CN102010429B - Synthesis process of ceftezole - Google Patents
Synthesis process of ceftezole Download PDFInfo
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- CN102010429B CN102010429B CN200910144826A CN200910144826A CN102010429B CN 102010429 B CN102010429 B CN 102010429B CN 200910144826 A CN200910144826 A CN 200910144826A CN 200910144826 A CN200910144826 A CN 200910144826A CN 102010429 B CN102010429 B CN 102010429B
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Abstract
The invention relates to a synthesis process of ceftezole, which mainly comprises the following steps of: taking 1H-tetrazoleacetic acid and mixing with tetrahydrofuran, and then dropping sulfoxide chloride to prepare a mixture A; then taking 7-amino-3[2-(1,3,4)-thiazole] thiomethy-3-cephem-4-carboxylic acid and mixing with ethyl acetate, and then adding methyl chlorosilane, reducing the temperature to prepare a reaction solution B; and mixing the mixture A with the reaction solution B, filtering, washing and drying to prepare the synthesized ceftezole. The synthesis process of the ceftezole has the advantages of simple steps, higher yield and lower processing cost.
Description
Technical field
The present invention relates to a kind of synthesis technique of ceftezole, belong to medical technical field.
Background technology
Ceftezole is the main raw material of preparation spore for azoles sodium.FR-10123; English name is CeftezoleSodium for Injection; Its chemical name is (6R; 7R)-3-[(1,3,4-thiadiazoles-2-yl) sulphomethyl]-8-oxo-7-[2-(1H-tetrazolium-1-yl) kharophen]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2 sodium formiate.Proterties: these article be white to light yellow crystalline powder, odorless, have draw moist.FR-10123 is semisynthetic cephalosporins derivatives, and its mechanism of action is through suppressing the synthetic anti-microbial activity of bringing into play of bacteria cell wall.FR-10123 can distribute extensively in vivo, and is wherein the highest with kidney, is followed successively by serum, liver, lung, the heart, spleen.A small amount of distribution is also arranged in the cerebrospinal fluid, but meninx inflammation time-division cloth increases obviously.Distribution in inflammatory exudate is compared with Cephazolin, Cephaloridine and cefoxitin, and ceftezole is for the highest.Experiment showed, and take FR-10123 after 5 hours in transudate, still to also have the ceftezole of a great deal of, obviously than the other medicines length of holding time.
At present there is following shortcoming in prior art at least for the complete processing of ceftezole: complex steps, yield is low, tooling cost is higher.
Summary of the invention
To the problems referred to above, the present invention provides that a kind of step is simple, yield is higher and tooling cost is lower, is fit to the ceftezole complete processing of producing in enormous quantities.
For realizing above goal of the invention, the present invention provides a kind of FR-10123 synthesis technique, and process step is following:
(1) get 1H-tetrazoleacetic acid and THF and mix stirring, simultaneously, dripping thionyl chloride is till reaction solution becomes clarification;
(2) absorb sour gas with ammoniacal liquor;
(3) steam except that the gained reaction solution, and cooling drying sealing preservation, make mixture A;
(4) getting 7-amino-3-[2-(1,3,4)-thiadiazolyl group] thiomethyl-3-cephem-4-carboxylic acid and ETHYLE ACETATE mixes stirring and is cooled to 0 ℃;
(5) in the reaction solution of step (4) preparation, add trimethylchlorosilane, and continue under 0 ℃ temperature, to stir;
(6) reaction solution is cooled to-5 ℃-0 ℃, makes reaction solution B;
(7) mixture A and reaction solution B are mixed, and with the ETHYLE ACETATE washing, and are controlled at-10 ℃--stir under 5 ℃ the temperature, elevated temperature to 0 stirs by ℃-5 ℃ again.
(8) reaction solution being cooled to-12 ℃--10 ℃ and the stirring of disposable adding yellow soda ash are elevated to 0 ℃-5 ℃ with temperature simultaneously
(9) in solution, drip frozen water, stir, filter after dripping.
