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With thionyl chloride; N,N-dimethyl-formamide In benzene |
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With oxalyl dichloride In toluene at 80℃; |
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With thionyl chloride for 2h; Ambient temperature; |
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With thionyl chloride for 24h; |
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With thionyl chloride In chloroform for 2h; Heating; |
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With thionyl chloride In benzene for 4h; Heating; |
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With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0℃; for 1h; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; |
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With thionyl chloride |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 1h; |
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With oxalyl dichloride; N,N-dimethyl-formamide at 0℃; |
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With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0℃; for 1h; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 1h; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 1.5h; |
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With thionyl chloride In dichloromethane at 0 - 20℃; |
1
Example 1 3-Furan-2-yl-1-morpholin-4-yl-propenone; [0227] Furylacrylic acid (25 g, 181 mmol) was added to 200 mL of methylene chloride and the reaction was cooled to 0°C. Thionyl chloride (19.8 mL, 272 mmol) was then added over 15 minutes. The solution was allowed to warm to room temperature overnight and the reaction went from cloudy to clear the next morning. In a separate flask 150 mL of methylene chloride and morpholine (47.5 mL, 545 mmol) were added and the flask was brought to 0°C. The solution containing the furan was then added dropwise by addition funnel to the cooled solution containing the morpholine. After addition the solution was allowed to warm to room temperature and stir for 1.5 hr. The reaction was then extracted twice with 1 N HCI, twice with brine, and dried over sodium sulfate. The organic layer was then decolorized by carbon and concentrated to dryness. This yielded a pale yellow solid (87% 32.5g, 156 mmol). ¹H NMR (CDCl3, 300 MHz) 8 3.60-3.78 (m, 8H), 6.48 (q, J=2 Hz, 1 H), 6.58 (d, J=3 Hz, 1 H), 6.78 (d, J=16 Hz, 1 H), 7.45-7.53 (m, 2H) ; MS (ESI (+)) m/z 208.1 (M+H+). |
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With thionyl chloride In dichloromethane at 0 - 20℃; |
1
Example 1 3-Furan-2-yl-1-morpholin-4-yl-propenone; [0227] Furylacrylic acid (25 g, 181 mmol) was added to 200 mL of methylene chloride and the reaction was cooled to 0°C. Thionyl chloride (19.8 mL, 272 mmol) was then added over 15 minutes. The solution was allowed to warm to room temperature overnight and the reaction went from cloudy to clear the next morning. In a separate flask 150 mL of methylene chloride and morpholine (47.5 mL, 545 mmol) were added and the flask was brought to 0°C. The solution containing the furan was then added dropwise by addition funnel to the cooled solution containing the morpholine. After addition the solution was allowed to warm to room temperature and stir for 1.5 hr. The reaction was then extracted twice with 1 N HCI, twice with brine, and dried over sodium sulfate. The organic layer was then decolorized by carbon and concentrated to dryness. This yielded a pale yellow solid (87% 32.5g, 156 mmol). ¹H NMR (CDCl3, 300 MHz) 8 3.60-3.78 (m, 8H), 6.48 (q, J=2 Hz, 1 H), 6.58 (d, J=3 Hz, 1 H), 6.78 (d, J=16 Hz, 1 H), 7.45-7.53 (m, 2H) ; MS (ESI (+)) m/z 208.1 (M+H+). |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; Inert atmosphere; |
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With thionyl chloride for 8h; Reflux; |
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With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran Cooling with ice; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 2h; Reflux; Inert atmosphere; |
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With thionyl chloride; N,N-dimethyl-formamide In 1,2-dichloro-ethane for 4h; Reflux; |
General procedure for the synthesis of (3E,5E)-1-((E)-3-arylacryloyl)-3,5-bis(pyridin-4-ylmethylene)piperidin-4-ones (8-17)
