CN113072483A - Refining method of nicardipine hydrochloride - Google Patents
Refining method of nicardipine hydrochloride Download PDFInfo
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- CN113072483A CN113072483A CN202110342246.7A CN202110342246A CN113072483A CN 113072483 A CN113072483 A CN 113072483A CN 202110342246 A CN202110342246 A CN 202110342246A CN 113072483 A CN113072483 A CN 113072483A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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Abstract
The invention belongs to the technical field of organic drug purification, and particularly relates to a method for refining nicardipine hydrochloride. The refining method of the nicardipine hydrochloride comprises the steps of hydrolyzing a crude nicardipine hydrochloride product under an alkaline condition, hydrolyzing impurities (shown in a formula 1) in the crude nicardipine hydrochloride product into impurities which can be removed easily, and then refining by using an organic solvent with high polarity, so that the content of the impurities is reduced. The invention can effectively remove the impurities, greatly reduce the content of the impurities in the product, does not need to increase the refining times and is beneficial to reducing the project cost. After detection, the impurity content is reduced from 0.422% to 0.067% and the purity of the obtained product is 99.7% -99.9%.
Description
Technical Field
The invention belongs to the technical field of organic drug purification, and particularly relates to a method for refining nicardipine hydrochloride.
Background
Nicardipine hydrochloride is used as calcium ion antagonist of dihydropyridines, is mainly used for treating cardiovascular and cerebrovascular diseases clinically, and has the effects of dilating coronary artery, improving myocardial ischemia, dilating peripheral blood vessels, reducing blood pressure and the like. At present, impurities (formula I) similar to polymers are generated in a synthetic route of nicardipine hydrochloride by an esterification method, the impurities are easy to remain in products in the subsequent refining process of a crude nicardipine hydrochloride product, the purity of the products is influenced, the refining times are increased, the yield is reduced, and the project cost is not easy to control.
Disclosure of Invention
Aiming at the problems, the invention provides a method for refining nicardipine hydrochloride, which can effectively remove the impurities and greatly reduce the content of the impurities in the product.
The method for refining the nicardipine hydrochloride comprises the steps of hydrolyzing a crude product of the nicardipine hydrochloride under an alkaline condition, and then crystallizing and refining by adopting a polar solvent.
The method comprises the following specific steps:
(1) adding an organic solvent I into the nicardipine hydrochloride crude product for dissolving, and removing the organic solvent I by reduced pressure evaporation to obtain an oily substance I;
(2) adding dichloromethane into the oily matter I, dissolving to clear, adding aqueous solution of alkaline substance, reacting at 10-60 deg.C for 0.5-5h, standing for layering, and concentrating under reduced pressure to obtain oily matter II;
(3) and adding an organic solvent II into the oily matter II, stirring, crystallizing and drying to obtain the nicardipine hydrochloride.
In the invention, the organic solvent I only needs to be capable of dissolving the crude nicardipine hydrochloride, and methanol is the best in solubility, so that the crude nicardipine hydrochloride is dissolved by methanol.
The dichloromethane is added in the step (2) for facilitating the subsequent layering with the aqueous solution of the alkaline substance, so that the impurities can be damaged and the nicardipine hydrochloride can not be damaged. The inventor finds that the crude product of nicardipine hydrochloride cannot be directly dissolved by simply using dichloromethane in the experimental process, so the inventor firstly adopts methanol for dissolving and cleaning, and then adds dichloromethane after distilling off the methanol. By mass ratio, dichloromethane: the crude nicardipine hydrochloride is 10-12: 1. The reaction temperature is preferably 40 ℃ and the reaction time is preferably 2 h.
The alkaline substance is sodium hydroxide or sodium carbonate or sodium bicarbonate or sodium ethoxide or sodium methoxide. The aqueous solution of the alkaline substance is 1mol/L, which can not only destroy impurities, but also ensure that the nicardipine hydrochloride is not destroyed. The aqueous solution of the alkaline substance comprises the following components in percentage by mass: the crude product of nicardipine hydrochloride is 11-12: 1.
After the oil I is added with the aqueous solution of the alkaline substance, the impurities in the oil I react as follows:
after the reaction is finished, standing for layering, washing an organic phase with water, and concentrating under reduced pressure to obtain an oily substance II; adding a polar organic solvent II such as ethanol or acetonitrile, preferably acetonitrile into the oily substance II, stirring at room temperature for crystallization for 12 hours, and drying to obtain nicardipine hydrochloride, wherein the mass ratio of the organic solvent II: the crude product of nicardipine hydrochloride is 5-10: 1. The room temperature range is 15-25 ℃.
By adopting the method, the impurities in the nicardipine hydrochloride crude product can be hydrolyzed into the impurities which can be removed easily, and then the organic solvent with larger polarity is used for refining, so that the content of the impurities can be reduced, the refining times do not need to be increased, and the project cost can be controlled. After detection, the purity of the obtained product is 99.7-99.9%, and the content of the impurities is reduced from 0.422% to 0.067%.
