* 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] ACS Catalysis, 2015, vol. 5, # 3, p. 1526 - 1529
[2] Science, 2013, vol. 342, # 6162, p. 1073 - 1076
[3] Patent: US4935051, 1990, A,
[4] Patent: US4713109, 1987, A,
[5] Journal of the Chemical Society, 1952, p. 2042,2044
[6] Patent: US4831148, 1989, A,
[7] Green Chemistry, 2015, vol. 17, # 2, p. 898 - 902
2
[ 5409-39-2 ]
[ 21427-62-3 ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: With hydrogenchloride In water at -10℃; Stage #2: With sodium nitrite In water at 0℃; for 2 h; Stage #3: With sodium hydroxide In water at -10 - 0℃;
5-Chloro-3-nitro-2-pyridinamine (5.0 g, 28.8 mmol) was dissolved in cone. HCI (50 mL) and cooled to -10 0C in an ice-salt bath. Sodium nitrite (4.97 g, 72 mmol) in water (10 mL) was added dropwise to the cooled solution over 1 h and stirred at 0 °C for 1 h longer. The reaction mixture was cooled to -10 0C in an ice-salt bath and neutralized with 2N sodium hydroxide to pH 9.0 keeping the temperature below 0 0C. EtOAc (150 mL) was added and the mixture was filtered. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to afford the title compound as 3.36 g (60percent yield) of a light brown solid; 1H NMR (cfe-DMSO) δ 8.62 (d, 1 H, 2.5 Hz), 8.26 (d, 1 H, 2.2 Hz).
58.5%
With hydrogenchloride; sodium nitrite In water at -10 - 0℃; for 1.5 h;
5-chloro-3-nitropyridine-2-amine 10.0g of (57.6 mmol) was dissolved in concentrated hydrochloric acid 100 mL, and stirred at -10 ° C.. Here, sodium nitrite 9.94g of (144 mmol) Yuki dropwise over 30 minutes a liquid obtained by dissolving water 20 mL, after the addition, the mixture was stirred 1 hour at 0 ° C.. By adding 1N aqueous sodium hydroxide solution to the reaction solution and pH 9, and extracted with ethyl acetate. Insolubles were removed by filtration, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. Filtered and the filtrate was evaporated under reduced pressure to give the title compound 6.50g of (58.5percent yield) as a solid.
58.5%
Stage #1: With hydrogenchloride; sodium nitrite In water at -10℃; for 0.5 h; Stage #2: With sodium hydroxide In water at 0℃; for 1 h;
5-chloro-3-nitropyridine-2-amine 10.0g of (57.6 mmol) was dissolved in concentrated hydrochloric acid 100 mL, and stirred at -10 ° C.. Here, sodium nitrite 9.94g of (144 mmol) add dropwise over 30 minutes a liquid obtained by dissolving water 20 mL, after the addition, the mixture was stirred 1 hour at 0 ° C.. By adding 1N aqueous sodium hydroxide solution to the reaction solution and pH 9, and extracted with ethyl acetate. Insolubles were removed by filtration, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. Filtered and the filtrate was evaporated under reduced pressure to give the title compound 6.50g of (58.5percent yield) as a solid.
58.5%
With hydrogenchloride; sodium nitrite In water at -10 - 0℃; for 1.5 h;
(Step 1) 2,5-Dichloro-3-nitropyridine 5-Chloro-3-nitropyridin-2-amine (10.0 g, 57.6 mmol) was dissolved in concentrated hydrochloric acid (100 mL), and the solution was stirred at -10°C. A solution of sodium nitrite (9.94 g, 144 mmol) dissolved in water (20 mL) was added dropwise thereto over 30 minutes. After the completion of the addition, the mixture was stirred at 0°C for 1 hour. The pH of the reaction solution was adjusted to 9 by the addition of a 1 N aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. Insoluble matter was removed by filtration, and the organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After filtration, the solvent in the filtrate was distilled off under reduced pressure to obtain the title compound (6.50 g, yield: 58.5percent) as a solid. 1H-NMR (CDCl3) δ: 8.60 (1H, d, J = 2.9 Hz), 8.24 (1H, d, J = 2.6 Hz).
