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Chloroquine phosphate enantiomer crystal form and preparation method thereof

A technology of chloroquine and chloroquine side chains, applied in the field of /- chloroquine phosphate crystals and its preparation, can solve the problems of cumbersome operation and low yield, and achieve the effect of stable and reliable quality and easy industrial production

Pending Publication Date: 2020-10-02
珠海润都制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] S-chloroquine or R-chloroquine can be prepared by condensation reaction of corresponding optically pure side chain S-chloroquine side chain or R-chloroquine side chain and 4,7-dichloroquinoline respectively, and S-chloroquine side chain or R -Chloroquine side chain can be prepared by splitting (±)-chloroquine side chain and corresponding chiral resolution reagent mandelic acid, such as the resolution method disclosed in patent CN107922404A, which requires multiple resolutions and crystallization, and the operation is cumbersome , low yield

Method used

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  • Chloroquine phosphate enantiomer crystal form and preparation method thereof
  • Chloroquine phosphate enantiomer crystal form and preparation method thereof
  • Chloroquine phosphate enantiomer crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] The preparation of embodiment 1 (S)-chloroquine side chain S-(+)-mandelate

[0069]

[0070] Weigh 72 g (0.48 mol) of chloroquine side chain in a 250 mL round bottom flask, add 150 g of isopropanol and stir to dissolve it; then weigh 36.5 g (0.24 mol) of L-mandelic acid and add to the system, stir at room temperature, A large amount of white solids precipitated; the resulting white solids were filtered by suction and placed in a vacuum oven at 50°C. After drying for 8 hours, 68.8 g of white solid (yield 94.9%) was obtained.

[0071] The measured specific rotation value: S-chloroquine side chain mandelate: =56.5° (c =1.0g / 100mL H 2 O)

Embodiment 2

[0072] The preparation of embodiment 2 S-chloroquine side chain

[0073]

[0074] Dissolve the (S)-chloroquine side chain S-(+)-mandelate prepared in Example 1 with 200 mL of water, add NaOH to adjust the pH to 8-9, add an appropriate amount of sodium chloride to the aqueous phase, and extract with dichloromethane ; Dry over anhydrous sodium sulfate and concentrate to give 35.3 g (1 equivalent, 0.251 mol) of a colorless oil.

Embodiment 3

[0075] The preparation of embodiment 3 (S)-chloroquine phosphate

[0076] All the S-chloroquine side chains prepared in Example 2 were transferred to a three-necked flask, weighed 44.8 g 4,7-dichloroquinoline (0.9 equivalents, 0.226mol), 6 mL Virahol, heated and stirred at 100 ° C . After reacting for 18 h, the raw materials basically reacted completely, stop the reaction, and wait for it to cool down naturally; add NaOH solution to adjust the pH to 12, extract and concentrate with DCM; add dilute HCl solution to adjust the pH to 2, and then adjust the aqueous phase back to alkaline, DCM extraction and concentration gave 72.4 g (HPLC showed product content 75%) yellow oil. Add 200 mL of absolute ethanol to dissolve the oil. Heat to reflux at 80°C for 15min to stabilize the temperature; add 2 equivalents of phosphoric acid (0.34mol, 17.7 mL) dropwise, and stir at 30°C for 1h. A large amount of white solids precipitated, stopped heating, cooled to room temperature; filtered, ...

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Abstract

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.

Description

technical field [0001] The invention relates to (R) / (S)-chloroquine phosphate crystals and a preparation method thereof. Background technique [0002] Chloroquine Phosphate (Chloroquine Phosphate) chemical name is 7-chloro-4-(4-diethylamino-1-methylbutylamino) quinoline diphosphate, the chemical structure is as shown in formula I, chloroquine is its free base, and its There is one chiral center, respectively S-chloroquine (formula II) and R-chloroquine (formula III). [0003] [0004] Clinically, racemic chloroquine is used to treat chloroquine-sensitive falciparum malaria, day-to-day abuse and three-day abuse. And can be used for the suppressive prevention of malaria symptoms. It can also be used to treat parenteral amoebiasis, connective tissue disease, photosensitivity disease (such as sun erythema), etc. [0005] Patent CN105693605B discloses an asymmetric synthesis method of optically pure R / S-chloroquine, but there are obvious differences in the pharmacological e...

Claims

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Application Information

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IPC IPC(8): C07D215/46C07C51/41C07C59/50C07C209/68C07C211/09
CPCC07D215/46C07C51/412C07C209/68C07B2200/13C07B2200/07C07C59/50C07C211/09
Inventor 李光辉覃志俊莫泽艺董雪林吴挺强胡双龙蔡强焦慎超
Owner 珠海润都制药股份有限公司
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