CN103044314A - Preparation method of amlodipine maleate - Google Patents
Preparation method of amlodipine maleate Download PDFInfo
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- CN103044314A CN103044314A CN2013100042917A CN201310004291A CN103044314A CN 103044314 A CN103044314 A CN 103044314A CN 2013100042917 A CN2013100042917 A CN 2013100042917A CN 201310004291 A CN201310004291 A CN 201310004291A CN 103044314 A CN103044314 A CN 103044314A
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- amlodipine
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Abstract
The invention provides a preparation method of amlodipine maleate, which comprises the following steps that a), maleic acid and amlodipine free alkali react in water, and an amlodipine maleate crude product is obtained; and b), the amlodipine maleate crude product obtained in Step a) is refined, and the amlodipine maleate is obtained. The preparation method takes the water as a reaction medium, and is low in price and environment-friendly; in addition, generation of impurities in a synthetic process is reduced by adjusting parameters such as the use amount of the water, maleic acid and amlodipine free alkali, reaction temperature and reaction time, so that contents of relevant substances in the amlodipine maleate are lower, and the yield of the amlodipine maleate is ensured. A result proves that the yield of the amlodipine maleate prepared by the preparation method is above 55%, the maximum content of the single impurity is less than 0.2%, and the total content of the relevant substances is less than 0.3%.
Description
Technical field
The invention belongs to field of medicine preparing technology, relate in particular to a kind of preparation method of amlodipine maleate.
Background technology
Amlodipine maleate is dihydropyridine type calcium antagonists, be applicable to hypertension and anginal treatment, its English name is Amlodipine Maleate, chemical name is the 2[(2-amino ethoxy) methyl]-4 (2-chloro-phenyl-s)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylic acid-3-ethyl-5-methyl esters maleic acid salt, molecular formula is C
24H
29ClN
2O
9, have formula (I) structure:
Prior art is generally take amlodipine as starting raw material, in solvent, prepare amlodipine maleate behind the salify with toxilic acid, solvent commonly used is generally methylamine alcohol or ethyl acetate, but, these two kinds of solvents are not only expensive, and need other solvent of adding to carry out follow-up refinement treatment, operate comparatively loaded down with trivial details.Application number is that 201110397020.3 Chinese patent discloses the method for preparing amlodipine maleate take toxilic acid and amlodipine free base as starting raw material, it at first adds toxilic acid in dehydrated alcohol or the mother liquor, heating for dissolving is filtered and is obtained the toxilic acid methanol solution; Then amlodipine free base is added anhydrous methanol dissolving, be stirred to complete molten transparently, cooling obtains the amlodipine free base methanol solution; The amlodipine free base methanol solution slowly is added drop-wise in the toxilic acid methanol solution, insulated and stirred, crystallization is left standstill in cooling; Crystal absolute ethanol washing with obtaining can obtain amlodipine maleate after the drying.Although the method does not adopt methylamine alcohol or ethyl acetate as reaction solvent, its operation is also comparatively loaded down with trivial details, and its related substances is higher in the finished product that obtain.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is to provide a kind of preparation method of amlodipine maleate, and preparation method provided by the invention is simple to operate, and its related substances is lower in the amlodipine maleate for preparing.
The invention provides a kind of preparation method of amlodipine maleate, may further comprise the steps:
A) toxilic acid and amlodipine free base react in water, obtain the amlodipine maleate crude product;
B) the amlodipine maleate crude product refining that described step a) is obtained obtains amlodipine maleate.
Preferably, in the described step a), the ratio of the mole number of described toxilic acid and the volume of water is 1mol:2L ~ 5L.
Preferably, in the described step a), the temperature of described reaction is 10 ℃ ~ 15 ℃, and the described reaction times is 1h ~ 2h.
Preferably, in the described step a), the mol ratio of described toxilic acid and amlodipine free base is 1:1 ~ 1.4.
Preferably, described step b) is specially:
The amlodipine maleate crude product that described step a) is obtained is scattered in the ethanol, obtains amlodipine maleate after stirring, filtration, the drying.
Preferably, the temperature of described stirring is-5 ℃ ~ 5 ℃, and the time of described stirring is 2h ~ 5h.
Preferably, the ratio of the volume of the quality of described amlodipine maleate crude product and ethanol is 1kg:6 ~ 14L.
