CN105669368A - High-purity low-chroma gemfibrozil preparation method - Google Patents
High-purity low-chroma gemfibrozil preparation method Download PDFInfo
- Publication number
- CN105669368A CN105669368A CN201610018652.7A CN201610018652A CN105669368A CN 105669368 A CN105669368 A CN 105669368A CN 201610018652 A CN201610018652 A CN 201610018652A CN 105669368 A CN105669368 A CN 105669368A
- Authority
- CN
- China
- Prior art keywords
- gemfibrozil
- crude product
- isobutyl ester
- colourity
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a high-purity low-chroma gemfibrozil preparation method. The method comprises 1, preparing a gemfibrozil isobutyl ester crude product and can also comprises 2, adding an alkali liquor II in the gemfibrozil isobutyl ester crude product until the system pH is in a range of 10.0-12 and carrying out reduced pressure rectification to obtain gemfibrozil isobutyl ester, 3, carrying out reflux alkaline hydrolysis on the gemfibrozil isobutyl ester and carrying out acid adjustment to obtain a gemfibrozil crude product, and 4, refining the gemfibrozil crude product through adding an alcohol-water solution into the gemfibrozil crude product, carrying out heating reflux, carrying out heat preservation for 0.5-1h, carrying out cooling to a temperature of 0-5 DEG C, carrying out thermal insulation stirring for 1.5-2.5h, carrying out filtration to obtain filter cake and drying the filter cake to obtain high-purity low-chroma gemfibrozil.
Description
Technical field
The present invention relates to a kind of high-purity, the preparation method for colourity gemfibrozil medicine, belong to field of pharmaceutical chemistry technology, be specifically related to that a kind of color is pure white, liquid phase normalizing content is more than 99.9%, the preparation method of colourity gemfibrozil below 3.0, in order to will not rubescent variable color when gemfibrozil preserves for a long time.
Background technology
Gemfibrozil (Gemfibrozil), chemistry 2,2-dimethyl-5-(2 by name, 5-xylyl oxygen base)-valeric acid, English 5-(2,5-dimethylphenoxy)-2 by name, 2-dimethylpentanoicacid, structural formula is as follows:
Gemfibrozil is chlorine shellfish butanoic acid class blood lipid regulation medicine, and for hyperlipemia, efficacy stability, untoward reaction rate is low, and safety is high, can long-term taking, and arteriosclerosis can be prevented, contribute to reducing myocardial infarction sickness rate. The U.S. listed in nineteen eighty-two, suitable in serious IV or V type hyperlipoproteinemia, risk of coronary heart disease be big diet control, the person of failing to respond to any medical treatment such as lose weight, be also applied for that II b type hyperlipoproteinemia, risk of coronary heart disease be big and diet control, lose weight, other blood lipid regulation Drug therapy nonresponder.
In the synthesis of gemfibrozil, kinds of processes route has been had to report both at home and abroad, ES549470, ES549469, US3674836, US4665226, DE1925423, organicprocessresearch&development (2013,17,963-966), the reported in literature such as CN101723823 synthetic method of gemfibrozil, it is possible to be summarised as shown in Fig. 1.
Above-mentioned preparation method is attributed to two routes substantially:
1) after xylenol and bromo-chloropropane or dibromopropane etherificate, then connect butanoic acid fragment structure and prepare gemfibrozil.
2) halovaleric acid and derivant fragment thereof are first prepared, then with xylenol fragment to being bonded into gemfibrozil.
But which kind of method ineffective, all be unable to do without 2,5-xylenols and participates in reaction. The concrete technology of domestic and international industrialization comparative maturity is as in figure 2 it is shown, but be all not directed in the literature procedures shown in Fig. 1 and Fig. 2 how to control the color of finished product gemfibrozil and the stability of colourity by the residual of 2,5-xylenols in control technical process at present.
