2-amino-4-methyl-5-nitropyridine (III) by a similar procedure (nitration and rearrangement to dinitropyridines). The residues were purified by crystallization from water to give 2-amino-4-methyl-3-nitropyridine, I (Yield: (27percent (10 g), m.p. 134(1) °C), 2-amino-4-methyl-3,5-dinitropyridine, II (Yield: 80percent (10.4 g), m.p. 197(1) °C) and 2-amino-4-methyl-5-nitropyridine, III (Yield: 40percent (15 g), m.p. 218(1) °C), respectively. Melting points were determined using a Köfler apparatus. The chemical composition of the obtained compounds was checked using the Carlo Erba Analyser, Model 1104.
Reference：
[1] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2012, vol. 96, p. 952 - 962
[2] Journal of the Chemical Society, 1954, p. 2448,2455
[3] Journal of the American Chemical Society, 1955, vol. 77, p. 3154
[4] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[5] Journal of Molecular Structure, 2013, vol. 1043, p. 15 - 27
[6] Organic Process Research and Development, 2007, vol. 11, # 5, p. 885 - 888
13
[ 33245-30-6 ]
[ 21901-40-6 ]
[ 6635-86-5 ]
Reference：
[1] Acta Chimica Hungarica, 1986, vol. 121, # 4, p. 333 - 338
[2] Acta Chimica Hungarica, 1986, vol. 121, # 4, p. 333 - 338
[3] Australian Journal of Chemistry, 1982, vol. 35, # 10, p. 2035 - 2040
[4] Organic Process Research and Development, 2007, vol. 11, # 5, p. 885 - 888
14
[ 33245-30-6 ]
[ 13466-41-6 ]
[ 21901-40-6 ]
[ 6635-86-5 ]
Reference：
[1] Australian Journal of Chemistry, 1983, vol. 36, # 6, p. 1159 - 1166
15
[ 33245-30-6 ]
[ 7664-93-9 ]
[ 21901-40-6 ]
[ 6635-86-5 ]
Reference：
[1] Chemische Berichte, 1924, vol. 57, p. 794
16
[ 21901-40-6 ]
[ 393-53-3 ]
Reference：
[1] Journal of Organic Chemistry, 1955, vol. 20, p. 1729,1731
17
[ 21901-40-6 ]
[ 66909-38-4 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 121, p. 143 - 157
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 21, p. 5229 - 5233
[3] Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 1, p. 66 - 81
18
[ 21901-40-6 ]
[ 76006-08-1 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 121, p. 143 - 157
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 21, p. 5229 - 5233
[3] Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 1, p. 66 - 81
19
[ 21901-40-6 ]
[ 301222-66-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 10, p. 2493 - 2497
With sulfuric acid; nitric acid; at 0 - 70℃; for 4h;
The syntheses of several 2-aminonitropyridines were described previously by Talik and Talik [29]. Their methods were applied in the syntheses of I-III compounds using commercially available 2-amino-4-methylpyridine (Fluka, >99%). These compounds were obtained as follows: 25 g of appropriate 2-amino-4-methylpyridine were dissolved in 125 cm3 of concentrated H2SO4 (Fluka, 96%). The reaction mixture was cooled under intensive stirring to 0 C by adding ice mixed with NaCl. Subsequently, 37.5 cm3 of HNO3 (Chempur, 65%, d = 1.4 g/cm3) were added in small portions keeping the temperature below 10 C. Then the mixture was stirred for 1.5 h with continuous cooling, and kept at ambient temperature for 1 h. Next, the reaction mixture was heated in a water bath for half an hour at 40 C, 1 h in the temperature range 60-70 C and half an hour in a boiling water bath. Then, the whole reaction mixture was cooled to ambient temperature, poured on ice and neutralized with ammonia to a slightly alkaline pH. The solid reaction product was filtered off under vacuum. Two nitro isomers (3 and 5) were separated by steam distillation. More volatile 3- nitro isomer (I) was distilled off and condensed as a pure compound (obtained after drying 10 g), while residual 5-nitro isomer (III) was filtered off and crystallized from water (with H2SO4 and active carbon added initially for dissolving the compound and removing impurities). After neutralization, filtering off and drying, about 15 g of 5-nitro isomer (III) was obtained. The 2-amino-4-methyl-3,5-dinitropyridine (II) was obtained from 2-amino-4-methyl-5-nitropyridine (III) by a similar procedure (nitration and rearrangement to dinitropyridines). The residues were purified by crystallization from water to give 2-amino-4-methyl-3-nitropyridine, I (Yield: (27% (10 g), m.p. 134(1) C), 2-amino-4-methyl-3,5-dinitropyridine, II (Yield: 80% (10.4 g), m.p. 197(1) C) and 2-amino-4-methyl-5-nitropyridine, III (Yield: 40% (15 g), m.p. 218(1) C), respectively. Melting points were determined using a Koefler apparatus. The chemical composition of the obtained compounds was checked using the Carlo Erba Analyser, Model 1104.
