* 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] Chemische Berichte, 1936, vol. 69, p. 2593,2604
2
[ 6298-19-7 ]
[ 39620-04-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
3
[ 6298-19-7 ]
[ 5028-20-6 ]
Yield
Reaction Conditions
Operation in experiment
70%
With copper(ll) sulfate pentahydrate In water at 160℃; for 1 h; Microwave irradiation
3-Amino-2-chloropyridine (400 mg, 3.1 mmol) and copper sulfate pentahydrate (78 mg, 0.31 mmol, 0.10 eq.) were added to a microwave pressure vessel with 40percent methylamine in water (2.33 ml) and heated at 160 °C for 1 h. The crude product was cooled to RT and filtered through Celite. The crude mixture was treated with aqueous sodium carbonate, extracted with EtOAc (2x), dried over anhydrous NaSO4 , filtered, and dried under vacuum. After purification by column chromatography, using a solvent gradient from hexane to EtOAc, the desired compound 22 was isolated as orange solid (70percent)
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 5, p. 1117 - 1123
[2] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 6, p. 1641 - 1649
[3] Chemische Berichte, 1936, vol. 69, p. 2593,2604
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; hydrogen bromide; sodium nitrite In water at 10 - 20℃; for 2 h;
Example 3 3-Bromo-2-chloropyridine (7) Water (45 ml) and 48percent hydrobromic acid (27 ml) were added to 3-amino-2-chloropyridine (6) (2.57 g, 20 mmol) at room temperature. To the mixed solution, 2,2,6,6-tetramethylpiperidine 1-oxyl (0.31 g, 2 mmol) was added at room temperature, and the mixture was cooled to 10° C. or lower. Then, sodium nitrite (4.14 g) dissolved in water (30 ml) was added thereto. After stirring at room temperature for approximately 2 hours, a 10 mol/L aqueous sodium hydroxide solution (40 ml) was added thereto, followed by extraction twice with toluene (300 ml). The toluene layers were combined and washed with water (50 ml). The solvent was distilled off by the concentration of the toluene layer under reduced pressure to obtain 3-bromo-2-chloropyridine (7) (3.08 g, 80.1percent).
Reference：
[1] Patent: US2013/144061, 2013, A1, . Location in patent: Paragraph 0229; 0230
[2] Journal of Organic Chemistry, 1995, vol. 60, # 5, p. 1408 - 1412
6
[ 6298-19-7 ]
[ 38240-21-0 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1980, vol. 17, # 1, p. 149 - 153
7
[ 6298-19-7 ]
[ 57-55-6 ]
[ 38240-21-0 ]
Reference：
[1] Patent: US5814651, 1998, A,
8
[ 6298-19-7 ]
[ 74-88-4 ]
[ 40932-43-2 ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78 - 0℃; for 1 h; Stage #2: at -78 - 20℃; for 16 h;
To a solution of 2-chloro-3-pyridinamine (0.0465 mol) in THF (45ml) at-78°C under N2 flow, LDA 2. 0M (0.0513 mol) was added dropwise. The mixture was allowed to warm to 0°C and was stirred for 1 hour and then cooled TO-78°C. Then CH3I (0.0582 mol) was added and the reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. A saturated NH4CL-SOLUTION was added and the mixture was extracted with AcOEt. The separated organic layer was dried (NA2S04), filtered and the solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: hexane/AcOEt 80/20). The product fractions were collected and the solvent was evaporated. Yield: 5. 91g of intermediate compound 1 (89percent).
With bis(tri-t-butylphosphine)palladium(0); triethylamine In cyclohexyl acetate at 150℃; for 40 h; Inert atmosphere
Triethylamine (13 mL), butyl acrylate (10 mL), and bis(tritert-butylphosphine)palladium (0) (350 mg) were added to a solution of 2-chloro-3-aminopyridine (6.00 g) in cyclohexyl acetate (60 mL), and the mixture was stirred at 150°C for 40 hours under a nitrogen atmosphere. The resulting mixture was left to be cooled at room temperature. When the mixture was cooled to 70°C, water (30 mL) was added thereto, and the resulting mixture was left to be cooled at room temperature under stirring. After subjecting the resulting mixture to sonication for 30 minutes, the mixture was filtered and the residue was washed with water (3 mL). The obtained residue was suspended in ethyl acetate (3 mL)/2-propanol (4 mL) and then subjected to sonication. Further, the suspension was filtered, and the residue was washed with ethyl acetate (3 mL) and hexane, and thereafter is dried to obtain a compound 0001-1 (2.51 g) as a pale yellow solid. 1H-NMR (DMSO-d6) δ: 11.90 (1H, s), 8.47 (1H, dd), 7.93 (1H, d), 7.68 (1H, ddd), 7.51 (1H, dd), 6.75 (1H, dd). MS m/z (M+H): 147.
Stage #1: With hydrogenchloride In water at 30 - 35℃; Stage #2: With dihydrogen peroxide In water at 10 - 19℃; for 8.33333 h; Stage #3: With sodium hydroxide In water; toluene at 25 - 35℃;
EXAMPLE 2; Preparation of 3-amino-2-chloropyridine 2 using hydrogen peroxide; 3-Aminopyridine 3 (30.0 g, 0.32 mole) was add to 300 mL of 37percent aqueous HC1 in a 1-L Morton flask with overhead stirring at about 30-35 °C. After the mixture was cooled to about 10 °C, 23 g (0.34 mol) of 50 percent hydrogen peroxide was added over 20 minutes at about 10-12 °C. The mixture was held at about 10 °C for 2 hours and then was allowed to warm to about 19 °C over 2 hours and held at that temperature for additional 4 hours. HPLC analysis showed approximately 90 percent conversion of 3-aminopyridine 3. After cooling the reaction mixture to 10 °C, a solution of 6 g of sodium sulfite in 50 mL of water was added. To the mixture were added 50 mL of toluene and 200 g (2.5 mol) of 50 percent aqueous sodium hydroxide at about 25-35 °C. Then water was added to dissolve precipitated NaCl, and the layers were separated. The organic phase was back-extracted with 45 g of 10 percent aqueous HC1 to recover some 3-amino-2-chloropyridine 2 in the toluene extract, and this was added back to the original aqueous phase. The combined aqueous phases were neutralized to pH 3 with 50 percent aqueous NaOH and extracted with toluene for 3 times. The toluene extracts were combined, washed with 30 mL of saturated aqueous NaCl, and concentrated to dryness to afford 33 g of crude 3-amino-2-chloropyridine 2 (76 percent yield) with 94 percent purity. The product contained about 3 wt percent 3-amino-2, 6-dichloropyridine by HPLC assay.