In Fig. 2: compound 1 is 5-chloro-2,2-dimethyl isobutyl isovalerate, and compound 2 is 2,5-xylenols, and compound 3 is gemfibrozil isobutyl ester. Majority of compounds 2 is dissolved in the water layer of lower floor with the form of sodium salt;But owing to having a molecular balance when 2,5-xylenols and sodium hydroxide generate sodium salt in water, so have the existence of minimal amount of free xylenol, residual and be extracted into upper organic layer and lucky non-isobutyl ester layer. Therefore, owing to gemfibrozil synthesis technique needing to use 2,5-xylenols, and 2,5-xylenol fusing point only has 75～77 DEG C, boiling point 210～212 DEG C, can distil, together can volatilize with water vapour, there is the abnormal smells from the patient of sootiness, have the feature that aldehydes matter is oxidizable concurrently simultaneously, therefore in technical process this compound once there be minimal residue to arrive follow-up workshop section, will easily because of illumination, be heated and after air contact eremacausis and cause that finished product gemfibrozil product is rubescent, dimmed, have abnormal flavour. When preparing lucky non-isobutyl ester, 2,5-remaining xylenols are more easy to change through high temperature distillation operation and minimal residue is in gemfibrozil, thus causing the problems such as gemfibrozil is defective, long storage periods is perishable.
Summary of the invention
The preparation method that the technical problem to be solved in the present invention is to provide a kind of colourity gemfibrozil high-purity, low.
In order to solve above-mentioned technical problem, the preparation method that the present invention provides a kind of colourity gemfibrozil high-purity, low, including step 1) the lucky non-isobutyl ester crude product of preparation: 2,5-xylenol in aqueous alkali under the catalytic action of tetrabutyl ammonium bromide, under reflux temperature with 5-chloro-2,2-dimethyl isobutyl isovalerate carries out condensation reaction; The organic layer (being positioned at upper strata) that the gains of condensation reaction separate washs through alkali liquor I, get Ji Fei isobutyl ester crude product; Further comprising the steps of:
2), in lucky non-isobutyl ester crude product, add alkali liquor II, until the pH value of gained system is 10.0～12 (being preferably 10.0～10.5), then rectifications under vacuum, obtain gemfibrozil isobutyl ester;
3), gemfibrozil isobutyl ester through backflow basic hydrolysis, acid adjustment, obtain crude product:
In step 2) the gemfibrozil isobutyl ester of gained adds alkali, Yu Shuizhong is hydrolyzed reaction 5～6 hours at a reflux temperature; Described alkali and step 1) in 5-chloro-2, the mol ratio of 2-dimethyl isobutyl isovalerate is 3.5～4.0:1;
The isobutanol that the hydrolysis product elder generation recovered under reduced pressure of gained generates; Then carry out extracting (utilizing petroleum ether), the water layer hydrochloric acid (concentrated hydrochloric acid) extracting gained adjusts pH=2.5～3, it is subsequently cooled to 0～5 DEG C (being incubated 0.5～1 hour), precipitates out gemfibrozil crude product (faint yellow);
4), crude product refining:
Gemfibrozil crude product adds alcohol-water solution, it is warming up to backflow and is incubated 0.5～1 hour, cool (rate of temperature fall is such as 1～2 DEG C/min) to 0～5 DEG C and insulated and stirred 1.5～2.5 hours (being preferably 2 hours), filter, the filter cake of gained is dried, obtain the gemfibrozil (that is, liquid phase normalizing content is more than 99.9%, and colourity is below 3.0) of high-purity, low colourity.
The improvement of the preparation method of colourity gemfibrozil high-purity as the present invention, low:
Step 2) alkali liquor II in alkali be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, it is preferable that potassium carbonate.
The further improvement of the preparation method of colourity gemfibrozil high-purity as the present invention, low:
Described step 4) in, according to the solid-liquid ratio of 1g/1.5～2ml, gemfibrozil crude product adds alcohol-water solution;
Described alcohol-water solution is volumetric concentration is the methanol aqueous solution of 80～90%.
The further improvement of the preparation method of colourity gemfibrozil high-purity as the present invention, low:
Described step 1) be:
2,5-xylenol in aqueous alkali under the catalytic action of tetrabutyl ammonium bromide with 5-chloro-2,2-dimethyl isobutyl isovalerate is carried out under reflux temperature condensation reaction 8～12 hours, described 2,5-xylenol and 5-chloro-2, the mol ratio of 2-dimethyl isobutyl isovalerate is 1.05～1.1:1, described alkali and 5-chloro-2, the mol ratio of 2-dimethyl isobutyl isovalerate is: 3.5～4.0:1, described tetrabutyl ammonium bromide and 5-chloro-2, the weight ratio of 2-dimethyl isobutyl isovalerate is: 5%～6%;
After the reactant liquor of gained is cooled to room temperature, static layering, the upper strata separated is organic layer; Organic layer is through the sodium hydroxide solution washing that mass concentration is 10%, get Ji Fei isobutyl ester crude product (as condensation product).
