CN102286003A - Synthesis method of ceftazidime - Google Patents
Synthesis method of ceftazidime Download PDFInfo
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Abstract
The invention relates to a synthesis method of ceftazidime. The synthesis method comprises the following steps: by taking 7-aminocephalosporanic acid (7-ACA) as a starting raw material, introducing a pyridine ion to 3-position methylene of 7-ACA so as to obtain 7-amino-3-(1-picolyl)-cephem acid (7-APCA) hydrochloride; then introducing a side chain with a thiazole ring on 7-position amino of the 7-APCA hydrochloride through acylation reaction; and carrying out hydrolyzing reaction, refining reaction and the like so as to obtain ceftazidime. The synthesis method for preparing the ceftazidime in the invention is simple to operate and high in yield, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method of cynnematin, be specifically related to a kind of synthetic method of ceftazime, belong to technical field of medicine synthesis.
Background technology
Ceftazime is the strongest microbiotic of anti Bacillus pyocyaneu Flugge effect in the third generation cephalosporin of GlaxoSmithKline PLC company initiative, is used for septicemia, lower respiratory infection, abdominal cavity and biliary tract infection, complicacy urinary tract infections and serious skin soft-tissue infection etc. due to the responsive gram negative bacilli.Particularly suitable for central nervous system infection due to the immune deficiency person's infection, nosocomial infection and the gram negative bacilli that cause by multiple resistance gram negative bacilli or the Pseudomonas aeruginosa.The production technique of using always is to introduce pyridine to 7-ACA C-3 position earlier, and then (WO:85 04659,1985-10-24.) for this condenses and ceftazime 7 β position side chain active thioesters reaction generation ceftazimes.
Ceftazime, chemical name are (6R, 7R)-7-[[(2-amino-4-thiazolyl)-1-[(1-carboxyl-1-methyl ethoxy) imino-] ethanoyl] amino]-2-carboxyl-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-3-picoline inner salt.Structural formula is:
At present, bibliographical information prepares ceftazime 3 kinds of diverse ways: first method is to be initial parent nucleus with 7-amino-cephalosporanic acid (7-ACA), under the effect of Iodotrimethylsilane (TMS I), react with pyridine, obtain 7-A PCA dihydrochloride, this disalt and BPTA reaction, obtain the ceftazime tert-butyl ester, this tert-butyl ester obtains ceftazidime pentahydrate through steps such as hydrolysis again, pentahydrate and yellow soda ash are mixed and made into injection bulk drug (Jiang Fengyang, ceftazime synthetic progress [J]. Shenyang chemical industry, 1996 (3): 22-25.).Second method is to be initial parent nucleus with 7-phenylacetamide-3-chloromethyl cephalosporin alkyl olefin(e) acid to methoxy benzyl ester (GCL E), react with potassiumiodide, obtain ceftazime intermediate 7-phenylacetylamino-3-iodomethyl-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester, this intermediate and pyridine carry out series reaction such as nucleophilic substitution obtain target product (Liu Yuting. third generation cephalosporin-ceftazime synthesising process research [D]. Shenyang: Shenyang Pharmaceutical University, 2007.).The third method is to be starting raw material with the domestic intermediate 7-ACA that relatively popularizes; with hexamethyldisilazane as silylation reagent; adopt rare gas element ammonia excretion and new impurity removing technology; make ceftazidime pentahydrate through 3 substitution reactions, 7 acylation reactions; finally obtain the target compound ceftazime (Zheng Yulin. the synthesis technique of ceftazime improves [J]. Chinese pharmaceutical chemistry magazine, 2010 (3): 198-200.).
Because aforesaid method exists reactions steps long, productive rate is lower, ceftazime crystal mass instability, shortcomings such as reaction back by-product contamination is bigger, the present invention proposes a kind of preparation method of ceftazime of suitable suitability for industrialized production newly, simple to operate, yield is high, gained ceftazime crystalline product quality is good.This operational path is simple to operate, with low cost, compares total recovery with existing technology and improves greatly.