74%
Stage #1: With hydrogenchloride In water at 30 - 35℃; Stage #2: With chlorine In water at 15 - 20℃; for 1.5 h; Stage #3: With sodium hydroxide In toku; water at 25 - 40℃;
EXAMPLE 3; Preparation of 3-amino-2-chloropyridine 2 using chlorine; 3-Aminopyridine 3 (21.0 g, 0.223 mol) was added to 90 mL (ca. 108 g, 1. 08 mol) of concentrated aqueous HC1 (ca. 37percent) in a 300-mL sidearm flask with magnetic stirring at 30-35 °C. The mixture was cooled to 15 °C (thick slurry) and chlorine gas was sparged just above the surface over about 1.5 hours at 15-20 °C. HPLC analysis showed approximately 93 percent conversion of 3-aminopyridine 3. The mixture was cooled to 10 °C and a solution of 6 g of sodium sulfite in 50 mL of water was added. To the mixture was added 30 mL of toluene and 80 g (1.0 mol) of 50 percent aqueous sodium hydroxide at about 25-40 °C. Then water was added to dissolve precipitated NaCI, and the layers were separated. The aqueous phase was extracted once more with 30 mL of toluene. To the aqueous phase was added 10 g of 50 percent NaOH, and extracted with another 50 mL of toluene to remove 3-amino-2, 6- dichloropyridine. The combined organic phase was back-extracted with 40 mL of 0.2 N aqueous HC1 to recover some 3-amino-2-chloropyridine 2 in the toluene extracts, and this was added back to the original aqueous phase. The combined aqueous phases were diluted with 100 mL of toluene and neutralized to pH 3 with about 20 g of 50percent aqueous NaOH at about 35 °C. The aqueous phase was extracted with two 50-mL portions of toluene. The toluene layers were combined and washed with 20 mL of saturated aqueous NaCI. The solution was concentrated to dryness to afford 21.4 g of crude 3-amino-2-chloropyridine 2 (74 percent yield) with 98.6 percent purity, which contained about 1.4 wt percent 3-amino-2,6- dichloropyridine.
Reference：
[1] Chemische Berichte, 1936, vol. 69, p. 2593,2604
18
[ 462-08-8 ]
[ 7647-01-0 ]
[ 7732-18-5 ]
[ 7722-84-1 ]
[ 6298-19-7 ]
[ 62476-56-6 ]
Reference：
[1] Chemische Berichte, 1936, vol. 69, p. 2593,2604
19
[ 6298-19-7 ]
[ 104830-06-0 ]
Reference：
[1] Chemical & Pharmaceutical Bulletin, 1985, vol. 33, # 11, p. 4764 - 4768
20
[ 6298-19-7 ]
[ 98-80-6 ]
[ 101601-80-3 ]
Yield
Reaction Conditions
Operation in experiment
90%
With sodium hydroxide; sodium carbonate; benzaldehyde In water; toluene
To 2-chloro-3-aminopyridine (1.06 g, 8.24 mmol) in toluene (25 mL) was added benzaldehyde (0.878 g, 8.27 mmol). The reaction mixture was stirred at reflux in a Dean-Stark apparatus until GC/MS analysis of the reaction mixture no longer showed starting material. The reaction mixture was cooled to room temperature and the toluene solution containing benzylidene-(2-chloro-pyridin-3-yl)-amine was added to a mixture of phenylboronic acid (1.30 g, 10.7 mmol), sodium carbonate (2.66 g, 25.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.38mol percent) in water (10 mL). The reaction mixture was heated to 100° C. for 30 minutes, cooled to room temperature and poured into 1N aqueous sodium hydroxide (10 mL). The aqueous layer was removed and the toluene layer was extracted with 1N aqueous hydrochloric acid (twice with 15 mL). The aqueous layer was neutralized to pH 12 with 6N aqueous sodium hydroxide and extracted with MTBE (twice with 20 mL). The MTBE extracts were dried over magnesium sulfate, filtered and concentrated to afford 2-phenyl-3-aminopyridine as a solid which crystallized from diisopropyl ether (1.26 g, 90percent yield). M. p.=87-68° C. 1H NMR (300 MHz, CDCl3) δ3.88 (bs, 2), 7.02-7.11 (m, 2), 7.28-7.53 (m, 3), 7.6714 7.71 (m, 2), 8.13-8.16 (m, 1). 13C NMR (100 MHz, CDCl3) δ122.57, 122.96, 128.14, 128.38, 128.72, 138.54, 139.86, 139.93, 144.93.
