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With phosphorus pentabromide In neat (no solvent) at 90℃; for 2 h; Inert atmosphere
Compound 1 was prepared via a slightly modified version frompreviously published [29]. Chelidamic acid monohydrate (2.20 g,10.9 mmol) and PBr5 (23.4 g, 54.3 mmol, 5 equiv) were heated neat to90 °C under N2 for 2 h. The deep red meltwas then cooled to roomtemperature,and CHCl3 (25 mL) was added. The solution was filtered, andfiltrate was cooled on ice (0 °C), while methanol (90 mL) was slowlyadded. Crystallization was induced with scratching, and the crystallinesolid was collected by vacuum filtration and further dried undervacuum to yield 1 as a crystalline white solid (2.82 g, 86percent). 1H NMR(300 MHz, CDCl3) δ 8.45 (s, 2H), 4.02 (s, 6H).
Reference：
[1] Journal of Inorganic Biochemistry, 2016, vol. 162, p. 253 - 262
[2] Organic Letters, 2011, vol. 13, # 3, p. 442 - 445
[3] Chemical Communications, 2012, vol. 48, # 80, p. 10025 - 10027
[4] Chemical Communications, 2014, vol. 50, # 68, p. 9665 - 9668
[5] Dalton Transactions, 2017, vol. 46, # 16, p. 5229 - 5239
[6] European Journal of Organic Chemistry, 2017, vol. 2017, # 35, p. 5252 - 5261
2
[ 67-56-1 ]
[ 499-51-4 ]
[ 162102-79-6 ]
Yield
Reaction Conditions
Operation in experiment
72%
Stage #1: at 100 - 120℃; for 3 h; Stage #2: at 0℃;
Dimethyl-4-bromo-2,6-pyridinedicarboxylate (Compound 2) A mixture of chelidamic acid monohydrate (8.42 g, 41.87 mmol) and PBr5 (93 g) in a dry Shlenk tube equipped with a reflux condenser was heated under a nitrogen atmosphere to 120° C. A melt formed which was stirred under a nitrogen atmosphere for 3 hours at 100° C. The resultant purple melt was cooled to room temperature and transferred to a round bottom flask equipped with a drying tube by washing with CHCl3 (3.x.50 mL). The solution was cooled to 0° C. and dry MeOH (150 mL) was slowly added. The resultant brown solution was stirred overnight and then concentrated in vacuo to a slurry. Solid was recrystallised from MeOH (175 mL), filtered, washed with ice cold MeOH (3.x.50 mL) and sucked dry, giving 2 as white needles (8.29 g, 72percent) 1H NMR (299.9 MHz, CDCl3) δ 8.46 (s, 2H, Ar-H), 4.04 (s, 6H, -OCH3) ppm; 13C NMR (125.7 MHz, CDCl3) δ 164.36 (carbonyl), 149.42 (aromatic), 135.37 (aromatic), 131.66 (protonated aromatic), 53.83 (methyl) ppm; Anal. Calcd. for C9H8NO4Br: C: 39.43, H: 2.94, N: 5.11, Found: C: 39.68, H: 2.92, N: 5.09; m.p. 166-167° C.
14,20-dimethoxy-11,11,14,17,17,20-hexamethyl-5-trimethylsilanylethynyl-1,9,12,18,22-pentaaza-tricyclo[7.6.6.13,7]docosa-3,5,7(22)-triene-13,19-dione[ No CAS ]
(14,20-dimethoxy-11,11,14,17,17,20-hexamethyl-13,19-dioxo-1,9,12,18,22-pentaaza-tricyclo[7.6.6.13,7]docosa-3,5,7(22)-trien-5-yl)-carbamic acid <i>tert</i>-butyl ester[ No CAS ]
With pyridine; dmap; sodium borohydrid; acetic anhydride; In tetrahydrofuran; methanol; acetone;
(b) 5 g of <strong>[162102-79-6]4-bromopyridine-2,6-dicarboxylic acid dimethyl ester</strong> are dissolved in 175 ml of tetrahydrofuran at room temperature. Then 75 ml of methanol are added. The mixture is cooled to 0 C.; 3.44 g of sodium borohydride are added in portions over a period of 45 minutes and the mixture is allowed to rise to room temperature. After 1 hour 30 ml of acetone are added dropwise within a period of 10 minutes. The reaction mixture is heated under reflux for 1 hour. The reaction mixture is then concentrated to dryness using a rotary evaporator. The residue is stirred at room temperature into 50 ml of pyridine. 0.1 g of 4-dimethylaminopyridine is added thereto and the mixture is then cooled to 0 C. 34.4 ml of acetic anhydride are added dropwise within a period of 30 minutes. The suspension is allowed to rise to room temperature. 50 ml of tetrahydrofuran are added. After being stirred overnight at room temperature, the reaction mixture is filtered and washed twice using 50 ml of tetrahydrofuran each time. The filtrate is concentrated using a rotary evaporator. 4-Bromo-2,6-di(acetoxymethyl)pyridine is obtained by crystallisation (melting point: 66-69 C.).
