- Preparation method and application of chiral chloroquine and phosphate thereof
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The invention discloses a preparation method and application of chiral chloroquine and phosphate thereof. The method comprises the following steps: in a resolving solvent, salifying and crystallizing chloroquine racemate and a resolving agent to separate out crystals; performing primary recrystallizing, dissociating the crystals in an alkaline solution; filtering and separating out the resolving agent; performing extracting with an organic solvent, and drying and concentrating organic phases to respectively obtain corresponding (R)/(S)-chloroquine; and further salifying the (R)/(S)-chloroquine with phosphoric acid in the solvent to respectively obtain corresponding (R)/(S)-chloroquine phosphate. By adopting the method provided by the invention, the optical purity ee value of a finished product can be greater than 80% after primary crystallization, and the product with higher purity can be obtained by primary recrystallization. The crystals are good in crystal form and easy to filter and separate; the method is simple and convenient in resolution operation, free of tedious purification processes such as column separation, high in product optical purity, and relatively high in yield; and the resolving agent is reusable, so that production cost is low, and the method has a good industrial application prospect.
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Paragraph 0080; 0093-0095; 0104-0106; 0113-0114
(2021/09/08)
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- Application of L-chiral chloroquine phosphate in preparation of medicine for treating coronavirus
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The invention discloses an application of L-chiral chloroquine phosphate in preparation of a medicine for treating coronavirus. Based on the fact that in an in-vitro cell experiment, L-chiral chloroquine phosphate has a remarkable inhibition effect on cytopathy caused by infection of Vero E6 cells by novel coronavirus SARS-CoV-2, the IC50 value is 1.45 mu g/mL, the inhibition concentration is remarkably lower than that of D-chloroquine phosphate and racemate chloroquine phosphate. The important significance is realized on the prevention, control and treatment of novel coronavirus infection.
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Page/Page column 0016; 0023-0024; 0034; 0038-0039
(2021/09/08)
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- Asymmetric synthesis method of (S)-chloroquine phosphate
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The invention provides a novel asymmetric synthesis method of (S) chloroquine. According to the invention, 5-(N-diethylamino)-2-pentanone and (S)-alpha-methyl benzylamine are adopted as raw materials,and in the presence of Lewis acid, an asymmetric reductive amination reaction is carried out to obtain (S,S)-5-(N'-diethylamino)-N-((1-phenyl)ethyl)-2-pentylamine, catalytic hydrogenation is performed to remove benzyl to obtain a side chain (S)-5-(N'-diethylamino)-2-amyl amine for synthesizing chloroquine, the (S)-5-(N'-diethylamino)-2-amyl amine is condensed with 4,7-dichloroquinoline to obtain(S)-chloroquine, salifying is performed with phosphoric acid, and recrystallizing is performed to obtain (S)-chloroquine phosphate with ee value of more than 99%, wherein the the total yield of the four-step reaction exceeds 70%; and the preparation method is stable, reliable, economical, efficient and easy to industrialize.
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- Preparation method of chloroquine phosphate
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The invention discloses a preparation method of chloroquine phosphate, namely 7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline diphosphate. The preparation method comprises the following steps: (1) carrying out a condensation reaction on 4,7-dichloroquinoline and 2-amino-5-diethylaminopentane, and carrying out alkalization extraction, concentration and crystallization to obtain chloroquine; and (2) salifying the chloroquine obtained in the step (1) and phosphoric acid to obtain chloroquine phosphate. The method avoids the use of phenol, is simple in reaction, and is beneficial to industrial production; and the chloroquine is crystallized to improve the purity and then salified with the phosphoric acid, so product appearance is good, the purity of the produced chloroquine phosphate is greater than or equal to 99.5%, and a single impurity is less than 0.1% (according to an HPLC area normalization method).
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Paragraph 0030; 0037-0038; 0039; 0046-0047; 0048; 0055-0056
(2021/05/26)
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- Synthesis method of high-purity chloroquine phosphate
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The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of chloroquine phosphate, and particularly provides a synthesis method of high-purity chloroquine phosphate. The synthesis method comprises the following steps: (1) condensation: reacting 4, 7-dichloroquinoline with 2-amido-5-diethylamine pentane to obtain a chloroquine crude product; and (2) refining: recrystallizing to obtain chloroquine with higher purity. (3) salifying: stirring and crystallizing the refined chloroquine and phosphoric acid for 2-3 hours, and filtering to obtain a chloroquine phosphate crude product; and (4) purification: recrystallizing the chloroquine phosphate crude product to obtain high-purity chloroquine phosphate. The method is high in atom utilization rate, high in yield, high in product purity, less in solid waste, beneficial to environmental protection and convenient for industrial application, and has a relatively good industrial prospect.
