CN102086190B - Cilostazol compound and novel preparation method thereof - Google Patents
Cilostazol compound and novel preparation method thereof Download PDFInfo
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- CN102086190B CN102086190B CN 201110032250 CN201110032250A CN102086190B CN 102086190 B CN102086190 B CN 102086190B CN 201110032250 CN201110032250 CN 201110032250 CN 201110032250 A CN201110032250 A CN 201110032250A CN 102086190 B CN102086190 B CN 102086190B
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- cilostazole
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Abstract
The invention discloses a cilostazol compound and a novel preparation method thereof. In the preparation method, a neutral alumina column chromatography method is adopted, a proper stationary phase and a proper flowing phase are used, specifically, neutral alumina with a specific size is used as the stationary phase, a certain ratio of a mixing solvent of chloroform and acetonitrile is used as the flowing phase, and the column temperature is maintained to be higher than room temperature, thereby effectively purifying the cilostazol. The yield and purity are high, thus the preparation method is an effective method for obtaining high-purity cilostazol. By using the preparation method in the invention, the quality of the cilostazol product is improved, and the clinical toxicity of cilostazol compound in preparing medicaments with vasodilation and blood cell resistant functions are reduced.
Description
Technical field
The present invention relates to a kind of process for purification of compound, be specifically related to a kind of process for purification of Cilostazole compound, belong to medical technical field.
Background technology
Cilostazole (Cliostazol), chemical name is: 6-[4-(1-hexamethylene-1H-tetrazolium-5-yl)-Ding oxygen]-3,4 dihydro-2 (1H) quinolizidine morpholine ketone, molecular formula: C
20H
27N
5O
2, molecular weight 369.47, white crystalline powder, fusing point 157-160 ℃, structural formula is:
Cilostazole (Cilostazol) belongs to quinoline derivatives, it is the medicine of big tomb drugmaker of the big tomb Co., Ltd. of Japan development, China was in approval Tianjin Otsuka Pharmaceutical (China) Co., Ltd. import Cilostazole bulk drug in 1996, effect with vasodilation and antiplatelet function, can be used for treatment by atherosclerosis, Takayasu arteritis, thromboangiitis obliterans, chronic arteria occlusion disease due to the diabetes, Cilostazole is by suppressing phosphodiesterase activity in thrombocyte and the vascular smooth muscle, cAMP concentration in platelet increasing and the unstriated muscle, the effect of performance antiplatelet and vasodilation.
The synthetic method of Cilostazole abroad is starting raw material mostly with oxyethane, and is synthetic through reactions such as cyano groupization, bromine replacement, acylations, condensations; The CN200510022602.8 report is raw material with 5-chlorine valeronitrile and hexalin, by the synthetic Cilostazole of reactions such as condensation, cyclisation, oxidation, replacement; " synthetic chemistry " report in 2003 is raw material with δ-Wu Neizhi and hexahydroaniline, synthesize by condensation, chlorination, cyclisation, substitution reaction, 2004 " Anhui chemical industry " report is raw material with p-ethoxyaniline and 3-chlorpromazine chloride, synthesizes by condensation, chlorination, cyclisation, substitution reaction; 2007 " chemical engineer " report is that starting raw material is synthetic with 5 one chlorine valeryl chlorides and Para-Anisidine.
In the existing bibliographical information, the preparation method who is suitable for suitability for industrialized production mainly contains following three kinds, but all has weak point:
US Patent No. 4277479 uses ethanol to be reaction solvent, and 1,8-diazacyclo [5,4,0] hendecene-7 (DBU) is catalysts, and chloroform prepares Cilostazole for the aftertreatment extraction solvent, but contains two major impurities in the products obtained therefrom, and quality is not good; In the later patents WO2006022488 of this patent, disclose by recrystallization and removed above-mentioned two major impurities with the method for acquisition high purity (purity 〉=99.8%) product, but the total recovery loss is serious;
US Patent No. 6630590 uses the mixed solution of toluene and water to be reaction solvent, the mixture of salt of wormwood, tertiary butyl chlorination ammonium and ammonium sulfate is catalysts, methyl alcohol is that recrystallization solvent prepares Cilostazole, but the toxicity of toluene is bigger, there is security threat in HUMAN HEALTH, and environmental pollution is bigger;
It is reaction solvent that US Patent No. 2007105898 makes water, the mixture of methyl-2-pyrrolidone and sodium hydroxide is catalysts, the mixed solution of isopropyl acetate and water is that to prepare purity be 99.53% Cilostazole to recrystallization solvent, but the price of methyl-2-pyrrolidone and isopropyl acetate is more expensive, causes production cost to increase.