Reference：
[1] Patent: WO2007/67875, 2007, A2, . Location in patent: Page/Page column 15
[2] Patent: JP2016/56134, 2016, A, . Location in patent: Paragraph 0165; 0166; 0167
[3] Patent: JP2016/56133, 2016, A, . Location in patent: Paragraph 0158; 0159
[4] Patent: EP3109239, 2016, A1, . Location in patent: Paragraph 0189
[5] Journal of the Chemical Society, 1952, p. 2042,2044
[6] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 10, p. 2625 - 2637
[7] Patent: US2007/167435, 2007, A1, . Location in patent: Page/Page column 29
3
[ 21427-61-2 ]
[ 21427-62-3 ]
Reference：
[1] Journal of the Chemical Society, 1952, p. 2042,2044
[2] Roczniki Chemii, 1968, vol. 42, p. 2079,2084[3] Chem.Abstr., 1969, vol. 70, p. 106327
[4] Yakugaku Zasshi, 1952, vol. 72, p. 431[5] Chem.Abstr., 1953, p. 6404
[6] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1980, vol. 16, # 12, p. 1234 - 1238[7] Khimiya Geterotsiklicheskikh Soedinenii, 1980, vol. 16, # 12, p. 1632 - 1636
[8] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 1, p. 73 - 76
[9] Patent: WO2005/97805, 2005, A1, . Location in patent: Page/Page column 57-58
[10] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3983 - 3987
4
[ 75-44-5 ]
[ 21427-61-2 ]
[ 21427-62-3 ]
Reference：
[1] Patent: US5274100, 1993, A,
5
[ 21427-61-2 ]
[ 21427-62-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 10, p. 2625 - 2637
6
[ 4214-79-3 ]
[ 21427-62-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 10, p. 2625 - 2637
7
[ 5409-39-2 ]
[ 21427-61-2 ]
[ 21427-62-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 10, p. 2625 - 2637
8
[ 4214-79-3 ]
[ 21427-62-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3983 - 3987
To a solution of 129.2 g (0.69 mol) of <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> in 1300 ml of dioxane is added 26 0 g of Raney-nickel, that has previously been washed with ethanol. This mixture is then hydrogenated with hydrogen under normal pressure at 20-35 C. After uptake of 20% of the theoretical amount of hydrogen, another 30 g of washed Raney-nickel catalyst are added. After hydrogenating for 22 hours, the catalyst is filtered off, the solvent is evaporated and the residue is crystallized from hexane/ ethyl acetate. Thus, 84.9 g of 3-amino-2,5-dichloropyridine (78% of the theory) are obtained, which melts at 129-132 C.
78%
nickel; In 1,4-dioxane;
To a solution of 129.2 g (0.69 mol) of <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> in 1300 ml of dioxane is added 26.0 g of Raney-nickel, that has previously been washed with ethanol. This mixture is then hydrogenated with hydrogen under normal pressure at 20-35 C. After uptake of 20% of the theoretical amount of hydrogen, another 30 g of washed Raney-nickel catalyst are added. After hydrogenating for 22 hours, the catalyst is filtered off, the solvent is evaporated and the residue is crystallized from hexane/ethyl acetate. Thus, 84.9 g of 3-amino-2,5-dichloropyridine (78% of the theory) are obtained, which melts at 129-132 C.
aluminum nickel; In 1,4-dioxane;
(a) 3-Amino-2,5-dichloropyridine 26.0 g of Raney nickel catalyst are washed with ethanol and then added to a solution of 129.2 g (0.69 mol) of <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> in 1300 ml of dioxane. This mixture is hydrogenated with hydrogen under normal pressure and at a temperature in the range from 20 to 35 C. After reaction of 20% of the required amount of hydrogen, a further 30.0 g of Raney nickel catalyst are added to the reaction mixture. After a hydrogenation period of 22 hours, the catalyst is removed, the solvent is evaporated off and the residue is crystallized from ethyl acetate/hexane, affording 84.9 g (78% of theory) of 3-amino-2,5-dichloropyridine, m.p. 129-132 C.
