CN101602709A - The preparation method of cilnidipine used as dihydropyridine calcium antagonist - Google Patents
The preparation method of cilnidipine used as dihydropyridine calcium antagonist Download PDFInfo
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- CN101602709A CN101602709A CNA200810038932XA CN200810038932A CN101602709A CN 101602709 A CN101602709 A CN 101602709A CN A200810038932X A CNA200810038932X A CN A200810038932XA CN 200810038932 A CN200810038932 A CN 200810038932A CN 101602709 A CN101602709 A CN 101602709A
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- cilnidipineb
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Abstract
The invention provides a kind of preparation method of cilnidipine used as dihydropyridine calcium antagonist.This method is: carry out ring-closure reaction with 2-(3-nitro benzylidene) etheric acid 2-methoxy ethyl ester 4 and beta-amino Ba Dousuan cinnamic ester 5 in alcoholic solvent, obtain cilnidipineb 1 crude product, get cilnidipineb 1 behind the recrystallization.The present invention has short, advantages such as aftertreatment is easy, synthetic route is simple, processing condition gentleness reaction time, is fit to suitability for industrialized production.
Description
Technical field
The present invention relates to medication preparation.Be specifically related to the preparation method of dihydropyridine type calcium antagonists cilnidipineb.
Background technology
Raising along with The development in society and economy and living standards of the people, the change of the structure of diet, cardiovascular disorder has become that to influence broad masses of the people healthy and hinder one of principal disease of Economic development, has brought very big pressure and burden for society, family.According to the statistics made by the departments concerned, hypertension up to 12%, and has the trend that progressively increases in the morbidity of Chinese population.Hypertension may be caused serious Secondary cases illnesss such as apoplexy, myocardial infarction as not controlling, and makes the patient disable, cause death.In a word, hypertension has become one of main diseases kind that threatens human longevity.Therefore developing hypertension agents has vast market prospect, and huge social benefit and economic benefit.
Cilnidipineb (chemical name: (±)-2,6-dimethyl-4-(3-nitrophenyl)-1,4 dihydropyridines-dicarboxylic acid-2-methoxyethyl (E)-3 phenyl-2 propenyl dibasic acid esters) be the new calcium antagonist of a kind of L of having concurrently type and N type calcium channel blocking action, nineteen ninety-five gets permission listing first and is used for the treatment of hypertension.Indication is essential hypertension, serious hypertension and with the hypertension of renal impairment.After per day for adults breakfast oral 1 time, dosage is 5mg～10mg.According to age and symptom, dosage can increase and decrease to some extent.Under insensitive situation, dosage can increase to 20mg.Average effectiveness level reaches more than 90%.Side effect is mainly the common adverse effect of dihydropyridine type calcium antagonists such as dizziness, headache, periphery edema, flushing, fash and gingival hyperplasia, and symptom is generally lighter, and incidence is lower than 10%.
The characteristics of this product are: (1) acts on the L type calcium channel except the same with most of calcium antagonists, this product can also act on the N type calcium channel that is present in SNE, suppress orthosympathetic activation, thereby produce exclusive clinical characters-do not increase essential hypertension people's heart rate and can obviously reduce patient's cardiothoracic ratio.Clinically be expected to be used to prevent that sympathetic activity is counter increases the high-risk heart attack of bringing out.(2) have higher step-down comprehensive therapeutic effect and atherosclerosis effect.Though this product antihypertensive activity and nifedipine, nicardipine are similar, onset is slow, the effect length of holding time, and only need take medicine once every day, do not increase heart rate, and cardiac muscle is suppressed more weak and also has stronger vasodilation effect.These comprehensive antihypertensive effects all are better than traditional antagonists such as nifedipine.Clinically show that also this product can also reduce lipid peroxidation enzyme and AI in step-down, and significantly increase superoxide dismutase sample activity, remove superoxide radical and antioxidant effect, prompting this product also has the atherosclerosis performance.Meaning in view of the above, cilnidipineb are the long-acting antihypertensive drug of first calcium antagonism in the world, are exactly calcium-channel antagonists of new generation from the day of its appearances simultaneously.
Cilnidipineb is typical dihydropyridine type calcium antagonists, and its synthetic method can be used the Hantzsch condensation method.Document Drugs Fut., 1996; 21 (3): 249-253 and Hypertension, 1999; The 33:1447-1452 reported method is a raw material with the 3-nitrobenzaldehyde, earlier with etheric acid cinnamic ester condensation prepared 2-(3-nitro benzylidene) etheric acid cinnamic ester (2), carry out ring-closure reaction with beta-amino Ba Dousuan 2-methoxy ethyl ester (3) again and make cilnidipineb (1), do not report yield.But, this method is in preparation process, the intermediate 2 that very difficult acquisition is purer, and, the impurity that intermediate 2 exists will bring complicated byproduct to reaction product as reacting with 3 without separating directly, and aftertreatment is had higher requirement, generally all must separate, thereby this method is difficult to carry out suitability for industrialized production with column chromatography.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, the cilnidipineb preparation method of a suitable suitability for industrialized production of design.