With sulfuric acid; sodium nitrite; at -5 - 0℃; for 3.16667h;
Weigh the starting material 2-amino-4-methyl-5-nitropyridine 23 (10 g) in a 250 ml round bottom flask and 70 ml of concentrated H2SO4Stirring dissolved, until the raw material is completely dissolved, the reaction flask placed in -5 low temperature cold bath, from the constant pressure low liquid funnel slowly dropping pre-configured NaNO2(6.76g) solution, resulting in a large number of bubbles, to avoid the temperature rise too fast to keep the whole process does not exceed the temperature of 0 , with the reaction, the reaction bottle gradually precipitated solid, drop Bi, stirring 10min reaction liquid into orange The solution was clarified and the reaction was continued at 0 C.TLC monitoring showed complete response after 3 h, stop the reaction.The reaction solution was poured into a beaker containing about 300 ml of water to precipitate a large amount of a yellow solid. After crystallization at room temperature for 3 hours, the solid was collected by filtration and dried under an infrared lamp to give 6.72 g of a yellow solid in 67.2% yield.
63.7%
With sulfuric acid; water; sodium nitrite; at 0 - 20℃; for 2h;
Synthesis of the compound 31 The compound 30 (17.4 g, 0.114 mol) was added into 300 mL of water, a concentrated sulphuric acid (30 mL) was slowly added with agitation and cooled to 0C in an ice bath. Sodium nitrite (17.5 g, 0.254 mol) was dissolved in 35 mL of water and added slowly beneath the reaction liquid surface of the reaction system via a long stem funnel. The reaction was run at room temperature for 2 h and boiled up until the reaction ends which was marked by no further brown gas was emitted. The reaction liquid was poured into broken ice, filtered, and dried to obtain 11.15g of the compound 31 with a yield of 63.7%. The melting point is 187.3-188.9C (ethanol) (M.P. 186C was reported in the reference)[J. Chem. Soc.. 1954, 2248 -2451].
Dissolve 4-methyl-5-nitro-pyridin-2-ylamine (3.0 mmol, 0.5 g) in 0.5 mL of sulfuric acid. Add 7.6 niL of water and cool the solution down to O C. Add sodium nitrite (4.5 mmol, 0.3 g) and stir the mixture for two hours, allowing to reach room temperature. Dilute with water and add aq. sodium hydroxide solution 10% until basic pH. Extract in ethyl acetate and wash combined organic layers with saturated aq. sodium chloride solution. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give 4- methyl-5-nitro-pyridin-2-ol. MS(ES): m/? = 155 [M+H].
With Sodium hydrogenocarbonate In 1,4-dioxane at 100℃; for 16h;
102 Example 102: SN40070 Ethyl 7-Methyl-6-((3-methyl-2-oxo-1-(tetrahydro-2H-pyran- 4-yl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-6-yl)amino)imidazo[1,2-a]pyridine-3- carboxylate (129)
. Ethyl 7-Methyl-6-nitroimidazo[1,2-a]pyridine-2-carboxylate. Ethyl bromopyruvate (1.90 g, 9.80 mmol) in dioxane (2 mL) was added to a stirred suspension of 4-methyl-5-nitropyridin- 2-amine (1.0 g, 6.53 mmol) and NaHCO3 (1.1 g, 13.1 mmol) in dioxane (25 mL) at 20 °C. The mixture was stirred at 100 °C for 16 h. The solvent was evaporated. The residue was suspended in water (100 mL) filtered and washed with pet. ether and dried to give ester (1.10 g, 68%) as a tan powder: mp (water) 160-162 °C; 1H NMR [(CD3)2SO] δ 9.71 (s, 1 H, H-5), 8.64 (d, J = 0.6 Hz, 1 H, H-3), 7.67 (d, J = 0.9 Hz, 1 H, H-8), 4.33 (q, J = 7.1 Hz, 2 H, CH2O), 2.39 (d, J = 0.9 Hz, 3 H, 7-CH3), 1.33 (t, J = 7.1 Hz, 3 H, CH3); MS m/z 250.1 (MH+, 100%); HRMS calcd for C11H12N3O4 (MH+) m/z 250.0822, found 250.0818 (1.8 ppm).