Summary of the invention
At the problems referred to above, the object of the present invention is to provide that a kind of to overcome the prior art reactions steps long, productive rate is lower, ceftazime crystal mass instability, the preparation method of the ceftazime of the big shortcoming of reaction back by-product contamination.
The present invention for achieving the above object, the technical scheme of taking is, a kind of preparation method of ceftazime, this method comprises:
With 7-amino-cephemcarboxylic acid (7-ACA) is starting raw material; introduce pyridinium ion at the 3-position of 7-ACA methylene radical and obtain 7-amino-3-(1-picolyl) cephemcarboxylic acid (7-APCA) hydrochloride; on the 7-of 7-APCA hydrochloride bit amino, introduce the side chain that has thiazole ring then, obtain ceftazime through hydrolysis, refining reaction etc. again by acylation reaction.
Detailed Description Of The Invention
The present invention relates to a kind of preparation method of ceftazime, it comprises following four steps:
With 7-amino-cephemcarboxylic acid (7-ACA) is starting raw material; introduce pyridinium ion at the 3-position of 7-ACA methylene radical and obtain 7-amino-3-(1-picolyl) cephemcarboxylic acid (7-APCA) hydrochloride; on the 7-of 7-APCA hydrochloride bit amino, introduce the side chain that has thiazole ring then, obtain ceftazime through hydrolysis, refining reaction etc. again by acylation reaction.
Specifically reactions steps is following describes in detail:
Step (1): 7-ACA 50g is joined in the 188ml organic solvent I, adds the 68ml hexamethyldisilazane then, reflux 35～45 ℃ of following stirring heating; Add trimethylchlorosilane, 35ml Iodotrimethylsilane under xylidene(s) catalysis, continue reaction 5 hours, it is residual to detect 7-ACA by high performance liquid phase, and 7-ACA≤0.5% reaction finishes.Add the 30ml pyridine; After finishing, reaction in 2～3 hours adds methyl alcohol, dilute hydrochloric acid successively, layering, and water added activated carbon decolorizing 20 minutes, filtered; Add C-I alcohol in the filtrate and do dispersion agent, transfer PH to 1.0～1.5 with triethylamine, stir and separate out crystallization in a large number, continuing to drop to pH value is 2.5～3.5.Suction filtration, after washed with isopropyl alcohol, vacuum-drying obtains the crystal of hydrochloride 62.2g of required product 7-APCA; Mass yield 124.4%, purity 99.2%;
Step (2): 50g 7-APCA and 70 g α-(thiazolamine-4-yl)-α-[(spy-butoxy carbonyl) isopropyl oxygen imino] acetate sulfydryl benzene isothiazole ester are joined in 188ml methylene dichloride and the 32ml methanol solvent, add the 32ml triethylamine then.10～15 ℃ of reactions 10～12 hours, it is residual to detect 7-APCA, and when 7-APCA≤0.5%, reaction finishes, and is cooled to 0～5 ℃, growing the grain.Filter, use the washed with dichloromethane filter cake, filtering after the dried final vacuum drying must ceftazime tert-butyl ester 74.6g, mass yield 149.2%, purity 98.9%;
Step (3): 50 g are dissolved in dilute hydrochloric acid with the ceftazime tertiary butyl ester: the weight ratio of formic acid is in the mixing solutions of 2:1～3:2, room temperature reaction.Slowly add acetone in the filtrate, carry out crystallization, after the filtering and washing, wet product vacuum-drying obtains ceftazime dihydrochloride 45.5g, mass yield 91%, purity 99.2%;
Step (4): 50 g are dissolved in the frozen water the ceftazime dihydrochloride, and decolouring is filtered, filtrate is in the time of 0～5 ℃, with NaOH, yellow soda ash weight ratio be the mixing solutions of 2:1 to regulate pH value be 4.0～4.2, growing the grain is to separating out in a large number, with sour 5 times repeatedly adjust pH be 4.0～4.2, adjust pH to 3.6～3.8 then, growing the grain, suction filtration is used cold water, washing with acetone filter cake and dry respectively, obtain white ceftazime crystal 4 7.3g, mass yield 94.6%.
Organic solvent I is selected from methylene dichloride, chloroform, ethyl acetate or tetracol phenixin in the above-mentioned steps (1), preferably from methylene dichloride.
