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
- chloroformate
- temperature
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- fataa
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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 30
- 229960004700 cefotiam hydrochloride Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 15
- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000011230 binding agent Substances 0.000 claims description 7
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 claims description 7
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- 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
- 238000000967 suction filtration Methods 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-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
- 239000003513 alkali Substances 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 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
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 2
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- -1 compound cefotiam hydrochloride Chemical class 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 4
- 150000008064 anhydrides Chemical class 0.000 abstract description 3
- 238000004519 manufacturing process Methods 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
- 238000003032 molecular docking 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 24
- 238000003786 synthesis reaction Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003756 stirring Methods 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
- 229960001242 cefotiam Drugs 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 210000001503 joint Anatomy 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 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 3
- 238000001035 drying Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 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 2
- 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
- 241000894006 Bacteria Species 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 208000019206 urinary tract infection Diseases 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- OKBVVJOGVLARMR-QMTHXVAHSA-N (6R,7R)-7-[[2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino)-1-oxoethyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1C(N)=NC(C(=NOCC(O)=O)C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QMTHXVAHSA-N 0.000 description 1
- ODDAWJGQWOGBCX-UHFFFAOYSA-N 1-[2-(dimethylazaniumyl)ethyl]tetrazole-5-thiolate Chemical compound CN(C)CCN1N=NN=C1S ODDAWJGQWOGBCX-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- MXBRIEOXXKWWCE-UHFFFAOYSA-N 2-(2-formamido-1,3-thiazol-4-yl)acetic acid Chemical compound OC(=O)CC1=CSC(NC=O)=N1 MXBRIEOXXKWWCE-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
- 206010061695 Biliary tract infection Diseases 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
- 241000588914 Enterobacter Species 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
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 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
- 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
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 230000008733 trauma Effects 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 invention relates to a preparation method of cefotiam hydrochloride, belonging to the field of pharmaceutical antibiotics.
Background
Cefotiam hydrochloride (cefotiam), the chemical name is: (6R-trans) -7- [ [ (2-amino-4-thiazolyl) acetyl]Amino group]-3- [ [1- [2- (dimethylamino) ethyl ] ethyl]-1H-tetrazol-5-yl]Thiomethyl radical]-8-oxo-5-thia-1-azabicyclo [4.2.0]2-ene-2-carboxylic acid dihydrochloride salt, formula: c18H23N9O4S3Molecular weight: 598.6, the structural formula is:
cefotiam is the second generation semi-synthetic cephalosporin antibiotics, which is first marketed in Japan in 1981, developed by Nippon Wutian drug industry Co. The product has similar effect on gram-positive bacteria as cefazolin, has excellent effect on gram-negative bacteria such as Haemophilus, Escherichia coli, Klebsiella and Proteus mirabilis, and also has antibacterial effect on enterobacter, Citrobacter and indole-positive proteus. Stable cefotiam dihydrochloride is clinically administered by intravenous injection and is used for treating infection caused by sensitive bacteria, such as pneumonia, bronchitis, biliary tract infection, peritonitis, urinary tract infection, infection and septicemia caused by operation and trauma, and the like.
The synthetic route of cefotiam hydrochloride takes 7-aminocephalosporanic acid (7-ACA) as a raw material, and the 3-side chain acetoxyl group reacts with the sulfydryl of 1- (2-dimethylaminoethyl) -1,2,3, 4-tetrazole-5-thiol (DMMT) to synthesize 7-ACMT through acid-base catalysis.
The intermediate 7-ACMT is butted with 2-amino-4-thiazole acetic acid (ATA) to prepare cefotiam hydrochloride. According to the synthesis strategy, two modes of first butt joint and then ring formation and first ring formation and then butt joint are mainly adopted. First, the reaction is carried out by butt joint and then cyclization, namely COBC method, amino of 7-ACMT is acylated by 4-chloro-3-oxobutyryl chloride (COBC), and then the amino reacts with thiourea for ring closure to obtain cefotiam. However, since COBC is unstable and not easily transported, the method is not suitable for industrial production. If ring formation is performed first and then butt joint is performed, the exposed amino group is unstable and needs to be protected. Chinese patent CN101045700A discloses a method for preparing cefotiam hydrochloride, which comprises adding ATA into solvent, introducing dry hydrogen chloride gas, and adding chlorinating agent to obtain ATA & HCl crystal; dissolving 7-ACMT with alkali in an aqueous solvent, adding ATA & HCl for acylation reaction, and adding hydrochloric acid to obtain cefotiam hydrochloride. The hydrogen chloride gas used in the method is difficult to control the reaction, is difficult to operate and has lower yield.
