CN105385746A - Method for synthesizing cefoxitin acid - Google Patents
Method for synthesizing cefoxitin acid Download PDFInfo
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- CN105385746A CN105385746A CN201510732285.2A CN201510732285A CN105385746A CN 105385746 A CN105385746 A CN 105385746A CN 201510732285 A CN201510732285 A CN 201510732285A CN 105385746 A CN105385746 A CN 105385746A
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- cefoxitin
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P35/00—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin
- C12P35/08—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin disubstituted in the 7 position
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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
- C07D501/02—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
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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
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
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- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a method for synthesizing cefoxitin acid. 7-aminocephalosporanic acid is adopted as a raw material and reacts with sodium methylate under protection of a protection agent, methoxy is introduced into the seventh bit of 7-aminocephalosporanic acid, and methoxide complex is obtained; after the reaction is finished, 2-thiophene acetyl chemical reagent is dropwise added for reacting, then solidifying enzyme is added to obtained wet feed in an alkaline solution for hydrolysis, and after hydrolysis is completed, solidifying enzyme is filtered out; after the reaction is finished, a benzathine diacetate water solution is dropwise added to reaction liquid, crystals are separated out, and a compound I is obtained; the compound I and an ammonia methoxyl acylation reagent act, a carbamyl methoxyl group is introduced to the third bit of the compound I, and cefoxitin acid is obtained. The synthesis process is simple, the steps are easy and convenient, implementation is easy, the yield is effectively increased, production cost is reduced, the production steps are reduced, the obtained product is high in purity, the impurity content is low, the color gradation is good, product quality is effectively improved, drug use safety is improved, and the method is suitable for mass production.
Description
Technical field
The present invention relates to technical field of medicine synthesis, specifically a kind of synthetic method of cefoxitin acid.
Background technology
Cefoxitin acid (Cefoxitinacid), chemistry (6R, 7S)-3-carboxamide oxygen methyl-7-methoxyl group-8-oxo-7-(2-(2-thiazolyl) acetamido)-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid by name.Cefoxitin acid is the semi-synthetic cephamycin-type microbiotic of MercK company of U.S. development, and its sodium salt cefoxitin sodium antimicrobial spectrum is balanced, and stablizes β-lactamase.There is more serious abuse phenomenon in current antibiotic, antibiotic resistance is increased gradually, and bacteriogenic resistance constitutes a serious threat to β-lactam antibitics.Under β-lactamase effect, hydrolysis is the major cause of this kind of microbiotic inactivation.Cefoxitin, as second generation cephalosporin, because it has high stability to β-lactamase, causes the attention of people again.Cause cefoxitin acid cost high in existing technology, once decolouring is aqueous phase decolouring, needs a step phase inversion, reduce the finished product yield before decolouring.
Summary of the invention
The object of the present invention is to provide the synthetic method of the cefoxitin acid that a kind of yield is high, production cost is low, purity is high, to solve the problem proposed in above-mentioned background technology.
For achieving the above object, the invention provides following technical scheme:
A synthetic method for cefoxitin acid, step is:
(1) take 7-amino-cephalosporanic acid as raw material, under protectant protection, react with sodium methylate, introduce methoxyl group, obtain methoxy substrate, after reaction terminates for 7 at 7-amino-cephalosporanic acid, drip 2-thiophene acetyl reagent react, then the wet feed obtained is added in basic solution harden monitoring hydrolysis, after being hydrolyzed, leach harden monitoring; React complete, in reaction solution, instill benzyl star two aqueous acetic acid, crystallize out, obtains Compound I; The structure of compound is such as formula shown in (I):
(2) Compound I and the effect of ammonia methoxy acylating reagent, introduces carboxamide methoxyl group, obtains cefoxitin acid for 3 in Compound I.
As the further scheme of the present invention: protective material is trimethylchlorosilane or BSA.
As the further scheme of the present invention: the mol ratio of 7-amino-cephalosporanic acid and sodium methylate is 1:1 ~ 2.