C-I alcohol is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols and isopropylcarbinol in the above-mentioned steps (1), preferably from Virahol.
In the above-mentioned steps (1) trimethylchlorosilane, Iodotrimethylsilane are mixed as silylating reagent.
Above-mentioned steps does not need to feed nitrogen protection in (1).
Above-mentioned steps does not need to add catalyzer in (2).
Above-mentioned steps (4) is that to regulate the pH value be 4.0～4.2 for the mixing solutions of 2:1 with NaOH, yellow soda ash weight ratio.
Above-mentioned steps (4) is that to regulate the pH value be 4.0 for the mixing solutions of 2:1 with NaOH, yellow soda ash weight ratio.
Compared with prior art, the claimed technical scheme of the present invention has following advantage:
(1), prior art adopts preparation 7-APCA(7-amino-3-propenylcephalosporaacid acid earlier) iodate, prepare the 7-APCA hydrochloride then, need the reaction of two steps.And the present invention adopts a step to prepare the 7-APCA hydrochloride, and the process time is short, the yield height; In the selection of dispersion agent, the C-I alcohols of adding selects for use Virahol to do dispersion agent, and alcoholic solvent toxicity is low, recycling easily, and the environmental protection that more becomes is beneficial to the protection of healthy and environment;
(2), do not need to feed nitrogen protection, but be beneficial to the discharge of ammonia, not only saved but also environmental protection and safety by the optimization of equipment;
(3), trimethylchlorosilane, Iodotrimethylsilane are mixed as silylating reagent, the hydrochloride cost of product 7-APCA is low, and quality is good, is beneficial to the production control of the ceftazime tert-butyl ester;
(4), under xylidene(s) protection, the consumption of Iodotrimethylsilane is few;
(5), in the preparation process of 7-APCA hydrochloride, regulate pH value with triethylamine, slowly transfer, the control speed of separating out, crystallization is slow, the purity height, intermediates purity (HPLC method) reaches 99%.In addition, by product is siloxanes or organoalkoxysilane, is easy to separate utilize again, and " three wastes " are easy to handle;
(6), prior art adopts catalyzer in step 2, the present invention does not adopt catalyzer.Because the purity height of the hydrochloride of 7-APCA utilizes stirring velocity faster, by adjusting the consumption of methylene dichloride, methyl alcohol, triethylamine, improve temperature of reaction, fast reaction speed obtains the purity height equally, the ceftazime tert-butyl ester of Functionality, quality and appealing design.Adopt the method for " cooking all things in one pot " and do not need the crystallization of ethyl acetate, not only reduce the solvent kind, shorten the process time, and be beneficial to big production control and environment protection;
(7), in the preparation process of ceftazime dihydrochloride, adjust the concentration and the proportioning of formic acid, hydrochloric acid, utilize the acetone crystallization, both improved the purity of intermediate, improved the yield of product again.
The present invention relates to a kind of preparation method of ceftazime, it comprises following four steps, further comprises:
Step (1): the preparation method of 7-APCA hydrochloride, it may further comprise the steps:
(1) 1 part of 7-ACA (7-amino-cephalosporanic acid) is joined in 5 parts the organic solvent I, adds 1 part of hexamethyldisilazane again, refluxed about 5 hours 40～45 ℃ of following stirring heating;
(2) under the xylidene(s) protection, add 0.05 part of trimethylchlorosilane, 1 part of Iodotrimethylsilane, continue reaction 5 hours, add 0.6 part of pyridine, by high performance liquid phase detection reaction process;
(3) (7-ACA residual≤0.5%) reaction finishes, and adds methyl alcohol, dilute hydrochloric acid, and layering, water added activated carbon decolorizing 20 minutes, filtered;
(4) add 0.5～2 part of C-I alcohols in the filtrate and do dispersion agent, transfer PH to 1.0～1.5, be stirred to crystallization and separate out in a large number, continue to drop to the terminal point pH value and reach 2.8～3.0 with triethylamine.Suction filtration, after 0.5 part of C-I alcohols washing, wet product vacuum-drying obtains the crystal of hydrochloride of required product 7-APCA, mass yield 〉=124%, purity 〉=99%.
