90.3% |
at 78 - 130℃; for 8.33333h; Inert atmosphere; |
1.a-4.a; 1; 2; 6 a. hydroxychloroquine preparation
100g of 4,7-dichloroquinoline and 110g of hydroxychloroquine side chain compound (5-(Ν-ethyl-N-2-hydroxy ethanediyl amino)-2-pentylamine, hereinafter referred to as side chain) were added to the reactor, passed nitrogen protection, heated at 78 ° C to dissolve 4,7-dichloroquinoline, heated at 120 ° C for 20 minutes, and heated at 130 ° C for 8 hours. After the reaction was completed, the temperature was lowered (below 80 ° C), adjusted to pH > 12 with sodium hydroxide solution (mass concentration 7%), extracted with dichloromethane, washed with water until neutral, and removed dichloromethane by vacuum distillation to give crude hydroxychloroquine 154 g. The yield was 90.7%, and the HPLC purity was 92.45%. To the crude hydroxychloroquine, 300 g of butanone and 300 g of ethyl acetate were added, and the mixture was heated at 75 ° C to dissolve. After 4 hours, the temperature was slowly lowered to 10 ° C, filtered, and the filter cake was washed with a mixed solvent of butanone and ethyl acetate to obtain a hydroxychloroquine wet product, which was dried at 60 ° C for 4 h to obtain hydroxychloroquine dry product, purity 99.93%, maximum single impurity 0.05%, yield 90.3%. |
89.1% |
at 70 - 137℃; for 10.16h; Inert atmosphere; |
1 Example 1 Synthesis of Hydroxychloroquine
100 g of 4,7-dichloroquinoline and 130 g of 5-(N-ethyl-N-2-hydroxyethylamine)-2-pentylamine were added to the reactor and protected with argon.4,7-dichloroquinoline is dissolved by heating at 70 ° C.The temperature was raised at 115 ° C for 10 minutes.The temperature was raised at 137 ° C for 10 hours.After the reaction is completed, the temperature is lowered (below 80 ° C).Adjust the pH to >12 with sodium hydroxide solution (mass concentration 6%).Dichloromethane extraction,Washed to neutral,Steaming under reduced pressureHydroxychloroquineCrude 157g,The yield was 92.5%.To the whole amount of hydroxychloroquine, 200 g of acetone and 250 g of methyl acetate were added and heated at 65 ° C to dissolve.Slowly cool to 10 ° C after 4 hours,filter,The filter cake is washed with a mixed solvent of a mixture of acetone and methyl acetate.Obtaining hydroxychloroquine wet product, drying at 60 ° C for 4 h, to obtain hydroxychloroquine dry product,The yield was 89.1%. |
88.9% |
With sodium tert-pentylate In Isopropyl acetate at 110 - 122℃; for 23h; |
1.1.1; 2.2.1; 3.3.1; 4.4.1; 5.5.1 Example 5 5.1 Preparation of hydroxychloroquine
In a three-necked round bottom flask, 4,7-dichloroquinoline (99. 0 g, 0.5 mol), hydroxychloroquine side chain (91.5 g, 0.525 mol) and isopropyl acetate 545 g were added, and sodium t-amylate was slowly added ( 11.0g, 0.1mol), slowly heated to reflux under stirring conditions, and then distilled isopropyl acetate, gradually heated to 110 ° C over 9 hours, then heated to 120 ° C ~ 122 ° C 10 hours, and finally kept 120 ° C ~ After reacting at 122 ° C for 4 hours, after the reaction was completed, the reaction solution was cooled to 90 ° C to 100 ° C, and 5% sodium hydroxide solution was added thereto to alkalinize to pH = 9 to 10. The distilled isopropyl acetate was extracted twice, and the layers were separated. 250 g of drinking water was added to the combined organic phase, washed, layered, and the above operation was repeated until the pH of the washing water was 7. After the completion of the washing, the temperature of the water was controlled to 65 ° C, and 100 to 150 g of isopropyl acetate was distilled off under reduced pressure. Then, 5.0 g of activated carbon was added, and the mixture was heated under reflux for 1 hour, and filtered while hot. The filtrate was naturally cooled to 15 ° C, and the mixture was allowed to stand for 2 hours, filtered, and dried at 65 ° C for 4 hours to obtain 149.0 g of crude hydroxychloroquine. The melting point is 89.4 ° C ~ 91.5 ° C, HPLC purity 99.5%, the largest single impurity <0.1%, yield 88.9%. |
88.03% |
With pyridine at 100℃; for 20h; |
1.1; 2.1; 3.1; 4.1; 5.1; 6.1; 1.1; 2.1; 3.1 Synthesis of hydroxychloroquine:
