CN103601738A - Preparation method of cefpirome hydriodate - Google Patents
Preparation method of cefpirome hydriodate Download PDFInfo
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- CN103601738A CN103601738A CN201310640923.9A CN201310640923A CN103601738A CN 103601738 A CN103601738 A CN 103601738A CN 201310640923 A CN201310640923 A CN 201310640923A CN 103601738 A CN103601738 A CN 103601738A
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- Prior art keywords
- cefpirome
- hydriodate
- ice bath
- preparation
- minutes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
Abstract
The invention discloses a preparation method of cefpirome hydriodate. According to the method, under a condition of the presence of excess trimethyliodosilane in a reaction system, dilute hydrochloric acid is used for replacing a mixed liquid of potassium iodide and hydrochloric acid in the prior art for crystallization, thus cefpirome hydriodate residues are reduced to zero, and at the same time, the product yield is ensured.
Description
Technical field
The present invention relates to a kind of preparation of cynnematin similar drug, specifically, relate to a kind of preparation of cefpirome hydriodate.
Background technology
Cefpirome is the outstanding new variety in the 4th generation cynnematin, there is anti-microbial effect strong, has a broad antifungal spectrum, has antimicrobial spectrum and stronger germicidal action widely to gram-positive microorganism (as Staphylococcus, enterococcus faecalis), Gram-negative bacteria (as Bu Lanshi Coccus, pseudomonas) and anerobe.Cefpirome has been successfully used to hospital and Community-acquired Serious Lower Respiratory Infection at present; Oligoleukocythemia patient's infection; The severe infections of intensive care patient; Septicemia/microbemia; Skin and soft tissue infection; The upper and lower urinary tract infection of complicacy; The treatment of meningitis etc.The vitriol of cefpirome can be absorbed well in stomach, so cefpirome is made into Cefpirome Sulfate conventionally, chemistry 1-[[(6R by name, 7R)-7-[(2Z)-(thiazolamine-4-yl) (methoxy imino) acetamido]-2-carboxyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-3-yl] methyl]-6,7-dihydro-5H-pentamethylene is [b] pyridinium inner salt vitriol also.
Cefpirome hydriodate is important intermediate product in synthetic Cefpirome Sulfate process, but when preparing this step of cefpirome hydriodate, prior art is and adds the mixed solution (or mixed solution of Potassium Bromide and hydrochloric acid) of potassiumiodide and hydrochloric acid to carry out crystallization, make to exist a small amount of potassiumiodide residual in cefpirome hydriodate, cause the residue of hydriodate higher, be mostly more than 10%, by refining being also difficult to, effectively remove, cause the residue of finished product higher, surpass standards of pharmacopoeia, quality product is defective.
Summary of the invention
In order to solve the defect existing in prior art, the invention provides a kind of preparation method of cefpirome hydriodate, in reaction system, exist under the condition of excessive Iodotrimethylsilane, use dilute hydrochloric acid to replace the mixed solution of potassiumiodide of the prior art and hydrochloric acid to carry out crystallization, thereby the residue that makes cefpirome hydriodate reduces to zero, guarantees product yield simultaneously.
The preparation method who the present invention relates to a kind of cefpirome hydriodate, is achieved through the following technical solutions:
A preparation method for cefpirome hydriodate, comprises following processing step:
(1) in four-necked bottle, add methylene dichloride, after ice bath cooling, add excessive Iodotrimethylsilane, then drip 2, the mixed solution of 3-cyclopenta pyridine and methylene dichloride, dropwise, ice bath stirs 30 minutes, adds cefotaxime acid, stirring at room 30 minutes, be heated to 35 ℃ of reactions 2 hours, then ice bath cooling, adds dilute hydrochloric acid, stir after 5 minutes and put into the standing refrigeration of refrigerator, growing the grain spends the night; ;
(2) solution step (1) being obtained carries out suction filtration, and the precipitation of using acetone to obtain suction filtration is washed, obtain cefpirome hydriodate after vacuum-drying.
