CN104450851B - A kind of preparation method for removing acetyl cefathiamidine - Google Patents
A kind of preparation method for removing acetyl cefathiamidine Download PDFInfo
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- CN104450851B CN104450851B CN201410829212.0A CN201410829212A CN104450851B CN 104450851 B CN104450851 B CN 104450851B CN 201410829212 A CN201410829212 A CN 201410829212A CN 104450851 B CN104450851 B CN 104450851B
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- cefathiamidine
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Abstract
The present invention relates to a kind of preparation method for removing acetyl cefathiamidine, and suitable for pharmacy corporation, it discloses step (1)：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；The amount of the water or water containing organic solvent is 2.5~4.0 times of cefathiamidine；Step (2)：After reaction terminates, filtering, pH to 5.0~5.5 is adjusted, is concentrated under reduced pressure, washed, filtered, vacuum drying, produce acetyl cefathiamidine solid.The present invention is prepared using enzyme process and removes acetyl cefathiamidine, and purity is high, and not less than 97%, the quality control of cefathiamidine bulk drug and its preparation can be used for as reference substance.
Description
Technical field
The invention belongs to pharmaceutical technology field, is related to a kind of preparation method for removing acetyl cefathiamidine.
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, the product is destroyed through acid, alkali, heat etc. or long-term storage, goes content meeting of the acetyl cefathiamidine as one of which impurity
Gradually increase, in order to better control over the quality of the product, further investigates stability of the impurity to Cefathiamidine for injection
And the influence of security, it is badly in need of confirming its structure and obtains reference substance.
The LC-MS methods of document report, it can only be pushed away according to its object information to going the structure of acetyl cefathiamidine to carry out analysis
It is disconnected, due to sample is not made, structural identification can not be carried out.
Patent CN102863461A discloses (6R, 7R) -3- methylols -7- [α-(N, N- diisopropylamidinateand sulfenyl)-acetyl
Amino] -8- oxo -5- thia -1- azabicyclos [4,2,0]-oct-2-ene -2- formic acid betaines, that is, remove acetyl cefathiamidine
Preparation method, it is specially：Using D-7-ACA as raw material, in water and the organic solvent two phase liquid not miscible with water, alkaline bar
Generation acetyl bromide D-7-ACA intermediates are reacted after being dissolved under part with bromoacetyl bromide, liquid separation water intaking phase, are with acid regulation aqueous phase pH
1.0~4.0, separate out intermediate；Intermediate after drying, acetyl is removed in organic phase with N, the reaction generation of N- di-isopropyl thioureas
Cefathiamidine.This method uses two-step reaction：First step two phase reaction, operating procedure is more, react the intermediate of generation need to separate out it is dry
It is dry；Second step anhydrous response, severe reaction conditions, it is desirable to which high, control is difficult.
The content of the invention
The invention provides a kind of simple preparation method for removing acetyl cefathiamidine, it is therefore intended for preparing going for high-purity
Acetyl cefathiamidine.
The preparation method of the present invention for removing acetyl cefathiamidine includes following two steps：
Step (1)：Cefathiamidine is dissolved in water or water containing 5%~20% organic solvent, 20 DEG C of temperature of control~
35 DEG C, 0.8~1.2 times of immobilization acetylesterase is added, while adds pH adjusting agent control system pH7.0~9.0, stirring is anti-
Should；The amount of the water or water containing organic solvent is 2.5~4.0 times of cefathiamidine；
Step (2)：After reaction terminates, filtering, pH to 5.0~5.5 is adjusted, is concentrated under reduced pressure, washed, filtered, vacuum drying,
Produce acetyl cefathiamidine solid；
Synthetic route is as follows：
Organic solvent is described in above-mentioned steps (1)：Methanol, ethanol, isopropanol, normal propyl alcohol, acetonitrile, acetone.
The pH adjusting agent of step (1) of the present invention is ammoniacal liquor or triethylamine.
The washer solvent of step (2) of the present invention is dichloromethane or acetone above.
It is to use chemical method that has reported, which goes the preparation of acetyl cefathiamidine, and two-step reaction, operating procedure is more, and reacts bar
Part is harsh；And advantage of the invention is that, mild condition high using enzyme process, reaction selectivity, side reaction are few；Reduce organic molten
The usage amount of agent；Immobilization acetylesterase is reusable, and cost is low；This preparation method single step reaction, it is simple to operate；It is prepared into
Go acetyl cefathiamidine purity high, not less than 97%, matter of the reference substance for cefathiamidine bulk drug and its preparation can be used as
Amount control, it can be used for preparing the cefathiamidine lactone of high-purity.
Brief description of the drawings
Accompanying drawing 1：Acetyl cefathiamidine UV is gone to scheme；
Accompanying drawing 2：Acetyl cefathiamidine IR is gone to scheme；
Accompanying drawing 3：Acetyl cefathiamidine MS is gone to scheme；
Accompanying drawing 4：Remove acetyl cefathiamidine1HNMR(D2O)；
Accompanying drawing 5：Remove acetyl cefathiamidine13CNMR spectrograms (D2O)。
Embodiment
Prepared by the present invention removes acetyl cefathiamidine, is examined through ultraviolet (UV), infrared (IR), mass spectrum (MS), nuclear-magnetism (NMR)
Survey, confirm its structure and remove acetyl cefathiamidine for the present invention.UV, IR, MS, NMR detection spectrogram refer to accompanying drawing 1- accompanying drawings 5.
Embodiment 1
Cefathiamidine 20g, purified water 50ml is added, control 20 DEG C~25 DEG C of temperature, stirred to dissolved clarification, add immobilization second
Acyl esterase 1.6g, and triethylamine control pH7.0~9.0 are constantly slowly added dropwise, stirring reaction to pH is basically unchanged.Filter off enzyme,
Salt acid for adjusting pH is added dropwise to 5.0~5.5, the filtrate that is concentrated under reduced pressure dichloromethane washing, is filtered to doing, vacuum drying, must remove acetyl
Cefathiamidine.
Detected through HPLC, purity 98%.
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, salt acid for adjusting pH is added dropwise to 5.0~5.5, the filtrate that is concentrated under reduced pressure acetone washing, is filtered to doing, vacuum drying, must go second
Acyl cefathiamidine.
Detected through HPLC, purity 97%.
Embodiment 3
Cefathiamidine 20g, purified water 70ml, ethanol 7ml are added, control 20 DEG C~25 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, dropwise addition salt acid for adjusting pH to 5.0~5.5 are filtered off, the filtrate that is concentrated under reduced pressure dichloromethane washing, is filtered, vacuum drying to doing,
Acetyl cefathiamidine must be removed.
Detected through HPLC, purity 97%.
Embodiment 4
Cefathiamidine 20g, purified water 80ml, isopropanol 12ml are added, control 30 DEG C~35 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, salt acid for adjusting pH is added dropwise to 5.0~5.5, the filtrate that is concentrated under reduced pressure acetone washing, is filtered, vacuum drying, obtained to doing
Remove acetyl cefathiamidine.
Detected through HPLC, purity 97%.
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, salt acid for adjusting pH is added dropwise to 5.0~5.5, the filtrate that is concentrated under reduced pressure dichloromethane washing, is filtered, vacuum to doing
Dry, acetyl cefathiamidine must be removed.
Detected through HPLC, purity 98%.
Embodiment 6
Cefathiamidine 20g, purified water 80ml, acetonitrile 15ml are added, control 25 DEG C~30 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, salt acid for adjusting pH is added dropwise to 5.0~5.5, the filtrate that is concentrated under reduced pressure acetone washing, is filtered, vacuum drying, must gone to doing
Acetyl cefathiamidine.
Detected through HPLC, purity 98%.
Embodiment 7
Cefathiamidine 20g, purified water 80ml, acetone 10ml are added, control 25 DEG C~30 DEG C of temperature, stir to dissolved clarification, add
Enter immobilization acetylesterase 2.0g, and triethylamine control pH7.0~9.0 are constantly slowly added dropwise, stirring reaction to pH is basically unchanged.
Enzyme is filtered off, salt acid for adjusting pH is added dropwise to 5.0~5.5, filtrate to dry, dichloromethane washing, filtering, the vacuum that be concentrated under reduced pressure is done
It is dry, acetyl cefathiamidine must be removed.
Detected through HPLC, purity 98%.
Claims (2)
1. a kind of preparation method for removing acetyl cefathiamidine, it is characterized in that：
Step (1)：Cefathiamidine is dissolved in water or water containing 5%~20% lower alcohol or acetonitrile or acetone, control temperature
20 DEG C~35 DEG C of degree, adds 0.8~1.2 times of immobilization acetylesterase, while adds ammoniacal liquor or triethylamine control system pH7.0
~9.0, stirring reaction；The amount of the water or water containing lower alcohol or acetonitrile or acetone is 2.5~4.0 times of cefathiamidine；
Step (2)：After reaction terminates, filtering, pH to 5.0~5.5 is adjusted, is concentrated under reduced pressure, is washed with dichloromethane or acetone, mistake
Filter, vacuum drying, produces acetyl cefathiamidine solid；
Synthetic route is as follows：
2. a kind of preparation method for removing acetyl cefathiamidine according to claim 1, it is characterised in that in the step (1)
Lower alcohol is methanol, ethanol, isopropanol, normal propyl alcohol.
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| CN104450851B true CN104450851B (en) | 2018-02-23 |
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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 CN201410829212.0A patent/CN104450851B/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 (1)
| Title |
|---|
| 两步酶法制备去乙酰基 7-氨基头孢烯酸;于海军;《精 细 化 工》;20060731;第23卷(第7期);667-670 * |
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