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With thionyl chloride for 2h; Heating; |
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With thionyl chloride; N,N-dimethyl-formamide In toluene at 60 - 70℃; for 0.5h; |
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With thionyl chloride for 2h; Heating; |
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With thionyl chloride |
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With thionyl chloride for 0.5h; Heating; |
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With thionyl chloride; N,N-dimethyl-formamide Heating; |
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With pyridine; thionyl chloride In toluene Heating; |
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With thionyl chloride In benzene |
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With thionyl chloride |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 10h; |
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With thionyl chloride at 90℃; for 4h; |
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With thionyl chloride In dichloromethane for 1h; Heating; |
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With thionyl chloride |
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With thionyl chloride Heating; |
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With thionyl chloride Reflux; |
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With thionyl chloride |
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With thionyl chloride |
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With thionyl chloride |
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With thionyl chloride Reflux; |
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With thionyl chloride |
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With thionyl chloride for 1h; Reflux; |
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With thionyl chloride for 3h; Reflux; |
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With thionyl chloride Reflux; |
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With thionyl chloride |
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With thionyl chloride Reflux; |
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With thionyl chloride |
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With thionyl chloride |
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With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.5h; Inert atmosphere; |
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With phosphorus pentachloride In toluene for 4h; Heating; |
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With thionyl chloride Heating; |
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With thionyl chloride; N,N-dimethyl-formamide at 80℃; for 2h; Inert atmosphere; |
Step A
General procedure: To the corresponding benzoic acid (3.3 mmol), thionyl chloride (10 mL) and a catalytic quantity of DMF were slowly added under an argon atmosphere. The suspension was refluxed until all the solid dissolved (2 h). Excess SOCl2 was then removed under reduced pressure, and the solid residue was co-evaporated twice with anhydrous toluene (2 x 10 mL). Crude benzoic acid chloride was immediately re-dissolved in dry toluene (20 mL) and drawn into a syringe for use in the following step. |
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With thionyl chloride for 3h; Reflux; |
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With thionyl chloride at 40 - 50℃; for 2h; |
4-{4'-[(E)-(4"-Propoxybenzoyl)oxyphenyl]diazenyl}-phthalonitrile (3c).
A mixture of 0.3 g (0.002 mol) of 4-(4'-propoxy)benzoic acid and 0.6 mL (0.005 mol) of thionyl chloride was heated at 40-50° at stirring till the gas evolution ceased (about 2 h). 0.9 g (0.0036 mol) of compound 3b and 1 mL of pyridine were then added, and the reaction mixture was refluxed at 85°C during 2 h. The obtained mass was poured into water; the precipitate was filtered off, washed with water till neutral reaction of the washings, and dried. The product was extracted with chloroform and purified by column chromatography (M60 silica gel, chloroform as eluent). Yield 0.7 g (47%), mp 148°C. IR spectrum (KBr), ν, cm-1: 2924 s, 2852 (CH), 2235 s (C≡N), 1729 s (C=O), 1267 s (Ar-O-Alk), 1608 s (N=N). 1H NMR spectrum (CDCl3), δ, ppm: 8.28 s (1H, H1), 8.19 m (1H, H3), 7.97 m (2H, H4), 7.95 m (1H, H2), 7.49 m (2H, H5), 7.03 m (2H, H7), 6.22 m (2H, H8), 1.61 m (2H, H9), 0.90 m (3H, H10). Electronic absorption spectrum, λmax, nm: 380 (chloroform); 387 (DMF). Found, %: C 69.93; H 4.12; N 13.18. C24H18N4O3. Calculated, %: C 70.23; H 4.42; N 13.65. |
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With hydrogenchloride; thionyl chloride In water |
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With thionyl chloride In N,N-dimethyl-formamide at 80℃; for 3h; Inert atmosphere; |
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With thionyl chloride at 50℃; for 0.5h; |
4
Example 4; (4-Propoxy-phenyl)-(2-(S)-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-methanone; Procedure F: 4-Propoxybenzoic acid (180 mg, 1.00 mmol) is dissolved in 2.0 mL of thionyl chloride and stirred at 50 0C for 30 min. The excess thionyl chloride is removed in vacuo. The residue is dissolved in 1.0 mL of CH2Cl2. (S)(+)-l-(2- pyrrolidinylmethyl)pyrrolidine (164 mg, 1.07mmol) and triethylamine (108 mg, 1.07 mmol) are dissolved in 3.0 mL of CH2Cl2 and cooled to 0 °C. The acid chloride solution is added to this mixture and stirred at room temperature for 1 h. The reaction mixture is diluted with CH2Cl2, washed with brine, dried over Na2Sθ4, filtered and evaporated.The crude product is applied to silica-gel column chromatography (CH2Cl2: 2M NH3 in MeOH = 20: 1) to provide 298 mg (94%) of the titled compound. Observed Mass: 317(M+1). |
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With thionyl chloride for 3h; Reflux; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 1h; Inert atmosphere; |
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With thionyl chloride for 2h; Reflux; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; Cooling with ice; |
35 Example 35. Preparation of compound 35 with lappaconitine and 4-n-propoxybenzoic acid:
Weigh 181mg of 4-n-propoxybenzoic acid in a 25ml dry round bottom flask, add 5ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, and add 381mg of oxalyl chloride in an ice bath. After reacting at room temperature for 2 hours, 4-n-propoxybenzoyl chloride was prepared. Weigh 89 mg of N-deacetyllappaconitine in a 25 ml round-bottom flask, and add 10 ml of dry dichloromethane to dissolve it. Add 105μl of dry pyridine under the protection of Ar gas, slowly add the prepared acid chloride dropwise to the substrate solution, and react at 35°C. The progress of the reaction is checked by thin-layer chromatography. The reaction is complete after 15 hours. Add a saturated aqueous sodium carbonate solution dropwise to the reaction solution to adjust the pH value of the reaction solution to 10. The reaction solution was extracted with dichloromethane, the dichloromethane layer was dried with anhydrous sodium sulfate, the sodium sulfate solid was filtered off, and the dichloromethane was spin-dried to obtain the crude product, which was separated and purified by column chromatography to obtain the target compound. Its structure and characteristics are as follows: |
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With thionyl chloride at 0℃; for 24h; Reflux; |
8.1.2.2. Method B, synthesis of amide bond using thionyl chloride.
General procedure: The appropriate carboxylic acid (1 eq.) was cooled to 0 C and then thionyl chloride (2 eq.) was added dropwise. The mixture was thenheated under reflux for 2 h, and the excess of thionyl chloride wasevaporated under vacuum. The acid chloride was dissolved in dryTHF and added dropwise to a solution of the appropriate amine (0.9eq.) and DIPEA (3 eq.) in THF. After completion, the reactionmixture was diluted with ethyl acetate and washed with a saturatedaqueous solution of ammonium chloride and brine. Theorganic layerwas dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified using columnchromatography (chloroform/methanol as eluents). The yieldswere around 50-70%. |
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