(10) filtrating is warming up to about 30 ℃, layering wherein adds acetone in water layer, regulates PH=1.2-2.0 with the hydrochloric acid soln of 5N again.
(11) reaction solution is continued down to stir at 0 ℃-5 ℃, and filter;
(12) with filter cake with washing with acetone, drain, drying, make the synthetic ceftezole;
Wherein, the mol ratio of said 1H-tetrazoleacetic acid four, sulfur oxychloride, 7-amino-3-[2-(1,3,4)-thiadiazolyl group] thiomethyl-3-cephem-4-carboxylic acid and yellow soda ash is 1: 1: 1: 1.
FR-10123 synthesis technique of the present invention has following advantage: step is simple, yield is higher, tooling cost is lower.。
Embodiment
In order to make those skilled in the art person understand the present invention program better, and make above-mentioned purpose of the present invention, feature and advantage can be more obviously understandable, below in conjunction with embodiment the present invention done further detailed explanation.
Embodiment 1
In the A reaction kettle, add 1H-tetrazoleacetic acid 5.12kg, THF 48L, stirring and dissolving at 45 ℃-50 ℃, stirs down slowly dripping thionyl chloride 7.16kg, and solution becomes clarification by muddiness gradually, absorbs sour gas with ammoniacal liquor.Dropping process holding temperature dropwised at 45 ℃-50 ℃ in about 50 minutes.Under this temperature, stirred 1.5 hours.Normal temperature steams the mixing liquid that removes chlorination sulfoxide and THF, gets the viscous fluid thing, and the cooling drying sealing is preserved with subsequent use.
In the B reaction kettle, add 7-amino-3-[2-(1,3,4)-thiadiazolyl group] thiomethyl-3-cephem-4-carboxylic acid 9.36kg; ETHYLE ACETATE 40L; Stirring is cooled to 0 ℃, and under the nitrogen protection, agitation and dropping is gone into trimethylchlorosilane 4.34kg; Solution becomes yellow solution, continues about 0 ℃, to stir 1 hour.Be cooled to-5 ℃-0 ℃, get B solution.
Pour the B solution about-5 ℃ into the A reaction kettle, with 4L ETHYLE ACETATE washing B reaction kettle.Controlled temperature is at-10 ℃--and 5 ℃, stirred 30 minutes, elevated temperature to 0 is ℃-5 ℃ then, stirs 2 hours.
Again solution is cooled to-12 ℃--10 ℃, disposable adding yellow soda ash 8.48kg, solution becomes clarification this moment.Be warming up to 0 ℃-5 ℃ under stirring, in solution, drip frozen water 72L, drip the process holding temperature at 0 ℃-8 ℃, the dropping time is about 40 minutes, drips the back and under this temperature, stirs 30 minutes, filters.And with the acetone soln drip washing of 8L, yellow transparent liquid.Filtrating is warming up to about 30 ℃, layering, water layer adds 40L acetone, regulates PH=1.2 with the hydrochloric acid soln of 5N.Continue to stir 2 hours at 0 ℃-5 ℃.Filter, 8L washing with acetone filter cake is drained.Vacuum-drying under the normal temperature gets ceftezole 7.98kg, yield 68.04%.
Embodiment 2
In the A reaction kettle, add 1H-tetrazoleacetic acid 5.12kg, THF 48L, stirring and dissolving at 45 ℃-50 ℃, stirs down slowly dripping thionyl chloride 7.16kg, and solution becomes clarification by muddiness gradually, absorbs sour gas with ammoniacal liquor.Dropping process holding temperature dropwised at 45 ℃-50 ℃ in about 50 minutes.Under this temperature, stirred 1.5 hours.Normal temperature steams the mixing liquid that removes chlorination sulfoxide and THF, gets the viscous fluid thing, and the cooling drying sealing is preserved with subsequent use.
In the B reaction kettle, add 7-amino-3-[2-(1,3,4)-thiadiazolyl group] thiomethyl-3-cephem-4-carboxylic acid 9.36kg; ETHYLE ACETATE 40L; Stirring is cooled to 0 ℃, and under the nitrogen protection, agitation and dropping is gone into trimethylchlorosilane 4.34kg; Solution becomes yellow solution, continues about 0 ℃, to stir 1 hour.Be cooled to-5 ℃-0 ℃, get B solution.
