CN106518806A - Preparation method for manidipine intermediate 2-(4-diphenylmethyl piperazine)ethyl acetoacetate - Google Patents
Preparation method for manidipine intermediate 2-(4-diphenylmethyl piperazine)ethyl acetoacetate Download PDFInfo
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- CN106518806A CN106518806A CN201610806254.1A CN201610806254A CN106518806A CN 106518806 A CN106518806 A CN 106518806A CN 201610806254 A CN201610806254 A CN 201610806254A CN 106518806 A CN106518806 A CN 106518806A
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- benzhydryl
- ethyl
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- piperazine
- manidipine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Abstract
The invention discloses a preparation method for a manidipine intermediate 2-(4-diphenylmethyl piperazine)ethyl acetoacetate, wherein the method comprises the following specific processes: adding an alkali catalyst into a reaction vessel containing an organic solvent, heating to make the temperature rise to 60-90 DEG C, then dissolving 1-diphenylmethyl-4-(2-hydroxyethyl)piperazine with trichloromethane, dropwise adding the dissolved 1-diphenylmethyl-4-(2-hydroxyethyl)piperazine into the reaction vessel, dropwise adding ethyl acetoacetate while stirring, carrying out heat preservation reaction until the reaction is completed, and carrying out reduced pressure concentration, extraction and purification of the reaction solution to obtain 2-(4-diphenylmethyl piperazine)ethyl acetoacetate. The method has the advantages of mild and safe whole reaction process and less impurity, the purity of the obtained product is as high as 99.5% or more, the yield is 99% or more, and the method is suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation of chemical intermediate, and in particular to a kind of manidipine intermediate 2- (4- hexichol first
Base piperazine) ethyl acetoacetic ester preparation method.
Background technology
Manidipine is widely used in cardiovascular disease, and its hydrochlorate is dihydropyridine calcium ion dual pathways antagonism of new generation
Agent, clinical effectiveness are good, and hypotensive effect is notable.But preparing CV-4093 intermediate 2- (4- benzhydryl piperazidines) ethyl
Exist during acetoacetic ester pollution environment and the difficult storage of raw material, explosive and have influence on large-scale industrial production.
Traditional handicraft is typically adopted with 1- benzhydryl -4- (2- ethoxys) piperazine as initiation material, is passed through and double ethylene
Keto acyl obtains intermediate 2- (4- benzhydryl piperazidines) ethyl acetoacetic ester.As patent EP94159, WO8304023,
EP138505, CN201210097005.1, US4603135A all describe the synthesis of CV-4093, are related to the conjunction of intermediate
Into；Xiao Fangqing et al. is in Chinese Journal of Pharmaceuticals 2004,35 (2):Similar synthetic method is reported on 65-66.It is this
Traditional preparation technology is big due to raw material ketene dimer toxicity, with extremely strong tearing property, and 33.89 DEG C of its flash-point, cause
The slightly higher danger for just easily occurring to explode of temperature, difficult control, so that the difficult operation of industrialization, is to solve above-mentioned technical problem,
A kind of preparation method of 2- (4- benzhydryl piperazidines) ethyl acetoacetic ester is provided in application number 2013102381412, but
It is that its reaction yield is still less high.
The content of the invention
It is an object of the invention to provide a kind of manidipine intermediate 2- (4- benzhydryl piperazidines) ethyl acetoacetic ester
Preparation method, the preparation process is simple and environmentally-friendly, safe, and high income is suitable to industrialized production.
For reaching above-mentioned purpose, the technical solution used in the present invention is：A kind of manidipine intermediate 2- (4- benzhydryls
Piperazine) ethyl acetoacetic ester preparation method, the method detailed process is as follows：
Base catalyst is added in the reaction vessel equipped with organic solvent, 60 ~ 90 DEG C is heated to, then using chloroform
By 1- benzhydryl -4- (2- ethoxys) piperazine dissolved, 1- benzhydryl -4- (2- ethoxys) piperazine after dissolving is added drop-wise to
In reaction vessel, agitation and dropping ethyl acetoacetate, insulation reaction are complete to reaction, reactant liquor Jing concentrating under reduced pressure, extraction, purification
2- (4- benzhydryl piperazidines) ethyl acetoacetic ester is obtained, wherein, described base catalyst is solid sodium hydroxide, described
Organic solvent is chloroform, in course of reaction, described base catalyst, ethyl acetoacetate, 1- benzhydryl -4- (2- hydroxyls
Ethyl) molar ratio of piperazine is：1~1.5:1~2:1.
Preferably, in the course of reaction, described base catalyst, ethyl acetoacetate, 1- benzhydryl -4- (2- hydroxyls
Ethyl) molar ratio of piperazine is：1.5:1.5:1.
Preferably, described reaction is carried out in 70 ~ 80 DEG C of organic solvent.