Step (2): the preparation of the ceftazime tert-butyl ester, it may further comprise the steps:
(1) 1 part of 7-APCA and 1.2～1.8 parts of α-(thiazolamine-4-yl)-α-[(spy-butoxy carbonyl) isopropyl oxygen imino] acetate sulfydryl benzene isothiazole esters (TAEM) are joined in 5 parts of methylene dichloride and 0.5～0.8 part of methanol solvent, stir and be cooled to 4 ℃;
(2) keep temperature to add 0.5～0.8 part of triethylamine after 5 minutes, temperature is controlled at 10～15 ℃;
After (3) 10 hours, it is residual to detect 7-APCA, by high performance liquid phase monitoring 7-APCA residual≤can be considered reaction during 2mg/ml finishes;
(4) be cooled to 0～3 ℃, growing the grain 3 hours.Filter, with about 1 part of washed with dichloromethane filter cake, filtering must the ceftazime tert-butyl ester behind the dry 4h of dried final vacuum.Mass yield 〉=148%, purity 〉=98%.
Step (3): the preparation method of ceftazime dihydrochloride, it may further comprise the steps:
(1) 1 part of ceftazime tertiary butyl ester is dissolved in 2 parts concentrated hydrochloric acid, formic acid and water (in the mixing solutions of concentrated hydrochloric acid: formic acid: the weight ratio 2:1:1 of water～3:2:2), room temperature reaction is until residual≤0.5% visual response end of the ceftazime tert-butyl ester;
(2) added activated carbon decolorizing 20 minutes, filter, with a small amount of purified water washing charcoal cake;
(3) slowly add acetone in the filtrate, carry out solvent crystal, when crystal solution occurs little when muddy, stop adding solvent, stirred growing the grain slowly 0.5 hour, after continuing to add remaining solvent, restir growing the grain 1 hour, after the filtering and washing, wet product vacuum-drying obtains the ceftazime dihydrochloride.Mass yield 〉=90%, product purity (HPLC method 〉=98%).
Step (4): the preparation method of ceftazime, it may further comprise the steps:
(1) 1 part of ceftazime dihydrochloride is dissolved in 2～4 parts the frozen water, this solution is filtered;
(2) filtrate is in the time of 0～5 ℃, pH transferred in 4.0,2 hours in 2 hours with the mixing solutions (the weight ratio 2:1 of NaOH and yellow soda ash) of NaOH, yellow soda ash and at the uniform velocity transfers pH to 3.6 with 3M HCl, growing the grain 3 hours;
(3) suction filtration with cold water, washing with acetone filter cake and dry, gets the white crystal product, mass yield 〉=93%, content 〉=98%.
Employing the inventive method prepares the ceftazime tert-butyl ester, the ceftazime dihydrochloride is simple to operate, yield is high, is fit to suitability for industrialized production.
Embodiment
Following examples only are used to further specify the present invention, but do not limit the present invention.
[embodiment 1] 7-APCA's is synthetic
To join 1.0 gram 7-ACA (7-amino-cephalosporanic acid) in 5.0 methylene dichloride that restrain, add 1.0 gram hexamethyldisilazanes again, reflux about 5 hours 35～45 ℃ of following stirring heating.Under xylidene(s) catalysis, add 0.05 gram trimethylchlorosilane, 1.0 gram Iodotrimethylsilanes, continue reaction 5 hours, add 1 gram pyridine, by high performance liquid phase detection reaction process.When record 7-ACA residual≤0.5% the time, reaction finishes, and adds methyl alcohol, dilute hydrochloric acid, layering, water added activated carbon decolorizing 20 minutes, filtered.In filtrate, add 0.5～2.0 gram Virahol then and do dispersion agent, transfer PH to 1.0～1.2, be stirred to crystallization and separate out in a large number, continue to drop to the terminal point pH value and reach 2.8～3.0 with triethylamine.Suction filtration, after 0.5 gram washed with isopropyl alcohol, wet product vacuum-drying obtains crystal of hydrochloride 1.246 grams of required product 7-APCA, mass yield 124.6%, purity 99.12%.
