CN103896878B - A kind of Purification decolorization method of cinepazide - Google Patents
A kind of Purification decolorization method of cinepazide Download PDFInfo
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- CN103896878B CN103896878B CN201210570975.9A CN201210570975A CN103896878B CN 103896878 B CN103896878 B CN 103896878B CN 201210570975 A CN201210570975 A CN 201210570975A CN 103896878 B CN103896878 B CN 103896878B
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- cinepazide
- dichloromethane
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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
- C07D295/16—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 acylated on ring nitrogen atoms
- C07D295/18—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 acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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Abstract
The Purification decolorization method of cinepazide disclosed by the invention, by directly adjusting the pH of cinepazide hydrochloric acid saline solution to alkalescent, complement filter operates, pigment and water-solubility impurity are realized with salt cinepazide and separated, the process operation is simple, high income, and colour removal is obvious, the quality of product is effectively improved, so as to improve the benefit of enterprise.
Description
Technical field
The present invention relates to a kind of processing method of bulk drug, more particularly to a kind of purifying decolouring side of basic materials medicine
Method, more particularly relate to a kind of Purification decolorization method of cinepazide.
Background technology
Cinepazide is a kind of peripheral vasodilator, and chemical name is：1- (pyrrolidin-1-yl formyl methyl) -4- (3,
4,5- trimethoxy cinnamoyls) piperazine, its pharmaceutical salts is along butadiene diacid salt, general entitled Cinepazide Maleate, is faced
Bed is applied to the treatment of cardiovascular and cerebrovascular superfine product, and cinepazide is its free alkali.The chemical formula structure of cinepazide such as formula（Ⅰ）Institute
Show.
Cinepazide Maleate is calcium ion channel blocker, by preventing Ca2+ cross-film intravasation smooth muscle cells
It is interior, make vascular smooth muscle relaxation, the cerebrovascular, coronary vasodilator and peripheral vascular expansion, so as to alleviate vasopasm, reduce blood vessel resistance
Power, increase CBF；Adenosine and CAMP can be strengthened（cAMP）Effect, reduce oxygen consumption；CAMP di-phosphate esters can be suppressed
Enzyme, make the increase of CAMP quantity；The pliability and morphotropism of red blood cell can be improved, improves its ability by minute blood vessel, is reduced
The viscosity of blood, improve microcirculation；This product can also improve the metabolism of brain by improving cerebrovascular CBF.It is clinically extensive
Treatment for cardiovascular and cerebrovascular disease.
The clinical common formulations of Cinepazide Maleate are injection, while as the purity of conventional medical drug product,
The quality that product can not only be influenceed also affects the health and therapeutic effect of patient, therefore its color and purity are wanted
Ask all extremely strict, how decolouring purifying is carried out to Cinepazide Maleate and be particularly important.
The refined of Cinepazide Maleate is often carried out into the finished product after maleate in existing process, and maleic acid
Cinepazide will be very restricted as organic salt to its purification process, and ideal is all not reaching to by experimental verification
Effect；And the purification process of cinepazide free alkali substantially recrystallizes such as in the organic solvents such as ethyl acetate, toluene
CN101492431A, CN1631877A, CN101531643A, CN101260092A, CN101508685A etc.；United States Patent (USP)
The decolouring purifying of cinepazide free alkali is not involved with US363441；CN1876646A is using the free alkali of compound to having
Machine phase and aqueous phase two-phase rejecting effect are post-processed；CN101260092A has added a step activated carbon decolorizing.
The content of the invention
To solve the above problems, the invention discloses a kind of Purification decolorization method of cinepazide, simple to operate, yield
Height, colour removal is obvious, is effectively improved the quality of product, so as to improve the benefit of enterprise.
The Purification decolorization method of cinepazide disclosed by the invention, comprises the following steps,（1）Cinepazide crude product is made
Dichloromethane solution；（2）Washing, then the salt cinepazide maleate aqueous solution is obtained by extraction with watery hydrochloric acid；（3）Regulating step（2）In
The pH value of the obtained salt cinepazide maleate aqueous solution is to 7~8；（4）System temperature is reduced to less than 0 DEG C, stirring insulation is small half
When；（5）By step（4）In obtain mixture filtering, collect filter cake, obtain cinepazide；（6）By step（5）In obtained osmanthus
The neat spy of piperazine is dissolved in dichloromethane, washes dichloromethane phase, after drying, is removed dichloromethane and is produced cinepazide decolouring purifying
Product.