9-1) Synthesis of a Picolinate Bromide Derivative of Formula (II) (0262) (0263) Chelidamic acid monohydrate 1?? (5 g, 24.9 mmol) and phosphorus pentabromide (34 g, 79.0 mmol) were heated at 90 C. Once a liquid mixture was obtained, heating was continued for 2 hours at 90 C. After cooling the mixture with ice, chloroform (100 mL) and MeOH (100 mL) were added. The solution is mixed for 20 hours at room temperature and the pH is adjusted to 7 with saturated NaHCO3 solution. The solvents were evaporated off and the aqueous phase was extracted using dichloromethane (3×100 mL). The organic phase was dried over MgSO4, filtered and concentrated to give compound 2?? in the form of a white solid (6.43 g, 94%). (0264) 1H NMR (300 MHz, CDCl3): delta 8.42 (s, 2H), 3.99 (s, 6H). (0265) 13C NMR (300 MHz, CDCl3): delta 164.02, 149.12, 135.13, 131.33, 53.52.
Example 1.1.15: (2,6-diisopropylpyridin-4-yl)methanamine; A solution of 1.14 g (6.2 mmol) of chelidamic acid hydrate (4-oxo-l,4- dihydropyridine-2,6-dicarboxylic acid) and about 10 g of PBrs was heated at 90 0C under a CaCl2 drying tube for 3.5 h. Chloroform (125 mL) was added, the mixture was filtered, and to the solution in a 500 mL round bottom flask was added 30 mL of MeOH dropwise over a period of 1 h. After 1 h, 120 mL of saturated NaHCO3 was added, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and <n="78"/>concentrated. Crude dimethyl 4-bromopyridine-2,6-dicarboxylate (1.72 g) was used without further purification.
Phosphorous pentabromide (42 g) was added to chelidemic acid (5.0 g, 0.025 mol) and heated 80C for 3 hours. After consumption of starting materials (TLC), the reaction mixture was cooled to room temperature, diluted with chloroform (400 mL) and filtered. The filtrate was cooled to -10C and methanol(75 mL) was added drop wise and the mixture was stirred at -10C. After lh, the reaction mixture was brought to room temperature and concentrated under vacuum. The resulting residue was diluted with ice-cold water (300 mL) to afford a precipitate. The solid precipitate was filtered, washed with water and dried under vacuum to afford dimethyl 4-bromopyridine-2,6-dicarboxylate., which wastaken to the next step without further purification. Crude yield: 5.2 g.HPLC-MS (method C): Rt= 2.72 mm, [M+H] mlz: 274.Yield: not purified.
4-bromo-6-(methoxycarbonyl)pyridine-2-carboxylic acid potassium salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In methanol; dichloromethane; water; at 20℃; for 3h;
(2) Synthesis of 4-bromo-6-(methoxycarbonyl)pyridine-2-carboxylic acid A mixture of 6.09 g of <strong>[162102-79-6]dimethyl 4-bromopyridine-2,6-dicarboxylate</strong>, 1.08 g of potassium hydroxide, 200 ml of methanol and 20 ml of methylene chloride was stirred at room temperature for 3 hours, and 200 ml of diethylether was added thereto. The resulting white solid was filtered, and then washed with ether. The obtained white solid was dissolved in water, and then 12 ml of hydrochloric acid (2 M) was added thereto. The resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo to give the title compound.
With hydrogenchloride; In methanol; at 20℃; for 15h;
(1) Synthesis of dimethyl 4-bromopyridine-2,6-dicarboxylate A mixture of 7.38 g of 4-bromopyridine-2,6-dicarboxylic acid synthesised in the method of), 10 ml of a hydrochloric acid-methanol reagent and 100 ml of methanol was stirred at room temperature for 15 hours, and the reaction mixture was concentrated in vacuo. Ethyl acetate was added to the residue and the mixture was washed three times with a mixed solution of brine-saturated sodium bicarbonate (1: 1). The organic layer was dried over anhydrous magnesium sulfate and was filtered. The filtrate was then concentrated in vacuo to give the title compound.