The invention provides a kind of preparation method of cilnidipine used as dihydropyridine calcium antagonist.
Method of the present invention is: carry out ring-closure reaction with 2-(3-nitro benzylidene) etheric acid 2-methoxy ethyl ester 4 and beta-amino Ba Dousuan cinnamic ester 5 in alcoholic solvent, obtain cilnidipineb 1 crude product, get cilnidipineb 1 behind the recrystallization.
The reaction formula of the inventive method:
Described ring-closure reaction 2-(3-nitro benzylidene) etheric acid 2-methoxy ethyl ester 4 is 1: 1～1: 1.8 with the mol ratio of beta-amino Ba Dousuan cinnamic ester 5; Alcohol is C
1～C
3Absolute alcohol: anhydrous methanol, dehydrated alcohol or anhydrous isopropyl alcohol, content 99.5%-100%, consumption are 1.2～2.0 mol ratios; Reaction refluxed 2～5 hours.Cilnidipineb 1 crude product can be with above-mentioned pure recrystallization.
Compound 4 is the intermediate of nimodipine, and manufacturer is more, can obtain by commercially available.
Another object of the present invention has provided the preparation method of intermediate beta-amino Ba Dousuan cinnamic ester 5, and this method is in alcoholic solvent, and etheric acid cinnamic ester and ammonia gas react make under the agitation condition.Described ammonia usage is 1～5 mol ratio, 0～5 ℃ of logical ammonia temperature, and the time is 2～5 hours; Alcohol is C
1～C
3Absolute alcohol: anhydrous methanol, dehydrated alcohol or anhydrous n-propyl alcohol, content 99.5%-100%, consumption are 1.0～2.5 mol ratios; Temperature of reaction is 0～5 ℃, is incubated 5～8 hours.
The reaction formula of compound 5 preparations:
The inventive method total recovery (in the etheric acid cinnamic ester) reaches more than 48%, and the physico-chemical property and the document of products obtained therefrom cilnidipineb 1 are in full accord.
The present invention has short, advantages such as aftertreatment is easy, synthetic route is simple, processing condition gentleness reaction time, is fit to suitability for industrialized production.
The invention will be further described below in conjunction with embodiment.
Embodiment
Embodiment 1
Preparation beta-amino Ba Dousuan cinnamic ester (5)
(100g 0.458mol) is dissolved in the dehydrated alcohol (50ml) the etheric acid cinnamic ester, stirs down, is cooled to 0～5 ℃, feed ammonia 3h, insulation (0～5 ℃) 6 hours, decompression extracts unreacted ammonia, cool overnight, filter white crystals 5, weight is 78.6g, yield 78.9%.
Embodiment 2
Preparation beta-amino Ba Dousuan cinnamic ester (5)
(100g 0.458mol) is dissolved in the anhydrous methanol (80ml) the etheric acid cinnamic ester, stirs down, is cooled to 0～5 ℃, feed ammonia 3h, insulation (0～5 ℃) 6 hours, decompression extracts unreacted ammonia, cool overnight, filter white crystals 5, weight is 82.5g, yield 82.8%.
Embodiment 3
Preparation beta-amino Ba Dousuan cinnamic ester (5)
(100g 0.458mol) is dissolved in the anhydrous n-propyl alcohol (45ml) the etheric acid cinnamic ester, stirs down, is cooled to 0～5 ℃, feed ammonia 3h, insulation (0～5 ℃) 6 hours, decompression extracts unreacted ammonia, cool overnight, filter white crystals 5, weight is 75.2g, yield 75.5%.
Embodiment 4
Preparation cilnidipineb (I)
With 4 (44g, 0.15mol), dehydrated alcohol (176ml) and 5 (35.8g, 0.165mol) add in the reaction flask, refluxed cool overnight 3 hours, filter, cold washing with alcohol, dehydrated alcohol (130ml) recrystallization gets object 1, is light yellow crystal, weight is 47.8g, 108～110 ℃ of yield 64.7%.mp (decomposition); 109.5 ℃ of mp.
Embodiment 5
Preparation cilnidipineb (I)
With 4 (44g, 0.15mol), anhydrous methanol (200ml) and 5 (35.8g, 0.165mol) add in the reaction flask, refluxed cool overnight 3 hours, filter, cold anhydrous methanol washing, anhydrous methanol (130ml) recrystallization gets object 1, is light yellow crystal, weight is 48.7g, 109～110 ℃ of yield 65.9%.mp (decomposition); 109.5 ℃ of mp.
