* 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.
EXAMPLE 93; Synthesis of 4-Hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-b]pyridine-2-yl)-amide; Step 1: To a mixture of 4-Methoxy-3-nitropyridine (5.0 g, 32.44 mmole) in ethanol (100 mL) was added 10 percent palladium on carbon catalyst (200 mg). The resulting mixture was allowed to shake under a hydrogen atmosphere (50 psi) for 6 h. at room temperature. TLC (50percent ethyl acetate/hexane) indicated complete consumption of starting material. Filtration through celite to remove the catalyst and concentration gave 3-Amino4 methoxypyridine (4.0 g, 32.44 mmol, 100percent yield) as dark red oil.
100%
With hydrogen In methanol at 20℃;
Step 1: 4-methoxypyridin-3-amineA solution of 4-methoxy -3-nitropyridine (100 g, 0.65 mol, Ouhe) and 10percent Pd/C (10 g) in MeOH (2 L) was stirred under 50 psi of hydrogen. The reaction mixture was stirred at rt overnight. The mixture was filtered and concentrated in vacuo to afford 4-methoxypyridin-3- amine (82.1 g, quantitative) as a yellow solid.
99%
With hydrogen In ethanol at 20℃; for 48 h;
Example 26Synthesis of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(4-methoxy-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amineThe compound was synthesized according to Method A.A mixture of 0.475 g (3.08 mmol) of 4-methoxy-3-nitropyridine (Org. Process Res. Dev. 2004, 8, 903-908) and 0.301 g (2.84 mmol) of 10percent palladium on carbon in ethanol (30 mL) was stirred under an atmosphere of hydrogen for 48 hrs. The catalyst was removed by filtration through a pad of celite, and the solvent was removed to give 0.380 mg (99percent) of 3-amino-4-methoxypyridine as a pink powder, which was used in the next step without further purification: 1H NMR (DMSO-d6) δ8.09 (dd, J=6.4, 1.2 Hz, 1H), 7.93 (d, J=1.2 Hz, 1H), 7.36 (d, J=6.4 Hz, 1H), 6.01 (br s, 2H), 4.06 (s, 3H).To a solution of 0.134 g (1.08 mmol) of 3-amino-4-methoxypyridine in THF (3 mL) was added 0.5 mL of butyllithium (2.5 M solution in hexanes), and the mixture was stirred for 15 min. A solution of 0.133 g (0.36 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (6 mL) was added and the resulting mixture was stirred for 1 hr. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried, and concentrated. Chromatography on alumina, eluting first with hexanes/EtOAc (1:1) and then with CH2Cl2/EtOAc (2:3) gave a white powder. Recrystallization from ethanol/CH2Cl2 gave 0.078 g (48percent yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(4-methoxy-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 161-163° C.; 1H NMR (DMSO-d6) δ9.43 (br s, 1H), 8.61-8.37 (m, 3H), 7.83-7.81 (m, 2H), 7.41 (br s, 2H), 7.20 (d, J=5.6 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 4H), 3.71 (s, 4H); Anal. Calcd. for C21H20F2N8O2: C, 55.5; H, 4.4; N, 24.7. Found: C, 55.5; H, 4.4; N, 24.5percent.
44%
With hydrogen In methanol at 20℃; for 10 h;
To a solution of 4-methoxy-3-nitropyridine (2.5 g, 16.2 mmol) in MeOH (50 mL) was added Pd/C 10percent wt/wt (0.5 g) and the mixture was stirred under 1 atm H2 for 10 hours at room temperature. The reaction mixture was filtered through celite and filtrate was concentrated. The crude residue was purified by flash chromatography (0-10percent MeOH/CH2Cl2) to give compound 16 (0.875 g, 44percent). 1H NMR (400 MHz, DMSO-D6) δ 7.83 (s, 1H) 7.70 (d, 1H) 6.79 (d, 1H) 4.79 (s, 2H) 3.79 (s, 3H).
Reference：
[1] Patent: US2007/270433, 2007, A1, . Location in patent: Page/Page column 47
[2] Patent: WO2012/67664, 2012, A1, . Location in patent: Page/Page column 53
[3] Inorganic Chemistry, 2013, vol. 52, # 7, p. 3653 - 3662
[4] Patent: US2011/9405, 2011, A1, . Location in patent: Page/Page column 49-50
[5] Chemistry - A European Journal, 2012, vol. 18, # 51, p. 16358 - 16368
[6] Journal of the American Chemical Society, 2015, vol. 137, # 24, p. 7552 - 7555
[7] Bulletin de la Societe Chimique de France, 1992, # 1, p. 79 - 84
[8] Patent: US2007/167497, 2007, A1, . Location in patent: Page/Page column 27
[9] Med. Ch. I.G., 1934, vol. 2, p. 384,388
[10] Journal of the Chemical Society, <1954> 4516, 4520,
[11] Justus Liebigs Annalen der Chemie, 1936, vol. 521, p. 286,293
[12] Patent: WO2011/78984, 2011, A1, . Location in patent: Page/Page column 62
[13] Patent: WO2012/58125, 2012, A1, . Location in patent: Page/Page column 142
[14] Organic and Biomolecular Chemistry, 2012, vol. 10, # 33, p. 6693 - 6704
Stage #1: at 100℃; for 16 h; Stage #2: at 5℃; for 0.166667 h;
Step 1: 3-Nitro-pyridin-4-ol 4-Methoxy-3-nitropyridine (25.0 g, 162 mmol) in 220 ml conc. hydrobromic acid (48percent) was refluxed at 100° C. for 16 hrs. The reaction mixture was cooled, poured into ice water and neutralized with 155 ml conc. NaOH (32percent). The suspension was stirred for 10 min. at 5° C. and filtered. The solid was washed with water and dried at 50° C. and <30 mbar for 1 hour. The desired product was obtained as a light yellow solid (20.2 g, 89percent).
EXAMPLE 1 endo-4-(1-Aza-bicyclo[2.2.1]hept-3-yloxy)-1-methyl-1H-imidazo[4,5-c]pyridine 4-Methoxy-3-nitropyridine (8.17 g, 53.0 mmol) was transferred to a bomb in EtOH (5-10 mL). To this was added a solution of methylamine in EtOH (26.4 mL, 8.03M, 0.212 mol). The bomb was sealed and lowered into an oil bath at 120° C. The bath temperature fell to 90° C. and remained that way for 2 hours. The temperature was raised to 140° C. over 0.5 hour and held there 0.5 hour. The contents were transferred to a flask with EtOH (not very soluble) and the solvent was evaporated. Flash chromatography on silica gel with a gradient of CH2 Cl2 /CH3 OH gave 7.17 g (88percent) of 4-methylamino-3-nitropyridine as a yellow solid: nap 155°-158° C.
88%
With methylamine In ethanol
EXAMPLE 1 endo-4-(1-Aza-bicyclo[2.2.1]hept-3-yloxy)-1-methyl-1H-imidazol[4,5-c]pyridine 4-Methoxy-3-nitropyridine (8.17 g, 53.0 mmol) was transferred to a bomb in EtOH (5-10 mL). To this was added a solution of methylamine in EtOH (26.4 mL, 8.03M, 0.212 mol). The bomb was sealed and lowered into an oil bath at 120° C. The bath temperature fell to 90° C. and remained that way for 2 hours. The temperature was raised to 140° C. over 0.5 hour and held there 0.5 hour. The contents were transferred to a flask with EtOH (not very soluble) and the solvent was evaporated. Flash chromatography on silica gel with a gradient of CH2 Cl2 /CH3 OH gave 7.17 g (88percent) of 4-methylamino-3-nitropyridine as a yellow solid: mp 155°-158° C.
Reference：
[1] Patent: US5571819, 1996, A,
[2] Patent: US5723468, 1998, A,
[3] Patent: US2011/21501, 2011, A1, . Location in patent: Page/Page column 92
[4] Patent: US2012/35143, 2012, A1,
6
[ 31872-62-5 ]
[ 74-89-5 ]
[ 1633-41-6 ]
Yield
Reaction Conditions
Operation in experiment
2.3 g
for 3 h; Reflux
30.1 methyl-(3-nitropyridin-4-yl)-amine 2.36 g 4-methoxy-3-nitro-pyridine and 2.33 ml methylamine (40percent in water) are refluxed in 25 ml of ethanol for 3 h. Then the reaction mixture is evaporated to dryness. 2.3 g product are obtained as a solid.
To cone. H2SO4 (5 mL) chilled in an ice bathm is added 4-methoxypyridine (0.5 mL, 4.9 mmol) dropwise over a 20 s period. Cone. Fuming nitric acid (5 mL) is added, and the reaction mixture is heated at 70 °C for 2.5 days. This mixture is cooled to rt, and then is poured into ice. Soild K2CO3 is added until the pH of the mixture is basic. The mixture is partitioned between H20 and EtOAc. The two layers is separated, and the aqueous layer is extracted with EtOAc once. The combined organic layers are washed with H2O and brine, dried over MgS04, filtered, and concentrated in vacuo to yield 0.7 g (92percent) of the product a yellow powder. 1H NMR (CDC13, 300 MHz) δ 9.02 (s, 1H), 8.65 (d, J= 5.8, 1 H), 7.04 (d, J = 5.9, 1H), 4.05 (s, 3H). LC Rt: 0.5 min; LCMS m/z 155 (M+l, 100percent).
Reference：
[1] Justus Liebigs Annalen der Chemie, 1937, vol. 529, p. 291
[2] Chemische Berichte, 1938, vol. 71, p. 2347,2358
[3] Chemische Berichte, 1942, vol. 75, p. 1936,1942
[4] Organic Letters, 2000, vol. 2, # 15, p. 2253 - 2256
16
[ 124-41-4 ]
[ 13091-23-1 ]
[ 31872-62-5 ]
Reference：
[1] Med.Ch.I.G., 1934, vol. 2, p. 384,387
17
[ 31872-62-5 ]
[ 75-04-7 ]
[ 562825-95-0 ]
Yield
Reaction Conditions
Operation in experiment
99%
at 85℃; for 2 h;
A solution consisting of 4-methoxy-3-nitropyridine (15.0 g, 97.3 MMOL) with ethyl amine (46.5 mL of 70percent aqueous solution, 584 MMOL) in ethanol (30 mL) was stirred at 85 °C in a sealed flask for 2 h. Removal of all VOLATILES IN VACUO afforded the title compound (16.2 g, 99 percent). MS: (M+H) + = m/z 168.
99%
at 85℃; for 2 h;
A solution consisting of 4-methoxy-3-nitropyridine (15.0 g, 97.3 mmol) with ethyl amine (46.5 mL of 70percent aqueous solution, 584 mmol) in ethanol (30 mL) was stirred at 85 °C in a sealed flask for 2 h. Removal of all volatiles in vacuo afforded the title compound (16.2 g, 99 percent). MS: (M+H) + = m/z 168.
Stage #1: With potassium <i>tert</i>-butylate; ammonia In tetrahydrofuran at -78℃; for 0.166667 h; Stage #2: With tert.-butylhydroperoxide In tetrahydrofuran at -78 - -40℃; for 1.33333 h;
Into a 1 L flask containing 250 ml_ of dry THF cooled to -78°C was condensed NH3 (100-150 ml_). Solid t-BuOK (200 mmole, 22.5 g) was added to the THF and was completely dissolved after 10 min of vigorous stirring. In a separate 500 ml_ flask, 10OmL of dry THF containing 4-methoxy-3-nitropyridine (12.3 g, 80 mmole) was cooled to 00C. To this solution was added t-BuOOH (88 mmole, 16 ml_). The t-BuOOH/THF solution was then added to the -78°C ammonia >solution over 20 min via dropping funnel. The reaction solution was allowed to warm to -400C and then stirred at this temperature for 1 h. The reaction was quenched with saturated NH4CI solution (20 mL) and the cooling bath removed. The reaction solution was allowed to stir overnight at RT. The precipitate was filtered and dried under vacuum to give (9.5 g, 70percent) of product as a tan solid: LC/MS: m/z 171 [M+H]+, single component.
51%
With tert.-butylhydroperoxide; potassium <i>tert</i>-butylate; ammonia In tetrahydrofuran; decane at -78 - 0℃; for 3.16667 h;
Step 1. 2-Hydroxy-4-methoxy-5-nitropyridine THF (100 mL) was cooled to-78 °C and anhydrous NH3 (-200 mL) was condensed into the THF. Potassium t-butoxid (45.5 g, 405 mmol) was added and the mixture was allowed to warm to--35 °C. 4-Methoxy-3-nitropyridine (25.0 g, 162 mmol) was cooled to 0 °C in THF (200 mL) and a solution of t-BuOOH (5 M in decane, 34 mL, 170 mmol) was added over 10 min. This solution was then added dropwise to the KOt-Bu solution over 1 h, then stirred for 2 h at-35 °C and then carefully quenched with-50 mL of sat. NH4C1 solution. The mixture was allowed to vent and warm to rt overnight, then the organics were concentrated and the residue made acidic with NH4C1 solution and filtered. The solid was washed with cold H20 and dried to give the title compound as a tan solid (14.0 g, 51percent).
51%
With tert.-butylhydroperoxide; potassium <i>tert</i>-butylate; ammonia In tetrahydrofuran; decane at -78 - 0℃; for 3.16667 h;
Step 1. 2-Hydroxy-4-methoxy-5-nitropyridine THF (100 mL) was cooled to-78 °C and anhydrous NH3 (-200 mL) was condensed into the THF. Potassium t-butoxid (45.5 g, 405 mmol) was added and the mixture was allowed to warm to--35 °C. 4-Methoxy-3-nitropyridine (25.0 g, 162 mmol) was cooled to 0 °C in THF (200 mL) and a solution of t-BuOOH (5 M in decane, 34 mL, 170 mmol) was added over 10 min. This solution was then added dropwise to the KOt-Bu solution over 1 h, then stirred for 2 h at-35 °C and then carefully quenched with-50 mL of sat. NH4C1 solution. The mixture was allowed to vent and warm to rt overnight, then the organics were concentrated and the residue made acidic with NH4C1 solution and filtered. The solid was washed with cold H20 and dried to give the title compound as a tan solid (14.0 g, 51percent).
90 g
With tert.-butylhydroperoxide; potassium <i>tert</i>-butylate; ammonia In tetrahydrofuran at -30 - -25℃; for 1 h;
Example 1 Preparation of 2-hydroxy-4-methoxy-5-nitro pyridine(4-methoxy-5-nitropyridin-2-ol) Charged ammonia gas at -70° C. to a solution of THF (1800 ml). After achieving 1.0 Kg, stopped the gas flow. Charged potassium tert butoxide (182 gms). Temperature was raised to -30° C., charged a solution of 4-methoxy-3-nitro pyridine (100 g) dissolved in THF (250 ml) and tert butyl hydro peroxide (144 ml) to the above mixture at -30 to -25° C. After addition, continued the reaction for 1.0 hr. Saturated ammonium chloride solution (450 ml) was cautiously added and the mixture was allowed to warm to room temperature. The ammonia was evaporated and the residue diluted with water (500 mL). The resulting solid was collected, washed with water and dried to give 2-hydroxy-4-methoxy-5-nitro pyridine(4-methoxy-5-nitropyridin-2-ol) (90.0 g).
Into a 1 L flask containing 250 ml_ of dry THF cooled to -78°C was condensed NH3 (100-150 ml_). Solid t-BuOK (200 mmole, 22.5 g) was added to the THF and was completely dissolved after 10 min of vigorous stirring. In a separate 500 ml_ flask, 10OmL of dry THF containing <strong>[31872-62-5]4-methoxy-3-nitropyridine</strong> (12.3 g, 80 mmole) was cooled to 00C. To this solution was added t-BuOOH (88 mmole, 16 ml_). The t-BuOOH/THF solution was then added to the -78°C ammonia >solution over 20 min via dropping funnel. The reaction solution was allowed to warm to -400C and then stirred at this temperature for 1 h. The reaction was quenched with saturated NH4CI solution (20 mL) and the cooling bath removed. The reaction solution was allowed to stir overnight at RT. The precipitate was filtered and dried under vacuum to give (9.5 g, 70percent) of product as a tan solid: LC/MS: m/z 171 [M+H]+, single component.
51%
With tert.-butylhydroperoxide; potassium tert-butylate; ammonia; In tetrahydrofuran; decane; at -78 - 0℃; for 3.16667h;
Step 1. 2-Hydroxy-4-methoxy-5-nitropyridine THF (100 mL) was cooled to-78 °C and anhydrous NH3 (-200 mL) was condensed into the THF. Potassium t-butoxid (45.5 g, 405 mmol) was added and the mixture was allowed to warm to--35 °C. <strong>[31872-62-5]4-Methoxy-3-nitropyridine</strong> (25.0 g, 162 mmol) was cooled to 0 °C in THF (200 mL) and a solution of t-BuOOH (5 M in decane, 34 mL, 170 mmol) was added over 10 min. This solution was then added dropwise to the KOt-Bu solution over 1 h, then stirred for 2 h at-35 °C and then carefully quenched with-50 mL of sat. NH4C1 solution. The mixture was allowed to vent and warm to rt overnight, then the organics were concentrated and the residue made acidic with NH4C1 solution and filtered. The solid was washed with cold H20 and dried to give the title compound as a tan solid (14.0 g, 51percent).
90 g
With tert.-butylhydroperoxide; potassium tert-butylate; ammonia; In tetrahydrofuran; at -30 - -25℃; for 1h;
Example 1 Preparation of 2-hydroxy-4-methoxy-5-nitro pyridine(4-methoxy-5-nitropyridin-2-ol) Charged ammonia gas at -70° C. to a solution of THF (1800 ml). After achieving 1.0 Kg, stopped the gas flow. Charged potassium tert butoxide (182 gms). Temperature was raised to -30° C., charged a solution of <strong>[31872-62-5]4-methoxy-3-nitro pyridine</strong> (100 g) dissolved in THF (250 ml) and tert butyl hydro peroxide (144 ml) to the above mixture at -30 to -25° C. After addition, continued the reaction for 1.0 hr. Saturated ammonium chloride solution (450 ml) was cautiously added and the mixture was allowed to warm to room temperature. The ammonia was evaporated and the residue diluted with water (500 mL). The resulting solid was collected, washed with water and dried to give 2-hydroxy-4-methoxy-5-nitro pyridine(4-methoxy-5-nitropyridin-2-ol) (90.0 g).
[0538] A solution of 643 mg (3.00 mmol) tert. butyl-4-aminomethyl-piperidin-1-carboxylate and 471 mg (3.00 mmol) <strong>[31872-62-5]4-methoxy-3-nitro-pyridine</strong> in 5 mL MeOH was refluxed for 2 hours and then evaporated down i. vac. The crude product was purified by column chromatography (silica gel, gradient dichloromethane/MeOH 100:0-->19:1 v/v) (Yield: 1.010 g, quantitative). [0539] The intermediate product was added to a suspension of 500 mg Raney nickel in 30 mL MeOH and the mixture was hydrogenated for 6 hours at 50° C. and 50 psi H2-pressure. The catalyst was filtered off and the filtrate evaporated i. vac. The crude product was purified by column chromatography (Alox (neutral, activity II-III), Gradient dichloromethane/MeOH 99:1-->19:1 v/v) purified. [0540] Yield: 0.480 g (53percent of theory) [0541] Rf=0.15 (silica gel, dichloromethane/MeOH 19/1 v/v) [0542] ESI-MS: (M+H)+=307
1-[[6-(4-amino-1-piperidinyl)-5-chloro-3-pyridinyl]carbonyl]pyrrolidine ditrifluoroacetate[ No CAS ]
[ 31872-62-5 ]
[ 749899-26-1 ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; for 3h;
