CN103408483A - Calcium ion channels antagonist manidipine preparation method - Google Patents
Calcium ion channels antagonist manidipine preparation method Download PDFInfo
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- CN103408483A CN103408483A CN201310298963XA CN201310298963A CN103408483A CN 103408483 A CN103408483 A CN 103408483A CN 201310298963X A CN201310298963X A CN 201310298963XA CN 201310298963 A CN201310298963 A CN 201310298963A CN 103408483 A CN103408483 A CN 103408483A
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Abstract
The present invention provides a calcium ion channel antagonist manidipine preparation method, which comprises that: methyl 2-(3-nitrobenzylidene)acetoacetate 2 and beta-amino crotonic acid diphenylmethyl piperazine ethyl ester 3 are subjected to a cyclization reaction in an alcohol solvent to obtain a manidipine 1 crude product, and re-crystallization is performed to obtain the manidipine 1. The preparation method has advantages of short reaction period, simple synthesis route, less impurities in a reaction process, simple post-treatment, mild process conditions and the like, and is suitable for industrial production, wherein a yield is more than 68%.
Description
Technical field
The present invention relates to the medicine preparation, be specifically related to a kind of preparation method of dihydropyridine calcium ion two channels antagonist Manidipine.
Background technology
Raising along with socioeconomic development and people's living standard, cardiovascular disorder has become affects one of healthy principal disease of broad masses of the people, hypertension is the principal element of cardiovascular and cerebrovascular diseases death, the number that cardiovascular and cerebrovascular diseases is died from the whole world every year approximately 1,500 ten thousand, account for 30% of total death toll, to people's life and the threat greatly of life formation.According to relevant department, estimate, China more than 15 years old the Hypertension number reached 1.3 hundred million, by 2015, estimate also can increase more than 64%.Visible, antihypertensive medicine has huge market potential and good economical, societal benefits.
Manidipine (chemical name: 1,4-dihydro-2,6 dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid 2-[4-(diphenyl-methyl)-1-piperazinyl] the ethyl-methyl ester) be a kind of dihydropyridine class calcium ion two channels antagonist, nineteen ninety goes on the market in Japan with trade(brand)name Calslot.It is having its unique curative effect in treatment aspect hypertension, has that the hypotensive effect time is long, blood concentration is comparatively stable and to characteristics such as the blood vessel selectivity are strong, thereby becomes one of safety, efficient first-selected hypertension therapeutic medicine.
Traditional technology is general to be adopted and take 1-diphenyl-methyl-4-(2-hydroxyethyl) piperazine and be starting raw material; through with the ketene dimer acidylate, obtaining intermediate 2-(4-benzhydryl piperazidine) ethyl acetoacetic ester; the latter carries out ring-closure reaction with m-nitrobenzaldehyde, METHYL 3 AMINO CROTONATE again and obtains Manidipine, and yield is 45% left and right only.As patent EP94159, WO8304023, EP138505, CN201210097005.1, the synthetic of CV-4093 all described; The people such as Xiao Fangqing are at Chinese Journal of Pharmaceuticals 2004,35 (2): on 65-66, reported similar synthetic method.But, the method is in preparation process, intermediate 2-(4-benzhydryl piperazidine) ethyl acetoacetic ester that very difficult acquisition is purer, and, the impurity that this intermediate exists, as without separating directly and the substance reaction of back, can bring complicated byproduct to reaction product, and aftertreatment is had to higher requirement, generally must separate with column chromatography, thereby be not suitable for suitability for industrialized production.
Summary of the invention
The technical problem to be solved in the present invention is to overcome above-mentioned weak point, the Manidipine preparation method of an applicable suitability for industrialized production of design.
The invention provides a kind of preparation method of calcium-ion channel antagonists Manidipine.
Method of the present invention is: in alcoholic solvent, use 2-(3-oil of mirbane methylene radical) methyl acetoacetate 2 and beta-amino β-crotonic acid two
Phenmethyl piperazine ethyl ester 3 carries out ring-closure reaction, obtains Manidipine 1 crude product, and recrystallization obtains Manidipine 1 (its building-up reactions formula is shown in Fig. 1).
Described ring-closure reaction 2-(3-oil of mirbane methylene radical) methyl acetoacetate 2 is 1～1.7 with the mol ratio of beta-amino β-crotonic acid benzhydryl piperazidine ethyl ester 3; Alcohol is C
1～C
3Absolute alcohol: anhydrous methanol, dehydrated alcohol or anhydrous isopropyl alcohol; Reaction refluxed 2～5 hours.Manidipine 1 crude product can be with above-mentioned pure recrystallization.