Preferably, the described decompress filter that is filtered into.
Preferably, described drying is drying under reduced pressure.
Preferably, the temperature of described drying under reduced pressure is 20 ℃ ~ 30 ℃.
Compared with prior art, the present invention prepares amlodipine maleate with water as reaction medium take toxilic acid and amlodipine free base as raw material, and is not only simple to operate, cheap, and environmental protection; Simultaneously, consumption and the parameters such as temperature of reaction, reaction times of the present invention by adjusting water, toxilic acid and amlodipine free base, reduced the generation of impurity in the building-up process, made and guaranteed its yield when its related substances is lower in the amlodipine maleate that obtains.The result shows, adopts the yield of the amlodipine maleate that method provided by the invention prepares more than 55%, and maximum single foreign matter content is below 0.2%, and the related substance summation is below 0.3%.
Further, the present invention directly is scattered in the amlodipine maleate crude product that makes in the ethanol and stirs, can obtain the extremely low amlodipine maleate of its related substances after filtration, the drying, owing to having reduced the step of temperature rising reflux recrystallization and remove impurity with active carbon, reduced the generation of impurity, when further reducing its related substances, reduce operation steps, simplified production technique.
Description of drawings
Fig. 1 is the high-efficient liquid phase chromatogram of the amlodipine maleate of the embodiment of the invention 1 preparation;
Fig. 2 is the high-efficient liquid phase chromatogram of the amlodipine maleate of the embodiment of the invention 2 preparations;
Fig. 3 is the high-efficient liquid phase chromatogram of the amlodipine maleate of the embodiment of the invention 3 preparations;
Fig. 4 is the high-efficient liquid phase chromatogram of first amlodipine maleate of the embodiment of the invention 4 preparations;
Fig. 5 is the high-efficient liquid phase chromatogram of the second batch amlodipine maleate of the embodiment of the invention 4 preparations;
Fig. 6 is the high-efficient liquid phase chromatogram of the 3rd batch of amlodipine maleate of the embodiment of the invention 4 preparations;
Fig. 7 is the high-efficient liquid phase chromatogram of the amlodipine maleate of the embodiment of the invention 5 preparations.
Embodiment
The invention provides a kind of preparation method of amlodipine maleate, may further comprise the steps:
A) toxilic acid and amlodipine free base react in water, obtain the amlodipine maleate crude product;
B) the amlodipine maleate crude product refining that described step a) is obtained obtains amlodipine maleate.
The present invention prepares amlodipine maleate with water as reaction medium take toxilic acid and amlodipine free base as raw material, and is not only simple to operate, and its related substances is extremely low in the amlodipine maleate for preparing.
The present invention is take toxilic acid as raw material, and described toxilic acid claims again maleic acid, and the present invention does not have particular restriction to its source, and the commercially available prod gets final product.
The present invention is take amlodipine free base as raw material, and described amlodipine free base claims again amlodipine base, and molecular formula is C
26H
31ClN
2O
8S.The present invention does not have particular restriction to its source, and the commercially available prod gets final product.
The present invention is preferably deionized water take water as reaction medium.
The present invention is scattered in toxilic acid and amlodipine free base in the water, and toxilic acid and amlodipine free base generation salt-forming reaction obtain the amlodipine maleate crude product.In the present invention, the ratio of the mole number of described toxilic acid and the volume of water is preferably 1mol:2L ~ 5L, 1mol:2.1L ~ 4L more preferably, most preferably be 1mol:2.13L ~ 2.2L, the consumption of toxilic acid and water is controlled within the above-mentioned scope, can so that toxilic acid and amlodipine free base in the short period complete reaction, thereby reduce the generation of impurity.The mol ratio of described toxilic acid and amlodipine free base is preferably 1:1 ~ 1.4,1:1.05 ~ 1.3 more preferably, most preferably be 1:1.1 ~ 1.2, the consumption of toxilic acid and amlodipine free base is controlled within the above-mentioned scope, can guarantees yield and the purity of amlodipine maleate, if the toxilic acid consumption is lower than aforementioned proportion, yield can descend, if the toxilic acid consumption is higher than aforementioned proportion, can manufactures difficulty to subsequent fine, and be unfavorable for the reduction of its related substances.
