CN110028454A - A kind of preparation method of cis- ozagrel - Google Patents
A kind of preparation method of cis- ozagrel Download PDFInfo
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- CN110028454A CN110028454A CN201910378098.7A CN201910378098A CN110028454A CN 110028454 A CN110028454 A CN 110028454A CN 201910378098 A CN201910378098 A CN 201910378098A CN 110028454 A CN110028454 A CN 110028454A
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C07B2200/09—Geometrical isomers
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Abstract
The present invention relates to disclose a kind of cis- ozagrelPreparation method, be using ozagrel methyl ester or ozagrel ethyl ester be that raw material obtains cis- ozagrel methyl ester or ozagrel ethyl ester, reaction is then hydrolyzed under the action of catalyst and blue light, it is obtained through preparation chromatographic isolation；Preparation method of the present invention, raw material is cheap and easy to get, and synthesis step is simple, and reaction condition is mild, process stabilizing, favorable reproducibility；The cis- ozagrel that preparation method of the present invention obtains is the necessity of ozagrel quality control, can effectively identify the impurity generated in ozagrel synthesis, and carry out detection and quantitative control to related substance.
Description
Technical field
The present invention relates to pharmaceutical technology field more particularly to a kind of preparation methods of cis- ozagrel.
Background technique
Ozagrel (formula II) is a kind of novel platelet aggregation inhibitor, is the thromboxane A of current first listing2Synthesis
Enzyme inhibitor.Its Chinese name is known as: trans- -3- [4- (1H- imidazoles -1- ylmethyl) phenyl] -2- acrylic acid；English name are as follows:
(E)-3-[4-(imidazol-1-ylmethyl)phenyl]prop-2-enoic acid.Its chemical structure are as follows:
Ozagrel can selectively inhibit Thromboxane synthetase, to inhibit thromboxane A2Generation and promote forefront ring
Element (PGI2) generation, improve the balance between the two, it is final to inhibit platelet aggregation and mitigate vasopasm, improve brain part
Microcirculation and energy metabolism impairment when ischemic, play the role of curing thrombus cerebral infarction.
Patent No. CN201110455771.6, discloses a kind of synthetic method of ozagrel, and this method is with by 4- first
Base ethyl cinnamate reacts to obtain 4- bromomethyl ethyl cinnamate with NBS；4- bromomethyl ethyl cinnamate reacts to obtain with imidazoles
Ozagrel ethyl ester；Ozagrel ethyl ester hydrolyzes to obtain ozagrel crude product, is refining to obtain ozagrel through double solvents.Synthesis
Route is as follows:
The health and lives that drug quality is directly related to patient are safe, are drugs concerning social the medical treatment safe problem
Safety, validity and stability premise.Impurity research is an important content of drug quality research；Impurity research
And control is one of the key element that drug quality guarantees.Cis- ozagrel is the isomer of ozagrel, is being synthesized
The impurity may be generated during ozagrel.Therefore, to the preparation of the impurity and research to ozagrel technical study
It has great significance with quality control.
There has been no the synthesis of the cis- ozagrel of relevant document report at present.Therefore, design safety is simple, Focus
Preparation method reduces by-product and generates, improves product yield, reduce the pass that cost is cis- ozagrel Study on preparation
Key, and the prior art can not be met；Therefore, the prior art is defective, needs to improve.
Summary of the invention
Present invention generally provides a kind of safety, simple process, and product yield is high, the system of low-cost cis- ozagrel
Preparation Method, and provide its application in the control of ozagrel quality.
In order to solve the above technical problems, one technical scheme adopted by the invention is that: the preparation method of cis- ozagrel,
The preparation method includes the following steps:
Under nitrogen protection, ozagrel methyl ester or ozagrel ethyl ester are dissolved in the first solvent, catalysis is added
Agent, at a temperature of first, with blue light light irradiation react 24 hours, filtering, filtrate concentration remove solvent, add the second solvent and
Alkali reacts 5 hours under second temperature, and prepared by products therefrom is made cis- ozagrel after purification.
