CN100486978C - Preparation process of ticarcillin disodium salt - Google Patents
Preparation process of ticarcillin disodium salt Download PDFInfo
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Abstract
The invention discloses a making method of penicillin antibiotic disodium tikaxilin salt, which comprises the following steps: adding diluent in the tikaxilin acid solution at -5-50 deg. c; decoloring through active carbon; filtering; adding salting agent; stirring; culturing crystal at -10-50 deg. c until the crystal is evolved completely; filtering; washing; drying in the vacuum under 20-80 deg. c; obtaining the product.
Description
Technical field
The present invention relates to the pharmaceutical products field, particularly the method for each broad-spectrum penicillin antibiotic ticarcillin disodium salt of system.
Technical background
Ticarcillin is semisynthetic penicillin. as far back as Japan's listing, be a kind of penicillin of new texture, and effective especially for serious gram positive bacterial infection.Its common dosage forms is injection Ticarcillin Disodium/Clavulanic Potassium.Its antimicrobial spectrum and Pyocianil are similar.But its anti-microbial activity to Pseudomonas aeruginosa is 2～4 times of Pyocianil.Lower to the gram-positive microorganism relative reactivity, and want high for the activity of Gram-negative bacteria.Many clinically compound preparations with Ticarcillin Disodium and Clavulanic Potassium, both cooperations had both enlarged antimicrobial spectrum, had strengthened anti-microbial activity again.Thereby play the excellent antibiotic effect.
Because the higher water absorbability of this product tool tool, have two carboxyls on the structure, two the equal energy of carboxyl salifies, but salifiable kinetic rate difference, salification process is easy to generate the mixture of single sodium salt and disodium salt, is non-medicinal forms, usually be paste, wrapped up in it than multi-solvent, cause the finished product solvent residual too high, the look level is higher, purity is low, and its less stable.At present, the method for preparing ticarcillin disodium salt mainly contains lyophilization, spray-drying process and Slurry method.
Lyophilization is modal a kind of method, and the disclosed preparation method of CN200410037727 at first obtains single sodium salt of ticarcillin, and then makes disodium salt with lyophilization.And " Chinese pharmaceutical chemistry magazine " (2006,16 (3): be to adopt lyophilization to prepare ticarcillin disodium salt equally 178～179).Lyophilization exists significant disadvantages and deficiency: the product poor crystal form that lyophilization is produced; The water content height is generally 3.0～6.0%, so can cause the degraded of product during long storage time; Because lyophilization does not play the effect of separating impurity, foreign matter content height; Because the existence of other salts is arranged, cause pH higher, the poor stability of product, and the cost height is arranged, the shortcoming that facility investment is high.
When US3282926 prepares ticarcillin disodium salt, after removing impurity and obtain ticarcillin acid by chromatographic separation, steaming desolventizes and obtains the ticarcillin sodium salt, obtain the sodium salt molar yield from 6-APA and only have 10.3%, purity has only 60%, poor product quality, yield is low, and this patent does not illustrate whether be disodium salt in the product.
US4171303 uses anhydrous magnesium sulfate drying with synthesis reaction solution after with ethyl acetate extraction, filter, add acetone diluted, and then add isocaproic acid sodium and be settled out product, drying, yield 80%, the purity of iodometric determination is 100%, but the resulting product stability of this method is also not so good, is not suitable for suitability for industrialized production.
The slurry method of GB131145, its shortcoming is also more outstanding, is exactly to take temperature programming crystalline method in paste liquid, and this can cause the product degraded, and impurity increases, and stability reduces.
After GB1449749 then adopts methyl iso-butyl ketone (MIBK) and dichloromethane extraction, the methyl isobutyl ketone solution that directly adds Sodium isooctanoate, be settled out product, in ticarcillin acid HPLC purity is 85%, but this method is separated out the mixture of single sodium salt and disodium salt easily, cause product pH value defective, and to the operational requirement harshness.
Summary of the invention
The object of the present invention is to provide a kind of method that directly prepares ticarcillin disodium salt from ticarcillin acid, this method is simple to operate, the product purity height that obtains, good stability.
The objective of the invention is to be achieved through the following technical solutions:
Under-5～50 ℃, in the resulting ticarcillin acid solution of penicillin building-up reactions, after the dilution of adding thinner, use decolorizing with activated carbon, filter; Add salt forming agent, growing the grain under-10～50 ℃ and agitation condition, complete until crystallization, filter washing; 20～80 ℃ of vacuum-dryings obtain ticarcillin disodium salt.
Described ticarcillin acid solution is with the ticarcillin acid extraction liquid after the extraction agent extraction.
