CN100384853C - Method for synthesizing ticarcillin sodium - Google Patents
Method for synthesizing ticarcillin sodium Download PDFInfo
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- CN100384853C CN100384853C CNB2004100377273A CN200410037727A CN100384853C CN 100384853 C CN100384853 C CN 100384853C CN B2004100377273 A CNB2004100377273 A CN B2004100377273A CN 200410037727 A CN200410037727 A CN 200410037727A CN 100384853 C CN100384853 C CN 100384853C
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Abstract
The present invention discloses a new method for preparing ticarcillin sodium salts, which is characterized in that the method comprises the following steps: (1) mixing isopropyl ether, 3-thiophene malonate diethyl ester and thionyl chloride for reaction, concentrating reaction liquid by reducing pressure, and storing the concentrated liquid for standby; (2) mixing 6-amino pencilliophytanic acid, sodium hydroxide, sodium bicarbonate and acetone with the reaction liquid prepared in step (1) for reaction, separating phases of the reaction liquid, decoloring and filtering the water phase, mixing the filtered liquid together, and adding diluted hydrochloric acid and methyl isobutyl ketone; separating phases of the solution; adding sodium isooctoate/acetone solution and crystal seeds in the obtained organic phase; cultivating crystals; (3) filtering the crystallized solution, washing the filtered cakes, and drying the filtered cakes to obtain simple ticarcillin sodium salts. (4) preparing the ticarcillin sodium salts and sodium hydroxide into aqueous solution, and then carrying out decolorization, filtration and freeze-drying to obtain ticarcillin sodium salts. The quality of the ticarcillin sodium salts prepared the present invention is in consistent with the specifications of ticarcillin sodium in the American pharmacopeia of the 26th version.
Description
Technical field
The present invention relates to a kind of synthetic method of Western medicine, relate in particular to a kind of synthetic method of Ticarcillin Disodium.
Background technology
Ticarcillin Disodium is the semisynthetic penicillin that Britain Beecham company is formulated.Synthetic method patent after existing up to now a lot of relevant Ticarcillin Disodium and the improvement thereof is not seen the domestic method report that carries out this product of scale operation at present.
Synthetic Ticarcillin Disodium at first needs to synthesize ticarcillin list sodium list hydrate, produce Ticarcillin Disodium by lyophilization or solvent method then, provide a kind of production simple, the preparation method of the Ticarcillin Disodium list hydrate that productive rate is high is a Ticarcillin Disodium synthetic key.
The ultimate principle of synthetic ticarcillin list sodium list hydrate is as follows:
3-thiophene malonic ester and thionyl chloride reaction require this reaction to form single acyl chlorides on the one hand, form the intramolecularly protection on the other hand, and removing desolvates reduces the superoxide that forms in the reaction process, realizes that safety in production is the key problem in technology of this step.When adding the aqueous solution of 6-amino-penicillanic acid (6-APA), reactant remains pH becomes buffer status, and control reaction temperature and adjusting add the speed of acid, guarantees that the ester on the ticarcillin side chain in the reaction solution becomes acid, and not decarboxylation.
When the ticarcillin in the solution at first is transformed into ticarcillin list sodium list hydrate; change sodium reagent and select a kind of weak acid strong alkali salt of long-chain, reaction conditions gentleness like this, beta-lactam nucleus is protected; and side chain has reduced decarboxylic reaction, thereby has reduced production of by-products.
Ticarcillin Disodium is to be transformed through freeze-drying by ticarcillin list sodium list hydrate, and the concentration and the freeze-drying curve that wherein freeze solution all are the keys of this step.
Summary of the invention
It is simple that the object of the invention provides a kind of production process, the preparation method of the Ticarcillin Disodium that productive rate is high.