Embodiment 6
Preparation cilnidipineb (I)
With 4 (44g, 0.15mol), anhydrous isopropyl alcohol (155ml) and 5 (35.8g, 0.165mol) add in the reaction flask, refluxed cool overnight 3 hours, filter, cold anhydrous isopropyl alcohol washing, anhydrous isopropyl alcohol (125ml) recrystallization gets object 1, is light yellow crystal, weight is 49.3g, 108～110 ℃ of yield 66.7%.mp (decomposition); 109.5 ℃ of mp.
Claims (7)
1, a kind of preparation method of cilnidipine used as dihydropyridine calcium antagonist, this method is: carry out ring-closure reaction with 2-(3-nitro benzylidene) etheric acid 2-methoxy ethyl ester 4 and beta-amino Ba Dousuan cinnamic ester 5 in alcoholic solvent, obtain cilnidipineb 1 crude product, get cilnidipineb 1 behind the recrystallization;
2, the preparation method of a kind of cilnidipine used as dihydropyridine calcium antagonist according to claim 1 is characterized in that described ring-closure reaction 2-(3-nitro benzylidene) the etheric acid 2-methoxy ethyl ester 4 and the mol ratio of beta-amino Ba Dousuan cinnamic ester 5 are 1: 1～1: 1.8; Alcohol is C
1～C
3Absolute alcohol, consumption is 1.2～2.0 mol ratios; Reaction refluxed 2～5 hours.
3, the preparation method of a kind of cilnidipine used as dihydropyridine calcium antagonist according to claim 1 is characterized in that described cilnidipineb 1 crude product C
1～C
3The absolute alcohol recrystallization.
4,, it is characterized in that described absolute alcohol is anhydrous methanol, dehydrated alcohol or anhydrous isopropyl alcohol, content 99.5%-100% according to claim 2 or 3 described methods.
5, the preparation method of a kind of cilnidipine used as dihydropyridine calcium antagonist according to claim 1 is characterized in that described intermediate beta-amino Ba Dousuan cinnamic ester 5 is by in alcoholic solvent, and under the agitation condition, etheric acid cinnamic ester and ammonia gas react make;
6, method according to claim 5 is characterized in that described ammonia usage is 1～5 mol ratio, 0～5 ℃ of logical ammonia temperature, and the time is 2～5 hours; Alcohol is C
1～C
3Absolute alcohol, consumption 1.0～2.5 mol ratios; Temperature of reaction is 0～5 ℃, is incubated 5～8 hours.
7, method according to claim 6 is characterized in that described absolute alcohol is anhydrous methanol, dehydrated alcohol or anhydrous n-propyl alcohol; Content 99.5%-100%.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102391173A (en) * | 2011-09-20 | 2012-03-28 | 海南美兰史克制药有限公司 | Cilnidipine compound and preparation method thereof |
| CN102746217A (en) * | 2011-04-18 | 2012-10-24 | 张兆勇 | Method for purifying dihydropyridine calcium channel retarder and preparing nanoparticles thereof |
| CN104557679A (en) * | 2013-10-23 | 2015-04-29 | 丹阳恒安化学科技研究所有限公司 | Synthesis method of cilnidipine |
| CN105384682A (en) * | 2015-12-21 | 2016-03-09 | 芮城县虹桥药用中间体有限公司 | Cilnidipine preparation method |
| CN112375031A (en) * | 2020-11-18 | 2021-02-19 | 蚌埠丰原医药科技发展有限公司 | Preparation method of cilnidipine |
-
2008
- 2008-06-13 CN CNA200810038932XA patent/CN101602709A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746217A (en) * | 2011-04-18 | 2012-10-24 | 张兆勇 | Method for purifying dihydropyridine calcium channel retarder and preparing nanoparticles thereof |
| WO2012142927A1 (en) * | 2011-04-18 | 2012-10-26 | 合肥贝霓医药科技有限公司 | Method for purification of calcium channel blockers of dihydropyridine type and preparation of nanoparticles thereof |
| CN102391173A (en) * | 2011-09-20 | 2012-03-28 | 海南美兰史克制药有限公司 | Cilnidipine compound and preparation method thereof |
| CN102391173B (en) * | 2011-09-20 | 2012-11-21 | 海南美兰史克制药有限公司 | Cilnidipine compound and preparation method thereof |
| CN104557679A (en) * | 2013-10-23 | 2015-04-29 | 丹阳恒安化学科技研究所有限公司 | Synthesis method of cilnidipine |
| CN105384682A (en) * | 2015-12-21 | 2016-03-09 | 芮城县虹桥药用中间体有限公司 | Cilnidipine preparation method |
| CN105384682B (en) * | 2015-12-21 | 2018-04-20 | 芮城县虹桥药用中间体有限公司 | A kind of preparation method of Cilnidipine |
| CN112375031A (en) * | 2020-11-18 | 2021-02-19 | 蚌埠丰原医药科技发展有限公司 | Preparation method of cilnidipine |
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Open date: 20091216 |