When growing the grain, precipitation agent can be dripped so that quicken crystallization.
Thinner is selected from the mixture of one or two or more kinds solvent in the alcohols that contains 1～3 carbon atom, dioxane, DMF, DMA, DMSO, the HPMA isopolarity solvent.
Extraction agent be selected from the acid of the halohydrocarbon that contains 1～4 carbon atom, 1～4 carbon atom and 1～4 carbon atom the ester that alcohol became, aromatic hydrocarbons, contain 2～10 carbon atoms ethers, contain the mixture of one or two or more kinds solvent in the ketone of 4～6 carbon atoms.
Extraction temperature is-5～50 ℃, and preferred extraction temperature is 0～20 ℃.
Salt forming agent is selected from sodium alkoxide, sodium soap or aromatic acid sodium, inorganic sodium or the mineral alkali that contains 1～5 carbon atom; Be specially sodium methylate, sodium ethylate, sodium butylate, sodium formiate, sodium acetate, Sodium isooctanoate, isocaproic acid sodium, fragrant sour sodium, sodium tartrate, sodium hydroxide, yellow soda ash, sodium bicarbonate.
Salt forming agent can directly add, also can be with adding after the dissolution with solvents; Described solvent is selected from the mixture of one or two or more kinds solvent in the alcohols that contains 1～3 carbon atom, water, dioxane, DMF, DMA, DMSO, the HPMA isopolarity solvent.
Precipitation agent be selected from the acid of the halohydrocarbon that contains 1～4 carbon atom, 1～4 carbon atom and 1～4 carbon atom the ester that alcohol became, contain the mixture of one or two or more kinds solvent in the ketone of 3～6 carbon atoms.
Ticarcillin acid: extraction agent: thinner: the ratio of the usage quantity of precipitation agent is: 1g:2～100mL:0.5～50mL:0～500mL;
Preferred Tc is 0～5 ℃.
According to the ultimate analysis of table 1 and
1HNMR, we can confirm that the chemical structure of product is a target product.Contrast these two kinds of resultant products of method of preparation method of the present invention (hereinafter to be referred as crystallization process) and lyophilization, data in associative list 2, table 3, the table 4, we may safely draw the conclusion: the present invention directly prepares the crystallized form of ticarcillin disodium salt, constant product quality, the crystal stable crystal form that is obtained from penicillinic acid, the content height, the purity height, water content is low, and product meets the requirement of American Pharmacopeia USP and Chinese Pharmacopoeia CP, and characteristics simple to operate, that running cost is low.The crystallization process data that illustrate in table 1, table 2, table 3, the table 4 are the analytical data to embodiment 1 gained material.The lyophilization data that illustrate in table 1, table 2, table 3, the table 4 are the analytical data to embodiment 13 gained materials.
Table 1 ultimate analysis
| Theoretical value | C?42.06％，H3.29％，N?6.54％，S?14.97％ |
| The crystallization process experimental value | C?40.20％，H4.09％，N?6.24％，S?14.20％ |
| The lyophilization experimental value | C?39.79％，H4.46％，N?6.14％，S?13.40％ |
Table 2 X-ray diffraction analysis
Table 3 thermogravimetric analysis
Other data contrasts of table 4 lyophilization product and crystalline product of the present invention
| Purity (%) (HPLC) | Maximum contaminant (%) | Total impurities (%) | Content (%) (HPLC) | Moisture (%) | pH | Weight loss on drying (%) | |
| Crystallization process | 98.5 | 0.6 | 1.5 | 97.3 | 2.1 | 6.9 | 2.6 |
| Lyophilization | 96.4 | 1.0 | 3.6 | 93.9 | 4.6 | 6.3 | 5.7 |
Embodiment
Ticarcillin acid synthetic has several different methods, and all embodiment of the present invention all adopt " Chinese pharmaceutical chemistry magazine ", and 2006,16 (3): (178～179) disclosed method.
Embodiment 1
Under 0 ℃, the reaction solution that will contain the acid of 50g ticarcillin merges the N-BUTYL ACETATE extraction liquid with 50mL * 2 N-BUTYL ACETATE extracting twice, use the 50mL acetone diluted, add the 2g activated carbon, behind the decolouring 30min, filter, in mother liquor, add the acetone soln of Sodium isooctanoate, add crystal seed, after stirring growing the grain 2.5h under 10 ℃, slowly add 100mL acetone again, finish, filtration under diminished pressure, 80 ℃ of vacuum-dryings obtain white ticarcillin disodium salt, yield 78%;
1HNMR (D2O): 7.44 (m, 1H), 7.34 (m, 1H), 7.13 (m, 1H), 5.58 (d, 1H), 5.47 (d, 1H), 4.68 (m, 1H), 4.24 (m, 1H), 1.5 (m, 6H).