Preferably, upon reaction completion, reactant liquor merges organic faciess Jing after concentrating under reduced pressure, extraction, is dried, is concentrated to give
Grease, is then dissolved in grease in ethyl acetate, is then passed through hydrogen chloride gas, stirring and crystallizing, and it is solid that sucking filtration obtains white
Body, then by white solid water dissolution, agitation and dropping concentration is 25 ~ 30% sodium hydroxide solution, to system pH up to 9 ~ 9.5,
1 ~ 2h is placed under the conditions of 0 DEG C, sucking filtration, is dried to obtain sterling 2- (4- benzhydryl piperazidines) ethyl acetoacetic ester.
Due to the utilization of above-mentioned technical proposal, the present invention has following advantages compared with prior art：The horse Buddhist nun of the present invention
The preparation method of Horizon intermediate 2- (4- benzhydryl piperazidines) ethyl acetoacetic ester, which employs solid sodium hydroxide conduct
Catalyst, and chloroform is employed as organic solvent so that safer, gentle, the obtained 2- of whole course of reaction
(4- benzhydryl piperazidines) ethyl acetoacetic ester product purity is high, and up to more than 99.5%, yield is up to more than 99%.
Specific embodiment
Technical scheme is further elaborated with reference to specific embodiment.It should be understood that these enforcements
Example is for illustrating the basic principles, principal features and advantages of the present invention, and the present invention is not limited by the following examples.Embodiment
The implementation condition of middle employing can be done according to specific requirement and further adjust, and not marked implementation condition is usually in normal experiment
Condition.Embodiment is raw materials used to be industrial goods.
Embodiment 1
This example provides the preparation method of a kind of manidipine intermediate 2- (4- benzhydryl piperazidines) ethyl acetoacetic ester, its
Step is as follows：
1）The chloroform of 300ml is added in the reactor of 500ml, then adds 13.5g（0.337mol）Solid hydroxide
Sodium, is heated to 70 DEG C, then using chloroform by 100g（0.337mol）1- benzhydryl -4- (2- ethoxys) piperazine
Dissolving, stirs 30min, Deca 65.75g（0.505mol）Ethyl acetoacetate, insulation reaction 5 hours；
2）By the reactant liquor of gained Jing after concentrating under reduced pressure, ethyl acetate is used（500mL×3）Extracted with saturated aqueous common salt, closed
And organic faciess, it is dried, is concentrated to give grease, the grease for obtaining is dissolved in 600 mL ethyl acetate, then leads to hydrogen chloride
Gas, stirring and crystallizing, sucking filtration obtain white solid；
3）Gained white solid is dissolved in the water of 20 times of volumes, under stirring condition, Deca concentration is 25% sodium hydroxide solution
To pH up to 9,0 DEG C is placed sucking filtration, dry 127.50 g manidipine intermediates 2- (4- benzhydryl piperazidines) after a period of time
Ethyl acetoacetic ester（Yield：99.44%, HPLC purity is 99.5%）.
Embodiment 2
This example provides the preparation method of a kind of manidipine intermediate 2- (4- benzhydryl piperazidines) ethyl acetoacetic ester, its
Step is as follows：
1）The chloroform of 600ml is added in the reactor of 1000ml, then adds 40.4g（1.011mol）Solid hydroxide
Sodium, is heated to 80 DEG C, then using chloroform by 200g（0.674mol）1- benzhydryl -4- (2- ethoxys) piperazine
Dissolving, stirs 30min, Deca 131.5g（1.011mol）Ethyl acetoacetate, insulation reaction 5 hours；
2）By the reactant liquor of gained Jing after concentrating under reduced pressure, ethyl acetate is used（800mL×3）Extracted with saturated aqueous common salt, closed
And organic faciess, it is dried, is concentrated to give grease, the grease for obtaining is dissolved in 600 mL ethyl acetate, then leads to hydrogen chloride
Gas, stirring and crystallizing, sucking filtration obtain white solid；
3）Gained white solid is dissolved in the water of 20 times of volumes, under stirring condition, Deca concentration is 30% sodium hydroxide solution
To pH up to 9.5,0 DEG C is placed sucking filtration, dry 255.45g manidipine intermediates 2- (4- benzhydryl piperazidines) after a period of time
Ethyl acetoacetic ester（Yield：99.61%, HPLC purity is 99.8%）.
Embodiment 3
This example provides the preparation method of a kind of manidipine intermediate 2- (4- benzhydryl piperazidines) ethyl acetoacetic ester, its
Step is as follows：
1）The chloroform of 300ml is added in the reactor of 500ml, then adds 16.17g（0.404mol）Solid hydroxide
Sodium, is heated to 70 DEG C, then using chloroform by 100g（0.337mol）1- benzhydryl -4- (2- ethoxys) piperazine
Dissolving, stirs 30min, Deca 87.67g（0.674mol）Ethyl acetoacetate, insulation reaction 5 hours；
2）By the reactant liquor of gained Jing after concentrating under reduced pressure, ethyl acetate is used（500mL×3）Extracted with saturated aqueous common salt, closed
And organic faciess, it is dried, is concentrated to give grease, the grease for obtaining is dissolved in 600 mL ethyl acetate, then leads to hydrogen chloride
Gas, stirring and crystallizing, sucking filtration obtain white solid；
3）Gained white solid is dissolved in the water of 20 times of volumes, under stirring condition, Deca concentration is 25% sodium hydroxide solution
To pH up to 9.5,0 DEG C is placed sucking filtration, dry 127.72 g manidipine intermediates 2- (4- benzhydryl piperazines after a period of time
Piperazine) ethyl acetoacetic ester（Yield：99.60%, HPLC purity is 99.6%）.
