CN107698513A - A kind of preparation method of sodium ozagrel - Google Patents
A kind of preparation method of sodium ozagrel Download PDFInfo
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- CN107698513A CN107698513A CN201711058278.4A CN201711058278A CN107698513A CN 107698513 A CN107698513 A CN 107698513A CN 201711058278 A CN201711058278 A CN 201711058278A CN 107698513 A CN107698513 A CN 107698513A
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- ethyl cinnamate
- imidazolmethyl
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- bromomethyl
- sodium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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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Abstract
The invention discloses a kind of preparation method of sodium ozagrel, this method includes：Using acetonitrile as solvent, under the initiation of azodiisobutyronitrile, bromination reaction is occurred to methyl cinnamyl acetoacetic ester and N bromo-succinimides, obtained to bromomethyl ethyl cinnamate；Using sodium hydroxide as acid binding agent, tetrahydrofuran is solvent, and condensation reaction occurs to bromomethyl ethyl cinnamate and imidazoles, obtains imidazolmethyl ethyl cinnamate；Imidazolmethyl ethyl cinnamate obtains sodium ozagrel through basic hydrolysis.The present invention is using sodium hydroxide as acid binding agent, tetrahydrofuran is that solvent carries out condensation reaction, so that without toxic component in the product finally obtained, and the yield and purity of product are effectively increased, the content of the genotoxicity impurity (to bromomethyl ethyl cinnamate and to dibromo methyl cinnamyl acetoacetic ester) in product is zero.
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly to a kind of preparation method of sodium ozagrel.
Background technology
Sodium ozagrel (sodium ozagrel), entitled trans -3- [4- (1H- imidazoles -1- methyl) the phenyl] -2- of chemistry
PAA was Japanese ONO Pharmaceutical Co., Ltd. in the first thrombus launched with trade name Cataclot in 1989
Plain synthetase inhibitors；It can hinder prostaglandin (PGH2) generation thromboxane (TXA2), promote PGH derived from blood platelet2Turn
To endothelial cell, endothelial cell is synthesizing PGI2, so as to improve TXA2With prostaglandin PGI2Balance it is abnormal.Ozagrel
Sodium has the function that to suppress hematoblastic aggregation and expansion blood vessel.Clinically, Sodium Ozagrel is mainly used in treating acute blood
Bolt cerebral infarction and the adjoint dyskinesia of cerebral infarction.
At present, the synthesis route of sodium ozagrel has several, and conventional is that methyl cinnamic acid lipid bromination will be obtained
To bromomethyl cinnamic acid lipid, bromomethyl cinnamic acid fat and imidazoles are reacted to obtain ozagrel esters, obtained after basic hydrolysis
To sodium ozagrel.This method comparative maturity, it is adapted to industrialized production, but the synthetic method has the defects of yield is relatively low.
On the other hand, the application for a patent for invention that application publication number is CN102558061A discloses a kind of synthesis side of ozagrel
Method, this method will react to obtain to bromomethyl ethyl cinnamate to methyl cinnamyl acetoacetic ester and N- bromo-succinimides；To bromine
Methyl cinnamyl acetoacetic ester reacts to obtain ozagrel ethyl ester with imidazoles；Ozagrel ethyl ester hydrolyzes to obtain ozagrel crude product, warp
Double solvents is refining to obtain ozagrel.The invention preparation method has the advantages of yield is high, and environmental pollution is small, is more suitable for
Industrialized production, ozagrel purity is up to more than 99.8%, and single impurity is less than 0.1%, and total impurities is less than 0.2%.
But in the above method to bromomethyl ethyl cinnamate and imidazoles it is the reaction carried out in acetone soln, acetone
Belong to easily system poison, purchase and management have larger problem；Secondly, had in the reaction to bromomethyl ethyl cinnamate and imidazoles
Imidazolmethyl ethyl cinnamate dimer produces, and have impact on the yield and purity of ozagrel ethyl ester, adds the difficulty of post processing
Degree；In addition, imidazolmethyl ethyl cinnamate synthesising reacting time is long, low production efficiency.
Therefore, it is necessary to probe into a kind of short reaction time, product yield and purity is high and the system of nontoxic sodium ozagrel
Standby technique, to solve the above problems.
The content of the invention
The invention discloses a kind of preparation method of sodium ozagrel, and the product that this method obtains is without toxic component, yield
High with purity, impurity content is extremely low.
Technical solution of the present invention is as follows：
A kind of preparation method of sodium ozagrel, comprises the following steps：
(1) using acetonitrile as solvent, under the initiation of azodiisobutyronitrile, to methyl cinnamyl acetoacetic ester and N- bromo succinyl
Bromination reaction occurs for imines, obtains to bromomethyl ethyl cinnamate；
(2) using sodium hydroxide as acid binding agent, tetrahydrofuran is solvent, and bromomethyl ethyl cinnamate is condensed with imidazoles
Annulation, obtain imidazolmethyl ethyl cinnamate；
(3) imidazolmethyl ethyl cinnamate obtains sodium ozagrel through basic hydrolysis.
The reaction equation of above-mentioned preparation method is as follows：
In the step of above-mentioned preparation method (2), using sodium hydroxide as acid binding agent, it is higher to prepare purity, impurity
The extremely low imidazolmethyl ethyl cinnamate of content, and the duration of the reaction is shortened, production efficiency significantly improves；Using tetrahydrochysene
Furans not only improves the reaction process for ensuring product, and can enough improves the purity of product, reduces the impurity in product as solvent
Content.
In step (1), the temperature of the bromination reaction is 78~85 DEG C, and the time is 1~3h；It is further preferred that the bromination is anti-
The temperature answered is 80 DEG C, time 2h.
After bromination reaction terminates, grease is obtained, purification process need to be carried out；Preferably, the method for the purifying, bag
Include：The solvent in the reaction solution after bromination reaction terminates is removed, adds ethyl acetate, after removing not tolerant, water is then added and enters
Row extraction, add anhydrous sodium sulfate and be dried, filtrate is spin-dried for after filtering, obtain after purification to bromomethyl cinnamic acid second
Ester, yield is up to 90%.
Preferably, the time of the drying is 2~3h；The temperature being spin-dried for is 55~65 DEG C, vacuum 0.06
~0.09MPa.
Preferably, the mol ratio to methyl cinnamyl acetoacetic ester, N- bromo-succinimides and azodiisobutyronitrile
For 1:1.1~1.3:0.02~0.05；It is 1 to the mass volume ratio of methyl cinnamyl acetoacetic ester and acetonitrile:2~3.
In step (2), the order of addition of raw material and to the charging rate of bromomethyl ethyl cinnamate to the miscellaneous of target product
Matter content has an impact, especially the content of imidazolmethyl ethyl cinnamate dimer.Preferably, in step (2), by imidazoles and
Sodium hydroxide is mixed, and obtains mixed solution；Bromomethyl ethyl cinnamate will be added dropwise in the mixed solution, continued again
Stirring, condensation reaction is carried out, obtains imidazolmethyl ethyl cinnamate.
Specifically, after the imidazoles is dissolved in tetrahydrofuran, then mixed with sodium hydroxide；To bromomethyl ethyl cinnamate
It is added dropwise to again in mixed solution after being dissolved in tetrahydrofuran.
Preferably, the time of the dropwise addition is 1.5~2.5h.
Further, after the mixed solution being cooled into 0~10 DEG C, then institute will be added dropwise to bromomethyl ethyl cinnamate
State in mixed solution.
Preferably, in step (2), the temperature of the condensation reaction is 0~15 DEG C, and the time is that 2~3.5h (drips
Add 0.5~1h after terminating)；Further, the temperature of the condensation reaction is 10 DEG C, and the time is that (i.e. 2h is added dropwise 2.5h
0.5h after end).
Preferably, in step (2), the mol ratio to bromomethyl ethyl cinnamate, imidazoles and sodium hydroxide is 1:
2.0~2.5:2.0；It is 1 to the mass volume ratio of bromomethyl ethyl cinnamate and tetrahydrofuran:6~8.
After condensation reaction terminates, need also exist for carrying out purification process；Preferably, the method for the purifying, including：
Reaction solution after being terminated with ethyl acetate dissolving condensation reaction, after washing, soda acid processing, anhydrous sodium sulfate drying, then
Use ethyl acetate：Hexamethylene (1:1) recrystallize, obtain imidazolmethyl ethyl cinnamate, purity more than 99%.