At present, cefotiam hydrochloride domestic preparation manufacturers mainly rely on imported raw material medicines for split charging, domestic manufacturers also produce the cefotiam hydrochloride preparation, but the yield and the product purity are lower.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of cefotiam hydrochloride with high yield and high product purity, and ensuring the safety of clinical application.
The technical scheme for solving the technical problems is as follows: a preparation method of cefotiam hydrochloride comprises the following steps:
1) mixing formic acid and acetic anhydride in a molar ratio of 1: 1-1: 3 to prepare methyl ethyl anhydride, then adding 0.2-1 equivalent of 2-aminothiazole-4-acetic acid (ATA for short), reacting at the temperature of 20-80 ℃, gradually dissolving the ATA with the reaction, gradually separating out a solid, then directly adding water for quenching, adjusting the pH = 2.8-3.0 by using alkali until the solid is completely separated out, and then directly performing suction filtration to obtain 2-formylaminothiazole-4-acetic acid (FATA for short); wherein the ATA has the following structural formula:
the FATA has the following structural formula:
2) suspending the FATA obtained in the step 1) in acetonitrile, cooling to-20 ℃, gradually dropwise adding chloroformate, reacting for 0.5-1.5 h, wherein the molar ratio of the FATA to the chloroformate is 1: 1-1: 1.5, and obtaining ethyl carbonate 2-formylaminothiazole-4-acetic anhydride (FATAA for short); wherein the structural formula of FATAA is as follows:
3) suspending 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 tetrafluoroborate (7-ACMT) in a solvent, cooling to-10 ℃, gradually dripping an acid-binding agent to obtain a mixed solution, dripping the mixed solution into the FATAA prepared in the step 2), wherein the molar ratio of the 7-ACMT to the FATAA is 1: 1-1: 3, and reacting at-60-0 ℃ for 1-3 hours to obtain Formyl Cefotiam (FCEFO); wherein,
the FCEFO has the following structural formula:
the solvent comprises any one of methanol, ethanol, acetone, acetonitrile or tetrahydrofuran;
4) adding the FCEFO prepared in the step 3) into concentrated hydrochloric acid, heating to 20-60 ℃, reacting for 4-6 hours, dropwise adding an organic solvent, wherein the molar ratio of the FCEFO to the concentrated hydrochloric acid is 1: 3-1: 8, standing at room temperature for crystallization, and after crystals are completely precipitated, carrying out suction filtration to obtain cefotiam hydrochloride; wherein the structural formula of the cefotiam hydrochloride is as follows:
the reaction process is as follows:
the invention has the beneficial effects that:
1. the synthesis of intermediate FATA is improved, the feeding mode is optimized, the consumption of formic acid is reduced, the prepared intermediate is directly separated out, the purity is high, the operation is simple and convenient, and the industrial production is convenient.
2. Optimizing the FCEFO preparation process, directly adding 7-ACMT and an acid-binding agent after preparing the mixed anhydride without separation by adopting continuous reaction, selecting a proper acid-binding agent to precipitate a product in a salt form, directly carrying out suction filtration to obtain the FCEFO, and being convenient to operate, wherein the purity of the prepared FCEFO is more than or equal to 99%, and then directly removing acyl to obtain CEFO, wherein the purity can reach more than 97%.
3. The method has the advantages of easy operation, simple and convenient treatment mode, better reaction reproducibility, easy central control, high product purity, stable yield and easy expanded production.
On the basis of the technical scheme, the invention is further improved as follows.
Further, in step 1), the alkali comprises any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or ammonia water. Preferably aqueous ammonia.
Further, the chloroformate includes any one of methyl chloroformate, ethyl chloroformate, or isopropyl chloroformate. Preferably ethyl chloroformate.
Further, the solvent is preferably acetonitrile.
Further, the acid-binding agent comprises any one of triethylamine, diisopropylethylamine, tri-N-butylamine or N-methylmorpholine, and is preferably tri-N-butylamine.