68%
With Sodium hydrogenocarbonate In 1,4-dioxane at 100℃; for 16h;
102 Example 102: SN40070 Ethyl 7-Methyl-6-((3-methyl-2-oxo-1-(tetrahydro-2H-pyran- 4-yl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-6-yl)amino)imidazo[1,2-a]pyridine-3- carboxylate (129)
. Ethyl 7-Methyl-6-nitroimidazo[1,2-a]pyridine-2-carboxylate. Ethyl bromopyruvate (1.90 g, 9.80 mmol) in dioxane (2 mL) was added to a stirred suspension of 4-methyl-5-nitropyridin- 2-amine (1.0 g, 6.53 mmol) and NaHCO3 (1.1 g, 13.1 mmol) in dioxane (25 mL) at 20 °C. The mixture was stirred at 100 °C for 16 h. The solvent was evaporated. The residue was suspended in water (100 mL) filtered and washed with pet. ether and dried to give ester (1.10 g, 68%) as a tan powder: mp (water) 160-162 °C; 1H NMR [(CD3)2SO] δ 9.71 (s, 1 H, H-5), 8.64 (d, J = 0.6 Hz, 1 H, H-3), 7.67 (d, J = 0.9 Hz, 1 H, H-8), 4.33 (q, J = 7.1 Hz, 2 H, CH2O), 2.39 (d, J = 0.9 Hz, 3 H, 7-CH3), 1.33 (t, J = 7.1 Hz, 3 H, CH3); MS m/z 250.1 (MH+, 100%); HRMS calcd for C11H12N3O4 (MH+) m/z 250.0822, found 250.0818 (1.8 ppm).
With copper(l) iodide; In N,N-dimethyl-formamide; at 120℃;
mixture of 2-bromo-5-mtro-4-pyridine (100 mg, 0.461 raraol), copper (I) iodide (73.1 mg, 0.384 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (177 mg, 117 muL, 0.922 mmol) in dry DMF (1 mL) was heated under N2 at 120 0C overnight. The reaction mixture was cooled to room temperature and diluted with saturated NH4Cl (3.6 mL) and NH4OH (0.4 mL). The mixture was stirred until homogenous (a little water was added). The mixture was extracted with EtOAc (3 x 20 mL). The combined extracts were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12 x 160 mm, 0-20% EtOAc in hexanes gradient) to afford 4- methyl-5-nitro-2-(trifluoromethyl)pyridine. LCMS calc. = 207.1; found = 207.1 (M+l)+. 1H NMR (500 MHz5 CDCl3): delta 9.17 (s, 1 H); 7.70 (s, 1 H); 2.72 (s, 3 H).
With tert.-butylnitrite; copper(I) bromide; In acetonitrile; at 60 - 70℃; for 2h;
Ste 2: 2-bromo-4-methyl-5-nitropyridineTo the mixture of tert-butyl nitrite (202 mg, 1.96 mmol) and CuBr (225 mg, 1.57 mmol) in CH3CN (2 mL), 4-methyl-5-nitropyridin-2-amine (200 mg, 1.31 mmol) was added portion wise at 60-65 C. The mixture was heated to 70 C for 2 hours, and then cooled and concentrated. The residue was poured into EtOAc, washed with water, brine, dried over Na2S04. The organic solvent was concentrated in vacuo and purified with Column Chromatography (petrol ether : EtOAc =10:1) to give the desired product (50 mg, 17%).1H NMR (CDCI3): delta 8.94 (1H, s), 7.53 (1H, s), 2.64 (3H, s).
Synthesis
Dissolved 4-hydroxybenzenesulfonic acid in water was addedto the solution of 2-amino-4-methyl-5-nitropyridine. The solutionwas slowly evaporated during a few days at room temperature.Crystals of AMNP-HBS (m.p. >330 C (dec.)), suitable for X-ray diffractionstudies, were obtained by re-crystallization from methanol-water mixture (2:1 v/v).
With benzamidine monohydrochloride; sodium t-butanolate; In water; toluene; at 130℃; for 28h;
<strong>[19346-47-5]2-fluoro-4-methyl-5-nitro-pyridine</strong> (1 mmol) was added to a 25 ml reaction tube.Phenylhydrazine hydrochloride (2 mmol), sodium tert-butoxide (3 mmol),H2O (0.5 mL) and toluene (2.5 mL). The reaction was carried out at 130 C.The reaction time was 28 hours, and after the reaction was completed, it was cooled to room temperature.The reaction was quenched by adding 10 mL of ethyl acetate, and washed with 6 mL of saturated brine.The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (6 mL of ethyl acetate each time). The organic phase was combined, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, including organic solvent and inorganic solvent. Said organic solvent, and then separated by column chromatography to obtain the target product,The yield was 95%.
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