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Paragraph 0043; 0048-0053; 0058-0062; 0067-0070; 0076-0077
(2021/02/10)
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- Preparation method of chiral aminochloroquinoline
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The invention discloses a preparation method of chiral aminochloroquinoline, which comprises the following steps: splitting a chiral side chain, preparing enantiomer salt, splitting the side chain andchiral acid crystals to obtain chiral acid salt, neutralizing the chiral acid salt to obtain free basic groups, and reacting the free basic groups with 4, 7-dichloroquinoline to obtain chiral aminochloroquinoline. The yield of the chiral aminochloroquinoline obtained by the method is high, and the purity reaches 99.7%.
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Paragraph 0028-0033; 0035
(2020/11/23)
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- Chloroquine phosphate enantiomer crystal form and preparation method thereof
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The invention discloses a chloroquine phosphate enantiomer crystal form and a preparation method thereof. The invention provides (R)/(S)-chloroquine phosphate and a preparation method thereof. According to the (S)-chloroquine phosphate provided by the invention, an X-ray powder diffraction pattern expressed by a 2theta angle has characteristic peaks at 10.4 degrees, 10.7 degrees, 15.6 degrees, 15.8 degrees, 17.8 degrees, 18.9 degrees, 21.3 degrees and 23.9 degrees +/-0.2 degrees. According to the (R)-chloroquine phosphate provided by the invention, an X-ray powder diffraction pattern expressedby a 2theta angle has characteristic peaks at 10.3 degrees, 15.5 degrees, 15.7 degrees, 17.8 degrees and 18.8 degrees +/-0.2 degrees.
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Paragraph 0030; 0031
(2020/10/14)
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- Application of chiral chloroquine, hydroxychloroquine or salt of the chiral chloroquine and hydroxychloroquine as anti-coronavirus drug target 3CL hydrolase inhibitor for reducing cardiotoxicity
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The invention discloses an application of chiral chloroquine, hydroxychloroquine or pharmaceutically acceptable salts of the chiral chloroquine and hydroxychloroquine in preparation of drugs used forpreventing and/or treating coronavirus pneumonia by using a coronavirus key drug target 3CL hydrolase (Mpro) as an action target. The chiral chloroquine and hydroxychloroquine have high bonding strength with the Mpro causing inflammation of the lung and the like; the activity of the Mpro can be significantly inhibited; and the chiral chloroquine and hydroxychloroquine are indicated to have the effect of preventing and treating pneumonia caused by coronaviruses and be able to be used as anti-pneumonia drugs. Through evaluation on the inhibitory activity of an hERG potassium ion channel, the concentration at which the chloroquine, hydroxychloroquine and enantiomers of the chloroquine and hydroxychloroquine are likely to generate cardiotoxicity to the hERG potassium ion channel is provided. The chiral chloroquine and hydroxychloroquine are prepared through chiral high-performance liquid chromatography and chiral synthesis; S-configuration chloroquine, hydroxychloroquine or salts of the chloroquine and hydroxychloroquine can be selected as a drug independently, or form a pharmaceutical composition for treating diseases caused by the coronaviruses; and due to higher activity and low cardiotoxicity of the chloroquine, hydroxychloroquine or salts of the chloroquine and hydroxychloroquine, the administration dosage range is greatly widened.
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- Chiral chloroquine, hydroxychloroquine and derivatives thereof as well as preparation method and application of chiral chloroquine, hydroxychloroquine and derivatives thereof
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The invention belongs to the field of drug synthesis, and discloses a compound with a structure as shown in a formula I (See the specification) and pharmaceutically acceptable salt, tautomer, polymorphic substance, isomer and solvate thereof. Secondly, the invention discloses a method for preparing chiral chloroquine and hydroxychloroquine through chiral high performance liquid chromatography. Finally, the invention discloses application of chiral chloroquine, hydroxychloroquine and salt derivatives thereof in preparation of drugs for treating novel coronavirus pneumonia.
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- Preparation process of chloroquine phosphate (by machine translation)
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The invention discloses a preparation process of chloroquine phosphate. The preparation process of the chloroquine phosphate comprises the following steps: (1) condensation reaction with 4,7 -amino 2 - diethylamino-pentane, and basifying and extracting to obtain chloroquine; (-5 -) synthesizing chloroquine and phosphoric acid obtained in the step (2 1) to obtain chloroquine phosphate. To the preparation process of chloroquine phosphate provided by the invention, the use of other catalysts such as benzene and other catalysts is avoided in the preparation process, the product purity is high, the single impurity is less than 0.1%, the operation is simple, the procedures are simplified, the production efficiency is improved, and the method is suitable for industrial production. (by machine translation)
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Paragraph 0041; 0043-0045; 0047-0049; 0051-0053; 0055-0057
(2020/09/23)
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- USE OF CHLOROQUINE AND CLEMIZOLE COMPOUNDS FOR TREATMENT OF INFLAMMATORY AND CANCEROUS CONDITIONS
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Disclosed herein are methods for use of R-chloroquine or clemizole or combinations of R- chloroquine and clemizole for the treatment of a subject in need thereof. Uses include methods of treating inflammatory' conditions, treating liver cancer or reducing the risk of developing liver cancer in a subject. Uses also include methods of treating non-alcoholic steatohepatitis in a subject.
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Paragraph 0058; 0059
(2017/01/23)
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