Pour the B solution about-5 ℃ into the A reaction kettle, with 4L ETHYLE ACETATE washing B reaction kettle.Controlled temperature is at-10 ℃--and 5 ℃, stirred 30 minutes, elevated temperature to 0 is ℃-5 ℃ then, stirs 2 hours.
Again solution is cooled to-12 ℃--10 ℃, disposable adding yellow soda ash 8.48kg, solution becomes clarification this moment.Be warming up to 0 ℃-5 ℃ under stirring, in solution, drip frozen water 72L, drip the process holding temperature at 0 ℃-8 ℃, the dropping time is about 40 minutes, drips the back and under this temperature, stirs 30 minutes, filters.And with the acetone soln drip washing of 8L, yellow transparent liquid.Filtrating is warming up to about 30 ℃, layering, water layer adds 40L acetone, regulates PH=1.6 with the hydrochloric acid soln of 5N.Continue to stir 2 hours at 0 ℃-5 ℃.Filter, 8L washing with acetone filter cake is drained.Vacuum-drying under the normal temperature gets ceftezole 8.02kg, yield 69.07%.
Embodiment 3
In the A reaction kettle, add 1H-tetrazoleacetic acid 5.12kg, THF 48L, stirring and dissolving at 45 ℃-50 ℃, stirs down slowly dripping thionyl chloride 7.16kg, and solution becomes clarification by muddiness gradually, absorbs sour gas with ammoniacal liquor.Dropping process holding temperature dropwised at 45 ℃-50 ℃ in about 50 minutes.Under this temperature, stirred 1.5 hours.Normal temperature steams the mixing liquid that removes chlorination sulfoxide and THF, gets the viscous fluid thing, and the cooling drying sealing is preserved with subsequent use.
In the B reaction kettle, add 7-amino-3-[2-(1,3,4)-thiadiazolyl group] thiomethyl-3-cephem-4-carboxylic acid 9.36kg; ETHYLE ACETATE 40L; Stirring is cooled to 0 ℃, and under the nitrogen protection, agitation and dropping is gone into trimethylchlorosilane 4.34kg; Solution becomes yellow solution, continues about 0 ℃, to stir 1 hour.Be cooled to-5 ℃-0 ℃, get B solution.
Pour the B solution about-5 ℃ into the A reaction kettle, with 4L ETHYLE ACETATE washing B reaction kettle.Controlled temperature is at-10 ℃--and 5 ℃, stirred 30 minutes, elevated temperature to 0 is ℃-5 ℃ then, stirs 2 hours.
Again solution is cooled to-12 ℃--10 ℃, disposable adding yellow soda ash 8.48kg, solution becomes clarification this moment.Be warming up to 0 ℃-5 ℃ under stirring, in solution, drip frozen water 72L, drip the process holding temperature at 0 ℃-8 ℃, the dropping time is about 40 minutes, drips the back and under this temperature, stirs 30 minutes, filters.And with the acetone soln drip washing of 8L, yellow transparent liquid.Filtrating is warming up to about 30 ℃, layering, water layer adds 40L acetone, regulates PH=2.0 with the hydrochloric acid soln of 5N.Continue to stir 2 hours at 0 ℃-5 ℃.Filter, 8L washing with acetone filter cake is drained.Vacuum-drying under the normal temperature gets ceftezole 8.02kg, yield 66.32%.
The above; Be merely embodiment of the present invention; Should be noted that protection scope of the present invention is not limited thereto; Any technician who is familiar with the present technique field is in the technical scope that the present invention discloses, and the variation that can expect easily or replacement all should be encompassed within protection scope of the present invention.Therefore, protection scope of the present invention should be as the criterion with the protection domain that claim was defined.
