CN103910749A - A preparation method of cefotiam hydrochloride - Google Patents
A preparation method of cefotiam hydrochloride Download PDFInfo
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- CN103910749A CN103910749A CN201410098587.4A CN201410098587A CN103910749A CN 103910749 A CN103910749 A CN 103910749A CN 201410098587 A CN201410098587 A CN 201410098587A CN 103910749 A CN103910749 A CN 103910749A
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- cefotiam hydrochloride
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- fataa
- cefotiam
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- 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 title claims abstract description 28
- 229960004700 cefotiam hydrochloride Drugs 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000011230 binding agent Substances 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 7
- 238000000967 suction filtration Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- LYUPJHVGLFETDG-UHFFFAOYSA-N 1-phenylbutan-2-ol Chemical compound CCC(O)CC1=CC=CC=C1 LYUPJHVGLFETDG-UHFFFAOYSA-N 0.000 claims description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 5
- 238000003032 molecular docking Methods 0.000 abstract description 5
- -1 compound cefotiam hydrochloride Chemical class 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 150000008064 anhydrides Chemical class 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 230000004913 activation Effects 0.000 abstract 1
- 230000006198 deformylation Effects 0.000 abstract 1
- 238000006344 deformylation reaction Methods 0.000 abstract 1
- 230000022244 formylation Effects 0.000 abstract 1
- 238000006170 formylation reaction Methods 0.000 abstract 1
- 238000012805 post-processing Methods 0.000 abstract 1
- 238000013341 scale-up Methods 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- 239000007788 liquid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- 229960001242 cefotiam Drugs 0.000 description 6
- 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 description 5
- 239000000725 suspension Substances 0.000 description 5
- WSHVQVCBPLNREW-UHFFFAOYSA-N 4-chloro-3-oxobutanoyl chloride Chemical compound ClCC(=O)CC(Cl)=O WSHVQVCBPLNREW-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 238000005352 clarification Methods 0.000 description 3
- 238000005516 engineering process 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 244000144992 flock Species 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- PISMJKGQNDOCGA-UHFFFAOYSA-N 2-(1,3-thiazol-4-yl)acetic acid Chemical compound OC(=O)CC1=CSC=N1 PISMJKGQNDOCGA-UHFFFAOYSA-N 0.000 description 1
- DYCLHZPOADTVKK-UHFFFAOYSA-N 2-(2-azaniumyl-1,3-thiazol-4-yl)acetate Chemical compound NC1=NC(CC(O)=O)=CS1 DYCLHZPOADTVKK-UHFFFAOYSA-N 0.000 description 1
- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010061695 Biliary tract infection Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- XHANLSMVTWDIDH-UHFFFAOYSA-N CC(CC1=CSC(C)=C(C)C1)=O Chemical compound CC(CC1=CSC(C)=C(C)C1)=O XHANLSMVTWDIDH-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000588923 Citrobacter Species 0.000 description 1
- 241000305071 Enterobacterales Species 0.000 description 1
- 241000588724 Escherichia coli 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
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 208000019206 urinary tract infection Diseases 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
- C07D501/02—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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a preparation method of cefotiam hydrochloride. ATA is adopted as a raw material. The method includes: performing formylation, and activation by mixed anhydride formation to obtain FATAA, docking the FATAA with 7-ACMT to obtain FCEFO, and performing deformylation to obtain the target compound cefotiam hydrochloride (CEFO). The preparation method has characteristics of cheap and easily available raw materials, mild and safe reaction conditions and simple post-processing operation, and is prone to industrial scale-up and production. The purity of the product of the preparation method can be higher than 97%.
Description
Technical field
The present invention relates to a kind of preparation method of cefotiam hydrochloride, belong to medicine field of antibiotics.
Background technology
Cefotiam hydrochloride (cefotiam); chemical name is: (6R-is trans)-7-[[(2-amino-4-thiazolyl) ethanoyl] amino]-3-[[1-[2-(dimethylamino) ethyl]-1H-TETRAZOLE-5-yl] sulphomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid dihydrochloride, molecular formula: C
18h
23n
9o
4s
3, molecular weight: 598.6, structural formula is:
Cefotiam is s-generation semi-synthetic cephalosporins microbiotic, is researched and developed by Japanese Takede Chemical Industries Ltd, within 1981, goes on the market first in Japan.Effect and the Cephazolin of this product to gram positive organism approaches, to gram-negative bacteria, as more excellent in effects such as influenzae, escherichia coli, klebsiella spp, Proteus mirabilises, enterobacteria, citrobacter, the positive Bacillus proteus of indoles etc. are also had to anti-microbial effect.The Cefotiam Dihydrochloride Bolos intravenous administration that clinical use is stable, is used for the treatment of the infection due to sensitive organism, as infection and septicemia etc. due to pneumonia, bronchitis, biliary tract infection, peritonitis, urinary tract infections and operation and wound.