Compound is for 2, No. CAS 39562-17-9, can be by commercially available acquisition.
Another object of the present invention has been to provide the preparation method of intermediate beta-amino β-crotonic acid benzhydryl piperazidine ethyl ester 3, the method is in inert solvent, the alkali of take is catalyzer, and (2-hydroxyethyl) piperazine of 1-diphenyl-methyl-4-under agitation condition (4) reacts and makes with beta-amino methyl crotonate (5).Described compound 4 and 5 mol ratio are 1～1.5; Temperature of reaction is 50 ℃～70 ℃; Reaction times is 3～7 hours; Catalyzer is sodium methylate, sodium ethylate or salt of wormwood etc.; Inert solvent is chloroform, benzene, toluene or dimethylbenzene.The building-up reactions equation of compound 3 is shown in Fig. 2.
The inventive method total recovery reaches more than 68%, and physico-chemical property and the document of products obtained therefrom Manidipine 1 are in full accord, its structure warp
1H NMR,
13C NMR and LC-MS authentication.
The invention has the beneficial effects as follows: have simple, the advantage such as reaction process impurity is few, aftertreatment is easy, processing condition are gentle of short, synthetic route reaction time, be applicable to suitability for industrialized production.
The accompanying drawing explanation
Fig. 1 is the synthetic of Manidipine (1).
Fig. 2 is the synthetic equation of intermediate (3).
Embodiment
For technique means, creation characteristic that the present invention is realized, reach purpose and effect is easy to understand, below in conjunction with specific embodiment, further set forth the present invention.
Embodiment 1
Prepare beta-amino β-crotonic acid benzhydryl piperazidine ethyl ester (3)
By beta-amino methyl crotonate (20g, 0.174mol) be dissolved in chloroform (100ml), add sodium methylate (11.28g, 0.209mol), under reflux conditions, drip 1-diphenyl-methyl-4-(2-hydroxyethyl) piperazine (77.17g, 0.260mmol) chloroform (50ml) solution, reflux 6h.Add water (50ml * 3) extraction, organic phase removes organic solvent under reduced pressure, adds the sherwood oil crystallization, obtains solid 55.10g, yield 83.58%.
Embodiment 2
Prepare beta-amino β-crotonic acid benzhydryl piperazidine ethyl ester (3)
By beta-amino methyl crotonate (20g, 0.174mol) be dissolved in toluene (100ml), add salt of wormwood (24.05g, 0.174mol), under 70 ℃, drip 1-diphenyl-methyl-4-(2-hydroxyethyl) piperazine (56.68g, 0.191mmol) toluene (50ml) solution, the insulation 4h.Remove solvent under reduced pressure, water (300ml) and methylene dichloride (80ml * 3) extraction, merge organic phase, and dry, steaming adds the sherwood oil crystallization except the organic solvent products therefrom, obtains solid 52.66g, yield 79.88%.
Embodiment 3
Prepare beta-amino β-crotonic acid benzhydryl piperazidine ethyl ester (3)
By beta-amino methyl crotonate (20g, 0.174mol) be dissolved in toluene (100ml), add sodium methylate (11.28g, 0.209mol), under 60 ℃, drip 1-diphenyl-methyl-4-(2-hydroxyethyl) piperazine (51.53g, 0.174mmol) toluene (50ml) solution, the insulation 4h.Remove solvent under reduced pressure, water (150ml) and methylene dichloride (50ml * 3) extraction, merge organic phase, and dry, steaming adds the sherwood oil crystallization except the organic solvent products therefrom, obtains solid 53.89g, yield 81.75%.
Embodiment 4
Prepare Manidipine (1)
Get 3 (50g, 0.132mol), anhydrous methanol (120ml) and 2 (36.11g, 0.145mol) add in reaction flask, backflow 3h, 4 ℃ of cool overnight, filter the gained filter cake and obtain 70.17g white solid 1 by the 90mL recrystallizing methanol, yield is 87.21%, mp126.1 ℃～126.5 ℃.
Embodiment 5
Prepare Manidipine (1)
Get 3 (50g, 0.132mol), dehydrated alcohol (150ml) and 2 (36.11g, 0.145mol) add in reaction flask, backflow 3h, 4 ℃ of cool overnight, filter the gained filter cake and obtain 69.32g white solid 1 with the 90mL ethyl alcohol recrystallization, yield is 86.16%, mp125.3 ℃～126.2 ℃.
Embodiment 6
Prepare Manidipine (1)
Get 3 (50g, 0.132mol), anhydrous isopropyl alcohol (100ml) and 2 (36.11g, 0.145mol) add in reaction flask, backflow 3h, 4 ℃ of cool overnight, filter the gained filter cake and obtain 71.54g white solid 1 with 75mL Virahol alcohol recrystallization, yield is 88.91%, mp125.6 ℃～126.5 ℃.
