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Example 1 Synthesis of 2,4'-bipyridine Tetrahydrofuran (10 ml) was charged in a nitrogen-substituted flask having an inner volume of 50 ml, cooled to -78C, and a solution (1.6 M, 10.3 ml, 16.4 mmol) of n-butyllithium in hexane was added. To this solution was added dropwise over 10 min a solution obtained by dissolving 4-bromopyridine (2.59 g, 16.4 mmol) in tetrahydrofuran (3 ml). The reaction mixture was stirred for 1 hr and a solution obtained by dissolving <strong>[24244-60-8]2-benzenesulfonylpyridine</strong> (3.00 g, 13.7 mmol) in tetrahydrofuran (5 ml) was added dropwise over 10 min. The reaction mixture was stirred for 3 hr, and isopropanol (1 ml) was added at the same temperature to stop the reaction. The obtained reaction mixture was added to water, and the mixture was extracted with ethyl acetate (15 ml*2). The extract was concentrated and purified by silica gel chromatography to give the title compound having the following analytical data (1.75 g, yield 81% based on <strong>[24244-60-8]2-benzenesulfonylpyridine</strong>) as a white solid. 1H-NMR spectrum (CDCl3) delta: 7.33-7.37 (m, 1H), 7.80-7.91 (m, 4H), 8.72-8.76 (m, 3H)
14.2 g (87 mmol) of 1,1,3,3-tetramethoxypropane, 10 g (83 mmol) of 4-acetylpyridine, 30 ml (500 mmol) of acetic acid and 39 g (500 mmol) of ammonium acetate were dissolved in 160 ml of 2-propanol, and the reaction solution was allowed to undergo the reaction at 80C for 9 hours. After completion of the reaction, this was cooled to room temperature, neutralized with 200 g (1.2 mol) of 25% sodium hydroxide aqueous solution and then extracted three times with 200 ml of toluene. The organic layer was concentrated and then purified by distillation under a reduced pressure to obtain 3.2 g (yield 27.6%) of the title compound (purity 98.2%).
12.3 g (79 mmol) of 1,1,3,3-tetramethoxypropane, 0.12 g (0.8 mmol) of 1-methyl-3-phenylurea, 9,6 g (79 mmol) of 4-acetylpyridine, 30 ml (500 mmol) of acetic acid and 39 g (500 mmol) of ammonium acetate were dissolved in 160 ml of 2-propanol, and the reaction solution was allowed to undergo the reaction at 80C for 9 hours. After completion of the reaction, this was cooled to room temperature, neutralized with 200 g (1.2 mol) of 25% sodiumhydroxide aqueous solution and then extracted three times with 200 ml of toluene. The organic layer was concentrated and then purified by distillation under a reduced pressure to obtain 7.8 g (yield 63.2%) of the title compound (purity 99.2%, melting point 55 - 57C).
14.0 g (87 mmol) of 1,3-dimethyl-2,3-dihydro-2-oxopyrimidinium chloride obtained in Example 1 was dissolved in 25 ml of acetonitrile and mixed with 10 g (83 mmol) of 4-acetylpyridine, and 12.6 g (125 mmol) of triethylamine was added dropwise thereto at 45C or less. After 30 minutes of the reaction at 45C, acetonitrile and triethylamine were evaporated under a reduced pressure, and 25 ml (416 mmol) of acetic acid and 39 g (454 mmol) of ammonium acetate were added to the residual liquid to carry out the reaction at 120C for 8 hours. After completion of the reaction, this was cooled to room temperature, neutralized with 217 g of 25% sodium hydroxide aqueous solution and then extracted three times with 200 ml of toluene. The organic layer was concentrated and then purified by distillation under a reduced pressure to obtain 10.3 g (yield 80%) of the title compound (purity 99.9%, melting point 56 - 57C).
15. 0 g (92 mmol) of 1,1,3,3-tetramethoxypropane and 20.5 g (119 mmol) of 1,3-di(n-butyl)urea were dissolved in 20 ml of 2-propanol, 13.0 g (125 mmol) of 35% hydrochloric acid was added thereto, and the mixture was refluxed for 1 hour. The reaction solution was cooled to room temperature, and 10.0 g (83 mmol) of 4-acetylpyridine and 7.1 g (89.8 mmol) of pyridine were added thereto. After 30 minutes of stirring at room temperature, 19 ml (416 mmol) of formic acid and 31.5 g (500 mmol) of ammonium formate were added to the reaction solution to carry out the reaction at 100C for 8 hours. After completion of the reaction, this was cooled to room temperature, neutralized with 200 g (1.2 mol) of 25% sodium hydroxide aqueous solution and then extracted three times with 200 ml of toluene. The organic layer was concentrated and then purified by distillation under a reduced pressure to obtain 9.9 g (yield 76.5%) of the title compound (purity 99.9%, melting point 55 - 57C).
EXAMPLE 1 Synthesis of 2,4'-dipyridyl (A-1) 100 ml of water, 100.0 g (0.96 mol) of 4-cyanopyridine and 48.0 g (0.96 mol) of hydrazine hydrate were charged in a 1000 ml 4-necked flask, and reacted at 50 C. for 4 hours under stirring. After confirming disappearance of the starting materials by HPLC analysis, 550 ml of water was further added thereto, and 139 g (0.96 mol) of 40% glyoxal aqueous solution was added thereto, followed by reacting at an outer temperature of 100 C. for 2 hours. After cooling, the reaction solution was subjected to extraction with xylene and separated. 882 g (9.6 mols) of 2,5-norbornadiene was added to the organic layer, and reaction was conducted for 4 hours under refluxing. After completion of the reaction, the organic layer was distilled under reduced pressure of 4.4 to 4.5 Torr to obtain a 134 to 136 C. fraction. Thus, there was obtained 109.3 g (yield: 72.9%) of the end product as pale yellow crystals. HPLC analysis revealed that purity of the product was 99.2%.
With ammonium acetate; sodium hydroxide; acetic acid; triethylamine; In tetrahydrofuran; water;
EXAMPLE 3 Synthesis of 2,4'-dipyridyl (VII) 2.91 g (0.024 mol) of 4-acetylpyridine and 2.97 g (0.030 mol) of 3-dimethylaminopropenal were dissolved in 100 ml of THF, 2.69 g (0.024 mol) of potassium t-butoxide was added, and heated at 60 C. for 10 minutes. Subsequently, 23.12 g (0.30 mol) of ammonium acetate and 60 ml of acetic acid were added and, after allowing to react at 60 C. for 3.5 hours, THF was removed in an evaporator. Then, 100 ml of water and 150 ml of a 25% NaOH aqueous solution were added, and the mixture was extracted with 4*100 ml ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under A reduced pressure, and recrystallized from hexane to obtain 1.92 g (yield: 51.2%) of colorless platy crystals. HPLC analysis (column: ODS-80TM; detecting UV: 264 nm; flow rate: 1.0 ml/min; eluant: acetonitrile/water=50/50; buffer: triethylamine 0.1%, acetic acid 0. 1%) revealed that purity of the product was 99.3%, melting point: 55.8 C. to 56.0 C.
1-benzyl-4-(pyridin-2-yl)-1,2,3,6-tetrahydropyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium tetrahydroborate; ammonia; In methanol; N,N-dimethyl-formamide; acetonitrile;
Step 1 1-Benzyl-4-(2-pyridyl)-1,2,3,6-tetrahydropyridine A Solution of 2 g (12.8 mmol) of <strong>[581-47-5]4-(2-pyridyl)pyridine</strong> (Aldrich) and 2.18 g (12.8 mmol) of benzylbromide in 15 mL of DMF and 15 mL of CH3CN was stirred at 95 C. for 4 h. The reaction mixture was then concentrated and redissolved in 20 mL of methanol. To the reaction mixture at 0 C. was added 0.95 g, (25.6 mmol) of NaBH4 and the reaction mixture was stirred for 1 h. The reaction was quenched with 6N HCl, and was partitioned between CH2Cl2 and 1N NaOH. The aqueous layer was extracted 3 times with CH2Cl2, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified chomatography [silica, CH2Cl2:ethyl acetate:(2M NH3 in MeOH), 100:100:2] to give 3.2 g of the title compound.
a. 1-Benzyl-4-[pyrid-2-yl]pyridinium bromide. A solution of 2,4'-dipyridyl (15.62 g, 0.1 mol) and benzyl bromide (17.104 g, 0.1 mol) in anhydrous EtOAc (600 mL) for 24 h. The pale yellow crystalline product formed was filtered and dried (32.7 g, 100%).
