CN108299469A - A kind of preparation method of cefotiam chloride - Google Patents
A kind of preparation method of cefotiam chloride Download PDFInfo
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- CN108299469A CN108299469A CN201710020768.9A CN201710020768A CN108299469A CN 108299469 A CN108299469 A CN 108299469A CN 201710020768 A CN201710020768 A CN 201710020768A CN 108299469 A CN108299469 A CN 108299469A
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- Prior art keywords
- cefotiam
- solvent
- preparation
- added
- triphenyl
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- 229960001242 cefotiam Drugs 0.000 title claims abstract description 30
- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 13
- -1 thiazole, 4 acetic acid trityl group ester Chemical class 0.000 claims abstract description 10
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims abstract description 5
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 5
- NZHXEWZGTQSYJM-UHFFFAOYSA-N [bromo(diphenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Br)C1=CC=CC=C1 NZHXEWZGTQSYJM-UHFFFAOYSA-N 0.000 claims description 4
- 238000005352 clarification Methods 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 230000000171 quenching effect Effects 0.000 claims description 4
- 241000534944 Thia Species 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- DKFCLGCDEMSYAW-UHFFFAOYSA-N [iodo(diphenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(I)C1=CC=CC=C1 DKFCLGCDEMSYAW-UHFFFAOYSA-N 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims description 2
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical compound CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 4
- 206010054949 Metaplasia Diseases 0.000 abstract 1
- 230000015689 metaplastic ossification Effects 0.000 abstract 1
- 238000012805 post-processing Methods 0.000 abstract 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 238000000034 method Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 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 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229960004700 cefotiam hydrochloride Drugs 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 241000588923 Citrobacter Species 0.000 description 1
- UISNQGBURSTLKO-UHFFFAOYSA-N Cl.Cl.CC(=CCCCCC)C(=O)O Chemical class Cl.Cl.CC(=CCCCCC)C(=O)O UISNQGBURSTLKO-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- WJGAPUXHSQQWQF-UHFFFAOYSA-N acetic acid;hydrochloride Chemical compound Cl.CC(O)=O WJGAPUXHSQQWQF-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- WVPKAWVFTPWPDB-UHFFFAOYSA-N dichlorophosphinic acid Chemical compound OP(Cl)(Cl)=O WVPKAWVFTPWPDB-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The present invention relates to a kind of preparation methods of cefotiam chloride, with 2 aminothiazole, 4 acetic acid（Abbreviation ATA）For raw material, 2 triphenylamino thiazole, 4 acetic acid trityl group ester is obtained by bi triphenyl（Abbreviation 2TrATA）, then dock to obtain triphenyl Cefotiam (abbreviation TrCEFO) with 7 ACMT, finally take off triphenyl and obtain target product --- cefotiam chloride（Abbreviation CEFO）.The raw material of the preparation method is simple and easy to get, post-processing operation is easy is easy to industrial metaplasia.
Description
Technical field
The present invention relates to a kind of synthetic methods of cefotiam chloride, belong to the field of pharmaceutical synthesis.
Background technology
Cefotiam chloride is second generation injection antibiotic, can be researched and developed by Japanese military field pharmaceutical industries strain formula, 1981
Year lists in Japan, its dihydrochloride of Clinical practice（Cefotiamdihydrochloride）Powder system is mixed with buffer sodium carbonate
Agent（Trade name Pansporin）.This product is close to the effect of gram positive bacteria with cephazoline, and to gram-negative bacteria,
It is excellent such as the effects that haemophilus, Escherichia coli, klebsiella bacillus, proteus mirabilis, to smooth bacillus, citrobacter, Yin
Diindyl positive proteus etc. also has antibacterial action.Clinically be applied to treatment sensitive bacteria caused by infection for example pneumonia, bronchitis,
Infection of biliary tract, peritonitis, urinary tract infections, and operation after or wound caused by infection and septicemia.Cefotiam chloride
Chemical name is (6R, 7R) -7- [[(2- amino -4- thiazolyls) acetyl group] amino] -3- [[1- [2- (dimethylamino) ethyl] -
1H-TETRAZOLE -5- bases] sulphomethyl] -8- oxos -5- thia -1- azabicyclos [4.2.0] oct-2-ene -2- carboxylic acid dihydrochlorides.
Its structural formula is:
The molecular structure of Cefotiam is broadly divided into three parts subelement, and structure is as follows：
In the prior art, the synthetic route of Cefotiam is prepared with 7-amino-cephalosporanic acid（Abbreviation 7-ACA）For raw material,
In 3 and 1-（2- decils）- 1,2,3,4- tetrazole -5- mercaptan（Abbreviation DMMT）Reaction forms thioether bond, generally exists
7-ACMT is prepared, then 7-ACMT's in sodium bicarbonate or dichloro phosphoric acid, trichlorine phosphoric acid under the catalysis of boron trifluoride etc.
By acylation reaction on 7 bit aminos, 2- amino -4- thiazole acetyl group is introduced, obtains Cefotiam, the structure of 7-ACMT is as follows：
By literature survey, a kind of method of cefotiam chloride is disclosed in Chinese patent CN101648961：It will be former
After expecting that solvent is added in ATA-HCl, chlorinating agent is instilled, catalyst is then added, reacts 2~4h in -15~0 DEG C, after reaction
Filter out ATC-HCl crystallizations；7-ACA and DMMT are mixed in solvent, boron trifluoride complex is added, react 1 in 0~65 DEG C~
2h, after reaction plus then water hydrolysis, addition antioxidant drip alkali, and cooling is stirred, and 7-ACMT borofluorides are obtained；By 7-
ACMT adds alkali soluble in aqueous solvent, and ATC-HCl is added and carries out acylation reaction, reacts 1~2h in -30~-10 DEG C, reaction terminates
After separate organic phase, be added concentrated hydrochloric acid in water phase, hydrophilic solvent be added, cefotiam chloride crystallization is precipitated.
A kind of preparation method of cefotiam chloride is disclosed in Chinese patent CN102850381A, with 2- (2- ammonia
Base thiazole-4-yl) acetic acid hydrochloride（Abbreviation ATA-HCl）It is that raw material prepares ATC-HCl with vilsmeier reagents；Contain in alkalinity
In aqueous organic solvent, after secondary filter, acetone, growing the grain is added in 7-DMT and ATC-HCl reactions, and filtering obtains Cefotiam.
Currently, the technique of domestic production cefotiam hydrochloride is mainly docked using intermediate 7-ACMT with ATA, but ATA
Amino is exposed, unstable, needs to protect amino, and not so impurity increases, and product quality reduces.
A kind of cefotiam hydrochloride preparation method is disclosed in Chinese patent CN101648961A, ATA is added molten
It is passed through dry hydrogen chloride gas after agent, chlorinating agent is then added, obtains ATA-HCl crystallizations；By 7-ACMT plus alkali soluble in containing water-soluble
In agent, ATA-HCl acylation reactions are added, add hydrochloric acid, cefotiam chloride is made.Hydrogen chloride gas is used in this method
Body, reaction is more difficult to control, not easy to operate, and yield is relatively low.
Invention content
Problem to be solved by this invention is to provide a kind of preparation side of high income and the high cefotiam chloride of purity
Method.The concrete scheme that the present invention solves above-mentioned technical problem is as follows：
A kind of preparation method of cefotiam chloride, includes the following steps：
1）It is 1 by molar ratio:2~1:3 ATA（Thiazolamine -4- acetic acid）It is mixed with triphenyl halide and is dissolved in solvent
In, the organic base of 3~5 equivalents is added, is reacted at a temperature of 20~60 DEG C, ATA gradually dissolves, and after the completion of reaction, water quenching is added to go out
Reaction, organic solvent extraction reaction, decompression volatilize solvent and obtain 2- triphenylamino thiazole -4- acetic acid trityl group esters（Letter
Claim 2TrATA）；Wherein, the structure of the ATA is as follows：
The structure of the 2TrATA is as follows：
2）By 7- amino -3- [1- (2- dimethylaminos) ethyl -1H- tetrazolium -5- sulfidomethyls] -8- oxos -5-
Thia -1- azabicyclos [4.2.0] octyl- 2- alkene -2- carboxylic acid tetrafluoroborates（7-ACMT）It is dissolved in solvent, cools down
To -5~5 DEG C, acid binding agent is slowly added dropwise.After being added dropwise, then obtained clear solution is added drop-wise to step 1 by system clarification）
In in the 2TrATA that is prepared, the molar ratio of the 7-ACMT and 2TrATA are 1: 1~1: 3, at a temperature of -40~0 DEG C
Reaction 5~10 hours, obtains triphenyl Cefotiam (TrCEFO)；The wherein triphenyl Cefotiam（TrCEFO）Knot
Structure formula is as follows：
The solvent includes any one in methanol, ethyl alcohol, acetone, acetonitrile or tetrahydrofuran；
The acid binding agent includes any one in triethylamine, tri-butylamine, diisopropyl ethyl amine；
3）Step 2）In the TrCEFO obtained be added in concentrated hydrochloric acid, be warming up to 0~40 DEG C of 2~5h of reaction, be slowly added dropwise
The molar ratio of solvent, the TrCEFO and concentrated hydrochloric acid is 1: 3~1: 6, is placed on room temperature crystallization, Cefotiam is obtained by filtration
Hydrochloride；Wherein, the structural formula of the cefotiam chloride is as follows：
To sum up reaction process is as follows：
The beneficial effects of the invention are as follows：
1. improving the synthesis of intermediate 2TrATA, reaction step is simplified, intermediate purity obtained is higher, easy to operate,
Convenient for industrialized production.
2. introducing triphenyl protecting group by ATA, both protected amino to be activated simultaneously to carboxyl, obtained
2TrATA。
3. having taken off the triphenyl protecting group on amino when final step hydrochloric acid salt simultaneously, kill two birds with one stone, present invention behaviour
Make easy, processing mode is easy, and reaction reproducibility is preferable, and product purity is higher.
Based on the above technical solution, the present invention is also improved as follows.
Further, in step 1）Described in triphenyl halide include triphenylchloromethane, triphenyl iodomethane, three
Any one in phenyl bromomethane, preferably triphenylbromomethane.
Further, the organic base includes any one in triethylamine, tri-butylamine, diisopropyl ethyl amine, excellent
Select diisopropyl ethyl amine.
Further, the solvent is acetonitrile, and extractant is dichloromethane.
Further, step 2）Described in acid binding agent include arbitrary in triethylamine, tri-butylamine, diisopropyl ethyl amine
One kind, preferably diisopropyl ethyl amine.
Further, the organic solvent includes any one in methanol, ethyl alcohol, acetone, acetonitrile or tetrahydrofuran, excellent
It is selected as tetrahydrofuran.
Further, step 3）Described in organic solvent include methanol, ethyl alcohol, acetone, acetonitrile, tetrahydrofuran or butanone
In any one, preferably butanone.
Further, step 1）In, the temperature is 20~60 DEG C；
Further, step 2）In, the temperature is -40~0 DEG C；
Further, step 3）In, the temperature is 0~40 DEG C.
Specific implementation mode
Embodiment 1
The synthesis of 1.2TrATA
By thiazolamine -4- acetic acid（ATA）（10.0g 0.0632mol）It is dissolved in 200ML acetonitriles, triphenylbromomethane is added
（51.07g,0.158mol）, diisopropyl ethyl amine is added（24.5g 0.1896mol）, 5h, TLC monitorings are reacted at 25 DEG C
The reaction was complete, purified water 100ml is added, reaction is quenched, and reaction solution is extracted with dichloromethane (200ML × 2), merges organic layer and uses
Saturated common salt water washing（100ML×2）It is dried with anhydrous magnesium sulfate, filtering decompression is spin-dried for obtaining 2TrATA, the solid of off-white color
36.70g, yield 90.8%, HPLC purity 97.6%.