A kind of improvement of the Purification decolorization method of cinepazide disclosed by the invention, the step（2）Middle addition watery hydrochloric acid
Molar concentration be 3~5mol/L.
Another improvement of the Purification decolorization method of cinepazide disclosed by the invention, the step（3）It is middle to use 3~6%
Sodium hydrate aqueous solution adjusts the pH value of the cinepazide aqueous solution.
The Purification decolorization method of cinepazide disclosed by the invention, by directly to the pH of cinepazide dichloromethane solution
Regulation, complement filter operation, pigment, triethylamine and water-solubility impurity are realized with cinepazide and separated, with maleic acid into salt, is obtained
Cinepazide Maleate, refine, finished color can reach below pharmacopeia 0.5, and HPLC is not less than 99.8%.
Embodiment
With reference to embodiment, the present invention is furture elucidated, it should be understood that following embodiments are only used for
The bright present invention rather than limitation the scope of the present invention.
The present invention synthesizes cinepazide with the following method：The dichloromethane of 3,4,5- trimethoxy cinnamoyl chlorides is molten
Liquid add to N- [（1- nafoxidine base carbonyls）Methyl] piperazine and triethylamine dichloromethane solution in, it is specific such as 53g3,4,5-
The 300g dichloromethane solutions of trimethoxy cinnamoyl chloride add 35.6gN- [（1- nafoxidine base carbonyls）Methyl] piperazine and
Cinepazide crude product is obtained in the 370g dichloromethane of 36g triethylamines.
The Purification decolorization method of cinepazide disclosed by the invention, comprises the following steps,（1）Cinepazide crude product is made
Dichloromethane solution；（2）Washing, then the salt cinepazide maleate aqueous solution is obtained by extraction with watery hydrochloric acid；（3）Regulating step（2）In
The pH value of the obtained salt cinepazide maleate aqueous solution is to 7~8；（4）System temperature is reduced to less than 0 DEG C, stirring insulation is small half
When；（5）By step（4）In obtain mixture filtering, collect filter cake, obtain cinepazide；（6）By step（5）In obtained osmanthus
The neat spy of piperazine is dissolved in dichloromethane, washes dichloromethane phase, after drying, is removed dichloromethane and is produced cinepazide decolouring purifying
Product.
A kind of improvement of the Purification decolorization method of cinepazide disclosed by the invention, the step（2）Middle addition watery hydrochloric acid
Molar concentration be 3~5mol/L.
Another improvement of the Purification decolorization method of cinepazide disclosed by the invention, the step（3）It is middle to use 3~6%
Sodium hydrate aqueous solution adjusts the pH value of the cinepazide aqueous solution.
Embodiment
Comparative example one
83.5g cinepazides are added in 670g dichloromethane, the washing of saturated sodium-chloride 150mL solution,
100ml4mol/L salt acid extractions, liquid separation, sour water layer adjust pH value to 7 with 5% sodium hydrate aqueous solution, and dichloromethane extraction is produced
Product, at room temperature saturation sodium hydroxide solution 150mL washings, remove water layer, it is neat that solvent evaporated obtains yellow oil product osmanthus piperazine
It is special.With maleic acid into after salt, color according to（《Chinese Pharmacopoeia》2010 editions A colour of solution method methods of annex Ⅸ）No. 1 is detected as,
The product regulation of correlation is not met.
Comparative example two
83.5g cinepazides are added in 670g dichloromethane, the washing of saturated sodium-chloride 150mL solution,
100ml4mol/L salt acid extractions, liquid separation, sour water layer adjust pH value to 7 with 5% sodium hydrate aqueous solution, and dichloromethane extraction is produced
Product, at room temperature saturation sodium hydroxide solution 150mL washings, remove water layer, it is neat that solvent evaporated obtains yellow oil product osmanthus piperazine
It is special.With maleic acid into after salt, color according to（《Chinese Pharmacopoeia》2010 editions A colour of solution method methods of annex Ⅸ）No. 1 is detected as,
The product regulation of correlation is not met.
Embodiment one
83.5g cinepazides are added in 670g dichloromethane, 100ml is washed twice, 100ml4mol/L hydrochloric acid extraction
Take, liquid separation, sour water layer adjusts pH value to 7 with 5% sodium hydrate aqueous solution, is cooled to less than 0 DEG C, stirring insulation half an hour；Cross
Filter, filter cake is collected, obtains salt cinepazide maleate；Filter cake is dissolved in 150g dichloromethane, 50ml water washings, removes water layer, 50g
Anhydrous magnesium sulfate is dried, and evaporated under reduced pressure dichloromethane obtains 75.2g products, yield 90.1%.Maximum contaminant：0.045% total impurities
0.18% HPLC99.82%.With maleic acid into after salt, color according to（《Chinese Pharmacopoeia》2010 editions A colour of solution methods of annex Ⅸ
Method）It is detected as being less than No. half, that is, reaches below pharmacopeia 0.5, meets injection product and provided on the product of color and purity.
Embodiment two
83.5g cinepazides are added in 670g dichloromethane, 100ml is washed twice, 100ml3mol/L hydrochloric acid extraction
Take, liquid separation, sour water layer adjusts pH value to 7 with 3% sodium hydrate aqueous solution, is cooled to less than 0 DEG C, stirring insulation half an hour；Cross
Filter, filter cake is collected, obtains salt cinepazide maleate；Filter cake is dissolved in 150g dichloromethane, 100ml water washings twice, remove water
Layer, 50g anhydrous magnesium sulfates are dried, and evaporated under reduced pressure dichloromethane obtains 75.4g products, yield 90.3%.Maximum contaminant：0.044% is total
The HPLC99.81% of impurity 0.17%.With maleic acid into after salt, color according to（《Chinese Pharmacopoeia》The 2010 editions A colors of annex Ⅸ inspections
Look into method method）It is detected as being less than No. half, that is, reaches below pharmacopeia 0.5, meet product of the injection product on color and purity
Regulation.
Embodiment three
83.5g cinepazides are added in 670g dichloromethane, 100ml is washed twice, 100ml5mol/L hydrochloric acid extraction
Take, liquid separation, sour water layer adjusts pH value to 8 with 6% sodium hydrate aqueous solution, is cooled to less than 0 DEG C, stirring insulation half an hour；Cross
Filter, filter cake is collected, obtains salt cinepazide maleate；Filter cake is dissolved in 150g dichloromethane, 80ml water washings twice, remove water
Layer, 50g anhydrous magnesium sulfates are dried, and evaporated under reduced pressure dichloromethane obtains 75.8g products, yield 90.8%.Maximum contaminant：0.042% is total
The HPLC99.83% of impurity 0.16%.With maleic acid into after salt, color according to（《Chinese Pharmacopoeia》The 2010 editions A colors of annex Ⅸ inspections
Look into method method）It is detected as being less than No. half, that is, reaches below pharmacopeia 0.5, meet product of the injection product on color and purity
Regulation.
The Purification decolorization method of cinepazide disclosed by the invention, by directly to the pH of cinepazide dichloromethane solution
Regulation, complement filter operation, pigment, triethylamine and water-solubility impurity are realized with cinepazide and separated, with maleic acid into salt, is obtained
Cinepazide Maleate, refine, finished color can reach below pharmacopeia 0.5, and HPLC is not less than 99.8%.
Technological means disclosed in the present invention program is not limited only to the technological means disclosed in above-mentioned technological means, in addition to
Formed technical scheme is combined by above technical characteristic.Described above is the embodiment of the present invention, should be referred to
Go out, for those skilled in the art, under the premise without departing from the principles of the invention, can also make some
Improvements and modifications, these improvements and modifications are also considered as protection scope of the present invention.