Embodiment 2
Under 50 ℃, the reaction solution that will contain the acid of 10g ticarcillin merges the N-BUTYL ACETATE extraction liquid with 10mL * 2 N-BUTYL ACETATE extracting twice, with the dilution of 50mL N-BUTYL ACETATE, add the 0.5g activated carbon, behind the decolouring 30min, filter, in mother liquor, add the acetone soln of isocaproic acid sodium, add crystal seed, after stirring growing the grain 2.5h under 5 ℃, slowly add 500mL acetone again, finish, filtration under diminished pressure, 40 ℃ of vacuum-dryings obtain white ticarcillin disodium salt, HPLC purity 99.1%, maximum contaminant 0.4%.
Embodiment 3
Under-5 ℃, will contain reaction solution 10mL * 2 dichloromethane extractions twice of 5g ticarcillin acid, the combined dichloromethane extraction liquid, with the dilution of 10mL methyl alcohol, add the 0.2g activated carbon, behind the decolouring 30min, filter, in mother liquor, add the methanol solution of sodium methylate, add crystal seed, after stirring growing the grain 2.5h under 10 ℃, slowly add 500mL acetone again, finish, filtration under diminished pressure, 20 ℃ of vacuum-dryings obtain white ticarcillin disodium salt, HPLC purity 99.0%, maximum contaminant 0.3%.
Embodiment 4
Under 10 ℃, the reaction solution that will contain the acid of 5g ticarcillin merges the ritalin extraction liquid with 50mL * 2 ritalin extracting twice, with the 5mLDMF dilution, add the 0.2g activated carbon, behind the decolouring 30min, filter, in mother liquor, add the acetone soln of sodium acetate, add crystal seed, after stirring growing the grain 2.5h under 0 ℃, slowly add 100mL acetone again, finish, filtration under diminished pressure, 30 ℃ of vacuum-dryings obtain white ticarcillin disodium salt, HPLC purity 97.5%, maximum contaminant 1.3%.
Embodiment 5
Under 25 ℃, the reaction solution that will contain the acid of 5g ticarcillin merges ethyl acetate extraction liquid with 250mL * 2 ethyl acetate extractions twice, use the 50mL acetone diluted, add the 0.2g activated carbon, behind the decolouring 30min, filter, in mother liquor, add the acetone soln of isocaproic acid sodium, add crystal seed, after stirring growing the grain 2.5h under 0 ℃, slowly add 200mL acetone again, finish, filtration under diminished pressure, 50 ℃ of vacuum-dryings obtain white ticarcillin disodium salt, HPLC purity 98.1%, maximum contaminant 0.8%.
Embodiment 6
Under 5 ℃, the reaction solution that will contain the acid of 5g ticarcillin merges first isobutyl ketone extraction liquid with 5mL * 2 first isobutyl ketone extracting twice, with the 250mLDMSO dilution, add the 0.2g activated carbon, behind the decolouring 30min, filter, in mother liquor, add the acetone soln of Sodium isooctanoate, add crystal seed, after stirring growing the grain 2.5h under 50 ℃, slowly add 300mL acetone again, finish, filtration under diminished pressure, 50 ℃ of vacuum-dryings obtain white ticarcillin disodium salt, HPLC purity 97.9%, maximum contaminant 0.6%.
Embodiment 7
Under 0 ℃, the reaction solution that will contain the acid of 5g ticarcillin merges the butanone extraction liquid with 200mL * 2 butanone extracting twice, with the dilution of 5mL water, add the 0.2g activated carbon, behind the decolouring 30min, filter, in mother liquor, add the aqueous solution of sodium acetate, add crystal seed, after stirring growing the grain 2.5h under-10 ℃, slowly add 400mL acetone again, finish, filtration under diminished pressure, 50 ℃ of vacuum-dryings obtain white ticarcillin disodium salt, HPLC purity 98.0%, maximum contaminant 0.5%.
Embodiment 8
Under 10 ℃, the reaction solution that will contain the acid of 5g ticarcillin merges the ritalin extraction liquid with 5mL * 2 ritalin extracting twice, use the 50mL acetone diluted, add the 0.2g activated carbon, behind the decolouring 30min, filter, in mother liquor, add the aqueous isopropanol of Sodium isooctanoate, add crystal seed, after stirring growing the grain 2.5h under 0 ℃, slowly add 450mL acetone again, finish, filtration under diminished pressure, 50 ℃ of vacuum-dryings obtain white ticarcillin disodium salt, HPLC purity 97.6%, maximum contaminant 2.4%.