As the further scheme of the present invention: the temperature of reaction of 7-amino-cephalosporanic acid and sodium methylate is-95 ~-55 DEG C, and the reaction times is 50 ~ 60min.
As the further scheme of the present invention: hydrolysis temperature is 20 ~ 30 DEG C, hydrolysis time is 30 ~ 40min.
As the further scheme of the present invention: step 2) in, temperature of reaction is-65 ~-55 DEG C.
As the further scheme of the present invention: 2-thiophene acetyl reagent adopts 2-thiophen acetyl chloride.
As the further scheme of the present invention: harden monitoring adopts and removes acyl enzyme.
As the further scheme of the present invention: ammonia methoxy acylating reagent adopts Sulfuryl chloride isocyanate.
Compared with prior art, the invention has the beneficial effects as follows:
Building-up process of the present invention is simple, and step is easy, easy to implement, effectively raises yield, reduce production cost, decrease production stage, products obtained therefrom purity is high, and foreign matter content is low, look level is good, effectively raises quality product, improves drug safety, and is applicable to producing greatly.
Accompanying drawing explanation
Fig. 1 is the schema that the present invention prepares cefoxitin acid.
Embodiment
Below in conjunction with the embodiment of the present invention, be clearly and completely described the technical scheme in the embodiment of the present invention, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
Embodiment 1
Refer to Fig. 1, in the embodiment of the present invention, a kind of synthetic method of cefoxitin acid, step is:
Take 7-amino-cephalosporanic acid as raw material, add the protective material such as trimethylchlorosilane or BSA respectively, after protection, add sodium methylate and t-butyl hypochlorate, and the mol ratio of 7-amino-cephalosporanic acid and sodium methylate is 1:1.Under the catalytic condition of t-butyl hypochlorate, react with sodium methylate, temperature of reaction is-95 DEG C, introduces methoxyl group, obtains methoxy substrate for 7 at 7-amino-cephalosporanic acid, terminate after reaction 50min, drip the reaction of 2-thiophen acetyl chloride, then the wet feed obtained is added acyl enzyme hydrolysis in basic solution, hydrolysis temperature is 20 DEG C, hydrolysis time is 30min, leaches acyl enzyme after hydrolysis; React complete, be down to room temperature, in reaction solution, instill benzyl star two aqueous acetic acid, crystallize out, obtains Compound I; The structure of compound is such as formula shown in (I):
In Compound I, add Sulfuryl chloride isocyanate again, under the effect of methoxyl group carboxamide, introduce carboxamide methoxyl group for 3 of Compound I, temperature of reaction is-65 DEG C, needs stir process during reaction, obtains cefoxitin acid.
Embodiment 2
In the embodiment of the present invention, a kind of synthetic method of cefoxitin acid, step is:
Take 7-amino-cephalosporanic acid as raw material, add the protective material such as trimethylchlorosilane or BSA respectively, after protection, add sodium methylate and t-butyl hypochlorate, and the mol ratio of 7-amino-cephalosporanic acid and sodium methylate is 1:2.Under the catalytic condition of t-butyl hypochlorate, react with sodium methylate, temperature of reaction is-60 DEG C, introduces methoxyl group, obtains methoxy substrate for 7 at 7-amino-cephalosporanic acid, terminate after reaction 60min, drip the reaction of 2-thiophen acetyl chloride, then the wet feed obtained is added acyl enzyme hydrolysis in basic solution, hydrolysis temperature is 25 DEG C, hydrolysis time is 40min, leaches acyl enzyme after hydrolysis; React complete, be down to room temperature, in reaction solution, instill benzyl star two aqueous acetic acid, crystallize out, obtains Compound I; The structure of compound is such as formula shown in (I):
In Compound I, add Sulfuryl chloride isocyanate again, under the effect of methoxyl group carboxamide, introduce carboxamide methoxyl group for 3 of Compound I, temperature of reaction is-55 DEG C, needs stir process during reaction, obtains cefoxitin acid.
Embodiment 3
In the embodiment of the present invention, a kind of synthetic method of cefoxitin acid, step is:
Take 7-amino-cephalosporanic acid as raw material, add the protective material such as trimethylchlorosilane or BSA respectively, after protection, add sodium methylate and t-butyl hypochlorate, and the mol ratio of 7-amino-cephalosporanic acid and sodium methylate is 1:1.5.Under the catalytic condition of t-butyl hypochlorate, react with sodium methylate, temperature of reaction is-55 DEG C, introduces methoxyl group, obtains methoxy substrate for 7 at 7-amino-cephalosporanic acid, terminate after reaction 55min, drip the reaction of 2-thiophen acetyl chloride, then the wet feed obtained is added acyl enzyme hydrolysis in basic solution, hydrolysis temperature is 30 DEG C, hydrolysis time is 35min, leaches acyl enzyme after hydrolysis; React complete, be down to room temperature, in reaction solution, instill benzyl star two aqueous acetic acid, crystallize out, obtains Compound I; The structure of compound is such as formula shown in (I):
In Compound I, add Sulfuryl chloride isocyanate again, under the effect of methoxyl group carboxamide, introduce carboxamide methoxyl group for 3 of Compound I, temperature of reaction is-50 DEG C, needs stir process during reaction, obtains cefoxitin acid.
To those skilled in the art, obviously the invention is not restricted to the details of above-mentioned one exemplary embodiment, and when not deviating from spirit of the present invention or essential characteristic, the present invention can be realized in other specific forms.Therefore, no matter from which point, all should embodiment be regarded as exemplary, and be nonrestrictive, scope of the present invention is limited by claims instead of above-mentioned explanation, and all changes be therefore intended in the implication of the equivalency by dropping on claim and scope are included in the present invention.
In addition, be to be understood that, although this specification sheets is described according to embodiment, but not each embodiment only comprises an independently technical scheme, this narrating mode of specification sheets is only for clarity sake, those skilled in the art should by specification sheets integrally, and the technical scheme in each embodiment also through appropriately combined, can form other embodiments that it will be appreciated by those skilled in the art that.
Claims (9)
1. a synthetic method for cefoxitin acid, is characterized in that, step is:
(1) take 7-amino-cephalosporanic acid as raw material, under protectant protection, react with sodium methylate, introduce methoxyl group, obtain methoxy substrate, after reaction terminates for 7 at 7-amino-cephalosporanic acid, drip 2-thiophene acetyl reagent react, then the wet feed obtained is added in basic solution harden monitoring hydrolysis, after being hydrolyzed, leach harden monitoring; React complete, in reaction solution, instill benzyl star two aqueous acetic acid, crystallize out, obtains Compound I; The structure of compound is such as formula shown in (I):
(2) Compound I and the effect of ammonia methoxy acylating reagent, introduces carboxamide methoxyl group, obtains cefoxitin acid for 3 in Compound I.
2. the synthetic method of cefoxitin acid according to claim 1, is characterized in that, protective material is trimethylchlorosilane or BSA.
3. the synthetic method of cefoxitin acid according to claim 1, is characterized in that, the mol ratio of 7-amino-cephalosporanic acid and sodium methylate is 1:1 ~ 2.
4. the synthetic method of cefoxitin acid according to claim 1, is characterized in that, the temperature of reaction of 7-amino-cephalosporanic acid and sodium methylate is-95 ~-55 DEG C, and the reaction times is 50 ~ 60min.
5. the synthetic method of cefoxitin acid according to claim 1, is characterized in that, hydrolysis temperature is 20 ~ 30 DEG C, and hydrolysis time is 30 ~ 40min.
6. the synthetic method of cefoxitin acid according to claim 1, is characterized in that, step 2) in, temperature of reaction is-65 ~-55 DEG C.
