CN112028807A - Refining method of glimepiride bulk drug - Google Patents
Refining method of glimepiride bulk drug Download PDFInfo
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- CN112028807A CN112028807A CN202010791655.0A CN202010791655A CN112028807A CN 112028807 A CN112028807 A CN 112028807A CN 202010791655 A CN202010791655 A CN 202010791655A CN 112028807 A CN112028807 A CN 112028807A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
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Abstract
The invention provides a refining method of a glimepiride raw material medicine, which comprises the following steps: (1) dissolving the crude glimepiride in purified water, and filtering to obtain filtrate; (2) acidifying the filtrate to produce a slurry, filtering to obtain a filter cake, and leaching the filter cake to neutrality by using purified water; (3) and adding the filter cake into a solvent, stirring and heating to reflux, keeping for 1-2 hours under the reflux condition, filtering while hot, leaching with acetone, draining, and drying to obtain the glimepiride refined pharmaceutical meeting the medicinal standard. The refining method of the glimepiride bulk drug provided by the invention has the advantages of high purification efficiency, simple and convenient operation steps, mild process conditions and low production cost, and is more suitable for large-scale production.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a refining method of a glimepiride raw material medicine.
Background
Glimepiride (Glimepiride) was first marketed in Sweden by Hoechst Marion Roussel, Germany in 1995 under the trade name
Glimepiride is third-generation sulfonylurea long-acting antidiabetic, has effects of inhibiting hepatic glucose synthesis, promoting peripheral glucose uptake of muscle tissue and promoting insulin secretion, and is suitable for simple diet control, exercise therapy and weight reductionPatients with type 2 diabetes.
Currently, most manufacturers prepare glimepiride according to US 4379785: the method comprises the following steps of firstly carrying out addition reaction on pyrrolinone (5) and phenethyl isocyanate (6) to obtain 3-ethyl-4-methyl-2-oxo-N- (2-phenethyl) -3-pyrroline-1-formamide (4), then sulfonating by chlorosulfonic acid to obtain sulfonyl chloride (3), then reacting with ammonia water to obtain benzenesulfonamide (2), and finally condensing with trans-4-methylcyclohexyl isocyanate (7) to obtain a target compound (1). The following formula:
in the process, the intermediate benzenesulfonamide (2) has low purity (about 85-88%), and glimepiride obtained by condensation with trans-4-methylcyclohexyl isocyanate (7) has the impurity III content of about 0.5-1%, and the purity does not meet the pharmaceutical requirements.
WO2006103690 discloses a process which comprises reacting benzenesulfonamide (2) with acyl chloride to obtain derivative (2-1), purifying the derivative, and condensing with (7) to obtain target compound (1). The following formula:
the process optimizes US4379785, and the benzene sulfonamide (2) is derived into an ester compound and then condensed with isocyanate (7), so that although the purity of glimepiride is improved, new pharmacopeia (second part of the 2015 version of Chinese pharmacopeia) containing impurities I and II can be generated, and the glimepiride does not meet the medicinal requirements.
The glimepiride prepared according to the process disclosed in US4379785 or WO2006103690 has a purity which does not reach the pharmaceutical standard, and the impurity limit exceeds the requirements of pharmacopoeia (second part of the Chinese pharmacopoeia 2015). Particularly, in the treatment operation after the reaction, glimepiride is hydrolyzed under alkaline conditions to generate impurity III, so that the content of the impurity III is 0.5-1.0%, and the limit of pharmacopoeia is greatly exceeded.
CN101486674B discloses a refining method of a glimepiride crude product, which comprises the steps of carrying out suction filtration on a mixture synthetic solution of the glimepiride crude product and potassium carbonate, adding an extract into pure water to dissolve the extract into a solution, and filtering to remove impurities to obtain a glimepiride aqueous solution; adding a hydrochloric acid solution into the glimepiride aqueous solution for acidification, and separating out a crude product; and adding acetone into the crude glimepiride product for refining, performing suction filtration, and performing vacuum drying to obtain a pure glimepiride product. During the treatment, glimepiride is hydrolyzed under alkaline conditions to generate impurity III, which results in the increase of the content of the impurity III. The method only adopts two simple filtrations, and the purification efficiency is not high.
