Synthesis method of zolpidem tartrate impurities

A technology for zolpidem tartrate and zolpidem tartrate tablets is applied in the field of synthesizing zolpidem tartrate impurities, and can solve the problems of differences in the type and quantity of impurities, uneven quality and inconsistency of zolpidem tartrate tablets, and narrow the quality gap. , the effect of improving international competitiveness

Inactive Publication Date: 2018-03-13
HUNAN INST FOR FOOD & DRUG CONTROL
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Problems solved by technology

Most of the literature related to this type of drug is adverse reaction, content determination, pharmacokinetic research and synthesis process. The impurity research only reports on the structure of 5 impurities (m / z253, 457, 354, 294 and 295) of the original drug Sinuosi. At present, domestic production enterprises have obtained approval documents earlier, and all production enterprises use the raw materials produced by their own enterprises to make preparations. Due to the differences in the synthesis process of raw materials, there are differences in the types and quantities of impurities, and the preparation process of zolpidem tartrate tablets The inconsistency of the quality of zolpidem tartrate tablets makes the quality of zolpidem tablets vary
The impurity profile of domestic zolpidem tartrate is inconsistent with that of the original drug, and the research on the impurity profile of domestic zolpidem tartrate raw materials and tablets has not been reported yet

Method used

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  • Synthesis method of zolpidem tartrate impurities
  • Synthesis method of zolpidem tartrate impurities
  • Synthesis method of zolpidem tartrate impurities

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Embodiment 1

[0019] Zolpidem (3.1 g, 10 mmoles) was suspended in 100 ml of dry THF solution, cooled to -78°C, and sodium hexamethyldisilazide was added dropwise to the THF solution (11.0 ml, 11.0 mmoles, 1.0M in THF), The dropwise addition was completed in 10 minutes. Stirring was continued for 2 hours, tert-butyl α-bromoacetate (1.61ml, 10.0mmoles) was added, the mixture was naturally raised to 25°C, and stirred overnight. On the next day, it was quenched by adding a saturated ammonium chloride solution dropwise, concentrated, and subjected to column chromatography to obtain impurity I and impurity II in zolpidem tartrate tablets respectively.

[0020] Impurity Ⅰ, m / z[M+H]+366.1916; 1H nmr(CD3OH,400MHz):δ2.47(s,3H,Ar-CH3),2.56(s,3H,Ar-CH3),2.93(s, 6H,N-(CH3)2),3.00(s,2H,CH2COOH),4.19(s,1H,Ar-CH),7.39(d,2H,Ar-H),7.45(d,2H,Ar-H ),7.96(s,2H,Ar-H),8.62(s,1H,Ar-H);

[0021] Impurity Ⅱ, m / z[M+H]+324.1609; 1H nmr(CDCl3,400MHz):δ2.24(s,3H,Ar-CH3),2.43(s,3H,Ar-CH3),2.69(s, 3H,N-CH3),2.87(s,3H,...

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Abstract

The invention discloses a synthesis method of two zolpidem tartrate impurities (m / z 366 and 324) unrecorded in the pharmacopoeias from various countries. The structures of the zolpidem tartrate impurities are confirmed by a mass spectrometry and nuclear magnetic resonance technology. The synthesis method is conducive to prescription optimization, product impurity content control and product quality improvement in the national zolpidem tartrate production enterprise, provides reference for improving national drug standards of zolpidem tartrate, shortens the quality difference between the domestic zolpidem tartrate and original research products, improves the international competitiveness of the products, has a certain social benefit, can provide a standard substance preparation method of zolpidem tartrate impurities for the national standard material center and has a certain economic benefit.

Description

technical field [0001] The present invention relates to the synthetic method of zolpidem tartrate impurity. Background technique [0002] Zolpidem Tartrate is the first new non-benzodiazepine sedative-hypnotics. Mainly used for short-term treatment of insomnia. Zolpidem tartrate belongs to the second category of psychotropic drugs. With the widespread use of domestic Zolpidem tartrate tablets, its quality problems have attracted more and more attention. Most of the literature related to this type of drug is adverse reaction, content determination, pharmacokinetic research and synthesis process. The impurity research only reports on the structure of 5 impurities (m / z253, 457, 354, 294 and 295) of the original drug Sinuosi. At present, domestic production enterprises have obtained approval documents earlier, and all production enterprises use the raw materials produced by their own enterprises to make preparations. Due to the differences in the synthesis process of raw mater...

Claims

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Application Information

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IPC IPC(8): C07D471/04
Inventor 马晓宁蒋涛
Owner HUNAN INST FOR FOOD & DRUG CONTROL
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