Example 10; (+/-)-9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-3-chloro-2-methoxy-6,7,8,9- tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester; Step 1;. Preparation of 5-Chloro-3-nitro-pyridine-2-carbonitrile; Add 3-nitro-5-chloro-pyridin-2-ol (3.9 g, 22.3 mmol) to a mixture of phosphorous oxychloride (4.17 mL) and dimethylformamide (10 mL). Heat the resulting mixture at 110 C for 30 min. Cool the reaction mixture to room temperature and pour onto ice- water. Add sodium bicarbonate slowly until neutralization occurs and extract with ethyl acetate. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Dissolve the residue in N-methyl pyrrolidinone (4 mL), add copper (I) cyanide (2.39 g, 26.7 mmol) and heat at 160 C for 15 min. Cool the reaction mixture to room temperature and pour onto ice water and ethyl acet ate. Add a saturated solution of sodium bicarbonate, separate the organic layer, and extract the aqueous layer with ethyl acetate. Dry the combined organic layers over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue using silica gel chromatography, eluting with ethyl acetate/hexanes 1: 3 to afford the title cornpound (1.01 g, 26%). H-NMR (CDC13, 300 MHz) : No. 8.61 (s, 1H), 8.95 (s, 1H).
1-[3-(4-fluoro-benzyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-2-hydroxy-ethanone[ No CAS ]
2-(5-Chloro-3-nitro-pyridin-2-yloxy)-1-[3-(4-fluoro-benzyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-ethanone[ No CAS ]
[ 21427-62-3 ]
Yield
Reaction Conditions
Operation in experiment
64%
In toluene;
2-(5-Chloro-3-nitro-pyridin-2-yloxy)-1-[3-(4-fluoro-benzyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-ethanone To a 0 C. solution of 1-[3-(4-fluoro-benzyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-2-hydroxy-ethanone (0.456 g, 1.64 mmol) in toluene (8.0 ml) is added sodium hydride (0.072 g. 1.80 mmol). The reaction mixture is stirred at 0 C. for 30 minutes. To the resulting reaction mixture is added 2,5-dichloro-3-nitro-pyridine (0.35 g. 1.80 mmol). The reaction mixture is heated to reflux for 2 hours, then cooled to ambient temperature, washed with saturated aqueous sodium hydrogen carbonate and brine. The aqueous layers are then extracted three times with ethyl acetate. The combined organics are dried over magnesium sulfate and concentrated in vacuo to give the title compound (0.76 g, 64%). The title compounds for Examples 16-17 are prepared by a method analogous to that described in Example 15.
1-[3-(4-fluoro-benzyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-2-hydroxy-ethanone[ No CAS ]
[ 21427-62-3 ]
2-(3-nitro-5-chloro-pyridin-2-yloxy)-l-[3-(4-fluoro-benzyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
In toluene;
EXAMPLE 85 To a 0 C. solution of 1-[3-(4-fluoro-benzyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-2-hydroxy-ethanone (0.253 g, 0.913 mmol) in toluene (2.0 ml) is added sodium hydride (0.042 g, 1.1 mmol), and the reaction mixture is stirred at 0 C. for 30 minutes. To the reaction mixture is then <strong>[21427-62-3]2,5-dichloro-3-nitro-pyridine</strong> (0.185 g, 0.98 mmol). The resulting mixture is refluxed for 2 hours, cooled to ambient temperature and concentrated in vacuo. Silica gel chromatography gave 2-(3-nitro-5-chloro-pyridin-2-yloxy)-l-[3-(4-fluoro-benzyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethanone (0.272 g, 68%).
EXAMPLE A3 Preparation of 2,5-dichloro-3-nitropyridine STR10 75 g of phosgene are introduced at a temperature of 85-95 C. over 1 hour into a mixture of 87.5 g of 5-chloro-2-hydroxy-3-nitropyridine in 500 ml of toluene and 3 ml of N,N-dimethylformamide. The reaction mixture is kept for 2 hours under reflux at 85-95 C. and then allowed to cool to room temperature over a period of 18 hours. The reaction mixture is washed 3 times with water and the organic phase is dried over sodium sulfate and thereafter concentrated by evaporation. The crude product, obtained in the form of a brown oil, is crystallized from 200 ml of n-hexane, giving 67.5 g of 2,5-dichloro-3-nitropyridine (70% of theory) with a melting point of 38-39 C.