The temperature of the ice bath cooling in described step (1) is below 5 ℃.
The mixed solution process temperature that drips 2,3-cyclopentenopyridine and methylene dichloride in described step (1) is controlled as being no more than 10 ℃.
Iodotrimethylsilane in described step (1) adds under nitrogen protection.
" excessive " that in the term of mentioning in content of the present invention " excessive " and chemical field, generally use has identical meanings,, in chemical reaction, the add-on of reactant is abundant to reach a reaction requirement with respect to other reactants, even after reaction, in reaction product, also has remaining this kind of reactant itself.Specifically, the present invention add excessive Iodotrimethylsilane object be guarantee cefotaxime acid and 2,3-cyclopentenopyridine reaction more complete.After having reacted, the Iodotrimethylsilane existing in system generates cefpirome hydriodate with reaction product above under the effect of hydrochloric acid.
The present invention is by the improvement to cefpirome hydriodate preparation technology, in reaction system, exist under the condition of excessive Iodotrimethylsilane, use dilute hydrochloric acid to replace the mixed solution of potassiumiodide of the prior art and hydrochloric acid to carry out crystallization, thereby obtain the cefpirome hydriodate that contains zero residue.In prior art, adding the mixed solution of potassiumiodide and hydrochloric acid to carry out crystallization object is to generate hydroiodic acid HI, thereby obtain cefpirome hydriodate, yet, potassiumiodide is inorganic salt, can remain in a large number in cefpirome hydriodate, by refining being also difficult to, removes totally, make the residue content of cefpirome hydriodate higher, finally cause the residue content of finished product to exceed standard, and the price comparison of potassiumiodide is expensive, causes product cost to improve.And the present invention is at crystallisation stage, in reaction system, there is enough Iodotrimethylsilanes and hydrochloric acid reaction, can generate hydroiodic acid HI, therefore the present invention needn't add potassiumiodide, only add appropriate hydrochloric acid, have cefpirome hydriodate and generate, solved the residue problem of inorganic salt potassiumiodides, make the residue content in cefpirome hydriodate reduce to zero; Avoid the potassiumiodide that uses price more expensive simultaneously, effectively reduce cost.In addition, reaction conditions of the present invention is gentle, without operations such as high temperature, backflows, saves the energy, is applicable to suitability for industrialized production.
Embodiment
By following examples, further describe the present invention, but should notice that scope of the present invention is not subject to any restriction of these embodiment.
embodiment 1
5000ml four-necked bottle adds 3000ml methylene dichloride, and ice bath is cooled to below 5 ℃, adds 670g Iodotrimethylsilane under nitrogen protection, then drips the mixed solution of 510g 2,3-cyclopentenopyridine and 500ml methylene dichloride, and this process temperature is no more than 10 ℃.Dropwise, ice bath stirs 30 minutes, adds 200g cefotaxime acid, removes ice bath, stirring at room 30 minutes, is heated to 35 ℃ of reactions 2 hours, stops heating, and ice bath is cooled to below 5 ℃, add 1200ml 4N hydrochloric acid, stir about 5 minutes, stop stirring, put into the standing growing the grain of refrigerator and spend the night.Next day, suction filtration, is used 500ml acetone to wash material 3 times, 30 ℃ of vacuum-drying 10 hours.The final cefpirome hydriodate 240g that obtains, molar yield 85%, without residue.
embodiment 2
5000ml four-necked bottle adds 3000ml methylene dichloride, and ice-water bath is cooled to below 5 ℃, adds 600g Iodotrimethylsilane under nitrogen protection, then drips the mixed solution of 510g 2,3-cyclopentenopyridine and 500ml methylene dichloride, and this process temperature is no more than 10 ℃.Dropwise, ice bath stirs 30 minutes, adds 200g cefotaxime acid, removes ice bath, stirring at room 30 minutes, is heated to 35 ℃ of reactions 2 hours, stops heating, and ice bath is cooled to below 5 ℃, add 1200ml4N hydrochloric acid, stir about 5 minutes, stop stirring, put into the standing growing the grain of refrigerator and spend the night.Next day, suction filtration, is used 500ml acetone to wash material 3 times, 30 ℃ of vacuum-drying 10 hours.The final cefpirome hydriodate 230g that obtains, molar yield 81.4%, without residue.
embodiment 3
5000ml four-necked bottle adds 3000ml methylene dichloride, and ice-water bath is cooled to below 5 ℃, adds 600g Iodotrimethylsilane under nitrogen protection, then drips the mixed solution of 500g 2,3-cyclopentenopyridine and 500ml methylene dichloride, and this process temperature is no more than 10 ℃.Dropwise, ice bath stirs 30 minutes, adds 200g cefotaxime acid, removes ice bath, stirring at room 30 minutes, is heated to 35 ℃ of reactions 2 hours, stops heating, and ice bath is cooled to below 5 ℃, add 1200ml4N hydrochloric acid, stir about 5 minutes, stop stirring, put into the standing growing the grain of refrigerator and spend the night.Next day, suction filtration, is used 500ml acetone to wash material 3 times, 30 ℃ of vacuum-drying 10 hours.The final cefpirome hydriodate 220g that obtains, molar yield 77.9%, without residue.
embodiment 4
5000ml four-necked bottle adds 3000ml methylene dichloride, and ice-water bath is cooled to below 5 ℃, adds 670g Iodotrimethylsilane under nitrogen protection, then drips the mixed solution of 510g 2,3-cyclopentenopyridine and 500ml methylene dichloride, and this process temperature is no more than 10 ℃.Dropwise, ice bath stirs 30 minutes, adds 200g cefotaxime acid, removes ice bath, stirring at room 30 minutes, is heated to 35 ℃ of reactions 2 hours, stops heating, and ice bath is cooled to below 5 ℃, add 1000ml5N hydrochloric acid, stir about 5 minutes, stop stirring, put into the standing growing the grain of refrigerator and spend the night.Next day, suction filtration, is used 500ml acetone to wash material 3 times, 30 ℃ of vacuum-drying 10 hours.The final cefpirome hydriodate 235g that obtains, molar yield 83.2%, without residue.
comparative example
5000ml four-necked bottle adds 3000ml methylene dichloride, and ice bath is cooled to below 5 ℃, adds 670g Iodotrimethylsilane under nitrogen protection, then drips the mixed solution of 510g 2,3-cyclopentenopyridine and 500ml methylene dichloride, and this process temperature is no more than 10 ℃.Dropwise, ice bath stirs 30 minutes, adds 200g cefotaxime acid, removes ice bath, stirring at room 30 minutes, be heated to 35 ℃ of reactions 2 hours, stop heating, ice bath is cooled to below 5 ℃, the mixed solution that adds 264g potassiumiodide and 1200ml 4N hydrochloric acid, stir about 5 minutes, stop stirring, put into the standing growing the grain of refrigerator and spend the night.Next day, suction filtration, is used 500ml acetone to wash material 3 times, 30 ℃ of vacuum-drying 10 hours.Final cefpirome hydriodate 245g, molar yield 86.7%, the residue 15%(mass percent of obtaining).
Obviously, in the cefpirome hydriodate that in employing prior art, the mixed solution crystallization of potassiumiodide and hydrochloric acid obtains, residue content is higher, thereby causes quality product to decline to a great extent, even unqualified.
Although illustrate and described exemplary embodiments more of the present invention, but those skilled in the art should know, without departing from the principles and spirit of the present invention, can make change to these exemplary embodiments, scope of the present invention is limited by claim and equivalent thereof.