In the present invention, concentrated hydrochloric acid refers to the hydrochloric acid that mass fraction is 36%.
Technical scheme is specific as follows:
By main material 2,5-xylenol in aqueous alkali with 5-chloro-2,2-dimethyl isobutyl isovalerate carries out condensation reaction, separates organic layer; Learn that the acid-base balance value of xylenol is between 7.8-10.0 by potentiometric titration, namely when pH value is less than 7.8, xylenol exists in the solution in a free form, when pH value is more than 10.0, then xylenol exists completely in a salt form, therefore the present invention adds appropriate alkali in the organic layer after condensation reaction, the pH value of fine adjustment system is at 8-12, preferably 10.0～12, more preferably 10.0-10.5, make the xylenol remaining in organic layer exist with the form of sodium salt or potassium salt, would not be distilled out of during such rectification under vacuum gemfibrozil isobutyl ester; But alkalescence when adjusting pH value before distillation can not be too strong simultaneously, in order to avoid in high temperature distillation process lucky non-isobutyl ester partial hydrolysis and cause that finished product gemfibrozil yield is low, such as pH is when 10.5, lucky non-isobutyl ester is distilled (5 hours in decompression, 10mmHg, 190 DEG C) time just have the percent hydrolysis of 2-5%, when pH value is higher than 13, same vapo(u)rizing temperature and have the non-isobutyl ester hydrolysis of Ji of 10-15% under the time. The gemfibrozil isobutyl ester steamed obtains crude product then through backflow basic hydrolysis, acid adjustment, and crude product is through the gemfibrozil of alcoholic solution refining high-purity, low colourity further.
The invention solves the gemfibrozil medicine of prior art existence because having the existence of 2, the 5-xylenols of 0.0005-0.001% and causing that color easily reddens, the problems such as colourity is higher, and long-term preservation is perishable; The gemfibrozil (that is, liquid phase normalizing content is more than 99.9%, and colourity is below 3.0) that gemfibrozil is high-purity, low colourity adopting the inventive method to prepare and to obtain. Specifically, adopting the gemfibrozil medicine color that the inventive method prepares pure white, colourity is relatively low, long-term stable experiment invariant color, not rubescent, it is simple to produces, store, transport, can thoroughly meet the high-end market high-quality requirements to gemfibrozil such as American-European-Japanese.
Accompanying drawing explanation
Below in conjunction with accompanying drawing, the specific embodiment of the present invention is described in further detail.
Fig. 1 is the synthetic route of existing gemfibrozil;
Fig. 2 is existing gemfibrozil industrial synthesis technique.
Detailed description of the invention
Embodiment 1, a kind of colourity gemfibrozil high-purity, low preparation method, be sequentially carried out following steps:
1), in 1000ml reaction bulb, put into 180ml water, 182 grams of 5-chloros-2,2-dimethyl isobutyl isovalerate (0.82mol, 2,5-xylenols 107 grams (0.87mol), sodium hydroxide 130 grams (3.2mol), tetrabutyl ammonium bromide 10 grams, heat temperature raising refluxes 10 hours. After reactant liquor is cooled to room temperature, static layering 30 minutes, after the upper organic layer separated washs (about 30ml*3 time) with 10% (quality %) sodium hydroxide solution, obtain the lucky non-isobutyl ester crude product of condensation product, standby distillation. Through Liquid Detection, 2,5-xylenol content are 0.021%.
Remarks illustrate: utilize 10% sodium hydroxide solution washing try one's best and many wash away the free 2,5-xylenol of remnants in organic layer.
2), non-for above-mentioned Ji isobutyl ester crude product is joined in the round-bottomed bottle of 500ml, add the sodium hydroxide solution of 70% (quality %), until regulating pH to 8-8.5, it is warming up to interior temperature 190 DEG C, decompression distillation (is boiled before removing, collect the fraction of 175-180 DEG C when 1-2mmHg) and is prepared gemfibrozil isobutyl ester distillation product, and liquid phase normalizing content is 99.5%, 2,5-xylenol liquid phase normalizing content are 0.0015%.
3), in above-mentioned gemfibrozil isobutyl ester distillation product, adding 120 grams of sheet alkali (3mol), 100 grams of water, temperature rising reflux is hydrolyzed, and refluxes 6 hours, the isobutanol that then recovered under reduced pressure generates under 0.05MPad pressure.