In the present invention, the temperature of described toxilic acid and amlodipine free base generation salt-forming reaction is preferably 10 ℃ ~ 15 ℃, more preferably 12 ℃ ~ 13 ℃; Time is preferably 1h ~ 2h, more preferably 1.2h ~ 1.8h.In above-mentioned temperature of reaction with in the reaction times, the reaction of toxilic acid and amlodipine free base is comparatively complete, and the phenomenon such as degraded can not occur causes its related substances increase.In order to make salt-forming reaction more abundant, the present invention preferably reacts toxilic acid and amlodipine free base under the condition that stirs.
React complete after, the reaction mixture that obtains is filtered, obtain the amlodipine maleate crude product.After obtaining the amlodipine maleate crude product, it is made with extra care, obtain the lower amlodipine maleate of its related substances.
The present invention does not have particular restriction to described process for purification, can be recrystallization well known to those skilled in the art, absorption, crystallization, the treating process such as centrifugal, specifically comprises:
The amlodipine maleate crude product is scattered in the ethanol, be heated to backflow after, add gac and continue to reflux, then be down to room temperature, at-5 ℃ ~ 5 ℃ lower crystallizatioies, obtain amlodipine maleate after centrifugal, the drying.
Generate in order to reduce impurity, reduce operation easier, the present invention preferably makes with extra care described amlodipine maleate crude product in accordance with the following methods:
Described amlodipine maleate crude product is scattered in the ethanol, obtains amlodipine maleate after stirring, filtration, the drying.
The present invention directly is scattered in the amlodipine maleate crude product in the ethanol, need not after the stirring that recrystallization and remove impurity with active carbon can filter, drying, not only reduce operation steps, and reduced in the recrystallization temperature rising reflux process amlodipine maleate degraded etc. occurs, reduced the generation of impurity.
The present invention is scattered in the amlodipine maleate crude product in the ethanol and stirs, and reduces the impurity component in the amlodipine maleate.The temperature of described stirring is preferably-5 ℃ ~ 5 ℃, more preferably-3 ℃ ~ 3 ℃, the time of described stirring is preferably 2h ~ 5h, more preferably 3h ~ 4h.In above-mentioned whipping temp scope, amlodipine maleate can not degraded owing to being heated, and can reduce the content of related substance.
In the present invention, the ratio of the quality of described amlodipine maleate crude product and the volume of ethanol is preferably 1kg:6 ~ 14L, and more preferably 1kg:6 ~ 12L most preferably is 1kg:6 ~ 8L.The consumption of amlodipine maleate crude product and ethanol is controlled within the above-mentioned scope, can either guarantees to reduce its related substances, can improve yield again.
Stir complete after, the mixed solution that obtains is filtered, the present invention does not have particular restriction to described filter method, is preferably decompress filter well known to those skilled in the art.
The solid that obtains behind the decompress filter is carried out drying under reduced pressure well known to those skilled in the art, can obtain the lower amlodipine maleate of its related substances.For reducing the generation of impurity, the temperature of described drying under reduced pressure is preferably 20 ℃ ~ 30 ℃, more preferably 22 ℃ ~ 28 ℃; The pressure of described drying under reduced pressure is preferred＞0.08MPa.
After obtaining amlodipine maleate, it is carried out high performance liquid chromatography detect, the result shows, its purity is more than 99.7%, and yield can reach more than 55%; Single maximum contaminant≤0.2%, related substance summation≤0.3% is no more than 0.5% far below the single maximum contaminant of national standard, and related substance comprehensively is no more than 1.0% regulation.
The present invention prepares amlodipine maleate with water as reaction medium take toxilic acid and amlodipine free base as raw material, and is simple to operate, not only cheap for the organic solvents such as methylamine alcohol or ethyl acetate, and environmental protection; Simultaneously, consumption and the parameters such as temperature of reaction, reaction times of the present invention by adjusting water, toxilic acid and amlodipine free base, reduced the generation of impurity in the building-up process, made and guaranteed its yield when its related substances is lower in the amlodipine maleate that obtains.Further, the present invention directly is scattered in the amlodipine maleate crude product that makes in the ethanol and stirs, can obtain the extremely low amlodipine maleate of its related substances after filtration, the drying, owing to having reduced the step of temperature rising reflux recrystallization and remove impurity with active carbon, reduced the generation of impurity, when further reducing its related substances, reduce operation steps, simplified production technique.