Therefore, the problem to be solved in the technical field of purification of the glimepiride bulk drug is to provide a refining method of the glimepiride bulk drug so as to obtain the glimepiride pharmaceutical meeting the medicinal standard.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the refining method of the glimepiride raw material medicine, which has simple and convenient operation steps, mild process conditions, is more suitable for large-scale production and has high purification efficiency.
The invention provides the following technical scheme:
a refining method of a glimepiride bulk drug comprises the following steps:
(1) dissolving the crude glimepiride in purified water, and filtering to obtain filtrate;
(2) acidifying the filtrate to produce a slurry, filtering to obtain a filter cake, and leaching the filter cake to neutrality by using purified water;
(3) and adding the filter cake into a solvent, stirring and heating to reflux, keeping for 1-2 hours under the reflux condition, filtering while hot, leaching with acetone, draining, and drying to obtain the glimepiride refined pharmaceutical meeting the medicinal standard.
Preferably, the weight ratio of the crude glimepiride product to the purified water in the step (1) is 1: 60-80.
In any of the above schemes, preferably, the acid used in the acidification of the filtrate in step (2) is hydrochloric acid.
In any of the above schemes, preferably, the weight ratio of the crude glimepiride to the solvent in step (3) is 1: 8 to 10.
In any of the above embodiments, it is preferable that the acidification temperature in the step (2) is 20 ℃ to 35 ℃.
In any of the above embodiments, it is preferable that the acidification temperature in the step (2) is 25 ℃ to 30 ℃.
In any of the above schemes, preferably, the concentration of the hydrochloric acid is 1-3 mol/L.
In any of the above embodiments, preferably, the hydrochloric acid concentration is 1 to 1.2 mol/L.
In any of the above embodiments, the pH of the slurry in the step (2) is preferably 1 to 5.
In any of the above embodiments, preferably, the pH of the slurry in the step (2) is 2 to 3.
In any of the above schemes, the water content in the filter cake in the step (2) is preferably 20-45%.
In any of the above schemes, the water content in the filter cake in the step (2) is preferably 25% to 35%.
In any of the above schemes, preferably, the solvent in step (3) is any one or a mixture of two or three of dichloromethane, ethyl acetate, toluene, methanol, ethanol, acetone and tetrahydrofuran.
In any of the above embodiments, preferably, the solvent in step (3) is a mixture of dichloromethane and acetone, and the ratio of dichloromethane: the weight ratio of acetone is 0.5-1.5: 8.
in any of the above embodiments, preferably, the solvent in step (3) is a mixture of dichloromethane and acetone, and the ratio of dichloromethane: the weight ratio of acetone is 1-1.5: 8.
the invention has the beneficial effects that: the refining method of the glimepiride bulk drug provided by the invention has the advantages that the refining process is kept for 1-2 hours under the reflux condition, the solubility of impurities is greatly increased, the purification efficiency of a glimepiride crude product is improved, the operation steps are simple and convenient, the process conditions are mild, the production cost is reduced, and the method is more suitable for large-scale production.
Drawings
FIG. 1 shows the detection result of a high performance liquid chromatograph for crude Glimepiride;
FIG. 2 shows the HPLC detection results of the glimepiride preparation obtained in example 1;
FIG. 3 shows the HPLC detection results of the glimepiride preparation obtained in example 2;
fig. 4 shows the detection results of the high performance liquid chromatograph for glimepiride preparation obtained in example 3.
Detailed Description
In order that the invention may be more fully understood, the following specific examples are set forth. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the invention in any way. All features of each aspect of the invention apply to all other aspects, mutatis mutandis. The practice of the invention is not limited to the following examples, and any modification or variation of the invention may be made without departing from the scope of the invention; and the methods in the following examples are conventional in the art unless otherwise specified.
The impurities II, III and IV can be found in the Chinese pharmacopoeia (2015 edition II).
The crude glimepiride product disclosed by the invention is prepared according to the process disclosed in example 2 of US 4379785. The purity of the crude glimepiride product is 98.165% and the impurity III is 0.989% by a high performance liquid chromatograph (instrument model Agilent G1314F 1260 VWD). The specific results are shown in FIG. 1.