The feed liquid (that is, the feed liquid after recovered under reduced pressure isobutanol) of hydrolysis is cooled to 50 DEG C, adds petroleum ether 100ml every time and extract 1 to 2 time, separate water layer. Water layer concentrated hydrochloric acid adjusts pH=2.5-3, and then brine ice is cooled to 0-5 DEG C and is incubated 0.5 hour, precipitates out faint yellow gemfibrozil crude product wet product about 200 grams.
4) in above-mentioned crude product, add the methanol aqueous solution of 350ml90%, it is warming up to backflow (about 65-70 DEG C) and is incubated 0.5 hour, it is cooled to 0-5 DEG C of also insulated and stirred 2 hours with the speed Slow cooling of 1-2 DEG C/min with cooling water, filter, 30-35 DEG C of decompression (20-40mmHg) dries to obtain 180 grams of gemfibrozils, yield 88%, liquid phase normalizing content is 99.86%, xylenol content is 0.0009%, colourity 3.7, wherein liquid phase and colourity all detect by USP standard compendial method.
Embodiment 2-1, a kind of colourity gemfibrozil high-purity, low preparation method:
Step 1) with the step 1 of embodiment);
2), non-for above-mentioned Ji isobutyl ester crude product is added in the round-bottomed bottle of 500ml, add a small amount of saturated sodium carbonate solution, regulate pH to 10.0-10.5, it is warming up to interior temperature 190 degree, decompression distillation prepares gemfibrozil isobutyl ester distillation product, liquid phase normalizing content is 99.87%, 2, and 5-xylenol content is 0.0004%.
Step 3) and step 4) be equal to the step 3 of embodiment 1) and step 4); Final gemfibrozil 182 grams, yield 89%, liquid phase normalizing content is 99.93%, and xylenol content is 0.0001%, colourity 1.6.
Embodiment 2-2～embodiment 2-4, the saturated sodium carbonate solution in embodiment 2-1 is made into respectively sodium hydroxide solution that mass concentration is 70%, mass concentration be 70% potassium hydroxide solution, unsaturated carbonate potassium solution; Also all regulating pH to 10.0-10.5, all the other contents are equal to embodiment 2-1, and the contrast of acquired results is described in table 1 below.
Table 1
Embodiment 3, a kind of colourity gemfibrozil high-purity, low preparation method:
Step 1) with the step 1 of embodiment);
2), non-for above-mentioned Ji isobutyl ester crude product is joined in the round-bottomed bottle of 500ml, add a small amount of unsaturated carbonate potassium solution, regulate pH to 11.5-12.0, it is warming up to interior temperature 190 degree, decompression distillation prepares gemfibrozil isobutyl ester distillation product, liquid phase normalizing content is 99.89%, and xylenol content is 0.0003%.
Step 3) and step 4) be equal to the step 3 of embodiment 1) and step 4); Final gemfibrozil 168 grams, yield 82%, liquid phase normalizing content is 99.95%, xylenol content for not detect, colourity 1.4.
Embodiment 4-1, a kind of colourity gemfibrozil high-purity, low preparation method:
Step 1) with the step 1 of embodiment);
2), non-for above-mentioned Ji isobutyl ester crude product is joined in the round-bottomed bottle of 500ml, it is added dropwise to 70% potassium hydroxide solution again, regulate pH to 13-13.5, it is warming up to interior temperature 190 degree, decompression distillation prepares gemfibrozil isobutyl ester distillation product, liquid phase normalizing content is 99.53%, and xylenol content is 0.0001%.
Step 3) and step 4) be equal to the step 3 of embodiment 1) and step 4); Final gemfibrozil 147 grams, yield 72%, liquid phase normalizing content is 99.88%, 2,5-xylenol content for not detect, colourity 1.8.
Embodiment 4-2, by embodiment 4-1 step 2) in " 70% potassium hydroxide solution " make into " unsaturated carbonate potassium solution ", pH still controls to 13-13.5; All the other are equal to embodiment 4-1.
Final gemfibrozil 168 grams, yield 82%, liquid phase normalizing content is 99.95%, xylenol content for not detect, colourity 1.4.
Comparative example 1, cancel " add a small amount of unsaturated carbonate potassium solution, regulate pH to 10.0-10.5 " of embodiment 2-4, i.e. lucky non-isobutyl ester crude product is directly warming up to interior temperature 190 degree, and decompression is distilled.
All the other contents are equal to embodiment 2-4, obtain gemfibrozil 185 grams, yield 90%, and liquid phase normalizing content is 99.76%, 2, and 5-xylenol content is 0.016%, colourity 6.2.