Further, the organic solvent includes any one of methanol, ethanol, acetone, acetonitrile or tetrahydrofuran, preferably acetone.
Further, in the step 1), the temperature is 30-50 ℃.
Further, in the step 2), the temperature is reduced to-10 ℃.
Further, in the step 3), the reaction temperature is-40 to-20 ℃.
Further, in the step 4), the temperature after the temperature rise is 25-35 ℃.
Drawings
FIG. 1 shows the preparation of cefotiam hydrochloride1H-NMR chart;
FIG. 2 shows the preparation of cefotiam hydrochloride13C-NMR chart.
Detailed Description
The principles and features of this invention are described below in conjunction with the following drawings, which are set forth by way of illustration only and are not intended to limit the scope of the invention.
Example 1 synthesis of FATA
326.4g（0.8mol）Ac2And O, dropwise adding 220.8g (4.8 mol) of HCOOH while stirring, raising the temperature, and stirring at room temperature for 0.5h to obtain a colorless and clear system. Adding 126.4g (0.8 mol) ATA, raising the temperature to 25 ℃, stirring and reacting for 4 hours at the temperature of 30-50 ℃, wherein the reaction solution becomes clear from turbid in about 1 hour, and then becomes turbid again. TLC monitored the reaction to completion. Cooling in ice water bath, dripping 500g of water, and controlling the internal temperature to be less than or equal to 35 ℃; dropwise adding ammonia water to adjust the pH to be 2.8-3.0, controlling the internal temperature to be less than or equal to 15 ℃, sharing 150.0g of the ammonia water, and stirring for 0.5h at the temperature of 0-10 ℃. The mixture was filtered with suction and washed with tap water (150 g. times.3). Drying at 75 ℃ for 10h under-0.08 to-0.09 MPa to obtain 115.2g of FATA white solid, wherein the yield is 77.4 percent and the HPLC purity is 96.5 percent.
Example 2 synthesis of FATAA
9.3g (0.05 mol) of FATA is suspended in 93g of acetonitrile, the temperature is reduced to-10 ℃, white suspension is added dropwise with 6.5g (0.06 mol) of ethyl chloroformate, the mixture is stirred and reacted for 1h at-10 ℃, the reaction solution becomes clear slightly, TLC monitors the complete reaction, the FATAA acetonitrile solution is directly added into the next reaction, and the HPLC purity is 95.4%.
Example 3 Synthesis of FCEFO
15.7g (0.033 mol) of 7-ACMT, 75g of acetonitrile and 31.5g (0.17 mol) of tri-N-butylamine are added dropwise under the protection of N2 and the temperature is reduced to minus 10-10 ℃, and a light yellow suspension becomes a brownish yellow clear solution. The liquid was added dropwise to the mixed anhydride prepared in "example 2", the internal temperature was controlled to-15 ℃ or lower, and the dropwise addition was completed within 0.5 h. Stirring and reacting for 2h at the temperature of minus 40 to minus 20 ℃. The reaction system state is as follows: near white suspension → pink white suspension → brown yellow clear solution → near white suspension. Suction filtration and washing with cold acetonitrile (20 g.times.2; -20 to-15 ℃), and washing with acetone (20 g.times.1). Drying at 35 ℃ for 5h under-0.08 to-0.09 MPa to obtain 16.8g of FCEFO as white solid with yield of 68.6% and HPLC purity of 99.4%.
Example 4CEFO Synthesis
3.9g (33.5 mmol) of 31% hydrochloric acid and 3.6g of water are stirred, 5.0g (6.78 mmol) of FCEFO is added at room temperature, and the mixture is heated to 25-35 ℃ and stirred for reaction for 5 hours. Adding 3.6g of water, dripping 66g of acetone at 25-35 ℃, and finishing dripping within 0.5 h. Layering, standing the lower layer of brown yellow liquid at room temperature overnight, and filling the bottle with nearly white flocculent precipitate. The flocculent precipitate was stirred well, filtered and washed with acetone (10 g × 2). Drying at 35 ℃ for 6h under-0.08-0.09 MPa to obtain 3.8g of CEFO as a light yellow solid, wherein the yield is 93.8 percent and the HPLC purity is 97.3 percent. As shown in FIGS. 1 and 2, 1H-NMR (500 MHz, D2O, DSS) was 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), and Δ 6.67(s, 1H).
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. The preparation method of cefotiam hydrochloride is characterized by comprising the following steps:
1) mixing formic acid and acetic anhydride in a molar ratio of 1: 1-1: 3 to prepare methyl acetic anhydride, then adding 0.2-1 equivalent of ATA, reacting at the temperature of 20-80 ℃, gradually dissolving the ATA with the reaction, gradually separating out a solid, then directly adding water for quenching, adjusting the pH = 2.8-3.0 with alkali until the solid is completely separated out, and then directly carrying out suction filtration to obtain FATA; wherein the ATA has the following structural formula:
the FATA has the following structural formula:
2) suspending the FATA obtained in the step 1) in acetonitrile, cooling to-20 ℃, gradually dropwise adding chloroformate, wherein the molar ratio of the FATA to the chloroformate is 1: 1-1: 1.5, and reacting for 0.5-1.5 hours to obtain FATAA; wherein the structural formula of FATAA is as follows:
3) suspending 7-ACMT in a solvent, cooling to-10 ℃, gradually dropwise adding an acid-binding agent to obtain a mixed solution after the dropwise adding is finished, dropwise adding the mixed solution into the FATAA prepared in the step 2), wherein the molar ratio of the 7-ACMT to the FATAA is 1: 1-1: 3, and reacting at-60-0 ℃ for 1-3 hours to obtain FCEFO; wherein the FCEFO has the following structural formula:
the solvent comprises any one of methanol, ethanol, acetone, acetonitrile or tetrahydrofuran;
4) adding the FCEFO prepared in the step 3) into concentrated hydrochloric acid, heating to 20-60 ℃, reacting for 4-6 hours, dropwise adding an organic solvent, wherein the molar ratio of the FCEFO to the concentrated hydrochloric acid is 1: 3-1: 8, standing at room temperature for crystallization, and after crystals are completely precipitated, carrying out suction filtration to obtain cefotiam hydrochloride; wherein the structural formula of the cefotiam hydrochloride is as follows:
2. the method for preparing cefotiam hydrochloride according to claim 1, wherein in step 1), the base comprises any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or ammonia water.
3. The method for preparing cefotiam hydrochloride according to claim 2, wherein the base is ammonia.
4. The method for preparing cefotiam hydrochloride according to claim 1, wherein, in step 2), the chloroformate comprises any one of methyl chloroformate, ethyl chloroformate or isopropyl chloroformate.
5. The method of claim 4, wherein the chloroformate is ethyl chloroformate.
6. The method for preparing cefotiam hydrochloride according to claim 1, wherein in step 3), the solvent is acetonitrile; the acid-binding agent comprises any one of triethylamine, diisopropylethylamine, tri-N-butylamine or N-methylmorpholine; in step 4), the organic solvent includes any one of methanol, ethanol, acetone, acetonitrile, or tetrahydrofuran.
7. The method for preparing cefotiam hydrochloride according to claim 6, wherein the acid-binding agent is tri-n-butylamine; the organic solvent is acetone.
8. The method for preparing cefotiam hydrochloride according to any one of claims 1 to 7, wherein the temperature in step 1) is 30-50 ℃.
9. The method for preparing cefotiam hydrochloride according to any one of claims 1 to 7, wherein in the step 2), the temperature reduction temperature is-10 to 10 ℃.
10. The method for preparing cefotiam hydrochloride according to any one of claims 1 to 7, wherein, in the step 3), the reaction temperature is-40 to-20 ℃; in the step 4), the temperature after temperature rise is 25-35 ℃.
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| EP1809638B1 (en) * | 2004-11-01 | 2010-02-17 | Hetero Drugs Limited | A novel process for preparation of cefprozil intermediate |
| 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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| US3978051A (en) * | 1973-08-23 | 1976-08-31 | E. R. Squibb & Sons, Inc. | 7-Methoxy 7-α-ureidothienylacetamidocephalosporins |
| CN1103403A (en) * | 1993-12-02 | 1995-06-07 | 山东新华制药厂 | Process for preparing cefalexin |
| EP1809638B1 (en) * | 2004-11-01 | 2010-02-17 | Hetero Drugs Limited | A novel process for preparation of cefprozil intermediate |
| 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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