Asymmetric synthesis method of optically pure (R)/(S)-hydroxychloroquine side chain

A synthetic method and technology of hydroxychloroquine, which is applied in the field of asymmetric synthesis of optically pure /- hydroxychloroquine side chains, can solve the problems of low ee value and low yield, and achieve material cost saving, high atom economy and conversion rate and highly selective effects

Pending Publication Date: 2022-02-18
SHENZHEN CATALYS SCI & TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The huge physiological and biochemical properties of the two isomers in the human body prompt people to further study the difference between (R) / (S)-hydroxychloroquine; currently there are split-related technology patents for the splitting of the side chain of hydroxychloroquine The problem of low post-ee value (<90%)
[0004] For example, in CN105693606 A, 4-amino-7-chloroquinoline and 5-ethyl (2-hydroxyethyl) amine-2-pentanone are used as starting materials, under the catalysis of chiral acid, through asymmetric reduction of ammonia Chemical reaction to obtain optically pure hydroxychloroquine, but the ee value of the final product is between 50% and 80%, and the yield is lower than 60%.

Method used

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  • Asymmetric synthesis method of optically pure (R)/(S)-hydroxychloroquine side chain
  • Asymmetric synthesis method of optically pure (R)/(S)-hydroxychloroquine side chain
  • Asymmetric synthesis method of optically pure (R)/(S)-hydroxychloroquine side chain

Examples

Experimental program
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Effect test

Embodiment 1

[0039] (1) Splitting of racemic hydroxychloroquine side chains

[0040]A 500mL jacketed bottle is equipped with mechanical stirring, a reflux condenser and a thermometer. Add 80g of hydroxychloroquine side chain and 60mL of isopropanol to the jacketed bottle and turn on the mechanical stirring. Add 36.32g of (S)-mandelic acid to the bottle, Connect the bottle to an 86°C circulating water bath. When the temperature reaches about 80°C, add 360mL of toluene to the bottle after it dissolves, and continue stirring for 1-2 hours after adding toluene (internal temperature 83-86°C). After 1 to 2 hours, the temperature began to drop. When the temperature dropped to 49°C, the system began to become turbid. After adding seed crystals into the bottle, the turbidity intensified, and a white solid was precipitated. Let it cool down to room temperature naturally under stirring. After cooling down to room temperature, remove the circulating water bath and connect to a circulating cooling bath...

Embodiment 2

[0051] The preparation method of embodiment 2 (S)-hydroxychloroquine side chain

[0052] Get 84.0 g of (S)-hydroxychloroquine side-chain mandelate obtained by splitting in Example 1 and dissolve it with 200 mL of water, add 1M NaOH solution, adjust pH=11-12, add appropriate amount of sodium chloride to the water phase, and use dichloro Methane was extracted three times; the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 44.8 g of a colorless oil, which was (S)-2-[(4-aminopentyl)ethylamino]ethanol ( That is, S-hydroxychloroquine side chain).

Embodiment 3

[0053] The preparation method of embodiment 3 (S)-hydroxychloroquine sulfate

[0054] The (S)-2-[(4-aminopentyl)ethylamino]ethanol obtained in Example 2 was transferred to a three-necked flask, and 56g of 4,7-dichloroquinoline and 8mL of isopropanol were weighed, heated to Stir at 130°C, react for 23 hours, stop the reaction, and cool naturally; add 2M HCl solution, adjust pH=2, wash away a small amount of unreacted 4,7-dichloroquinoline with dichloromethane; add 1M NaOH solution to the above water phase Adjust the pH to >12, extract with dichloromethane, wash the organic phase with water until the pH of the aqueous phase = 7-8, to remove residual chiral side chains. The organic phase was rotary evaporated to a brown extract with no change in quality to obtain the crude product of (S)-hydroxychloroquine free base, weighing 78.6 g.

[0055] Add the crude product of (S)-hydroxychloroquine free base to 325g of 95% ethanol (about 4 times the mass of the extract), and stir to diss...

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Abstract

The invention provides a method for synthesizing optically pure (R) / (S)-hydroxychloroquine, which comprises the following steps: resolving (+ / -)-2-[(4-aminoamyl)ethylamino]ethanol by using a resolving reagent, recrystallizing and purifying the compound to obtain optically pure (R) / (S)-2-[(4-aminoamyl)ethylamino]ethanol; and reacting the obtained single-configuration hydroxychloroquine side chain with 4,7-dichloroquinoline to obtain the hydroxychloroquine sulfate of single configuration. The method has the advantages of simple route, easily available raw materials, high yield, good stereoselectivity (ee% is greater than 99%), simple operation, greenness and environmental protection, and is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemical synthesis, and in particular relates to an asymmetric synthesis method of optically pure (R) / (S)-hydroxychloroquine side chains. Background technique [0002] Hydroxychloroquine (Hydroxychloroquine), chemical name 2-[[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino]-ethanol, has (R)-hydroxychloroquine and (S)- Two optical isomers of hydroxychloroquine belong to 4-aminoquinoline drugs, and are administered as racemic compounds in clinical use. It was first used in the treatment of malaria parasites. The phosphate and sulfate of hydroxychloroquine are now widely used in the clinical treatment of discoid lupus erythematosus and systemic lupus erythematosus; in addition, hydroxychloroquine is also used in immunosuppression and anti-inflammatory reactions. . [0003] At the same time, studies on the metabolism of hydroxychloroquine in humans have shown that the absorption, distribution, me...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/46C07B53/00
CPCC07D215/46C07B53/00C07B2200/07
Inventor 赵金辉丁小兵郑勇鹏刘创基
Owner SHENZHEN CATALYS SCI & TECH CO LTD
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