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Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at -78 - 20℃; for 3 h;
2,5-dichloropyridine-4-carbaldehvde A solution of 2,5-dichloropyridine (27.0 g, 180 mmol) in THF (65 mL) was added via cannula to a cooled solution of LDA (100 mL of a 1 .8 M solution, 180 mmol) in THF (80 mL) at -78 °C. The mixture was stirred at -78 °C for 30 mins, then a solution of DMF (21.1 mL, 271 mmol) in THF (25 mL) was added slowly via syringe. The reaction was stirred at -78 °C for 3 hours and was then warmed to R.T. gradually. The solution was poured into a mixture of ice (800 mL) and cone. HCI (150 mL) and stirred for 20 mins before being basified with NaOH (3.0 M) to pH 9-10, and extracted with Et20 (2 x 500 mL). The combined organic layers were dried over MgS04 and concentrated to give the crude product as pale yellow solid. This solid was suspended in n-hexane with trace EtOAc and boiled for 5 mins. The liquors were decanted and stripped to yield a yellow solid which was purified by Biotage flash chromatography (65i, loaded in DCM / EtOAc, eluted with heptane - 20 percent EtOAc / heptane over 8 CV, then holding for 5 CV) to afford the title compound (17.9 g, 56 percent) as a pale yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1 H) 8.76 (s, 1 H) 10.22 (s, 1 H).
Intermediate 9: (2. 5-Dichloro-4-pyridinvl) methanedivl diacetate; Concentrated sulfuric acid (3 drops) was added to a suspension of 2, 5-dichloro-4- pyridinecarbaldehyde (Intermediate 8,4. 0g) in acetic anhydride (25ml) and the mixture was stirred at room temperature for 20h. The acetic anhydride was removed under vacuum to give the title compound as a pale brown oil. LC-MS: Rt 2.94min, MH+ 278
2,5-dichloropyridine-4-carbaldehvde A solution of 2,5-dichloropyridine (27.0 g, 180 mmol) in THF (65 mL) was added via cannula to a cooled solution of LDA (100 mL of a 1 .8 M solution, 180 mmol) in THF (80 mL) at -78 C. The mixture was stirred at -78 C for 30 mins, then a solution of DMF (21.1 mL, 271 mmol) in THF (25 mL) was added slowly via syringe. The reaction was stirred at -78 C for 3 hours and was then warmed to R.T. gradually. The solution was poured into a mixture of ice (800 mL) and cone. HCI (150 mL) and stirred for 20 mins before being basified with NaOH (3.0 M) to pH 9-10, and extracted with Et20 (2 x 500 mL). The combined organic layers were dried over MgS04 and concentrated to give the crude product as pale yellow solid. This solid was suspended in n-hexane with trace EtOAc and boiled for 5 mins. The liquors were decanted and stripped to yield a yellow solid which was purified by Biotage flash chromatography (65i, loaded in DCM / EtOAc, eluted with heptane - 20 % EtOAc / heptane over 8 CV, then holding for 5 CV) to afford the title compound (17.9 g, 56 %) as a pale yellow solid, 1H NMR (400 MHz, DMSO-d6) delta 7.85 (s, 1 H) 8.76 (s, 1 H) 10.22 (s, 1 H).
With n-butyllithium;
2,5-Dichloropyridine-4-carboxaldehyde was prepared from 2.5-dichloropyridine using the procedure described in Eur. J. Org. Chem. 2001, 1371-1376 (E. Marzi, A. Bigi, M. Schlosser ) and converted to 2-(2,5-dichloro-pyridin-3-yl)-lH- benzoimidazole using the method in route 1 step 4. This was aminated as described for compound 34 and the aminopyridine converted to compound 38 using the method in route 1 step 1
Intermediate 8: 2, 5-Dichloro-4-pyridinecarbaldehyde; Diisopropylamine (7. 5ml) was dissolved in THF (47ml) and the solution was cooled to -35C. n-Butyl lithium (1.6M in hexanes, 44ml) was added slowly maintaining the temperature below-30C. After the addition the reaction mixture was cooled to-75C and a solution of 2, 5-dichloropyridine (8.9g) in THF (27ml) was added dropwise. The mixture was stirred at-75C for a further 30min and a solution of DMF (7. Oml) in THF (14ml) was added dropwise. The reaction mixture was stirred at-75C for 1.5h then allowed to warm to 10C over 2.5h. The solution was poured onto a mixture of ice (500ml) and concentrated hydrochloric acid (45ml) and stirred for 15min. The mixture was basified to pH8 with sodium hydroxide (2N), extracted with ether (x3) and the combined organic extracts were washed with brine, dried (magnesium sulfate) and reduced to dryness under vacuum. The resulting oil was applied to a silica column (50g) and eluted with cyclohexane/ethyl acetate (100: 0 to 80: 20) The product obtained was recrystallised from cyclohexane to give the title compound as beige needles (6.65g). NMR: [8H d6-DMSO] 10.20 (1H, s), 8.75 (1H, s), 7.83 (1H, s)
The organic solutions were combined, washed with saturated NaCl solution, dried and evaporated to dryness to give about 22 g of 2,5-dichloro-4-pyridinecarboxaldehyde.
