* 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.
With chloric acid; tin(ll) chloride In water at 90℃; for 3 h; Heating / reflux
J. 2-Chloro-N4-methyl-pyridine-3, 4-diamine 0.61 G (4.0 MMOL) METHYL- (3-NITRO-PYRIDIN-4-YL)-AMINE were dissolved in 3.5 ml conc. chloric acid and the mixture heated to 90 C. A suspension of 3.5 G (15 MMOL) stannous chloride in conc. chloric acid (4 ML) was slowly added and the reaction was refluxed for 3 h. The suspension was cooled to room temperature, poured into water (75 ml) and extracted with DICHLOROMETHANE (2 x 30 ML). The organic layers were dried over magnesium sulphate and concentrated in vacuo to afford 0.60 G (95percent) of the title compound as a white solid. M. p. 168-169 C.
Reference：
[1] Patent: WO2005/26164, 2005, A1, . Location in patent: Page/Page column 42
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 22, p. 6887 - 6896
[3] Patent: EP1568699, 2005, A1, . Location in patent: Page/Page column 82
2
[ 1633-41-6 ]
[ 50432-68-3 ]
[ 50432-67-2 ]
Reference：
[1] Patent: US4654350, 1987, A,
3
[ 1633-41-6 ]
[ 50432-67-2 ]
Reference：
[1] Patent: US5723468, 1998, A,
4
[ 50432-67-2 ]
[ 122-51-0 ]
[ 50432-68-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 22, p. 6887 - 6896
5
[ 50432-67-2 ]
[ 122-51-0 ]
[ 50432-68-3 ]
Reference：
[1] Patent: US5571819, 1996, A,
[2] Patent: US5723468, 1998, A,
With chloric acid; tin(ll) chloride; In water; at 90℃; for 3h;Heating / reflux;
J. 2-Chloro-N4-methyl-pyridine-3, 4-diamine 0.61 G (4.0 MMOL) METHYL- (3-NITRO-PYRIDIN-4-YL)-AMINE were dissolved in 3.5 ml conc. chloric acid and the mixture heated to 90 C. A suspension of 3.5 G (15 MMOL) stannous chloride in conc. chloric acid (4 ML) was slowly added and the reaction was refluxed for 3 h. The suspension was cooled to room temperature, poured into water (75 ml) and extracted with DICHLOROMETHANE (2 x 30 ML). The organic layers were dried over magnesium sulphate and concentrated in vacuo to afford 0.60 G (95%) of the title compound as a white solid. M. p. 168-169 C.
82b) 2-Chloro-N*4*-methylpyridine-3,4-diamine; [] A solution of methyl-(3-nitro-pyridin-4-yl)amine (7.00 g) in concentrated hydrochloric acid (150 mL) was heated to 90C. Tin(II) chloride dihydrate (52.2 g) was then added, and this was heated at 90C for 30 minutes. The reaction solution was cooled to 0C, iced water (700 mL) was added, and this was stirred for 30 minutes. The solution was concentrated under reduced pressure, and then ammonia-saturated methanol solution (700 mL) was added to the residue, and this was stirred at 5C for 15 hours. The solvent was removed by concentration under reduced pressure. The residue was suspended in ethyl acetate (500 mL), and this was filtered through celite. The celite and the suspended material were washed five times with 250 mL of ethyl acetate, then the organic layers were combined, and this was concentrated under reduced pressure to give the title compound (7.22 g).
K. 4-Chloro-1, 2-dimethyl-1 H-imidazo [4,5-c] pyridine 5.0 G (31.7 MMOL) 2-CHLORO-N4-METHYL-PYRIDINE-3, 4-diamine were suspended in 25 ml acetic anhydride and the suspension was heated at 50 C for 1H. The reaction was poured into water (50 ML) and concentrated in vacuo. The residue was suspended in 50 ml water and the precipitate collected by filtration to give 4.6 G (80%) of the title compound as a beige solid. m. p. 197-198 C.