Above are only part embodiment of the present invention, only as explanation of the present invention is not produced to restriction to the present invention.
Claims (6)
1. the preparation method of a calcium-ion channel antagonists Manidipine, the method is: with 2-(3-oil of mirbane methylene radical) methyl acetoacetate 2 and beta-amino β-crotonic acid benzhydryl piperazidine ethyl ester 3, carry out ring-closure reaction in alcoholic solvent, obtain Manidipine 1 crude product, recrystallization obtains Manidipine 1.
2. the preparation method of a kind of calcium-ion channel antagonists Manidipine according to claim 1, is characterized in that described ring-closure reaction 2-(3-oil of mirbane methylene radical) methyl acetoacetate 2 and the mol ratio of beta-amino β-crotonic acid benzhydryl piperazidine ethyl ester 3 are 1～1.7; Alcohol is C
1～C
3Absolute alcohol; Reaction refluxed 2～5 hours.
3. the preparation method of a kind of calcium-ion channel antagonists Manidipine according to claim 1, is characterized in that described Manidipine crude product C
1～C
3The absolute alcohol recrystallization.
4. according to claim 2 and 3 described methods, it is characterized in that described absolute alcohol or alcohol are methyl alcohol, ethanol or Virahol.
5. the preparation method of a kind of calcium-ion channel antagonists Manidipine according to claim 1, it is characterized in that described intermediate beta-amino β-crotonic acid benzhydryl piperazidine ethyl ester 3 is by inert solvent, the alkali of take is catalyzer, and (2-hydroxyethyl) piperazine of 1-diphenyl-methyl-4-under agitation condition (4) reacts and makes with beta-amino methyl crotonate (5).
6. method according to claim 5, the mol ratio that it is characterized in that described compound 4 and 5 is 1～1.5; Temperature of reaction is 50 ℃～70 ℃; Reaction times is 3～7 hours; Catalyzer is sodium methylate, sodium ethylate or salt of wormwood etc.; Inert solvent is chloroform, benzene, toluene or dimethylbenzene.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106380442A (en) * | 2016-09-07 | 2017-02-08 | 张家港威胜生物医药有限公司 | Preparation method of calcium ion channel antagonist manidipine |
| CN108218765A (en) * | 2017-11-24 | 2018-06-29 | 扬子江药业集团北京海燕药业有限公司 | A kind of production method for improving manidipine hydrochloride II crystal forms |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4894460A (en) * | 1982-06-03 | 1990-01-16 | Pierrel S.P.A. | Basic esters exhibiting an antagonistic activity to calcium, process for the preparation thereof and pharmaceutical compositions therefrom |
| CN1041939A (en) * | 1987-11-04 | 1990-05-09 | 拜尔公司 | New fluorine methoxyphenyl dihydropyridine, its preparation method and its application aspect medicine |
| JP2005289894A (en) * | 2004-03-31 | 2005-10-20 | Konica Minolta Chemical Co Ltd | Preparation method for dihydropyridine derivative |
-
2013
- 2013-07-17 CN CN201310298963XA patent/CN103408483A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4894460A (en) * | 1982-06-03 | 1990-01-16 | Pierrel S.P.A. | Basic esters exhibiting an antagonistic activity to calcium, process for the preparation thereof and pharmaceutical compositions therefrom |
| CN1041939A (en) * | 1987-11-04 | 1990-05-09 | 拜尔公司 | New fluorine methoxyphenyl dihydropyridine, its preparation method and its application aspect medicine |
| JP2005289894A (en) * | 2004-03-31 | 2005-10-20 | Konica Minolta Chemical Co Ltd | Preparation method for dihydropyridine derivative |
Non-Patent Citations (2)
| Title |
|---|
| KANJI MEGURO等: "New 1,4-Dihydropyridine Derivative with Potent and Long-Lasting Hypotensive Effect", 《CHEM. PHARM. BULL.》 * |
| 王庆军等: "酯交换法制备甲基丙烯酸类酯催化剂研究进展", 《精细石油化工进展》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106380442A (en) * | 2016-09-07 | 2017-02-08 | 张家港威胜生物医药有限公司 | Preparation method of calcium ion channel antagonist manidipine |
| CN108218765A (en) * | 2017-11-24 | 2018-06-29 | 扬子江药业集团北京海燕药业有限公司 | A kind of production method for improving manidipine hydrochloride II crystal forms |
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Application publication date: 20131127 |