In order to further specify the present invention, below in conjunction with embodiment the preparation method of amlodipine maleate provided by the invention is described in detail.
Embodiment 1
1mol toxilic acid and 1.1mol amlodipine free base are scattered in the 2.2L water, and 10 ℃ of lower stirring reaction 2h filter the reaction mixture that obtains, and obtain the amlodipine maleate crude product; Described amlodipine maleate crude product is scattered in the ethanol, the ratio of the quality of the volume of described ethanol and described amlodipine maleate crude product is 14L:1kg, add the 0.03g Medicinal Charcoal after the reflux, backflow 30min, be down to room temperature ,-5 ℃ lower centrifugal after placing crystallization 4h, then 25 ℃,＞dry under the condition of 0.08MPa, obtain amlodipine maleate, yield is 65%.
Described amlodipine maleate is carried out efficient liquid phase chromatographic analysis, the result is referring to Fig. 1, Fig. 1 is the high-efficient liquid phase chromatogram of the amlodipine maleate of the embodiment of the invention 1 preparation, as shown in Figure 1, the present invention has prepared amlodipine maleate, its purity is 99.7%, and single maximum contaminant is 0.12%, and total impurities is 0.28%.
Embodiment 2
2mol toxilic acid and 2.2mol amlodipine free base are scattered in the 4.4L water, and 15 ℃ of lower stirring reaction 1h filter the reaction mixture that obtains, and obtain the amlodipine maleate crude product; Described amlodipine maleate crude product is scattered in the ethanol, the ratio of the quality of the volume of described ethanol and described amlodipine maleate crude product is 14L:1kg, decompress filter behind-5 ℃ of lower stirring 4h, then 23 ℃,＞dry under the condition of 0.08MPa, obtain amlodipine maleate, yield is 60%.
Described amlodipine maleate is carried out efficient liquid phase chromatographic analysis, the result is referring to Fig. 2, Fig. 2 is the high-efficient liquid phase chromatogram of the amlodipine maleate of the embodiment of the invention 2 preparations, as shown in Figure 2, the present invention has prepared amlodipine maleate, its purity is 99.8%, and single maximum contaminant is 0.11%, and total impurities is 0.22%.
1mol toxilic acid and 1.1mol amlodipine free base are scattered in the 2.2L water, and 12 ℃ of lower stirring reaction 1.5h filter the reaction mixture that obtains, and obtain the amlodipine maleate crude product; Described amlodipine maleate crude product is scattered in the ethanol, the ratio of the quality of the volume of described ethanol and described amlodipine maleate crude product is 6L:1kg, decompress filter behind 0 ℃ of lower stirring 4h, then 28 ℃,＞dry under the condition of 0.08MPa, obtain amlodipine maleate, yield is 57%.
Described amlodipine maleate is carried out efficient liquid phase chromatographic analysis, the result is referring to Fig. 3, Fig. 3 is the high-efficient liquid phase chromatogram of the amlodipine maleate of the embodiment of the invention 3 preparations, as shown in Figure 3, the present invention has prepared amlodipine maleate, its purity is 99.7%, and single maximum contaminant is 0.13%, and total impurities is 0.24%.
Embodiment 4
5mol toxilic acid and 5.5mol amlodipine free base are scattered in the 11L water, and 13 ℃ of lower stirring reaction 1.8h filter the reaction mixture that obtains, and obtain the amlodipine maleate crude product; Described amlodipine maleate crude product is scattered in the ethanol, the ratio of the quality of the volume of described ethanol and described amlodipine maleate crude product is 6L:1kg, decompress filter behind 5 ℃ of lower stirring 4h, then 28 ℃,＞dry under the condition of 0.08MPa, obtain amlodipine maleate, the yield of continuous 3 batches of products is respectively 69%, 67% and 69%.