The present invention seeks to realize by following approach:
1) in isopropyl ether, adds 3-thiophene diethyl malonate, to add catalyzer and thionyl chloride again after the mixed solution intensification, after the constant temperature reaction reaction solution be lowered the temperature and concentrating under reduced pressure, until removing all superoxide, it is standby in 0 ℃ of preservation at last the solution of gained to be pressed into high level tank
2) preparation Sodium isooctanoate/acetone soln, it is standby that the solution for preparing is pressed into the high level tank preservation,
3) 6-amino-penicillanic acid is dissolved in the distilled water, after its cooling, add sodium hydroxide and make the 6-amino-penicillanic acid dissolving, after adjusting pH value is 7.4-7.8, add the prepared reaction solution of sodium bicarbonate, acetone and step 1) more successively, after the reaction, make the solution phase-splitting, keep water, reclaim organic phase, under low temperature, decolour, filter at aqueous phase adding gac and filtering material, after filter cake washing, merging filtrate adds dilute hydrochloric acid and methyl iso-butyl ketone (MIBK) to retort, makes the solution phase-splitting, it is standby to keep organic phase
4) organic phase of gained in the step 3) is added step 2) Sodium isooctanoate/acetone soln of being prepared, regulating pH value is to add crystal seed behind the 3.5-3.8, growing the grain,
5) solution after the step 4) crystallization is filtered, use the washing with acetone filter cake, the filter cake vacuum-drying with after the washing promptly gets ticarcillin list sodium salt,
6) ticarcillin list sodium salt and sodium hydroxide are mixed with the aqueous solution, add gac in low temperature decolouring down, sterile filtration promptly gets the ticarcillin sodium salt with filtrate press filtration to sterilisable chamber freeze-drying.
Among the above-mentioned preparation method, the catalyzer described in the step 1) is a triethylamine.
The mol ratio of 3-thiophene diethyl malonate described in the step 1) and thionyl chloride is 1: 1.3～1.5, and the weight of isopropyl ether is 5～6 times of 3-thiophene propanedioic acid.
The concentration of the Sodium isooctanoate/acetone step 2) is 1mol/L.
The mol ratio of the 3-thiophene diethyl malonate in 6-amino-penicillanic acid described in the step 3) and the step 1) is 1: 0.8～1.4, the weight of the used distilled water of dissolving 6-amino-penicillanic acid is 5～6 times of 6-amino-penicillanic acid, and the weight of acetone is 1/4～1/3 of water weight.
The concentration of the dilute hydrochloric acid described in the step 3) is 15% (v/v).
Described vacuum-drying temperature in the step 5) is 30 ℃.
The mol ratio of ticarcillin list sodium salt described in the step 6) and sodium hydroxide is 1: 1, and the percentage concentration of the aqueous solution that is made into is 30%.
The requirement of preparation method's of the present invention industrial chemicals is:
Content contains moisture less than 1.5% greater than 99%, and total impurities is less than 1%.
Further describe beneficial effect of the present invention by the following examples, it should be understood that these embodiment only are used for the purpose of illustration, never limit the scope of the invention.
Embodiment
The preparation of [embodiment] Ticarcillin Disodium
Adding 360kg isopropyl ether and 56kg 3-thiophene diethyl malonate are heated 50 ℃ in retort, again to wherein adding 230g triethylamine and 43.2kg thionyl chloride, reduced to room temperature reaction 1 hour, cool to 10 ℃ subsequently, decompression steams 170kg solution under 20 ℃, cool to 0 ℃, continue to concentrate, it is standby that the reaction solution of gained is pressed into 0 ℃ of preservation of high level tank.
Adding 335kg distilled water cools to 10 ℃ in retort, adds the 59.5kg 6-amino-penicillanic acid and add 12kg sodium hydroxide down at 10 ℃ to make the 6-amino-penicillanic acid dissolving, and pH is in 7.4～7.8 scopes in adjusting.Add 100kg sodium bicarbonate and 100kg acetone, cool to-5 ℃, step reactant in the adding, in adition process, pH is controlled between 6.8～7.2.Add back 0 ℃ of reaction 1 hour.It is 5.0 that dilute hydrochloric acid with 15% is transferred pH.Phase-splitting, water add the 4.5kg gac and 8kg pearl salt decoloured 30 minutes down in 5 ℃, filters, with 50kg water washing filter cake, merging filtrate adds dilute hydrochloric acid and the 500kg methyl iso-butyl ketone (MIBK) of 122kg 15% to retort, phase-splitting keeps organic phase, and control organic phase moisture content is no more than 6%.
25 ℃, Sodium isooctanoate/acetone soln of adding 210kg 1mol/L is regulated the pH value between 3.5～3.8 in organic phase, adds crystal seed, growing the grain 1 hour.Filter, the filter cake after washing with twice, 30 ℃ of vacuum-drying of 200kg washing with acetone filter cake 4 hours gets ticarcillin list sodium 94kg.
In dissolving vessel,, add 9.3kg sodium hydroxide, add the 5kg activated carbon decolorizing then the solution of ticarcillin list sodium melt into 30%, sterile filtration, press filtration to sterilisable chamber is gone into the Freeze Drying Equipment freeze-drying and is promptly got aseptic ticarcillin sodium salt then.
The quality test of the Ticarcillin Disodium of [test example] the present invention's preparation
1, for test agent, the Ticarcillin Disodium that the embodiment of the invention is prepared.
2, test method and result:
According to the every requirement under the 26 edition ticarcillin item of American Pharmacopeia, trial-product is completely examined.
Every assay sees Table 1
The quality test of the Ticarcillin Disodium that table 1 the present invention is prepared
Annotate: related substance refers to comprise that Ticarcillin Disodium is degraded into all analogues with the Ticarcillin Disodium structural similitude of decarboxylation Ticarcillin Disodium.
Assay: quality test shows that the prepared Ticarcillin Disodium quality of the present invention meets the every regulation under the 26 edition Ticarcillin Disodium item of American Pharmacopeia, shows that the prepared Ticarcillin Disodium quality of the present invention meets the requirements.
Claims (6)
1. the preparation method of a ticarcillin sodium salt is characterized in that may further comprise the steps:
1) in isopropyl ether, adds 3-thiophene diethyl malonate, to add thionyl chloride and catalyst of triethylamine again after the mixed solution intensification, after the constant temperature reaction reaction solution be lowered the temperature and concentrating under reduced pressure, until removing all superoxide, it is standby in 0 ℃ of preservation at last the reaction solution of gained to be pressed into high level tank
2) compound concentration is Sodium isooctanoate/acetone soln of 1mol/L, and it is standby that the solution for preparing is pressed into the high level tank preservation,
3) 6-amino-penicillanic acid is dissolved in the distilled water, after its cooling, add sodium hydroxide and make the 6-amino-penicillanic acid dissolving, after adjusting pH value is 7.4-7.8, add the prepared reaction solution of sodium bicarbonate, acetone and step 1) more successively, after the reaction, make the solution phase-splitting, keep water, reclaim organic phase, under low temperature, decolour, filter at aqueous phase adding gac and filtering material, after filter cake washing, merging filtrate adds dilute hydrochloric acid and methyl iso-butyl ketone (MIBK) to retort, makes the solution phase-splitting, it is standby to keep organic phase
4) organic phase of gained in the step 3) is added step 2) Sodium isooctanoate/acetone soln of being prepared, regulating pH value is to add crystal seed behind the 3.5-3.8, growing the grain,
5) solution after the step 4) crystallization is filtered, use the washing with acetone filter cake, the filter cake vacuum-drying with after the washing promptly gets ticarcillin list sodium salt,
6) ticarcillin list sodium salt and sodium hydroxide are mixed with the aqueous solution, add gac in low temperature decolouring down, sterile filtration promptly gets the ticarcillin sodium salt with filtrate press filtration to sterilisable chamber freeze-drying.
2. the preparation method of ticarcillin sodium salt according to claim 1 is characterized in that the mol ratio of 3-thiophene diethyl malonate and thionyl chloride is 1: 1.3～1.5 in the step 1), and the weight of isopropyl ether is 5～6 times of 3-thiophene propanedioic acid.
