CN107382970A - A kind of synthetic method of Cilostazol - Google Patents
A kind of synthetic method of Cilostazol Download PDFInfo
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- CN107382970A CN107382970A CN201710618563.0A CN201710618563A CN107382970A CN 107382970 A CN107382970 A CN 107382970A CN 201710618563 A CN201710618563 A CN 201710618563A CN 107382970 A CN107382970 A CN 107382970A
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- Prior art keywords
- cilostazol
- synthetic method
- alcohol
- reaction
- sodium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a kind of synthetic method of Cilostazol, is catalyst using inorganic base in alcohol-water system, and Carbostyril derivative and tetranitroazole derivative are carried out into reaction generation Cilostazol at 75~80 DEG C.For the present invention using alcohol water mixed system as reaction media, course of reaction is homogeneous system, is not in that liquid expands, the full kettle problem of foam.After completion of the reaction, refining effect can be reached, product purity can be to more than 99.6% with standing separation lower floor phase containing buck, upper organic phase decrease temperature crystalline simultaneously.
Description
Technical field
The invention belongs to organic chemical synthesis field, and in particular to a kind of synthetic method of Cilostazol.
Background technology
Cilostazol, also known as Xi Sita azoles, the entitled 6- [4- (1- cyclohexyl -1H- pentylenetetrazole -5- bases) butoxy] of chemistry -
(the 1H)-quinolone of 3,4- dihydro -2, can suppress platelet aggregation, have antithrombotic effect, be that known antithrombotic, Brain circlulation change
Kind agent, antiinflammatory, antiulcer agent, hypotensor, antiasthmatics and phosphodiesterase inhibitors.The following institute of Cilostazol structural formula
Show：
International patent application WO2002/014283 discloses a kind of known method for producing Cilostazol, including：Turn in phase
In the presence of shifting catalyst, Carbostyril derivative and terazole derivatives are reacted, when being reacted with single solvent, and
Two reactions of solid-liquid, inorganic base are not dissolved in solvent, cause course of reaction slower, raw material conversion is not thorough.
International patent application WO2004/024716 discloses a kind of method for synthesizing Cilostazol, and it using single water is anti-to be
Medium is answered, is occurred in experimentation, reaction solution swelling, solid caused by reaction is insoluble in water, forms two-phase point
From reaction temperature is higher, and reaction solution color is also relatively deep.
The content of the invention
The invention provides it is a kind of be not in liquid expansion and the high Cilostazol of product purity synthetic method, with alcohol
Water mixed system is reaction media, and course of reaction is homogeneous system, is not in that liquid expands, the full kettle problem of foam.Exist simultaneously
After the completion of reaction, refining effect, product purity, can be reached at upper organic phase decrease temperature crystalline with standing separation lower floor phase containing buck
Can be to more than 99.6%.
A kind of synthetic method of Cilostazol, it is characterised in that it is catalyst using inorganic base in alcohol-water system, will
Carbostyril derivative and tetranitroazole derivative carry out reaction generation Cilostazol, and reaction equation is：
Wherein, X represents halogen.
Further, Carbostyril derivative is 6- hydroxyl -3,4- dihydro-quinolones, tetranitroazole derivative be 1- cyclohexyl -
5- (4- chlorobutyls) -1,2,3,4- tetrazoliums.
The ratio between amount of material of Carbostyril derivative and tetranitroazole derivative is 1:1~2.
The mass ratio of Carbostyril derivative and alcohol water is 1:5~10.
The ratio between amount of material of Carbostyril derivative and inorganic base is 1:1~6.
Alcohol in alcohol-water system is lower alcohol, and the volume of alcohol accounts for the 40% to 80% of alcohol-water system.
The lower alcohol is ethanol, isopropanol, ethylene glycol or butanol.
Inorganic base is potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium acid carbonate, saleratus, gold
Belong to one or more in sodium, metallic potassium.
To prevent reaction color from deepening, sodium sulfite or sodium thiosulfate can be added in reaction system, with quinolone
The ratio between amount of material of derivative is 0.06~1:1.
Reaction terminates rear reaction solution stratification, separates buck phase, organic phase decrease temperature crystalline, obtains Cilostazol.
Research is found, when by the use of pure water as reaction media, with the extension in reaction time, the reaction later stage occurs largely
Solid, there is swelling in reactor, and mixing effect is restricted, and is unfavorable for late phase reaction progress.Simultaneous reactions temperature mistake
Height, a part of impurity can accordingly occur.