[60] In a sealed tube, a mixture of 1 [61] (2.74 g,10 mmol) and (R or S)-phenylglycinol (3.43 g, 25 mmol) in methanol (10 mL) was stirred at 115 C for 12 h. After cooling toroom temperature, the crude product was poured into ice water(100 mL), stirred for 15 min, filtered, washed with water(20 mL 3) and the residues was dried under vacuum. The whiteproduct was used for the next step without further purification (4.41 g, 91%). 1H NMR (400 MHz, CDCl3): d 8.60 (d, J 7.6 Hz, 2 H),8.45 (s, 2 H), 7.37-7.29 (m, 10 H), 5.26-5.22 (m, 2 H), 4.01 (d,J 4.4 Hz, 4 H), 2.21 (br, 2 H).
With phosphorus pentabromide; In neat (no solvent); at 90℃; for 2h;Inert atmosphere;
Compound 1 was prepared via a slightly modified version frompreviously published [29]. Chelidamic acid monohydrate (2.20 g,10.9 mmol) and PBr5 (23.4 g, 54.3 mmol, 5 equiv) were heated neat to90 C under N2 for 2 h. The deep red meltwas then cooled to roomtemperature,and CHCl3 (25 mL) was added. The solution was filtered, andfiltrate was cooled on ice (0 C), while methanol (90 mL) was slowlyadded. Crystallization was induced with scratching, and the crystallinesolid was collected by vacuum filtration and further dried undervacuum to yield 1 as a crystalline white solid (2.82 g, 86%). 1H NMR(300 MHz, CDCl3) delta 8.45 (s, 2H), 4.02 (s, 6H).
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In methanol; water; toluene; at 70℃; for 2.5h;Inert atmosphere;
A mixture of 4-bromopyridine-2,6-dicarboxylic acid methyl ester (548 mg, 2.00 mmol), benzothiophene-2-boronic acid (401 mg, 2.25 mmol), sodium bicarbonate (332 mg, 3.95 mmol), and tetrakis(triphenylphosphine)palladium (119 mg, 0.10 mmol) was placed in a 100 mL-flask and dried under vacuum for 2.5 h. In a separate flask, a mixture of toluene (20 mL), methanol (5 mL) and water (5 mL) was degassed by bubbling argon gas for 2.5 h, and added to the flask containing reagents. The resulting mixture was stirred under argon atmosphere at 70 C for 2.5 h. The mixture was cooled to room temperature and evaporated to dryness. The residue was partitioned between dichloromethane and water, and the organic phase was collected, washed with brine and dried over sodium sulfate. After rotary evaporation, the residue was crystallized from ethyl acetate-hexanes to afford 1 (488 mg) as a white powder. Chromatography of the mother liquor on silica gel (10-60% ethyl acetate in hexanes) afforded an additional 19 mg of the product, providing 507 mg of 1 in total (77% yield). 1H NMR (400 MHz, CDCl3) delta 8.58 (s, 2H), 7.97 (s, 1H), 7.90 (m, 2H), 7.44 (m, 2H), 4.07 (s, 6H). 13C NMR (101 MHz, CDCl3) delta 165.20, 149.12, 144.62, 140.48, 140.08, 138.87, 126.39, 125.42, 124.88, 124.50, 124.09, 122.76, 53.56.
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In methanol; water; toluene; at 70℃; for 19h;Inert atmosphere;
A mixture of <strong>[162102-79-6]4-bromopyridine-2,6-dicarboxylic acid dimethyl ester</strong> (548 mg, 2.00 mmol), 1-methylindole-2-boronic acid (402 mg, 2.30 mmol), sodium bicarbonate (342 mg, 4.07 mmol), and tetrakis(triphenylphosphine)palladium (68 mg, 0.08 mmol) was placed in a 100 mL-flask and dried under vacuum for 2.5 h. In a separate flask, a mixture of toluene (30 mL), methanol (7.5 mL) and water (7.5 mL) was degassed by bubbling argon gas for 2.5 h. The degassed solvent mixture was added to the dried reagents and the combined ingredients were stirred under argon atmosphere at 70 C. After stirring for 19 h, the mixture was cooled to room temperature, diluted with dichloromethane, washed with brine and dried over sodium sulfate. After rotary evaporation, the residue was purified using silica gel chromatography (40% ethyl acetate in hexanes) to provide 5 (420 mg, 59% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.47 (s, 2H), 7.69 (td, J = 1.00, 7.60 Hz, 1H), 7.42 (dd, J = 0.80, 8.40 Hz, 1H), 7.35 (dt, J = 1.20, 8.40 Hz, 1H), 7.20 (ddd, J = 1.20, 7.20, 8.00 Hz, 1H), 6.91 (d, J = 0.80 Hz, 1H), 4.07 (s, 6H), 3.88 (s, 3H). 13C NMR (101 MHz, CDCl3) delta 165.26, 148.76, 143.28, 139.89, 136.60, 127.66, 127.00, 123.88, 121.62, 120.86, 110.23, 105.73, 53.54, 31.97.
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