In a 500mL three-necked flask, add 4,7-dichloroquinoline: 100.0g (0.51mol) and hydroxychloroquine side chain: 88.0g (0.57mol), add 1.0eq of pyridine (39.2g) and raise the temperature to 100°C, after reacting for 20 hours, HPLC monitors that the content of 4,7-dichloroquinoline is less than 2.5%, add 300g of water, separate the phases, keep the water phase, cool to room temperature, keep incubating for crystallization, reduce to 4°C, keep heat for crystallization, filter with suction, and vacuum dry the filter cake. About 149.3g of hydroxychloroquine was obtained, the yield was 88.03%, and the HPLC purity was 96.83%. The maximum single impurity content is 0.09%. |
87.6% |
With potassium etoxide In Isopropyl acetate at 110 - 122℃; for 23h; |
5 Comparative Example 5
In a three-necked round bottom flask, 4,7-dichloroquinoline (198 g, 1.0 mol), hydroxychloroquine side chain (182 g, 1.05 mol) and isopropyl acetate 1089 g were added, and sodium ethoxide (13.6 g, 0.2 mol) was slowly added. The temperature is slowly raised to reflux under stirring conditions, and then isopropyl acetate is distilled off, and the temperature is gradually raised to 110 ° C over 9 hours, then heated to 120-122 ° C for 10 hours, and finally heated at 120-122 ° C for 4 hours, until the reaction is complete. Thereafter, the reaction solution was cooled to 90 to 100 ° C, directly added to a 5% sodium hydroxide solution, and alkalized to neutrality. The distilled isopropyl acetate was extracted twice in two portions, and the layers were separated. To the combined organic phase, 500 g of drinking water was added and washed, and the above operation was repeated until the pH of the washing water was 7. After washing, the water temperature was controlled to 65 ° C, and isopropyl acetate was distilled off under reduced pressure to obtain crude hydroxychloroquine. The HPLC purity was 91.78%. To the crude hydroxychloroquine, 300 g of methyl ethyl ketone and 300 g of ethyl acetate were added, and the mixture was heated at 75 ° C to dissolve. After 4 h, the temperature was slowly lowered to 10 ° C, filtered, and the filter cake was washed with a mixed solvent of methyl ethyl ketone and ethyl acetate to obtain hydroxychloroquine. The wet product was dried at 60 ° C for 4 h to obtain hydroxychloroquine dry product with a purity of 99.8%, a maximum single impurity of 0.17%, and a yield of 87.6%. |
85.7% |
Stage #1: 4,7‐dichloroquinoline With potassium fluoride; N-hexadecyl-N,N,N-trimethylammonium bromide In acetonitrile at 80℃; for 2h; Inert atmosphere;
Stage #2: 5-(N-ethyl-N-2-hydroxyethylamine)-2-pentylamine In acetonitrile for 3h; Heating; |
1.1; 2-5; 1-2
(1)Put 4,7-dichloroquinoline (198.0g, 1.0mol), anhydrous KF (116.2g, 2.0mol), cetyltrimethylammonium bromide (10.9g, 0.03mol) and acetonitrile into the reaction flask (693 mL), replaced with nitrogen. The temperature was raised to 80°C, and the reaction was carried out for 2 hours, monitored by TLC, and the reaction was complete. Add 5-(N-ethyl-N-2-hydroxyethylamine)-2-pentylamine (217.9g, 1.25mol), keep warm and continue the reaction for 3h, after the reaction, the temperature is reduced to 30, filtered with suction, and the filtrate is decompressed concentrate. 400 mL of purified water was added to the concentrate, the pH was adjusted to 10 with 5% sodium hydroxide, a solid was precipitated, and the crude hydroxychloroquine was obtained by suction filtration. Add n-heptane (800mL) to the crude product, heat to reflux, slurries, cool to 0°C, keep for 2h, filter, and dry at 60°C for 4h to obtain hydroxychloroquine (287.9g), yield 85.7%, purity 99.8% , The maximum single impurity is 0.05%. |
84% |
With triethanolamine at 130 - 140℃; for 8h; Inert atmosphere; Industrial scale; |
1-4 Example 3: Preparation of hydroxychloroquine