Preferably, the first solvent described in above-mentioned steps are as follows: Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, methanol, ethyl alcohol, isopropyl
Alcohol, acetonitrile, any one in acetone, and its volume (V) that the first solution is added and ozagrel methyl ester or ozagrel
Ethyl ester quality (M) ratio are as follows: V:M=5~15:1；Further, the first solution is acetonitrile, and the volume (V) and ozagrel of acetonitrile
Methyl esters or ozagrel ethyl ester quality (M) are than being 10:1.
Preferably, the catalyst described in above-mentioned steps are as follows: dichloro four [2- (2- pyridyl group) phenyl] two iridium (III), three
(acetylacetone,2,4-pentanedione root) closes iridium (III), three (1- Phenylpyrazoles) close iridium (III), three (1- phenyl-isoquinolin) close iridium (III), three (2- benzene
Yl pyridines) close any one in iridium (III), and the amount (mol) for the catalyst material being added and ozagrel methyl ester or difficult to understand prick
The amount (mol) of the substance of Gray's ethyl ester is than being 0.01~0.2:1；Further, catalyst is that three (2- phenylpyridines) close iridium (III),
And three (2- phenylpyridine) amount for closing the amount (mol) of iridium (III) substance and the substance of ozagrel methyl ester or ozagrel ethyl ester
(mol) than being 0.03:1.
Preferably, the first temperature described in above-mentioned steps are as follows: 10~50 DEG C；Further, the first temperature is 25 DEG C.
Preferably, the blue-ray light described in above-mentioned steps are as follows: the LED light or fluorescent lamp of 36W~100W；Further,
Blue-ray light is the LED light of 100W.
Preferably, the second solvent being added in above-mentioned steps is methanol, ethyl alcohol, tetrahydrofuran, any one in DMF
The mixed solvent that kind is formed with water, and the volume ratio of the second solvent and water is 5.0~9.0:1；Further, the second solvent is first
Alcohol/water mixed solvent, and the volume ratio of methanol and water is 8.0:1.
Preferably, the alkali described in above-mentioned steps are as follows: sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, ethyl alcohol
Any one in sodium, and the substance of the amount (mol) of the substance for the alkali being added and ozagrel methyl ester or ozagrel ethyl ester
Amount (mol) than be 1.0~3.0:1；Further, alkali is sodium hydroxide, and be added sodium hydroxide substance amount (mol) with
The amount (mol) of the substance of ozagrel methyl ester or ozagrel ethyl ester is than being 2.0:1.
Preferably, the second temperature described in above-mentioned steps are as follows: 20~70 DEG C, further, second temperature is 45 DEG C.
Beneficial effect compared with the existing technology is, using the above scheme, by the present invention in that with ozagrel methyl ester or
Person's ozagrel ethyl ester is that raw material obtains cis- ozagrel methyl ester or ozagrel under the action of catalyst and blue light
Then reaction is hydrolyzed in ethyl ester, be made through preparation chromatographic isolation；And it is cheap and easy to get to prepare cis- ozagrel raw material, synthesis
Step is simple, and reaction condition is mild, process stabilizing, favorable reproducibility；Moreover, cis- ozagrel is ozagrel matter in the present invention
The necessity for measuring control can effectively identify the impurity generated in ozagrel synthesis, and related substance is detected and determined
Amount control.
Detailed description of the invention
Illustrate embodiment or technical solution in the prior art in order to clearer, it below will be to embodiment or the prior art
The required attached drawing used is briefly described in description, it is clear that, the accompanying drawings in the following description is only some realities invented
Example is applied, it for those of ordinary skill in the art, without creative efforts, can also be according to these attached drawings
Obtain other attached drawings.
Fig. 1 is the MS spectrogram of cis- ozagrel in embodiment 1；
Fig. 2 is cis- ozagrel in embodiment 11HNMR spectrogram；
Fig. 3 is the HPLC spectrogram of cis- ozagrel in embodiment 2；
Fig. 4 is the HPLC positioning spectrogram that cis- ozagrel is detected in ozagrel in embodiment 2.
