CN102766137A - Method for preparing high-purity isradipine - Google Patents
Method for preparing high-purity isradipine Download PDFInfo
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- CN102766137A CN102766137A CN2012102785182A CN201210278518A CN102766137A CN 102766137 A CN102766137 A CN 102766137A CN 2012102785182 A CN2012102785182 A CN 2012102785182A CN 201210278518 A CN201210278518 A CN 201210278518A CN 102766137 A CN102766137 A CN 102766137A
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- isrodipine
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- high purity
- temperature
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- XKORCTIIRYKLLG-ARJAWSKDSA-N C/C(/N)=C/C(OC)=O Chemical compound C/C(/N)=C/C(OC)=O XKORCTIIRYKLLG-ARJAWSKDSA-N 0.000 description 1
- ANDHTDVJGVDLJA-UHFFFAOYSA-N CC(C)OC(C(Cc1cccc2n[o]nc12)C(C)=[U])=O Chemical compound CC(C)OC(C(Cc1cccc2n[o]nc12)C(C)=[U])=O ANDHTDVJGVDLJA-UHFFFAOYSA-N 0.000 description 1
- LYQYUATXRGBQIB-SSDOTTSWSA-N O=CC1=CC=CC2=NON[C@H]12 Chemical compound O=CC1=CC=CC2=NON[C@H]12 LYQYUATXRGBQIB-SSDOTTSWSA-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 Isrodipine.
Background technology
Isrodipine (Isradipine) structural formula is following:
Isrodipine is a kind of dihydropyridines calcium antagonists, and is high to the selectivity of blood vessel, ability diastole peripheral blood vessel, coronary vasodilator and the cerebrovascular; Less to action of the heart; Only suppress the spontaneous activity of sinus node, be used for hypertension, coronary heart disease and stenocardia, also can be used for congestive heart failure.
U.S. Pat 4466972 discloses the compound method of Isrodipine; This method adopts " one kettle way " preparation Isrodipine; This method can't be carried out quality control to midbody; Therefore the product of preparation contains a certain amount of following formula homologue impurity, and the difficult removal of homologue impurity, and its impurity structure is following:
In the following formula, R
1, R
2Be methyl, ethyl and sec.-propyl at the same time or separately.Said homologue impurity and Isrodipine are separated very difficulty, cause effectively purifying Isrodipine.
Application number is that 200810205014.1 one Chinese patent application discloses a kind of method for preparing Isrodipine.Adopt methyl acetoacetate, the amino Ba Dousuan isopropyl ester of 3-, 4-carboxaldehyde radicals benzo furazan one kettle way to prepare Isrodipine in this method.Because the amino Ba Dousuan isopropyl ester of 3-fusing point is lower, normal temperature is liquid down, therefore can't obtain solid at normal temperatures; Therefore the amino Ba Dousuan isopropyl ester of preparation 3-adopts ISOPROPYL ACETOACETATE and ammonium acetate reaction in this method; Through washing, concentrate, the method that cut is collected in distillation prepares.The ISOPROPYL ACETOACETATE aftertreatment of this method preparation is comparatively loaded down with trivial details.
Summary of the invention
The objective of the invention is to overcome the deficiency that above-mentioned prior art exists, a kind of process stabilizing, easy and simple to handle is provided, constant product quality, the method for preparing the high purity Isrodipine that purity is high, yield is high.
For realizing above-mentioned purpose, the technical solution adopted for the present invention to solve the technical problems is:
A kind of preparation method of high purity Isrodipine may further comprise the steps:
A, in inert solvent, be that 4-carboxaldehyde radicals benzo furazan, the ISOPROPYL ACETOACETATE of 1:1～3 carries out dehydrating condensation and form 2-ethanoyl-3-benzo furazan-4-base-isopropyl acrylate, i.e. formula 2 compounds in the presence of catalyzer with ratio
B, methyl acetoacetate is carried out ammonia separate, form METHYL 3 AMINO CROTONATE, i.e. formula 4 compounds
The METHYL 3 AMINO CROTONATE that C, 2-ethanoyl-3-benzo furazan-4-base-isopropyl acrylate that steps A is obtained and step B obtain proportionally reacts in inert solvent 1:1～1.5, forms Isrodipine
As optimal way, in the said steps A, inert solvent is selected from ethanol, one or both in the Virahol or the trimethyl carbinol.
As optimal way, in the said 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 benzo furazan is: 1:10～3.
As optimal way, among the said step C, inert solvent is selected from one or more in methyl alcohol, ethanol, Virahol or the trimethyl carbinol.
As optimal way, in the said steps A, temperature of reaction is-10～10 ℃, and the reaction times is 0.5～10 hour.
Further preferred, in the said steps A, temperature of reaction is 0～5 ℃, and the reaction times is 1～2 hour.
As optimal way, among the said step B, temperature of reaction is-10～20 ℃, and the reaction times is 1～10 hour.
Further preferred, among the said step B, temperature of reaction is-5～5 ℃, and the reaction times is 2～5 hours.
As optimal way, among the said step C, temperature of reaction is 0～80 ℃, and the reaction times is 6～48 hours.