Above-mentioned synthetic method, yield is low, and the final product purity that obtains is not high, can not be used for large-scale production.In addition, deposit improper or shelf-time when long at compound, can cause active constituents of medicine content to reduce, color and luster is strengthened, and its related substances raises.In some cases, because controlling of production process is improper, cause pharmaceutical purity also undesirable.Prior art does not disclose special purification process, therefore is necessary underproof product is further carried out purifying, provides highly purified compound with high yield.
In view of this, the object of the present invention is to provide a kind of process for purification of Cilostazole, product yield height, quality are good, and avoid using toxic agent and expensive reagent, and environmental pollution is little, and production cost is low, is suitable for suitability for industrialized production.
Summary of the invention
Aspect separation and purification, the technician that this area has a universal experience knows clearly and is obtaining to face all difficulties aspect the high yield compound of high purity, all these just can be expected by the theory of existing general separation and purification absolutely not solution need overcome many difficult problems.
Generally speaking, conventional separation method has, and for example comprises the cooling of reaction mixture, collects the method for crystallization then after filtration; Comprise adding thermal crystalline, and with for example methyl alcohol or the washing of its analogue of alcohol, distill the method that desolventizing and cooling obtain crystallization then; Solvent extration; Dilution method; Recrystallization method; Column chromatography; Methods such as preparation thin-layer chromatography.
The applicant is on the basis of a large amount of existing documents, experiment by a large amount of screenings, find above-mentioned document and general method for purifying and separating for example method such as crystallization be difficult to obtain the compound of high purity high yield, and various separation purification method and multiple conditional parameter exist possibility and the unpredictability of varied combination.The inventor is through long-term conscientious research, and accident has been found a kind of refining purification process of Cilostazole compound, has obtained the highly purified product of high yield astoundingly.
The invention provides a kind of method of utilizing the neutral alumina column chromatography for separation and low-purity Cilostazole compound is carried out the method for purifying.
In embodiments of the invention, the invention provides a kind of process for purification of Cilostazole compound, it is characterized in that obtaining the pure product of Cilostazole by column chromatography for separation, the operation steps of this process is:
(1) the Cilostazole crude product is carried out sample on the chromatography column with after the moving phase dissolving;
(2) use the moving phase wash-out;
(3) collect Cilostazole wash-out position, get the pure product of Cilostazole after the desolventizing.
Wherein, described column chromatography be with neutral alumina as stationary phase, the mixed solvent of chloroform and acetonitrile is as moving phase, and is higher than under the room temperature condition at column temperature and carries out.
The applicant in the separation and purification process, has screened various filler chromatographic columns such as silica gel, aluminum oxide or macroporous resin through long-term conscientious big quantity research, and for example the particle diameter of silica gel is that 45-250 μ m, aperture are
Silica gel; Aluminum oxide or neutral alumina particle diameter are aluminum oxide or the neutral alumina of 18-200 μ m, the macroporous resin model is Amberlite XAD-6, Amberlite XAD-7, Amberlite XAD-8, Diaion HP2MG, GDX-501, HPD400, HPD450, HPD750, Amberlite XAD-9, Amberlite XAD-10, GDX-401, macroporous resins such as GDX-601, the unexpected application macroporous resin of finding of the inventor does not have clear improvement to the purity of product, silica gel is also undesirable, and special-purpose neutral alumina not only can fully adsorb composition impurity and other pigment in the upper prop thing, also this product purifying is had original windfall effect, and operation is simpler and easy.
In one aspect of the invention, the particle diameter of described stationary phase is 18-200 μ m, and the aperture is the pore neutral alumina of about 6nm.
In one aspect of the invention, neutral alumina can be for example for the ICNallumina N preferable particle size of supplier ICN be 18-63 μ m, and the aperture is the pore neutral alumina of 6nm, pH 7.5, preferable particle size is 18-32 μ m, and the aperture is the pore neutral alumina of 6nm, and pH 7.5.Perhaps, neutral alumina for example is supplier Baker column chromatography special neutral aluminum oxide, and particle diameter is 50-200 μ m, and the aperture is 6nm, pH 7.0 or pH 7.5.
In one aspect of the invention, as preferably, the quality of each purifying medicine is 1 with the ratio of the quality of chromatographic column filler: 10-200, the preferred mass ratio is 1: 15-100.The consumption of moving phase is as long as satisfy medicine wash-out fully basically, flow point Fractional Collections behind the wash-out, the content difference of the flow point Chinese traditional medicine of different sections, in order to obtain highly purified medicine (for example purity is greater than 99.5%), need medicament contg is merged greater than 85% flow point, preferably medicament contg is merged greater than 90% flow point.
In one aspect of the invention, the required purity that obtains in the methods of the invention depends on the amount of impurity and the operating environment of chromatographic column to a certain extent.The selection of organic solvent and consumption must be controlled in moving phase, make can not come out the impurity wash-out prematurely.Generally speaking, the chromatographic column of the used chromatographic column of the present invention comprises that diameter is about 0.1 to about 200cm, is preferably 3cm at least.The chromatogram column length scope is preferably about 10 centimetres to about 100 centimetres, and more preferably length range is about 20 centimetres to about 30 centimetres, and most preferred length is 25 centimetres.
As the present invention's one preferred embodiment, wherein the pressure of column chromatography is 0.1-3.0pa, is preferably 0.5-1.5pa.
As the present invention's one preferred embodiment, wherein the flow velocity of column chromatography is 0.5-2.1ml/min.
As the present invention's one preferred embodiment, wherein said column temperature keeps 35～40 ℃.
As the present invention's one preferred embodiment, wherein said moving phase is that chloroform and acetonitrile volume ratio are (4～8): 1 mixed solvent; Preferred described moving phase is that chloroform and acetonitrile volume ratio are 6: 1 mixed solvent.
As the present invention's one preferred embodiment, wherein step (3) is collected Cilostazole wash-out position, wash with water, and the solid drier drying, concentrating under reduced pressure steams except elutriant, gets the pure product of Cilostazole.
As the present invention's one preferred embodiment, wherein said solid drier is selected from one or more in anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate and the active neutral alumina.
The inventor carries out a large amount of optimization experiment on the basis of the above, screening has obtained suitable moving phase, therefore in one aspect of the invention, preferably, chromatographic column purification condition described in the above-mentioned process for purification is: fixed phase stuffing special neutral aluminum oxide, described moving phase is that chloroform and acetonitrile volume ratio are (4～8): 1 mixed solvent, and the column temperature of described column chromatography keeps 35～40 ℃, and the pressure of column chromatography is 0.5-1.5pa.
The process for purification that the present invention is described above, the purity of the pure product of wherein said Cilostazole is not less than 99.6%.
As the present invention's one preferred embodiment, the particle diameter of wherein said stationary phase is 18-63 μ m, and the aperture is the pore neutral alumina of 6nm; Preferable particle size is 18-32 μ m, and the aperture is the pore neutral alumina of 6nm.
Method for detecting purity is high performance liquid chromatography: chromatographic column: Alltima C
18Post (4.6mm * 150mm, 5 μ m), moving phase: acetonitrile: (potassium primary phosphate of 0.01mol/L PH7.4) is 6: 1 to phosphate buffered saline buffer, flow velocity: 1.0mi/min, column temperature: 30 ℃, detect wavelength: 254nm.
The application of Cilostazole compound in the medicine of preparation vasodilation and antiplatelet function of the inventive method preparation is provided in one aspect of the invention.
The present invention selects the neutral alumina column chromatography method for use, uses suitable stationary phase and moving phase, specifically, the employing neutral alumina is stationary phase, a certain proportion of chloroform and acetonitrile mixed solvent are moving phase, keep column temperature to be higher than room temperature, can make with extra care efficiently and the purifying Cilostazole.Its yield and purity are all very high, are a kind of simple effective methods that obtains the high purity Cilostazole.
The Cilostazole that the present invention makes has improved the quality product of preparation, has reduced toxic side effect.And compared with prior art, present method technology is simple and easy to do, the reaction conditions gentleness, and cost is low, the yield height, the product purity height is suitable for suitability for industrialized production.
Embodiment
Further specify the present invention by the following examples, but should not be construed as limitation of the present invention.
Embodiment 1
10g Cilostazole crude product (purity 95.5%) is dissolved in 200ml chloroform and the acetonitrile (6: 1), is added to the post top, weighting agent is particle diameter 18-32 μ m, the ICN alluminaN neutral alumina of aperture 6nm.The long 25cm of pillar, diameter 5cm, post is pressed 1.2pa, pump into chloroform and acetonitrile (6: 1) again and carry out column chromatography, flow velocity is 1.6ml/min, and column temperature keeps 35 ℃, pick up counting sampling, tracking monitor, carry out Fractional Collections, collect the Cilostazole elutriant, wash with water, anhydrous sodium sulfate drying, concentrating under reduced pressure, steaming desolventizes, get the pure product 9.1g of Cilostazole, yield 95%, purity 99.9%.