The present invention is using Carbostyril derivative as starting material, with tetranitroazole derivative under the catalytic action of inorganic base, closes
Into Cilostazol.Wherein tetranitroazole derivative can not only react synthesis target product with Carbostyril derivative, moreover it is possible to Xi Luota
Azoles further reacts synthesis Cilostazol impurity C, so to control reaction temperature, and material ratio in preparation process.
Carbostyril derivative of the present invention and four azo-cycle derivatives reactions, can efficiently, and high-purity prepares Cilostazol, due to
Reaction temperature is reacted between 75 to 80 DEG C, and the effective four azo-cycle derivatives that reduce further react with Cilostazol；The present invention
From beginning end, reaction is all homogeneous reaction, avoids occurring expansion of solids phenomenon in course of reaction, reduces work safety accident, instead
It is homogeneous reaction to answer liquid, after the reaction the phase can direct stratification, separation lower floor buck layer, the direct decrease temperature crystalline of organic phase,
Centrifugation.The present invention can greatly reduce waste water, reduce and rinse filter cake process with a large amount of water in centrifugal process, and ethanol mother liquor can return
Receipts are applied mechanically, and are reduced production cost, are reduced environmental pollution.
Embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in
This：
Embodiment 1
In 2000L reactors, 1- cyclohexyl -5- (4- chlorobutyls) -1,2,3,4- tetrazolium 135g (0.556mol) is added,
6- hydroxyl -3,4- dihydro-quinolone 90g (0.552mol), potassium carbonate 152g (1.1mol), sodium hydroxide 18g (0.45mol) are sub-
Sodium sulphate 4.5g (0.036mol), 66.7% ethanol 780g, reaction 8 hours are maintained the reflux for, reaction, which finishes, adds water 300g, stirring
Flow back 30min, stratification, and alkaline aqueous phase is transferred to waste water system, and organic phase is down to 10 degree, stirred crystallization, filtered, with part second
Alcohol elutes.85 DEG C are dried under reduced pressure, white solid 175.2g, yield 86%, purity 99.81%.159 DEG C of fusing point.
The detection method of purity：
It is filler with octadecylsilane chemically bonded silica；Using acetonitrile as mobile phase A, water is Mobile phase B；Flow velocity is every point
Clock 1ml；Column temperature is 40 DEG C；Detection wavelength is 254nm；According to the form below carries out gradient elution.
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 50 | 50 |
| 9 | 50 | 50 |
| 20 | 72 | 28 |
| 22 | 72 | 28 |
| 22.1 | 50 | 50 |
| 35 | 50 | 50 |
Take Cilostazol reference substance and impurity reference substance each appropriate, add acetonitrile-water (50:50) dissolve and dilute and be made often
Containing about Cilostazol 0.05mg and impurity 0.01mg mixed solution in 1ml, as system suitability solution.Take system suitability
The separating degree of solution 20ul, injection liquid chromatograph, record chromatogram, Cilostazol and impurity should be not less than 3.0, theoretical tray
Number must not be less than 5000 based on Cilostazol peak.
Embodiment 2
In 2000L reactors, 1- cyclohexyl -5- (4- chlorobutyls) -1,2,3,4- tetrazolium 140g (0.577mol) is added,
6- hydroxyl -3,4- dihydro-quinolone 90g (0.552mol), potassium carbonate 192.5g (1.39mol), sodium sulfite 4.5g
(0.036mol), 50% ethanol 800g, reaction 9 hours are maintained the reflux for, reaction, which finishes, adds water 200g, is stirred at reflux 30min, quiet
Layering is put, alkaline aqueous phase is transferred to waste water system, and organic phase is down to 10 degree, stirred crystallization, filtered, with part ethanol rinse.85℃
It is dried under reduced pressure, white solid 167.5g, yield 82.2%, purity 99.75%.158 DEG C of fusing point.