General procedure: The mixture of appropriate substituted trans-cinnamic acid(3 mmol), thionyl chloride (6 mmol) and DMF (1 drop) in dry 1,2-dichloroethane (10 ml) were refluxed for 4 h under anhydrous conditions. Volatiles were then removed under reduced pressure at 50 °C. The residue (acid chloride) was dissolved in 1,2-dichloroethane (5 ml). This solution was added dropwise to an ice-cold stirred solution of 6 (2 mmol) and triethylamine (9 mmol) in 1,2-dichloroethane (20 ml) over 10 min under anhydrous conditions. The reaction mixture was stirred for an additional 17 h at room temperature. Upon completion of the reaction (monitored byTLC, solvent system 10% MeOH in DCM), the reaction mixture was washed successively with a saturated NaHCO3 solution (50 ml) and water (2 50 ml). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was rotary-evaporated to dryness to yield the crude product which was column-chromatographed on silica gel (eluent 2% MeOH in DCM) to obtain the pure product. |
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With thionyl chloride; N,N-dimethyl-formamide In 1,2-dichloro-ethane for 4h; Reflux; |
3.3 General procedure for the synthesis of (3E,5E)-1-((E)-3-arylacryloyl)-3,5-bis(pyridin-4-ylmethylene)piperidin-4-ones (8-17)
General procedure: The mixture of appropriate substituted trans-cinnamic acid (3mmol), thionyl chloride (6mmol) and DMF (1 drop) in dry 1,2-dichloroethane (10ml) were refluxed for 4h under anhydrous conditions. Volatiles were then removed under reduced pressure at 50°C. The residue (acid chloride) was dissolved in 1,2-dichloroethane (5ml). This solution was added dropwise to an ice-cold stirred solution of 6 (2mmol) and triethylamine (9mmol) in 1,2-dichloroethane (20ml) over 10min under anhydrous conditions. The reaction mixture was stirred for an additional 17h at room temperature. Upon completion of the reaction (monitored by TLC, solvent system 10% MeOH in DCM), the reaction mixture was washed successively with a saturated NaHCO3 solution (50ml) and water (2×50ml). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was rotary-evaporated to dryness to yield the crude product which was column-chromatographed on silica gel (eluent 2% MeOH in DCM) to obtain the pure product. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 25 - 30℃; for 3h; |
4.2 General procedure for the synthesis of title compounds 8
General procedure: To a methylene chloride (10mL) solution of substituted Carboxylic acid 3 (5mmol) in an ice bath was added oxalyl chloride (10mmol), and catalytic N,N-dimethylformamide, while the reaction contents were stirred continuously. The reaction mixture was allowed to stand at 25-30°C for 3h. Solvent distilled under reduced pressure and dried under high vacuum to remove oxalyl chloride. Reaction mass was dissolved in dichloromethane (10mL). The solution was added to the mixture of amine 7 (4.5mmol) and TEA (10mmol) and then allowed to stir at room temperature for overnight. Reaction mixture was washed with saturated sodium bicarbonate (20mL) and then with water (20mL). Organic solvent was dried over anhydrous Na2SO4, filtrated, and then evaporated to give solid. Crude solid product was recrystallized from suitable solvent to give title compounds 8a-e (Scheme 1) as solids. |
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With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0℃; for 0.5h; |
6.5. General methods for 11,12-cyclic carbonate azithromycin 4"-O-(trans-β-arylacrylamido)carbamoyl analogs (5-16)
General procedure: General methods for 11,12-cyclic carbonate azithromycin 4"-O-(trans-β-arylacrylamido)carbamoyl analogs (5-16) To a solution of L1 (0.41 g, 2.74 mmol) in THF was added oxalyl chloride (1.03 g, 8.22 mmol) drop by drop and DMF (three drops) at 0 °C. The resulting solution was stirred for 0.5 h at the same temperature. Subsequently, the reaction was quenched in vacuum to remove THF and oxalyl chloride and afforded light-yellow residue. A solution of the key intermediate 4 (3 g, 3.43 mmol) and NaHCO3 (0.23 g, 2.74 mmol) in anhydrous THF was stirred at 0 °C. After addition of the above residue in THF drop by drop, the resulting solution was stirred for another 2 h at the same temperature. Then the reaction was concentrated in vacuum to remove THF and quenched with saturated NaHCO3. Subsequently, the aqueous layer was extracted with ethyl acetate (2 * 25 mL) and the combined organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to afford a crude product. A solution of the above crude product in methanol was heated to 55 °C and stirred for 12 h at the same temperature. Subsequent concentration of the reaction solution in vacuum provided the crude product of 5. The above crude product was purified by flash column chromatography eluting with 30:1 dichloromethane/methanol to afford the desired product 5. According to the above procedure, corresponding compounds 6-16 were prepared in yields ranging from 66% to 73%. |
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With oxalyl dichloride; N,N-dimethyl-formamide Inert atmosphere; Reflux; |
