CN101638379A - Preparation method for dihydropyridine type compound - Google Patents
Preparation method for dihydropyridine type compound Download PDFInfo
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- CN101638379A CN101638379A CN200910063677A CN200910063677A CN101638379A CN 101638379 A CN101638379 A CN 101638379A CN 200910063677 A CN200910063677 A CN 200910063677A CN 200910063677 A CN200910063677 A CN 200910063677A CN 101638379 A CN101638379 A CN 101638379A
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Abstract
The invention relates to a preparation method for dihydropyridine type compound and relates to a preparation method for dihydropyridine type compound. The preparation method is as follows: (I) is prepared by the cyclization reaction of compound in general formula (III) and 2, 3-dichlor benzal etheric acid methyl ester (IV), and reaction formula is as above; the (1) compound prepared by the preparation method has high compound yield, few amount of waste gas, waste water and industrial residue and high purity; the preparation method successfully realizes the industrialization production and is economical, effective, environmental and has good industrialization production value.
Description
Technical field:
The invention belongs to the chemical pharmaceutical technical field, relate to a kind of preparation method of dihydropyridine compounds.
Background technology:
Butyrate clevidipine (clevidipine butyrate) is a kind of fugitive dihydropyridine calcium channel blocker.The butyrate clevidipine used for intravenous injection emulsion (Cleviprex) that U.S. FDA is ratified The Medicines Company company in August, 2008 goes on the market, and is used for the invalid hyperpietic's of unsuitable oral pharmaceutical or oral pharmaceutical treatment.This medicine is the first novel used for intravenous injection antihypertensive drug of drugs approved by FDA over 10 years.
In the prior art, U.S. Pat 5856346 discloses the synthetic method of butyrate clevidipine (VI).6350877 pairs of these synthetic methods of U.S. Pat are improved, and it is with 4-(2 ', 3 '-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-dinicotinic acid-(2-cyano group second) methyl esters (formula V) is a raw material, obtain butyrate clevidipine through hydrolysis, condensation, its reaction formula is as follows:
Summary of the invention
Purpose of the present invention is exactly the defective at prior art, and a kind of preparation method of dihydropyridine compounds is provided, and more specifically provides a kind of fugitive dihydropyridine compounds butyrate clevidipine intermediates preparation.
The present invention is by following general formula (III) compound and 2, and 3-dichlorin benzylidene methyl acetoacetate (IV) the cyclization prepared in reaction takes place obtains (I), and its reaction formula is as follows:
The present invention is better, and concrete technical scheme is: be starting raw material with the ketene dimer, prepare through addition, amination, ring-closure reaction, total recovery 50～65%.Its preparation method is following steps:
A. addition: with the ketene dimer is starting raw material, through compound shown in the addition production (II);
B. amination: formula (II) compound need not purifying, and directly amination obtains compound shown in the formula (III);
C. cyclization: formula (III) compound and 2, ring-closure reaction takes place in 3-dichlorin benzylidene methyl acetoacetate (IV), obtains compound shown in the formula (I).
Its reaction formula is as follows:
More than in all structural formulas, n is 0 to 6 integer, R is the H atom, halogen contains alkyl, alkoxyl group, halo alkyl or the phenyl ring of 1 to 5 carbon atom.
For example:
Work as n=1, R is the H atomic time, and (I) compound is 4-(2 ', 3 '-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-dinicotinic acid-(2-cyano group second) methyl esters (formula V), and (V) be the preparation fugitive dihydropyridine compounds butyrate clevidipine intermediate.
Work as n=0, R is the H atomic time, and (I) compound is a compound shown in the formula (VII).
Work as n=2, R is the chlorine atomic time, and (I) compound is a compound shown in the formula (VIII).
Work as n=4, R is-OCH
3The time, (I) compound is a compound shown in the formula (IX).
Work as n=2, R is-CH
2CH
2During Cl, (I) compound is a compound shown in the formula (X).
Work as n=3, R is
The time, (I) compound is a compound shown in the formula (XI).
Among the preparation method of the present invention, starting raw material general formula (III) compound and 2 of cyclization step, the mol ratio of 3-dichlorin benzylidene methyl acetoacetate (IV) is 1: 0.95～2.0, preferred 1: 1～1.8.
Among the preparation method of the present invention, cyclization step is to carry out in being selected from alcoholic solvent, particular methanol, ethanol or Virahol.The bulking value proportioning of general formula (III) compound and alcoholic solvent is 1: 3～12, and the preferred weight volume proportion is 1: 4～9, and the volume that adds alcoholic solvent in promptly every gram (III) compound is 3～12mL.
Among the preparation method of the present invention, cyclization step return time 3-10 hour.
The most preferred technical scheme of the present invention is: described ring-closure reaction is by the amino Ba Dousuan of 3--(2-cyano group) ethyl ester and 2,3-dichlorin benzylidene methyl acetoacetate carries out ring-closure reaction, prepare 4-(2 ', 3 '-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-dinicotinic acid-(2-cyano group second) methyl esters.
