CN103508932B - Method for synthesizing diabetes drug-glimepiride - Google Patents
Method for synthesizing diabetes drug-glimepiride Download PDFInfo
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- CN103508932B CN103508932B CN201310431326.5A CN201310431326A CN103508932B CN 103508932 B CN103508932 B CN 103508932B CN 201310431326 A CN201310431326 A CN 201310431326A CN 103508932 B CN103508932 B CN 103508932B
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- glimepiride
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- C—CHEMISTRY; METALLURGY
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for synthesizing a diabetes drug-glimepiride. The innovation points are as follows: a compound 3 (the name of the raw material: N-4-[2-(3-ethyl-4-methyl-2-oxidation-3-pyrroline-1-formamide) ethyl]-benzene sulfonamide) and a compound 2 (the name: trans-methyl cyclohexyl amine) perform a phosgene reaction at a low temperature, and the acetone extract is subjected to aftertreatment to be prepared into a finished product. The method has the advantages of simple process, high easiness in operation and high product yield.
Description
Technical field
The present invention relates to the synthetic method of diabetes medicament glimepiride, belong to compou nd synthesis technical field.
Background technology
Glimepiride is third generation sulfonylurea oral hypoglycemic, and the dominant mechanism of its hypoglycemic activity stimulates islet β cell Regular Insulin, and part improves surrounding tissue to the susceptibility of Regular Insulin.This product be combined with insulin receptor and dissociation speed comparatively Glyburide be fast, lessly cause heavier hypoglycemia.After oral administration, glimepiride 100% is in gastrointestinal absorption.Within 2-3 hour, Plasma Concentration reaches peak value (Cmax), and protein binding rate is greater than 99.5%.Glimepiride is by the complete metabolism of oxidative biotransformation effect, main metabolites is cyclohexyl hydroxymethyl derivative (M1) and carboxylation derivant (M2), through one or several cytosol enzyme effect, further metabolism is M2 to M1, and M1 has the pharmacologically active of about 1/3 on animal model compared with its parent.And M2 does not have this active.
Summary of the invention
The object of the invention is to for deficiency of the prior art, provide a kind of technique simple, the method for safe and reliable benzsulfamide easy synthesis diabetes medicament glimepiride.
For solving the problems of the technologies described above, the present invention adopts following technical scheme to realize:
By compound 3(material name: N-4-［ 2-(3-ethyl-4-methyl-2-is oxidized-3-pyrroline-1-formamido-) ethyl ］-benzsulfamide) and compound 2(title: opposition methylcyclohexyl amine) and solvent add in large reactor, control temperature-40 ~ 50 DEG C, preferably-20 ~ 5 DEG C, pass into phosgene, start reaction, react after 2 ~ 10 hours, point plate disappears to starting compound 3, and crystallisation by cooling stirs, refinement treatment after filtering, obtain qualified product, reaction formula is:
。
The mol ratio of described compound 3, compound 2, phosgene and solvent is 1:0.8 ~ 1.5:0.8 ~ 1.5:2 ~ 50.
Beneficial effect of the present invention: present invention process is simple, safety is easy to operate, and product yield is high.
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is elaborated.
Embodiment 1
1000 milliliters of vinyl acetic monomers are added in the there-necked flask of 3000 milliliters, intermediate 3(0.6mol) 211 grams, intermediate 2(0.6mol) 66.8 grams, control temperature-10 passes into 60 grams, the phosgene (1mol) of metering to 0 DEG C, within about 2 hours, has led to, lead to rear continuation reaction 3 hours, then be warmed up to stirring at room temperature to terminate to reaction for 2 hours, concentrated desolventizing 400 milliliters of vinyl acetic monomers, cooled and filtered, acetone refining obtains target product, white solid 230 grams (HPLC 99.2%).