Under the protection of nitrogen, add 3kg (15.15mol) into a 10L reactor 4,7-Dichloroquinoline, 3.15kg (18.18mol)2-[(4-Aminopentyl)(ethyl)amino]ethanol and 2.03kg (13.64mol) triethanolamine, slowly increase the temperature to 130-140°C, keep the temperature for 8 hours; reduce the temperature to 70-80°C, add 7% Adjust the pH of the reaction solution to 12-13 with aqueous sodium hydroxide, add ethyl acetate for extraction, wash the organic phase with water, and recover the ethyl acetate under reduced pressure. Add 9kg of ethyl acetate to the concentrate to dissolve at 50-70°C, and cool to 25- At 35°C, heat preservation and stirring for 12h to crystallize, continue to lower the temperature to 5-10°C, crystallize for 6 hours, and filter to obtain the crude compound of formula (I).The crude hydroxychloroquine was recrystallized with a mixed solution of ethyl acetate and isopropanol, filtered and dried to obtain 4.2 kg of the compound of formula (I) with a yield of 84%. |
81.8% |
With potassium iodide In pentan-1-ol at 137 - 147℃; for 15h; Inert atmosphere; |
1.1; 2.1; 3.1; 4.1; 5.1; 6.1 Preparation of crude hydroxychloroquine:
4,7-dichloroquinoline 100.01g (0.50mol),Aminopentylamino alcohol (i.e. amino side chain) 105.68g (0.61mol),Potassium iodide 0.858g (0.005mol),BHA 4.54 g (0.025mol) and 200 mL of n-pentanol were added to the reactor,Replace with nitrogen 3 times and pass nitrogen protection,Heat to reflux (137-147°C) and react for 15 hours.The temperature was lowered to below 90°C, and the solvent was evaporated under reduced pressure.Cool down to below 70 and add dilute hydrochloric acid (56% dilute hydrochloric acid) to adjust the pH to 13,The water phase was washed with ethyl acetate 200mL x 3,Then add 500mL of dichloromethane, stir and cool to below 20°C,Slowly add 40% sodium hydroxide aqueous solution, adjust the pH to about 12,Separate the liquids, and extract the aqueous phase twice with dichloromethane (500mL, 200mL),Combine the organic phases.The organic phase was washed 400mL x 4 with purified water, and the solvent was replaced by 500mL ethyl acetate by distillation under reduced pressure.Heat to reflux, then cool to 010 to crystallize, filter,The filter cake was rinsed with ethyl acetate,The wet product was vacuum dried at 50°C for 27 hours to obtain 125.76 g (0.37 mol) of crude hydroxychloroquine.The HPLC purity is 98.47%, and the yield is 74.1%. |
78% |
With potassium carbonate; triethylamine In ethanol at 125℃; for 6h; Inert atmosphere; Flow reactor; |
Synthesis of 2-((4-((7-chloroquinolin-4-yl)amino)-pentyl)(ethyl)amino)ethan-1-ol (1)
Batch: In a CSTR reactor, to a mixture of 4,7-dichloroquinoline(200 mg, 1.0 mmol), compound 12 (208 mg, 1.2 mmol), triethylamine(0.069 mL, 0.5 mmol, 0.5 equiv) and potassiumcarbonate (69 mg, 0.5 mmol, 0.5 equiv) was added ethanol(1.0 mL). The ethanol was distilled off from the reaction mixtureand kept under nitrogen atmosphere (15 psi). The reactionwas left at 125 °C in the nitrogen atmosphere for 6 h. Aftercooling, the mixture was transferred into a separatory funnelusing 1 M aqueous sodium hydroxide (5 mL) and dichloromethane(2 × 20 mL). The organic phases were separated andthe aqueous phase was re-extracted with dichloromethane(2 × 10 mL). The organic layers were combined and dried oversodium sulfate and evaporated in vacuo. The crude material waspurified using flash chromatography with DCM/Et3N/MeOH95:3:2 to give a white solid (0.263 g, 78%). 1H NMR(600 MHz, CDCl3) δ 8.48 (d, J = 5.4 Hz, 1H), 7.93 (d, J = 5.4 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.34 (dd, J = 8.8, 7.3 Hz,1H), 6.39 (d, J = 5.4 Hz, 1H), 4.96 (d, J = 7.5 Hz, 1H), 3.70 (sx,J = 6.8 Hz, 1H), 3.55 (m, 2H), 2.57 (m, 5H), 2.49 (m, 2H),1.74-1.62 (m, 1H), 1.65-1.53 (m, 3H), 1.31 (d, J = 6.9 Hz, 3H),1.24 (d, J = 7.2 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 152.2,149.5, 149.2, 135.0, 129.0, 125.4, 121.2, 117.4, 99.4, 58.6, 54.9,53.18, 48.5, 47.9, 34.5, 24.1, 20.6, 11.9. Spectra were obtainedin accordance with those previously reported [38,39]. |
78% |
With potassium carbonate; triethylamine In ethanol at 125℃; for 6h; Inert atmosphere; |
Synthesis of 2-((4-((7-chloroquinoIm-4-yI)amino)pentyl)(ethyl)amino)ethan-l-oI (1):