With potassium hydroxide; In water; N,N-dimethyl-formamide;
EXAMPLE A4 Preparation of 2-(4-(5-chloro-3-nitropyridin-2-yloxy)phenoxy)propionic acid STR11 56.1 g of a 50% aqueous solution of potassium hydroxide are added dropwise at room temperature to a suspension of 91 g of water and 92.3 g of 2-(4-hydroxy)phenoxypropionic acid. After the removal of water by distillation, the potassium salt so obtained is dissolved in 390 g of N,N-dimethylformamide, and then 108.1 g of <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> in 95 g of N,N-dimethylformamide are added dropwise at 85 C. The reaction mixture is stirred for 90 minutes at 85 C., then poured into water and 100 ml of concentrated hydrochloric acid are added dropwise. The oily crude product is extracted with toluene. The organic phase is concentrated by evaporation, giving 188 g (92% of theory) of 2-(4-(5-chloro-3-nitropyridin-2-yloxy)phenoxy)propionic acid.
methyl 2-[4-(5-chloro-3-nitropyridin-2-yloxy)phenoxy]propionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium iodide; potassium carbonate; In acetonitrile;
(a) Methyl 2-[4-(5-chloro-3-nitropyridin-2-yloxy)phenoxy]propionate 38.6 g (0.20 mole) of 2.5-dichloro-3-nitropyridine, 41.2 g (0.21 mole) of methyl 2-(4-hydroxyphenoxy)propionate, 400 ml of acetonitrile, 35.9 g (0.26 mole) of potassium carbonate and 0.33 g (0.002 mole) of potassium iodide are heated for 13 hours to 80 C. The reaction mixture is filtered and the filter cake is washed with acetonitrile. The filtrate is concentrated by evaporation and the residue is taken up in 500 ml of methlyene chloride. After treating the solution with 15 g of activated carbon, it is filtered through a layer of silica gel and the filtrate is concentrated by evaporation. The residue is crystallized from a mixture of hexane and ethyl acetate, affording 65.7 g (93.1% of theory) of methyl 2-[4-(5-chloro-3-nitropyridin-2-yloxy)phenoxy]propionate with a melting point of 91-92 C.
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 24h;
To a stirred solution of the <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> (2 g) and methyl 2- hydroxybenzoate (1.4 ml) in DMF (10 ml) was added potassium carbonate. The resultant mixture was heated to 50 0C for 24 hours. The crude reaction was cooled and partitioned between ethyl acetate and water (75 ml each), separated and the aqueous extracted with ethyl acetate (225 ml total). The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated in vacuo to afford 3.24 g of the title compound; MH+ 309.
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 1h;
A solution of <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> (1.93 g) in DMF (10 ml_) was prepared and 2 mL of this solution added to 2-methyl-3-hyroxypyridine (229 mg). Potassium carbonate (1.5 eq) was added and the mixture heated to 90 C for one hour. The mixture was then cooled and concentrated, dissolved in DCM and concentrated a second time. The resulting solid was partitioned between chloroform and water (5 ml_ each) and separated. <n="19"/>The chloroform layer was blown down to provide the crude product. 1H NMR (CDCI3) delta 8.47 (dd, 1H), 8.38 (d, 1H), 8.26 (d, 1H), 7.43 (dd, 1H), 7.23 (dd, 1 H), 2.47 (s, 3H).
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 70℃; for 75.5h;
To a solution of <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> (386 mg) and 4-methyl-2(1 H)-pyridinone (241 mg) in DMF (10 ml) was added potassium carbonate (552 mg). The resultant mixture was heated to 50 0C for 11/2 h then at 70 C for 2 h before been cooled to room temperature and stirred for 72 h. The mixture was concentrated to give a solid which was partitioned between DCM/water, the layers were separated and water layer extracted with further DCM. The combined DCM extracts were washed (water), dried over sodium sulfate and concentrated in vacuo to afford a brown oil. The oil was purified by silica gel SPE (20- 40% ethyl acetate in cyclohexane) to afford 197 mg of the title compound; MH+ 266.
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 2h;
A solution of 2-(4-morpholinylmethyl)-3-pyridinol (251 mg) in DMF (2.5ml_) was prepared and added to <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> (238 mg). Potassium carbonate (255 eq) was added and the mixture heated to 90 0C for 2 hours. The mixture was then cooled and concentrated. The resulting solid was partitioned between DCM and water (5 mL each) and separated. The DCM layer was concentrated and re-dissolved in DCM (3.3 mL) then added to 5% platinum on carbon (Degussa-type, 203 mg). Ammonium formate (1.0 g) was added and the mixture heated at reflux for 24 hours. The reaction mixture was filtered through Celite (2x2 mL DCM wash) and the filtrate concentrated to give 224 mg of the product; 1H NMR (CDCI3) 8.45 (d, 1 H), 7.51 (m, 2H), 7.26 (m, 2H), 7.02 (d, 1 H), 4.58 (br.s, 2H), 3.76 (s, 2H), 3.53 (m, 4H), 2.46 (m, 4H).