Reference：
[1] Patent: US6316632, 2001, B1,
21
[ 6298-19-7 ]
[ 98-80-6 ]
[ 101601-80-3 ]
Yield
Reaction Conditions
Operation in experiment
97%
With sodium carbonate; benzaldehyde; triphenylphosphine In water; toluene
A solution of palladium acetate (224.5 mg, 1.00 mmol) and triphenylphosphine (1.05 g, 4.00 mmol) in toluene (1000 mL) was stirred at room temperature for 15 minutes. Phenylboronic acid (114 g, 935 mmol), 2-chloro-3-aminopyridine (100 g, 778 mmol), benzaldehyde (83.4 g, 786 mmol), and toluene (500 mL) were then added followed by a solution of sodium carbonate (200 g, 1.89 mol) in water (1500 mL). The mixture was heated to reflux for 18 hours, cooled to room temperature, and the layers were separated. The organic layer was washed with water (500 mL) and 2.5M aqueous hydrochloric acid was added (630 mL). The aqueous layer was separated and washed with toluene (300 mL). The pH was adjusted to 12-13 using 50percent aqueous sodium hydroxide and the mixture was extracted with methyl-tert-butyl ether (500 mL). The organic layer was concentrated and the product was crystallized from diisopropyl ether to afford 2-phenyl-3-aminopyridine (128 g, 97percent yield). M. p.=67-68° C. 1H NMR (300 MHz, CDCl3) δ3.88 (bs, 2), 7.02-7.11 (m, 2). 7.28-7.53 (m, 3), 7.67-7.71 (m, 2), 8.,13-8.16 (m, 1). 13C NMR (100 MHz, CDCl3) δ122.57, 122.96, 128.14, 128.38, 128.72, 138.54, 139.86, 139.93, 144.93.
88%
With potassium phosphate; tetrabutylammomium bromide In water at 90℃; for 6 h; Green chemistry
General procedure: To a 10-mL reaction vial, heteroaryl halide (1.0 mmol), boronic acid (1.2 mmol), K3PO4 (2.0 mmol), tetra-butylammonium bromide (TBAB) (0.5 mmol), and 4 (0.1 mol percent) in water (3.5 mL) were added. The reaction mixture was stirred at 85 °C and the reaction progress was monitored by GC–MS analysis. After completion of the reaction, it was diluted with H2O and CH2Cl2. The organic layer was separated from mixture, the dried organic layer over MgSO4, and evaporated under reduced pressure. The crude reaction product was purified using column chromatography on silica-gel to afford the corresponding product with isolated yield up to 98percent.
71%
Stage #1: With bis-triphenylphosphine-palladium(II) chloride In 1,4-dioxane at 20℃; for 0.5 h; Inert atmosphere Stage #2: With sodium carbonate In 1,4-dioxane; water at 80℃; for 8 h; Inert atmosphere
General procedure: 3-Amino-2-chloropyridine (0.5g, 3.9mmol), phenylboronic acid (0.47 g, 3.9 mmol), and bis(triphenylphosphine)palladium dichloride (0.137 g, 0.195 mmol) were added to 1,4-dioxane (20ml). Under nitrogen atmosphere the mixture was stirred at room temperature for 30 minutes. 1M aqueous sodium carbonate (8 ml) was poured in, and the temperature was raised to 80°C. After the reaction at 80°C for 8 hours, the mixture was distilled off under reduced pressure. The residue was extracted with addition of ethyl acetate and water. The impurities were filtered off from the organic layer, and the solvent was distilled off under reduced pressure. The purification by column chromatography gave the title compound (0.47 g, 71.0percent yield).
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 24, p. 9412 - 9415
[2] Patent: US6316632, 2001, B1,
[3] European Journal of Organic Chemistry, 2012, # 31, p. 6248 - 6259,12
[4] European Journal of Organic Chemistry, 2012, # 31, p. 6248 - 6259
[5] Tetrahedron Letters, 2005, vol. 46, # 20, p. 3573 - 3577
[6] Advanced Synthesis and Catalysis, 2009, vol. 351, # 17, p. 2912 - 2920
[7] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 9, p. 1478 - 1485
[8] Journal of Organic Chemistry, 2005, vol. 70, # 1, p. 388 - 390
[9] Green Chemistry, 2010, vol. 12, # 11, p. 2024 - 2029
[10] Bulletin of the Korean Chemical Society, 2010, vol. 31, # 10, p. 3010 - 3012
[11] Patent: EP2599771, 2013, A1, . Location in patent: Paragraph 0350
[12] Advanced Synthesis and Catalysis, 2013, vol. 355, # 11-12, p. 2274 - 2284
[13] New Journal of Chemistry, 2017, vol. 41, # 24, p. 15420 - 15432
Reference：
[1] Chemistry - A European Journal, 2015, vol. 21, # 21, p. 7690 - 7694
[2] Tetrahedron Letters, 1998, vol. 39, # 36, p. 6441 - 6444
24
[ 6298-19-7 ]
[ 101601-80-3 ]
Reference：
[1] Organic Process Research and Development, 2001, vol. 5, # 3, p. 254 - 256
25
[ 6298-19-7 ]
[ 30458-68-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 5, p. 1117 - 1123
26
[ 6298-19-7 ]
[ 21991-39-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 5, p. 1117 - 1123
27
[ 6298-19-7 ]
[ 134-20-3 ]
[ 885-70-1 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With potassium <i>tert</i>-butylate In toluene at 50℃; for 1 h; Stage #2: With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 110℃; for 24 h;
(1) 300 ml of toluene was added to the reaction vessel,257 g of 2-chloro-3-aminopyridine was dissolved in toluene,Stir with a mechanical stirrer.Slowly 292 grams of potassium t-butoxide were added thereto,Add a rate of 5percent / min,Stir evenly.Then 393 g of methyl anthranilate was added dropwise to the reaction solvent,Dropping speed is 3percent Dosage / min.The reaction was carried out at 50 ° C for 1 hour,After the reaction,Add 400 ml of toluene,4.49 grams of palladium acetate and12.5 grams of binaphthalene diphenylphosphine,The reaction temperature was raised to 110 ° C for 24 hours.After completion of the reaction, the solvent was distilled off under reduced pressure, and the white solid was collected by suction filtration. The mixture was recrystallized from 600 ml of a mixed solvent of 50percent acetone and water. The mixture was filtered and washed with petroleum ether to obtain a cyclized intermediate benzodiazepine 66 g of the compound, the product yield was 95percent and the purity was 99percent.
Reference：
[1] Patent: CN106432227, 2017, A, . Location in patent: Paragraph 0017; 0018
[2] Journal of Heterocyclic Chemistry, 1998, vol. 35, # 3, p. 675 - 686
28
[ 6298-19-7 ]
[ 87-25-2 ]
[ 885-70-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1989, vol. 32, # 8, p. 1718 - 1724
29
[ 109-01-3 ]
[ 6298-19-7 ]
[ 5028-17-1 ]
Reference：
[1] Organic Preparations and Procedures International, 1998, vol. 30, # 6, p. 709 - 713
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 660 - 668
32
[ 617-35-6 ]
[ 6298-19-7 ]
[ 17288-32-3 ]
Yield
Reaction Conditions
Operation in experiment
190 mg
Stage #1: at 20℃; for 24 h; Stage #2: at 160℃; for 0.333333 h; Microwave irradiation
3-Amino-2-chloro-pyridine 4f (150 mg, 1.17 mmol), ethyl pyruvate 8 (0.25 ml, 2.00 mmol), pyridinium p-toluenesulfonate, (73 mg, 0.29 mmol) and tetraethoxy-silane (0.26 ml, 1.18 mmol) were suspended in 0.4 ml pyridine and stirred for 24 h at 20 °C. Afterwards Pd[P(C6H6)3]4 (70 mg, 0.06 mmol) and N,N-dicyclohexylmethylamine (0.35 ml, 2.06 mmol) were added and the reaction mixture was heated in a microwave oven to 160 °C for 20 min. The reaction mixture is diluted with 100 ml dichloromethan and extracted two times with 50 ml of a half saturated aqueous sodium hydrogencarbonat solution. The organic layer was dried with sodium sulfate, the solvent was evaporated under reduced pressure and the crude product was purified using chromatography method P3, yielding 190 mg (1.00 mmol) of 1H-Pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester. The ester was dissolved in 17 ml ethanol and 5 ml water. To this solution lithium hydroxide (120 mg, 5.00 mmol) was added. After 16 h the pH value of the reaction mixture was adjusted to pH 4 and the solvent is evaporated in vacuum. The crude product was purified using an acid ion exchanger (Strata-X-C, Phenomenex), yielding of 155 mg (82percent) of the title compound. Purity by method A1: >95percent; MS (ESI) m/z 163 (M + H)+; 1H NMR (DMSO) δ (ppm) 13.34 (br, 1H), 8.77 (d, J = 5.3 Hz, 1H), 8.53 (d, J = 8.3 Hz, 1H), 7.73 (dd, J = 5.4 Hz, J = 8.3 Hz, 1H), 7.33 (br, 1H); 13C NMR (500 MHz, DMSO) δ (ppm) 161.4 (s), 138.0 (s), 136.1 (s), 135.8 (s), 132.7 (s), 128.6 (s), 119.6 (s), 101.2 (s).
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 39, p. 11859 - 11862[2] Angew. Chem., 2016, vol. 128, p. 12038 - 12041,4
[3] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 660 - 668
33
[ 6298-19-7 ]
[ 17288-32-3 ]
Reference：
[1] Synthesis, 2005, # 15, p. 2571 - 2577
EXAMPLE 2; Preparation of 3-amino-2-chloropyridine 2 using hydrogen peroxide; 3-Aminopyridine 3 (30.0 g, 0.32 mole) was add to 300 mL of 37percent aqueous HC1 in a 1-L Morton flask with overhead stirring at about 30-35 °C. After the mixture was cooled to about 10 °C, 23 g (0.34 mol) of 50 percent hydrogen peroxide was added over 20 minutes at about 10-12 °C. The mixture was held at about 10 °C for 2 hours and then was allowed to warm to about 19 °C over 2 hours and held at that temperature for additional 4 hours. HPLC analysis showed approximately 90 percent conversion of 3-aminopyridine 3. After cooling the reaction mixture to 10 °C, a solution of 6 g of sodium sulfite in 50 mL of water was added. To the mixture were added 50 mL of toluene and 200 g (2.5 mol) of 50 percent aqueous sodium hydroxide at about 25-35 °C. Then water was added to dissolve precipitated NaCl, and the layers were separated. The organic phase was back-extracted with 45 g of 10 percent aqueous HC1 to recover some 3-amino-2-chloropyridine 2 in the toluene extract, and this was added back to the original aqueous phase. The combined aqueous phases were neutralized to pH 3 with 50 percent aqueous NaOH and extracted with toluene for 3 times. The toluene extracts were combined, washed with 30 mL of saturated aqueous NaCl, and concentrated to dryness to afford 33 g of crude 3-amino-2-chloropyridine 2 (76 percent yield) with 94 percent purity. The product contained about 3 wt percent 3-amino-2, 6-dichloropyridine by HPLC assay.
74%
EXAMPLE 3; Preparation of 3-amino-2-chloropyridine 2 using chlorine; 3-Aminopyridine 3 (21.0 g, 0.223 mol) was added to 90 mL (ca. 108 g, 1. 08 mol) of concentrated aqueous HC1 (ca. 37percent) in a 300-mL sidearm flask with magnetic stirring at 30-35 °C. The mixture was cooled to 15 °C (thick slurry) and chlorine gas was sparged just above the surface over about 1.5 hours at 15-20 °C. HPLC analysis showed approximately 93 percent conversion of 3-aminopyridine 3. The mixture was cooled to 10 °C and a solution of 6 g of sodium sulfite in 50 mL of water was added. To the mixture was added 30 mL of toluene and 80 g (1.0 mol) of 50 percent aqueous sodium hydroxide at about 25-40 °C. Then water was added to dissolve precipitated NaCI, and the layers were separated. The aqueous phase was extracted once more with 30 mL of toluene. To the aqueous phase was added 10 g of 50 percent NaOH, and extracted with another 50 mL of toluene to remove 3-amino-2, 6- dichloropyridine. The combined organic phase was back-extracted with 40 mL of 0.2 N aqueous HC1 to recover some 3-amino-2-chloropyridine 2 in the toluene extracts, and this was added back to the original aqueous phase. The combined aqueous phases were diluted with 100 mL of toluene and neutralized to pH 3 with about 20 g of 50percent aqueous NaOH at about 35 °C. The aqueous phase was extracted with two 50-mL portions of toluene. The toluene layers were combined and washed with 20 mL of saturated aqueous NaCI. The solution was concentrated to dryness to afford 21.4 g of crude 3-amino-2-chloropyridine 2 (74 percent yield) with 98.6 percent purity, which contained about 1.4 wt percent 3-amino-2,6- dichloropyridine.
With copper(ll) sulfate pentahydrate; In water; at 160℃; for 1h;Microwave irradiation;
3-Amino-2-chloropyridine (400 mg, 3.1 mmol) and copper sulfate pentahydrate (78 mg, 0.31 mmol, 0.10 eq.) were added to a microwave pressure vessel with 40% methylamine in water (2.33 ml) and heated at 160 C for 1 h. The crude product was cooled to RT and filtered through Celite. The crude mixture was treated with aqueous sodium carbonate, extracted with EtOAc (2x), dried over anhydrous NaSO4 , filtered, and dried under vacuum. After purification by column chromatography, using a solvent gradient from hexane to EtOAc, the desired compound 22 was isolated as orange solid (70%)
Example 1; Preparation of N-(2-chloropyridin-3-yl)-2-nitrobenzamide:A mixture of 3-amino-2-chloropyridine (3.85 g, 29.95 mmol) and 2- nitrobenzoyl chloride (5.56 g, 29.95 mmol) in pyridine (50 mL) was stirred at 0 0C for 1 h and then at room temperature overnight. Water was added and the precipitate formed was collected by filtration and dried to give N-(2-chloropyridin-3-yl)-2- nitrobenzamide as a white solid (8.52 g, crude yield: >100 %).
100%
With pyridine; In tetrahydrofuran; at 20℃; for 2.0h;
To a solution of 2-nitrobenzoyl chloride (5,55 g. 29.9 mmol) in THF (120 mL) was added pyridine (14.5 mL, 0.18 mol) and 3-amino-2-chloropyridine (4.23 g, 32.9 mmol) causing a precipitate to form. The reaction stirred at RT for 2 h before being diluted with 10% aq citric acid and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried ( gSO t) and concentrated in vacuo to give the product as a buff coloured solid (8.6 g, quant.). Material was used without purification. NMR (400 MHz, d6-DMSO) delta 10.61 (1H, s), 8.31 (1H, dd. ./ 4.3, 1.5 Hz), 8.25-8.16 (2H, m), 7.94-7.87 (1H, m), 7.84-7.75 (2H, m), 7.54 (1H, dd, J
In toluene; at 80℃; for 2.0h;
A solution of 2-nitrobenzoylchloride (7.2 g) in 100 ml toluene was added dropwise to a stirring solution of 2-chloro-3-amino-pyridine (10.0 g) in 100 ml toluene. After the entire amount was added, the mixture was heated to 80 C for 120 min. After the reaction mixture was cooled down and the resulting 2- nitro-N-(2-chloro-pyridin-3-yl)-benzamide was isolated by filtration. Yield 10.0 g, mp 158-161 C.
With pyridine; at 0 - 20℃;
A mixture of 3-amino-2-chloropyridine (3.85 g, 29.95 mmol) and 2- nitrobenzoyl chloride (5.56 g, 29.95 mmol) in pyridine (50 mL) was stirred at 0 0C for 1 h and then at room temperature overnight. Water was added and the precipitate formed was collected by filtration and dried to give N-(2-chloropyridin-3-yl)-2- nitrobenzamide as a white solid (8.52 g, crude yield: >100 %)
243 g
With triethylamine; In dichloromethane; at 15 - 30℃; for 1.0h;
(2) Take 2-chloro-3-aminopyridine 124g, DCM 600ml,Triethylamine 111g,Add to the 2000 ml reaction flask.Take the DCM solution of the step acid chloride,Slowly drip into the reaction solution,Maintain internal temperature 15-20 C;After the completion of the dropwise addition, the reaction solution is maintained at 20-30 C for about 1 h;TLC, complete reaction to 2-chloro-3-aminopyridine;The reaction solution was poured into 800 ml of ice water.Adjust the pH to 9-11 with sodium hydroxide, stir for 30 minutes;The aqueous phase was extracted once with 300 ml of DCM; the organic phases were combined; dried over anhydrous sodium sulfate;Concentrated dryMade a pale yellow solid (2) 243g,The yield in two steps was 90.4% and the purity was 97%.
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; hydrogen bromide; sodium nitrite; In water; at 10 - 20℃; for 2h;
Example 3 3-Bromo-2-chloropyridine (7) Water (45 ml) and 48% hydrobromic acid (27 ml) were added to 3-amino-2-chloropyridine (6) (2.57 g, 20 mmol) at room temperature. To the mixed solution, 2,2,6,6-tetramethylpiperidine 1-oxyl (0.31 g, 2 mmol) was added at room temperature, and the mixture was cooled to 10 C. or lower. Then, sodium nitrite (4.14 g) dissolved in water (30 ml) was added thereto. After stirring at room temperature for approximately 2 hours, a 10 mol/L aqueous sodium hydroxide solution (40 ml) was added thereto, followed by extraction twice with toluene (300 ml). The toluene layers were combined and washed with water (50 ml). The solvent was distilled off by the concentration of the toluene layer under reduced pressure to obtain 3-bromo-2-chloropyridine (7) (3.08 g, 80.1%).
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 4h;
A sample of 2-chloropyridin-3-amine (10 mmol, 1.28 g CAS: [169833-70-9]) and N-brom-succinamide (20 mmol, 3.56 g) in 40 ml of DMF were stirred at ambient temperature for 4 h. After this time, the mixture was poured into water and extracted with ethyl acetate (three times) The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo.. The crude product was purified by column chromatography on silica gel to give the title compound. H-NMR (400Mz, DMSO-c/6) delta: 5.71 (s, 2 H), 7.10 (d, 1 H), 7.31 (d, 1 H).
With sodium hydroxide; bromine; In methanol; water;
EXAMPLE 14 2-Chloro-3-aminopyridine To a solution of 9.8 g (240 mmol) NaOH in 104 mL of water was added 12.5 g (78 mmol) of Br2 at 5 C. The mixture was stirred for 10 minutes and 10 g (64 mmol) of <strong>[10366-35-5]2-chloro-3-pyridinecarboxamide</strong> was added at once. After stirring at 5 C. for 15 minutes, the resulting clear solution was heated at 75 C. for 90 minutes, cooled to room temperature, extracted with methylene chloride, and dried. Concentration followed by recrystalization from 30 mL of 6:1 mixture of H2 O and MeOH gave 5.9 g of the title compound (72%, m.p. 76-77.5 C., uncorrected).
(1) 300 ml of toluene was added to the reaction vessel,257 g of 2-chloro-3-aminopyridine was dissolved in toluene,Stir with a mechanical stirrer.Slowly 292 grams of potassium t-butoxide were added thereto,Add a rate of 5% / min,Stir evenly.Then 393 g of methyl anthranilate was added dropwise to the reaction solvent,Dropping speed is 3% Dosage / min.The reaction was carried out at 50 C for 1 hour,After the reaction,Add 400 ml of toluene,4.49 grams of palladium acetate and12.5 grams of binaphthalene diphenylphosphine,The reaction temperature was raised to 110 C for 24 hours.After completion of the reaction, the solvent was distilled off under reduced pressure, and the white solid was collected by suction filtration. The mixture was recrystallized from 600 ml of a mixed solvent of 50% acetone and water. The mixture was filtered and washed with petroleum ether to obtain a cyclized intermediate benzodiazepine 66 g of the compound, the product yield was 95% and the purity was 99%.
12.8 g of 2-chloro-3-aminopyridine was suspended in 120 mL of 60% aqueous hexafluorophosphoric acid, and 9.0 g sodium nitrite was added little by little thereto at 0C to precipitate crystals. The crystals were collected by filtration and washed with diethyl ether to give 15.75 g diazonium salt. Subsequently, the diazonium salt was suspended in 100 mL xylene and heated at 85C for 3 hours, 28 mL triethylamine was added thereto, and the reaction mixture was diluted with an aqueous saturated sodium bicarbonatesolution and then extracted with ethyl acetate. The extract was washed with brine, and the organic layer was dried over anhydrous sodium sulfate and then filtered through silica gel. The ethyl acetate was removed, and to the resulting xylene solution was added 6.0 mL 2-aminoethanol, and the mixture was heated at 130C for 10 hours. Then, the same procedure as in Production Example 231 was carried out, whereby 385 mg of the title compound (yellowoil) was obtained as a mixture.1H-NMR (CDCl3) delta: 3.60-3.68(m, 2H), 3.84(t, J=4.8Hz, 2H), 6.52-6.60(m, 1H), 7.12-7.20(m, 1H), 7.80-7.85(m, 1H)
EXAMPLE 13 N-(1-Methyl-1H-indol-5-yl)-N'-(2-chloropyrid-3-yl)urea hydrochloride (E13) A stirred suspension of carbonyl diimidazole (0.34 g, 2.1 mM) in dry dichloromethane (5 ml) was treated with a solution of <strong>[102308-97-4]5-amino-1-methyl-1H-indole</strong> (D3) (0.29 g, 2 mM) in dry dichloromethane (5 ml). After 0.25 h the reaction mixture was evaporated to dryness, and the residue dissolved in dimethylformamide (10 ml). 3-Amino-2-chloro-pyridine (0.23 g, 22 mM) was added to the reaction mixture which was heated to 90 C. for 1 h, then cooled and added to water (200 ml) with vigorous stirring. The precipitate was filtered, dried and recrystallized from ethanol affording the title compound as an off white solid (0.25 g; 42%) which was converted to the hydrochloride salt using hydrogen chloride in ether, m.p. 155 C.
Reference Example 189 Pyrido[2,3-b][1,4]benzoxazepin-6(5H)-one A mixture of 21.4 g of phenyl salicylate, 25.71 g 3-amino-2-chloropyridine and 20 ml of 1,2,4-trichlorobenzene is refluxed for 1 hour under argon and the liberated phenol and HCl simultaneously distilled (from the refluxing mixture) and collected in a solution of 1N NaOH. The hot mixture is poured into 200 ml of ethanol and the precipitated solid collected by filtration. The solid is washed with ethanol and dried Recrystallization from methanol--DMF (6:1) gives 6.0 g of product, m.p. 268-270 C.
2-amino-N-(2-chloro-pyridin-3-yl)-4-methyl-benzamide[ No CAS ]
[ 18595-17-0 ]
[ 118306-19-7 ]
Yield
Reaction Conditions
Operation in experiment
With conc. sulphuric acid; In thiophene; dichloromethane; toluene;
EXAMPLE C 5,11-Dihydro-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 127.0 g (0.485 mol) of 2-amino-N-(2-chloro-pyridin-3-yl)-4-methyl-benzamide (m.p. 150-152 C.) prepared analogously to Example A from 2-chloro-3-amino-pyridine and <strong>[18595-17-0]methyl 2-amino-4-methyl-benzoate</strong> (see F. Mayer and R. Schulze, Ber. Dtsch. Chem. Ges. 58, 1465 [1925]) were suspended in 500 ml of sulpholane and after the addition of 1.4 ml of conc. sulphuric acid the suspension was heated for 3 hours to 130 C. with stirring. It was then left to cool to 80 C., 500 ml of toluene were added and the mixture was left to stand overnight at ambient temperature. The crystals formed were suction filtered, suspended in 0.75 liters of dichloromethane, suction filtered once more and thoroughly washed with dichloromethane. After drying in a circulating air dryer, 70.2 g (64% of theory) of very slightly yellow crystals were obtained, m.p. 286-288 C., which were further reacted without any further purification.
N-(2-chloropyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane;
Example 186 N-(2-Chloropyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide 3-Amino-2-chloropyridine (0.206 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.271 g, 1.604 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate: hexane = 1:1) to obtain the titled compound (0.140 g, 0.289 mmol, 54percent).
N-(2-chloropyridin-3-yl)-5-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In hexane; dichloromethane; ethyl acetate;
Example 236 N-(2-Chloropyridin-3-yl)-5-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide 3-Amino-2-chloropyridine (0.141 g, 1.096 mmol), triethylamine (0.111 g, 1.096 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.185 g, 1.096 mmol) were added to a methylene chloride solution (100 ml) of 5-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.730 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform: methanol = 10:1) and then recrystallized from a mixed solvent of ethyl acetate and hexane (2:1) to obtain the titled compound (0.149 g, 0.329 mmol, 45percent).
Step 1. The 500 mL round-bottom flask, equipped with magnetic stirrer and reflux condenser was charged with 5-chloro-2-methoxyphenylboronic acid (9.78 g, 52 mmol), 3-amino-2-chloropyridine (7.00 g, 55 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-Phos, 0.43 g, 2 mol %), palladium (II) acetate (112 mg, 1 mol %), potassium carbonate (21.7 g, 157 mmol), 180 mL of acetonitrile and 20 ml of water. The flask was filled with nitrogen and heated to reflux under nitrogen atmosphere for 24 hours. Then the reaction was cooled down to room temperature, diluted with 500 mL of water and extracted with ethyl acetate (5*40 mL). Organic fractions were combined, dried over sodium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica gel with eluent hexane/ethyl acetate gradient mixture, providing 2-(5-chloro-2-methoxyphenyl)pyridin-3-amine as white crystals (9.5 g, NMR confirmed the structure).
To 3-amino-2-chloropyridine (2.87 g, 22.3 mmol) in THF (13 mL) cooled in a -10C bath was added sodium hexamethyldisilazide (51 mL, 51 mmol, 1M in THF). The mixture was stirred for 1 hr, then a suspension of imidazole carbonyl dimer (2 g, 10.6 mmol, see 15 in Scheme III above) in THF (20 mL) was added and let warm to room temperature. The mixture was stirred for 2 h then quenched with acetic acid. The reaction was concentrated in vacuo followed by the addition of water and saturated sodium bicarbonate. The solid product was collected by filtration with a water and hexane wash, then dried in vacuo to give the desired product 1A.
To a mixture of 3-methyl-2-oxobutanoic acid sodium salt (0.84 g, 6.0 mmol) in CHCl3 (5 mL) at rt was added 4 M HCl in dioxane (1.5 mL, 6.0 mmol). The mixture was stirred for 0.5 h at rt then cooled to -5 C and was added 3-amino-2-chloropyridine (0.77 g, 6.0 mmol), followed by DCC (1.24 g, 6.0 mmol) under N2 protection. The mixture was stirred at -5 C for 2 h, then concentrated. To the residue was added AcOEt (20 mL) and the white precipitate was removed by filtration. The filtrate was concentrated. The crude material was loaded on a 40 g silica gel column and purified on a Teledyne Isco instrument, eluting with 0-30% ethyl acetate in heptane to provide 4g (0.93 g, 68%) as an oil. 1H NMR (400 MHz, CDCl3) delta 1.17 (dt, J = 7.0, 1.4 Hz, 6H), 3.53-3.71 (m, 1H), 7.24-7.29 (m, 1H), 8.13 (dq, J = 4.7, 1.6 Hz, 1H), 8.67-8.80 (m, 1H), 9.34 (br s, 1H); 13C NMR (100 MHz, CDCl3) delta 18.0, 34.1, 123.4, 128.5, 130.9, 141.0, 144.9, 157.8, 201.2. MS (ESI) m/z 227.1 (M+H)
3-Amino-2-chloro-pyridine 4f (150 mg, 1.17 mmol), ethyl pyruvate 8 (0.25 ml, 2.00 mmol), pyridinium p-toluenesulfonate, (73 mg, 0.29 mmol) and tetraethoxy-silane (0.26 ml, 1.18 mmol) were suspended in 0.4 ml pyridine and stirred for 24 h at 20 °C. Afterwards Pd[P(C6H6)3]4 (70 mg, 0.06 mmol) and N,N-dicyclohexylmethylamine (0.35 ml, 2.06 mmol) were added and the reaction mixture was heated in a microwave oven to 160 °C for 20 min. The reaction mixture is diluted with 100 ml dichloromethan and extracted two times with 50 ml of a half saturated aqueous sodium hydrogencarbonat solution. The organic layer was dried with sodium sulfate, the solvent was evaporated under reduced pressure and the crude product was purified using chromatography method P3, yielding 190 mg (1.00 mmol) of 1H-Pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester. The ester was dissolved in 17 ml ethanol and 5 ml water. To this solution lithium hydroxide (120 mg, 5.00 mmol) was added. After 16 h the pH value of the reaction mixture was adjusted to pH 4 and the solvent is evaporated in vacuum. The crude product was purified using an acid ion exchanger (Strata-X-C, Phenomenex), yielding of 155 mg (82percent) of the title compound. Purity by method A1: >95percent; MS (ESI) m/z 163 (M + H)+; 1H NMR (DMSO) delta (ppm) 13.34 (br, 1H), 8.77 (d, J = 5.3 Hz, 1H), 8.53 (d, J = 8.3 Hz, 1H), 7.73 (dd, J = 5.4 Hz, J = 8.3 Hz, 1H), 7.33 (br, 1H); 13C NMR (500 MHz, DMSO) delta (ppm) 161.4 (s), 138.0 (s), 136.1 (s), 135.8 (s), 132.7 (s), 128.6 (s), 119.6 (s), 101.2 (s).