Finally, in addition it is also necessary to be only several specific embodiments of the present invention it is noted that listed above. It is clear that the invention is not restricted to above example, it is also possible to there are many deformation. All deformation that those of ordinary skill in the art can directly derive from present disclosure or associate, are all considered as protection scope of the present invention.
Claims (5)
1. the preparation method of colourity gemfibrozil high-purity, low, including step 1) the lucky non-isobutyl ester crude product of preparation: 2,5-xylenol in aqueous alkali under the catalytic action of tetrabutyl ammonium bromide, under reflux temperature with 5-chloro-2,2-dimethyl isobutyl isovalerate carries out condensation reaction; The organic layer that the gains of condensation reaction separate is through alkali liquor I washing, get Ji Fei isobutyl ester crude product; It is characterized in that further comprising the steps of:
2), in lucky non-isobutyl ester crude product, alkali liquor II is added, until the pH value of gained system is 10.0～12, then rectification under vacuum, obtain gemfibrozil isobutyl ester;
3), gemfibrozil isobutyl ester through backflow basic hydrolysis, acid adjustment, obtain crude product:
In step 2) the gemfibrozil isobutyl ester of gained adds alkali, Yu Shuizhong is hydrolyzed reaction 5～6 hours at a reflux temperature; Described alkali and step 1) in 5-chloro-2, the mol ratio of 2-dimethyl isobutyl isovalerate is 3.5～4.0:1;
The isobutanol that the hydrolysis product elder generation recovered under reduced pressure of gained generates, then extracts, and the water layer hydrochloric acid extracting gained adjusts pH=2.5～3, is subsequently cooled to 0～5 DEG C, precipitates out gemfibrozil crude product;
4), crude product refining:
Adding alcohol-water solution in gemfibrozil crude product, be warming up to backflow and be incubated 0.5～1 hour, cool to 0～5 DEG C of also insulated and stirred 1.5～2.5 hours, filtration, the filter cake of gained is dried, and obtains the gemfibrozil of high-purity, low colourity.
2. the preparation method of colourity gemfibrozil high-purity, low according to claim 1, is characterized in that:
Step 2) alkali liquor II in alkali be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
3. the preparation method of colourity gemfibrozil high-purity, low according to claim 1 and 2, is characterized in that:
Described step 4) in, according to the solid-liquid ratio of 1g/1.5～2ml, gemfibrozil crude product adds alcohol-water solution;
Described alcohol-water solution is volumetric concentration is the methanol aqueous solution of 80～90%.
4. the preparation method of colourity gemfibrozil high-purity, low according to claim 1 and 2, is characterized in that:
Described step 2) in, the pH value of regulation system is 10.0～10.5.
5. the preparation method of colourity gemfibrozil high-purity, low according to claim 1 and 2, is characterized in that:
Described step 1) be:
2,5-xylenol in aqueous alkali under the catalytic action of tetrabutyl ammonium bromide with 5-chloro-2,2-dimethyl isobutyl isovalerate carries out condensation reaction 8～12 hours under reflux temperature, described 2,5-xylenol and 5-chloro-2, the mol ratio of 2-dimethyl isobutyl isovalerate is 1.05～1.1:1, described alkali and 5-chloro-2, the mol ratio of 2-dimethyl isobutyl isovalerate is: 3.5～4.0:1, described tetrabutyl ammonium bromide and 5-chloro-2, the weight ratio of 2-dimethyl isobutyl isovalerate is: 5%～6%;
After the reactant liquor of gained is cooled to room temperature, static layering, the upper strata separated is organic layer; Organic layer is through the sodium hydroxide solution washing that mass concentration is 10%, get Ji Fei isobutyl ester crude product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610018652.7A CN105669368B (en) | 2016-01-12 | 2016-01-12 | The preparation method of high-purity low colourity Gemfibrozil Capsules |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610018652.7A CN105669368B (en) | 2016-01-12 | 2016-01-12 | The preparation method of high-purity low colourity Gemfibrozil Capsules |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105669368A true CN105669368A (en) | 2016-06-15 |
| CN105669368B CN105669368B (en) | 2018-02-06 |
Family
ID=56300151