The synthetic route of cefotiam chloride is all taking 7-amino-cephalosporanic acid (7-ACA) as raw material, by acid-base catalysis, its 3 side chain acetoxyl groups and 1-(2-dimethylaminoethyl)-1,2, the synthetic 7-ACMT of sulfydryl reacting thiourea etherificate of 3,4-tetrazole-5-mercaptan (DMMT).
Intermediate 7-ACMT docks and makes cefotiam hydrochloride with 2-amino-4-thiazolyl acetic acid (ATA).According to synthesis strategy, mainly contain the rear Cheng Huan of first docking and two kinds of modes of the rear docking of XianCheng's ring.First docking afterwards ring is COBC method, adopts 4-chloro-3-oxo butyryl chloride (COBC) by the amino acidylate of 7-ACMT, then reacts closed loop with thiocarbamide and obtains cefotiam.But because COBC is very unstable, be difficult for transport, this method is not suitable for industrial production.As docking after XianCheng's ring, exposed amino is unstable, need protect amino.In Chinese patent CN101045700A, disclose a kind of cefotiam hydrochloride preparation method, passed into dry hydrogen chloride gas after ATA is added to solvent, then added chlorizating agent, obtained ATAHCl crystallization; 7-ACMT is added to alkali and be dissolved in water-containing solvent, add ATAHCl acylation reaction, then add hydrochloric acid, make cefotiam chloride.In the method, use hydrogen chloride gas, react more difficult control, not easy to operate, and also yield is lower.
At present, the domestic each preparation of cefotiam hydrochloride manufacturer relies on imported raw material medicine to carry out packing, and domestic also have manufacturer production this product, but yield and product purity are all lower.
Summary of the invention
Technical problem to be solved by this invention is to provide the preparation method of the high and cefotiam hydrochloride that product purity is high of a kind of yield, has ensured the security of clinical application.
The technical scheme that the present invention solves the problems of the technologies described above is as follows: a kind of preparation method of cefotiam hydrochloride, comprises the following steps:
1) formic acid that is 1:1～1:3 by mol ratio and diacetyl oxide mix and are prepared into acetic formic anhydride, and then add thiazolamine-4-acetic acid (be called for short ATA) of 0.2～1 equivalent, at the temperature of 20～80 DEG C, react, along with the carrying out of reaction, ATA dissolves gradually, separates out gradually solids, then cancellation directly adds water, regulate pH=2.8～3.0 to separating out completely with alkali again, and then direct suction filtration, 2-formamido group thiazole-4-acetic acid (being called for short FATA) obtained; Wherein, the structural formula of described ATA is as follows:
The structural formula of described FATA is as follows:
2) the described FATA obtaining in step 1) is suspended in acetonitrile, be cooled to-20～20 DEG C, be added dropwise to gradually chloro-formic ester, described FATA and chloro-formic ester mol ratio are 1:1～1:1.5, reaction 0.5～1.5h, makes ethyl-carbonate 2-formamido group thiazole-4-diacetyl oxide (being called for short FATAA); Wherein, the structural formula of described FATAA is as follows:
3) by 7-amino-3-[1-(2-dimethylamino) ethyl-1H-TETRAZOLE-5-thiomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid a tetrafluoro borate (be called for short 7-ACMT) is suspended in solvent, be cooled to-10～10 DEG C, drip gradually acid binding agent, dropwise, obtain mixing solutions, then described mixing solutions is added drop-wise to step 2) in the described FATAA that makes, the mol ratio of described 7-ACMT and FATAA is 1:1～1:3, and react 1～3h at the temperature of-60～0 DEG C, obtain formyl cefotiam (FCEFO); Wherein,
The structural formula of described FCEFO is as follows:
Described solvent comprises any one in methyl alcohol, ethanol, acetone, acetonitrile or tetrahydrofuran (THF);
4) the described FCEFO making in step 3) is added in concentrated hydrochloric acid, be warming up to 20～60 DEG C of reaction 4～6h, dropwise add organic solvent, the mol ratio of described FCEFO and concentrated hydrochloric acid is 1:3～1:8, room temperature is placed crystallization, and after crystal is separated out completely, suction filtration obtains described cefotiam hydrochloride; Wherein, the structural formula of described cefotiam hydrochloride is as follows:
Reaction process is as follows:
The invention has the beneficial effects as follows:
1, improved the synthetic of intermediate FATA, optimized feed way, reduced formic acid consumption, made intermediate and directly separate out, purity is high, easy and simple to handle, is convenient to suitability for industrialized production.
2, optimize FCEFO preparation technology; preparation mixed anhydride after without separation; adopt successive reaction; directly add 7-ACMT and acid binding agent, select suitable acid binding agent to make product become to salt out, directly suction filtration obtains FCEFO; easy to operate; make FCEFO purity >=99%, then directly piptonychia acyl group obtains CEFO, and purity is more than 97%.