The synthesis of 2.TrCEFO
7-ACMT (10.0g, 0.0218mol) is suspended in solvents tetrahydrofurane 200ML, is cooled to 0 DEG C, it is different to be slowly added dropwise two
Ethylamine（8.45g 0.0654mol）, it is added dropwise, system clarification.Obtained clear solution is added drop-wise to 2TrATA's
In tetrahydrofuran solution（15.4g, 0.0239mol are dissolved in 100ML tetrahydrofurans）5h, TLC monitoring reactions are reacted at -10 DEG C
Completely, water quenching is added to go out reaction, system layering, organic layer is washed twice with saturated common salt, and anhydrous magnesium sulfate drying is filtered, subtracted
Pressure volatilizes solvent and obtains TrCEFO, off-white powder 14.73g, yield 88%, purity 97.2%.
The synthesis of 3.CEFO
TrCEFO (10.8g, 0.01302mol) is dissolved in butanone 110ML, concentrated hydrochloric acid is added dropwise（37%）4.5ML, in 38 DEG C of temperature
Lower reaction 3h, with the progress of reaction, solid is precipitated in system, and the reaction was complete for TLC monitorings, and filtering, filter cake is washed with butanone, uses second
Ether washs, and obtains the hydrochloride of Cefotiam, faint yellow solid 7.0g, yield 90%, purity 97.1%.MS[M++1ESI+]:
526,1H-NMR (500MHz, D2O):δ3.01（S,6H）；δ 3.60~3.80（M, 6H）；δ 4.12~4.28（Dd, 4H）；δ4.88
（T, 2H）；δ5.10（D, 1H）；δ5.64（D, 1H）；δ6.65（S, 1H）.
Embodiment 2
1. the synthesis of 2TrATA
By thiazolamine -4- acetic acid（ATA）（5.80g 0.0366mol）It is dissolved in 100ML acetonitriles, triphenylbromomethane is added
（29.62g,0.0916mol）, diisopropyl ethyl amine is added（24.5g 0.1896mol）, 3h, TLC monitorings are reacted at 40 DEG C
The reaction was complete, purified water 80ml is added, reaction is quenched, and extracts reaction solution with dichloromethane (100ML × 2), merging organic layer is used full
And brine It（100ML×2）It is dried with anhydrous magnesium sulfate, filtering decompression is spin-dried for obtaining 2TrATA, the solid of off-white color
21.17g, yield 90%, HPLC purity 97.5%.
The synthesis of 2.TrCEFO
7-ACMT (5.50g, 0.0149mol) is suspended in solvents tetrahydrofurane 100ML, is cooled to 0 DEG C, it is different to be slowly added dropwise two
Ethylamine（5.81g 0.0449mol）, it is added dropwise, system clarification.Obtained clear solution is added drop-wise to 2TrATA's
In tetrahydrofuran solution（10.62g, 0.0164mol are dissolved in 80ML tetrahydrofurans）4h, TLC monitoring reactions are reacted at -5 DEG C
Completely, water quenching is added to go out reaction, system layering, organic layer is washed twice with saturated common salt, and anhydrous magnesium sulfate drying is filtered, subtracted
Pressure volatilizes solvent and obtains TrCEFO, off-white powder 9.72g, yield 85%, purity 97.8%.
The synthesis of 3.CEFO
TrCEFO (6.80g, 0.00819mol) is dissolved in butanone 70ML, concentrated hydrochloric acid is added dropwise（37%）2.83ML, in 25 DEG C of temperature
Lower reaction 6h, with the progress of reaction, solid is precipitated in system, and the reaction was complete for TLC monitorings, and filtering, filter cake is washed with butanone, uses second
Ether washs, and obtains the hydrochloride of Cefotiam, faint yellow solid 4.51g, yield 92%, purity 97.6%.