With potassium carbonate; potassium iodide; In toluene; at 110℃; for 8h;
A mixture of pyridine derivative 39 (15.0 g, 78.1 mmol), compound 10, K2CO3 (21.5 g, 156 mmol) and KI (1 g) in toluene (200 mL) was heated at 110 C. for 8 h. The mixture was cooled to room temperature and partitioned with DCM (500 mL) and water (400 mL). Layers were separated, and the aqueous phase was extracted with a second portion of DCM (300 mL). Combined extracts were washed with brine (250 mL), dried over anhydrous MgSO4, filtered and concentrated under vacuum to provide 35.3 g of compound 40 as a dark red solid.
The boronic acid 1 (2.0 g, 8.0 mmol) prepared according to the literature was added to a solution of potassium carbonate (2.2 g in 8 mL H2O) and <strong>[21427-62-3]2,5-dichloro-3-nitro pyridine</strong> 2g (1.4 g, 7.3 mmol) in 100 mL toluene/EtOH (8:1). This mixture was deoxygenated in vacuo and refilled with nitrogen. After stirring the mixture under nitrogen for 30 min, palladium tetrakistriphenylphosphine (250 mg) was added to the mixture. The solution was heated <n="34"/>to 80 C. until complete conversion (no starting material) according to TLC (50/50 Hexanes/EtOAc). The reaction was then extracted with water and the toluene layer was dried and concentrated to yield a crude oil which was columned on silica gel to afford the desired isomer 3g in 45% yield (1.20 g). 1H NMR (CDCl3) delta 8.26 (d, IH), 7.45 (m, 3H), 7.34 (m, 2H), 3.99 (m, IH), 3.41 (m, IH), 1.38 (bs, 9H), 1.21 (d, 3H).
2-(5-Chloro-3-Nitro-Pyridin-2-Yloxy)-1-[4-(4-Fluoro-Benzyl)-(2R,5S)-2,5-Dimethyl-Piperazin-1-Yl]Ethanone To a solution of 1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-hydroxy-ethanone (0.90 g, 3.2 mmol) in toluene (20 mL) at 0 C. was added sodium hydride (0.18 g, 4.5 mmol, 60% dispersion in mineral oil). The reaction was stirred for 15 minutes, then <strong>[21427-62-3]2,5-dichloro-3-nitro-pyridine</strong> (0.65 g, 3.38 mmol) was added and the solution was stirred at ambient temperature for 18 hours. The reaction was quenched by the slow addition of water (5 mL) then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel gave the title compound (1.25 g).
2-(5-Chloro-3-Nitro-Pyridin-2-Yloxy)-1-[4-(4-Fluoro-Benzyl)-(2R)-2-Methyl-Piperazin-1-Yl]-Ethanone To a solution of 1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-hydroxy-ethanone (0.77 g, 2.9 mmol) in dry toluene (30 mL) at 0 C. was added sodium hydride (0.13 g, 3.2 mmol, 60% dispersion in mineral oil). The reaction was stirred for 30 minutes at 0 C. followed by addition of <strong>[21427-62-3]2,5-dichloro-3-nitro-pyridine</strong> (0.60 g, 3.18 mmol) as a solution in toluene (5 mL). The reaction was stirred at ambient temperature overnight. The reaction was concentrated and chromatographed on silica gel to give the title compound (0.96 g).
