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A kind of preparation method and use of impurity compound in key intermediate for synthesizing sulpiride

A compound and impurity technology, applied in the field of medicine, can solve the problems of easy generation of impurities and unstable preparation process, and achieve the effect of ensuring drug safety

Active Publication Date: 2020-03-06
唯智医药科技(北京)有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, the key intermediate (compound IV) for the preparation of sulpiride is unstable during the preparation process and is prone to produce impurities. There are no reports and records of its related impurities.

Method used

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  • A kind of preparation method and use of impurity compound in key intermediate for synthesizing sulpiride
  • A kind of preparation method and use of impurity compound in key intermediate for synthesizing sulpiride
  • A kind of preparation method and use of impurity compound in key intermediate for synthesizing sulpiride

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Experimental program
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Effect test

Embodiment 1

[0034] Add 5.32g of compound II and 3.09g of compound III into the reaction flask, add 20ml of dichloromethane, after the dissolution is complete, add 1.50g of triethylamine, stir at 20°C for about 5h, the reaction is complete, wash twice with 50ml of purified water, reduce Concentrate under pressure to dryness to obtain an oily substance, add 30ml of purified water to precipitate a large amount of solids, filter the solids, rinse with 10ml of purified water, and dry in the air to obtain 4.32g of compound Ⅰ. Yield 80%, adopt HPLC peak area normalization method, record its content and be 97.175%

[0035] The chemical structural formula of compound I is:

[0036] The structural characterization diagram of compound Ⅰ is shown in Figure 1-3 .

[0037] Structure analysis:

[0038]

[0039] from figure 1 It can be seen from the hydrogen spectrum that δ3.772ppm, δ3.829ppm, and δ3.974ppm are methyl hydrogen H-16 / H-8 / H-17; there are eight hydrogens in the benzene ring hydroge...

Embodiment 2

[0044] According to the synthetic method of sulpiride (Wang Fulan, Li Guiling, Tang Dengfeng. Synthesis of sulpiride, Chinese Journal of Pharmaceutical Industry, 1999, 27 (11): 487-488), compound IV was prepared, and 5.3 g of compound IV was used for preparative HPLC. Separation, the mobile phase used is acetonitrile-water (v:v=1:1), the detection wavelength is 240nm, the flow rate is 10ml / min, the column temperature is 30°C, the sample is injected into the chromatograph, the corresponding effluent is collected, and the product fractions are combined to receive the product The fractions were combined and concentrated to dryness under reduced pressure. The obtained compound I was 20mg, which was a white solid. The content was measured as 96.305% by HPLC peak area normalization method.

Embodiment 3

[0046] Application of compound Ⅰ as a reference substance in the impurity detection of sulpiride key intermediate 3 (compound Ⅳ)

[0047] Preparation of compound Ⅰ reference substance solution:

[0048] Take an appropriate amount of compound I prepared in the above example 1, put it in a 20ml volumetric flask, add acetonitrile aqueous solution, acetonitrile: water = 15:85 (v:v), dilute to the mark, ultrasonicate, shake well, and make each 1ml containing compound Ⅰ A solution of about 1 mg is used as the impurity control solution.

[0049] Preparation of the test solution:

[0050]Take an appropriate amount of compound IV sample prepared according to the above-mentioned synthetic method of sulpiride (Wang Fulan, Li Guiling, Tang Dengfeng. The synthesis of sulpiride, Chinese Journal of Pharmaceutical Industry, 1999, 27 (11): 487-488), put it in a 20ml volumetric flask, add Acetonitrile aqueous solution, acetonitrile: water=15:85 (v:v), dilute to the mark, ultrasonically dissol...

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Abstract

The invention belongs to the technical field of medicines, and especially relates to a preparation method of an impurity compound in a key intermediate for synthesizing sulpiride and an application thereof. The impurity compound can be obtained through a condensation reaction by placing a compound II and a compound III in a solvent, or the impurity compound can be obtained by refining a compound IV and taking a filtrate, or the impurity compound can be obtained by separating and purifying from the compound IV. The standard substance of the impurity compound prepared by the preparation method can be used for analysis and detection of impurities in the key intermediate drug of sulpiride, and the technical problem that impurity compounds and other acceptable salt standard substances used as analysis and comparison compounds do not exist so far is solved, thereby medication safety of sulpiride is improved and guaranteed.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method and application of impurity compounds in key intermediates for synthesizing sulpiride. Background technique [0002] Sulpiride, chemically named N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxy-5-(aminosulfonyl)benzamide, has the structure of formula (Ⅴ) , is a class of potent dopamine D2 receptor blockers. Synthesized by the French in 1967, and then listed in many countries around the world. Sulpiride has the effect of antidepressant and treatment of mental disorders, because of its strong antipsychotic effect and few adverse reactions, it has been used clinically for many years at home and abroad. [0003] [0004] With the continuous improvement of people's drug safety requirements, the quality requirements of drugs and the impurities in pharmaceutical raw materials need to be further clarified and controlled. Therefore, the research on impur...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C311/29C07C303/40G01N30/02
CPCC07C303/40C07C311/29G01N30/02
Inventor 张建楼左伟初野赵卫国
Owner 唯智医药科技(北京)有限公司
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