Claims (1)
- A kind of 1. Purification decolorization method of cinepazide, it is characterised in that：Comprise the following steps,（1）Obtained cinepazide slightly produces The dichloromethane solution of product；（2）Washing, then the salt cinepazide maleate aqueous solution is obtained by extraction with watery hydrochloric acid；（3）Regulating step（2） In the obtained pH value of the salt cinepazide maleate aqueous solution to 7~8；（4）System temperature is reduced to less than 0 DEG C, half of stirring insulation Hour；（5）By step（4）In obtain mixture filtering, collect filter cake, obtain salt cinepazide maleate；（6）By step（5）In To cinepazide be dissolved in dichloromethane, wash dichloromethane phase, dry after, remove dichloromethane produce cinepazide decolouring Purifying product；The step（2）The middle molar concentration for adding watery hydrochloric acid is 3~5mol/L；The step（3）It is middle to use 3~6% hydrogen Aqueous solution of sodium oxide adjusts the pH value of the cinepazide aqueous solution.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3634411A (en) * | 1968-04-03 | 1972-01-11 | Delalande Sa | Derivatives of 1-(3 4 5-trimethoxy cinnamoyl)-piperazine and process for their preparation |
| CN101717382A (en) * | 2008-10-10 | 2010-06-02 | 齐鲁制药有限公司 | Method for synthesizing cinepazide |
| CN101768140A (en) * | 2010-01-13 | 2010-07-07 | 安徽金太阳生化药业有限公司 | Preparation method of cinepazide maleate |
| CN101774983A (en) * | 2010-01-21 | 2010-07-14 | 海南美兰史克制药有限公司 | Cinepazide maleate compound with novel route |
| CN102229583A (en) * | 2011-05-13 | 2011-11-02 | 江苏神龙药业有限公司 | Method for synthesizing cinepazide |
-
2012
- 2012-12-26 CN CN201210570975.9A patent/CN103896878B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3634411A (en) * | 1968-04-03 | 1972-01-11 | Delalande Sa | Derivatives of 1-(3 4 5-trimethoxy cinnamoyl)-piperazine and process for their preparation |
| CN101717382A (en) * | 2008-10-10 | 2010-06-02 | 齐鲁制药有限公司 | Method for synthesizing cinepazide |
| CN101768140A (en) * | 2010-01-13 | 2010-07-07 | 安徽金太阳生化药业有限公司 | Preparation method of cinepazide maleate |
| CN101774983A (en) * | 2010-01-21 | 2010-07-14 | 海南美兰史克制药有限公司 | Cinepazide maleate compound with novel route |
| CN102229583A (en) * | 2011-05-13 | 2011-11-02 | 江苏神龙药业有限公司 | Method for synthesizing cinepazide |
Non-Patent Citations (1)
| Title |
|---|
| 一种简化的马来酸桂哌齐特的合成方法;金晓峰 等;《黑龙江大学工程学报》;20110228;第2卷(第1期);第58页 1.2.1 * |
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Address after: 221004 No. 6, Yang Shan Road, Jinshan Development Zone, Jiangsu, Xuzhou Co-patentee after: SHANGHAI FOSUN PHARMACEUTICAL(GROUP)CO., Ltd. Patentee after: JIANGSU WANBANG BIOPHARMACEUTICAL GROUP CO.,LTD. Address before: 221004 No. 6, Yang Shan Road, Jinshan Development Zone, Jiangsu, Xuzhou Co-patentee before: SHANGHAI FOSUN PHARMACEUTICAL(GROUP)CO., Ltd. Patentee before: Jiangsu Wan Bang Biochemical Medicine Co.,Ltd. Address after: 221004 No. 6, Yang Shan Road, Jinshan Development Zone, Jiangsu, Xuzhou Co-patentee after: SHANGHAI FOSUN PHARMACEUTICAL(GROUP)CO., Ltd. Patentee after: Jiangsu Wan Bang Biochemical Medicine Co.,Ltd. Address before: 221004 No. 6, Yang Shan Road, Jinshan Development Zone, Jiangsu, Xuzhou Co-patentee before: SHANGHAI FOSUN PHARMACEUTICAL(GROUP)CO., Ltd. Patentee before: JIANGSU WANBANG BIOPHARMACEUTICALS Co.,Ltd. |
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Effective date of registration: 20180126 Address after: 221004 No. 6, Yang Shan Road, Jinshan Development Zone, Jiangsu, Xuzhou Patentee after: JIANGSU WANBANG BIOPHARMACEUTICAL GROUP CO.,LTD. Address before: 221004 No. 6, Yang Shan Road, Jinshan Development Zone, Jiangsu, Xuzhou Co-patentee before: SHANGHAI FOSUN PHARMACEUTICAL(GROUP)CO., Ltd. Patentee before: JIANGSU WANBANG BIOPHARMACEUTICAL GROUP CO.,LTD. |
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