CN102766137B - Method for preparing high-purity isradipine - Google Patents
Method for preparing high-purity isradipine Download PDFInfo
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- CN102766137B CN102766137B CN201210278518.2A CN201210278518A CN102766137B CN 102766137 B CN102766137 B CN 102766137B CN 201210278518 A CN201210278518 A CN 201210278518A CN 102766137 B CN102766137 B CN 102766137B
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- YHARUZIVZSIUQD-UHFFFAOYSA-N CC(C)=[O]C(C(C1c2cccc3n[o]nc23)=C(C)NC(C)=C1C(OC)=O)=O Chemical compound CC(C)=[O]C(C(C1c2cccc3n[o]nc23)=C(C)NC(C)=C1C(OC)=O)=O YHARUZIVZSIUQD-UHFFFAOYSA-N 0.000 description 1
- YBBRQAXNTWMMFZ-UHFFFAOYSA-N O=Cc1cccc2n[o]nc12 Chemical compound O=Cc1cccc2n[o]nc12 YBBRQAXNTWMMFZ-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a method for preparing high-purity isradipine. The method includes dehydrating and condensating 4-formaldehyde benzofuroxan in atent solvent to form 2-acetyl-3-benzofuroxan-4-base-isopropyl acrylate; subjecting methyl acetoacetate to ammonolysis to form 3-amino crotonic acid methyl ester; subjecting 2-acetyl-3-benzofuroxan-4-base-isopropyl acrylate and 3-amino crotonic acid methyl ester to reaction to form isradipine. The method for preparing high-purity isradipine is simple in operation process, convenient to operate, high in yield and capable of preparing high-purity isradipine.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, relate to a kind of preparation method of high-purity isradipine.
Background technology
Isrodipine (Isradipine) structural formula is as follows:
Isrodipine is a kind of Dihydropyridine calcium antagonist, high to the selectivity of blood vessel, energy diastole peripheral blood vessel, coronary vasodilator and the cerebrovascular, less to action of the heart, only suppress the spontaneous activity of sinus node, for hypertension, coronary heart disease and stenocardia, also can be used for congestive heart failure.
US Patent No. 4466972 discloses the synthetic method of Isrodipine, the method adopts " one kettle way " to prepare Isrodipine, the method cannot carry out quality control to intermediate, therefore the product prepared contains a certain amount of following formula homologue impurity, and homologue impurity is not easily removed, its impurity structure is as follows:
In above formula, R
1, R
2be methyl, ethyl and sec.-propyl at the same time or separately.Described homologue impurity and Isrodipine are separated very difficulty, causing cannot effective purifying Isrodipine.
Application number be 200810205014.1 Chinese patent application disclose a kind of method preparing Isrodipine.Adopt the amino β-crotonic acid isopropyl ester of methyl acetoacetate, 3-in the method, 4-carboxaldehyde radicals benzofuraxan one kettle way prepares Isrodipine.Because 3-amino β-crotonic acid isopropyl ester fusing point is lower, is liquid under normal temperature, therefore cannot obtains solid at normal temperatures, therefore preparing the amino β-crotonic acid isopropyl ester of 3-in the method adopts ISOPROPYL ACETOACETATE and ammonium acetate to react, by washing, concentrated, the method that cut is collected in distillation prepares.ISOPROPYL ACETOACETATE aftertreatment prepared by the method is comparatively loaded down with trivial details.
Summary of the invention
The object of the invention is to overcome the deficiency that above-mentioned prior art exists, a kind of process stabilizing, easy and simple to handle, constant product quality, the method preparing high-purity isradipine that purity is high, yield is high are provided.
For achieving the above object, the technical solution adopted for the present invention to solve the technical problems is:
A preparation method for high-purity isradipine, comprises the following steps:
A, in inert solvent, be the 4-carboxaldehyde radicals benzofuraxan of 1:1 ~ 3 by ratio, ISOPROPYL ACETOACETATE carries out dehydrating condensation in the presence of a catalyst and form 2-ethanoyl-3-benzofuraxan-4-base-isopropyl acrylate, i.e. formula 2 compound
；
B, ammonia solution is carried out to methyl acetoacetate, form METHYL 3 AMINO CROTONATE, i.e. formula 4 compound
；
The METHYL 3 AMINO CROTONATE that C, 2-ethanoyl-3-benzofuraxan-4-base-isopropyl acrylate steps A obtained and step B obtain proportionally is reacted 1:1 ~ 1.5 in inert solvent, forms Isrodipine
。
As optimal way, in described steps A, inert solvent is selected from ethanol, one or both in Virahol or the trimethyl carbinol.