4
[ 102645-33-0 ]
2,5-dichloro-4-pyridinecarboxaldehyde oxime[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22.8 g (85%)
With hydrogenchloride; hydroxylamine hydrochloride; In isopropyl alcohol;
This aldehyde was dissolved in 100 ml of 2-propanol, mixed with 13.8 g of hydroxylamine hydrochloride and 20 drops of concentrated HCl and heated on a steambath for 1 hour. The mixture was then poured onto 200 g of ice, stirred well and filtered leaving a solid residue. The solid was vacuum dried to give 22.8 g (85%) of the desired <strong>[102645-33-0]2,5-dichloro-4-pyridinecarboxaldehyde</strong> oxime STR6 m.p. 173-174 C.
With sulfur; In dimethyl sulfoxide; at 20 - 60℃; for 2.58333h;
To a solution of <strong>[102645-33-0]2,5-dichloropyridine-4-carbaldehyde</strong> (2.75 g, 15.62 mmol) in DMSO (63 mL) was added /V-methyl-O-phenylenediamine (1.91 g, 15.62 mmol) and the mixture stirred at ambient temperature for 5 mins. Sulfur (500 mg, 15.62 mmol) was added and the mixture warmed to 60 C and allowed to stir for 2.5 hrs. The reaction was then cooled to R.T. and added to a bi-phasic stirred solution of DCM and water (200 mL ea). The resulting emulsion was extracted with DCM (3 x 100 mL) and the combined organics were washed with water (3 x 100 mL), dried over MgS04, filtered and stripped to a crude red gum which was purified by Biotage flash chromatography (45 M loaded with DCM, eluting with EtOAc / heptane 5-30 % over 10 CV, then holding for 5 CV) to afford the title compound (3.22 g, 74 %) as a pale orange solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 3.72 (s, 3 H) 7.26 - 7.35 (m, 1 H) 7.35 - 7.44 (m, 1 H) 7.69 (d, J=8.1 Hz, 1 H) 7.74 (d, J=8.1 Hz, 1 H) 7.95 (s, 1 H) 8.78 (s, 1 H). m/z (APCI+) for Ci3H9N3Cl2 278.05 / 280.00 (M+H)+.
(1) After replacing nitrogen with a three-port reaction flask equipped with mechanical stirring, thermometer, and constant pressure dropping funnel,Add the raw materials 1a-1 (200mmol) and 500.0ml THF in sequence, start stirring, and lower the temperature to -85 -90 ,Add 2mol / L n-butyllithium (210mmol) dropwise, keep the temperature at -85 -90 during the dropwise addition, keep the temperature for 1h after the dropwise addition,A solution of the raw material <strong>[102645-33-0]2,5-dichloropyridine-4-aldehyde</strong> (200 mmol) + 140.0 ml of THF was added dropwise.After the dropwise addition, the temperature was kept for 0.5h, and the temperature was naturally raised to room temperature for 3h.The reaction solution was poured into a 10% ammonium chloride aqueous solution, extracted with 320.0 ml of toluene, and the solution was separated.The aqueous phase was extracted once with 320.0 ml of toluene, the organic phases were combined, and washed twice with 260.0 ml of water.Separate the liquid, add 12g of anhydrous sodium sulfate to the organic phase, dry, filter, and concentrate the organic phase (-0.08 -0.09MPa, 55 65 ) until150.0 ml of petroleum ether was added and stirred for 0.5 h, filtered, and the filter cake was rinsed with petroleum ether to obtain intermediate 1a-2 (150 mmol) with a yield of 75%.
(2) To be equipped with mechanical stirring, thermometer,After nitrogen substitution in the three-port reaction flask of the constant pressure dropping funnel,Add the raw materials 4a-1 (200mmol) in sequence,500.0ml tetrahydrofuran, start stirring, and cool down to -85 -90 ,Add 2mol / L n-butyllithium (210mmol) dropwise,The temperature during the dropping is maintained at -85 -90 , and the temperature is kept for 1h after the dropping is completed.A solution of the raw material <strong>[102645-33-0]2,5-dichloropyridine-4-aldehyde</strong> (200 mmol) + 140.0 ml of tetrahydrofuran was added dropwise.After the dropwise addition, the temperature was kept for 0.5h, and the temperature was naturally raised to room temperature for 3h.The reaction solution was poured into 10% aqueous ammonium chloride solution, and extracted with 320.0 ml of toluene,Separate the liquid and extract the aqueous phase once with 320.0 ml of toluene,Combine the organic phases, wash twice with 260.0 ml of water, and separate.The organic phase is dried by adding 12g of anhydrous sodium sulfate and filtered,The organic phase is concentrated (-0.08 -0.09MPa, 55 65 ) to no avail,Add 150.0ml petroleum ether and stir for 0.5h, filter, rinse the filter cake with petroleum ether,Intermediate 4a-2 (150 mmol) was obtained with a yield of 75%.
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