CN101045733B - Preparation method of cefotiam chloride - Google Patents
Preparation method of cefotiam chloride Download PDFInfo
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- CN101045733B CN101045733B CN2007100368831A CN200710036883A CN101045733B CN 101045733 B CN101045733 B CN 101045733B CN 2007100368831 A CN2007100368831 A CN 2007100368831A CN 200710036883 A CN200710036883 A CN 200710036883A CN 101045733 B CN101045733 B CN 101045733B
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- 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 title claims abstract description 26
- 229960001242 cefotiam Drugs 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 title claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 15
- 238000002425 crystallisation Methods 0.000 claims description 13
- 230000008025 crystallization Effects 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000007789 gas Substances 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229960001701 chloroform Drugs 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 239000008346 aqueous phase Substances 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 239000013078 crystal Substances 0.000 abstract description 2
- 239000007864 aqueous solution Substances 0.000 abstract 1
- 239000012320 chlorinating reagent Substances 0.000 abstract 1
- 238000000034 method Methods 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- WSHVQVCBPLNREW-UHFFFAOYSA-N 4-chloro-3-oxobutanoyl chloride Chemical compound ClCC(=O)CC(Cl)=O WSHVQVCBPLNREW-UHFFFAOYSA-N 0.000 description 3
- SJSWRKNSCWKNIR-UHFFFAOYSA-N azane;dihydrochloride Chemical compound N.Cl.Cl SJSWRKNSCWKNIR-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000003068 static effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 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 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 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 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 238000013022 venting Methods 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- JFPVXVDWJQMJEE-QMTHXVAHSA-N Cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)C(=NOC)C1=CC=CO1 JFPVXVDWJQMJEE-QMTHXVAHSA-N 0.000 description 1
- 241000305071 Enterobacterales Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 241001263448 Mycetozoa Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 108010073038 Penicillin Amidase Proteins 0.000 description 1
- 206010035742 Pneumonitis Diseases 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940059260 amidate Drugs 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229950003988 decil Drugs 0.000 description 1
- WVPKAWVFTPWPDB-UHFFFAOYSA-N dichlorophosphinic acid Chemical compound OP(Cl)(Cl)=O WVPKAWVFTPWPDB-UHFFFAOYSA-N 0.000 description 1
- CNTIXUGILVWVHR-UHFFFAOYSA-N diphosphoryl chloride Chemical compound ClP(Cl)(=O)OP(Cl)(Cl)=O CNTIXUGILVWVHR-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
This invention relates to a preparation method of cefotiam muriaficus. It includes follows steps:(1) add raw material ATA to solvent, inlet dryness hydrochloric acid gas, then join chlorinating agent, temperature as 0 to 30 deg. C, and flit out ATC.HCL crystal after reaction; (2) add 7 - ACMT with alkalify to aqueous solution, join ATC.HCL for acidylation reaction, temperature for 10 below zero deg to 35 deg, diverge out organic solvent after reaction, add hydrochloric acid to water phase, join hydrophile solvent with 3 to 6 times dose of water layer volume, and separate out cefotiam muriaficus crystallize.
Description
Technical field
The invention belongs to the medicine field of antibiotics, particularly a kind of preparation method of cefotiam chloride.
Background technology
Cefotiam chloride is a s-generation injection microbiotic, and its dihydrochloride of clinical use (Cefotiam Dihydrochloride) mixes powder preparation (trade(brand)name Pansporin) with buffer reagent yellow soda ash.This product is close to the effect and the Kefzol of gram-positive microorganism, to intestinal bacteria, and the Ke Shi pulmonitis strain, proteus mirabilis, influenzae has very strong anti-microbial effect.To citric acid bacillus, enterobacteria, the positive mycetozoan of indoles also has anti-microbial effect.
The synthetic route of cefotiam chloride is a raw material with 7-amino-cephalosporanic acid (7-ACA) all, its 3 with 1-(2-decil)-1,2,3,4---the strong reaction of mercaptan of four ammonia azoles-5-mercaptan (DMMT) is generally at sodium bicarbonate or dichloro phosphoric acid (dichloro phosphoric anhydride), Tricholroacetic Acid can synthesize 7-ACMT under the catalysis such as boron trifluoride.
The acylation reaction that its 7 bit amino is introduced 2-amino-4-thiazole ethanoyl generally has two kinds of methods:
Method one: earlier carry out amidate action with 4-chloro-3-oxo butyryl chloride (COBC), after again with thiocarbamide reaction closed loop.JP52083871 has reported this method, and the total total recovery of two step reactions is 50-60%, and reaction product also needs the finally synthetic cefotiam of reaction method again with DMMT, because COBC is very unstable, be difficult for transportation, so this method is not suitable for industrial production.
Method two: the ATA with amido protecting is prepared into ATC, and acidylate 7-ACMT makes the cefotiam of band protecting group again, sloughs protecting group with acid or enzyme at last and obtains cefotiam.USP441874 has reported the ATC-2 acidylate 7-ACMT that makes with ATA-2, and products therefrom obtains the method for cefotiam with penicillin acylase deprotection base, is 48-52% with the total recovery of the synthetic cefotiam two steps reaction of ATC-2.USP6787649 has reported with ATA-1 and has prepared ATC-1, acidylate 7-ACMT then, and products therefrom makes the method for cefotiam chloride with hydrochloric acid hydrolysis deprotection base, and the total recoverys of two steps reaction are 74%.
Two kinds of methods comparison shows that, though method two ratio method one is reasonable, connect protecting group and the deprotection base has all increased operation steps, have reduced yield and have improved production cost again.
ATCHCl preparation method of the present invention and be that the method for the synthetic cefotiam of raw material there is no bibliographical information up to now with ATCHCl.
Summary of the invention
Technical problem to be solved by this invention provides a kind of preparation method of cefotiam chloride, with ATA for the raw material single step reaction prepares ATC.HCL, with ATC.HCL acidylate 7-ACMT, this method yield 84%, easy and simple to handle, cost is low, is applicable to suitability for industrialized production.
Chemical equation of the present invention is as follows:
The preparation method of a kind of cefotiam chloride of the present invention comprises the steps:
(1) with ATA is feedstock production ATC.HCL crystallization
With feeding dry hydrogen chloride gas behind the ATA raw material adding solvent, add chlorizating agent then, temperature is 0～30 ℃, reaction leaches the ATC.HCL crystallization after finishing;
(2) be that the directly synthetic cephalo of raw material is for amine hydrochlorate with ATC.HCL
7-ACMT is added alkali be dissolved in the water-containing solvent, add the ATC.HCL acylation reaction, temperature-10～35 ℃; reaction is told organic solvent after finishing, and adds hydrochloric acid at aqueous phase, adds hydrophilic solvent; consumption is 3-6 a times of water layer volume, separates out cephalo for the amine hydrochlorate crystallization.
Nitrile solvents such as described step (1) chlorizating agent can be used chloralkanes such as methylene dichloride, trichloromethane, ethylene dichloride, acetonitrile and dimethyl formamide, N,N-DIMETHYLACETAMIDE isopolarity aprotic solvent, these solvents can be used alone or as a mixture;
The feeding amount of described step (1) hydrogen chloride gas is 5～15 times of ATA mole number, and is generally best with 8～12 times;
Described step (1) temperature of reaction is preferably in 0～15 ℃;
Described step (2) organic solvent can be used nitrile solvents such as chloroparaffins such as methylene dichloride, trichloromethane, ethylene dichloride or acetonitrile;
Described step (2) alkali can be used organic basess such as mineral alkalis such as yellow soda ash, sodium bicarbonate and triethylamine, Tributylamine; The institute
Preferably 0～3 ℃ of described step (2) temperature of reaction;
Described step (2) hydrophilic solvent can be used ketones solvents such as lower alcohols such as ethanol, Virahol or acetone.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Example one
7-ACMT fluoroborate 4.73g (0.01mol.7-ACMT content is 79.2%) is suspended in the 20ml acetonitrile, 25ml acetone, in the 8ml water, be as cold as 0-5 ℃ and add the 5.98ml Tributylamine, 0～5 ℃ was stirred after 20 minutes, add ATC.HCL2.35g (0.011mol) and stir the 3 hours complete 8ml of adding of reaction water below 5 ℃, 30ml methylene dichloride and 7ml concentrated hydrochloric acid, stirred 10 minutes, static layering, divide water-yielding stratum to be warmed up to 25 ℃, add 170ml acetone, 20～25 ℃ were stirred 3 hours, filtering for crystallizing, with 15ml * 2 time washing with acetone crystallization, vacuum-drying below 45 ℃ 3 hours, get 5.3g off-white color cephalo for amine dihydrochloride crystalline powder (HPLC purity 99.2%, moisture content 6.1%, acetone 2.5%) yield 84.5%.
Example two
Nitrile, 4ml water, the 30ml methylene dichloride, be as cold as 0 ℃ and stir adding 3.5ml triethylamine, 0～5 ℃ was stirred after 20 minutes, adding ATC.HCL2.66g (0.012mol) reacted 3 hours below 5 ℃, adding 15ml water and the dense salt of 7ml are finished in reaction, stir 10 minutes static layering and divide water-yielding stratum, be controlled at 20～50 ℃ and add 170ml acetone, 20～25 ℃ are stirred 3 hours filtering for crystallizing, with 15ml * 2 time washing with acetone crystallization, vacuum-drying below 45 ℃ got 5.32g off-white color cephalo in 3 hours for amine dihydrochloride crystalline powder (HPLC purity 98.7%, moisture content 5.95%, acetone 3.1%) yield 84.72%
Example three
7-ACMT fluoroborate 10g (0.021ml, 7ACMT content are 79.2%) is suspended in 42ml acetonitrile, 15ml water, 25ml acetone, is as cold as 0～5 ℃, adds the 7.35ml triethylamine, and 0～5 ℃ is stirred in 20 minutes, adds ATC.HCL5.37g (0.025mol).0～5 ℃ was stirred 3 hours, adding 31.5ml water is finished in reaction, the 14ml concentrated hydrochloric acid, stirred 10 minutes, static layering, divide water-yielding stratum, be controlled at 20～25 ℃ and add 160ml acetone, cool to 50 ℃ then, stir and slowly separate out white crystals after 10 minutes, continue stirring post crystallization half an hour and separate out in a large number, control 5 ℃ and add the 190ml acetone, stir after 2 hours, filtering for crystallizing 50ml * 2 time washing with acetone crystallization, vacuum-drying below 35 ℃ 5 hours gets 10.54g white cephalo for amine dihydrochloride crystallization (HPLC purity 99.65%, moisture content 5.35%, acetone 0.01%) yield 83.25%.
Example four
ATA15.8g (0.1mol) is suspended in the 120ml methylene dichloride, be as cold as-5 ℃, add the 10ml dimethyl formamide, stir and fed dry hydrogen chloride gas about 2.5 hours, not having hydrogen chloride gas up to the reaction flask venting port overflows, the feeding total amount is 39.5g, stop logical hydrogenchloride, add phosphorus pentachloride solid 27.02g (0.13mol) ,-5 ℃ were stirred 2 hours, filter, wash secondary with the 50ml methylene dichloride, room temperature vacuum-drying 3 hours gets the yellow ATC.HCL crystallization of class 17.25g, yield 85%, chloride ion content are 34.44% (theoretical 33.33%)
Example five
ATA15.8g (0.1mol) is suspended in the 60ml methylene dichloride, the 40ml acetonitrile, be as cold as 0 ℃, add the 10ml dimethyl formamide, stir and fed dry hydrogen chloride gas about 2.5 hours, do not have hydrogen chloride gas up to the reaction flask venting port and overflow, the feeding total amount is 40.15g, stops logical hydrogenchloride, add Phosphorus Oxychloride 18.36g (0.12mol), 0 ℃ was stirred 2 hours, and filtering for crystallizing is washed secondary with the 50ml methylene dichloride, room temperature vacuum-drying 3 hours, get the yellowy ATC.HCL crystallization of 16.6g, yield 78%, chloride ion content 34.38%.
Claims (8)
1. the preparation method of a cefotiam chloride is characterized in that: comprise the steps:
(1) with ATA is feedstock production ATC.HCl crystallization
With feeding dry hydrogen chloride gas behind the ATA raw material adding solvent, add chlorizating agent then, temperature is 0～30 ℃, reaction leaches the ATC.HCl crystallization after finishing;
(2) with ATC.HCl be the directly synthetic cefotiam chloride of raw material
7-ACMT is added alkali is dissolved in the water-containing solvent, add the ATC.HCl acylation reaction, temperature-10～35 ℃, reaction is told organic solvent after finishing, and adds hydrochloric acid at aqueous phase, adds hydrophilic solvent, consumption be the water layer volume 3-6 doubly, separate out the cefotiam chloride crystallization
2. the preparation method of a kind of cefotiam chloride according to claim 1 is characterized in that: the feeding amount of hydrogen chloride gas is 5～15 times of ATA mole number in the step (1).
3. the preparation method of a kind of cefotiam chloride according to claim 1, it is characterized in that: step (1) temperature of reaction is 0～15 ℃.
4. the preparation method of a kind of cefotiam chloride according to claim 1 is characterized in that: step (2) organic solvent is selected from a kind of in methylene dichloride, trichloromethane, ethylene dichloride or the acetonitrile.
5. the preparation method of a kind of cefotiam chloride according to claim 1 is characterized in that: alkali is yellow soda ash, sodium bicarbonate, triethylamine or Tributylamine in the step (2).
6. the preparation method of a kind of cefotiam chloride according to claim 1 is characterized in that: hydrophilic solvent is ethanol, Virahol or acetone in the step (2).
7. the preparation method of a kind of cefotiam chloride according to claim 1, it is characterized in that: step (2) temperature of reaction is 0～3 ℃.
8. the preparation method of a kind of cefotiam chloride according to claim 1 and 2 is characterized in that: the feeding amount of hydrogen chloride gas is 8～12 times of ATA mole number in the step (1).
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Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101633666B (en) * | 2009-08-26 | 2010-08-18 | 海南永田药物研究院有限公司 | Cefotiam hydrochloride compound in new path |
| CN101817796A (en) * | 2010-05-28 | 2010-09-01 | 山东金城医药化工股份有限公司 | Method for preparing cefotiam side chain |
| CN102659818B (en) * | 2012-04-19 | 2014-02-19 | 海南合瑞制药股份有限公司 | Hydrochloric acid cefotiam crystalline compound, preparation method thereof and medicine combination containing compound |
| CN102898441A (en) * | 2012-10-11 | 2013-01-30 | 南通康鑫药业有限公司 | Method for synthesizing cefotiam |
| CN103012436B (en) * | 2012-12-04 | 2015-07-01 | 山东鑫泉医药有限公司 | Preparation method of cefotiam hydrochloride |
| CN103232476B (en) * | 2013-04-25 | 2015-09-23 | 四川海思科制药有限公司 | A kind of antimicrobial compounds |
| CN103446047A (en) * | 2013-09-11 | 2013-12-18 | 杭州通盛医药科技有限公司 | Cefotiam hydrochloride pharmaceutical composition for injection and preparation method thereof |
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| CN108299469B (en) * | 2017-01-12 | 2020-07-14 | 重庆常捷医药有限公司 | Preparation method of cefotiam hydrochloride |
| CN107383063B (en) * | 2017-07-14 | 2020-07-31 | 浙江永宁药业股份有限公司 | Novel crystal form of cefotiam hydrochloride and preparation method |
| CN107383065A (en) * | 2017-07-14 | 2017-11-24 | 浙江永宁药业股份有限公司 | A kind of cefotiam chloride crystalline compounds and preparation method thereof |
| CN107987091A (en) * | 2017-11-07 | 2018-05-04 | 河北九派制药股份有限公司 | A kind of preparation method of cefotiam hydrochloride impurity 3- methyl cefotiam chlorides |
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| US4446318A (en) * | 1980-11-11 | 1984-05-01 | Takeda Chemical Industries, Ltd. | Method for producing 7-aminocephem compounds |
| CN1082610A (en) * | 1992-08-07 | 1994-02-23 | 芬佩尔有限公司 | The method of the 7-amino on the acidylate cephalonic acid ring |
| CN1426416A (en) * | 2000-04-28 | 2003-06-25 | 生物化学有限公司 | Cephalosporin Intermediates |
-
2007
- 2007-01-26 CN CN2007100368831A patent/CN101045733B/en not_active Ceased
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4446318A (en) * | 1980-11-11 | 1984-05-01 | Takeda Chemical Industries, Ltd. | Method for producing 7-aminocephem compounds |
| CN1082610A (en) * | 1992-08-07 | 1994-02-23 | 芬佩尔有限公司 | The method of the 7-amino on the acidylate cephalonic acid ring |
| CN1426416A (en) * | 2000-04-28 | 2003-06-25 | 生物化学有限公司 | Cephalosporin Intermediates |
Non-Patent Citations (1)
| Title |
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| JP-平5-286980A 1993.11.02 |
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