CN102675343A - Method for preparing cefotiam hexetil hydrochloride by cefotiam hydrochloride - Google Patents
Method for preparing cefotiam hexetil hydrochloride by cefotiam hydrochloride Download PDFInfo
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- CN102675343A CN102675343A CN2011100614620A CN201110061462A CN102675343A CN 102675343 A CN102675343 A CN 102675343A CN 2011100614620 A CN2011100614620 A CN 2011100614620A CN 201110061462 A CN201110061462 A CN 201110061462A CN 102675343 A CN102675343 A CN 102675343A
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- cefotiam
- hydrochloride
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- 229960004700 cefotiam hydrochloride Drugs 0.000 title claims abstract description 57
- 229950010227 cefotiam hexetil Drugs 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 24
- SVSFIELZISOJDT-XRZFDKQNSA-N (6r,7r)-7-[[2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-3-[[1-[2-(dimethylamino)ethyl]tetrazol-5-yl]sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrochloride Chemical compound Cl.CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 SVSFIELZISOJDT-XRZFDKQNSA-N 0.000 title abstract description 23
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 39
- -1 cyclohexyl ethyl Chemical class 0.000 claims abstract description 35
- QYQDKDWGWDOFFU-IUODEOHRSA-N Cefotiam Chemical compound CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 QYQDKDWGWDOFFU-IUODEOHRSA-N 0.000 claims abstract description 34
- VVFDMWZLBPUKTD-ZKRNHDOASA-N cefotiam hexetil ester Chemical compound O=C([C@@H](NC(=O)CC=1N=C(N)SC=1)[C@H]1SCC=2CSC=3N(N=NN=3)CCN(C)C)N1C=2C(=O)OC(C)OC(=O)OC1CCCCC1 VVFDMWZLBPUKTD-ZKRNHDOASA-N 0.000 claims abstract description 34
- 229960001242 cefotiam Drugs 0.000 claims abstract description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 235000017557 sodium bicarbonate Nutrition 0.000 claims abstract description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 239000007788 liquid Substances 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 21
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 10
- 239000001103 potassium chloride Substances 0.000 claims description 10
- 235000011164 potassium chloride Nutrition 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000000725 suspension Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- GCFAUZGWPDYAJN-UHFFFAOYSA-N cyclohexyl 3-phenylprop-2-enoate Chemical compound C=1C=CC=CC=1C=CC(=O)OC1CCCCC1 GCFAUZGWPDYAJN-UHFFFAOYSA-N 0.000 claims description 9
- 125000004494 ethyl ester group Chemical group 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 159000000000 sodium salts Chemical class 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 8
- 239000010410 layer Substances 0.000 claims description 8
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 claims description 8
- 229910052753 mercury Inorganic materials 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 7
- 230000006837 decompression Effects 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 4
- 229960001701 chloroform Drugs 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- 238000000638 solvent extraction Methods 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000011260 aqueous acid Substances 0.000 claims description 2
- 210000005252 bulbus oculi Anatomy 0.000 claims description 2
- 238000007710 freezing Methods 0.000 claims description 2
- 230000008014 freezing Effects 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000007790 solid phase Substances 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- BWRRTAXZCKVRON-DGPOFWGLSA-N cefotiam dihydrochloride Chemical compound Cl.Cl.CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 BWRRTAXZCKVRON-DGPOFWGLSA-N 0.000 claims 9
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000001514 detection method Methods 0.000 abstract description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 abstract 3
- 235000015497 potassium bicarbonate Nutrition 0.000 abstract 3
- 239000011736 potassium bicarbonate Substances 0.000 abstract 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 abstract 3
- 238000000746 purification Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 14
- 241000894006 Bacteria Species 0.000 description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 230000000845 anti-microbial effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 210000002421 cell wall Anatomy 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 201000009240 nasopharyngitis Diseases 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N p-menthan-3-ol Chemical compound CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000588923 Citrobacter Species 0.000 description 1
- 101710116957 D-alanyl-D-alanine carboxypeptidase Proteins 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 210000004027 cell 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
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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Abstract
The invention discloses a method for preparing cefotiam hexetil hydrochloride by cefotiam hydrochloride, belonging to medicines. The method comprises the steps of leading the cefotiam hydrochloride and potassium bicarbonate or sodium bicarbonate to react to prepare cefotiam, wherein the cefotiam hydrochloride is produced in an industrialized scale manner andthe charging mol ratio of the cefotiam hydrochloride and potassium bicarbonate or sodium bicarbonate is 1:2.5-10; then reacting with carbonic acid 1-iodinated cyclohexyl ethyl ester to obtain cefotiam hexetil; and conducting purification and hydrochloric acid acidization to obtain cefotiam hexetil hydrochloride. According to the method, especially the cefotiam is prepared by reacting cefotiam hydrochloride with 2.5-10 times of mol ratio of potassium bicarbonate or sodium bicarbonate in water, the prepared cefotiam hexetil hydrochloride has high purity, the total quantity of related substances in the prepared product is smaller than 1.5% by adopting a HPLC (high performance liquid chromatograp) method for detection, the yield rate is larger than 90%, and the production cost is low, thus being beneficial to industrialized manufacturing.
Description
Technical field
The present invention relates to prepare the method for cefotiam hydrochloride ester, relate in particular to the saleratus of 2.5～10 times of cefotiam hydrochloride and its mol ratios or sodium hydrogencarbonate makes cefotiam salt in water method, belong to the pharmaceutical field with cefotiam hydrochloride.
Background technology
Cefotiam hydrochloride is a second generation cephalosporin, and the domestic existing many enterprises of cefotiam hydrochloridefor inj produce and external import, and are clinical widely-used; Its structural formula is suc as formula shown in (I); After cefotiam hydrochloride becomes sylvite or sodium salt, react with carbonic acid-1-iodine ethyl ester cyclohexyl ester again, after purified again and the salt acidifying; Obtain the cefotiam hydrochloride ester, its structural formula is suc as formula shown in (II).
The active body of these article is a cefotiam, and oral back is converted into cefotiam in the enteron aisle hydrolysis, and anti-microbial effect mechanism is for suppressing the synthetic of bacteria cell wall.These article have stronger anti-microbial activity to be to Gram-negative bacteria because it has good permeability to the bacterial cell adventitia and be more stable and high to the penicillin-binding protein affinity to β-Nei Xiananmei, thereby have strengthened the restraining effect of pair cell wall mucopeptide cross bracing.Gram-negative bacteria and positive bacteria all there is anti-microbial effect widely.Especially Staphylococcus, streptococcus pneumoniae, hemophilus influenzae, streptococcus, intestinal bacteria, klebsiella bacillus, Bacillus proteus, NEISSERIA GONORRHOEAE, catarrh mora bacterium (catarrh Blanc Chinese bacterium) etc. demonstrates stronger anti-microbial activity.In addition, citrobacter is also demonstrated good antibacterial activity.
Cefotiam hydrochloridefor inj is widely used clinical at present; According to principle of medication; Injection should not reach effect or patient at oral prepns and could use can't be oral the time; Therefore the blank of cefotiam oral prepns has been filled up in the exploitation of cefotiam hydrochloride ester oral prepns, helps clinical rational drug use.
Document (The journal of antidiotics vol.XXXIX NO.9,1986; XL NO.1986) lists respectively in through cefotiam potassium and carbonic acid-1-iodine ethyl ester cyclohexyl at N; The method of prepared in reaction cefotiam hexetil in the dinethylformamide; But this preparing method's yield low (less than 20%); The product related substance is high, and purifying needs to handle through resin column, is difficult for carrying out industrialized production.
Publication number is the patented claim of 101619069A; Provide the reaction of cefotiam and acetate and make cefotiam salt, process cefotiam hexetil then again, it is insufficient that this is reacted into cefotiam salt; Final cefotiam hydrochloride ester yield is lower, and produces pollutions such as acetic acid is arranged.
Publication number is the patented claim of 101955493A, provides a kind of employing cefotiam and carbonate reaction and prepares cefotiam salt, with the reaction of carbonic acid 1-iodine ethyl ester cyclohexyl ester, after extraction, freeze-drying, prepares cefotiam hexetil hydrochloride again.The used carbonate of this method is strong than the alkalescence of acid carbonate, and gained cefotiam salt is impure higher, takes freeze-drying to come the oral raw material of purifying in addition, and power consumption is high and be unfavorable for suitability for industrialized production.
Publication number is the patented claim of 101948476A; Provide a kind of employing cefotiam and acid carbonate (mol ratio 1: 1～2) prepared in reaction and obtain cefotiam salt; Prepare cefotiam hexetil with the preparation and carbonic acid-1-iodate ethyl ester cyclohexyl ester and the cefotiam reactant salt of purifying, obtain cefotiam hexetil hydrochloride after the purified again and salt acidifying.The cefotiam that this method adopted is unstable under normal condition, be prone to the moisture absorption, can't preserve; Can only face and use new system, influence the industrialized production in batches of these article, directly and after the acid carbonate reaction can form jelly; The decon that is unfavorable for the later stage is handled; Acid carbonate is not only reactant in reaction in addition, and is a kind of catalyzer, and acid carbonate uses quantity not sufficient in the material proportion of given cefotiam and acid carbonate (mol ratio 1: 1～2); Can cause cefotiam salt yield low, and then cause the cefotiam hexetil hydrochloride yield lower.
Summary of the invention
The object of the present invention is to provide a kind of employing commercial scale prodn and can stablize the cefotiam hydrochloride of depositing and prepare highly purified cefotiam salt; Carry out esterification, purifying and hydrochloric acid and turn to high yield, highly purified cefotiam hydrochloride ester, be applicable to industrialized production.
Result of the present invention realizes through following scheme:
A kind of compound method of cefotiam hydrochloride ester is characterized in that comprising following synthesis step:
Step is cefotiam hydrochloride and saleratus or reaction of sodium bicarbonate 1., obtains cefotiam sylvite or sodium salt;
1. 2. step react, and the cefotiam salt and the carbonic acid-1-iodate ethyl ester cyclohexyl ester reaction of gained generate cefotiam hexetil;
3. step to 2. adding organic solvent extraction in the reaction solution, adds the inhibitor aqueous solution and washs in extraction liquid, separate organic layer, gets the cefotiam ester solution;
4. gained cefotiam ester solution adds aqueous hydrochloric acid to step reacting 3., collects water layer and gets the cefotiam hydrochloride ester solution;
5. step will react the cefotiam hydrochloride aqueous solution of ester of 4. gained and handle the back, use organic solvent extraction again with buck, and it is for use to get the organic phase that contains cefotiam hexetil;
6. step will react the 5. cefotiam ester solution of gained, add organic solvent and be evaporated to proper volume, and freezing crystallization spends the night; The suspension that must contain cefotiam; Suction filtration, wet article must contain the mixed organic solvents suspension of cefotiam hydrochloride ester with the organic solvent salt acidifying that contains HCL;
Step is the 6. suspension of gained of filtering reaction 7., and respectively with the different organic solvents washing, low-temperature reduced-pressure is dry with the wet article of cefotiam hydrochloride ester, acquisition cefotiam hydrochloride solid phase prod.
1. step provides the preparation method of a kind of cefotiam sylvite or sodium salt, it is characterized in that adopting suitability for industrialized production and can stablize the cefotiam hydrochloride deposited and saleratus or sodium hydrogencarbonate react, and generates cefotiam sylvite or sodium salt.
The mol ratio of the 1. described cefotiam hydrochloride of step and saleratus or sodium hydrogencarbonate is a cefotiam hydrochloride: saleratus or sodium hydrogencarbonate=1: (2.5～10), and as most preferably being cefotiam hydrochloride: saleratus or sodium hydrogencarbonate mol ratio=1: (4～6).
After step reaction 1. finishes, keep negative pressure for some time, discharge carbonic acid gas and promote reaction, preferred vacuum tightness 1～100mm mercury column, vacuum tightness 5～50mm mercury column most preferably, 5-60 minute negative pressure time, most preferably 10-20 minute.
Step temperature of reaction 1. is controlled at 0～50 ℃, and preferable reaction temperature is 25～35 ℃.
The 2. middle esterification reaction temperature of step is-30～0 ℃, preferred-10～-20 ℃, and 5～60 minutes reaction times, preferred 10-30 minute.
The step 4. concentration of used salt aqueous acid is 0.5～5%, and preferred concentration is 1～2%.
The 7. middle vacuum decompression exsiccant temperature of step can be selected 0～60 ℃, and preferred 20～50 ℃, most preferably 30～40 ℃; Vacuum tightness is selected 5～80mm mercury column, most preferably 5～20mm mercury column; In the operating process, 30-35 ℃ of drying under reduced pressure, continues drying under reduced pressure below 35 ℃ and finishes at 0.3% following drying under reduced pressure to containing acetone after the pulverize at low temperature to containing acetone below 3%, and emptying should feed nitrogen protection.
Compare with prior art, the present invention has following beneficial effect:
1. the inventive method prepares cefotiam hydrochloride used in process technical scale production, low, the stable in properties of cost, and suitability for industrialized production is convenient in the ability standing storage.
2. the purity of the cefotiam hydrochloride ester of the inventive method preparation is high; Through the HPLC inspection, product related substance total amount is less than 1.5%, far below 6% of defined in the JP15 standard; The isomer proportion scope is higher than 0.45～0.55 limited range of JP15 between 0.48～0.52.
3. prior art for preparing high-purity hydrochloric acid cefotiam hexetil need adopt the resin column purifying, and complicated operation, organic solvent consumption be many, it is big to pollute, and is unfavorable for suitability for industrialized production; And the present invention adopts twice one-tenth cefotiam hexetil free alkali and salt acidifying step; Different through cefotiam hexetil free alkali (ester dissolubility) with its hydrochloride (water-soluble) solvability, removed water-soluble respectively and the ester solubility impurity, obtained highly purified product; Used organic solvent can be used by recovery set; Reduced cost, product yield is higher than 90%, is beneficial to suitability for industrialized production.
4. the dry hydrochloric acid cefotiam hexetil of prior art adopts freeze-drying or carbon dioxide upercritical fluid extraction to be highly energy-consuming technology, and the present invention adopts the vacuum decompression drying can remove organic solvent to the acceptability limit of product, and has reduced power consumption.
Description of drawings
Fig. 1 is that cefotiam hydrochloride ester related substance spectrogram Fig. 2 that embodiment 1 uses HPLC to press JP15 standard method detection presses the cefotiam hydrochloride ester related substance spectrogram that the JP15 standard method detects as embodiment 2 usefulness HPLC
Embodiment
Embodiment 1: a kind of preparation method of cefotiam hydrochloride ester comprises following preparation process:
1. KHCO3100g adds entry 60ml, stirs fast, under 25-30 ℃ of condition, slowly adds cefotiam hydrochloride 120g, finishes, and continues 30 fens kinds of insulated and stirred under the 25-30 ℃ of condition.Reacted 30-40 minute under the reduced pressure, in reactive system, add the acetone of 25 times (water) amount again, in 30 minutes, cool the temperature to 0 ℃, stop to stir, static layering shifted supernatant more than 30 minutes, got cefotiam sylvite.
2. adding is preheated to 30-40 ℃ of N in cefotiam sylvite, dinethylformamide 550ml, and mixed system stirred 1 hour in decompression below 30 ℃; Make the sylvite dissolving; Dissolving back cooling is cooled to-15～-20 ℃, precooling to the carbonic acid below-15 ℃-1-iodate ethyl ester cyclohexyl ester is added in the reaction system, temperature control-15～-20 ℃ stir 30 minutes after; Add and be cooled to ETHYLE ACETATE 3500ml and the 0.5% sodium metabisulfite solution 1700ml about 0 ℃; After the stirring, left standstill 20 minutes, separate organic layer.
3. the 2% hydrochloric acid soln 2800ml that in organic layer, adds 0 ℃ stirred 5 minutes, left standstill 30 minutes, collected water layer, and washed water layer with amount of ethyl acetate, obtained the aqueous solution of hydrochloric cefotiam hexetil.
4. in the aqueous solution of hydrochloric cefotiam hexetil, add and be cooled to the CH below 5 ℃
2Cl
22500ml, below 5 ℃ with 5% the slow regulator solution of ammoniacal liquor PH to 8-9 between, collect the dichloromethane layer contain cefotiam hexetil.
The dichloromethane solution that 5. will contain cefotiam hexetil is concentrated into 25% of original volume below 30 ℃, add the mixed solution of acetone 700ml and isopropyl ether 1300ml, is cooled to 0 ℃ of stirred crystallization; In one hour, add the isopropyl ether 2500ml about 0 ℃ again; Be evaporated to about liquor capacity 2800ml about 0 ℃, stopping to stir, at 0 ℃ of left and right sides hold over night crystallization; Get the cefotiam hexetil suspension, with the wet article of the filtering cefotiam hexetil of suspension.
6. the 2300ml isopropyl ether is added in the wet article of cefotiam hexetil, the stirring suspendible adds the isopropyl ether solution that contains 15%HCL then, is stirring 1 hour below 0 ℃, filters, and filter cake washs with isopropyl ether, with the washing of acetone multiple low-temperature, gets filter cake again.
7. with cefotiam hydrochloride ester filter cake, 30-35 ℃ of drying under reduced pressure after the pulverize at low temperature, continues drying under reduced pressure below 35 ℃ to containing acetone below 0.3% to containing acetone below 3%, promptly gets cefotiam hydrochloride ester finished product.In the operating process, during decompression emptying, after the inflated with nitrogen protection, discharging again.
The cefotiam hydrochloride ester that embodiment 1 obtains adopts HPLC to detect, and the RT of two main peaks was respectively 11.657 minutes and 14.083 minutes among the figure, yield 95.1%; Principal constituent content 99.4%, total impurities is less than 1.0%; Isomer proportion 0.51.
Embodiment 2: a kind of preparation method of cefotiam hydrochloride ester comprises following preparation process:
1. NaHCO380g adds entry 30ml, acetone 60ml mixed solution, stirs fast, under 25-30 ℃ of condition; Slowly add cefotiam hydrochloride 100g, reaction is 30-40 minute under the reduced pressure, in reactive system, adds the acetone of 50 times (water) amount again; In 30 minutes, cool the temperature to 0～-5 ℃, stop to stir, static layering is more than 30 minutes; Remove supernatant, get the cefotiam sodium salt.
2. adding is preheated to 30-35 ℃ of DMAC N,N 500ml in the cefotiam sodium salt, and mixed system stirred 1.5 hours in decompression below 35 ℃; Make the sodium salt dissolving; Dissolving back cooling is cooled to-15～-20 ℃, precooling to the carbonic acid 1-iodate ethyl ester cyclohexyl ester below-15 ℃ is added in the reaction system, temperature control-5～-10 ℃ stir 25 minutes after; Add and be cooled to ETHYLE ACETATE 3500ml and the 0.6% sodium sulfite solution 1500ml below 2 ℃; After the stirring, left standstill 30 minutes, separate organic layer.
3. the 2% hydrochloric acid soln 2500ml that in organic layer, adds 0 ℃ stirred 10 minutes, left standstill 30 minutes, collected water layer, and washed water layer with amount of ethyl acetate, obtained the aqueous solution of hydrochloric cefotiam hexetil.
4. in the aqueous solution of hydrochloric cefotiam hexetil, add and be cooled to the CH below 5 ℃
2Cl
22500ml, below 5 ℃ with 1% the slow regulator solution of sodium hydroxide solution PH to 8-9 between, collect the dichloromethane layer contain cefotiam hexetil.
The dichloromethane solution that 5. will contain cefotiam hexetil is concentrated into 20% of original volume below 35 ℃, add the mixed solution of acetone 600ml and isopropyl ether 1200ml, is cooled to-5～0 ℃ of stirred crystallization; In one hour, add the isopropyl ether 2200ml about 0 ℃ again; Be evaporated to about liquor capacity 2500ml about 0 ℃, stopping to stir, at 0 ℃ of following hold over night crystallization; Get the cefotiam hexetil suspension, with the wet article of the filtering cefotiam hexetil of suspension.
6. the 2500ml isopropyl ether is added in the wet article of cefotiam hexetil, the stirring suspendible adds the isopropyl ether solution that contains 12%HCL then, is stirring 1 hour below 0 ℃, filters, and filter cake is used the isopropyl ether cold washing, with the washing of acetone multiple low-temperature, gets filter cake again.
7. with cefotiam hydrochloride ester filter cake, 30-35 ℃ of drying under reduced pressure after the pulverize at low temperature, continues drying under reduced pressure below 35 ℃ to containing acetone below 0.3% to containing acetone below 3%, promptly gets cefotiam hydrochloride ester finished product.In the operating process, during decompression emptying, after the inflated with nitrogen protection, discharging again.
The cefotiam hydrochloride ester that embodiment 2 obtains adopts HPLC to detect, and the RT of two main peaks was respectively 11.670 minutes and 14.097 minutes among the figure, yield 93.1%, principal constituent content 98.9%; Total impurities is less than 1.5%; Isomer proportion 0.51.
Claims (14)
1. one kind prepares the method for cefotiam hydrochloride ester with cefotiam hydrochloride, it is characterized in that with the saleratus of cefotiam hydrochloride and its mol ratio (1: 2.5～10) or the method that sodium hydrogencarbonate makes cefotiam sylvite or sodium salt.
2. preparation method according to claim 1 is characterized in that cefotiam hydrochloride and the saleratus of suitability for industrialized production or sodium hydrogencarbonate react, and generate cefotiam sylvite or sodium salt.
3. according to claim 1; The reaction consumption mol ratio that it is characterized in that its cefotiam hydrochloride and saleratus or sodium hydrogencarbonate is a cefotiam hydrochloride: saleratus or sodium hydrogencarbonate=1: (2.5～10) most preferably are cefotiam hydrochlorides: the mol ratio of saleratus or sodium hydrogencarbonate=1: (4～6).
4. according to claim 1, it prepares after the reaction of cefotiam sylvite or sodium salt finishes with cefotiam hydrochloride, further promotes reaction through reducing pressure, preferred vacuum tightness 1～100mm mercury column, most preferably vacuum tightness 5～50mm mercury column.
5. according to claim 1, reaction solvent can be selected one or more mixed solvents of water, acetone, second eyeball, and preferably water and acetone (1: 2) is as solvent, most preferably with water as solvent.
6. according to claim 1, temperature of reaction can be controlled at 0～50 ℃, and preferable reaction temperature is 25～35 ℃.
7. the present invention prepares the method for cefotiam hydrochloride ester with cefotiam hydrochloride, and its characteristic also is following preparation process:
1. cefotiam potassium or sodium salt and carbonic acid-1-iodate ethyl ester cyclohexyl ester reaction generates cefotiam hexetil;
2. 1. add organic solvent extraction in the reaction solution, in extraction liquid, adding the inhibitor aqueous solution and wash, separating organic layer, getting the cefotiam ester solution;
3. 2. adding aqueous hydrochloric acid in the reaction solution, collecting water layer and get the cefotiam hydrochloride ester solution;
4. handle the back, use organic solvent extraction again with buck at the cefotiam hydrochloride aqueous solution of ester that 3. reacts gained, it is for use to get the organic phase that contains cefotiam hexetil;
5. will react the 4. cefotiam ester solution of gained, and add organic solvent and be evaporated to proper volume, freezing crystallization spends the night; The suspension that must contain cefotiam; Suction filtration, wet article must contain the mixed organic solvents suspension of cefotiam hydrochloride ester with the organic solvent salt acidifying that contains HCL;
6. the 5. suspension of gained of filtering reaction, respectively with the different organic solvents washing, low-temperature reduced-pressure is dry with the wet article of cefotiam hydrochloride ester, acquisition cefotiam hydrochloride solid phase prod.
8. according to claim 7, step 1. in used carbonic acid-1-iodate ethyl ester cyclohexyl ester use new system for facing.
9. according to claim 7, the 1. middle esterification reaction temperature of step is-30～0 ℃, preferred-10～-20 ℃, and 5～60 minutes reaction times, preferred 10-30 minute.
10. according to claim 7, step 2. in extraction use organic solvent to be one or more the mixed solvent in ETHYLE ACETATE, methylene dichloride, the trichloromethane, ethyl acetate; The oxidation resistant aqueous solution can be selected a kind of or mixed aqueous solution in Sodium Pyrosulfite, the sodium sulfite anhy 96, and the concentration of the inhibitor aqueous solution is between 0.1～2%, and preferred 0.5%～1%.
11. according to claim 7, the step 3. concentration of middle used salt aqueous acid is 0.5～5%, preferred concentration is 1～2%.
12. according to claim 7, step 4. in extraction can be one or more the mixed solvent in ETHYLE ACETATE, methylene dichloride, the trichloromethane with organic solvent, preferred methylene dichloride.Buck can be used one or more mixing solutionss such as ammoniacal liquor, aqueous sodium hydroxide solution, potassium hydroxide aqueous solution.
13. according to claim 7, step 5. in the crystallization solvent can select one or more mixed solvent of isopropyl ether, Virahol, acetone, the mixed solvent ratio of preferred isopropyl ether and acetone is (2: 1); The organic solvent of salt acidifying cefotiam hexetil can be selected one or more mixed solvent of isopropyl ether, Virahol, acetone, preferably uses isopropyl ether, and the washing leaching cake preferred solvent is an acetone.
14. according to claim 7, step 6. in vacuum decompression exsiccant temperature can select 0～60 ℃, preferred 20～50 ℃, most preferably 30～40 ℃; Vacuum tightness is selected 5～80mm mercury column, most preferably 5～20mm mercury column; In the operating process, 30-35 ℃ of drying under reduced pressure, continues drying under reduced pressure below 35 ℃ and finishes at 0.3% following drying under reduced pressure to containing acetone after the pulverize at low temperature to containing acetone below 3%, and emptying should feed nitrogen protection.
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| CN103030650A (en) * | 2012-11-23 | 2013-04-10 | 深圳华润九新药业有限公司 | Method for preparing cefotiam hexetil and method for preparing cefotiam hexetil dihydrochloride |
| CN103641848A (en) * | 2013-11-28 | 2014-03-19 | 山东鑫泉医药有限公司 | Method for refining cefotiam hexetil hydrochloride |
| CN106349256A (en) * | 2016-08-24 | 2017-01-25 | 成都倍特药业有限公司 | Method for preparing cefotiam hexetil hydrochloride |
| CN106632398A (en) * | 2016-09-24 | 2017-05-10 | 北京满格医药科技有限公司 | Method for preparing cefotiam hexetil |
| CN106749334A (en) * | 2016-11-23 | 2017-05-31 | 扬子江药业集团北京海燕药业有限公司 | A kind of preparation method of high-purity cefotiam hexetil dihydrochloride |
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| CN106749334A (en) * | 2016-11-23 | 2017-05-31 | 扬子江药业集团北京海燕药业有限公司 | A kind of preparation method of high-purity cefotiam hexetil dihydrochloride |
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