In step (3), basic hydrolysis is carried out using sodium hydroxide, the temperature of basic hydrolysis is 50~60 DEG C, the time is 1~
2h。
Compared with prior art, the invention has the advantages that：
For the present invention using sodium hydroxide as acid binding agent, tetrahydrofuran is that solvent carries out condensation reaction so that final
Without toxic component in the product of acquisition, and the yield and purity of product are effectively increased, the genotoxicity impurity in product is (to bromine
Methyl cinnamyl acetoacetic ester and to dibromo methyl cinnamyl acetoacetic ester) content be zero.
Embodiment
It is clearly and completely described below in conjunction with the technical scheme of the embodiment of the present invention, it is clear that described implementation
Example only part of the embodiment of the present invention, rather than whole embodiments.It is common based on the embodiment in the present invention, this area
The every other embodiment that technical staff is obtained under the premise of creative work is not made, belong to the model that the present invention protects
Enclose.
Embodiment 1
A kind of preparation method of sodium ozagrel, is comprised the following steps that：
(1) 20g is placed in three-necked flask to methyl cinnamyl acetoacetic ester, adds 0.05g azo isobutyronitriles, 50ml thereto
Acetonitrile, it is heated to 65 DEG C；20.6g N- bromo-succinimides are added, 80 DEG C is warming up to, back flow reaction 2 hours, samples, inspection
Survey (HPLC) is to the purity of bromomethyl ethyl cinnamate：81.01%, stop reaction, obtain reaction solution I.
After reaction terminates, vacuum distillation reaction solution I solvent acetonitrile (60 DEG C), obtain grease and (include solid granular
Material, predominantly succimide)；40ml ethyl acetate is added into grease, after stirring 0.5h, filtering, filters off insoluble matter
(succimide), solid is washed with a small amount of ethyl acetate, 40ml water is added into ethyl acetate, after stirring 15min, stood and divide
Layer, separates water layer and ethyl acetate layer；It is washed with water and washs twice, uses water 40ml every time, added into the ethyl acetate layer of gained
Anhydrous sodium sulfate is dried, and stirs and dries 2.5h, filtering, and filtrate is spin-dried for (55 DEG C, vacuum -0.07, under solvent-free dripping),
Oily solid is obtained to bromomethyl meat silester, quality 36.2g.
(2) to step (1) reaction obtain in bromomethyl ethyl cinnamate, add 34ml tetrahydrofurans, stirring makes pair
Bromomethyl ethyl cinnamate dissolves, and obtains solution A.
11.48g imidazoles is added in three-necked flask, adds tetrahydrofuran 102ml, is stirred, repeated hydrogenation sodium oxide molybdena 6.74g is cold
But 10 DEG C of temperature is controlled, stirring, obtains solution B；Being dripped to bromomethyl ethyl cinnamate (solution A) in tetrahydrofuran will be dissolved in
Enter into the solution B cooled down, time for adding is 2 hours, stirring reaction 0.5h, and temperature control after completing reaction, obtains at 10 DEG C
To reaction solution II, HPLC monitoring is carried out, bromomethyl ethyl cinnamate is tied when reaction solution HPLC middle peak of spectrograms area is less than 1%
Shu Fanying.
After reaction completely, filtering reacting liquid II, filtrate is put in cucurbit, and less than 40 DEG C are evaporated under reduced pressure to without distillate；Add
Enter ethyl acetate 113ml and water 113ml, stir 20min, stand more than 1h, extract upper strata ethyl acetate phase, continuously add water
113ml, stir 15min；Concentrated hydrochloric acid is added, adjusts pH to 3；After stirring 20min, more than 1h is stood, extraction lower floor aqueous phase, is added fresh
Ethyl acetate 113ml, 15min is stirred, add sodium acid carbonate and adjust pH to 7.0, continued to stir 20min, more than 1h is stood, in extraction
Layer ethyl acetate phase；In water layer plus fresh ethyl 46ml, 20min is stirred, stands more than 1h, extracts upper strata ethyl acetate
Phase.