82c) 4-Chloro-1-methyl-1,3-dihydroimidazo[4.5-c]pyridin-2-one; [] N,N'-disuccinimidyl carbonate (3.035 g) was added to a solution of <strong>[50432-67-2]2-chloro-N*4*-methylpyridine-3,4-diamine</strong> (1.38 g) in acetonitrile (300 mL). The solution was stirred at room temperature for 48 hours, then additional N,N'-disuccinimidyl carbonate (3.035 g) was added, and this was heated at 50C for eight hours. The solvent was removed by concentration under reduced pressure, water (500 mL) was added, and this was extracted four times with dichloromethane (200 mL). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography, and the dichloromethane:ethyl acetate 1:1 fraction gave the title compound (1.038 g).
4-Methylamino-3-nitropyridine (7.17 g, 46.8 mmol) was reductively chlorinated with SnCl2.2H2 O (42.26g, 0.187 mol) according to the procedure described by Houston et al., J. Med. Chem. 28,467-471 (1985), with the following modifications. The reaction was worked up by evaporation of the reaction mixture, addition of water (approximately 650 mL) with heating to dissolve most of the solid. The suspension was cooled in an ice bath and 2M ammonium hydroxide solution was added. When the precipitate persisted, additional 2M ammonium hydroxide (134 mL) was added. This mixture (pH 6) was stored overnight in the refrigerator. The solid was removed by filtration and washed with H2 O (1.35 L). Evaporation of the combined filtrate and wash gave 63 g of residue. An additional water wash (500 mL) of the solid gave another 2 g of residue. Most of this solid was NH4 Cl. An excess of Amberlite IRA-400(OH) ion exchange resin was stirred in CH3 OH and the residue from the evaporation was added. After stirring for 0.5 to 1 hour, the solvent was removed by evaporation under reduced pressure and the residue was azeotroped with absolute EtOH two times to give 5.94 g (81%) of 3-amino-2-chloro-4-methylaminopyridine as an oil which was one spot by TLC (silica gel, 1:9 MeOH: CH2 Cl2); 1 H NMR (200 MHz, DMSO-d6) delta 7.41 (1H, d, J=6.6 Hz), 6.34 (1H, d, J=6.6 Hz), 5.88 (1H, poorly resolved quartet), 4.67 (2H, s), 2.74 (3H, d, J=5.3 Hz).
12
conc. H2 SO4[ No CAS ]
[ 50432-67-2 ]
[ 122-51-0 ]
[ 50432-68-3 ]
Yield
Reaction Conditions
Operation in experiment
5.65 g (91%)
In dichloromethane;
To a heterogeneous mixture of 3-amino-2-chloro-4-methylaminopyridine (5.9 g, 37 mmol) and triethyl orthoformate (12.92 mL, 87.2mmol) was added 5 drops of conc. H2 SO4. A short path distillation apparatus was attached. The reaction flask was lowered into a hot oil bath and stirred. at 110 C. to 190 C. The time spent heating was 20-25 minutes. On cooling, the thick residue was dissolved in CH2 Cl2 (40 mL) and was allowed to stir overnight with a little CaO. The solid was removed by filtration and the filtrate was concentrated. Flash chromatography on silica gel eluding with (CH2 Cl2 /CH3 OH, 95:5) gave 5.65 g (91%) of 4-chloro-1-methyl-1H-imidazo[4,5c]pyridine as a light yellow solid: mp 127-131 C.; MS 167 (M+).
5.65 g (91%)
In dichloromethane;
To a heterogeneous mixture of 3-amino-2-chloro-4-methylaminopyridine (5.9 g, 37 mmol) and triethyl orthoformate (12.92 mL, 87.2 mmol) was added 5 drops of conc. H2 SO4. A short path distillation apparatus was attached. The reaction flask was lowered into a hot oil bath and stirred at 110 C. to 190 C. The time spent heating was 20-25 minutes. On cooling, the thick residue was dissolved in CH2 Cl2 (40 mL) and was allowed to stir overnight with a little CaO. The solid was removed by filtration and the filtrate was concentrated. Flash chromatography on silica gel eluding with (CH2 Cl2 /CH3 OH, 95:5) gave 5.65 g (91%) of 4-chloro-1-methyl-1H-imidazo[4,5-c]pyridine as a light yellow solid: mp 127-131 C.; MS 167 (M+).
endo-4-(1-Aza-bicyclo[2.2.1]hept-3-yloxy)-1-methyl-1H-imidazol[4,5-c]pyridine[ No CAS ]
[ 50432-67-2 ]
Yield
Reaction Conditions
Operation in experiment
5.94 g (81%)
In methanol; ammonium hydroxide; water;
4-Methylamino-3-nitropyridine (7.17 g, 46.8 mmol) was reductively chlorinated with SnCl2.2H2 O (42.26 g, 0.187 mol) according to the procedure described by Houston et al., J. Med. Chem. 28, 467-471 (1985), with the following modifications. The reaction was worked up by evaporation of the reaction mixture, addition of water (approximately 650 mL) with heating to dissolve most of the solid. The suspension was cooled in an ice bath and 2M ammonium hydroxide solution was added. When the precipitate persisted, additional 2M ammonium hydroxide (134 mL) was added. This mixture (pH 6) was stored overnight in the refrigerator. The solid was removed by filtration and washed with H2 O (1.35 L). Evaporation of the combined filtrate and wash gave 63 g of residue. An additional water wash (500 mL) of the solid gave another 2 g of residue. Most of this solid was NH4 Cl. An excess of Amberlite IRA-400(OH) ion exchange resin was stirred in CH3 OH and the residue from the evaporation was added. After stirring for 0.5 to 1 hour, the solvent was removed by evaporation under reduced pressure and the residue was azeotroped with absolute EtOH two times to give 5.94 g (81%) of 3-amino-2-chloro-4-methylaminopyridine as an oil which was one spot by TLC (silica gel, 1:9 MeOH: CH2 Cl2); 1 H NMR (200 MHz, DMSO-d6) delta7.41 (1H, d, J=6.6 Hz), 6.34 (1H, d, J=6.6 Hz), 5.88 (1H, poorly resolved quartet), 4.67 (2H, s), 2.74 (3H, d, J=5.3 Hz).
4-(1-benzothienyl-3-methoxy)-1-methyl-1H-imidazo(4,5-c)pyridine[ No CAS ]
[ 50432-67-2 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; NaH; stannous chloride; In N-methyl-acetamide;
EXAMPLE 1 15.84 g of 1-benzothienyl-3-methanol is dissolved in 110 ml of dimethylformamide; 2.88 g of NaH is added and the mixture is stirred at 20 for 1 hour. After a solution of 16.76 g of <strong>[50432-68-3]4-chloro-1-methyl-1H-imidazo(4,5-c)pyridine</strong> [m.p. 132-134; obtainable by reaction of 4-methylamino-3-nitropyridine with HCl/SnCl2 to give 3-amino-2-chloro-4-methylaminopyridine (m.p. 170-173) and reaction with HCOOH/acetic anhydride] in 70 ml of dimethylformamide has been added, the mixture is stirred at 90-95 for 15 hours. The mixture is evaporated and the residue is worked up in the customary manner to give 4-(1-benzothienyl-3-methoxy)-1-methyl-1H-imidazo(4,5-c)pyridine of m.p. 200-204 (from ethyl acetate/tetrahydofuran).
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 70℃; for 16h;
Example A29 a) Preparation of intermediate 72Et3N (2.65 ml, 19 mmol), and 3-amino-4-methylamino-2-chloropyridine (1500 mg, 9.52 mmol) were added to a sol. of HBTU (4.51 g, 11.9 mmol) and 4-chloro-3- methoxy-benzoic acid (1776 mg, 9.52 mmol) in DMF (30ml). The r.m. was stirred at 70 0C for 16 h. The r.m. was diluted with DCM, and the mixture was washed with a sat. aq. Na2CO3. sol. and water. Yield: 1.8 g of crude intermediate 72 (58 %), which was used as such in the next reaction step.