3, the present invention operates easy row, and processing mode is easy, and reaction circulation ratio is better, is easy to middle control, and product purity is high, and stable yield is easy to expanding production.
On the basis of technique scheme, the present invention also improves as follows.
Further, in step 1), described alkali comprises any one in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood or ammoniacal liquor.Be preferably ammoniacal liquor.
Further, described chloro-formic ester comprises any one in methyl-chloroformate, Vinyl chloroformate or isopropyl chlorocarbonate.Be preferably Vinyl chloroformate.
Further, described solvent is preferably acetonitrile.
Further, described acid binding agent comprises any one in triethylamine, diisopropylethylamine, tri-n-butylamine or N-methylmorpholine, is preferably tri-n-butylamine.
Further, described organic solvent comprises any one in methyl alcohol, ethanol, acetone, acetonitrile or tetrahydrofuran (THF), is preferably acetone.
Further, in step 1), described temperature is 30～50 DEG C.
Further, in step 2) in, described cooling temperature is-10～10 DEG C.
Further, in step 3), described temperature of reaction is-40～-20 DEG C.
Further, in step 4), the temperature after described intensification is 25～35 DEG C.
Brief description of the drawings
Fig. 1 is cefotiam hydrochloride of the present invention
1h-NMR figure;
Fig. 2 is cefotiam hydrochloride of the present invention
13c-NMR figure.
Embodiment
Below in conjunction with accompanying drawing, principle of the present invention and feature are described, example, only for explaining the present invention, is not intended to limit scope of the present invention.
Embodiment 1FATA's is synthetic
326.4g(0.8mol) Ac
2o, stirs the lower 220.8g(4.8mol of dropping) HCOOH, temperature raises, stirring at room temperature 0.5h, system is achromaticity and clarification state.Add 126.4g(0.8mol) ATA, temperature is increased to 25 DEG C, 30～50 DEG C of stirring reaction 4h, about 1h reaction solution becomes clarification by muddiness, after muddy again.TLC monitoring reaction is carried out completely.Ice-water bath cooling, drips water 500g, temperature in controlling≤35 DEG C; Drip ammoniacal liquor and adjust pH=2.8～3.0, temperature in controlling≤15 DEG C, shares deammoniation water 150.0g, and 0～10 DEG C is stirred 0.5h.Suction filtration, tap water washing (150g × 3).-0.08～-0.09MPa, 75 DEG C of dry 10h, obtaining FATA is off-white color solid 115.2g, yield 77.4%, HPLC purity 96.5%.
Embodiment 2FATAA's is synthetic
9.3g(0.05mol) FATA is suspended in 93g acetonitrile, be cooled to-10～10 DEG C, white suspension liquid, dropwise add 6.5g(0.06mol) Vinyl chloroformate ,-10～10 DEG C of stirring reaction 1h, reaction solution slightly becomes clarification, TLC monitoring reaction is carried out completely, the acetonitrile solution of FATAA, directly drop into the next step, HPLC purity 95.4%.
Embodiment 3FCEFO's is synthetic
15.7g(0.033mol) 7-ACMT, acetonitrile 75g, N2 protection borehole cooling, to-10～10 DEG C DEG C, drips 31.5g(0.17mol) tri-n-butylamine, faint yellow suspension liquid becomes brown color clear liquid.This fluid drips is added in mixed anhydride prepared by " embodiment 2 ", temperature in controlling≤-15 DEG C, 0.5h dropwises.-40～-20 DEG C of stirring reaction 2h.Reaction system state: near-white suspension liquid → white powder suspension liquid → brown color clear liquid → near-white suspension liquid.Suction filtration, cold acetonitrile washing (20g × 2;-20～-15 DEG C), washing with acetone (20g × 1).-0.08～-0.09MPa, 35 DEG C of dry 5h, obtaining FCEFO is off-white color solid 16.8g, yield 68.6%, HPLC purity 99.4%.
Embodiment 4CEFO's is synthetic
3.9g(33.5mmol) 31% hydrochloric acid, water 3.6g, stirs, and under room temperature, adds 5.0g(6.78mmol) FCEFO, rise to 25～35 DEG C of stirring reaction 5h.Add water 3.6g, drip acetone 66g at 25～35 DEG C, 0.5h dropwises.Layering, lower floor's brown color liquid, room temperature is placed and is spent the night, and in bottle, is full of near-white flocks.Flocks is stirred, filter washing with acetone (10g × 2).-0.08～-0.09MPa, 35 DEG C of dry 6h, obtaining CEFO is faint yellow solid 3.8g, yield 93.8%, HPLC purity 97.3%.As shown in Figure 1 and Figure 2,1H-NMR(500MHz, D2O, DSS): δ 3.02 (s, 6H); δ 3.66～3.84 (m, 6H); δ 4.17～4.29 (dd, 4H, J=13.6Hz); δ 4.76 (D2O); δ 4.90 (t, 2H); δ 5.15 (d, 1H); δ 5.65 (d, 1H); δ 6.67 (s, 1H).