Merge above ethyl acetate phase, add anhydrous sodium sulfate, stir 2 hours, filtering, filtrate is put in cucurbit, 50 DEG C
(more than vacuum 0.07MPa) distillation is depressurized to without distillate, imidazolmethyl ethyl cinnamate crude product 19.98g is obtained, samples, examine
The purity for surveying (HPLC methods) imidazolmethyl ethyl cinnamate is 96.80%.
Imidazolmethyl ethyl cinnamate crude product is taken, adds ethyl acetate/hexamethylene (1.2:1) mixed solvent 40ml, adds
Heat 0 DEG C of crystallization 2h, filters to obtain filter cake, is dried in vacuo to obtain the brilliant thing 15.02g of imidazolmethyl ethyl cinnamate one to 55 DEG C of dissolved clarifications；Will
One brilliant thing of imidazolmethyl ethyl cinnamate adds 28ml ethyl acetate/hexamethylene (1.2:1) in the mixed solvent, 55 DEG C are heated to
Dissolving, 0 DEG C of crystallization 2h, filters to obtain filter cake, is dried in vacuo, and obtains 12.6g imidazolmethyl ethyl cinnamates, the imidazoles first of HPLC detections
Base ethyl cinnamate purity is 99.29%, mass yield 63%.
(3) 1.88g sodium hydroxides are taken, are put in three-necked flask, add 24ml purified waters, stirring dissolves sodium hydroxide, to
11.6g imidazolmethyl ethyl cinnamates are wherein added, are heated to 55 DEG C, 1.5h is stirred, solution clarification, adds 0.24g activated carbons,
Continue to stir 30min, cool down, filtering, filtrate adjusts pH to 8.2 with hydrochloric acid；Filtrate is transferred in revolving bottle, 90 DEG C of decompressions are steamed
Evaporate, obtain off-white powder.
Gained off-white powder is put into xeothermic baking oven 105 DEG C of dryings 4 hours, crushes, it is thick to obtain 9.88g sodium ozagrels
Product.
It is refined：9.88g sodium ozagrel crude products are taken, are placed in 80% ethanol solution, add activated carbon 0.1g, agitating and heating
To 75 DEG C, flow back 2 hours；Filter while hot, after filtrate is cooled to room temperature, is placed at 0 DEG C and is incubated crystallization 48 hours；Filtering, filter cake
It is dried under reduced pressure 2 hours (temperature 60 C, pressure：-0.07MPa)；Obtain white crystal 5.06g.
Comparative example 1
This comparative example using acetonitrile in step (2) in addition to tetrahydrofuran is replaced as solvent, remaining content and embodiment 1
It is identical.
As a result：
Obtained imidazolmethyl ethyl cinnamate crude product is 17.26g, sampling, detects (HPLC methods) imidazolmethyl cinnamic acid
The purity of ethyl ester is 80.19%.
Take imidazolmethyl ethyl cinnamate crude product, using with 1 identical purification step of embodiment, obtain 9.21g's
Imidazolmethyl ethyl cinnamate, the imidazolmethyl ethyl cinnamate purity of HPLC detections is 98.16%, and mass yield is
46.05%.
Comparative example 2
This comparative example using natrium carbonicum calcinatum in step (2) in addition to sodium hydroxide is replaced as acid binding agent, remaining content
It is identical with embodiment 1.
As a result：Obtained imidazolmethyl ethyl cinnamate crude product 18.16g, sampling, detect (HPLC methods) imidazolmethyl Chinese cassia tree
The purity of acetoacetic ester is 50.06%.
Take imidazolmethyl ethyl cinnamate crude product, using with 1 identical purification step of embodiment, obtain 3.27g's
Imidazolmethyl ethyl cinnamate, the imidazolmethyl ethyl cinnamate purity of HPLC detections is 96.04%, and mass yield is
16.35%.
Comparative example 3
This comparative example is removed replaces sodium hydroxide as acid binding agent, acetonitrile replacement four in step (2) using natrium carbonicum calcinatum
Outside hydrogen furans, remaining content is identical with embodiment 1.
As a result：Obtained imidazolmethyl ethyl cinnamate crude product is 18.16g, sampling, detects (HPLC methods) imidazolmethyl meat
The purity of ethyl cinnamate is 10%, and the imidazolmethyl ethyl cinnamate dimer of products therefrom is 86.01%, is not almost obtained
Target product.
Comparative example 4
For this comparative example in addition to acetonitrile is replaced as solvent using acetone in step (1), remaining content and embodiment 1 are complete
It is identical.
As a result：Obtained imidazolmethyl ethyl cinnamate crude product is 19.16g, sampling, detects (HPLC methods) imidazolmethyl meat
The purity of ethyl cinnamate is 88.17%.
Take imidazolmethyl ethyl cinnamate crude product, using with 1 identical purification step of embodiment, obtain 7.68g's
Imidazolmethyl ethyl cinnamate, the imidazolmethyl ethyl cinnamate purity of HPLC detections is 98.04%, and mass yield is
38.4%.
Comparative example 5
This comparative example is removed replaces tetrahydrofuran as solvent in step (2) using dichloromethane, is made using imidazoles itself
Outside for acid binding agent, remaining content is identical with embodiment 1.
As a result：Obtained imidazolmethyl ethyl cinnamate crude product is 14.15g, sampling, detects (HPLC methods) imidazolmethyl meat
The purity of ethyl cinnamate is 80.97%.
Take imidazolmethyl ethyl cinnamate crude product, using with 1 identical purification step of embodiment, obtain 9.4g miaow
Azoles methyl cinnamyl acetoacetic ester, the imidazolmethyl ethyl cinnamate purity of HPLC detections is 99.2%, mass yield 47%.
Comparative example 6
This comparative example in step (2) in addition to potassium tert-butoxide is used as acid binding agent, remaining content and 1 complete phase of embodiment
Together.
As a result：Obtained imidazolmethyl ethyl cinnamate crude product is 16.02g, sampling, detects (HPLC methods) imidazolmethyl meat
The purity of ethyl cinnamate is 88.0%.
Take imidazolmethyl ethyl cinnamate crude product, using with 1 identical purification step of embodiment, obtain 7.26g's
Imidazolmethyl ethyl cinnamate, the imidazolmethyl ethyl cinnamate purity of HPLC detections is 99.03%, and mass yield is
36.3%, it is substantially against regulation according to the embodiment products obtained therefrom color and luster.
Sodium ozagrel product prepared by embodiment 1 and comparative example 1~6 is placed in high temperature (60 DEG C), strong light (4500lx)
Under the conditions of high humidity (92.5%), the comparison of product quality is carried out；Total matter is the mass fraction of total impurities in product；Maximum contaminant
For the mass fraction of maximum contaminant in product.
Under the hot conditions of table 1 mass ratio of embodiment or comparative example sodium ozagrel product compared with
Embodiment or comparative example ozagrel under the intense light conditions of table 2Sodium productMass ratio compared with
Under the super-humid conditions of table 3 embodiment or contrast sodium ozagrel production mass ratio compared with
As a result as shown in table 1~3, show：The imidazolmethyl ethyl cinnamate of the gained of embodiment 1 obtains after crystallization is hydrolyzed
To sodium ozagrel compared with the sodium ozagrel of comparative example 1~6, there is the high advantage of high income, content；Also, pass through
Research to study on the stability data, the product of embodiment 1 quality under conditions of high temperature, high humidity and strong light is stable, impurity inspection
Extracting rate is zero, and the content of other comparative example products and relevant material are unstable.
Claims (8)
- A kind of 1. preparation method of sodium ozagrel, it is characterised in that including：(1) using acetonitrile as solvent, under the initiation of azodiisobutyronitrile, to methyl cinnamyl acetoacetic ester and N- bromo-succinimides Generation bromination reaction, obtain to bromomethyl ethyl cinnamate；(2) using sodium hydroxide as acid binding agent, tetrahydrofuran is solvent, and cyclic condensation occurs to bromomethyl ethyl cinnamate and imidazoles Reaction, obtains imidazolmethyl ethyl cinnamate；(3) imidazolmethyl ethyl cinnamate obtains sodium ozagrel through basic hydrolysis.
- 2. preparation method as claimed in claim 1, it is characterised in that in step (1), the temperature of the bromination reaction for 78~ 85 DEG C, the time is 1~3h.
- 3. preparation method as claimed in claim 1, it is characterised in that described to methyl cinnamyl acetoacetic ester, N- in step (1) The mol ratio of bromo-succinimide and azodiisobutyronitrile is 1:1.1~1.3:0.02~0.05；To methyl cinnamyl acetoacetic ester Mass volume ratio with acetonitrile is 1:2~3.
- 4. preparation method as claimed in claim 1, it is characterised in that in step (2), imidazoles and sodium hydroxide are mixed Close, obtain mixed solution；Bromomethyl ethyl cinnamate will be added dropwise in the mixed solution, lasting stirring, be condensed again Annulation, obtain imidazolmethyl ethyl cinnamate.
- 5. preparation method as claimed in claim 4, it is characterised in that the time of the dropwise addition is 1.5~2.5h.
- 6. preparation method as claimed in claim 1, it is characterised in that in step (2), the temperature of the condensation reaction is 0~10 DEG C, the time is 2~3 hours.
- 7. preparation method as claimed in claim 1, it is characterised in that in step (2), it is described to bromomethyl ethyl cinnamate, The mol ratio of imidazoles and sodium hydroxide is 1:2.0~2.5:2.0；To the quality volume of bromomethyl ethyl cinnamate and tetrahydrofuran Than for 1:6.
- 8. preparation method as claimed in claim 1, it is characterised in that in step (3), alkaline water is carried out using sodium hydroxide Solution, the temperature of basic hydrolysis is 50~60 DEG C, and the time is 1~2h.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109796338A (en) * | 2019-01-15 | 2019-05-24 | 深圳市第二人民医院 | Synthetic method of the ozagrel intermediate to bromomethyl cinnamate |
| CN110028454A (en) * | 2019-05-08 | 2019-07-19 | 深圳市澳泽药物开发有限公司 | A kind of preparation method of cis- ozagrel |
| CN111116481A (en) * | 2019-12-25 | 2020-05-08 | 深圳振强生物技术有限公司 | Novel preparation method of ozagrel impurity |
| 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 |
| CN114230459A (en) * | 2021-12-10 | 2022-03-25 | 武汉九州钰民医药科技有限公司 | Preparation method and analysis and detection method of compound |
| CN114436964A (en) * | 2020-10-16 | 2022-05-06 | 赤峰经方医药技术开发有限责任公司 | Continuous preparation method of ozagrel |
| CN115141098A (en) * | 2022-07-28 | 2022-10-04 | 赤峰经方医药技术开发有限责任公司 | Method for preparing ozagrel intermediate through microchannel reaction |
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- 2017-11-01 CN CN201711058278.4A patent/CN107698513A/en active Pending
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| 薛叙明，等: "奥扎格雷合成工艺", 《化工进展》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109796338A (en) * | 2019-01-15 | 2019-05-24 | 深圳市第二人民医院 | Synthetic method of the ozagrel intermediate to bromomethyl cinnamate |
| CN109796338B (en) * | 2019-01-15 | 2022-05-06 | 深圳市第二人民医院 | Synthetic method of ozagrel intermediate p-bromomethyl cinnamate |
| CN110028454A (en) * | 2019-05-08 | 2019-07-19 | 深圳市澳泽药物开发有限公司 | A kind of preparation method of cis- ozagrel |
| CN111116481A (en) * | 2019-12-25 | 2020-05-08 | 深圳振强生物技术有限公司 | Novel preparation method of ozagrel impurity |
| 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 |
| CN111333581B (en) * | 2020-04-22 | 2021-10-15 | 北京哈三联科技有限责任公司 | Synthetic method of ozagrel sodium |
| CN114436964A (en) * | 2020-10-16 | 2022-05-06 | 赤峰经方医药技术开发有限责任公司 | Continuous preparation method of ozagrel |
| CN114230459A (en) * | 2021-12-10 | 2022-03-25 | 武汉九州钰民医药科技有限公司 | Preparation method and analysis and detection method of compound |
| CN115141098A (en) * | 2022-07-28 | 2022-10-04 | 赤峰经方医药技术开发有限责任公司 | Method for preparing ozagrel intermediate through microchannel reaction |
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