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
- acetyl
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- acetone
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- 229950005040 cefathiamidine Drugs 0.000 title claims abstract description 51
- -1 acetyl cefathiamidine Chemical compound 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- JYXACOFERDBGGQ-RHSMWYFYSA-N cefathiamidine Chemical compound S1CC(COC(C)=O)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CSC(NC(C)C)=NC(C)C)[C@H]21 JYXACOFERDBGGQ-RHSMWYFYSA-N 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 238000003756 stirring Methods 0.000 claims abstract description 14
- 108010013043 Acetylesterase Proteins 0.000 claims abstract description 10
- 102100036617 Monoacylglycerol lipase ABHD2 Human genes 0.000 claims abstract description 10
- 238000001291 vacuum drying Methods 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 5
- 239000007787 solid Substances 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 108090000790 Enzymes Proteins 0.000 abstract description 9
- 102000004190 Enzymes Human genes 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 7
- 238000000034 method Methods 0.000 abstract description 7
- 239000003960 organic solvent Substances 0.000 abstract description 6
- 239000013558 reference substance Substances 0.000 abstract description 6
- 239000003002 pH adjusting agent Substances 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 description 11
- 239000002253 acid Substances 0.000 description 9
- 238000005352 clarification Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000011017 operating method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
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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| CN201410829212.0A CN104450851B (en) | 2014-12-25 | 2014-12-25 | A kind of preparation method for removing acetyl cefathiamidine |
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| CN104450851A CN104450851A (en) | 2015-03-25 |
| CN104450851B true CN104450851B (en) | 2018-02-23 |
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| CN115124552B (en) * | 2022-06-16 | 2024-11-05 | 国药集团威奇达药业有限公司 | Preparation method of deacetyl cefathiamidine |
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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