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Method for effectively removing impurities in lansoprazole crude products

A technology for crude lansoprazole and lansoprazole, which is applied in the field of medicine, can solve the problems of difficult impurity removal, low selectivity, low yield of repeated dissolution and the like, and achieves the effect of removing impurities

Active Publication Date: 2017-11-21
桂林华信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Impurity control in chemical medicine is an important content in the quality control of medicines, and known impurity in lansoprazole mainly comprises impurity A, impurity B, impurity C, impurity D and impurity E, and prior art prepares lansoprazole The high level of impurities in the process is mainly due to the low selectivity in the oxidation step and the resulting production of benzimidazole N-oxides and the corresponding sulfone by-products, which can be produced by oxidation of nitrogen and excessive oxidation of sulfides, respectively , impurity control is more difficult when scaling up prior art methods
[0005] In order to avoid the increase of impurity content, the reaction product is generally treated by other means first and then recrystallized and refined. For example, the patent CN102367250A discloses that the crude product is first separated and purified by a macroporous resin column, and then the eluent is subjected to negative pressure crystallization, and finally Obtain refined products, but due to the small amount of macroporous resin processed at one time, large-scale processing cannot be realized
[0006] CN102659763A prepares dexlansoprazole by asymmetric oxidation. After the reaction, the reaction mixture is poured into a large amount of sherwood oil, and the oil is precipitated. The crude product obtained by this method is difficult to separate, and the oil is adsorbed on the wall of the reactor. Dissolve with ethyl acetate, then wash, centrifuge and add n-hexane to separate out the product, the operation is complicated, the yield is low after repeated solvent dissolution, the total yield is only about 40%, and the follow-up treatment is also difficult to remove all kinds of impurities Effective removal

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Step 1: Dissolve 50 g of crude lansoprazole in 635 mL of methanol, and ultrasonically shake at 15 ° C for 4 min;

[0033] Step 2: Add 5.42mL of sodium methoxide to the solution after ultrasonic oscillation, stir for 30min, cool to 5°C for 5h and filter to obtain a solid;

[0034] The third step: the obtained solid is dissolved in the mixed solvent of water / isopropanol / ethyl acetate, stirred and dissolved, wherein the quality of water, isopropanol, and ethyl acetate in the mixed solvent are respectively 109.50g, 122.77g, 267.73g;

[0035] Step 4: Add 0.5 g of activated carbon to the solution obtained in Step 3, decolorize for 15 minutes, and then filter;

[0036] Step 5: Distill the obtained filtrate under reduced pressure, increase from normal temperature to 50°C at a rate of 1°C / min, and distill at 50°C for 15 minutes at a vacuum of -100KPa;

[0037] Step 6: After the vacuum distillation, the remaining solution is returned to normal temperature and pressure, using ac...

Embodiment 2

[0039] Step 1: Dissolve 80 g of crude lansoprazole in 1410 mL of ethanol, and ultrasonically shake at 25 ° C for 4 min;

[0040] Step 2: Add 14.20 g of sodium ethylate to the solution after ultrasonic oscillation, stir for 60 minutes, cool to 0°C for 2 hours, and filter to obtain a solid;

[0041] The third step: the obtained solid is dissolved in the mixed solvent of water / isopropanol / ethyl acetate, stirred and dissolved, wherein the quality of water, isopropanol, and ethyl acetate in the mixed solvent are respectively 142.50g, 316.71g, 580.79g;

[0042] Step 4: Add 2.4 g of activated carbon to the solution obtained in Step 3, decolorize it for 20 minutes, and then filter it;

[0043] Step 5: Distill the obtained filtrate under reduced pressure, increase from normal temperature to 55°C at a rate of 3°C / min, and distill at 55°C for 10 minutes at a vacuum degree of -50KPa;

[0044] Step 6: After the vacuum distillation, the remaining solution is returned to normal temperature...

Embodiment 3

[0046] Step 1: Dissolve 100 g of crude lansoprazole in 1520 mL of ethanol, and ultrasonically shake at 20 ° C for 2 min;

[0047]Step 2: Add 10.43g of sodium hydroxide to the solution after ultrasonic oscillation, stir for 45min, cool to 2°C for 4h and filter to obtain a solid;

[0048] The third step: the obtained solid is dissolved in the mixed solvent of water / isopropanol / ethyl acetate, stirred and dissolved, wherein the quality of water, isopropanol, and ethyl acetate in the mixed solvent are respectively 185.58g, 309.34g, 605.08g;

[0049] The fourth step: add 2g of activated carbon to the solution obtained in the third step, decolorize for 25 minutes and then filter;

[0050] Step 5: Distill the obtained filtrate under reduced pressure, raise it from normal temperature to 45°C at a rate of 1°C / min, and distill at 45°C for 20min at a vacuum degree of -80KPa;

[0051] Step 6: After the vacuum distillation, the remaining solution is returned to normal temperature and pres...

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Abstract

The invention discloses a method for effectively removing impurities in lansoprazole crude products. The method includes converting the lansoprazole crude products into lansoprazole salt and then dissolving the lansoprazole salt in organic mixed solvents; carrying out reduced-pressure distillation; then carrying out conversion to obtain lansoprazole and dissolving out the lansoprazole. The method has the advantages that the characteristic of high stability of the lansoprazole salt as compared with the lansoprazole is utilized, and accordingly the lansoprazole refining yield can reach 84.7% at least; the impurities in the lansoprazole can be effectively removed, the contents of impurities A, impurities B, impurities C and impurities E in refined products are lower than 0.011%, 0.013%, 0.012% and 0.015%, and impurities D cannot be detected.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a method for effectively controlling the content of various impurities in the crude product of lansoprazole. Background technique [0002] Lansoprazole chemical name: 2-[[[3-methyl-4(2,2,2-trifluoroethoxy)-2pyridyl]methyl]sulfinyl]-1H-benzimidazole , which belongs to the substituted benzimidazole gastric acid inhibitors, was developed and marketed by Takeda Corporation of Japan in 1991. The substance acts on the H of gastric parietal cells. + -K + -ATPase can reduce gastric acid secretion, thereby effectively treating various types of peptic ulcer and diseases caused by hypersecretion of gastric acid, with remarkable therapeutic effect and good acceptance. [0003] The chemical properties of Lansoprazole are unstable, easy to decompose in acid, and sensitive to light, heat, humidity, etc. Studies have shown that the degradation products of Lansoprazole have severe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 陈华兆张胜军唐世锭
Owner 桂林华信制药有限公司