To a solution of 2-chloro-3-aminopyridine (585 mg) in dimethoxyethane (20 mL) were added (3-cyano-4- fluorophenyl) boronic acid (0.50 g) , tetrakis (triphenylphosphine) palladium (0) (263 mg) , 2M aqueous sodium carbonate solution (4.6 mL) under nitrogen stream, and the mixture was stirred overnight at 800C. The reaction mixture was allowed to cool, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to NH-silica gel column chromatography (eluate: ethyl acetate) . The obtained powder was collected and washed with isopropyl ether. To a toluene solution (15 mL) of this <n="136"/>powder were added acetic acid (0.19 mL) and 2, 5-hexanedione (0.32 mL) , and the mixture was heated overnight under reflux in a reaction container attached to a Dean-Stark and diluted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5:1) to give the title compound (307 mg, yield 35%) as pale- yellow crystals. 1H NMR (300 MHz, CDCl3) delta ppm 1.83 (6 H, s) 5.96 (2 H, s) 7.10 (1 H, t, J=S.1 Hz) 7.28 - 7.38 (1 H, m) 7.39 - 7.52 (2 H, m) 7.69 (1 H, dd, J^8.0, 1.5 Hz) 8.78 (1 H, dd, J=A.5, 1.5 Hz) .
With bis(tri-t-butylphosphine)palladium(0); triethylamine; In cyclohexyl acetate; at 150℃; for 40h;Inert atmosphere;
Triethylamine (13 mL), butyl acrylate (10 mL), and bis(tritert-butylphosphine)palladium (0) (350 mg) were added to a solution of 2-chloro-3-aminopyridine (6.00 g) in cyclohexyl acetate (60 mL), and the mixture was stirred at 150C for 40 hours under a nitrogen atmosphere. The resulting mixture was left to be cooled at room temperature. When the mixture was cooled to 70C, water (30 mL) was added thereto, and the resulting mixture was left to be cooled at room temperature under stirring. After subjecting the resulting mixture to sonication for 30 minutes, the mixture was filtered and the residue was washed with water (3 mL). The obtained residue was suspended in ethyl acetate (3 mL)/2-propanol (4 mL) and then subjected to sonication. Further, the suspension was filtered, and the residue was washed with ethyl acetate (3 mL) and hexane, and thereafter is dried to obtain a compound 0001-1 (2.51 g) as a pale yellow solid. 1H-NMR (DMSO-d6) delta: 11.90 (1H, s), 8.47 (1H, dd), 7.93 (1H, d), 7.68 (1H, ddd), 7.51 (1H, dd), 6.75 (1H, dd). MS m/z (M+H): 147.
ethyl 2-[3-(2-chloropyridin-3-yl)ureido]-2-methylpropionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.6 g
Reference Example 3 Ethyl 2-[3-(2-chloropyridin-3-yl)ureido]-2-methylpropionate (0373) 1.57 g (7.79 mmol) of (4-nitrophenyl) chloroformate were added in portions over 30 minutes with ice cooling to a mixed solution of 1.00 g (7.78 mmol) of 3-amino-2-chloropyridine, 620 mg (7.84 mmol) of pyridine and 20 ml methylene chloride. After completion of the addition, said reaction mixture was stirred for 2 hours with ice cooling. After this, 1.30 g (7.76 mmol) of ethyl 2-amino-2-methylpropionate hydrochloride and 2.00 g (15.84 mmol) of N,N-diisopropylethylamine were added with ice cooling to said reaction mixture. After completion of the addition, said reaction mixture liquid was stirred overnight with ice cooling. After completion of the addition, the reaction was stopped by addition of 30 ml of water, and said reaction liquid was extracted with methylene chloride (2×300 ml). The organic layer obtained was dried with anhydrous sodium sulfate, and the solvent distilled off under reduced pressure. The residue obtained was purified by silica gel chromatography (n-hexane:ethyl acetate=9:1 to 3:7), and 1.60 g of the desired compound were obtained as a white solid. (0374) 1H-NMR (CDCl3, Me4Si, 300 MHz): delta 8.56-8.51 (m, 1H), 8.02-7.99 (m, 1H), 7.27-7.16 (m, 1H), 6.84 (brs, 1H), 5.58 (brs, 1H), 4.19 (q, 2H, J=7.2 Hz), 1.63 (s, 6H), 1.28 (t, 3H, J=7.2 Hz).
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 8h;
To a solution of monomethyl 5-nitrobenzene-1,3-dicarboxylate (2.0 g, 8.9 mmol) in DMF(50ml) was added 3-amino-2-chloropyridine (1.1 g, 8.9 mmol), HATU (3.7 g, 9.8 mmol) and DIPEA(4.7 mL, 26.7 mmol) at room temperature. The solution was stirred for 8 h and concentrated. Theresidue was extracted with ethyl acetate (70 mL), washed with saturated NaHCO3 aqueoussolution, dried over Na2SO4, filtered, and concentrated. The residue was then purified by SiO2flash chromatography (60% EtOAc/hexanes) to afford S3 (1.5 g, 51%).
1-(2-chloropyridin-3-yl)-3-cyclopropylurea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With [m-(1,4-diazabicyclo[2.2.2]octanekN1:kN4)]hexamethyldialuminum; In tetrahydrofuran-d8; for 0.08333330000000001h;Microwave irradiation;
General procedure: A mixture of 2-chloropyridin-3-amine (1, 1 mmol) and tert-butyl substituted carbamates (2a-j) (1 mmol) in THF (2 mL) and catalytic amount of bis(trimethylaluminum)-1,4-diazabicyclo[2,2,2]octane (DABAL-Me3) was taken into quartz tube and subjected to microwave irradiation at 300 watts for 5-10 min with an every 30 s intervals. The reaction was monitored by TLC, after completion of reaction, it was quenched with 1 N HCl and neutralized with 10 % NaHCO3 solution. The compound extracted with ethyl acetate (2 × 20 mL), then the extracted solvent washed with water, dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to afford pure compounds (3a-j).
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