Drawings
FIG. 1 shows the structural formula of the impurity.
Detailed Description
Example 1
The refining method of nicardipine hydrochloride comprises the following specific steps:
(1) pumping 120Kg of methanol into a 500L dissolving tank, adding 8.5Kg of nicardipine hydrochloride crude product, stirring to dissolve the clear solution, heating the solution to 50 ℃ by steam, and removing the methanol by decompression to obtain an oily substance I;
(2) adding 100Kg of dichloromethane into the oily matter I, stirring to dissolve the oily matter I, after the solution is clarified, adding 100Kg of 1M sodium carbonate aqueous solution, heating to 40 ℃, stirring to react for 2 hours, standing for layering, taking the lower layer organic phase, adding 50Kg of water, washing for 1 time, layering, and concentrating the organic phase under reduced pressure to obtain an oily matter II;
(3) and adding 85Kg of acetonitrile into the oily matter II, stirring and crystallizing at 20 ℃ for 12 hours, and drying a centrifuged wet product for 8 hours to obtain 7Kg of nicardipine hydrochloride finished product with the purity of 99.9 percent and the impurity content of 0.067 percent.
Example 2
The refining method of nicardipine hydrochloride comprises the following specific steps:
(1) pumping 120Kg of methanol into a 500L dissolving tank, adding 8.5Kg of nicardipine hydrochloride crude product, stirring to dissolve the clear solution, heating the solution to 50 ℃ by steam, and removing the methanol by decompression to obtain an oily substance I;
(2) adding 85Kg of dichloromethane into the oily matter I, stirring to dissolve the oily matter I, after the solution is clear, adding 100Kg of 1M sodium bicarbonate aqueous solution, heating to 20 ℃, stirring to react for 2 hours, standing for layering, taking the lower layer organic phase, adding 50Kg of water, washing for 1 time, layering, and concentrating the organic phase under reduced pressure to obtain an oily matter II;
(3) and adding 45Kg of acetonitrile into the oily matter II, stirring and crystallizing at 20 ℃ for 12 hours, and drying a centrifuged wet product for 8 hours to obtain 6.8Kg of nicardipine hydrochloride finished product with the purity of 99.7 percent and the impurity content of 0.068 percent.
Example 3
The refining method of nicardipine hydrochloride comprises the following specific steps:
(1) pumping 120Kg of methanol into a 500L dissolving tank, adding 8.5Kg of nicardipine hydrochloride crude product, stirring to dissolve the clear solution, heating the solution to 50 ℃ by steam, and removing the methanol by decompression to obtain an oily substance I;
(2) adding 90Kg of dichloromethane into the oily matter I, stirring and dissolving the oily matter I, after the solution is clarified, adding 95Kg of 1M sodium hydroxide aqueous solution, heating to 50 ℃, stirring and reacting for 1 hour, standing and layering, taking the lower organic phase, adding 50Kg of water, washing for 1 time, layering, and concentrating the organic phase under reduced pressure to obtain an oily matter II;
(3) and adding 50Kg of acetonitrile into the oily matter II, stirring and crystallizing at 20 ℃ for 12 hours, and drying a centrifuged wet product for 8 hours to obtain 7.2Kg of nicardipine hydrochloride finished product with the purity of 99.8 percent and the impurity content of 0.067 percent.
Example 4
The refining method of nicardipine hydrochloride comprises the following specific steps:
(1) pumping 120Kg of methanol into a 500L dissolving tank, adding 8.5Kg of nicardipine hydrochloride crude product, stirring to dissolve the clear solution, heating the solution to 50 ℃ by steam, and removing the methanol by decompression to obtain an oily substance I;
(2) adding 95Kg of dichloromethane into the oily substance I, stirring to dissolve the oily substance I, after the solution is clarified, adding 95Kg of 1M sodium ethoxide aqueous solution, heating to 60 ℃, stirring to react for 0.5 hour, standing for layering, taking the lower organic phase, adding 50Kg of water, washing for 1 time, layering, and concentrating the organic phase under reduced pressure to obtain an oily substance II;
(3) adding 60Kg of ethanol into the oily matter II, stirring and crystallizing at 20 ℃ for 12 hours, and drying the centrifuged wet product for 8 hours to obtain 6.7Kg of nicardipine hydrochloride finished product with the purity of 99.7 percent and the impurity content of 0.069 percent.