3. the preparation method of ticarcillin sodium salt according to claim 1, the mol ratio that it is characterized in that the 3-thiophene diethyl malonate in the 6-amino-penicillanic acid and step 1) in the step 3) is 1: 0.8～1.4, the weight of the used distilled water of dissolving 6-amino-penicillanic acid is 5～6 times of 6-amino-penicillanic acid, and the weight of acetone is 1/4～1/3 of water weight.
4. the preparation method of ticarcillin sodium salt according to claim 1, the concentration that it is characterized in that the dilute hydrochloric acid described in the step 3) are 15% (v/v).
5. the preparation method of ticarcillin sodium salt according to claim 1 is characterized in that the vacuum-drying temperature in the step 5) is 30 ℃.
6. the preparation method of ticarcillin sodium salt according to claim 1 is characterized in that the mol ratio of ticarcillin list sodium salt and sodium hydroxide is 1: 1 in the step 6), and the percentage concentration of the aqueous solution that is made into is 30%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100377273A CN100384853C (en) | 2004-05-10 | 2004-05-10 | Method for synthesizing ticarcillin sodium |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100377273A CN100384853C (en) | 2004-05-10 | 2004-05-10 | Method for synthesizing ticarcillin sodium |
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| CN1696133A CN1696133A (en) | 2005-11-16 |
| CN100384853C true CN100384853C (en) | 2008-04-30 |
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| CNB2004100377273A Expired - Fee Related CN100384853C (en) | 2004-05-10 | 2004-05-10 | Method for synthesizing ticarcillin sodium |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101671347B (en) * | 2009-09-29 | 2012-05-02 | 齐鲁天和惠世制药有限公司 | Carboxylic acid penicillin amine salt and application thereof in preparing high-purification sodium oxacillin salt |
| CN102311451A (en) * | 2010-07-07 | 2012-01-11 | 胡梨芳 | Ticarcillin disodium hydrate and preparation method as well as application thereof |
| CN102464655B (en) * | 2010-10-30 | 2016-05-25 | 山东新时代药业有限公司 | A kind of synthetic method of ticarcillin disodium intermediate |
| CN102250118B (en) * | 2011-05-26 | 2013-10-02 | 朗致集团博康药业有限公司 | Method for synthesizing nafcillin sodium from 1-chloroformyl-2-naphthyl ethyl ether solid |
| CN102250121B (en) * | 2011-05-26 | 2013-11-06 | 华北制药集团山西博康药业有限公司 | Synthesizing method of nafcillin acid |
| CN106967088B (en) * | 2017-04-20 | 2019-05-07 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of ticarcillin sodium |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1553647A (en) * | 1976-05-20 | 1979-09-26 | Bayer Ag | Process for the preparation of -carboxybenzylpenicillin |
| US4298732A (en) * | 1978-01-17 | 1981-11-03 | Glaxo Group Limited | Crystallization process |
| GB2200355A (en) * | 1987-01-29 | 1988-08-03 | Beecham Group Plc | Potassium clavulanate |
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2004
- 2004-05-10 CN CNB2004100377273A patent/CN100384853C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1553647A (en) * | 1976-05-20 | 1979-09-26 | Bayer Ag | Process for the preparation of -carboxybenzylpenicillin |
| US4298732A (en) * | 1978-01-17 | 1981-11-03 | Glaxo Group Limited | Crystallization process |
| GB2200355A (en) * | 1987-01-29 | 1988-08-03 | Beecham Group Plc | Potassium clavulanate |
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Owner name: HEBEI NEW ZHANG MEDICINE CO., LTD. Free format text: FORMER OWNER: HEBEI ZHANG MEDICINE CO., LTD. Effective date: 20090710 |
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Effective date of registration: 20090710 Address after: 24, Jianguo Road, Zhangjiakou, Hebei, Hebei Province, Limited by Share Ltd research and Development Department Patentee after: Hebei Xinzhang Pharmaceutical Co., Ltd. Address before: No. 24 Jianguo Road, Hebei, Zhangjiakou Patentee before: Zhangyao Co., Ltd., Hebei |
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