CN104480180B - A kind of preparation method of cefathiamidine lactone - Google Patents
A kind of preparation method of cefathiamidine lactone Download PDFInfo
- Publication number
- CN104480180B CN104480180B CN201410831348.5A CN201410831348A CN104480180B CN 104480180 B CN104480180 B CN 104480180B CN 201410831348 A CN201410831348 A CN 201410831348A CN 104480180 B CN104480180 B CN 104480180B
- Authority
- CN
- China
- Prior art keywords
- cefathiamidine
- lactone
- water
- preparation
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of preparation method of cefathiamidine lactone：Cefathiamidine is dissolved in water or water containing 5%~20% organic solvent, controls 20 DEG C~35 DEG C of temperature, adds 0.8~1.2 times of immobilization acetylesterase, while adds pH adjusting agent control system pH7.0~9.0, stirring reaction；After reaction terminates, enzyme is filtered off, is diluted with water, and acid adding separates out solid to below pH1.0, filters, washing, be drying to obtain cefathiamidine lactone, the amount of the water or the water containing organic solvent is 2.5~4.0 times of cefathiamidine.The present invention is reacted using enzyme process, simple to operate, and obtained cefathiamidine lactone purity is high, the quality control available for the bulk drug and preparation of cefathiamidine lactone.
Description
Technical field
The invention belongs to pharmaceutical technology field, is related to a kind of preparation method of cefathiamidine lactone.
Technical background
Medicine in Clinical practice caused adverse reaction except the pharmacological activity with medicine in itself have outside the Pass, also and medicine
Present in impurity it is closely bound up, so impurity research is drug quality research, the emphasis of quality control and safety research, relate to
And qualitative research and quantitative study, through the overall process of study of pharmacy.
Impurity reference substance is the important key of impurity of the drug research, but the impurity of most drug does not have reference substance and carried
For the acquisition of i.e. impurity reference substance has become the bottleneck of most drug impurity research.
The source of impurity includes process contaminants (the complete reactant of unreacted and reagent, intermediate, accessory substance in synthesis
Deng), catabolite, mixed impurity etc. from reactant and reagent.
Cefathiamidine for injection is the unique independent research in China and carries out the first generation cephalo of clinical research and application first
Rhzomorph, destroy through acid or deposit for a long time, its content can gradually increase cefathiamidine lactone as one of which impurity, in order to more preferable
Ground controls the quality of the product, further investigates influence of the impurity to the stability and security of Cefathiamidine for injection, anxious
Its structure need to be confirmed and obtain reference substance.
Yuan Min etc. by LC-MS methods be inferred in cefathiamidine more than reporting limit four kinds of impurity (Yuan Min, Huang Xiufen,
" major impurity in LC-MS methods analysis cefathiamidine ", study of pharmacy 2013,32 (4)：196-199), acetyl head is respectively removed
Spore sulphur amidine, cefathiamidine lactone, 7-BCA and the isomers of cefathiamidine Δ 2.
Hu Min etc. is inferred to two kinds of degradation impurities in cefathiamidine, (Hu Min, Hu Changqin, " LC-MS also by LC-MS methods
Method analysis cefathiamidine catabolite ", Acta Pharmaceutica Sinica 2006,41 (10)：It is respectively 1015-1019) to remove acetyl cefathiamidine, head
Spore sulphur amidine lactone.
Above-mentioned two documents push away merely by the object information that LC-MS methods obtain to the structure of cefathiamidine lactone
It is disconnected, sample is not made, also without progress structural identification.
Through consulting, not on cefathiamidine lactone preparation method and its document and patent report of structural identification.
The content of the invention
The invention provides a kind of preparation method of cefathiamidine lactone, it is therefore intended for preparing in the cefathiamidine of high-purity
Ester.
The preparation method of cefathiamidine lactone provided by the invention is：Cefathiamidine is dissolved in water or containing 5%~20%
In the water of organic solvent, 20 DEG C~35 DEG C of temperature is controlled, adds 0.8~1.2 times of immobilization acetylesterase, while adds pH tune
Save agent control system pH7.0~9.0, stirring reaction；Reaction terminate after, filter off enzyme, be diluted with water, and acid adding to pH1.0 with
Under, solid is separated out, is filtered, washing, is drying to obtain cefathiamidine lactone.The amount of the water or water containing organic solvent is cephalo sulphur
2.5~4.0 times of amidine.
Organic solvent of the present invention is methanol, ethanol, isopropanol, normal propyl alcohol, acetonitrile, acetone.
PH adjusting agent of the present invention is ammoniacal liquor or triethylamine.
Acid of the present invention is hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid.
Advantage of the invention is that this preparation method is reacted using enzyme process, reaction selectivity is high, mild condition, side reaction
It is few；Without using organic solvent；Immobilization acetylesterase is reusable, and cost is low；This preparation method single step reaction, operation letter
It is single.Cefathiamidine lactone purity prepared by the present invention is high, not less than 96%, can be used as reference substance be used for cefathiamidine bulk drug and
The quality control of its preparation.
Brief description of the drawings
Accompanying drawing 1：Cefathiamidine lactone UV schemes；
Accompanying drawing 2：Cefathiamidine lactone IR schemes；
Accompanying drawing 3：Cefathiamidine lactone MS schemes；
Accompanying drawing 4：Cefathiamidine lactone1HNMR(MeOD)；
Accompanying drawing 5：Cefathiamidine lactone13CNMR spectrograms (MeOD).
Embodiment
Cefathiamidine lactone prepared by the present invention, detected through ultraviolet (UV), infrared (IR), mass spectrum (MS), nuclear-magnetism (NMR),
It is cefathiamidine lactone of the present invention that its structure, which can be confirmed, and structure is as follows：
UV, IR, MS, NMR detection spectrogram refer to accompanying drawing 1- accompanying drawings 5.
Embodiment 1
Cefathiamidine 20g, add water 50ml, control 20 DEG C~25 DEG C of temperature, stir to dissolved clarification.Add immobilization acetylesterase
1.6g, and triethylamine control pH7.0-9.0 is constantly added dropwise, to being held essentially constant.Enzyme is filtered off, adds water 50ml, is added dropwise dense
Salt acid for adjusting pH<1, stir 3h.Filtering, wash, vacuum drying, obtain cefathiamidine lactone.
Detected through HPLC, purity 96%.
Embodiment 2
Cefathiamidine 20g, purified water 60ml, methanol 3ml are added, control 20 DEG C~25 DEG C of temperature, stirred to dissolved clarification, add
Immobilization acetylesterase 2.0g, and ammoniacal liquor control pH7.0~9.0 are constantly slowly added dropwise, stirring reaction to pH is basically unchanged.Filtering
Enzyme is removed, water 140ml is added in filtrate, dilute sulfuric acid regulation pH is added dropwise<1, stir 6h.Filtering, wash, vacuum drying, obtain cephalo sulphur
Amidine lactone.
Detected through HPLC, purity 97%.
Embodiment 3
Cefathiamidine 20g, purified water 70ml, ethanol 7ml are added, control 25 DEG C~30 DEG C of temperature, stirred to dissolved clarification, add
Immobilization acetylesterase 2.2g, and triethylamine control pH7.0~9.0 are constantly slowly added dropwise, stirring reaction to pH is basically unchanged.Cross
Enzyme is filtered off, water 255ml is added in filtrate, hydrobromic acid regulation pH is added dropwise<1, stir 9h.Filtering, wash, vacuum drying, obtain cephalo
Sulphur amidine lactone.
Detected through HPLC, purity 97%.
Embodiment 4
Cefathiamidine 20g, purified water 80ml, isopropanol 12ml are added, control 25 DEG C~30 DEG C of temperature, stir to dissolved clarification,
Immobilization acetylesterase 2.0g is added, and ammoniacal liquor control pH7.0~9.0 are constantly slowly added dropwise, stirring reaction to pH is basically unchanged.