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610018652.7A Active CN105669368B (en) | 2016-01-12 | 2016-01-12 | The preparation method of high-purity low colourity Gemfibrozil Capsules |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105669368B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111116324A (en) * | 2019-12-30 | 2020-05-08 | 安徽海华科技有限公司 | Purification method of o-cresol |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1078967A (en) * | 1992-05-19 | 1993-12-01 | 北京师范大学 | 5-(2, the 5-xylyloxy)-2, the synthesis method of 2-dimethyl valeric acid |
| US5654476A (en) * | 1993-05-20 | 1997-08-05 | Recordati S.A. Chimical And Pharmaceutical Company | Process for the preparation of gemfibrozil |
| CN101723823A (en) * | 2009-12-14 | 2010-06-09 | 上海应用技术学院 | Gemfibrozil composite method |
-
2016
- 2016-01-12 CN CN201610018652.7A patent/CN105669368B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1078967A (en) * | 1992-05-19 | 1993-12-01 | 北京师范大学 | 5-(2, the 5-xylyloxy)-2, the synthesis method of 2-dimethyl valeric acid |
| US5654476A (en) * | 1993-05-20 | 1997-08-05 | Recordati S.A. Chimical And Pharmaceutical Company | Process for the preparation of gemfibrozil |
| CN101723823A (en) * | 2009-12-14 | 2010-06-09 | 上海应用技术学院 | Gemfibrozil composite method |
Non-Patent Citations (1)
| Title |
|---|
| SURI BABU MADASU, ET AL.,: "Improved Process for Preparation of Gemfibrozil, an Antihypolipidemic", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111116324A (en) * | 2019-12-30 | 2020-05-08 | 安徽海华科技有限公司 | Purification method of o-cresol |
| CN111116324B (en) * | 2019-12-30 | 2023-04-14 | 安徽海华科技集团有限公司 | Purification method of o-cresol |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105669368B (en) | 2018-02-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110028399B (en) | Preparation method of 2-methyl-4-chlorophenoxyacetic acid | |
| CN105669368A (en) | High-purity low-chroma gemfibrozil preparation method | |
| CN106397247A (en) | Synthesis method of intermediate N-p-hydroxyphenyl salicylamide of oxophenamide drug | |
| CN106187929A (en) | The production method of metamitron | |
| CN111635375B (en) | Method for synthesizing thiothiazole | |
| CN102617595A (en) | Preparation method of fluoroquinolone antibacterial medicament marbofloxacin | |
| KR101705208B1 (en) | Method of preparing composition of chlorohydrins and method of preparing epichlorohydrin using composition of chlorohydrins prepared by the same | |
| CN105732700B (en) | A kind of method for preparing β sodium glycero-phosphates | |
| KR101705209B1 (en) | Method of preparing composition of chlorohydrins and method of preparing epichlorohydrin using composition of chlorohydrins prepared by the same | |
| CN104557814A (en) | Furfural production process | |
| JP4815421B2 (en) | Postprandial blood neutral fat concentration inhibitor and food and drink | |
| CN107652323A (en) | A kind of synthetic method of phosphopyridoxal pyridoxal phosphate | |
| CN103804289B (en) | The synthetic method of 6-methoxy quinoline | |
| CN109651324A (en) | A kind of preparation method of natural VE | |
| CN107286093B (en) | The preparation method of 6 chloromethyl morphanthridines | |
| CN112724033A (en) | Synthesis method and application of deet | |
| CN115232138B (en) | Huperzine A intermediate and nontoxic synthesis process of raw materials thereof | |
| CN110841075A (en) | Preparation method of paeonol inclusion compound | |
| CN105481833B (en) | A kind of preparation method of Rupatadine fumarate | |
| CN105801551A (en) | Clean production method of vitamin E acetate | |
| CN108530352A (en) | A kind of synthetic method of 2,6- dichlor-4-trifluoromethyls niacinamide | |
| CN102827014B (en) | Preparation method of L(-)-carnitine | |
| CN106279018A (en) | Beta 2-receptor analeptic and its preparation method and application | |
| CN107868006B (en) | A kind of method of purification of the chloro- 4,6- dinitroresorcinol of 2- | |
| CN106986848B (en) | The method that base catalysis prepares 2- hydroxyl cyclohexadienylidene acetic acid enol lactone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation method of high-purity and low chromaticity gemfibrozil Effective date of registration: 20230914 Granted publication date: 20180206 Pledgee: Agricultural Bank of China Limited Taizhou Huangyan sub branch Pledgor: ZHEJIANG EXCEL PHARMACEUTICAL Co.,Ltd. Registration number: Y2023330002033 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |