CN1765901A - One-step preparation process of aseptic cefotaxime sodium for injection - Google Patents
One-step preparation process of aseptic cefotaxime sodium for injection Download PDFInfo
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- CN1765901A CN1765901A CN 200510118235 CN200510118235A CN1765901A CN 1765901 A CN1765901 A CN 1765901A CN 200510118235 CN200510118235 CN 200510118235 CN 200510118235 A CN200510118235 A CN 200510118235A CN 1765901 A CN1765901 A CN 1765901A
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- sodium
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- aseptic
- cefotaxime sodium
- preparation process
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- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 title claims abstract description 34
- 229960002727 cefotaxime sodium Drugs 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000002347 injection Methods 0.000 title claims description 13
- 239000007924 injection Substances 0.000 title claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 claims abstract description 18
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 18
- 239000003960 organic solvent Substances 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 238000002425 crystallisation Methods 0.000 claims abstract description 15
- 230000008025 crystallization Effects 0.000 claims abstract description 15
- 150000002148 esters Chemical class 0.000 claims abstract description 12
- 150000001412 amines Chemical class 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 239000012046 mixed solvent Substances 0.000 claims description 19
- 239000000047 product Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 229910052708 sodium Inorganic materials 0.000 claims description 13
- 239000011734 sodium Substances 0.000 claims description 13
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical class C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 238000005352 clarification Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 150000001555 benzenes Chemical class 0.000 claims description 6
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 claims description 4
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 claims description 4
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 4
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 229960004756 ethanol Drugs 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 2
- 239000012433 hydrogen halide Substances 0.000 claims description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 claims description 2
- 238000011146 sterile filtration Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 12
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 239000013078 crystal Substances 0.000 abstract description 6
- 159000000000 sodium salts Chemical class 0.000 abstract description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract 3
- 239000007810 chemical reaction solvent Substances 0.000 abstract 1
- 230000007423 decrease Effects 0.000 abstract 1
- 235000019439 ethyl acetate Nutrition 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- 239000007788 liquid Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 description 17
- 239000011259 mixed solution Substances 0.000 description 13
- 238000005406 washing Methods 0.000 description 12
- 238000007664 blowing Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 5
- -1 Sodium isooctanoates Chemical class 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000012467 final product Substances 0.000 description 5
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 229960004261 cefotaxime Drugs 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 229960004249 sodium acetate Drugs 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
Abstract
The invention relates to a preparation technique for cefotaxime sodium, which comprises: in solvent, reacting between 7-ACA and AE-active ester with amine as intermediate; adding benzothiazole as assisting solvent and sodium salt agent, separating and crystallizing to obtain the product. Wherein, the reaction solvent comprises benzene organic solvent, acetic ester or acetone and alcohol; stirring the 7-ACA and AE-active ester till clear, adding assisting solvent to benzothiazole; degerming, filtering, adding sodium salt agent for reaction; when liquid shows turbid, feeding crystal; separating the crystal by insoluble solvent to cefotaxime sodium, taking crystallization post-treatment and obtaining the product. This invention needs just one-step operation, has good crystallization and short production period, improves product yield, and decreases solvent harm to operation crews.
Description
Technical field
The present invention relates to a kind of preparation technology of cefotaxime sodium, belong to the preparing technical field of compound.
Background technology
Cefotaxime sodium belongs to the derivative of third generation cephalosporin, is widely used in treating the infection at positions such as sensitive bacterial causes septicemia, purulent meningitis and respiratory tract, urinary tract, biliary tract, bone and joint, skin and soft tissue, abdominal cavity, digestive tube, face, sexual organ.Existing cefotaxime sodium preparation technology operates in two steps, in the single solvent of methylene dichloride, is reacted under the effect of amine intermediate reaction thing by 7-ACA and AE-active ester, adds hydrochloric acid then and carries out acidifying, and the crystallization of lowering the temperature again obtains cefotaxime; Second step added salt forming agent and is carried out to reactant salt again with the cefotaxime dissolving, with acetone crystallisate was separated out.The operation of two step process, crystallization is in bad order, influences quality product, and the solvent usage quantity is big, and is seriously polluted, and labour intensity is big, and the production cycle is long, and power consumption is big, the production cost height, product yield is low.
Summary of the invention
The object of the present invention is to provide a kind of one-step preparation process of aseptic cefotaxime sodium for injection, the solvent usage quantity is few, and labour intensity is little, and is with short production cycle, and production cost is low, the product yield height, and quality is good.
The one-step preparation process of aseptic cefotaxime sodium for injection of the present invention, in solvent, react under the effect of amine intermediate reaction thing by 7-ACA and AE-active ester, add the benzothiazole solubility promoter, adding sodium salt-forming agent again reacts and separates out crystallization and make, its action solvent is by benzene class organic solvent, the mixed solvent that ethyl acetate or acetone and alcohol organic solvent are formed, the stirring reaction of 7-ACA and AE-active ester is to clarification, add the benzothiazole solubility promoter then, Sterile Filtration directly adds sodium salt-forming agent and is carried out to reactant salt, when question response becomes muddy, carrying out growing the grain handles, with the insoluble organic solvent of cefotaxime sodium crystallization is separated out then, get the cefotaxime sodium finished product through conventional crystallization aftertreatment at last.
Reaction equation is: (videing infra)
Technology of the present invention is owing to adopted mixed solvent, can not need at first to be made into cefotaxime, be carried out to reactant salt again and prepare cefotaxime sodium, but directly prepare cefotaxime sodium from 7-ACA, technological process has been simplified in the operation of one step process, and the crystallization situation is good, with short production cycle, shorten the time of half, labour intensity is little, and power consumption is few, production cost is low, can also improve content about 2%, yield reaches (in 7-ACA) more than 88%, and the solvent usage quantity reduces, only be original 75%, reduced the harm of solvent operator.
Among the present invention:
The composition volume ratio of mixed solvent is:
Benzene class organic solvent, ethyl acetate or acetone: alcohol organic solvent=1: (1～0.5).
The benzothiazole solubility promoter is a kind of in two (trichloromethyl) carbonic ether, carbonochloridic acid three chloromethyl esters, hydrogen halide or other halogenide.
Benzene class organic solvent is toluene or dimethylbenzene etc.
Alcohol organic solvent is methyl alcohol, ethanol or Virahol etc.
Amine intermediate reaction thing is triethylamine, Diisopropylamine or tertiary amine etc.
Salt forming agent is a kind of in the organic or inorganic sodium salts such as Sodium isooctanoate, sodium-acetate (sodium acetate), sodium methylate, yellow soda ash, can directly use solid, also can use solution.Solution is dissolved in or is mixed in the mixed solvent by sodium salt to be made, and uses identical solvent, and it is convenient to handle.
The insoluble organic solvent of cefotaxime sodium is toluene, acetone, ethyl acetate, dehydrated alcohol or Virahol etc., can select one or mix to use.
When salt-forming reaction question response solution becomes was muddy, adding cefotaxime sodium powder was done crystal seed and is carried out the growing the grain processing again, can improve the crystallization situation, improves crystalline quality.
Washing soln can use the mixed solution of ethyl acetate and dehydrated alcohol or methylene dichloride and methyl alcohol, and the mixed volume ratio can be 10: (1～2).
Using sodium salt as salt forming agent, after the crystallization filter cake is washed, is that the acetone soln of 3～5% water carries out agitator treating and handles the assurance quality product with volume ratio preferably again.
The production of product will meet industry requirement, and the same routine operation of other process condition of not mentioning in detail, as the batching situation of reactant meet that reactional equation requires, the adding situation of amine intermediate reaction thing and 7-ACA consumption proportion relation, benzothiazole solubility promoter and salt forming agent (solubility promoter and salt forming agent add-on are 7-ACA charging capacity 0.5～2%), 4～10 ℃ of temperature of reaction, rearing crystal time 0.5～1 hour, crystalline washing requirement, 40～50 ℃ of drying temperatures, vacuum drying vacuum degree control be 0.095～0.099MPa, or the like.
Process using of the present invention mixed solvent, directly prepare cefotaxime sodium, step process operation from 7-ACA, simplified technological process, the crystallization situation is good, and is with short production cycle, and labour intensity is little, power consumption is few, production cost is low, can also improve product yield, and the solvent usage quantity reduces, reduced the harm of solvent, be beneficial to industrial practicing operator.
Embodiment
The invention will be further described below in conjunction with embodiment.
Embodiment 1
The preparation technology of cefotaxime sodium of the present invention is as follows:
Adding 120ml volume ratio is 1: 1 toluene and a methyl alcohol composition mixed solvent in three-necked bottle, the 20ml triethylamine, cool to 5 ℃, add 20 gram 7-ACA, 28 gram AE-active ester, keep 5 degree reactions 60 minutes, after the reaction clarification, add 3 milliliters of concentrated hydrochloric acids, add Sodium isooctanoate solution salt forming agent and 0.1g sodium bisulfite oxidation inhibitor under the room temperature, reacted after 10 minutes again the crystal seed growing the grain 30 minutes, and then drip toluene 150ml, drip the toluene process temperature and be controlled at 20 ℃, dripped off in 2 hours, drip off back growing the grain 30 minutes blowings,, and then will expect that cake is added to stir in the mixed solution of 140ml acetone and 6ml water and wash blowing after 30 minutes with the mixed solution washing material cake of 50ml ethyl acetate and 5ml dehydrated alcohol, with small amount of acetone washing material cake, wet product material is at 50 ℃ again for the material cake, vacuum tightness is-got final product in dry 3 hours under the condition of 0.097MPa.Receive dry product cefotaxime sodium 31 grams, product yield is 88% (in 7-ACA).
Wherein: salt forming agent is dissolved in the mixed solution of 15ml toluene and 15ml methyl alcohol by 13 gram Sodium isooctanoates to be made.
Embodiment 2
Adding 120ml volume ratio is 1: 1 toluene and a methyl alcohol composition mixed solvent in three-necked bottle, the 20ml triethylamine, cool to 7 ℃, add 20 gram 7-ACA, 28 gram AE-active ester, keep 7 degree reactions 63 minutes, reaction clarification back adds the 3ml concentrated hydrochloric acid, add salt forming agent (13 gram Sodium isooctanoates dissolve in the mixed solution of 15ml toluene and 15ml methyl alcohol and make) under the room temperature, 0.1g sodium bisulfite, drip toluene again to little growing the grain 30 minutes when turbid, and then drip remaining toluene, dropping toluene process temperature is controlled at 22 ℃, adds 120ml altogether, is controlled to drip off in 1.5 hours, drip off 30 minutes blowings of back growing the grain, with the mixed solution of 50ml ethyl acetate and 5ml Virahol washing material cake, and then will expect that cake is added to stir in the mixed solution of 140ml acetone and 6ml water and wash blowing after 20 minutes that the material cake is expected cake with the small amount of acetone washing again, wet product material 50 degree vacuum-dryings got final product in 3 hours, received dry product cefotaxime sodium 31.2 grams. yield 88.1%.
Embodiment 3
Adding 120ml volume ratio is 1: 0.8 toluene and a methyl alcohol composition mixed solvent in three-necked bottle, the 20ml triethylamine, cool to 4 ℃, add 20 gram 7-ACA, 28 gram AE-active ester, keep 5 degree reactions 65 minutes, reaction clarification back adds 1g carbonochloridic acid three chloromethyl esters, add salt forming agent (13 gram Sodium isooctanoates dissolve in the 30ml mixed solvent and make) under the room temperature, 0.1g sodium bisulfite added the crystal seed growing the grain 30 minutes, and then dripped remaining toluene, drip the toluene process temperature and be controlled at 18 ℃, add 120ml altogether, be controlled at and dripped off 30 minutes blowings of growing the grain after dripping off in 1.8 hours, mixed solution washing material cake with 50ml ethyl acetate and 5ml dehydrated alcohol, and then will expect that cake is added to stir in the mixed solution of 150ml acetone and 6ml water and wash blowing after 25 minutes that with small amount of acetone washing material cake, spend vacuum-dryings get final product again by wet product 50 for the material cake.
Embodiment 4
Adding 120ml volume ratio is 1: 0.5 toluene and a methyl alcohol composition mixed solvent in three-necked bottle, the 20ml triethylamine, cool to 6 ℃, add 20 gram 7-ACA, 28 gram AE-active ester, keep 5 degree reactions 55 minutes, reaction clarification back adds 1g carbonochloridic acid three chloromethyl esters, add salt forming agent (13 gram Sodium isooctanoates dissolve in the 30ml mixed solvent and make) under the room temperature, 0.1g sodium bisulfite, drip toluene again to little growing the grain 30 minutes when turbid, and then drip remaining toluene, drip the toluene process temperature and be controlled at 19 ℃, add 120ml altogether, be controlled at and dripped off 30 minutes blowings of growing the grain after dripping off in 1.6 hours, mixed solution washing material cake with 60ml acetone and 5ml Virahol, and then will expect that cake is added to stir in the mixed solution of 150ml acetone and 6ml water and wash blowing after 25 minutes that with small amount of acetone washing material cake, spend vacuum-dryings 3 hour get final product again by wet product 50 for the material cake.
Embodiment 5
Adding 120ml volume ratio is 1: 0.6 toluene and a methyl alcohol composition mixed solvent in three-necked bottle, the 20ml triethylamine, cool to 6.5 ℃, add 20 gram 7-ACA, 28 gram AE-active ester, keep 6.5 degree reactions 60 minutes, reaction clarification back adds 1g two (trichloromethyl) carbonic ether, add salt forming agent 10 gram Sodium isooctanoates under the room temperature, 0.1g sodium bisulfite drips toluene again to little growing the grain 30 minutes when turbid, and then drips remaining toluene, drip the toluene process temperature and be controlled at 23 ℃, add 120ml altogether, be controlled at and dripped off 40 minutes blowings of growing the grain after dripping off in 1.8 hours, mixed solution washing material cake with 50ml acetone and 10ml dehydrated alcohol, and then will expect that cake is added to stir in the mixed solution of 140ml acetone and 6ml water and wash blowing after 30 minutes that with small amount of acetone washing material cake, spend vacuum-dryings 3 hour get final product again by wet product material 50 for the material cake.
Embodiment 6～10
Toluene in the mixed solvent is replaced by dimethylbenzene, and other situation is respectively with embodiment 1～5.
Embodiment 11～15
Toluene in the mixed solvent is replaced by ethyl acetate, and other situation is respectively with embodiment 1～5.
Embodiment 16～20
Toluene in the mixed solvent is replaced by acetone, and other situation is respectively with embodiment 1～5.
Embodiment 21～40
Methyl alcohol in the mixed solvent is replaced by ethanol, and other situation is respectively with embodiment 1～20.
Embodiment 41～80
Amine intermediate reaction thing triethylamine is replaced by Diisopropylamine, and other situation is respectively with embodiment 1～40.
Select for use insoluble organic solvent test for wherein two or more arbitrary proportion mixes, the test situation proof all can.
Claims (9)
1, a kind of one-step preparation process of aseptic cefotaxime sodium for injection, in solvent, react under the effect of amine intermediate reaction thing by 7-ACA and AE-active ester, add the benzothiazole solubility promoter, adding sodium salt-forming agent again reacts and separates out crystallization and make, it is characterized in that action solvent is by benzene class organic solvent, the mixed solvent that ethyl acetate or acetone and alcohol organic solvent are formed, the stirring reaction of 7-ACA and AE-active ester is to clarification, add the benzothiazole solubility promoter then, Sterile Filtration directly adds sodium salt-forming agent and is carried out to reactant salt, when question response becomes muddy, carrying out growing the grain handles, with the insoluble organic solvent of cefotaxime sodium crystallization is separated out then, get the cefotaxime sodium finished product through conventional crystallization aftertreatment at last.
2, the one-step preparation process of aseptic cefotaxime sodium for injection according to claim 1 is characterized in that the composition volume ratio of mixed solvent is: benzene class organic solvent, ethyl acetate or acetone: alcohol organic solvent=1: (1～0.5).
3, the one-step preparation process of aseptic cefotaxime sodium for injection according to claim 1 is characterized in that the benzothiazole solubility promoter is a kind of in carbonochloridic acid three chloromethyl esters, hydrogen halide or other halogenide.
4, the one-step preparation process of aseptic cefotaxime sodium for injection according to claim 1 and 2 is characterized in that benzene class organic solvent is toluene or dimethylbenzene.
5, the one-step preparation process of aseptic cefotaxime sodium for injection according to claim 1 and 2 is characterized in that alcohol organic solvent is a kind of in methyl alcohol or the ethanol.
6, the one-step preparation process of aseptic cefotaxime sodium for injection according to claim 1 is characterized in that amine intermediate reaction thing is triethylamine or Diisopropylamine.
7, the one-step preparation process of aseptic cefotaxime sodium for injection according to claim 1 is characterized in that salt forming agent is a Sodium isooctanoate solution, is dissolved in the mixed solvent by Sodium isooctanoate and makes.
8, the one-step preparation process of aseptic cefotaxime sodium for injection according to claim 1, the insoluble organic solvent that it is characterized in that cefotaxime sodium are one or more the mixing in toluene, dimethylbenzene, acetone, ethyl acetate, dehydrated alcohol or the Virahol.
9, the one-step preparation process of aseptic cefotaxime sodium for injection according to claim 8, it is characterized in that the crystallization filter cake is washed after, be that the acetone soln of 3～5% water carries out agitator treating and handles with volume ratio again.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101182351A CN100361995C (en) | 2004-10-27 | 2005-10-21 | One-step preparation process of aseptic cefotaxime sodium for injection |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410155402 CN1634932A (en) | 2004-10-27 | 2004-10-27 | Process for preparing cefotaxime sodium |
| CN200410155402.5 | 2004-10-27 | ||
| CNB2005101182351A CN100361995C (en) | 2004-10-27 | 2005-10-21 | One-step preparation process of aseptic cefotaxime sodium for injection |
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| CN100361995C CN100361995C (en) | 2008-01-16 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104840423A (en) * | 2015-04-27 | 2015-08-19 | 四川制药制剂有限公司 | Preparation process of cefotaxime sodium for injection |
| CN107049958A (en) * | 2017-04-26 | 2017-08-18 | 四川制药制剂有限公司 | The preparation technology of cefotaxime sodium for injection powder-injection |
| CN110283187A (en) * | 2019-07-10 | 2019-09-27 | 辽宁美亚制药有限公司 | A kind of preparation method promoting Cefotaxime Sodium product quality |
| CN111647006A (en) * | 2020-04-25 | 2020-09-11 | 广东金城金素制药有限公司 | Cefotaxime sodium pharmaceutical preparation and new indications for treating salmonella infection including typhoid fever and paratyphoid fever |
| CN113024580A (en) * | 2021-03-10 | 2021-06-25 | 苏州东瑞制药有限公司 | Preparation method of cefotaxime sodium |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101613360B (en) * | 2009-08-07 | 2011-04-27 | 哈药集团制药总厂 | Method for preparing cefotaxime |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2400519A1 (en) * | 1977-08-17 | 1979-03-16 | Roussel Uclaf | CRYSTALLINE FORM OF SODIUM SALT OF AN OXIMIN DERIVATIVE OF 7-AMINO-THIAZOLYL ACETAMIDO CEPHALOSPORANIC, ITS PREPARATION PROCESS AND ITS APPLICATION AS A MEDICINAL PRODUCT |
| US5574154A (en) * | 1994-09-29 | 1996-11-12 | Alnejma Bulk Pharmaceutical Co. A.B.P.C. | Process for the preparation of cephalosporanic compounds |
| AU690482B2 (en) * | 1996-03-18 | 1998-04-23 | Ranbaxy Laboratories Limited | Process for producing cephalosporin antibiotics |
| CN1164593C (en) * | 2002-07-05 | 2004-09-01 | 上海新亚药业有限公司 | Method for synthesizing cefotaxime sodium |
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| CN104840423A (en) * | 2015-04-27 | 2015-08-19 | 四川制药制剂有限公司 | Preparation process of cefotaxime sodium for injection |
| CN107049958A (en) * | 2017-04-26 | 2017-08-18 | 四川制药制剂有限公司 | The preparation technology of cefotaxime sodium for injection powder-injection |
| CN110283187A (en) * | 2019-07-10 | 2019-09-27 | 辽宁美亚制药有限公司 | A kind of preparation method promoting Cefotaxime Sodium product quality |
| CN111647006A (en) * | 2020-04-25 | 2020-09-11 | 广东金城金素制药有限公司 | Cefotaxime sodium pharmaceutical preparation and new indications for treating salmonella infection including typhoid fever and paratyphoid fever |
| CN113024580A (en) * | 2021-03-10 | 2021-06-25 | 苏州东瑞制药有限公司 | Preparation method of cefotaxime sodium |
| CN113024580B (en) * | 2021-03-10 | 2022-02-25 | 苏州东瑞制药有限公司 | Preparation method of cefotaxime sodium |
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| CN100361995C (en) | 2008-01-16 |
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