Embodiment 3
In 2000L reactors, 1- cyclohexyl -5- (4- chlorobutyls) -1,2,3,4- tetrazolium 148g (0.61mol) is added,
6- hydroxyl -3,4- dihydro-quinolone 90g (0.552mol), potassium carbonate 192.5g (1.39mol), sodium hydroxide 18g
(0.45mol), sodium sulfite 4.5g (0.036mol), 66.7% ethanol 800g, reaction 8 hours are maintained the reflux for, reaction, which finishes, to be added
Entering water 300g, be stirred at reflux 30min, stratification, alkaline aqueous phase is transferred to waste water system, and organic phase is down to 10 degree, stirred crystallization,
Filtering, with part ethanol rinse.85 DEG C are dried under reduced pressure, white solid 187.5g, yield 92%, purity 99.83%.Fusing point 159
℃。
Embodiment 4
In 2000L reactors, 1- cyclohexyl -5- (4- chlorobutyls) -1,2,3,4- tetrazolium 148g (0.61mol) is added,
6- hydroxyl -3,4- dihydro-quinolone 90g (0.552mol), potassium carbonate 152g (1.1mol), potassium hydroxide 18.5g (0.33mol),
Sodium sulfite 5.5g (0.044mol), 66.7% ethanol 800g, reaction 9 hours are maintained the reflux for, reaction, which finishes, adds water 300g, stirs
Backflow 30min, stratification are mixed, alkaline aqueous phase is transferred to waste water system, and organic phase is down to 10 degree, stirred crystallization, filtering, uses part
Ethanol rinse.85 DEG C are dried under reduced pressure, white solid 179.8g, yield 88.2%, purity 99.73%.159 DEG C of fusing point.
Embodiment 5
In 2000L reactors, 1- cyclohexyl -5- (4- chlorobutyls) -1,2,3,4- tetrazolium 215g (0.886mol) is added,
6- hydroxyl -3,4- dihydro-quinolone 90g (0.552mol), potassium carbonate 192.5g (1.39mol), sodium hydroxide 18g
(0.45mol), sodium sulfite 4.5g (0.036mol), 66.7% ethanol 800g, reaction 7 hours are maintained the reflux for, reaction, which finishes, to be added
Entering water 300g, be stirred at reflux 30min, stratification, alkaline aqueous phase is transferred to waste water system, and organic phase is down to 10 degree, stirred crystallization,
Filtering, with part ethanol rinse.85 DEG C are dried under reduced pressure, white solid 185.4g, yield 91%, purity 99.81%.Fusing point 159
℃。
Embodiment 6
In 5000L reactors, 1- cyclohexyl -5- (4- chlorobutyls) -1,2,3,4- tetrazolium 296g (1.22mol) is added,
6- hydroxyl -3,4- dihydro-quinolone 180g (1.1mol), potassium carbonate 385g (2.79mol), sodium hydroxide 36g (0.9mol) are sub-
Sodium sulphate 9g (0.071mol), 66.7% ethanol 1600g, reaction 8 hours are maintained the reflux for, reaction, which finishes, adds water 600g, stirring
Flow back 40min, stratification, and alkaline aqueous phase is transferred to waste water system, and organic phase is down to 5 degree, stirred crystallization, filtered, with part second
Alcohol elutes.85 DEG C are dried under reduced pressure, white solid 377g, yield 92.5%, purity 99.8%.159 DEG C of fusing point.
Embodiment 7
In 1500L reactors, 1- cyclohexyl -5- (4- brombutyls) -1,2,3,4- tetrazolium 165.7g is added
(0.577mol), 6- hydroxyl -3,4- dihydro-quinolone 90g (0.552mol), potassium carbonate 192.5g (1.39mol), sodium sulfite
4.5g (0.036mol), 50% ethanol 800g, reaction 12 hours are maintained the reflux for, reaction, which finishes, adds water 200g, is stirred at reflux
30min, stratification, alkaline aqueous phase are transferred to waste water system, and organic phase is down to 10 degree, stirred crystallization, filtering, drenched with part ethanol
Wash.85 DEG C are dried under reduced pressure, white solid 160g, yield 78.5%, purity 99.75%.158 DEG C of fusing point.
With 1- cyclohexyl -5- (4- brombutyls) -1,2,3,4- tetrazoliums replace 1- cyclohexyl -5- (4- chlorobutyls) -1,2,3,
When 4- tetrazoliums react with 6- hydroxyls -3,4- dihydro-quinolone, the reaction time is longer, is unfavorable for workshop industrialization progress.Another original
Cause, in price than 1- cyclohexyl -5- (4- chlorobutyls) -1,2,3,4- tetrazoliums are expensive, after the completion of reaction, in the wastewater treatment stage,
KBr is more than potassium chloride quantity, and recovery processing is cumbersome, increases solid waste salt treatment cost.In production, X is chlorine atom
More, use is more universal.