As optimal way, in described steps A, catalyzer is selected from concentrated hydrochloric acid, the vitriol oil, the PPA/ vitriol oil or diacetyl oxide/vitriol oil, and the ratio of catalyzer and 4-carboxaldehyde radicals benzofuraxan is: 1:10 ~ 3.
As optimal way, in described step C, inert solvent be selected from methyl alcohol, ethanol, Virahol or the trimethyl carbinol one or more.
As optimal way, in described steps A, temperature of reaction is-10 ~ 10 DEG C, and the reaction times is 0.5 ~ 10 hour.
Further preferably, in described steps A, temperature of reaction is 0 ~ 5 DEG C, and the reaction times is 1 ~ 2 hour.
As optimal way, in described step B, temperature of reaction is-10 ~ 20 DEG C, and the reaction times is 1 ~ 10 hour.
Further preferably, in described step B, temperature of reaction is-5 ~ 5 DEG C, and the reaction times is 2 ~ 5 hours.
As optimal way, in described step C, temperature of reaction is 0 ~ 80 DEG C, and the reaction times is 6 ~ 48 hours.
Further preferably, in described step C, temperature of reaction is 20 ~ 30 DEG C, and the reaction times is 16 ~ 24 hours.
The present inventor, through deeply studying widely, improves existing Isrodipine preparation technology, thus the highly purified Isrodipine of preparation that can be efficient, easy.
In the present invention, term " Isrodipine " refers to that structure represents compound as shown in the formula I, also can comprise the pharmacy acceptable salt of formula I:
（I）
Isrodipine preparation method of the present invention can represent by following flow process:
More specifically this flow process is described below:
A, by 4-carboxaldehyde radicals benzofuraxan and ISOPROPYL ACETOACETATE in the presence of a catalyst low temperature dewatering form 2-ethanoyl-3-benzofuraxan-4-base-isopropyl acrylate.(compound 2)
In this step, the catalyzer used is preferably the vitriol oil or diacetyl oxide-vitriol oil.
Temperature of reaction is not particularly limited, and is generally-10 ~ 10 DEG C, is preferably 0 ~ 5 DEG C.
Reaction times is not particularly limited, and is generally 0.5 ~ 10 hour, is preferably 1 ~ 2 hour.
B, ammonia solution is carried out to methyl acetoacetate, form METHYL 3 AMINO CROTONATE.(compound 3)
In this step, temperature of reaction is not particularly limited, and is generally-10 ~ 20 DEG C, is preferably-5 ~ 5 DEG C.
Reaction times is not particularly limited, and is generally 1 ~ 10 hour, is preferably 2 ~ 5 hours.
C, 2-ethanoyl-3-benzofuraxan-4-base-isopropyl acrylate and METHYL 3 AMINO CROTONATE are reacted in inert solvent, form Isrodipine.
In this step, spendable inert solvent comprises methyl alcohol, ethanol, Virahol, the trimethyl carbinol or its both combinations arbitrarily.Preferred Virahol.
Temperature of reaction is not particularly limited, and is generally 0 ~ 80 DEG C, is preferably 20 ~ 30 DEG C.
Reaction times is not particularly limited, and is generally 6 ~ 48 hours, is preferably 16 ~ 24 hours.
Contriver has carried out large quantifier elimination to the preparation method of Isrodipine, by experiment many times, the discovery that we are surprised, when adopting the Isrodipine preparation method described in the present invention, this preparation method reaches the technique effect out of expection on the whole, effectively raises end product quality.
Beneficial effect of the present invention is:
Abandon " one kettle way " of the present invention prepares Isrodipine technique, and adopt a point one step preparation method, intermediate is quality controllable, follow-up finished product purification process is convenient, easy, so reach process stabilizing, easy and simple to handle, constant product quality, the effect that purity is high, yield is high.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments only do not limit the scope of the invention for illustration of the present invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.
