CN101575313B - Production technique for synthesizing Manidipine Hydrochloride through separation with non-column chromatography - Google Patents
Production technique for synthesizing Manidipine Hydrochloride through separation with non-column chromatography Download PDFInfo
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- CN101575313B CN101575313B CN2009100641137A CN200910064113A CN101575313B CN 101575313 B CN101575313 B CN 101575313B CN 2009100641137 A CN2009100641137 A CN 2009100641137A CN 200910064113 A CN200910064113 A CN 200910064113A CN 101575313 B CN101575313 B CN 101575313B
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Abstract
The invention discloses a new method for removing impurities from Manidipine coarse alkali product. The adopted technical proposal includes the steps of: taking Manidipine coarse alkali product, adding ethyl acetate for dissolution, adding warm water for rinsing, drying, salifying and obtaining Manidipine Hydrochloride. The technique can be used as a substitute for silica gel column chromatographyto remove impurities, is more applicable to industrial production, and not only has good impurity removal effect, no harm to the physical and psychological health of operating staffs and no pollution to the environment, but also can improve the purity and yield of the finished products of Manidipine Hydrochloride.
Description
Technical field
The invention discloses a kind of need not and remove impurity through silica gel column chromatography, the method for synthetic hydrochloric acid Manidipine is applicable to suitability for industrialized production.Belong to the Chemicals production technical field, especially relevant with the impurity-removing method of CV-4093 raw material before salify.
Background technology
CV-4093 is a kind of raw material of antihypertensive drug.1992 the earliest by Japan's military field research and development, list marketing, and in states such as Korea S, Italy, Britain listing is arranged all with its good blood pressure lowering effect.The listing of present domestic this product of nothing and sale, the inventor be domestic first successfully develop and accomplish 3.1 kind new medicine clinical studyes of State Food and Drug Administration approval and the unit that declaration is produced.
This product foreign patent is expired, and China does not have the patent protection of this product at present.Impurity-removing method before the known production CV-4093 salify is: Manidipine alkali bullion → trichloromethane → washing removal of impurities → drying → salify → CV-4093.This existing impurity-removing method is to use trichloromethane to be solvent, through washing the impurity in the Manidipine alkali bullion is removed, and has following defective in the removal of impurities process:
(1) because trichloromethane is a kind of great toxicity material; Very easily to the infringement of operator's toxigenicity, the physical and mental health that threatens operator contacts trichloromethane for a long time in the production; Cause the kidney damage to encircle, have a liking for diseases such as chloroform addiction probably, and chloroform contain carcinogens.
(2) in chloroform, use cold water to wash, removal of impurity poor effect, product is difficult for crystallization behind the salify, and is all influential to product yield and purity.
Summary of the invention
To adopting trichloromethane in the impurity-removing method before the existing CV-4093 salify is solvent; Jeopardize operator's physical and mental health and the defective that is difficult for removal of impurities, the invention discloses a kind of new impurity-removing method, utilize this method to remove the impurity in the Manidipine alkali bullion; Good impurity removing effect not only; Do not endanger operator's physical and mental health, free from environmental pollution, and can improve the purity and the yield of CV-4093 finished product.
Realize that the technical scheme that the object of the invention is taked is:
Manidipine alkali bullion → add acetic acid ethyl dissolution → add warm water washing → drying → salify → CV-4093
Manidipine alkali bullion of the present invention, ETHYLE ACETATE, its ratio is 1: 3～8; ETHYLE ACETATE, its ratio of water are 6: 2～4; The temperature of water is 30 ℃～80 ℃.
Advantage of the present invention is to utilize the low solvent of poisoning, and through experimental study, has confirmed the concrete composition of impurity; Utilize the physical properties of impurity in the bullion--solvability is different in 30 ℃～80 ℃ of different water temperatures, washes removal of impurities with the water of this temperature, has removed impurity to greatest extent; The physical and mental health that helps operator; Improve the quality of products and yield, reduced production cost, reduced environmental pollution.
Description of drawings
Below in conjunction with accompanying drawing further explain technical characterictic of the present invention:
Accompanying drawing is removal of impurities production technique figure before the CV-4093 salify of mentioning among the present invention.
Embodiment
Shown in accompanying drawing, the production technique that the present invention compares with document technology before the removal of impurities is basic identical with removal of impurities production technique afterwards, repeats no more at this.
Impurity-removing method of the present invention is:
Get 1 part of Manidipine alkali bullion and 3～8 parts of ETHYLE ACETATE, stir and make Manidipine alkali dissolving crude product; Be incorporated as ETHYLE ACETATE volume 1/3～2/3 then, temperature is 40 ℃～70 ℃ water, the washing removal of impurities; The removal of impurities after drying feeds HCL gas and processes CV-4093.
Embodiment 1
Getting Manidipine alkali bullion 10kg and 70kg ETHYLE ACETATE, stir and to make Manidipine alkali dissolving crude product, is 60 ℃ 25kg water with temperature, wash three removal of impurities, the removal of impurities after drying, and feeding HCL gas is processed CV-4093
Embodiment 2
Getting Manidipine alkali bullion 10kg and 80kg ETHYLE ACETATE, stir and to make Manidipine alkali dissolving crude product, is 50 ℃ 50kg water with temperature, wash four removal of impurities, the removal of impurities after drying, and feeding HCL gas is processed CV-4093
Use the inventive method removal of impurities, can make the purity of CV-4093 bring up to 92.2% by 75.8% of traditional method removal of impurities purification; Yield brings up to 68% by 48.2%, and does not endanger operator's physical and mental health, has reduced the pollution to environment.
Claims (2)
1. the impurity-removing method before the CV-4093 salify, described impurity-removing method is:
2. by the impurity-removing method before the described a kind of CV-4093 salify of claim 1, it is characterized in that: Manidipine alkali bullion, ETHYLE ACETATE, its ratio are 1: 3～8; ETHYLE ACETATE, water, its ratio are 6: 2～4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100641137A CN101575313B (en) | 2009-01-20 | 2009-01-20 | Production technique for synthesizing Manidipine Hydrochloride through separation with non-column chromatography |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100641137A CN101575313B (en) | 2009-01-20 | 2009-01-20 | Production technique for synthesizing Manidipine Hydrochloride through separation with non-column chromatography |
Publications (2)
| Publication Number | Publication Date |
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| CN101575313A CN101575313A (en) | 2009-11-11 |
| CN101575313B true CN101575313B (en) | 2012-04-18 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2009100641137A Active CN101575313B (en) | 2009-01-20 | 2009-01-20 | Production technique for synthesizing Manidipine Hydrochloride through separation with non-column chromatography |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875451B (en) * | 2012-04-05 | 2014-12-03 | 常州制药厂有限公司 | Improved method for synthesis process of manidipine hydrochloride |
| CN103351362A (en) * | 2013-06-17 | 2013-10-16 | 张家港威胜生物医药有限公司 | Preparation method of manidipine intermediate 2-(4-diphenylmethyl piperazinyl)ethyl acetoacetate |
| CN104292150A (en) * | 2013-07-19 | 2015-01-21 | 许昌恒生制药有限公司 | Synthetic process of manidipine hydrochloride |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0094159A1 (en) * | 1982-05-10 | 1983-11-16 | Takeda Chemical Industries, Ltd. | Dihydropyridine derivatives, their production and use |
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2009
- 2009-01-20 CN CN2009100641137A patent/CN101575313B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0094159A1 (en) * | 1982-05-10 | 1983-11-16 | Takeda Chemical Industries, Ltd. | Dihydropyridine derivatives, their production and use |
Non-Patent Citations (3)
| Title |
|---|
| JP特开平6-199789A 1994.07.19 |
| 党小荣 等.二氢吡啶类钙拮抗剂——马尼地平.《西北药学杂志》.1997,第12卷(第2期),第86-87页. * |
| 肖方青 等.盐酸马尼地平的合成.《中国医药工业杂志》.2004,第35卷(第2期),第65-66页. * |
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| CN101575313A (en) | 2009-11-11 |
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