Embodiment 2
1000 milliliters of chloroforms are added in the there-necked flask of 3000 milliliters, intermediate 3(0.6mol) 211 grams, intermediate 2(0.6mol) 66.8 grams, control temperature-10 passes into 60 grams, the phosgene (1mol) of metering to 0 DEG C, within about 2 hours, has led to, lead to rear continuation reaction 3 hours, then be warmed up to stirring at room temperature to terminate to reaction for 2 hours, concentrated desolventizing 400 milliliters of vinyl acetic monomers, cooled and filtered, acetone refining obtains target product, white solid 218 grams (HPLC 99.1%).
Above-described embodiment is only in order to illustrate technical scheme of the present invention; but not design of the present invention and protection domain are limited; those of ordinary skill of the present invention is modified to technical scheme of the present invention or equivalent replacement; and not departing from aim and the scope of technical scheme, it all should be encompassed in right of the present invention.
Claims (2)
1. the synthetic method of diabetes medicament glimepiride, is characterized in that: compound 3 and compound 2 are uniformly mixed in a solvent at low temperatures, cooling, pass into phosgene, start reaction, TLC analyzes raw material and disappears, obtain crude product through aftertreatment, after solvent treatment, obtain product, reaction formula:
;
Above-mentioned solvent is vinyl acetic monomer or chloroform, temperature of reaction
-40 DEG C ~ 50 DEG C
;
In above-mentioned reaction, the mol ratio of compound 3, compound 2, phosgene and solvent is 1:0.8 ~ 1.5:0.8 ~ 1.5:2 ~ 50.
2. the synthetic method of diabetes medicament glimepiride according to claim 1, is characterized in that: described temperature of reaction is-20 DEG C ~ 5 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310431326.5A CN103508932B (en) | 2013-09-22 | 2013-09-22 | Method for synthesizing diabetes drug-glimepiride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310431326.5A CN103508932B (en) | 2013-09-22 | 2013-09-22 | Method for synthesizing diabetes drug-glimepiride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103508932A CN103508932A (en) | 2014-01-15 |
| CN103508932B true CN103508932B (en) | 2015-06-10 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310431326.5A Expired - Fee Related CN103508932B (en) | 2013-09-22 | 2013-09-22 | Method for synthesizing diabetes drug-glimepiride |
Country Status (1)
| Country | Link |
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| CN (1) | CN103508932B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1109872A (en) * | 1993-12-30 | 1995-10-11 | 赫彻斯特股份公司 | Substituted benzenesulfonylureas and -thioureas, preparation processes and possible uses of pharmaceutical preparations b ased on these compounds |
| WO2004073585A2 (en) * | 2003-02-21 | 2004-09-02 | Zentiva, A. S. | Methode of manufacturing glimepiride and the respective intermediate |
| 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 |
-
2013
- 2013-09-22 CN CN201310431326.5A patent/CN103508932B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1109872A (en) * | 1993-12-30 | 1995-10-11 | 赫彻斯特股份公司 | Substituted benzenesulfonylureas and -thioureas, preparation processes and possible uses of pharmaceutical preparations b ased on these compounds |
| WO2004073585A2 (en) * | 2003-02-21 | 2004-09-02 | Zentiva, A. S. | Methode of manufacturing glimepiride and the respective intermediate |
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| 三光气法合成降糖药格列美脲;刘占科等;《精细化工中间体》;20060830(第03期);第17页左栏2.2.2和右栏2.2.5，第17-18页3.1.2 * |
| 降血糖新药――格列美脲合成工艺研究;邓勇等;《中国药物化学杂志》;20000620(第02期);第134-137页 * |
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| CN103508932A (en) | 2014-01-15 |
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| CB03 | Change of inventor or designer information |
Inventor after: Wang Defeng Inventor after: Yu Jianjun Inventor before: Wang Defeng Inventor before: Wang Bingcai Inventor before: Zhang Yaobin Inventor before: Cheng Wei Inventor before: Yu Jianjun |
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| COR | Change of bibliographic data |
Free format text: CORRECT: INVENTOR; FROM: WANG DEFENG WANG BINGCAI ZHANG YAOBIN CHENG WEI YU JIANJUN TO: WANG DEFENGYU JIANJUN |
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