Enzyme is filtered off, water 90ml is added in filtrate, dust technology regulation pH is added dropwise<1, stir 12h.Filtering, wash, vacuum drying, obtain head
Spore sulphur amidine lactone.
Detected through HPLC, purity 96%.
Embodiment 5
Cefathiamidine 20g, purified water 80ml, normal propyl alcohol 16ml are added, control 30 DEG C~35 DEG C of temperature, stir to dissolved clarification,
Immobilization acetylesterase 2.4g is added, and triethylamine control pH7.0~9.0 are constantly slowly added dropwise, stirring reaction to pH is substantially not
Become.Enzyme is filtered off, water 180ml is added in filtrate, concentrated hydrochloric acid regulation pH is added dropwise<1, stir 16h.Filtering, wash, vacuum drying,
Obtain cefathiamidine lactone.
Detected through HPLC, purity 96%.
Embodiment 6
Cefathiamidine 20g, purified water 80ml, acetonitrile 15ml are added, control 30 DEG C~35 DEG C of temperature, stir to dissolved clarification, add
Enter immobilization acetylesterase 1.8g, and ammoniacal liquor control pH7.0~9.0 are constantly slowly added dropwise, stirring reaction to pH is basically unchanged.Cross
Enzyme is filtered off, water 275ml is added in filtrate, dilute sulfuric acid regulation pH is added dropwise<1, stir 20h.Filtering, wash, vacuum drying, obtain cephalo
Sulphur amidine lactone.
Detected through HPLC, purity 98%.
Embodiment 7
Cefathiamidine 20g, purified water 80ml, acetone 10ml are added, control 20 DEG C~25 DEG C of temperature, stir to dissolved clarification, add
Enter immobilization acetylesterase 2.0g, and ammoniacal liquor control pH7.0~9.0 are constantly slowly added dropwise, stirring reaction to pH is basically unchanged.Cross
Enzyme is filtered off, water 90ml is added in filtrate, dust technology regulation pH is added dropwise<1, stir 24h.Filtering, wash, vacuum drying, obtain cephalo
Sulphur amidine lactone.
Detected through HPLC, purity 98%.
Claims (3)
1. a kind of preparation method of cefathiamidine lactone, it is characterized in that：Cefathiamidine is dissolved in water or rudimentary containing 5%~20%
In the water of alcohol or acetonitrile or acetone, 20 DEG C~35 DEG C of temperature is controlled, adds 0.8~1.2 times of immobilization acetylesterase, simultaneously
Add ammoniacal liquor or triethylamine control system pH7.0~9.0, stirring reaction；After reaction terminates, enzyme is filtered off, is diluted with water, and added
Inorganic acid separates out solid to below pH1.0, filters, washing, is drying to obtain cefathiamidine lactone, the water or containing lower alcohol or
The amount of the water of acetonitrile or acetone is 2.5~4.0 times of cefathiamidine.
2. the preparation method of a kind of cefathiamidine lactone according to claim 1, it is characterised in that the lower alcohol is first
Alcohol, ethanol, isopropanol, normal propyl alcohol.