With sodium iodide; In N,N-dimethyl-formamide; at 160℃; for 15.5h;
2,5-Dichloro-3-nitropyridine 1.00 g, 2-cyclohexylimidazole 1.56 g, sodium iodide 500 mg and N,N-dimethylformamide 25 mL were mixed and stirred at 160C for 15.5 hours. The reaction liquid was poured in ice water and extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was subjected to silica gel chromatography (hexane: ethyl acetate = 2:1) to provide 1.08 g of the title compound. 1H-NMR(CDCl3, delta): 1.1-1.4(3H, m), 1.5-1.9(7H, m), 2.4-2.6(1H, m), 6.84(1H, d, J=1.5Hz), 7.09(1H, d, J=1.5Hz), 8.37(1H, d, J=2.3Hz), 8.77(1H, d, J=2.3Hz). MS(m/z): 308(M++2), 306(M+), 55(base).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1h;
Example 6: Synthesis of N-(5-Chloro-2-{4-[2-(4-chloro-3,5-dimethyl-2H-pyrrol-2- yl)-acetyl]-piperazin-l-yl}-pyridin-3-yl)-3-trifluoromethyl-benzamide To a solution of <strong>[21427-62-3]2,5-dichloro-3-nitro-pyridine</strong> (2.50 g, 13.0 mmol) in N,N- dimethylformamide (100 niL) is added l-£-Boc-piperazine (2.80 g, 15.0 mmol) followed by potassium carbonate (9.00 g, 65.0 mmol). The mixture is stirred at room temperature for 1 h and then poured over ice water and stirred until all of the ice melts. During this time a solid precipitates from solution. The yellow solid is collected by filtration, washed with water, and dried on the filter pad to provide 4.40g of 4-(5-chloro-3-nitro-pyridin-2- yl)-piperazine-l-carboxylic acid tert-butyl ester in 99% yield.
With N-ethyl-N,N-diisopropylamine; In propan-1-ol; at 120℃; for 3h;Sealed tube;
PREPARATION 5 (R)-6-chloro-1-methyl-3-(pyrrolidin-3-yl)-1 H-imidazo[4,5-b]pyridin-2(3H)-oneStep 1; A heavy-walled glass tube was charged with (R)-tert-butyl 3- aminopyrrolidine-1-carboxylate (1.35 g, 7.15 mmol), <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> (1.04 g, 5.4 mmol), i-Pr2NEt (2.6 mL, 14.3 mmol) and n-PrOH (1 O mL). The tube was sealed and the mixture was heated and stirred at 120 0C in an oil bath for 3 h. The mixture was concentrated and the residue was taken up in EtOAc (200 mL), washed with 1% aq HCI (2 x 40 mL), satd aq NaHCO3 (40 mL) and brine (40 mL), and dried over Na2SO4. Removal of the solvent afforded a brown oil (1.91 g) which was chromatographed a 40-g silica cartridge eluted with a 0 - 50% EtOAc in hexanes gradient to afford (R)-tert-butyl 3-(5-chloro-3-nitropyridin-2- ylamino)pyrrolidine-1-carboxylate (1.57 g, 85%) as a yellow oil. LC-MS Method 1 tR = 2.05 min, m/z = 343, 287.
A mixture of 0.500 g (2.60 mmol) of 2,5-dichloronitrobenzene and 1.0 mL ( mmol) of 2- (piperdin-4-yl)-acetic acid ethyl ester is heated overnight at 105 C. The mixture is cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.803 g (94.4%) of [l-(4-chloro-2-nitro-phenyl)-piperidin-4- yl] -acetic acid ethyl ester as a red oil
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
To a solution of 1.0 g (5.2 mmol) of 3-nitro-2,5-dichloropyridine inN,N- dimethylformamide (20 mL) is added 0.75 g (5.8 mmol) of methyl isonipocoate followed by 7 g (50 mmol) of potassium carbonate. The mixture is stirred at room temperature overnight then diluted with water and extracted with ethyl acetate. The combined organic phase is washed with water followed by brine then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 1.1 g (71%) of 5'-chloro-3'-nitro-3,4,5,6-tetrahydro-2H- [l,2']bipyridinyl-4-carboxylic acid methyl ester as a red oil.
PREPARATION 23; 5-Chloro-2-methoxypyridin-3-amine a) 5-Chloro-2-methoxy-3-nitropyridineA solution of sodium methoxide (0.84 g, 16.6 mmol) in methanol (4 mL) was added dropwise to a solution of <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> (1.00 g, 5.2 mmol) in methanol (10 mL) and the mixture was stirred and heated to reflux. After 7 hours, the mixture was cooled and diluted with water and the precipitate was filtered and washed with water to give the title compound (0.95 g, 97%) as a white solid.H NMR 5 (300 MHz, CDCI3): 4.11 (s, 3H), 8.23 (s, 1 H), 8.32 (s, 1 H).