7. the synthetic method of cefoxitin acid according to claim 1, is characterized in that, 2-thiophene acetyl reagent adopts 2-thiophen acetyl chloride.
8. the synthetic method of cefoxitin acid according to claim 1, is characterized in that, harden monitoring adopts and removes acyl enzyme.
9. the synthetic method of cefoxitin acid according to claim 1, is characterized in that, ammonia methoxy acylating reagent adopts Sulfuryl chloride isocyanate.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106995453A (en) * | 2017-04-01 | 2017-08-01 | 齐鲁安替制药有限公司 | Crystallization of the alpha methoxy cefoxitin of cephalosporin intermediate 7 and preparation method thereof |
CN110204556A (en) * | 2019-07-16 | 2019-09-06 | 重庆医药高等专科学校 | (RS)-methoxyl group Cefoxitin preparation method |
Citations (5)
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US4297488A (en) * | 1970-06-16 | 1981-10-27 | Merck & Co., Inc. | 7-α-Methoxy cephalosporins |
CN101007812A (en) * | 2007-01-26 | 2007-08-01 | 深圳信立泰药业有限公司 | Antibacterial drugs cefoxitin preparation process |
CN101235045A (en) * | 2008-02-26 | 2008-08-06 | 芦红代 | Method for preparing cefoxitin sodium |
CN103012437A (en) * | 2012-12-04 | 2013-04-03 | 山东鑫泉医药有限公司 | Method for preparing cefoxitin acid as antibacterial medicament |
CN104447800A (en) * | 2014-11-21 | 2015-03-25 | 辽宁天华化工有限责任公司 | Synthesis technology of cefoxitin acid |
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2015
- 2015-11-02 CN CN201510732285.2A patent/CN105385746A/en active Pending
Patent Citations (5)
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US4297488A (en) * | 1970-06-16 | 1981-10-27 | Merck & Co., Inc. | 7-α-Methoxy cephalosporins |
CN101007812A (en) * | 2007-01-26 | 2007-08-01 | 深圳信立泰药业有限公司 | Antibacterial drugs cefoxitin preparation process |
CN101235045A (en) * | 2008-02-26 | 2008-08-06 | 芦红代 | Method for preparing cefoxitin sodium |
CN103012437A (en) * | 2012-12-04 | 2013-04-03 | 山东鑫泉医药有限公司 | Method for preparing cefoxitin acid as antibacterial medicament |
CN104447800A (en) * | 2014-11-21 | 2015-03-25 | 辽宁天华化工有限责任公司 | Synthesis technology of cefoxitin acid |
Non-Patent Citations (4)
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王艳峰等: "头抱西丁合成工艺的改进", 《化工生产与技术》 * |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106995453A (en) * | 2017-04-01 | 2017-08-01 | 齐鲁安替制药有限公司 | Crystallization of the alpha methoxy cefoxitin of cephalosporin intermediate 7 and preparation method thereof |
CN106995453B (en) * | 2017-04-01 | 2019-05-03 | 齐鲁安替制药有限公司 | The crystallization and preparation method thereof of 7 α of cephalosporin intermediate-methoxyl group cefoxitin |
CN110204556A (en) * | 2019-07-16 | 2019-09-06 | 重庆医药高等专科学校 | (RS)-methoxyl group Cefoxitin preparation method |
CN110204556B (en) * | 2019-07-16 | 2020-09-18 | 重庆医药高等专科学校 | Preparation method of (RS) -methoxy cefoxitin |
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Address after: District Center Industrial Park, 638400 Guang'an City, Sichuan Province Industrial wusheng County Applicant after: Sichuan Qing Shan green water medicine chemical Limited by Share Ltd Address before: District Center Industrial Park in Sichuan Province, Guang'an City Industrial wusheng County Applicant before: SICHUAN QINGSHANLVSHUI INDUSTRIAL DEVELOPMENT CO., LTD. |
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Application publication date: 20160309 |