Example 2 Production Method of 2,4'-Dipyridyl Using Bis(triohenylphosphine) Nickel (II) Dibromide as Nickel Complex (2-Chloropyridine:4-Chloropyridine=3:2) The method of Example 1 was repeated except that the amounts of the 2-chloropyridine, 4-chioropyridine hydrochloride, and triethylamine were changed to 285 mul (3 mmoles), 300 mg (2 mmoles), and 280 mul (2 mmoles), respectively, and the 4,4'-dipyridyl was eluted with ethyl acetate after the elution of 2,4'-dipyridyl to thereby obtain 45 mg of 2,2'-dipyridyl (yield 19%, calculated from 2-chloropyridyl), 193 mg of 2,4'-dipyridyl (yield 61%, calculated from 4-chloropyridine), and 57 mg of 4,4'-dipyridyl (yield 36%, calculated from 2-chloropyridine).
68
[ 109-09-1 ]
[ 626-61-9 ]
aqueous copper sulfate[ No CAS ]
[ 581-47-5 ]
Yield
Reaction Conditions
Operation in experiment
31%
In toluene;
Example 13 The method used in Example 12 was carried out by ice cooling the reaction solution at the time when the 2-chloropyridine and 4-chloropyridine were added and by carrying out the reaction at room temperature, without heating. The separation of the 2,4'-dipyridyl with copper sulfate was simplified by the following method. This dipyridyl isomer mixture was dissolved in 10 ml of toluene, 20 ml of a 0.1M aqueous copper sulfate solution was added, and the resultant mixture was stirred, whereby insolubles were formed. The insolubles were filtered out using Celite. The toluene-aqueous copper sulfate solution was adjusted to a pH 9 with ammonia water, then extracted two times with 10 ml of toluene. The organic layer was washed with saturated saline and concentrated under reduced pressure, whereby a further 122 mg (yield 31%) of 2,4'-dipyridyl was obtained. The presence of a minute amount of 4,4'-dipyridyl was observed in this product.
3-chloro-4,5-dihydro-4-(4-(4-(pyridin-2-yl)pyridinio-1-yl)butyl)-1,4-benzoxazepin-5-one chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With sodium iodide; In acetone;
Example 23 Synthesis of 3-chloro-4,5-dihydro-4-(4-(4-(2-pyridyl)pyridinio-1-yl)butyl)-1,4-benzoxazepin-5-one chloride 200 mg of the compound of Example 16 was dissolved in 2 ml of acetone, 21 mg (2 equivalents) of sodium iodide and 120 mg (1.1 equivalents) of 2,4'-dipyridine were added, then the resultant mixture was heated and refluxed for 30 hours. This was allowed to cool, then the precipitated crystal was obtained by filtration and was recrystallized by a mixed solvent of methanol, acetone, and ether to obtain the above-referenced compound in an amount of 298 mg (yield of 96%).
With sodium hydroxide; In methanol; at 20℃; for 0.0833333h;
General procedure: A solution of H2bzgluO (25.1 mg, 0.1 mmol) and 2,2'-bipy(15.6 mg, 0.1 mmol) in MeOH (8 ml) was slowly added to an aqueous solution (10 mL) containing Cu(NO3)23H2O (24.2 mg,0.1 mmol). The solution was adjusted to pH = 5.1 with addition of a dilute aqueous 2 mol L-1 NaOH solution. The mixture was stirred for 5 min at room temperature and then filtered. The filtrate was left to stand at room temperature for one week or so to deposit blue colored crystals of compound 1 with 51% Yield based on Cu