Claims (4)
1. a preparation method for cefpirome hydriodate, said method comprising the steps of:
(1) in four-necked bottle, add methylene dichloride, after ice bath cooling, add excessive Iodotrimethylsilane, then drip 2, the mixed solution of 3-cyclopenta pyridine and methylene dichloride, dropwise, ice bath stirs 30 minutes, adds cefotaxime acid, stirring at room 30 minutes, be heated to 35 ℃ of reactions 2 hours, then ice bath cooling, adds dilute hydrochloric acid, stir after 5 minutes and put into the standing refrigeration of refrigerator, growing the grain spends the night;
(2) solution step (1) being obtained carries out suction filtration, and the precipitation of using acetone to obtain suction filtration is washed, obtain cefpirome hydriodate after vacuum-drying.
2. the preparation method of cefpirome hydriodate according to claim 1, is characterized in that: the temperature of the ice bath cooling in described step (1) is below 5 ℃.
3. the preparation method of cefpirome hydriodate according to claim 1, is characterized in that: the process temperature that drips the mixed solution of 2,3-cyclopentenopyridine and methylene dichloride in described step (1) is controlled as being no more than 10 ℃.
4. the preparation method of cefpirome hydriodate according to claim 1, is characterized in that: the Iodotrimethylsilane in described step (1) adds under nitrogen protection.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310640923.9A CN103601738A (en) | 2013-12-04 | 2013-12-04 | Preparation method of cefpirome hydriodate |
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| CN201310640923.9A CN103601738A (en) | 2013-12-04 | 2013-12-04 | Preparation method of cefpirome hydriodate |
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| CN103601738A true CN103601738A (en) | 2014-02-26 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109651400A (en) * | 2018-12-06 | 2019-04-19 | 淄博鑫泉医药技术服务有限公司 | The synthetic method of Cefpirome Sulfate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4667028A (en) * | 1983-05-07 | 1987-05-19 | Hoechst Aktiengesellschaft | Process for the preparation of cephem compounds |
| US4692516A (en) * | 1983-05-07 | 1987-09-08 | Hoechst Aktiengesellschaft | Process for the manufacture of 3-pyridinium-methyl-cephalosporins |
| CN101224195A (en) * | 2008-01-18 | 2008-07-23 | 山东罗欣药业股份有限公司 | Compounding method of cefpirome sulfate raw material and uses thereof |
| CN101284840A (en) * | 2008-05-29 | 2008-10-15 | 管小明 | Synthetic method of cefpirome sulfate |
| CN101456870A (en) * | 2007-12-11 | 2009-06-17 | 北京琥珀光华医药科技开发有限公司 | Novel process for synthesizing cefpirome sulfate |
-
2013
- 2013-12-04 CN CN201310640923.9A patent/CN103601738A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4667028A (en) * | 1983-05-07 | 1987-05-19 | Hoechst Aktiengesellschaft | Process for the preparation of cephem compounds |
| US4692516A (en) * | 1983-05-07 | 1987-09-08 | Hoechst Aktiengesellschaft | Process for the manufacture of 3-pyridinium-methyl-cephalosporins |
| CN101456870A (en) * | 2007-12-11 | 2009-06-17 | 北京琥珀光华医药科技开发有限公司 | Novel process for synthesizing cefpirome sulfate |
| CN101224195A (en) * | 2008-01-18 | 2008-07-23 | 山东罗欣药业股份有限公司 | Compounding method of cefpirome sulfate raw material and uses thereof |
| CN101284840A (en) * | 2008-05-29 | 2008-10-15 | 管小明 | Synthetic method of cefpirome sulfate |
Non-Patent Citations (2)
| Title |
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| 张会欣, 等: "硫酸头孢匹罗的合成工艺", 《河北师范大学学报(自然科学版)》, vol. 34, no. 3, 31 May 2010 (2010-05-31), pages 315 - 317 * |
| 王元有，等: "三甲基碘硅烷的合成与分析", 《当代化工》, vol. 37, no. 6, 31 December 2008 (2008-12-31) * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109651400A (en) * | 2018-12-06 | 2019-04-19 | 淄博鑫泉医药技术服务有限公司 | The synthetic method of Cefpirome Sulfate |
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Application publication date: 20140226 |