Above-described embodiment technology design only to illustrate the invention and feature, its object is to allow person skilled in the art's energy
Solution present disclosure much of that is simultaneously carried out, and can not be limited the scope of the invention with this, all according to spirit of the invention
Equivalence changes or modification that essence is made, should all cover within the scope of the present invention.
Claims (4)
1. a kind of preparation method of manidipine intermediate 2- (4- benzhydryl piperazidines) ethyl acetoacetic ester, its feature exist
In the method detailed process is as follows：
Base catalyst is added in the reaction vessel equipped with organic solvent, 60 ~ 90 DEG C is heated to, then using chloroform
By 1- benzhydryl -4- (2- ethoxys) piperazine dissolved, 1- benzhydryl -4- (2- ethoxys) piperazine after dissolving is added drop-wise to
In reaction vessel, agitation and dropping ethyl acetoacetate, insulation reaction are complete to reaction, reactant liquor Jing concentrating under reduced pressure, extraction, purification
2- (4- benzhydryl piperazidines) ethyl acetoacetic ester is obtained, wherein, described base catalyst is solid sodium hydroxide, described
Organic solvent is chloroform, in course of reaction, described base catalyst, ethyl acetoacetate, 1- benzhydryl -4- (2- hydroxyls
Ethyl) molar ratio of piperazine is：1~1.5:1~2:1.
2. the preparation of manidipine intermediate 2- (4- benzhydryl piperazidines) ethyl acetoacetic ester according to claim 1
Method, it is characterised in that in the course of reaction, described base catalyst, ethyl acetoacetate, 1- benzhydryl -4- (2- hydroxyls
Ethyl) molar ratio of piperazine is：1.5:1.5:1.
3. the preparation of manidipine intermediate 2- (4- benzhydryl piperazidines) ethyl acetoacetic ester according to claim 1
Method, it is characterised in that described reaction is carried out in 70 ~ 80 DEG C of organic solvent.
4. the preparation of manidipine intermediate 2- (4- benzhydryl piperazidines) ethyl acetoacetic ester according to claim 1
Method, it is characterised in that upon reaction completion, reactant liquor merge organic faciess Jing after concentrating under reduced pressure, extraction, are dried, are concentrated to give
Grease, is then dissolved in grease in ethyl acetate, is then passed through hydrogen chloride gas, stirring and crystallizing, and it is solid that sucking filtration obtains white
Body, then by white solid water dissolution, agitation and dropping concentration is 25 ~ 30% sodium hydroxide solution, to system pH up to 9 ~ 9.5,
1 ~ 2h is placed under the conditions of 0 DEG C, sucking filtration, is dried to obtain sterling 2- (4- benzhydryl piperazidines) ethyl acetoacetic ester.
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| CN201610806254.1A CN106518806A (en) | 2016-09-07 | 2016-09-07 | Preparation method for manidipine intermediate 2-(4-diphenylmethyl piperazine)ethyl acetoacetate |
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| CN201610806254.1A CN106518806A (en) | 2016-09-07 | 2016-09-07 | Preparation method for manidipine intermediate 2-(4-diphenylmethyl piperazine)ethyl acetoacetate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0094159A1 (en) * | 1982-05-10 | 1983-11-16 | Takeda Chemical Industries, Ltd. | Dihydropyridine derivatives, their production and use |
| CN103351362A (en) * | 2013-06-17 | 2013-10-16 | 张家港威胜生物医药有限公司 | Preparation method of manidipine intermediate 2-(4-diphenylmethyl piperazinyl)ethyl acetoacetate |
-
2016
- 2016-09-07 CN CN201610806254.1A patent/CN106518806A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0094159A1 (en) * | 1982-05-10 | 1983-11-16 | Takeda Chemical Industries, Ltd. | Dihydropyridine derivatives, their production and use |
| CN103351362A (en) * | 2013-06-17 | 2013-10-16 | 张家港威胜生物医药有限公司 | Preparation method of manidipine intermediate 2-(4-diphenylmethyl piperazinyl)ethyl acetoacetate |
Non-Patent Citations (2)
| Title |
|---|
| TAAKASHI KOBAYAHI ET AL.: "Novel 2-amino-1,4-dihydropyridine calcium antagonists. II. Synthesis and antihypertensive effects of 2-amino-1,4-dihydropyridine derivatives having N,N-dialkylaminoalkoxycarbonyl groups at 3- and/or 5-position", 《CHEM.PHARM.BULL.》 * |
| 肖方青等: "盐酸马尼地平的合成", 《中国医药工业杂志》 * |
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