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Preparation method of hydroxychloroquine

A technology for hydroxychloroquine and hydroxyl protection, applied in the field of preparation of hydroxychloroquine, can solve the problems of high industrialization cost, low purity of crude product, difficult post-processing, etc.

Pending Publication Date: 2021-05-04
NANJING GRITPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] (1) Using high-boiling point phenol as a solvent, the post-processing is difficult and the pollution is serious
[0013] (2) The reaction time is long. No matter whether solvent is added or not, it needs to be reacted at a temperature above 120°C for 18-48 hours, and even high temperature and high pressure are required, which leads to high energy consumption and high risk of safety production.
[0014] (3) Since 4,7-dichloroquinoline has two substitution positions, both the side chain amino group and the hydroxyl group can react with the quinoline ring chlorine, resulting in many side reactions, low purity of the crude product, increased post-processing difficulty, and low overall yield. High cost of industrialization

Method used

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  • Preparation method of hydroxychloroquine
  • Preparation method of hydroxychloroquine
  • Preparation method of hydroxychloroquine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The synthesis of embodiment one hydroxychloroquine

[0035] Under nitrogen protection, add 5-(N-ethyl-N-hydroxyethyl)-2-aminopentane (IIb, 174.3g, 1mol), tetrahydrofuran (872ml), N,N-diisopropyl Ethylethylamine (258.5g, 2mol), cooled to 0-10°C in an ice-water bath, and trimethylchlorosilane (163g, 1.5mol) was added dropwise. / L, 1.5L), continue to stir at the same temperature for 1h, add 4.7-dichloroquinoline (IIa, 174.3g, 1mol), and stir for 3h. Add saturated ammonium chloride solution (1 L), quench the reaction, stir for 30 min, and precipitate a solid, filter, wash with water and n-hexane respectively, and dry to obtain 306 g of hydroxychloroquine as a solid, with a yield of 91.1% (melting point: 89-91.5°C; ESI (+): 336.18; 1HNMR (600MHz, CDCl3) δ8.48 (d, J = 5.4Hz, 1H), 7.93 (d, J = 5.4Hz, 1H), 7.70 (d, J = 9.2Hz, 1H) ,7.34(dd,J=8.8,7.3Hz,1H),6.39(d,J=5.4Hz,1H),4.96(d,J=7.5Hz,1H),3.70(sx,J=6.8Hz,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...

Embodiment 2

[0036] The synthesis of embodiment dihydroxychloroquine

[0037] Under nitrogen protection, add 5-(N-ethyl-N-hydroxyethyl)-2-aminopentane (IIb, 348.6g, 2mol), toluene (1.3L), N,N-diiso Propylethylamine (387.8g, 3mol), trimethylchlorosilane (217g, 2mol) was added dropwise at 20-30°C, after the dropwise addition was completed, kept at the same temperature for 1h, LiHMDS tetrahydrofuran solution (1mol / L, 3L ), continue to stir at the same temperature for 1 h, add 4.7-dichloroquinoline (IIa, 174.3 g, 1 mol), and stir for 2 h at the same temperature. Add saturated ammonium chloride solution (1.5L), quench the reaction, stir for 30min, precipitate solid, filter, wash with water and n-hexane respectively, and dry to obtain hydroxychloroquine solid 298.3g, yield 88.8% (melting point: 89~91.0 °C; ESI, [M+1] + :336.2;)

Embodiment 3

[0038] The synthesis of embodiment trihydroxychloroquine

[0039] Under nitrogen protection, add 5-(N-ethyl-N-hydroxyethyl)-2-aminopentane (IIb, 872g, 5mol), tetrahydrofuran (4.4L), N,N-diisopropyl Ethylethylamine (646.3g, 3mol), cooled to 0-5°C in an ice-water bath, and trimethylchlorosilane (542.5g, 5mol) was added dropwise. 1mol / L, 5L), continue to stir at the same temperature for 1h, add 4.7-dichloroquinoline (IIa, 174.3g, 1mol), and stir at 60-65°C for 2h. Add saturated ammonium chloride solution (1 L), quench the reaction, stir for 1 h, and precipitate a solid, filter, wash with water and n-hexane respectively, and dry to obtain 310 g of hydroxychloroquine as a solid, with a yield of 92.3% (melting point: 89.5-91.5°C; ESI,[M+1] + :336.2;)

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Abstract

The invention relates to a preparation method of hydroxychloroquine, which comprises the following steps: protecting hydroxyl of 5-(N-ethyl-N-ethoxyl)-2-aminopentane through a silanization reagent, removing amino protons from tetrahydrofuran or toluene by using a bis(trimethylsilyl lithium amide) solution to form amino anions, and carrying out a substitution reaction with 4.7 dichloroquinoline to generate hydroxychloroquine. The hydroxychloroquine and sulfuric acid are salified in an alcoholic solution to generate hydroxychloroquine sulfate, and the hydroxychloroquine sulfate preparation method provided by the invention has the characteristics of low toxicity, low pollution, high purity, low reaction temperature, short reaction time, high yield and the like, and is suitable for industrialization.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of hydroxychloroquine. Background technique [0002] Hydroxychloroquine sulfate (Hydroxychloroquine sulfate), developed by Winthrop (now Sanofi) Pharmaceutical Company, is indicated for rheumatoid arthritis, discoid and systemic lupus erythematosus, juvenile chronic arthritis, and skin conditions caused or exacerbated by sunlight The disease is mainly related to the quinoline ring it contains, and its mechanism of action is complex and unclear, mainly inhibiting immune response and anti-inflammation. Hydroxychloroquine sulfate (HCQ) is a drug with a wide range of effects, such as lymph node effects and antimalarial effects. The development of this drug dates back to the 1950s. At present, it has been approved in more than 70 countries including the United States, Europe, and Japan. [0003] Hydroxychloroquine sulfate, the chemical name is 2[[4-[(7-chloro-4-qu...

Claims

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Application Information

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IPC IPC(8): C07D215/46
CPCC07D215/46Y02P20/55
Inventor 杨建楠徐珂耿聪聪陆滢炎朱丽君魏伟业赵卿霍立茹李战
Owner NANJING GRITPHARMA CO LTD
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