Batch: In a CSTR reactor, 4,7-Dichloroquinoline (200 mg, 1.0 mmol), compound (12) (208 mg, 1.2 mmol), triethylamine (0.069 mL, 0.5 mmol, 0.5 equiv) and potassium carbonate (69 mg, 0.5 mmol, 0.5 equiv) were combined and to this mixture was added ethanol (1.0 mL). The ethanol was distilled off from the reaction mixture and kept under nitrogen atmosphere (15 psi). The reaction was left at 125 °C in the nitrogen atmosphere for 6h. After cooling, the mixture was transferred into a separatory funnel using 1 M aqueous sodium hydroxide (5 mL) and dichloromethane (2x20mL). The organic phases were separated and the aqueous phase was re-extracted with dichloromethane (2x10 mL). The organic layers were combined and dried over sodium sulfate and evaporated in vacuo. The crude material was purified using flash chromatography with DCM:Et3N:MeOH (95:3:2) to give a white solid (0.263 g, 78%). 'H NMR (600 MHz, CDC13): S 8.48 (d, =5.4 Hz, 1H), 7.93 (d, J =5.4 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.34 (dd, J= 8.8, 7.3 Hz, 1H), 6.39 (d, J=5.4 Hz, 1H), 4.96 (d,.7=7.5 Hz, 1H), 3.70 (sx, J = 6.8 Hz, 1H), 3.55 (m, 2H), 2.57 (m, 5H), 2.49 (m, 2H), 1.74-1.62 (m, 1H), 1.65-1.53 (m, 3H), 1.31 (d, J = 6.9 Hz, 3H), 1.24 (d, J = 7.2 Hz, 2H); 13C NMR (125 MHz, CDCI3): d 152.2, 149.5, 149.2, 135.0, 129.0, 125.4, 121.2, 1 17.4, 99.4, 58.6, 54.9, 53.18, 48.5, 47.9, 34.5, 24.1, 20.6, 1 1.9; |
74.7% |
With N-ethyl-N,N-diisopropylamine at 125 - 135℃; for 8h; Inert atmosphere; |
Example:
To a 3000 mL three-necked flask equipped with a reflux condenser, 4,7-dichloroquinoline (500 g, 2.5 mol), 5- (N-ethyl-N-2-hydroxyethylamino) -2-pentylamine ( 668g, 3.8mol) and N, N-diisopropylethylamine (323g, 2.5mol), protected by nitrogen, and started mechanical stirring,The temperature was slowly raised to 125-135 ° C and the reaction was refluxed for 8 hours.After the concentrated solution is cooled below 50 ° C, 1500 mL of water is added;After stirring for 15min, the reaction solution was lowered below 40 ° C, and extracted with isopropyl acetate (3000mL * 3). The organic phase was washed with water (3000mL * 2), and saturated brine (3000mL * 1).Recover 2/3 isopropyl acetate under reduced pressure, and then slowly reduce it to 0 5 for 1h;801 g (wet weight) of off-white solid was obtained by suction filtration using a Buchner funnel.And then recrystallized from isopropyl acetate to obtain a white powdery solid with a wet weight of 710 g,Vacuum dried at 40 ° C for 6h to obtain 627g of white solid (HPLC: 99.83%),The total yield was 74.7%. |
62.3% |
In phenol at 120℃; for 18h; |
General procedure for the synthesis of chloroquine (3)/hydroxychloroquine (4)
General procedure: In an RBF 4,7-dichloroquinoline (1.0mmol), novoldiamine (1.2mmol)/ hydroxynovaldiamine(1.2mmol) and phenol (3.00mmol) were charged. The reaction was allowed to heatat 120 C with continuous stirring for 18 h. After 18 h, the reaction mixture was cooled toroom temperature and diluted with dichloromethane. The resulting mixture was washedwith 1.5M NaOH solution and the wash was back-extracted with dichloromethane. Thecombined organic layer was extracted with 1M hydrochloric acid. The aqueous extractwas basified to pH 12 with potassium carbonate solution and extracted with dichloromethane.The organic extract was dried over sodium sulfate and concentrated under reducedpressure. The residue was then purified by column chromatography. |
|
at 100 - 130℃; for 21h; Inert atmosphere; Green chemistry; |
1 Example 1: Preparation of hydroxychloroquinoline
20g side chain,22.4g4.7-dichloroquinoline was added to a three-necked flask, protected by argon gas, and heated to 100 ° C.Stir for 1 h, then raise the temperature to 120-130 ° C for 20 h. After the reaction is completed, the temperature is lowered slightly.Add 40g of water to the reaction solution, add 20g of concentrated sulfuric acid, and add 80g of liquid alkali after stirring.The mixture was stirred for 30 min, and the aqueous phase was discarded; 60 g of ethyl acetate was added to the organic phase, and the organic phase was dissolved.Then cool down to 0 ~ 10 ° C, keep warm for 2h, suction filtration, drying,Obtaining crude hydroxychloroquinoline34g,The yield was 89% and HPLC was ≥95%. |