Further preferred, among the said step C, temperature of reaction is 20～30 ℃, and the reaction times is 16～24 hours.
Extensive studies has been improved existing Isrodipine preparation technology to the inventor through going deep into, thus the highly purified Isrodipine of preparation that can be efficient, easy.
In the present invention, term " Isrodipine " refers to that structure representes compound as shown in the formula I, also can comprise the pharmacy acceptable salt of formula I compound:
Isrodipine preparation method of the present invention can represent with following flow process:
This flow process is described below more specifically:
A, 4-carboxaldehyde radicals benzo furazan and ISOPROPYL ACETOACETATE low temperature dewatering in the presence of catalyzer is formed 2-ethanoyl-3-benzo furazan-4-base-isopropyl acrylate.(compound 2)
In this step, employed catalyzer is preferably the vitriol oil or diacetyl oxide-vitriol oil.
The not special restriction of temperature of reaction is generally-10～10 ℃, and preferable is 0～5 ℃.
Not special restriction of reaction times is generally 0.5～10 hour, and preferable is 1～2 hour.
B, methyl acetoacetate is carried out ammonia separate, form METHYL 3 AMINO CROTONATE.(compound 3)
In this step, the not special restriction of temperature of reaction is generally-10～20 ℃, and preferable is-5～5 ℃.
Not special restriction of reaction times is generally 1～10 hour, and preferable is 2～5 hours.
C, 2-ethanoyl-3-benzo furazan-4-base-isopropyl acrylate and METHYL 3 AMINO CROTONATE react 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.
The not special restriction of temperature of reaction is generally 0～80 ℃, and preferable is 20～30 ℃.
Not special restriction of reaction times is generally 6～48 hours, and preferable is 16～24 hours.
The contriver has carried out a large amount of research to the preparation method of Isrodipine; Through experiment many times; The discovery that we are surprised; When adopting the Isrodipine preparation method that the present invention put down in writing, this preparation method has reached the technique effect out of expection on the whole, effectively raises end product quality.
Beneficial effect of the present invention is:
Of the present invention having abandoned " one kettle way " preparation Isrodipine technology adopts and divides one step preparation method, and midbody is quality controllable; Convenient, the easy row of follow-up finished product purification process; So reached 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, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and do not limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
The preparation of embodiment 1:2-ethanoyl-3-benzo furazan-4-base-isopropyl acrylate (compound 2)
22.2g (0.15mol) ISOPROPYL ACETOACETATE and 10ml acetic anhydride are joined in the reaction flask, and cryosel is bathed and is cooled to below 5 ℃, drips the 1ml vitriol oil, finishes the back and slowly adds 2; 1,3-benzo oxadiazoles-4-formaldehyde 14.8g (0.1mol) after finishing, removes cryosel and bathes; Solid continued insulation reaction 3.5 hours, liquid phase monitoring reaction to 2,1 after stirring complete dissolving; 3-benzo oxadiazoles-4-formaldehyde residual content adds the 20ml Virahol and stirs less than 1% o'clock termination reaction, cooling, and ice bath stirred 1 hour; Filter, filter cake is used a small amount of washed with isopropyl alcohol, washs with massive laundering then; Get the 23.9g yellow crystals after the drying, yield is 86.6%, HPLC Purity (suitable, anteiso-structure purity sum) >=99.0%.
The preparation of the amino methyl crotonate of embodiment 2:3-(compound 3)
Methyl acetoacetate 55ml is added in three mouthfuls of round-bottomed flasks, be cooled to below 0 ℃, insulation fed the ammonia stirring reaction 2 hours; The TLC monitoring finishes-10 ℃ of following hold over night, suction filtration to reaction; Get solid 53.6g behind the drying under reduced pressure, fusing point: 82～83 ℃, yield is 93.2%.
Comparative Examples 1:
According to application number is that the method that 200810205014.1 one Chinese patent application are put down in writing prepares METHYL 3 AMINO CROTONATE
With the 54ml methyl acetoacetate, 57.8g ammonium acetate and 600ml methyl alcohol join in the 2L reaction flask, add the 100g4A molecular sieve, reflux 6h; The TLC detection reaction finishes, stop the heating, be cooled to room temperature after; Cross and filter yellow solution, be concentrated into absence of liq and steam, debris is dissolved in the 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; Get the 90g crude product after pressurization concentrates, cut (vacuum tightness 0.09MPa) more than 100 ℃ is collected in underpressure distillation, will collect liquid and place-10 ℃ of following hold over night.0 ℃ is filtered down rapidly, weigh 38.8g (yield 67.5%)
Embodiment 4: the preparation of Isrodipine
In reaction flask, add METHYL 3 AMINO CROTONATE 11g and Virahol 60ml, stir adding 2-ethanoyl-3-benzo furazan-4-base-isopropyl acrylate 23.9g down, lucifuge stirring reaction 20 hours; Reaction solution is concentrated into dried, adds ETHYLE ACETATE 100ml, water 20ml, stir the back separatory; Organic phase reclaims ETHYLE ACETATE to doing with anhydrous sodium sulfate drying, filtration, obtains Isrodipine bullion 31g; Bullion is added in the 40ml Virahol heating for dissolving, filtered while hot; Filtrate in leaving standstill crystallization below 5 ℃ 16 hours, filter, filter cake with a small amount of freezing washed with isopropyl alcohol after in 40 ℃ of following vacuum-dryings; Get yellow Isrodipine 25.7g, yield 80% (HPLC purity is 99.4%, and the homologue foreign matter content is less than 0.1%).
Embodiment 5: repeat embodiment 3, difference is to replace Virahol that bullion is made with extra care with isopropanol.Yield 86.1% (HPLC purity is 99.7%, and the homologue foreign matter content is less than 0.1%).
Comparison example 2
Prepare Isrodipine according to U.S. Pat 4466972 methods:
In there-necked flask with 2; 1; 3-benzo oxadiazoles-4-formaldehyde 14.8g, the amino Ba Dousuan isopropyl ester of 3-13.3g, methyl acetoacetate 17.3g, acetic anhydride 20g, vitriol oil 1ml and ethanol 320ml mix stirring, and liquid phase monitoring reaction thing residue is less than at 1% o'clock, termination reaction.Reactant is concentrated, and residue dissolves with methylene dichloride, washing, and drying concentrates, and oil pump is drained, and gets 29.8g spumescence solid.Add the ethanol heating for dissolving, stirring and crystallizing (spending the night), pale yellow powder Isrodipine 20.2g (HPLC purity: 99.0%, the homologue foreign matter content is greater than 0.3%), yield 54.4%.
Visible 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 obviously is better than prior art.
Claims (10)
1. the preparation method of a high purity Isrodipine is characterized in that may further comprise the steps:
A, in inert solvent, be that 4-carboxaldehyde radicals benzo furazan, the ISOPROPYL ACETOACETATE of 1:1～3 carries out dehydrating condensation and form 2-ethanoyl-3-benzo furazan-4-base-isopropyl acrylate, i.e. formula 2 compounds in the presence of catalyzer with part by weight
B, methyl acetoacetate is carried out ammonia separate, form METHYL 3 AMINO CROTONATE, i.e. formula 4 compounds
；
The METHYL 3 AMINO CROTONATE that C, 2-ethanoyl-3-benzo furazan-4-base-isopropyl acrylate that steps A is obtained and step B obtain reacts in inert solvent according to part by weight 1:1～1.5, forms Isrodipine
2. the preparation method of a kind of high purity Isrodipine as claimed in claim 1 is characterized in that: in the said steps A, inert solvent is selected from ethanol, one or both in the Virahol or the trimethyl carbinol.
3. the preparation method of a kind of high purity Isrodipine as claimed in claim 1; It is characterized in that: in the said steps A; Catalyzer is selected from concentrated hydrochloric acid, the vitriol oil, the PPA/ vitriol oil or diacetyl oxide/vitriol oil, and the part by weight of catalyzer and 4-carboxaldehyde radicals benzo furazan is: 1:10～3.
4. the preparation method of a kind of high purity Isrodipine as claimed in claim 1 is characterized in that: among the said step C, inert solvent is selected from one or more in methyl alcohol, ethanol, Virahol or the trimethyl carbinol.
5. the preparation method of a kind of high purity Isrodipine as claimed in claim 1 is characterized in that: in the said steps A, temperature of reaction is-10～10 ℃, and the reaction times is 0.5～10 hour.
6. the preparation method of a kind of high purity Isrodipine as claimed in claim 5 is characterized in that: in the said steps A, temperature of reaction is 0～5 ℃, and the reaction times is 1～2 hour.
7. the preparation method of a kind of high purity Isrodipine as claimed in claim 1 is characterized in that: among the said step B, temperature of reaction is-10～20 ℃, and the reaction times is 1～10 hour.
8. the preparation method of a kind of high purity Isrodipine as claimed in claim 7 is characterized in that: among the said step B, temperature of reaction is-5～5 ℃, and the reaction times is 2～5 hours.
9. the preparation method of a kind of high purity Isrodipine as claimed in claim 1 is characterized in that: among the said step C, temperature of reaction is 0～80 ℃, and the reaction times is 6～48 hours.
10. the preparation method of a kind of high purity Isrodipine as claimed in claim 9 is characterized in that: among the said step C, temperature of reaction is 20～30 ℃, and the reaction times is 16～24 hours.
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| CN201210278518.2A CN102766137B (en) | 2012-08-07 | 2012-08-07 | Method for preparing high-purity isradipine |
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| CN201210278518.2A CN102766137B (en) | 2012-08-07 | 2012-08-07 | Method for preparing high-purity isradipine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103613584A (en) * | 2013-11-27 | 2014-03-05 | 沈阳药科大学 | Post-processing method of isradipine synthetic product |
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| 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 |
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2012
- 2012-08-07 CN CN201210278518.2A patent/CN102766137B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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| 黄震华,等: "新型钙通道阻滞剂伊拉地平", 《中国新药杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103613584A (en) * | 2013-11-27 | 2014-03-05 | 沈阳药科大学 | Post-processing method of isradipine synthetic product |
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