Embodiment 9
Under 10 ℃, the reaction solution that will contain the acid of 5g ticarcillin merges the N-BUTYL ACETATE extraction liquid with 5mL * 2 N-BUTYL ACETATE extracting twice, use the 50mL alcohol dilution, add the 0.2g activated carbon, behind the decolouring 30min, filter, in mother liquor, add the aqueous isopropanol of Sodium isooctanoate, add crystal seed, after stirring growing the grain 2.5h under 5 ℃, slowly add the 300mL Virahol again, finish, filtration under diminished pressure, 60 ℃ of vacuum-dryings obtain white ticarcillin disodium salt, HPLC purity 99.1%, maximum contaminant 0.2%.
Embodiment 10
Under 0 ℃, the reaction solution that will contain the acid of 5g ticarcillin merges the N-BUTYL ACETATE extraction liquid with 50mL * 2 N-BUTYL ACETATE extracting twice, use the 2.5mL acetone diluted, add the 0.2g activated carbon, behind the decolouring 30min, filter, in mother liquor, add the isopropyl ether solution of Sodium isooctanoate, add crystal seed, after stirring growing the grain 2.5h under-5 ℃, slowly add 350mL acetone again, finish, filtration under diminished pressure, 50 ℃ of vacuum-dryings obtain white ticarcillin disodium salt, HPLC purity 98.2%, maximum contaminant 0.8%.
Embodiment 11
Under 15 ℃, the reaction solution that will contain the acid of 5g ticarcillin merges the ritalin extraction liquid with 50mL * 2 ritalin extracting twice, uses the 200mL acetone diluted, adds the 0.2g activated carbon, behind the decolouring 30min, filters, and adds Na in mother liquor
2CO
3The aqueous solution, add crystal seed, 0 ℃ stir growing the grain 2.5h down after, slowly add 250mL acetone again, finish, filtration under diminished pressure, 20 ℃ of vacuum-dryings obtain white ticarcillin disodium salt, HPLC purity 98.2%, maximum contaminant 0.8%.
Embodiment 12
Under 0 ℃, the reaction solution that will contain the acid of 5g ticarcillin merges the N-BUTYL ACETATE extraction liquid with 50mL * 2 N-BUTYL ACETATE extracting twice, use the 75mL acetone diluted, add the 0.2g activated carbon, behind the decolouring 30min, filter, in mother liquor, add the isopropyl ether solution of Sodium isooctanoate, add crystal seed, after stirring growing the grain 2.5h under 5 ℃, filtration under diminished pressure, 50 ℃ of vacuum-dryings obtain white ticarcillin disodium salt, HPLC purity 98.4%, maximum contaminant 0.8%.
Embodiment 13
The present embodiment comparative example, (2006,16 (3): 178～179) disclosed lyophilization prepares ticarcillin disodium salt according to " Chinese pharmaceutical chemistry magazine ".
The disclosed embodiment of above-mentioned document is: 6 one Aminopenicillin alkanoic acids (6 one APA) 15g (69mmol) are dissolved in the 100mL tetrahydrofuran (THF), stir, add N, O one or two (trimethyl silicon based) ethanamide (BSA) 21.2g (0.1mol), 25 ℃ are stirred 12h down, add 15.7g (69retool) compound 7, stir 2h.Concentrating under reduced pressure is removed tetrahydrofuran (THF), adds entry 50mL, ethyl acetate 50mL, tell organic layer,, extract (30mL * 3) with sodium hydrogen carbonate solution again with 0.5toolL-1 hydrochloric acid (25mL * 2) and washing (25mL * 2), divide water-yielding stratum, add gac 1g, decolour under the room temperature, filter, filter cake water (5mL * 2) is washed, merge water, sterile filtration, freeze-drying.Get off-white color solid 25.4g.
The document claims that this legal system is equipped with ticarcillin disodium salt yield 83.5%, mp201 ℃ (decomposition), and it is 97.89% that the HPLC method detects purity.And the applicant prepares the yield 81.3% of ticarcillin disodium salt according to this method, mp201 ℃ (decomposition), and it is 96.4% that the HPLC method detects purity.
The above embodiment of the present invention should not be regarded as limiting the scope of the invention, and those skilled in the art is under the enlightenment of technical solution of the present invention, and conspicuous improvement of making or change all should fall into protection scope of the present invention.More satisfactory extraction agent is little and to the big solvent of the free acid solubility of ticarcillin, as N-BUTYL ACETATE with water solubility; In order to obtain more crystallization effect, thinner that is adopted and used extraction agent should have mutual solubility preferably; Selecting for use according to the mutual solubility of itself and extraction agent and thinner of precipitation agent carried out, and preferably selects the good solvent of mutual solubility.
Claims (14)
1, a kind of preparation method of ticarcillin disodium salt is characterized in that, it comprises the steps:
Under-5～50 ℃, in the resulting ticarcillin acid solution of penicillin building-up reactions, after the dilution of adding thinner, use decolorizing with activated carbon, filter; Add salt forming agent, growing the grain under-10～50 ℃ and agitation condition, complete until crystallization, filter washing; 20～80 ℃ of vacuum-dryings obtain ticarcillin disodium salt.
2, the preparation method of ticarcillin disodium salt according to claim 1 is characterized in that, described ticarcillin acid solution is with the ticarcillin acid extraction liquid after the extraction agent extraction.
3, the preparation method of ticarcillin disodium salt according to claim 2 is characterized in that, extraction temperature is-5～50 ℃.
4, the preparation method of ticarcillin disodium salt according to claim 3 is characterized in that, extraction temperature is 0～20 ℃.
5, according to the preparation method of claim 2 or 3 described ticarcillin disodium salts, it is characterized in that, extraction agent be selected from the acid of the halohydrocarbon that contains 1～4 carbon atom, 1～4 carbon atom and 1～4 carbon atom the fat that alcohol became, aromatic hydrocarbons, contain 2～10 carbon atoms ethers, contain the mixture of one or two or more kinds solvent in the ketone of 4～6 carbon atoms.
6, according to the preparation method of claim 1 or 2 or 3 described ticarcillin disodium salts, it is characterized in that, when growing the grain, drip precipitation agent so that quicken crystallization.
7, the preparation method of ticarcillin disodium salt according to claim 6, it is characterized in that, precipitation agent be selected from the acid of the halohydrocarbon that contains 1～4 carbon atom, 1～4 carbon atom and 1～4 carbon atom the fat that alcohol became, contain the mixture of one or two or more kinds solvent in the ketone of 3～6 carbon atoms.
8, the preparation method of ticarcillin disodium salt according to claim 6 is characterized in that, ticarcillin acid: extraction agent: thinner: the ratio of the usage quantity of precipitation agent is: 1g:2～100ml: 0.5～50ml: 0～500ml.
According to the preparation method of claim 1 or 2 or 3 described ticarcillin disodium salts, it is characterized in that 9, thinner is selected from the mixture of one or two or more kinds solvent among the alcohols that contains 1～3 carbon atom, dioxane, DMF, DMA, DMSO, the HPMA.
According to the preparation method of claim 1 or 2 or 3 described ticarcillin disodium salts, it is characterized in that 10, salt forming agent is selected from the sodium alkoxide, sodium soap or the aromatic acid sodium that contain 1～5 carbon atom, one or two or more kinds the mixture in the inorganic sodium.
11, the preparation method of ticarcillin disodium salt according to claim 10, it is characterized in that salt forming agent is selected from one or two or more kinds the mixture in sodium methylate, sodium ethylate, sodium butylate, sodium formiate, sodium acetate, Sodium isooctanoate, isocaproic acid sodium, fragrant sour sodium, sodium tartrate, sodium hydroxide, yellow soda ash, the sodium bicarbonate.
According to the preparation method of claim 1 or 2 or 3 described ticarcillin disodium salts, it is characterized in that 12, salt forming agent directly adds or with adding after the dissolution with solvents.
13, the preparation method of ticarcillin disodium salt according to claim 12 is characterized in that, described solvent is selected from the mixture of one or two or more kinds solvent among the alcohols that contains 1～3 carbon atom, dioxane, DMF, DMA, DMSO, the HPMA.
According to the preparation method of claim 1 or 2 or 3 described ticarcillin disodium salts, it is characterized in that 14, Tc is 0～10 ℃.
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| CN101735244B (en) * | 2008-11-05 | 2012-01-18 | 鲁南制药集团股份有限公司 | Method for preparing broad-spectrum penicillin antibiotic ticarcillin sodium |
| CN102040507B (en) * | 2009-10-10 | 2013-12-04 | 台州市华南医化有限公司 | Preparation methods of 7-phenyl-6-heptynoic acid and reactant of sodium 5-bromo-pentanoate |
| CN102311451A (en) * | 2010-07-07 | 2012-01-11 | 胡梨芳 | Ticarcillin disodium hydrate and preparation method as well as application thereof |
| 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 |
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