Example 5
The refining method of nicardipine hydrochloride comprises the following specific steps:
(1) pumping 120Kg of methanol into a 500L dissolving tank, adding 8.5Kg of nicardipine hydrochloride crude product, stirring to dissolve the clear solution, heating the solution to 50 ℃ by steam, and removing the methanol by decompression to obtain an oily substance I;
(2) adding 100Kg of dichloromethane into the oily substance I, stirring to dissolve the oily substance I, after the solution is clarified, adding 100Kg of 1M sodium methoxide aqueous solution, heating to 60 ℃, stirring to react for 0.5 hour, standing for layering, taking the lower organic phase, adding 50Kg of water, washing for 1 time, layering, and concentrating the organic phase under reduced pressure to obtain an oily substance II;
(3) and adding 70Kg of acetonitrile into the oily matter II, stirring and crystallizing at 20 ℃ for 12 hours, and drying a centrifuged wet product for 8 hours to obtain 7.1Kg of nicardipine hydrochloride finished product with the purity of 99.9 percent and the impurity content of 0.068 percent.
Claims (9)
1. The method for refining the nicardipine hydrochloride is characterized in that a nicardipine hydrochloride crude product is hydrolyzed under an alkaline condition and then is crystallized and refined by adopting a polar solvent to obtain the nicardipine hydrochloride.
2. The refining method of nicardipine hydrochloride as claimed in claim 1, which comprises the following steps:
(1) adding an organic solvent I into the nicardipine hydrochloride crude product for dissolving, and removing the organic solvent I by reduced pressure evaporation to obtain an oily substance I;
(2) adding dichloromethane into the oily matter I, dissolving to clear, adding aqueous solution of alkaline substance, reacting at 10-60 deg.C for 0.5-5h, standing for layering, and concentrating under reduced pressure to obtain oily matter II;
(3) and adding an organic solvent II into the oily matter II, stirring, crystallizing and drying to obtain the nicardipine hydrochloride.
3. The method for refining nicardipine hydrochloride as claimed in claim 2, wherein the organic solvent I is methanol.
4. The method for refining nicardipine hydrochloride as claimed in claim 2, characterized in that, in mass ratio, dichloromethane: the crude nicardipine hydrochloride is 10-12: 1.
5. The method for refining nicardipine hydrochloride as claimed in claim 2, wherein the alkaline substance is sodium hydroxide or sodium carbonate or sodium bicarbonate or sodium ethoxide or sodium methoxide.
6. The method for refining nicardipine hydrochloride as claimed in claim 2, wherein the aqueous solution of the alkaline substance is 1 mol/L.
7. The method for refining nicardipine hydrochloride of claim 2, characterized in that the aqueous solution of the alkaline substance is: the crude product of nicardipine hydrochloride is 11-12: 1.
8. The method for refining nicardipine hydrochloride as claimed in claim 2, wherein the organic solvent II is ethanol or acetonitrile.
9. The method for refining nicardipine hydrochloride as claimed in claim 2, characterized in that the mass ratio of the organic solvent II: the crude product of nicardipine hydrochloride is 5-10: 1.
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| CN202110342246.7A CN113072483A (en) | 2021-03-30 | 2021-03-30 | Refining method of nicardipine hydrochloride |
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| CN202110342246.7A CN113072483A (en) | 2021-03-30 | 2021-03-30 | Refining method of nicardipine hydrochloride |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115260087A (en) * | 2022-09-30 | 2022-11-01 | 济南良福精合医药科技有限公司 | Nicardipine hydrochloride impurity and synthesis method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4769465A (en) * | 1985-05-21 | 1988-09-06 | Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, N.Sol.O. | Process for the preparation of 2-(N-benzyl-N-methylamino)-ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride salt |
| WO2011115069A1 (en) * | 2010-03-19 | 2011-09-22 | 第一三共株式会社 | Exhaustive searching for crystals |
| CN105439942A (en) * | 2015-12-02 | 2016-03-30 | 扬子江药业集团北京海燕药业有限公司 | Preparation method of (S)-manidipine |
-
2021
- 2021-03-30 CN CN202110342246.7A patent/CN113072483A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4769465A (en) * | 1985-05-21 | 1988-09-06 | Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, N.Sol.O. | Process for the preparation of 2-(N-benzyl-N-methylamino)-ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride salt |
| WO2011115069A1 (en) * | 2010-03-19 | 2011-09-22 | 第一三共株式会社 | Exhaustive searching for crystals |
| CN105439942A (en) * | 2015-12-02 | 2016-03-30 | 扬子江药业集团北京海燕药业有限公司 | Preparation method of (S)-manidipine |
Non-Patent Citations (1)
| Title |
|---|
| 曹悦兴: "盐酸马尼地平片的处方工艺研究", 《中国优秀博硕士学位论文全文数据库(硕士)工程科技Ⅰ辑》, no. 5, 15 May 2014 (2014-05-15), pages 72 - 73 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115260087A (en) * | 2022-09-30 | 2022-11-01 | 济南良福精合医药科技有限公司 | Nicardipine hydrochloride impurity and synthesis method and application thereof |
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