The preparation of embodiment 1:2-ethanoyl-3-benzofuraxan-4-base-isopropyl acrylate (compound 2)
By 22.2g(0.15mol) ISOPROPYL ACETOACETATE and 10ml acetic anhydride join in reaction flask, cryosel bath is cooled to less than 5 DEG C, drip the 1ml vitriol oil, finish and slowly add 2 afterwards, 1, 3-benzo oxadiazoles-4-formaldehyde 14.8g (0.1mol), after finishing, remove cryosel bath, solid stir entirely molten after, continue insulation reaction 3.5 hours, liquid phase monitoring reaction is to 2, 1, termination reaction when 3-benzo oxadiazoles-4-formaldehyde residual content is less than 1%, add 20ml Virahol to stir, cooling, ice bath stirs 1 hour, filter, the a small amount of washed with isopropyl alcohol of filter cake, then wash by massive laundering, 23.9g yellow crystals is obtained after drying, yield is 86.6%, HPLC Purity(is suitable, anti-isomeric purities sum) >=99.0%.
The preparation of the amino methyl crotonate (compound 3) of embodiment 2:3-
Added by methyl acetoacetate 55ml in three mouthfuls of round-bottomed flasks, be cooled to less than 0 DEG C, insulation passes into ammonia stirring reaction 2 hours, TLC monitors to reacting end, less than-10 DEG C hold over night, suction filtration, obtain solid 53.6g after drying under reduced pressure, fusing point: 82 ~ 83 DEG C, yield is 93.2%.
Comparative example 1:
The method being 200810205014.1 Chinese patent application records according to application number prepares METHYL 3 AMINO CROTONATE
By 54ml methyl acetoacetate, 57.8g ammonium acetate and 600ml methyl alcohol join in 2L reaction flask, add 100g4A molecular sieve, reflux 6h, TLC detection reaction is complete, stop heating, after being cooled to room temperature, filter to obtain yellow solution, be concentrated into absence of liquid to steam, debris is dissolved in 300ml methylene dichloride, saturated sodium bicarbonate aqueous solution washing (300ml × 2), washing (300ml × 2) saturated sodium-chloride water solution washing (300ml × 2), anhydrous sodium sulfate drying, 90g crude product is obtained after pressurization is concentrated, more than 100 DEG C cuts (vacuum tightness 0.09MPa) are collected in underpressure distillation, hold over night at collection liquid is placed in-10 DEG C.Rapid filtration at 0 DEG C, 38.8g(yield 67.5% of weighing to obtain)
Embodiment 4: the preparation of Isrodipine
METHYL 3 AMINO CROTONATE 11g and Virahol 60ml is added in reaction flask, 2-ethanoyl-3-benzofuraxan-4-base-isopropyl acrylate 23.9g is added under stirring, lucifuge stirring reaction 20 hours, reaction solution is concentrated into dry, add ethyl acetate 100ml, water 20ml, separatory after stirring, organic phase anhydrous sodium sulfate drying, filter, reclaim ethyl acetate to dry, obtain Isrodipine crude product 31g, crude product is added in 40ml Virahol, heating for dissolving, filtered while hot, filtrate leaves standstill crystallization 16 hours in less than 5 DEG C, filter, filter cake vacuum-drying at 40 DEG C after a small amount of chilled isopropyl alcohol washing, obtain yellow Isrodipine 25.7g, yield 80%(HPLC purity is 99.4%, homologue foreign matter content is less than 0.1%).
Embodiment 5: repeat embodiment 3, difference is to replace Virahol to refine crude product by isopropanol/water.Yield 86.1%(HPLC purity is 99.7%, and homologue foreign matter content is less than 0.1%).
Comparison example 2
Isrodipine is prepared according to US Patent No. 4466972 method:
By 2 in there-necked flask, 1,3-benzo oxadiazoles-4-formaldehyde 14.8g, 3-amino β-crotonic acid isopropyl ester 13.3g, methyl acetoacetate 17.3g, acetic anhydride 20g, vitriol oil 1ml and ethanol 320ml mix and blend, when liquid phase monitoring reactant residue is less than 1%, termination reaction.Concentrated by reactant, residue methylene dichloride dissolves, washing, dry, and concentrated, oil pump is drained, and obtains 29.8g foaming solid.Add ethanol heating for dissolving, stirring and crystallizing (spending the night), obtain pale yellow powder Isrodipine 20.2g(HPLC purity: 99.0%, homologue foreign matter content is greater than 0.3%), yield 54.4%.
From above-mentioned experimental data, the inventive method is easy and simple to handle, and prepared product purity is high, and foreign matter content is few, and yield is high, and quality product is significantly better than prior art.
Claims (1)
1. a preparation method for high-purity isradipine, is characterized in that comprising the following steps:
A, in inert solvent; be the 4-carboxaldehyde radicals benzofuraxan of 1:1 ~ 3 by part by weight, ISOPROPYL ACETOACETATE carries out dehydrating condensation in the presence of a catalyst and form 2-ethanoyl-3-benzofuraxan-4-base-isopropyl acrylate; i.e. formula 2 compound; catalyzer is selected from concentrated hydrochloric acid, the vitriol oil, the PPA/ vitriol oil or diacetyl oxide/vitriol oil; the part by weight of catalyzer and 4-carboxaldehyde radicals benzofuraxan is: 1:10 ~ 3; temperature of reaction is 0 ~ 5 DEG C; reaction times is 1 ~ 2 hour; inert solvent is selected from ethanol, one or both in Virahol or the trimethyl carbinol
；
B, carry out ammonia solution to methyl acetoacetate, form METHYL 3 AMINO CROTONATE, i.e. formula 4 compound, temperature of reaction is-5 ~ 5 DEG C, and the reaction times is 2 ~ 5 hours
；
The METHYL 3 AMINO CROTONATE that C, 2-ethanoyl-3-benzofuraxan-4-base-isopropyl acrylate steps A obtained and step B obtain is reacted in inert solvent according to part by weight 1:1 ~ 1.5; form Isrodipine; temperature of reaction is 20 ~ 30 DEG C; reaction times is 16 ~ 24 hours, inert solvent be selected from methyl alcohol, ethanol, Virahol or the trimethyl carbinol one or more
。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103613584B (en) * | 2013-11-27 | 2016-04-27 | 沈阳药科大学 | The method of a kind of Isrodipine synthetic product aftertreatment |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2117761A (en) * | 1982-03-10 | 1983-10-19 | Sandoz Ltd | 1 4-dihydropyridine derivatives their preparation and pharmaceutical composition |
| US4466972A (en) * | 1977-06-20 | 1984-08-21 | Sandoz Ltd. | Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing them |
| WO2005005437A1 (en) * | 2003-07-15 | 2005-01-20 | Shasun Chemicals And Drugs Limited | An improved process for the manufacture of isradipine. |
| CN1847233A (en) * | 2005-04-12 | 2006-10-18 | 圣玛精细化工有限责任公司 | Method for preparing 4-formoxylbenzofuran |
| CN101768153A (en) * | 2008-12-30 | 2010-07-07 | 上海阳帆医药科技有限公司 | Method for preparing israbipine medicament for treating hypertension |
| CN102276547A (en) * | 2011-05-04 | 2011-12-14 | 山东省医药工业研究所 | Preparation method of isradipine key intermediate 4-formoxylbenzofuran |
-
2012
- 2012-08-07 CN CN201210278518.2A patent/CN102766137B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4466972A (en) * | 1977-06-20 | 1984-08-21 | Sandoz Ltd. | Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing them |
| GB2117761A (en) * | 1982-03-10 | 1983-10-19 | Sandoz Ltd | 1 4-dihydropyridine derivatives their preparation and pharmaceutical composition |
| WO2005005437A1 (en) * | 2003-07-15 | 2005-01-20 | Shasun Chemicals And Drugs Limited | An improved process for the manufacture of isradipine. |
| CN1847233A (en) * | 2005-04-12 | 2006-10-18 | 圣玛精细化工有限责任公司 | Method for preparing 4-formoxylbenzofuran |
| CN101768153A (en) * | 2008-12-30 | 2010-07-07 | 上海阳帆医药科技有限公司 | Method for preparing israbipine medicament for treating hypertension |
| CN102276547A (en) * | 2011-05-04 | 2011-12-14 | 山东省医药工业研究所 | Preparation method of isradipine key intermediate 4-formoxylbenzofuran |
Non-Patent Citations (1)
| Title |
|---|
| 新型钙通道阻滞剂伊拉地平;黄震华,等;《中国新药杂志》;19931215;第2卷(第06期);第12-14页 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103613584B (en) * | 2013-11-27 | 2016-04-27 | 沈阳药科大学 | The method of a kind of Isrodipine synthetic product aftertreatment |
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