Prepared formula (I) compound H PLC purity is greater than 99.0% according to the present invention, product yield 75～95%.(I) compound yield height that preparation method of the present invention obtains, quantity of three wastes is few, the product purity height, and successfully realized suitability for industrialized production, and be a kind of economy, efficient, environmental protection, have the preparation method that good suitability for industrialized production is worth.
Embodiment
The following example is used for further narrating the present invention, but it is not any restriction to scope of the present invention.
The content and the purity testing of formula (I) compound are measured on the HP1100 high performance liquid chromatograph.
Embodiment 1:
It is to be starting raw material with the ketene dimer, prepares through addition, amination, ring-closure reaction, and its preparation method is following steps:
A. addition: with the ketene dimer is starting raw material, through compound shown in the addition production (II);
B. amination: the direct amination of formula (II) compound obtains compound shown in the formula (III);
C. cyclization: formula (III) compound and 2, ring-closure reaction takes place in 3-dichlorin benzylidene methyl acetoacetate (IV), obtains compound shown in the formula (I).Its reaction formula is as follows:
Step a and b are that therefore typical chemical reaction is not given unnecessary details, and ring-closure reaction is specific as follows:
The amino Ba Dousuan of 3--(2-cyano group) ethyl ester (7g, 45.4mmol) with 2,3-dichlorin benzylidene methyl acetoacetate (13g, 47.6mmol) join in the Virahol (50mL), back flow reaction 5～6 hours, faint yellow solid is separated out in cooling, filter, drying gets product (15.8g, 38.6mmol), be 4-(2 ', 3 '-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-dinicotinic acid-(2-cyano group second) methyl esters (V), HPLC purity 99.13%, yield 85.03%.
Embodiment 2:
Step a and b are typical chemical reaction, and with embodiment 1, ring-closure reaction is specific as follows:
The amino Ba Dousuan of 3--(2-cyano group) ethyl ester (32.4g, 0.210mol) and 2, (67.7g 0.248mol) joins in the methyl alcohol (200mL) 3-dichlorin benzylidene methyl acetoacetate, back flow reaction 8 hours, faint yellow solid is separated out in cooling, filters drying, get (V) product (77.5g, 0.189mol), HPLC purity 99.36%, yield 90.11%.
Embodiment 3:
Step a and b are typical chemical reaction, and with embodiment 1, ring-closure reaction is specific as follows:
The amino Ba Dousuan of 3--(2-cyano group) methyl esters (14.0g, 0.100mol) and 2, (34.0g 0.125mol) joins in the Virahol (100mL) 3-dichlorin benzylidene methyl acetoacetate, back flow reaction 6 hours, faint yellow solid is separated out in cooling, filters drying, get (VII) product (34.7g, 0.0878mol), HPLC purity 99.28%, yield 87.85%.
Embodiment 4:
Step a and b are typical chemical reaction, and with embodiment 1, ring-closure reaction is specific as follows:
The amino Ba Dousuan of 3--(2-cyano group) ethyl ester (20.5g, 0.133mol) and 2, (50.8g 0.186mol) joins in the ethanol (160mL) 3-dichlorin benzylidene methyl acetoacetate, back flow reaction 5 hours, faint yellow solid is separated out in cooling, filters drying, get (V) product (45.1g, 0.110mol), HPLC purity 99.24%, yield 82.69%.
Embodiment 5:
Step a and b are typical chemical reaction, and with embodiment 1, ring-closure reaction is specific as follows:
The amino Ba Dousuan of 3--(2-cyano group) ethyl ester 20kg and 2,3-dichlorin benzylidene methyl acetoacetate 42kg joins among the Virahol 115kg, back flow reaction 7 hours, faint yellow solid is separated out in cooling, and is centrifugal, drying, get (V) product 47kg, HPLC purity 99.17%, yield 88.53%.
Embodiment 6:
Step a and b are typical chemical reaction, and with embodiment 1, ring-closure reaction is specific as follows:
The amino Ba Dousuan of 3--(2-cyano group) methyl esters 56kg and 2,3-dichlorin benzylidene methyl acetoacetate 140kg joins among the methyl alcohol 320kg, back flow reaction 8 hours, faint yellow solid is separated out in cooling, and is centrifugal, drying, get (VII) product 142kg, HPLC purity 99.19%, yield 89.87%.
Embodiment 7:
Step a and b are typical chemical reaction, and with embodiment 1, ring-closure reaction is specific as follows:
The amino Ba Dousuan of 3--(2-cyano group) ethyl ester 36kg and 2,3-dichlorin benzylidene methyl acetoacetate 64kg joins among the methyl alcohol 150kg, back flow reaction 5 hours, faint yellow solid is separated out in cooling, and is centrifugal, drying, get (V) product 77.4kg, HPLC purity 99.06%, yield 80.99%.
Embodiment 8:
Step a and b are typical chemical reaction, and with embodiment 1, ring-closure reaction is specific as follows:
The amino Ba Dousuan of 3--(2-cyano group) ethyl ester 150kg and 2,3-dichlorin benzylidene methyl acetoacetate 400kg joins among the ethanol 900kg, back flow reaction 8 hours, faint yellow solid is separated out in cooling, and is centrifugal, drying, get (V) product 367kg, HPLC purity 99.41%, yield 92.17%.