The water content of the filter cake according to the invention can be measured by loss on drying determination.
Example 1
A refining method of a glimepiride bulk drug comprises the following steps:
10g of crude glimepiride is stirred and added into 600g of purified water, the temperature is raised to 65 ℃, the mixture is stirred and dissolved until the solution is clear, and the solution is filtered while the solution is hot. Cooling the filtrate to 30 ℃, adjusting the pH value to 2 by using 2mol/L hydrochloric acid to obtain slurry, keeping the temperature, stirring for 1 hour, centrifuging, filtering to obtain a filter cake, leaching the filter cake to be neutral by using purified water, and controlling the water content of the filter cake to be 25%.
And adding the filter cake into a mixed solvent of 11g of dichloromethane and 89g of acetone, stirring and heating to reflux, filtering while the mixture is hot after 1 hour, leaching the filter cake with acetone, and draining. And drying at 60 ℃ to obtain 9.50g of glimepiride.
The purity of the glimepiride refined drug measured by a high performance liquid chromatograph is 99.423%, and the content of impurity III is 0.237%, as shown in figure 2.
Example 2
Adding 10g of crude glimepiride into 800g of purified water while stirring, heating to 60 ℃, stirring to dissolve until the solution is clear, filtering while the solution is hot, cooling the filtrate to 20 ℃, then adjusting the pH to 5 by using 3mol/L hydrochloric acid to obtain slurry, stirring for 1 hour while keeping the temperature, centrifuging, filtering to obtain a filter cake, leaching the filter cake to be neutral by using purified water, and controlling the water content of the filter cake to be 40%. And adding the filter cake into a mixed solvent of 10g of dichloromethane and 70g of acetone, stirring and heating to reflux, filtering while the mixture is hot after 1 hour, leaching the filter cake with acetone, and draining. Drying at 65 ℃ to obtain 9.43g of glimepiride.
The purity of the glimepiride refined drug is 99.537% and the content of impurity III is 0.280% measured by a high performance liquid chromatograph, as shown in figure 3.
Example 3
Adding 20g of crude glimepiride into 1400g of purified water while stirring, heating to 70 ℃, stirring to dissolve until the solution is clear, filtering while hot, cooling the filtrate to 25 ℃, adjusting the pH to 3 with 1mol/L hydrochloric acid to obtain a slurry, stirring for 1 hour while keeping the temperature, centrifuging, filtering to obtain a filter cake, leaching the filter cake with purified water to be neutral, and controlling the water content of the filter cake to be 30%.
And adding the filter cake into a mixed solvent of 20g of dichloromethane and 160g of acetone, stirring and heating to reflux, filtering while hot after refluxing for 2 hours, leaching the filter cake with acetone, and draining. Drying at 60 ℃ to obtain 18.92g of glimepiride.
The purity of the glimepiride refined drug measured by a high performance liquid chromatograph is 99.621%, and the content of impurity III is 0.211%, as shown in figure 4.
It should be noted that the above embodiments are only used for illustrating the technical solution of the present invention, and not for limiting the same; although the foregoing embodiments illustrate the invention in detail, those skilled in the art will appreciate that: it is possible to modify the technical solutions described in the foregoing embodiments or to substitute some or all of the technical features thereof, without departing from the scope of the technical solutions of the present invention.
Claims (10)
1. A refining method of a glimepiride bulk drug comprises the following steps:
(1) dissolving the crude glimepiride in purified water, and filtering to obtain filtrate;
(2) acidifying the filtrate to produce a slurry, filtering to obtain a filter cake, and leaching the filter cake to neutrality by using purified water;
(3) and adding the filter cake into a solvent, stirring and heating to reflux, keeping for 1-2 hours under the reflux condition, filtering while hot, leaching with acetone, draining, and drying to obtain the glimepiride refined pharmaceutical meeting the medicinal standard.
2. The refining method of a Glimepiride drug substance according to claim 1, wherein the weight ratio of the crude Glimepiride product to the purified water in the step (1) is 1: 60-80.
3. The refining method of glimepiride bulk drug according to claim 1, characterized in that the acid used in the acidification of the filtrate in step (2) is hydrochloric acid.