Claims (1)
1. ceftezole synthesis technique is characterized in that process step is following:
(1) get 1H-tetrazoleacetic acid and THF and mix stirring, simultaneously, dripping thionyl chloride is till reaction solution becomes clarification;
(2) absorb sour gas with ammoniacal liquor;
(3) steam except that the gained reaction solution, and cooling drying sealing preservation, make mixture A;
(4) getting 7-amino-3-[2-(1,3,4)-thiadiazolyl group] thiomethyl-3-cephem-4-carboxylic acid and ETHYLE ACETATE mixes stirring and is cooled to 0 ℃;
(5) in the reaction solution of step (4) preparation, add trimethylchlorosilane, and continue under 0 ℃ temperature, to stir;
(6) reaction solution is cooled to-5 ℃～0 ℃, makes reaction solution B;
(7) mixture A and reaction solution B are mixed, and with the ETHYLE ACETATE washing, and be controlled under-10 ℃～-5 ℃ the temperature and stir, elevated temperature to 0 ℃～5 ℃ stirs again;
(8) reaction solution is cooled to-12 ℃～-10 ℃ and the stirring of disposable adding yellow soda ash, simultaneously temperature is elevated to 0 ℃～5 ℃;
(9) in solution, drip frozen water, stir, filter after dripping;
(10) filtrating is warming up to about 30 ℃, layering wherein adds acetone in water layer, regulates PH=1.2～2.0 with the hydrochloric acid soln of 5N again;
(11) reaction solution is continued down to stir at 0 ℃～5 ℃, and filter;
(12) with filter cake with washing with acetone, drain, drying, make the synthetic ceftezole;
Wherein, the mol ratio of said 1H-tetrazoleacetic acid, sulfur oxychloride, 7-amino-3-[2-(1,3,4)-thiadiazolyl group] thiomethyl-3-cephem-4-carboxylic acid and yellow soda ash is 1: 1: 1: 1.
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| CN200910144826A CN102010429B (en) | 2009-09-04 | 2009-09-04 | Synthesis process of ceftezole |
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| CN200910144826A CN102010429B (en) | 2009-09-04 | 2009-09-04 | Synthesis process of ceftezole |
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| CN102010429A CN102010429A (en) | 2011-04-13 |
| CN102010429B true CN102010429B (en) | 2012-09-26 |
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| CN105055423A (en) * | 2015-09-16 | 2015-11-18 | 青岛华之草医药科技有限公司 | Medicine ceftezole sodium composition for curing infectious diseases |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES462495A1 (en) * | 1977-09-20 | 1978-07-16 | Antibioticos Sa | Procedure for preparation of amidas and esteres. (Machine-translation by Google Translate, not legally binding) |
| ES480325A1 (en) * | 1979-04-17 | 1980-04-01 | Ferrer Int | Procedure for obtaining a derivative of 7-aminocephalosporanic acid. (Machine-translation by Google Translate, not legally binding) |
| CN1803803A (en) * | 2006-01-10 | 2006-07-19 | 哈药集团制药总厂 | Process for preparing ceftezode three-position intermediate |
| CN101229129A (en) * | 2008-01-18 | 2008-07-30 | 山东罗欣药业股份有限公司 | Ceftezole sodium powder injection and synthesizing method thereof |
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2009
- 2009-09-04 CN CN200910144826A patent/CN102010429B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES462495A1 (en) * | 1977-09-20 | 1978-07-16 | Antibioticos Sa | Procedure for preparation of amidas and esteres. (Machine-translation by Google Translate, not legally binding) |
| ES480325A1 (en) * | 1979-04-17 | 1980-04-01 | Ferrer Int | Procedure for obtaining a derivative of 7-aminocephalosporanic acid. (Machine-translation by Google Translate, not legally binding) |
| CN1803803A (en) * | 2006-01-10 | 2006-07-19 | 哈药集团制药总厂 | Process for preparing ceftezode three-position intermediate |
| CN101229129A (en) * | 2008-01-18 | 2008-07-30 | 山东罗欣药业股份有限公司 | Ceftezole sodium powder injection and synthesizing method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 余江河等.头孢替唑钠合成路线图解.《南阳师范学院学报》.2006,第5卷(第9期),52-54. * |
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