| 88.5% |
With trichlorophosphate for 2h; Heating / reflux; |
49
Phosphorus oxychloride (4mL, 429 mmol) was added to 7-chloro-4-hydroxyquinoline 2.86g, 15. 9mmol) in a round bottom flask equipped with a reflux condenser. The mixture was heated to reflux for 2h, then allowed to cool to room temperature. The solution was concentrated III vacuo to a thick oil, then dumped over cracked ice. The resulting solution was neutralized with saturated NAHC03 (aq). The slurry was filtered and washed with water. The solids were dried under vacuum, afforded 4,7-dichloroquinoline as a white solid (2.79g, 88. 5% yield). |
| 81.6% |
With trichlorophosphate for 6h; Reflux; |
4.2.3. Preparation of 4,7-Dichloro-quinoline29 (4)
A Phosphorus oxychloride (10 mL, 1 vol) was added to 7-chloro-4-hydroxyquinoline (3) (10 g, 0.055 mol) in a round bottom flask equipped with a reflux condenser. The mixture was heated to reflux for 6 h, then allowed to cool to room temperature. The solution was concentrated under high vacuum to a thick oil, then dumped over cracked ice. The resulting solution was neutralized with saturated NaHCO3 (aq), solid precipitated was filtered and washed with water. The solids were dried under vacuum and the crude compound was purified by column chromatography over silica gel using eluent 30 % ethyl acetate in hexane to afford 4,7-dichloroquinoline as a white solid. Yield; 8 g (81.6 %) |
| 81.6% |
With trichlorophosphate for 6h; Reflux; |
Preparation of 4,7-Dichloro-quinoline (Int-4):
A Phosphorus oxychloride (10 mL, 1 vol) was added to 7-chloro-4-hydroxyquinoline (3) (10 g, 0.055 mol) in a round bottom flask equipped with a reflux condenser. The mixture was heated to reflux for 6 h, then allowed to cool to room temperature. The solution was concentrated under high vacuum to a thick oil, then dumped over cracked ice. The resulting solution was neutralized with saturated NaHCCh (aq), solid precipitated was filtered and washed with water. The solids were dried under vacuum. The crude compound was purifiedby column chromatography over silica gel using eluent 30 % ethyl acetate in hexane to afford 4,7-dichloroquinoline as a white solid Yield: 8 g (81.6 %) (analytical data reference of step-2, 3 and 4: Synthesis and Antitumor Activity of Halogen-Substituted 4-(3,3-Dimethyl-l-triazeno)quinolones, Journal q Medicinal Chemistry, 1978, Vol. 2i, No. 3) |
| 79% |
With trichlorophosphate at 120℃; for 6h; Inert atmosphere; |
4,7-Dichloroquinoline (25)
In a 100 mL, double neck RBF, 7-chloroquinolin-4-ol (89.0 mmol) was poured under dry atmosphere. Phosphorus oxychloride (536.0 mmol) was added into reaction flask at room temperature. The reaction mixture was allowed to reflux at 120 °C for 6 h. Reaction was monitored on TLC plate. After completion of reaction, excess of phosphorus oxychloride was removed under reduced pressure. The crude reaction mass was treated with 2N NaOH to get the precipitates. The precipitates were collected, washed with water and recrystallized with chloroform: Hexane (1:1) to get the pure 4,7-dichloroquinoline (25) as yellow solid (13.8 g, 79% yield). m.p. 95-96.4 1H NMR (400 MHz, CDCl3): δ 8.79 (d, J = 4.8 Hz, 1H); 8.12 (d, J = 8.8 Hz, 1H); 8.13 (d, J = 2 Hz, 1H); 7.61 (dd, J = 8.8, 2 Hz, 1H); 7.49 (d, J = 4.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 151.1, 149.6, 142.8, 136.6, 128.9, 128.8, 125.7, 125.1, 121.6. HRMS (ESI-ToF): m/z [M+H]+ calcd for C9H6Cl2 : 197.9872; found : 197.9871. |
| 77% |
With trichlorophosphate In toluene at 100 - 110℃; for 5h; |
4-5 Synthesis of Z5
Add 100ml of toluene, 3.2mol of phosphorus oxychloride, and 2.67mol of 4-hydroxy-7-chloroquinoline into the reaction vessel. After reacting at 100-110°C for 5 hours, after the reaction, the toluene and unreacted trichloride are evaporated under reduced pressure. Phosphorus oxide, add 200ml of water, neutralize the liquid caustic soda (30% sodium hydroxide) to a pH value of 5-6, after filtering, add EDTA and activated carbon to the filtrate for decolorization, adjust the pH value to stabilize at 5-6 with acetic acid, filter and use alkali (Sodium carbonate or sodium bicarbonate) adjust the pH value to 7-8, precipitate the product, filter, and dry to obtain an off-white 4,7-dichloroquinoline 2.06 mol with a yield of 77%. |
| 72.7% |
With trichlorophosphate for 6h; Reflux; |
|
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With trichlorophosphate |
|
|
With trichlorophosphate at 100℃; |
|
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With trichlorophosphate for 3h; Heating; |
|
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With trichlorophosphate at 150℃; for 3h; |
|
|
With bis(trichloromethyl) carbonate; N,N-dimethyl-formamide; triphenylphosphine In toluene at 50 - 100℃; |
1-2 Example 1 Preparation of 4,7-dichloroquinoline
300 g of toluene, 5 g of N, N-dimethylformamide, 5 g of triphenylphosphine, and 100 g of 7-chloro-4-hydroxyquinoline were sequentially added to the reaction flask. The stirring was started, and the temperature was raised to 50 ° C to 100 ° C.287 g of a 23% triphosgene solution in toluene was prepared and completely dissolved and placed in a constant-pressure dropping funnel. While maintaining the temperature in the reaction flask at 50 ° C to 100 ° C, the 23% triphosgene toluene solution was slowly added dropwise to control the dropwise addition time to 1 to 8 hours. After the dropwise addition was completed, the reaction was continued until the reaction was monitored by TLC (the reaction was completed in about 1 to 3 hours). After the reaction is completed, the distillation is performed under reduced pressure at 50 ° C to 100 ° C, and the distillation is stopped after the reduced pressure is distilled until there are no obvious droplets in the condenser. 300 g of absolute ethanol and 1 to 5 g of activated carbon were added under stirring, and the temperature was raised to reflux for 1 hour to decolorize. The filtrate was filtered while hot, and then cooled to 10 ° C to 30 ° C to obtain a filter cake. The filter cake was washed with 10-50 g of absolute ethanol and dried, and the wet product was dried under reduced pressure at 60 ° C to obtain 4,7-dichloroquinoline. |
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