Synthesizing of [embodiment 2] ceftazime tert-butyl ester
1.0 gram 7-APCA and 1.8 gram α-(thiazolamine-4-yl)-α-[(spy-butoxy carbonyl) isopropyl oxygen imino] acetate sulfydryl benzene isothiazole esters (TAEM) are joined in 5 gram methylene dichloride and the 0.7 gram methanol solvent, stir and be cooled to 4 ℃.Keep temperature to add 0.7 gram triethylamine after 5 minutes, temperature is controlled at 0～10 ℃.After 10 hours, it is residual to detect 7-APCA, by high performance liquid phase monitoring 7-APCA residual≤can be considered reaction during 2mg/ml finishes.Be cooled to 0～3 ℃, growing the grain 3 hours.Filter, use the washed with dichloromethane filter cake, filter behind the dry 4h of dried final vacuum to such an extent that the ceftazime tert-butyl ester 1.482 restrains.Mass yield 148.2%.Ceftazime tert-butyl ester purity 98.1% in the product after testing.
Synthesizing of [embodiment 3] ceftazime dihydrochloride
1.0 gram ceftazime tertiary butyl ester are dissolved in the hydrochloric acid, formic acid of 2 grams, and (in the mixing solutions of hydrochloric acid: the weight ratio 2:1 of formic acid～3:2), room temperature reaction finishes until residual≤0.5% visual response of the ceftazime tert-butyl ester.Slowly add acetone in the filtrate, carry out solvent crystal, when crystal solution occurs little when muddy, stop adding solvent, stirred growing the grain slowly 0.5 hour, after continuing to add remaining solvent, restir growing the grain 1 hour, after the filtering and washing, wet product vacuum-drying obtains ceftazime dihydrochloride 0.91 gram.Mass yield 91%, ceftazime dihydrochloride product purity 98.3% in the product after testing.
Synthesizing of [embodiment 4] ceftazime
1.0 gram ceftazime dihydrochlorides are dissolved in the frozen water of 4 grams, this solution is filtered; Filtrate transfers to pH in 4.0,2 hours in 2 hours with the mixing solutions (the weight ratio 2:1 of NaOH and yellow soda ash) of NaOH, yellow soda ash and at the uniform velocity to transfer pH to 3.6 with 3M HCl, growing the grain 3 hours in the time of 0～5 ℃; Suction filtration with cold water, washing with acetone filter cake and dry, gets white crystal product 0.937 gram, mass yield 93.7%, content 98.2%.
Claims (8)
1. the synthetic method of the ceftazime compound shown in the formula (I),
It is characterized in that, comprise following four synthesis steps:
Step (1): 7-ACA is joined in the organic solvent I, adds hexamethyldisilazane then, reflux 35～45 ℃ of following stirring heating; Under xylidene(s) catalysis, add trimethylchlorosilane, Iodotrimethylsilane, continue reaction 5 hours, add pyridine; Reaction adds methyl alcohol, dilute hydrochloric acid after finishing successively, layering, and aqueous phase adds the C-I alcohols and does dispersion agent, transfers PH to 1.0～1.5 with triethylamine, and stir and separate out crystallization in a large number, growing the grain 30 minutes, continuing to drop to pH value is 3.0～3.5; Suction filtration, after the washing of C-I alcohol, vacuum-drying obtains the crystal of hydrochloride of required product 7-APCA;
Step (2): 7-APCA and α-(thiazolamine-4-yl)-α-[(spy-butoxy carbonyl) isopropyl oxygen imino] acetate sulfydryl benzene isothiazole ester are joined in methylene dichloride and the methanol solvent, add triethylamine then, 10～15 ℃ were reacted 10～12 hours, it is residual to detect 7-APCA, when 7-APCA≤0.5%, reaction finishes; Be cooled to 0～5 ℃, growing the grain; Filter, use the washed with dichloromethane filter cake, filtering after the dried final vacuum drying must the ceftazime tert-butyl ester;
Step (3): the ceftazime tertiary butyl ester is dissolved in concentrated hydrochloric acid: the formic acid weight ratio is in the mixing solutions of 2:1～3:2, room temperature reaction; Slowly add acetone in the filtrate, carry out crystallization, after the filtering and washing, wet product vacuum-drying obtains the ceftazime dihydrochloride;
Step (4): the ceftazime dihydrochloride is dissolved in the frozen water, filters, filtrate is in the time of 0～5 ℃, with NaOH, yellow soda ash weight ratio is the mixing solutions adjusting pH value of 2:1, growing the grain, suction filtration, with cold water, washing with acetone filter cake and dry, obtain white ceftazime crystal.