Claims (5)
1. a kind of preparation method of cefotiam chloride, which is characterized in that include the following steps：
1）It is 1 by molar ratio:2~1:3 thiazolamine -4- acetic acid（Abbreviation ATA）It mixes and is dissolved in triphenyl halide
In solvent, the organic base of 3~5 equivalents is added, is reacted at 20~60 DEG C, ATA gradually dissolves, and after the completion of reaction, water quenching is added to go out
Reaction, organic solvent extraction reaction, decompression volatilize solvent and obtain 2- triphenylamino thiazole -4- acetic acid trityl group esters（Letter
Claim 2TrATA）；Wherein, the structure of the ATA is as follows：
；
The structure of the 2TrATA is as follows：
；
2）7- amino -3- [1- (2- dimethylaminos) ethyl -1H-TETRAZOLE -5- sulfidomethyls] -8- oxo -5- thia -1- azepines is double
Ring [4.2.0] oct-2-ene -2- carboxylic acid tetrafluoroborates（Abbreviation 7-ACMT）It is dissolved in solvent, is cooled to -5~5 DEG C, slowly drip
Add acid binding agent；After being added dropwise, then obtained clear solution is added drop-wise to step 1 by system clarification）In be prepared
In 2TrATA, the molar ratio of the 7-ACMT and 2TrATA are 1: 1~1: 3, react 5~10 hours, obtain at -40~0 DEG C
It is as follows to triphenyl Cefotiam (abbreviation TrCEFO) structural formula：
；
3）Step 2）In TrCEFO obtained be added in concentrated hydrochloric acid, be warming up to 0~40 DEG C and react 2~5 hours, be slowly added dropwise organic
The molar ratio of solvent, TrCEFO and concentrated hydrochloric acid is 1: 3~1: 6, and cefotiam chloride is obtained by filtration in room temperature crystallization；Structural formula
It is as follows：
。
2. the preparation method of cefotiam chloride according to claim 1, which is characterized in that in step 1）In, it is described
Alkali include any one in triethylamine, tri-n-butyl amine, diisopropyl ethyl amine.
3. the preparation method of cefotiam chloride according to claim 1, in step 1）In, the triphenyl is halogenated
Methane includes triphenylchloromethane, triphenyl iodomethane, any one in triphenylbromomethane.
4. the preparation method of cefotiam chloride according to claim 1, step 2）In, the acid binding agent includes institute
The alkali stated includes any one in triethylamine, tri-n-butyl amine, diisopropyl ethyl amine；The solvent includes methanol, second
Any one in alcohol, acetone, acetonitrile or tetrahydrofuran.
5. the preparation method of cefotiam chloride according to claim 1, step 3）In, the organic solvent is third
Any one of ketone, butanone, acetonitrile or tetrahydrofuran.
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| CN109517001A (en) * | 2018-11-19 | 2019-03-26 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of cefotiam hydrochloride |
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| CN101045733A (en) * | 2007-01-26 | 2007-10-03 | 上海宁瑞生化技术有限公司 | Preparation method of cefotiam chloride |
| CN101648961A (en) * | 2009-08-25 | 2010-02-17 | 哈药集团制药总厂 | Method and equipment for preparing cefotiam hydrochloride |
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| CN101045733A (en) * | 2007-01-26 | 2007-10-03 | 上海宁瑞生化技术有限公司 | Preparation method of cefotiam chloride |
| CN101648961A (en) * | 2009-08-25 | 2010-02-17 | 哈药集团制药总厂 | Method and equipment for preparing cefotiam hydrochloride |
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| CN109517001B (en) * | 2018-11-19 | 2020-06-09 | 山东罗欣药业集团股份有限公司 | Preparation method of cefotiam hydrochloride |
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