The foregoing is only preferred embodiment of the present invention, in order to limit the present invention, within the spirit and principles in the present invention not all, any amendment of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (10)
1. a preparation method for cefotiam hydrochloride, is characterized in that, comprises the following steps:
1) formic acid that is 1:1～1:3 by mol ratio and diacetyl oxide mix and are prepared into acetic formic anhydride, and then add the ATA of 0.2～1 equivalent, at the temperature of 20～80 DEG C, react, along with the carrying out of reaction, ATA dissolves gradually, then separates out gradually solids, then cancellation directly adds water, regulate pH=2.8～3.0 to separating out completely with alkali again, and then direct suction filtration, FATA obtained; Wherein, the structural formula of described ATA is as follows:
The structural formula of described FATA is as follows:
2) the described FATA obtaining in step 1) is suspended in acetonitrile, is cooled to-20～20 DEG C, be added dropwise to gradually chloro-formic ester, described FATA and chloro-formic ester mol ratio are 1:1～1:1.5, react 0.5～1.5 hour, make FATAA; Wherein, the structural formula of described FATAA is as follows:
3) 7-ACMT is suspended in solvent, be cooled to-10～10 DEG C, drip gradually acid binding agent, dropwise, obtain mixing solutions, then described mixing solutions be added drop-wise to step 2) in the described FATAA that makes, the mol ratio of described 7-ACMT and FATAA is 1:1～1:3, and at the temperature of-60～0 DEG C, react 1～3 hour, obtain FCEFO; Wherein, the structural formula of described FCEFO is as follows:
Described solvent comprises any one in methyl alcohol, ethanol, acetone, acetonitrile or tetrahydrofuran (THF);
4) the described FCEFO making in step 3) is added in concentrated hydrochloric acid, be warming up to 20～60 DEG C of reactions 4～6 hours, dropwise add organic solvent, the mol ratio of described FCEFO and concentrated hydrochloric acid is 1:3～1:8, room temperature is placed crystallization, and after crystal is separated out completely, suction filtration obtains described cefotiam hydrochloride; Wherein, the structural formula of described cefotiam hydrochloride is as follows:
2. the preparation method of cefotiam hydrochloride according to claim 1, is characterized in that, in step 1), described alkali comprises any one in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood or ammoniacal liquor.
3. the preparation method of cefotiam hydrochloride according to claim 2, is characterized in that, described alkali is ammoniacal liquor.
4. the preparation method of cefotiam hydrochloride according to claim 1, is characterized in that, in step 2) in, described chloro-formic ester comprises any one in methyl-chloroformate, Vinyl chloroformate or isopropyl chlorocarbonate.
5. the preparation method of cefotiam hydrochloride according to claim 4, is characterized in that, described chloro-formic ester is Vinyl chloroformate.
6. the preparation method of cefotiam hydrochloride according to claim 1, is characterized in that, in step 3), described solvent is acetonitrile; Described acid binding agent comprises any one in triethylamine, diisopropylethylamine, tri-n-butylamine or N-methylmorpholine; In step 4), described organic solvent comprises any one in methyl alcohol, ethanol, acetone, acetonitrile or tetrahydrofuran (THF).
7. the preparation method of cefotiam hydrochloride according to claim 6, is characterized in that, described acid binding agent is tri-n-butylamine; Described organic solvent is acetone.
8. according to the preparation method of the cefotiam hydrochloride described in claim 1 to 7 any one, it is characterized in that, in step 1), described temperature is 30～50 DEG C.
9. according to the preparation method of the cefotiam hydrochloride described in claim 1 to 7 any one, it is characterized in that, in step 2) in, described cooling temperature is-10～10 DEG C.
10. according to the preparation method of the cefotiam hydrochloride described in claim 1 to 7 any one, it is characterized in that, in step 3), described temperature of reaction is-40～-20 DEG C; In step 4), the temperature after described intensification is 25～35 DEG C.
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| CN101648961A (en) * | 2009-08-25 | 2010-02-17 | 哈药集团制药总厂 | Method and equipment for preparing cefotiam hydrochloride |
| EP1809638B1 (en) * | 2004-11-01 | 2010-02-17 | Hetero Drugs Limited | A novel process for preparation of cefprozil intermediate |
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| US3978051A (en) * | 1973-08-23 | 1976-08-31 | E. R. Squibb & Sons, Inc. | 7-Methoxy 7-α-ureidothienylacetamidocephalosporins |
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