3. the preparation method of a kind of cefathiamidine lactone according to claim 1, it is characterised in that described inorganic acid is
Hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410831348.5A CN104480180B (en) | 2014-12-25 | 2014-12-25 | A kind of preparation method of cefathiamidine lactone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410831348.5A CN104480180B (en) | 2014-12-25 | 2014-12-25 | A kind of preparation method of cefathiamidine lactone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104480180A CN104480180A (en) | 2015-04-01 |
| CN104480180B true CN104480180B (en) | 2018-02-23 |
Family
ID=52754783
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410831348.5A Active CN104480180B (en) | 2014-12-25 | 2014-12-25 | A kind of preparation method of cefathiamidine lactone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104480180B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321721A (en) * | 2011-10-25 | 2012-01-18 | 石药集团河北中润制药有限公司 | Process for preparing 3-deacetylate-7-aminocephalosporanic acid |
| CN102505035A (en) * | 2011-10-25 | 2012-06-20 | 石药集团河北中润制药有限公司 | Preparation process of 3-deacetylated-7-amino-cephalosporanic acid |
| CN103570745A (en) * | 2013-10-10 | 2014-02-12 | 哈药集团制药总厂 | Preparation method of cefotiam hydrochloride lactone |
-
2014
- 2014-12-25 CN CN201410831348.5A patent/CN104480180B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321721A (en) * | 2011-10-25 | 2012-01-18 | 石药集团河北中润制药有限公司 | Process for preparing 3-deacetylate-7-aminocephalosporanic acid |
| CN102505035A (en) * | 2011-10-25 | 2012-06-20 | 石药集团河北中润制药有限公司 | Preparation process of 3-deacetylated-7-amino-cephalosporanic acid |
| CN103570745A (en) * | 2013-10-10 | 2014-02-12 | 哈药集团制药总厂 | Preparation method of cefotiam hydrochloride lactone |
Non-Patent Citations (3)
| Title |
|---|
| Deacetylcephalosporin C;J. D"A. JEFFERY;《Biochem. J.》;19611231;第81卷;591-596 * |
| Detection of a Cephalosporin C Acetyl Esterase in the Carbamate Cephalosporin Antibiotic-Producing Culture, Streptomyces clavuligerus;D. R. BRANNON,;《ANTIMICROBIAL AGENTS AND CHEMOTHERAPY》;19720331;第1卷(第3期);p. 237-241 * |
| The Structure of Cephalosporin C;E. P. ABRAHAM;《Biochem. J.》;19611231;第79卷;377-393 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104480180A (en) | 2015-04-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110467604B (en) | Preparation method of losartan | |
| CN105503739A (en) | Preparation method of high-purity olaparib | |
| CN104418927B (en) | A kind of isolation and purification method of doractin | |
| CN113861057A (en) | Oseltamivir phosphate intermediate impurity compound and preparation method and application thereof | |
| CN112979480A (en) | Preparation method and application of salbutamol impurity | |
| CN103571907A (en) | Separation and purification method for cefaclor by enzymatic synthesis | |
| CN110734467A (en) | method for extracting and purifying spinosad from fermentation liquor | |
| CN104480180B (en) | A kind of preparation method of cefathiamidine lactone | |
| CN107417603B (en) | Preparation method of crizotinib intermediate | |
| CN103360374A (en) | Synthesis method of vilazodone and salt thereof | |
| CN111004179B (en) | Resolution method of 5' -methoxylapatin | |
| CN109912512B (en) | New telmisartan impurity compound and preparation method and application thereof | |
| CN107880063B (en) | A kind of synthetic method of dauricine | |
| CN104450851B (en) | A kind of preparation method for removing acetyl cefathiamidine | |
| CN103450157B (en) | Preparation method for high-purity hydroxyfasudil semihydrate | |
| CN112047942B (en) | Synthesis method of 7-fluoroimidazo [1,2-A ] pyridine | |
| CN109134331A (en) | The synthetic method of azithromycin genotoxicity impurity | |
| CN106220646B (en) | A kind of method of enzymatic clarification cefalexin mother liquor recycled | |
| CN1023121C (en) | Crystal of hydrochloric salt of etoposide-2-dimethylamino compounds and process for preparing them | |
| CN103554058B (en) | Preparation method of linezolid derivative | |
| CN109096273A (en) | The method for separating and preparing of mezlocillin sodium impurity C, D and F | |
| CN102702197B (en) | Olprinone hydrochloride derivative and preparation method thereof | |
| CN110105371B (en) | Impurities in doladazole bulk drug and preparation method thereof | |
| CN107915735A (en) | The improvement in synthesis of istradefylline | |
| CN117843545A (en) | Preparation method of 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile and hydrochloride thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |