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Synthesis method of di-deuterated primaquine

A technology of primaquine and a synthetic method, which is applied in the field of deuterated drug production, can solve the problems of cumbersome operation, long route, high cost, etc., and achieve the effect of easy-to-obtain raw materials, high yield, and low cost

Inactive Publication Date: 2019-03-08
KANGHUA SHANGHAI DRUG RES DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the technical problems of long route, high cost, cumbersome operation and low yield in existing synthetic methods

Method used

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  • Synthesis method of di-deuterated primaquine
  • Synthesis method of di-deuterated primaquine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] To the three-necked flask, add primaquine phosphate (200 mg), heavy water (2 mL), add concentrated sulfuric acid (0.1 mL), heat to 95 °C, react for 8 h, pour into saturated sodium carbonate solution (20 mL) after the reaction is complete , extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain dideuterated primaquine (109 mg, 95% yield). 1 H NMR (300MHz, DMSO-d 6 ):8.21(dd, J = 4.5Hz, 1.2Hz, 1H), 8.01 (dd, J = 8.4Hz, 1.2Hz, 1H), 7.31 (dd, J =8.4Hz, 4.5Hz, 1H), 3.44(s, 3H), 3.19(m, 1H), 2.70(m, 2H), 1.40(m, 4H), 0.91(d, J = 6.0 Hz, 3H); 13 C NMR (75MHz, DMSO-d 6 ): 159.76, 144.28, 138.92, 138.07, 131.04, 124.54, 121.33, 55.60, 48.65, 39.33, 31.59, 23.26, 18.20.

Embodiment 2

[0019] To the three-necked flask, add primaquine phosphate (200 mg), heavy water (2 mL), add concentrated sulfuric acid (0.1 mL), heat to 55 °C, and react for 24 h. After the reaction is completed, pour it into saturated sodium carbonate solution (20 mL) , extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain dideuterated primaquine (103 mg, 90% yield).

Embodiment 3

[0021] To the three-necked flask, add primaquine phosphate (200 mg), heavy water (2 mL), add concentrated sulfuric acid (0.1 mL), heat to 110 °C, react for 4 h, pour into saturated sodium carbonate solution (20 mL) after the reaction is complete , extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain dideuterated primaquine (102 mg, 89% yield).

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Abstract

The invention relates to a synthesis method of di-deuterated primaquine. According to the synthesis method, the technical problems of the existing synthesis method that the path is long, the cost is high, the operation is complex, the yield is low, etc. are mainly solved. The synthesis method is realized by adopting the following technical scheme: the synthesis method of the di-deuterated primaquine is characterized by comprising the following steps: taking primaquine phosphate as a starting material and heavy water as a solvent, adding the catalytic amount of acid, performing a heating reaction, pouring reaction solution into alkaline water after the reaction is ended, and extracting, drying and concentrating the mixed solution, so as to obtain the di-deuterated primaquine. The synthesismethod of the di-deuterated primaquine has the advantages of being simple in path, easily available in raw materials, high in yield, low in cost, convenient in postprocessing and high in product purity and deuterium abundance and the like.

Description

technical field [0001] The invention relates to a method for synthesizing di-deuterated primaquine, which belongs to the field of deuterated medicine production. Background technique [0002] In many cases, replacing the few hydrogen atoms in a drug with deuterium slows the enzymatic breakdown of the carbon-deuterium bond, allowing it to remain in the body longer while reducing the formation of toxic metabolites. Therefore, in general, compared with non-deuterated drugs, deuterated drugs have the functions of reducing toxic side effects, increasing drug stability, enhancing curative effect, and prolonging drug biological half-life. In April 2017, Teva's AUSTEDO™ (deutetrabenazine) became the first FDA-approved deuterated drug. The research and development of deuterated drugs has attracted extensive interest from domestic and foreign pharmaceutical companies. [0003] According to literature reports (WO 2011091035), using p-nitrophenol as the starting material, the key inte...

Claims

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Application Information

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IPC IPC(8): C07D215/40
CPCC07B2200/05C07D215/40
Inventor 徐红岩殷海峰李响杨新贺
Owner KANGHUA SHANGHAI DRUG RES DEV CO LTD
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