- Optically active chloroquine and hydroxychloroquine and analogues thereof, and preparation method, composition and application of optically active chloroquine and hydroxychloroquine
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The invention provides a rapid and simple method for preparing optically active chloroquine, hydroxychloroquine and analogues thereof, which comprises the following steps: reacting racemates of chloroquine, hydroxychloroquine and analogues thereof with an acidic chiral resolution reagent to generate corresponding salts, and separating and purifying to obtain optically pure salts of chloroquine, hydroxychloroquine and analogues thereof, and reacting with alkali to obtain (R)- or (S)- chloroquine with high optical purity and (R)- or (S)- hydroxychloroquine and analogues thereof. The method is simple and convenient to operate and low in cost, the enantiomer purity can reach 99.9% ee, and industrial production of chloroquine, hydroxychloroquine and analogues thereof with single chiral configuration is easy to realize. The invention also provides (R)- or (S)- chloroquine and (R)- or (S)- hydroxychloroquine and analogues thereof, pharmaceutical compositions and uses thereof, optically activechloroquine and hydroxychloroquine and analogues thereof reduce toxic and side effects, and have better treatment effects on coronavirus, influenza virus and autoimmune diseases.
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Paragraph 0297; 0301-0303; 0317; 0321-0323
(2021/03/11)
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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 enantiomer pure chloroquine and chloroquine phosphate
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The invention discloses a preparation method of enantiomer pure chloroquine and chloroquine phosphate, which comprises the following steps of: salifying racemic 2-amino-5-diethylaminopentane under theaction of single-configuration acid to form diastereomer salt, separating out the diastereomer salt from the solution to obtain single-configuration 2-amino- 5-diethylaminopentane intermediate salt,and the like. According to the method, racemic 2-amino- 5-diethylaminopentane is salified under the action of single-configuration acid to form diastereomer salt. On the basis of synthesizing chloroquine/chloroquine phosphate in the prior art, 2-amino-5-diethylaminopentane is used as a raw material to form diastereomer salt to resolve chiral raw materials. The method is high in purity, green and suitable for large-scale production, hazardous chemicals do not need to be introduced, salifying resolution is achieved, reaction energy barriers are reduced through catalyst application, the reactionrate is increased, side reactions are reduced, the optical purity of the product is improved through HPLC determination, the resolution cost is reduced, and the method is suitable for large-scale production.
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Paragraph 0047; 0051
(2021/01/29)
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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 0029
(2020/10/14)
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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
(2020/11/23)
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- Chemoenzymatic dynamic kinetic resolution of primary amines catalyzed by CAL-B at 38-40°c
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The (R)-selective chemoenzymatic dynamic kinetic resolution of primary amines was performed at 38-40 °C in MTBE, in good to high yields and with high enantiomeric excesses. These reactions associating CAL-B to octanethiol as radical racemizing agent were carried out in the presence of methyl β-methoxy propanoate as acyl donor, under photochemical irradiation at 350 nm in glassware.
- Poulhes, Florent,Vanthuyne, Nicolas,Bertrand, Michele P.,Gastaldi, Stephane,Gil, Gerard
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experimental part
p. 7281 - 7286
(2011/10/10)
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- Highly selective enzymatic kinetic resolution of primary amines at 80°C: A comparative study of carboxylic acids and their ethyl esters as acyl donors
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(Chemical Equation Presented) Optimization of the kinetic resolution of 2-amino-4-phenyl-butane was achieved at 80°C using CAL-B-catalyzed aminolysis of carboxylic acids and their ethyl esters. The reactions carried out with long chain esters and the corresponding acids as acyl donors proceeded with remarkably high enantioselectivity. The use of carboxylic acids as acylating agents led to a marked acceleration of the reaction rate compared to their ester counterparts. Laurie acid led to enantiomeric excesses superior to 99.5% for both the remaining amine and the corresponding lauramide at 50% conversion (reached in 3 h). These optimized conditions were applied to the resolution of a series of aliphatic and benzylic amines.
- Nechab, Malek,Azzi, Nadia,Vanthuyne, Nicolas,Bertrand, Michele,Gastaldi, Stephane,Gil, Gerard
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p. 6918 - 6923
(2008/02/11)
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