Comparative Examples 1
10g Cilostazole crude product (purity 95.5%) is dissolved in 200ml chloroform and the acetonitrile (6: 1), is added to the post top, weighting agent is particle diameter 18-32 μ m, the Kiselgel A of aperture 6nm.The long 25cm of pillar, diameter 5cm, post is pressed 1.2pa, pump into chloroform and acetonitrile (6: 1) again and carry out column chromatography, flow velocity is 1.6ml/min, and column temperature keeps 35 ℃, pick up counting sampling, tracking monitor, carry out Fractional Collections, collect the Cilostazole elutriant, wash with water, anhydrous sodium sulfate drying, concentrating under reduced pressure, steaming desolventizes, get Cilostazole purifying product 8.24g, yield 86.3%, purity 96.2%.
Embodiment 2
44g Cilostazole crude product (purity 94.3%) is dissolved in 700ml chloroform and the acetonitrile (4: 1), is added to the post top, the long 25cm of pillar, diameter 5cm, post is pressed 1.0pa, and weighting agent is particle diameter 18-32 μ m, the pore neutral alumina of the ICN allumina N of aperture 6nm.Pump into chloroform and acetonitrile (4: 1) again and carry out column chromatography, flow velocity is 0.5ml/min, and column temperature keeps 30 ℃, pick up counting sampling, tracking monitor, carry out Fractional Collections, collect the Cilostazole elutriant, wash with water, anhydrous sodium sulfate drying, concentrating under reduced pressure, steaming desolventizes, and gets the pure product 38.8g of Cilostazole, yield 93.5%, purity 99.8%.
Comparative Examples 2
44g Cilostazole crude product (purity 94.3%) is dissolved in 700ml chloroform and the acetonitrile (4: 1), is added to the post top, the long 25cm of pillar, diameter 5cm, post is pressed 1.0pa, and weighting agent is particle diameter 18-32 μ m, the Kiselgel A of aperture 6nm.Pump into chloroform and acetonitrile (4: 1) again and carry out column chromatography, flow velocity is 0.5ml/min, and column temperature keeps 30 ℃, pick up counting sampling, tracking monitor, carry out Fractional Collections, collect the Cilostazole elutriant, wash with water, anhydrous sodium sulfate drying, concentrating under reduced pressure, steaming desolventizes, and gets the pure product 35.2g of Cilostazole, yield 84.8%, purity 96.4%.
Embodiment 3
40g Cilostazole crude product (purity 96.1%) is dissolved in 700ml chloroform and the acetonitrile (8: 1), is added to the post top, the long 25cm of pillar, diameter 5cm, post is pressed 1.0pa, and weighting agent is particle diameter 50-200 μ m, the Baker pore neutral alumina of aperture 6nm.Pump into chloroform and acetonitrile (8: 1) again and carry out column chromatography, flow velocity is 2.1ml/min, and column temperature keeps 40 ℃, pick up counting sampling, tracking monitor, carry out Fractional Collections, collect the Cilostazole elutriant, wash with water, anhydrous sodium sulfate drying, concentrating under reduced pressure, steaming desolventizes, and gets the pure product 35.9g of Cilostazole, yield 93.4%, purity 99.8%.
Comparative Examples 3
40g Cilostazole crude product (purity 96.1%) is dissolved in 700ml chloroform and the acetonitrile (8: 1), is added to the post top, the long 25cm of pillar, diameter 5cm, post is pressed 1.0pa, and weighting agent is the pore macroporous resin of the Amberlite XAD-6 of aperture 6.3nm.Pump into chloroform and acetonitrile (8: 1) again and carry out column chromatography, flow velocity is 2.1ml/min, and column temperature keeps 40 ℃, pick up counting sampling, tracking monitor, carry out Fractional Collections, collect the Cilostazole elutriant, wash with water, anhydrous sodium sulfate drying, concentrating under reduced pressure, steaming desolventizes, and gets the pure product 32.7g of Cilostazole, yield 85.1%, purity 94.0%.
Comparative Examples 4
10g Cilostazole crude product (purity 95.5%) is dissolved in 200ml chloroform and the acetonitrile (1: 1), is added to the post top, weighting agent is particle diameter 18-32 μ m, the ICN alluminaN neutral alumina of aperture 6nm.The long 25cm of pillar, diameter 5cm, post is pressed 1.2pa, pump into chloroform and acetonitrile (1: 1) again and carry out column chromatography, flow velocity is 2.5ml/min, and column temperature keeps 25 ℃, pick up counting sampling, tracking monitor, carry out Fractional Collections, collect the Cilostazole elutriant, wash with water, anhydrous sodium sulfate drying, concentrating under reduced pressure, steaming desolventizes, get the pure product 8.5g of Cilostazole, yield 89.0%, purity 98.4%.
Compare by above-described embodiment and the used parameter of comparative example and result, as can be seen, the process for purification of Cilostazole compound provided by the invention, the purifying product yield height that makes, purity is good; Obtain beyond thought technique effect, can't expect in theory, obtained the highly purified product of high yield.
It is the purification process of the ion exchange resin exchange column of weighting agent that the inventor has also screened some macroporous resins owing to use the ion exchange resin exchange column can introduce foreign ion, purity also not be improved significantly.The inventor finds that in screening experiment neutral alumina column method of the present invention significantly is better than these purification process.
Foregoing description of the present invention is intended to explaining, rather than restriction.Concerning the art technology people, can carry out multiple variation or modification in the embodiment described herein.Do not depart from the scope of the present invention or spirit in can obtain these variations.Each reference that the application quotes is incorporated herein by reference in full at this.
Claims (10)
1. the process for purification of the Cilostazole compound of a structure as follows,
It is characterized in that: this method comprises the process that obtains the pure product of Cilostazole by column chromatography for separation, and the operation steps of this process is:
(1) the Cilostazole crude product is carried out sample on the chromatography column with after the moving phase dissolving;
(2) use the moving phase wash-out;
(3) collect Cilostazole wash-out position, get the pure product of Cilostazole after the desolventizing;
Wherein, described column chromatography be with neutral alumina as stationary phase, the mixed solvent of chloroform and acetonitrile is as moving phase, and is higher than under the room temperature condition at column temperature and carries out.
2. process for purification according to claim 1, it is characterized in that: the particle diameter of described stationary phase is 18-200 μ m, the aperture is the pore neutral alumina of 6nm.
3. process for purification according to claim 1 and 2, it is characterized in that: the pressure of column chromatography is 0.1-3.0Pa.
4. process for purification according to claim 3, it is characterized in that: the pressure of column chromatography is 0.5-1.5Pa.
5. process for purification according to claim 4, it is characterized in that: the flow velocity of column chromatography is 0.5-2.1ml/min.
6. process for purification according to claim 5 is characterized in that: 30～40 ℃ of described column temperature maintenances.
7. process for purification according to claim 6 is characterized in that: described moving phase is that chloroform and acetonitrile volume ratio are (4～8): 1 mixed solvent.
8. process for purification according to claim 7, it is characterized in that: described moving phase is that chloroform and acetonitrile volume ratio are 6: 1 mixed solvent.
9. process for purification according to claim 8, it is characterized in that: step (3) is collected Cilostazole wash-out position, wash with water, the solid drier drying, concentrating under reduced pressure, steam except elutriant, get the pure product of Cilostazole, wherein said solid drier is selected from one or more in anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate and the active neutral alumina.
10. process for purification according to claim 9, the purity of the pure product of wherein said Cilostazole is not less than 99.6%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1469864A (en) * | 2000-08-14 | 2004-01-21 | ������ҩ��ҵ����˾ | Process for preparing cilostazol |
| CN1553908A (en) * | 2002-09-10 | 2004-12-08 | ��V��ҩ��ʽ���� | Method for producing cilostazol |
| US7524960B2 (en) * | 2004-03-16 | 2009-04-28 | Chemagis Ltd. | Highly pure cilostazol and an improved process for obtaining same |
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| KR100633232B1 (en) * | 2004-08-25 | 2006-10-11 | 주식회사유한양행 | A novel method for purification of 6-[4-1-cyclohexyl-1h-tetrazol-5-ylbutoxy-3,4-dihydro-21h-quinolinone having high purity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1469864A (en) * | 2000-08-14 | 2004-01-21 | ������ҩ��ҵ����˾ | Process for preparing cilostazol |
| CN1553908A (en) * | 2002-09-10 | 2004-12-08 | ��V��ҩ��ʽ���� | Method for producing cilostazol |
| US7524960B2 (en) * | 2004-03-16 | 2009-04-28 | Chemagis Ltd. | Highly pure cilostazol and an improved process for obtaining same |
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