Specific embodiment
To facilitate the understanding of the present invention, in the following with reference to the drawings and specific embodiments, the present invention will be described in more detail.
A better embodiment of the invention is given in the attached drawing.But the invention can be realized in many different forms, and unlimited
In this specification described embodiment.On the contrary, purpose of providing these embodiments is makes to the disclosure
Understand more thorough and comprehensive.
It should be noted that it can directly on the other element when element is referred to as " being fixed on " another element
Or there may also be elements placed in the middle.When an element is considered as " connection " another element, it, which can be, is directly connected to
To another element or it may be simultaneously present centering elements.Term used in this specification " fixation ", " integrated molding ",
For illustrative purposes only, the similar unit of structure is to identical label in the figure for "left", "right" and similar statement
Mark.
Unless otherwise defined, technical and scientific term all used in this specification is led with technology of the invention is belonged to
The normally understood meaning of the technical staff in domain is identical.Used term is only in the description of the invention in this specification
The purpose of description specific embodiment is not intended to the limitation present invention.
As shown in Figure 1, one embodiment of the present of invention is:
The cis- ozagrel of embodiment 1 the preparation method is as follows:
Under nitrogen protection, ozagrel methyl ester (2.42g, 10mmol, 1.0eq) is dissolved in acetonitrile (24mL), is added
Three (2- phenylpyridines) close iridium (III) (196mg, 0.3mmol, 0.03eq), anti-with 100W LED blue light light irradiation at 25 DEG C
24 lab scales are answered, are filtered, insoluble matter is removed, after filtrate is spin-dried for concentration, are added methanol/water (V:V=8:1,19mL), sodium hydroxide
(1.00g, 25mmol, 2.5eq), charging, which finishes, is warming up to 45 DEG C of reactions 5 hours, through preparing chromatogram purification after concentration removing solvent
Cis- ozagrel 950mg, yield 41.7%, HPLC purity 99.78% is made.
MS (m/z): 229.1 (M+H)+1H NMR (400MHz, DMSO-d6): δ 9.21 (s, 1H), 7.78 (s, 1H), 7.67
(s, 1H), 7.63 (d, J=8.4Hz, 2H), 7.39 (d, J=8.4Hz, 2H), 6.93 (d, J=12.8Hz, 1H), 6.01 (d, J
=12.8Hz, 1H), 5.44 (s, 2H).
The HPLC of the cis- ozagrel of embodiment 2 is detected
The HPLC detection method of cis- ozagrel is as follows:
Chromatographic column: YMC-Pack Pro C18 4.6X250mm5 μm
Mobile phase:
A: methanol B:5g/L ammonium acetate solution
Mobile phase ratio: A:B=50:50
Column temperature: 35 DEG C
Detection wavelength: 257nm
Flow velocity: 0.6mL/min
Time: 20.00min.
It should be noted that above-mentioned each technical characteristic continues to be combined with each other, the various embodiments not being enumerated above are formed,
It is accordingly to be regarded as the range of description of the invention record；Also, for those of ordinary skills, it can add according to the above description
To improve or convert, and all these modifications and variations should all belong to the protection domain of appended claims of the present invention.
Claims (8)
1. a kind of preparation method of cis- ozagrel, which is characterized in that the preparation method includes the following steps:
Under nitrogen protection, ozagrel methyl ester or ozagrel ethyl ester are dissolved in the first solvent, catalyst is added, in
It at a temperature of first, is reacted 24 hours with blue light light irradiation, filtering, filtrate concentration removes solvent, the second solvent and alkali are added, in
It is reacted 5 hours under second temperature, prepared by products therefrom is made cis- ozagrel after purification.
2. the preparation method of cis- ozagrel according to claim 1, which is characterized in that first solvent are as follows: Isosorbide-5-Nitrae-
Dioxane, tetrahydrofuran, methanol, ethyl alcohol, isopropanol, acetonitrile, any one in acetone, and the volume of the first solution is added
(V) compare with ozagrel methyl ester or ozagrel ethyl ester quality (M) are as follows: V:M=5~15:1.
3. the preparation method of cis- ozagrel according to claim 1, which is characterized in that the catalyst are as follows: dichloro four
[2- (2- pyridyl group) phenyl] two iridium (III), three (acetylacetone,2,4-pentanedione roots) close iridium (III), three (1- Phenylpyrazoles) close iridium, three (1-
Phenyl-isoquinolin) close iridium (III), three (2- phenylpyridines) close iridium in any one, and be added catalyst substance amount
(mol) with ozagrel methyl ester or the amount (mol) of the substance of ozagrel ethyl ester than being 0.01~0.2:1.
4. the preparation method of cis- ozagrel according to claim 1, which is characterized in that first temperature are as follows: 10~
50℃。
5. the preparation method of cis- ozagrel according to claim 1, which is characterized in that the blue-ray light are as follows: 36W~
The LED light or fluorescent lamp of 100W.
6. the preparation method of cis- ozagrel according to claim 1, which is characterized in that it is first that the second solvent, which is added,
The mixed solvent of alcohol, ethyl alcohol, tetrahydrofuran, any one in DMF with water composition, and the volume ratio of the second solvent and water is
5.0~9.0:1.
7. the preparation method of cis- ozagrel according to claim 1, which is characterized in that the alkali are as follows: sodium hydroxide, hydrogen
Potassium oxide, lithium hydroxide, sodium methoxide, any one in sodium ethoxide, and the amount (mol) and ozagrel of the substance for the alkali being added
The amount (mol) of the substance of methyl esters or ozagrel ethyl ester is than being 1.0~3.0:1.
8. the preparation method of cis- ozagrel according to claim 1, which is characterized in that the second temperature are as follows: 20~
70℃。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111855842A (en) * | 2020-06-30 | 2020-10-30 | 武汉九州钰民医药科技有限公司 | Detection method and application of related substances of ozagrel sodium |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558061A (en) * | 2011-12-31 | 2012-07-11 | 北京易明康元医药科技有限公司 | Synthetic method of ozagrel |
| CN107698513A (en) * | 2017-11-01 | 2018-02-16 | 浙江科瑞医药科技有限公司 | A kind of preparation method of sodium ozagrel |
| CN111333581A (en) * | 2020-04-22 | 2020-06-26 | 北京哈三联科技有限责任公司 | Synthetic method of ozagrel sodium |
-
2019
- 2019-05-08 CN CN201910378098.7A patent/CN110028454A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558061A (en) * | 2011-12-31 | 2012-07-11 | 北京易明康元医药科技有限公司 | Synthetic method of ozagrel |
| CN107698513A (en) * | 2017-11-01 | 2018-02-16 | 浙江科瑞医药科技有限公司 | A kind of preparation method of sodium ozagrel |
| CN111333581A (en) * | 2020-04-22 | 2020-06-26 | 北京哈三联科技有限责任公司 | Synthetic method of ozagrel sodium |
Non-Patent Citations (3)
| Title |
|---|
| FUMITOSHI HIRAYAMA ET AL.: "Prominent inclusion effect of dimethyl-β-cyclodextrin on photoisomerization of the thromboxane synthetase inhibitor (E)-4-(1-imidazoylmethyl)cinnamic acid", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
| KUN ZHAN ET AL.: "Visible-Light Photocatalytic E to Z Isomerization of Activated Olefins and Its Application for the Syntheses of Coumarins", 《CATALYSTS》 * |
| 王道林 等: "奥扎格雷钠的合成", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111855842A (en) * | 2020-06-30 | 2020-10-30 | 武汉九州钰民医药科技有限公司 | Detection method and application of related substances of ozagrel sodium |
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Application publication date: 20190719 |