4. The refining method of a Glimepiride bulk drug according to claim 1, wherein the weight ratio of the Glimepiride crude product to the solvent in step (3) is 1: 8 to 10.
5. The refining method of a Glimepiride bulk drug according to claim 1, wherein the acidification temperature in the step (2) is 20 ℃ to 35 ℃.
6. The refining method of a Glimepiride bulk drug according to claim 1, wherein the acidification temperature in the step (2) is 25 ℃ to 30 ℃.
7. The refining method of a glimepiride bulk drug according to claim 3, wherein the concentration of the hydrochloric acid is 1-3 mol/L.
8. The refining method of a glimepiride bulk drug according to claim 3, wherein the concentration of the hydrochloric acid is 1-1.2 mol/L.
9. The method for refining a glimepiride bulk drug according to claim 1, wherein the pH of the slurry in the step (2) is 1-5.
10. The method for refining a glimepiride bulk drug according to claim 1, wherein the pH of the slurry in the step (2) is 2-3.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4379785A (en) * | 1979-12-19 | 1983-04-12 | Hoechst Aktiengesellschaft | Heterocyclic substituted sulfonyl ureas, and their use |
| WO2004073585A2 (en) * | 2003-02-21 | 2004-09-02 | Zentiva, A. S. | Methode of manufacturing glimepiride and the respective intermediate |
| WO2006103690A1 (en) * | 2005-04-01 | 2006-10-05 | Usv Limited | A novel process for preparation of substantially pure glimepiride |
| CN101486674A (en) * | 2008-12-19 | 2009-07-22 | 江苏万邦生化医药股份有限公司 | Preparation of glimepiride raw material |
| CN101658487A (en) * | 2008-08-28 | 2010-03-03 | 北京天川军威医药技术开发有限公司 | Glimepiride aqueous solution administration system and preparation method thereof |
| CN101671290A (en) * | 2009-10-11 | 2010-03-17 | 沧州那瑞化学科技有限公司 | Preparation method for Glimepiride bulk drug |
| CN108383768A (en) * | 2018-04-13 | 2018-08-10 | 江西博雅欣和制药有限公司 | A kind of Glimepiride bulk drug synthesis technology |
| CN110885306A (en) * | 2018-09-11 | 2020-03-17 | 江苏海悦康医药科技有限公司 | Preparation method of high-purity glimepiride |
-
2020
- 2020-08-07 CN CN202010791655.0A patent/CN112028807A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4379785A (en) * | 1979-12-19 | 1983-04-12 | Hoechst Aktiengesellschaft | Heterocyclic substituted sulfonyl ureas, and their use |
| WO2004073585A2 (en) * | 2003-02-21 | 2004-09-02 | Zentiva, A. S. | Methode of manufacturing glimepiride and the respective intermediate |
| WO2006103690A1 (en) * | 2005-04-01 | 2006-10-05 | Usv Limited | A novel process for preparation of substantially pure glimepiride |
| CN101658487A (en) * | 2008-08-28 | 2010-03-03 | 北京天川军威医药技术开发有限公司 | Glimepiride aqueous solution administration system and preparation method thereof |
| CN101486674A (en) * | 2008-12-19 | 2009-07-22 | 江苏万邦生化医药股份有限公司 | Preparation of glimepiride raw material |
| CN101671290A (en) * | 2009-10-11 | 2010-03-17 | 沧州那瑞化学科技有限公司 | Preparation method for Glimepiride bulk drug |
| CN108383768A (en) * | 2018-04-13 | 2018-08-10 | 江西博雅欣和制药有限公司 | A kind of Glimepiride bulk drug synthesis technology |
| CN110885306A (en) * | 2018-09-11 | 2020-03-17 | 江苏海悦康医药科技有限公司 | Preparation method of high-purity glimepiride |
Non-Patent Citations (2)
| Title |
|---|
| 刘胜高: "格列美脲的制备工艺研究", 《山东化工》 * |
| 国家药典委员会: "《中华人民共和国药典 2015年版 二部》", 30 June 2015, 中国医药科技出版社 * |
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Application publication date: 20201204 |