General procedure: In a screw-cap vial, the diamine (1 mmol) was dissolved in trifluoroacetic acid (2 mL, 0.5 M) and the reaction was stirred at 70 C for 16 hours. Trifluoroacetic acid was then evaporated under reduced pressure and triethylamine (1 mL) was added. The reaction was then stirred at 70 C for an additional hour. Triethylamine was then evaporated under reduced pressure and the crude product was purified by silica gel column chromatography to yield the corresponding product.
With 2 % platinum on carbon; hydrogen; In tetrahydrofuran; water; at 20 - 30℃; under 1500.15 Torr;Autoclave;
A reactor was charged with catalyst [2% Pt on charcoal, 59 %wt. water] (0.0004 equivalents Pt), damp 2-chloro-/V-methyl-3-nitropyridin-4-amine from step 1 and 9.4 volumes of THF. The solution was stirred, and then the suspension was transferred from the glass-reactor to an autoclave. The line was rinsed with 1.2 volumes of THF into the autoclave, and the autoclave was purged with nitrogen for 15 minutes at 50 rpm, followed by hydrogen for 15 minutes at 150 rpm. The autoclave was closed, and the hydrogen pressure was adjusted to 2 bar at 20-30 C. The reaction mixture was stirred for 4-8 hours at 2 bar and 20-30 C. Next, the autoclave was released to atmospheric pressure and purged with nitrogen for at least 15 minutes. Conversion to the product was verified by HPLC, and then the catalyst was removed by filtration. The filtered catalyst was rinsed with 1.3 volumes of THF and the filtrates were combined. The combined filtrates were charged to a second reactor via a particle filter, and the line was rinsed with 0.5 volumes of THF. The solution was concentrated to a final volume of 2.5 volumes by distillation under reduced pressure at 40-45 C. The solution was then diluted with 10 volumes of THF in portions while concentrating the solution to a final volume of 2.5 volumes by distillation under reduced pressure at 45-50 C. The reactor was purged with nitrogen to atmospheric pressure, and 5.0 volumes of heptane were added to the residue at 40-50 C. The reaction mixture was cooled over 2 hours to 20-25 C, and stirring was continued for 1 hour. The reaction mixture was then further cooled to 0-5 C over 1 hour, and stirring was continued for 1 hour. The precipitated product was collected by filtration, rinsed via the reactor with 5.0 volumes of heptane, and the damp filter cake was dried in a vacuum drying oven at max. 40 C until loss on drying was < 2 % weight, giving 2-chloro-/V4-methylpyridine-3, 4-diamine in 85% yield.
A reactor was charged with 2-chloro-/V4-methylpyridine-3, 4-diamine and 4 volumes of formic acid. The reaction mixture was heated to smooth reflux within one hour, and reflux was maintained for 6 hours. The reaction mixture was then cooled to approximately 60 C, and conversion to the product was verified by HPLC. [00189] The reaction mixture was then concentrated by distillation under reduced pressure at 60-80 C to a final volume of 2 volumes. The temperature of the solution was adjusted to 60 C, maintaining the temperature above 50 C to avoid precipitation. Next, a second reactor was charged with 10 volumes of acetone, and heated to gentle reflux. The product solution from the first reactor was slowly transferred to the acetone in the second reactor over 20 minutes, and the line was rinsed with approximately 0.05 volumes of formic acid. Reflux of the obtained suspension was maintained for 15 minutes. The slurry was cooled to 0 C within 1 hour, and stirring was continued for 1 hour at that temperature. The precipitate was collected by filtration, and the filter cake was rinsed via the reactor with 3.7 volumes of cold acetone at 0-10 C. The filter cake was dried in a flow of dry nitrogen or in a vacuum drying oven at 50 C until loss on drying was
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