97%
In methanol; for 7h;Reflux;
a) 5-Chloro-2-methoxy-3-nitropyridine A solution of sodium methoxide (0.84 g, 16.6 mmol) in methanol (4 mL) was added dropwise to a solution of <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> (1.00 g, 5.2 mmol) in methanol (10 mL) and the mixture was stirred and heated to reflux. After 7 hours, the mixture was cooled and diluted with water and the precipitate was filtered and washed with water to give the title compound (0.95 g, 97%) as a white solid. 1H NMR delta (300 MHz, CDCl3): 4.11 (s, 3H), 8.23 (s, 1H), 8.32 (s, 1H).
97%
In methanol; for 7h;Reflux;
-Chloro-2-methoxypyridin-3 -amine a) 5-Chloro-2-methoxy-3-nitropyridineA solution of sodium methoxide (0.84 g, 16.6 mmol) in methanol (4 mL) was added dropwise to a solution of <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> (1.00 g, 5.2 mmol) in methanol (10 mL) and the mixture was stirred and heated to reflux. After 7 hours, the mixture was cooled and diluted with water and the precipitate was filtered and washed with water to give the title compound (0.95 g, 97%) as a white solid.1H NMR delta (300 MHz, CDCI3): 4.1 1 (s, 3H), 8.23 (s, 1 H), 8.32 (s, 1 H).
97%
In methanol; for 7h;Reflux;
a) 5-Chloro-2-methoxy-3-nitropyridine A solution of sodium methoxide (0.84 g, 16.6 mmol) in methanol (4 mL) was added dropwise to a solution of <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> (1.00 g, 5.2 mmol) in methanol (10 mL) and the mixture was stirred and heated to reflux. After 7 hours, the mixture was cooled and diluted with water and the precipitate was filtered, washed with water and dried to give the title compound (0.95 g, 97%) as a white solid.1H NMR delta (CDCIs): 4.1 1 (s, 3H), 8.23 (s, 1 H), 8.32 (s, 1 H).
97%
In methanol; for 7h;Reflux;
A solution of sodium methoxide (0.84 g, 16.6 mmol) in methanol (4 mL) was added dropwise to a solution of <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> (1.00 g, 5.2 mmol) in methanol (10 mL) and the mixture was stirred and heated to reflux. After 7 hours, the mixture was cooled and diluted with water and the precipitate was filtered, washed with water and dried to give the title compound (0.95 g, 97%) as a white solid. 1H NMR delta (CDCl3): 4.11 (s, 3H), 8.23 (s, 1H), 8.32 (s, 1H).
96%
In methanol; at 25℃; for 2h;
To a (OeC) cooled and stirred solution of <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> (3.0 g, 15.55 mmol) in MeOH (60 mL) was added dropwise sodium methoxide (5M in methanol, 31.1 mL, 155 mmol) and the reaction was allowed to stir at 25eC for 2 h. Upon completion, cold water (10 mL) was added and the mixture was extracted with EtOAc (2/150 mL), dried over Na2S04, filtered and rotary evaporated to afford 5-chloro-2-methoxy-3-nitropyridine (2.81 g, 96%). 1HNMR (400 MHz, DMSO-d6) U8.64 (d, J = 2.4 Hz, 1H), 8.62 (d, J = 2.4 Hz, 1H), 4.03 (s, 3H); ESI-MS (m/z) 188.9 (MH)
(Example 63-1) An ethanol solution (10 ml) of <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong> (1.11 g) and thiourea (916 mg) was heated at reflux for 5 hours. After the reaction solution was cooled to 0C, a 2N aqueous sodium hydroxide solution (8 ml) was added, and stirred for 30 minutes. 2N hydrochloric acid was added to the reaction solution, and extracted with dichloromethane. The collected organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue (972 mg) was dissolved in N,N-dimethylformamide (10 ml), and potassium carbonate (1.25 g) and tert-butyl 2-bromo-2-methylpropanoate (0.774 ml) were added at room temperature. After the reaction solution was stirred for 5 hours, tert-butyl 2-bromo-2-methylpropanoate (0.774 ml) was added, and further stirred overnight. Water was added to the reaction solution, and extracted with ethyl acetate. The collected organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 2-[(5-chloro-3-nitropyridin-2-yl)thio]-2-methylpropanoate (489 mg). 1H NMR (400 MHz, CDCl3) delta: 1. 40 (s, 9H), 1.66 (s, 6H), 8.48 (dd, 1H, J = 2.3, 0.8 Hz), 8.56 (dd, 1H, J = 2.3, 0.8 Hz).
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