Claims (7)
1, a kind of preparation method of dihydropyridine compounds, it is by following general formula (III) compound and 2, and the cyclization prepared in reaction takes place and obtains (I) in 3-dichlorin benzylidene methyl acetoacetate (IV), and its reaction formula is as follows:
2, the preparation method of a kind of dihydropyridine compounds according to claim 1, it is to be starting raw material with the ketene dimer, prepares through addition, amination, ring-closure reaction, its preparation method is following steps:
A. addition: with the ketene dimer is starting raw material, through compound shown in the addition production (II);
B. amination: the direct amination of formula (II) compound obtains compound shown in the formula (III);
C. cyclization: formula (III) compound and 2, ring-closure reaction takes place in 3-dichlorin benzylidene methyl acetoacetate (IV), obtains compound shown in the formula (I).
Its reaction formula is as follows:
Wherein, n is 0 to 6 integer, and R is the H atom, and halogen contains alkyl, alkoxyl group, halo alkyl or the phenyl ring of 1 to 5 carbon atom.
3, the preparation method of a kind of dihydropyridine compounds according to claim 1 and 2, general formula (III) compound and 2 during ring-closure reaction wherein, the mol ratio of 3-dichlorin benzylidene methyl acetoacetate (IV) reaction is 1: 0.95～2.0.
4, the preparation method of a kind of dihydropyridine compounds according to claim 3, wherein said ring-closure reaction is to carry out in alcoholic solvent.
5, the preparation method of a kind of dihydropyridine compounds according to claim 3, wherein said alcoholic solvent is methyl alcohol, ethanol or Virahol.
6, the preparation method of a kind of dihydropyridine compounds according to claim 3, the weightmeasurement ratio of wherein said ring-closure reaction formula of (III) compound and alcoholic solvent is 1: 3～12.
7, the preparation method of a kind of dihydropyridine compounds according to claim 3, wherein said ring-closure reaction is by the amino Ba Dousuan of 3--(2-cyano group) ethyl ester and 2,3-dichlorin benzylidene methyl acetoacetate carries out ring-closure reaction, prepare 4-(2 ', 3 '-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-dinicotinic acid-(2-cyano group second) methyl esters.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103073485A (en) * | 2013-01-17 | 2013-05-01 | 北京嘉林药业股份有限公司 | Preparation method for clevidipine butyrate |
| CN103242220A (en) * | 2012-02-08 | 2013-08-14 | 上海医药工业研究院 | Preparation method of clevidipine butyrate |
| CN103420899A (en) * | 2012-05-25 | 2013-12-04 | 四川科伦药物研究有限公司 | Purification method of clevidipine butyrate |
| CN105367487A (en) * | 2014-08-23 | 2016-03-02 | 南京海纳医药科技有限公司 | Novel synthesis method of clevidipine butyrate important intermediate |
| CN105461619A (en) * | 2015-12-10 | 2016-04-06 | 合肥久诺医药科技有限公司 | Method for preparing high-purity cleviprex |
| CN107389843A (en) * | 2017-07-29 | 2017-11-24 | 黑龙江谱尼测试科技有限公司 | The detection method of dihydropyridine in a kind of feed |
-
2009
- 2009-08-21 CN CN200910063677A patent/CN101638379A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103242220A (en) * | 2012-02-08 | 2013-08-14 | 上海医药工业研究院 | Preparation method of clevidipine butyrate |
| CN103242220B (en) * | 2012-02-08 | 2016-03-09 | 上海医药工业研究院 | The preparation method of butyrate clevidipine |
| CN103420899A (en) * | 2012-05-25 | 2013-12-04 | 四川科伦药物研究有限公司 | Purification method of clevidipine butyrate |
| CN103420899B (en) * | 2012-05-25 | 2016-01-27 | 四川科伦药物研究有限公司 | A kind of purification process of butyrate clevidipine |
| CN103073485A (en) * | 2013-01-17 | 2013-05-01 | 北京嘉林药业股份有限公司 | Preparation method for clevidipine butyrate |
| CN105367487A (en) * | 2014-08-23 | 2016-03-02 | 南京海纳医药科技有限公司 | Novel synthesis method of clevidipine butyrate important intermediate |
| CN105461619A (en) * | 2015-12-10 | 2016-04-06 | 合肥久诺医药科技有限公司 | Method for preparing high-purity cleviprex |
| CN105461619B (en) * | 2015-12-10 | 2019-01-25 | 合肥久诺医药科技有限公司 | A kind of preparation method of butyrate clevidipine |
| CN107389843A (en) * | 2017-07-29 | 2017-11-24 | 黑龙江谱尼测试科技有限公司 | The detection method of dihydropyridine in a kind of feed |
| CN107389843B (en) * | 2017-07-29 | 2020-03-31 | 黑龙江谱尼测试科技有限公司 | Method for detecting dihydropyridine in feed |
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Application publication date: 20100203 |