(E)-3-chloro-1-cinnamoyl-5,6-dihydropyridin-2(1H)-one (ZM90)
General procedure: A solution of E-cinnamic acid (74 mg, 0.5 mmol) and oxalyl chloride (254 mg, 2 mmol) in dry THF was refluxed for 4 h under N2 atmosphere. The reaction was cooled to 0 °C and triethylamine (101 mg, 1 mmol) was dropwise added. The reaction solution was stirred for another 15 minutes at 0 °C. Then the lactam (66 mg, 0.5 mmol) in dry THF was slowly added and stirred at room temperature for overnight. The mixture was diluted with DCM (30 mL) and washed with saturated ammonium chloride solution (20 mL) and saturated saline solution (20 mL), dried over Na2SO4, concentrated and purified by column chromatography (Rf = 0.7, Ethyl Acetate/Petroleum Ether = 1:1) to afford ZM90, 100 mg, white solid, yield 76.9%. |
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With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0℃; for 1.5h; Inert atmosphere; |
General Method for Synthesis of Intermediate Acid Chlorides
General procedure: To the acid (1 eq) in 1 mL of THF and 1 drop of DMF at 0°C, oxalyl chloride (1.2 eq) was added. The reaction was stirred under nitrogen for 1.5 hours and then the solution was concentrated. The acid chloride was continued to the next step. |
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With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 5h; Inert atmosphere; |
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With thionyl chloride In tetrahydrofuran for 2h; Reflux; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 25 - 30℃; for 3h; |
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With thionyl chloride In dichloromethane Reflux; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 30℃; |
4.9. General procedure for synthesis of intermediates 19a~c
General procedure: Cinnamic acid 14a (1.05 g, 6.76 mmol) and oxalyl chloride(1.16 mL, 14.01 mmol), were dissolved in dry DCM (20 mL) at 0 °Cusing DMFas catalyst. Stirringwas kept for 2-3 h at 25-30° C. Afterthat time, the DCM was evaporated off under vacuum. The oil crudewas directly used in next step with no further purification. TheDCM (1 mL) solution of corresponding acyl chloride was added to the solution of methyl 3-amino-2-thiophenecarboxylate (1.06 g,6.75 mmol), TEA (0.94 mL, 6.8 mmol) in DCM (10 mL). Stirring waskept for 6-7 h at about 25 °C. After that time, the organic layer waswashed with saturated citric acid, water. At last, the organic layerwas dried by anhydrous Na2SO4.The DCM was evaporated to obtaincrude. The crude was purified by recrystallization using ethanol assolution to obtain title compound 15a.Compound 15a (1.00 g, 3.48 mmol) was dissolved in methanol(15 mL). 5 N NaOH solution (2 mL) was added to the mixture. Thenstirring was kept for 2-3 h at 60° C. While the reaction wasfinished, 2 N HCl solution was added until the value at pH 1. Andthen methanol was removed under reduced pressure. The precipitatewas filtered to give compound 16a.Compound 16a (1.00 g, 3.66 mmol) were dissolved in dry DCMand oxalyl chloride (0.62 mL, 7.32 mmol) was added slowly in icebath. Then DMF was added as catalyst. The mixture was warmed to25-30 °C and stirred for 3 h. After that time, the solution wasremoved and directly used without further purification. The crudewas dissolved in acetone (15 mL) and was slowly added NH3H2O(8 mL) in ice bath. After the operation, stirringwas kept for 3e4 h at25e30 C. While the reaction was finished, acetone was remove.The crude was added 2 N HCl solution until the value at pH 7. Theprecipitate was filtered to afford compound 17a.Compound 17a (1.00 g, 3.67 mmol) was suspended in methanoland cooled to 0° C. Sodium methoxide (30%, 5.5 mL) solution wasadded slowly drop-wise. And then, the mixture was refluxed for2-3 h. After that time, it was cooled to room temperature. Thesolvent was removed and acidified to pH 6-7 with 2 N HCl. Theprecipitate was produced and filtered, washed with water. Thecrude was recrystallized from acetone to obtain compound 18a.Compound 18a (1.11 g, 3.93 mmol) was added to phosphorusoxychloride (POCl3) (5 mL, 53.75 mmol) in ice bath. The suspensionwas heated and stirred at about 100 °C for 6-12 h under N2 atmosphere.After that time, the mixture was cooled to room temperatureand poured into ice/water (50 g). The suspension wasextracted with ethyl acetate (150 mL 3). The ethyl acetate layerwas washed with saturated NaHCO3, dried through anhydrousNa2SO4. Ethyl acetate was removed in vacuum to get intermediate19a. Compounds 19b ~ c were prepared according to the sameprocedure as compound 19a. |
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With oxalyl dichloride In dichloromethane for 2h; Inert atmosphere; |
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