2. the synthetic method of ceftazime compound according to claim 1 is characterized in that, organic solvent I is selected from one or both mixture of methylene dichloride, chloroform, ethyl acetate or tetracol phenixin in the described step (1), is preferably methylene dichloride.
3. the synthetic method of ceftazime compound according to claim 1 is characterized in that, C-I alcohol is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols and isopropylcarbinol in the described step (1), is preferably Virahol.
4. the synthetic method of ceftazime compound according to claim 1 is characterized in that, in the described step (1) trimethylchlorosilane, Iodotrimethylsilane is mixed as silylating reagent.
5. the synthetic method of ceftazime compound according to claim 1 is characterized in that, described step does not need to feed nitrogen protection in (1).
6. the synthetic method of ceftazime compound according to claim 1 is characterized in that, described step does not need to add catalyzer in (2).
7. the synthetic method of ceftazime compound according to claim 1 is characterized in that, it is 4.0～4.2 that described step (4) is regulated initial pH value.
8. the synthetic method of ceftazime compound according to claim 1 is characterized in that, it is 3.6～3.8 that described step (4) is regulated endpoint pH.
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| CN102964359A (en) * | 2012-11-23 | 2013-03-13 | 苏州中联化学制药有限公司 | Method for preparing ceftazidime dihydrochloride |
| CN103030651A (en) * | 2012-12-25 | 2013-04-10 | 深圳华润九新药业有限公司 | Method for preparing ceftazidime hydrochloride |
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| CN102964359A (en) * | 2012-11-23 | 2013-03-13 | 苏州中联化学制药有限公司 | Method for preparing ceftazidime dihydrochloride |
| CN103030651A (en) * | 2012-12-25 | 2013-04-10 | 深圳华润九新药业有限公司 | Method for preparing ceftazidime hydrochloride |
| CN103030651B (en) * | 2012-12-25 | 2014-03-12 | 深圳华润九新药业有限公司 | Method for preparing ceftazidime hydrochloride |
| CN104761570A (en) * | 2015-04-27 | 2015-07-08 | 四川制药制剂有限公司 | Preparation technology for ceftazidime for injection |
| CN104860964A (en) * | 2015-04-27 | 2015-08-26 | 四川制药制剂有限公司 | Product zero load avoiding injection ceftazidime preparation method |
| CN104892638A (en) * | 2015-05-28 | 2015-09-09 | 齐鲁安替制药有限公司 | Method for preparing ceftazidime by one-pot process |
| CN105646541A (en) * | 2015-12-30 | 2016-06-08 | 中山市金城道勃法制药有限公司 | Original development quality ceftazidime and medicine preparation thereof |
| CN109111467A (en) * | 2017-06-22 | 2019-01-01 | 宁应 | One kind 51/4His acridine compound of head spore and its drug combination preparation |
| CN110396104A (en) * | 2018-07-26 | 2019-11-01 | 赛法洛抗生素有限公司 | The new indication of Tai Siting cefotaxime pharmaceutical preparation treatment gynecological infection |
| CN109912625A (en) * | 2019-03-04 | 2019-06-21 | 辽宁美亚制药有限公司 | A kind of process reducing cefotaxime impurity H |
| CN109912625B (en) * | 2019-03-04 | 2021-01-12 | 辽宁美亚制药有限公司 | Process method for reducing ceftazidime impurity H |
| CN113583023A (en) * | 2021-06-24 | 2021-11-02 | 山东睿智医药科技有限公司 | Process method for preventing ceftazidime tert-butyl ester from generating ceftazidime H impurities |
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