The product from example 43 step a) (0.9g) was added to a stirred solution of 4- methoxy-3-nitropyridine (0.32g) and Hunigs base (LML) in NMP (3ml) and heated at 120 C for 3h. The mixture was allowed to cool and partitioned between ethyl acetate and water. The phases were separated and the aqueous extracted with ethyl acetate. The combined organic phases were dried (NA2SO4) and concentrated in vacuo to give a yellow gum which was purified by column chromatography (ethyl acetate: isohexane (1: 1), then dichloromethane: methanol (10: 1) ) to give the sub-title compound as a yellow solid (0.28g). MS (APCI+) 431/3 [M+H] + H NMR 6 (DMS0) 9.05 (s, lH), 8.40 (d, lH), 8. 30 (d, LH), 8.10 (d, lH), 7.93 (d, LH), 7.19 (d, LH), 4.00 (d, LH), 3.88 (d, 2H), 3.54-3. 43 (m, 4H), 3.11 (t, 2H), 2.07 (d, 2H), 1.90-1. 69 (m, 6H)
With sodium acetate; In ethanol; for 54h;Heating / reflux;
A mixture of <strong>[31872-62-5]4-methoxy-3-nitropyridine</strong> (4.34 g, 28.1 MMOL), 4-AMINO-1- benzypiperidine (6.01 g, 30.9 MMOL), and NaOAc (2.31 g, 28.1 MMOL) in absolute ethanol (20 mL) was stirred at reflux for 54 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in CH2CI2 (100 mL) and washed with water (2 x 30 mL). The organic layer was dried over anhydrous MgS04 and concentrated in vacuo to provide the product (8. 78 g) as a dark yellow solid. 1 H NMR (400 MHz, CDCI3) 5 9.21 (s, 1 H), 8.26 (dd, J = 6.0, 0. 4 Hz, 1 H), 8.20 (broad d, J = 7.1 Hz, 1 H), 7.34-7. 25 (complex m, 5 H), 6.70 (d, J = 6.0 Hz, 1 H), 3.62-3. 53 (m, 1 H), 3.55 (s, 2 H), 2. 89-2. 79 (m, 2 H), 2.30-2. 20 (m, 2 H), 2.10-2. 00 (m, 2 H), 1.76-1. 65 (m, 2 H).
4-METHOXY-3-NITROPYRIDINE (10.0 g, 64 MMOL), cyclopropylmethyl amine (4.56 g, 64 MMOL), and EtOH (7 mL) were combined in a sealed tube and heated to 85 °C with vigourous shaking for 48 h. The mixture was concentrated in vacuo to afford the desired compound as a solid (12.0 g). MS (ES+) m/z 194 [M+H] +.
A solution of <strong>[31872-62-5]4-methoxy-3-nitropyridine</strong> (5.00 g, 32.4 MMOL) and 2,2- dimethyl-1, 3-propanediamine (16.2 g, 161 MMOL) in DMF (100 mL) was heated at 100 °C for 5 h. The solvent was removed under reduced pressure to give 7.30 g of the desired COMPOUND. 1H NMR (400 MHz, CDCL3) 8 9.20 (s, 2H), 9.10 (br, 1H), 8.20 (d, 1H), 6.70 (d, 1 H), 3.25 (d, 2H), 2.60 (s, 2H), 1.25 (br, 2H), 0.95 (s, 6H).
With N-ethyl-N,N-diisopropylamine; In ethanol; for 3h;Reflux;
Step 1: Synthesis of N-cyclopropyl-3-nitropyridin-4-amine 5-b4- Methoxy-3-nitropyridine 5-a (CAS 31872-62-5) (200 g, 1300 mmol), cyclopropylamine (CAS 765-30-0) (185.5 g, 3250 mmol) and DIEA (CAS 7087-68-5) (336 g, 2600 mmol) in dry ethanol (800 mL) were refluxed for 3 hours. The mixture was cooled to 0°C. The solid was collected by filtration. The filter cake was washed with cold ethanol (150 mL). The solid was dried to afford compound 5-b as a white powder (167 g, 72percent).
72%
With N-ethyl-N,N-diisopropylamine; In ethanol; for 3h;Reflux;
<strong>[31872-62-5]4-methoxy-3-nitropyridine</strong> 7-a (CAS 31872-62-5) (200 g, 1300 mmol), cyclopropyl- amine (185.5 g, 3250 mmol) and diisopropyl ethyl amine (336 g, 2600 mmol) in dry ethanol (800 mL) were refluxed for 3 hours. The mixture was cooled to 0°C. The solid was collected by filtration. The filter cake was washed with cold ethanol (150 mL). The solid was dried to afford the title compound 7-b (167 g, 72percent yield) as a white powder.
72%
With N-ethyl-N,N-diisopropylamine; In ethanol; for 3h;Reflux;
Scheme 5: Synthesis of l-cyclopropyl-lH-imidazo[4,5-c]pyridin-2(3H)-one (5-d) Step 1: Synthesis of N-cyclopropyl-3-nitropyridin-4-amine (5-b)<strong>[31872-62-5]4-Methoxy-3-nitropyridine</strong> 5-a (CAS 31872-62-5) (200 g, 1300 mmol), cyclopropyl- amine (CAS 765-30-0) (185.5 g, 3250 mmol) and DIEA (CAS 7087-68-5) (336 g, 2600 mmol) in dry ethanol (800 mL) was refluxed for 3 hours. The mixture was cooled to 0°C. The solid was collected by filtration. The filter cake was washed with cold ethanol (150 mL). The solid was dried to afford compound 5-b as a white powder (167 g, 72percent).
72%
With N-ethyl-N,N-diisopropylamine; In ethanol; for 3h;Reflux;
The mixture of <strong>[31872-62-5]4-methoxy-3-nitropyridine</strong> 10-a (200 g, 1300 mmol, CAS 31872-62-5), cyclopropylamine (185.5 g, 3250 mmol) and diisopropyl ethyl amine (336 g, 2600 mmol) in dry ethanol (800 mL) was refluxed for 3 hours. The mixture was cooled to 0°C. The solid was collected by filtration. The filter cake was washed with cold ethanol (150 mL). The solid was dried to afford the title compound 10-b as a white powder (167 g, 72percent).
72%
With N-ethyl-N,N-diisopropylamine; In ethanol; for 3h;Reflux;
<strong>[31872-62-5]4-methoxy-3-nitropyridine</strong> 7-a (CAS 31872-62-5) (200 g, 1300 mmol), cyclopropyl-amine (185.5 g, 3250 mmol) and diisopropyl ethyl amine (336 g, 2600 mmol) in dry ethanol (800 mL) were refluxed for 3 hours. The mixture was cooled to 0° C. The solid was collected by filtration. The filter cake was washed with cold ethanol (150 mL). The solid was dried to afford the title compound 7-b (167 g, 72percent yield) as a white powder.
In ethanol;
Cyclopropyl-(3-nitro-pyridin-4-yl)-amine A solution of <strong>[31872-62-5]4-methoxy-3-nitropyridine</strong> (7.71 g, 50 mmol) and cyclopropylamine (7.14 g, 125 mmol) in EtOH (20 mL) was heated at 80° C. in a sealed tube for 2 h. The solvent was evaporated to give cyclopropyl-(3-nitro-pyridin-4-yl)-amine as a yellow solid. 1H NMR (CD3OD) delta: 0.72-0.75 (m, 2 H), 0.99-1.03 (m, 2 H), 2.63-2.68 (m, 1 H), 7.19 (d, J=6.2 Hz, 1 H), 8.26 (b, 1 H), 8.35 (d, J=6.2 Hz, 1 H), 9.22 (s, 1 H); IR (KBr, cm-1): 3369, 1613, 1560, 1515, 1406, 1254, 1195, 1039, 881, 846, 769, 545; MS m/e 180 (MH+).
With N-ethyl-N,N-diisopropylamine; In ethanol; for 3h;Reflux;
A solution of 10a1 (4 g, 26 mmol) (Molekula), cyclopropylamine 10a2 (4.5 ml_, 64.9 mmol) (Avra) and N, N-diisopropylethylamine (8.9 ml_, 54 mmol) in EtOH (15 mL) is refluxed for 3 h. The reaction mixture is cooled to 0QC and the solid in suspension is collected by filtration. The solid obtained is washed with cold EtOH to afford intermediate 10a3.
EXAMPLE 1 endo-4-(1-Aza-bicyclo[2.2.1]hept-3-yloxy)-1-methyl-1H-imidazo[4,5-c]pyridine <strong>[31872-62-5]4-Methoxy-3-nitropyridine</strong> (8.17 g, 53.0 mmol) was transferred to a bomb in EtOH (5-10 mL). To this was added a solution of methylamine in EtOH (26.4 mL, 8.03M, 0.212 mol). The bomb was sealed and lowered into an oil bath at 120° C. The bath temperature fell to 90° C. and remained that way for 2 hours. The temperature was raised to 140° C. over 0.5 hour and held there 0.5 hour. The contents were transferred to a flask with EtOH (not very soluble) and the solvent was evaporated. Flash chromatography on silica gel with a gradient of CH2 Cl2 /CH3 OH gave 7.17 g (88percent) of 4-methylamino-3-nitropyridine as a yellow solid: nap 155°-158° C.
7.17 g (88%)
With methylamine; In ethanol;
EXAMPLE 1 endo-4-(1-Aza-bicyclo[2.2.1]hept-3-yloxy)-1-methyl-1H-imidazol[4,5-c]pyridine <strong>[31872-62-5]4-Methoxy-3-nitropyridine</strong> (8.17 g, 53.0 mmol) was transferred to a bomb in EtOH (5-10 mL). To this was added a solution of methylamine in EtOH (26.4 mL, 8.03M, 0.212 mol). The bomb was sealed and lowered into an oil bath at 120° C. The bath temperature fell to 90° C. and remained that way for 2 hours. The temperature was raised to 140° C. over 0.5 hour and held there 0.5 hour. The contents were transferred to a flask with EtOH (not very soluble) and the solvent was evaporated. Flash chromatography on silica gel with a gradient of CH2 Cl2 /CH3 OH gave 7.17 g (88percent) of 4-methylamino-3-nitropyridine as a yellow solid: mp 155°-158° C.
With methylamine; In ethanol; water; for 3h;Reflux;
Example 210 55.1 methyl-(3-nitropyridin-4-yl)-amine 2.36 g <strong>[31872-62-5]4-methoxy-3-nitro-pyridine</strong> and 2.33 ml methylamine (40percent in water) are refluxed in 25 ml of ethanol for 3 h. Then the reaction mixture is evaporated to dryness. 2.3 g product are obtained as a solid.
With methylamine; In ethanol; water;
30.1methyl-(3-nitropyridin-4-yl)-amine2.36 g <strong>[31872-62-5]4-methoxy-3-nitro-pyridine</strong> and 2.33 ml methylamine (40percent in water) are refluxed in 25 ml of ethanol for 3 h.Then the reaction mixture is evaporated to dryness.2.3 g product are obtained in the form of a solid.
A mixture of g-1 (0.0078 mol) and g-2 (0.0094 mol) in ethanol (10 ml) was stirred and refluxed for 24 hours, then cooled down to 0°C. The precipitate was filtered off, washed with ethanol and dried, yielding 1.8 g of intermediate g-3 (88percent, melting point: 154°C).
Step 1: 3-Nitro-pyridin-4-ol <strong>[31872-62-5]4-Methoxy-3-nitropyridine</strong> (25.0 g, 162 mmol) in 220 ml conc. hydrobromic acid (48percent) was refluxed at 100° C. for 16 hrs. The reaction mixture was cooled, poured into ice water and neutralized with 155 ml conc. NaOH (32percent). The suspension was stirred for 10 min. at 5° C. and filtered. The solid was washed with water and dried at 50° C. and <30 mbar for 1 hour. The desired product was obtained as a light yellow solid (20.2 g, 89percent).
To cone. H2SO4 (5 mL) chilled in an ice bathm is added 4-methoxypyridine (0.5 mL, 4.9 mmol) dropwise over a 20 s period. Cone. Fuming nitric acid (5 mL) is added, and the reaction mixture is heated at 70 °C for 2.5 days. This mixture is cooled to rt, and then is poured into ice. Soild K2CO3 is added until the pH of the mixture is basic. The mixture is partitioned between H20 and EtOAc. The two layers is separated, and the aqueous layer is extracted with EtOAc once. The combined organic layers are washed with H2O and brine, dried over MgS04, filtered, and concentrated in vacuo to yield 0.7 g (92percent) of the product a yellow powder. 1H NMR (CDC13, 300 MHz) delta 9.02 (s, 1H), 8.65 (d, J= 5.8, 1 H), 7.04 (d, J = 5.9, 1H), 4.05 (s, 3H). LC Rt: 0.5 min; LCMS m/z 155 (M+l, 100percent).
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