Respectively described amlodipine maleate is carried out efficient liquid phase chromatographic analysis, the result is referring to Fig. 4, Fig. 5 and Fig. 6, Fig. 4 is the high-efficient liquid phase chromatogram of first amlodipine maleate of the embodiment of the invention 4 preparations, Fig. 5 is the high-efficient liquid phase chromatogram of the second batch amlodipine maleate of the embodiment of the invention 4 preparations, and Fig. 6 is the high-efficient liquid phase chromatogram of the 3rd batch of amlodipine maleate of the embodiment of the invention 4 preparations.By Fig. 4, Fig. 5 and Fig. 6 as can be known, the present invention has prepared amlodipine maleate, and its purity is respectively 99.8%, 99.8% and 99.8%, and single maximum contaminant is respectively 0.08%, 0.08% and 0.07%, and total impurities is respectively 0.24%, 0.23% and 0.19%.
100mol toxilic acid and 110mol amlodipine free base are scattered in the 220L water, and 15 ℃ of lower stirring reaction 1.2h filter the reaction mixture that obtains, and obtain the amlodipine maleate crude product; Described amlodipine maleate crude product is scattered in the ethanol, the ratio of the quality of the volume of described ethanol and described amlodipine maleate crude product is 6L:1kg, decompress filter behind 0 ℃ of lower stirring 4h, then 25 ℃,＞dry under the condition of 0.08MPa, obtain amlodipine maleate, yield is respectively 65%.
Respectively described amlodipine maleate is carried out efficient liquid phase chromatographic analysis, the result is referring to Fig. 7, Fig. 7 is the high-efficient liquid phase chromatogram of the amlodipine maleate of the embodiment of the invention 5 preparations, as shown in Figure 7, the present invention has prepared amlodipine maleate, its purity is 99.7%, and single maximum contaminant is 0.13%, and total impurities is 0.29%.
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. the preparation method of an amlodipine maleate may further comprise the steps:
A) toxilic acid and amlodipine free base react in water, obtain the amlodipine maleate crude product;
B) the amlodipine maleate crude product refining that described step a) is obtained obtains amlodipine maleate.
2. preparation method according to claim 1 is characterized in that, in the described step a), the ratio of the mole number of described toxilic acid and the volume of water is 1mol:2L ~ 5L.
3. preparation method according to claim 1 is characterized in that, in the described step a), the temperature of described reaction is 10 ℃ ~ 15 ℃, and the described reaction times is 1h ~ 2h.
4. preparation method according to claim 1 is characterized in that, in the described step a), the mol ratio of described toxilic acid and amlodipine free base is 1:1 ~ 1.4.
5. preparation method according to claim 1 is characterized in that, described step b) is specially:
The amlodipine maleate crude product that described step a) is obtained is scattered in the ethanol, obtains amlodipine maleate after stirring, filtration, the drying.
6. preparation method according to claim 5 is characterized in that, the temperature of described stirring is-5 ℃ ~ 5 ℃, and the time of described stirring is 2h ~ 5h.
7. preparation method according to claim 5 is characterized in that, the ratio of the quality of described amlodipine maleate crude product and the volume of ethanol is 1kg:6 ~ 14L.
8. preparation method according to claim 5 is characterized in that, the described decompress filter that is filtered into.
9. preparation method according to claim 5 is characterized in that, described drying is drying under reduced pressure.
10. preparation method according to claim 9 is characterized in that, the temperature of described drying under reduced pressure is 20 ℃ ~ 30 ℃.
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| WO2005089353A2 (en) * | 2004-03-16 | 2005-09-29 | Sepracor Inc. | (s)-amlodipine malate |
| WO2008060093A1 (en) * | 2006-11-14 | 2008-05-22 | Cj Cheiljedang Corporation | Crystalline s-(-)-amlodipine maleic acid salt anhydride and preparation method thereof |
| CN101531629A (en) * | 2009-04-17 | 2009-09-16 | 江苏先声药物研究有限公司 | Method for preparing levamlodipine from racemic amlodipine maleate |
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2013
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| US4572909A (en) * | 1982-03-11 | 1986-02-25 | Pfizer Inc. | 2-(Secondary aminoalkoxymethyl) dihydropyridine derivatives as anti-ischaemic and antihypertensive agents |
| CN1263525A (en) * | 1998-04-09 | 2000-08-16 | 阿达梅德公司 | Process for preparation of amlodipine benzenesulphonate |
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| WO2008060093A1 (en) * | 2006-11-14 | 2008-05-22 | Cj Cheiljedang Corporation | Crystalline s-(-)-amlodipine maleic acid salt anhydride and preparation method thereof |
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Application publication date: 20130417 |