Claims (10)
1. a kind of synthetic method of Cilostazol, it is characterised in that be catalyst using inorganic base, by quinoline in alcohol-water system
Promise ketone derivatives and tetranitroazole derivative carry out reaction generation Cilostazol at 75~80 DEG C, and reaction equation is：
Wherein, X represents halogen.
2. the synthetic method of Cilostazol according to claim 1, it is characterised in that：Carbostyril derivative be 6- hydroxyls-
3,4- dihydro-quinolones, tetranitroazole derivative are 1- cyclohexyl -5- (4- chlorobutyls) -1,2,3,4- tetrazoliums.
3. the synthetic method of Cilostazol according to claim 1, it is characterised in that：Carbostyril derivative spreads out with tetrazole
The ratio between amount of material of biology is 1:1~2.
4. the synthetic method of Cilostazol according to claim 1, it is characterised in that：The matter of Carbostyril derivative and alcohol water
Amount is than being 1:5~10.
5. the synthetic method of Cilostazol according to claim 1, it is characterised in that：Carbostyril derivative and inorganic base
The ratio between amount of material is 1:1~6.
6. the synthetic method of Cilostazol according to claim 1, it is characterised in that：Alcohol in alcohol-water system is rudimentary
Alcohol, the volume of alcohol account for the 40% to 80% of alcohol-water system.
7. the synthetic method of Cilostazol according to claim 1, it is characterised in that：The lower alcohol is ethanol, isopropyl
Alcohol, ethylene glycol or butanol.
8. the synthetic method of Cilostazol according to claim 1, it is characterised in that：Inorganic base is potassium hydroxide, hydrogen-oxygen
Change one or more in sodium, lithium hydroxide, potassium carbonate, sodium carbonate, sodium acid carbonate, saleratus, metallic sodium, metallic potassium.
9. the synthetic method of Cilostazol according to claim 1, it is characterised in that：Sodium sulfite is added in reaction system
Or sodium thiosulfate, it is 0.06~1 with the ratio between the amount of material of Carbostyril derivative:1.
10. the synthetic method of Cilostazol according to claim 1, it is characterised in that：Reaction terminates rear reaction solution and stood
Layering, buck phase is separated, organic phase decrease temperature crystalline, obtains Cilostazol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710618563.0A CN107382970A (en) | 2017-07-26 | 2017-07-26 | A kind of synthetic method of Cilostazol |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710618563.0A CN107382970A (en) | 2017-07-26 | 2017-07-26 | A kind of synthetic method of Cilostazol |
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| Publication Number | Publication Date |
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| CN107382970A true CN107382970A (en) | 2017-11-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710618563.0A Pending CN107382970A (en) | 2017-07-26 | 2017-07-26 | A kind of synthetic method of Cilostazol |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279072A (en) * | 2015-06-23 | 2017-01-04 | 中美华世通生物医药科技（武汉）有限公司 | Compound as well as preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1469864A (en) * | 2000-08-14 | 2004-01-21 | ������ҩ��ҵ����˾ | Process for preparing cilostazol |
| WO2004024716A1 (en) * | 2002-09-10 | 2004-03-25 | Otsuka Pharmaceutical Co., Ltd. | Process for producing cilostazol |
| CN101434598A (en) * | 2008-12-19 | 2009-05-20 | 重庆康乐制药有限公司 | Preparation of cilostazol |
-
2017
- 2017-07-26 CN CN201710618563.0A patent/CN107382970A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1469864A (en) * | 2000-08-14 | 2004-01-21 | ������ҩ��ҵ����˾ | Process for preparing cilostazol |
| WO2004024716A1 (en) * | 2002-09-10 | 2004-03-25 | Otsuka Pharmaceutical Co., Ltd. | Process for producing cilostazol |
| CN1553908A (en) * | 2002-09-10 | 2004-12-08 | ��V��ҩ��ʽ���� | Method for producing cilostazol |
| CN101434598A (en) * | 2008-12-19 | 2009-05-20 | 重庆康乐制药有限公司 | Preparation of cilostazol |
| CN101434598B (en) * | 2008-12-19 | 2012-11-07 | 重庆康乐制药有限公司 | Preparation of cilostazol |
Non-Patent Citations (1)
| Title |
|---|
| 柳丽艳等: "新型药物西洛他唑的合成", 《化学工程师》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279072A (en) * | 2015-06-23 | 2017-01-04 | 中美华世通生物医药科技（武汉）有限公司 | Compound as well as preparation method and application thereof |
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Application publication date: 20171124 |