CN1315844C - Derivant of gamma carbon alkenyl cephalosporin, preparing method and application - Google Patents
Derivant of gamma carbon alkenyl cephalosporin, preparing method and application Download PDFInfo
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- CN1315844C CN1315844C CNB2004100509130A CN200410050913A CN1315844C CN 1315844 C CN1315844 C CN 1315844C CN B2004100509130 A CNB2004100509130 A CN B2004100509130A CN 200410050913 A CN200410050913 A CN 200410050913A CN 1315844 C CN1315844 C CN 1315844C
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- thiazolinyl
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- 229910052799 carbon Inorganic materials 0.000 title claims abstract description 22
- -1 carbon alkenyl cephalosporin Chemical class 0.000 title claims abstract description 19
- 229930186147 Cephalosporin Natural products 0.000 title abstract description 8
- 229940124587 cephalosporin Drugs 0.000 title abstract description 8
- 241001597008 Nomeidae Species 0.000 title abstract description 5
- 238000000034 method Methods 0.000 title description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000002253 acid Substances 0.000 claims abstract description 6
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 14
- 150000001780 cephalosporins Chemical class 0.000 claims description 12
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 12
- 239000011707 mineral Substances 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 10
- 150000007530 organic bases Chemical class 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 4
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000001117 sulphuric acid Substances 0.000 claims description 3
- 235000011149 sulphuric acid Nutrition 0.000 claims description 3
- 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 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- 238000006482 condensation reaction Methods 0.000 claims 2
- 150000002148 esters Chemical class 0.000 claims 2
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims 1
- 101150065749 Churc1 gene Proteins 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 1
- 102100038239 Protein Churchill Human genes 0.000 claims 1
- 150000007513 acids Chemical class 0.000 claims 1
- 229940043232 butyl acetate Drugs 0.000 claims 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 abstract description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract description 8
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 241000192125 Firmicutes Species 0.000 abstract description 3
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 27
- 239000000543 intermediate Substances 0.000 description 19
- 239000005457 ice water Substances 0.000 description 15
- 238000001035 drying Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- 238000010792 warming Methods 0.000 description 12
- 230000000845 anti-microbial effect Effects 0.000 description 10
- 241000894006 Bacteria Species 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 8
- 229960002129 cefixime Drugs 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000005864 Sulphur Substances 0.000 description 6
- YKSNHLNTLVRITE-UHFFFAOYSA-N [Br].CC(Br)=O Chemical compound [Br].CC(Br)=O YKSNHLNTLVRITE-UHFFFAOYSA-N 0.000 description 6
- 238000005352 clarification Methods 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical compound CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 description 5
- 241000193998 Streptococcus pneumoniae Species 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 241000191940 Staphylococcus Species 0.000 description 3
- 241001312524 Streptococcus viridans Species 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 description 3
- 229960003719 cefdinir Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 241000606768 Haemophilus influenzae Species 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- 150000001409 amidines Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229960004261 cefotaxime Drugs 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 229940124588 oral cephalosporin Drugs 0.000 description 2
- 125000006238 prop-1-en-1-yl group Chemical group [H]\C(*)=C(/[H])C([H])([H])[H] 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- KFCMZNUGNLCSJQ-NFBKMPQASA-N (4-methoxyphenyl)methyl (6r,7r)-3-(chloromethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)C1=C(CCl)CS[C@H]2N1C(=O)[C@H]2NC(=O)CC1=CC=CC=C1 KFCMZNUGNLCSJQ-NFBKMPQASA-N 0.000 description 1
- GQLGFBRMCCVQLU-XCGJVMPOSA-N (6r)-7-amino-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(C=C)=C(C(O)=O)N2C(=O)C(N)[C@H]21 GQLGFBRMCCVQLU-XCGJVMPOSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 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 1
- 102100025142 Beta-microseminoprotein Human genes 0.000 description 1
- 101100185029 Homo sapiens MSMB gene Proteins 0.000 description 1
- MBVQBOFJRFWMHR-UHFFFAOYSA-N NC(=N)N.CN(C)C Chemical compound NC(=N)N.CN(C)C MBVQBOFJRFWMHR-UHFFFAOYSA-N 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 150000001721 carbon Chemical class 0.000 description 1
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 1
- 229960002588 cefradine Drugs 0.000 description 1
- 229940047526 cephalexin monohydrate Drugs 0.000 description 1
- 150000001782 cephems Chemical class 0.000 description 1
- RDLPVSKMFDYCOR-UEKVPHQBSA-N cephradine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1 RDLPVSKMFDYCOR-UEKVPHQBSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- YGZIWEZFFBPCLN-UHFFFAOYSA-N n,3-bis(2-chloroethyl)-4-hydroperoxy-2-oxo-1,3,2$l^{5}-oxazaphosphinan-2-amine Chemical compound OOC1CCOP(=O)(NCCCl)N1CCCl YGZIWEZFFBPCLN-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229950009506 penicillinase Drugs 0.000 description 1
- 150000005331 phenylglycines Chemical class 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229940081561 rocephin Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- KTAVBOYXMBQFGR-MAODNAKNSA-J tetrasodium;(6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyimino-1-oxidoethylidene]amino]-3-[(2-methyl-5,6-dioxo-1h-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C KTAVBOYXMBQFGR-MAODNAKNSA-J 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The present invention relates to a derivant of gamma carbon alkenyl cephalosporin, a preparation method and application, which discloses a derivant gamma carbon alkenyl cephalosporin, a preparation method and application. The present invention uses 7-amido-3-alkenyl-3-cephem-4-carboxylic acid cephalo-alkyl acid generating reaction with bromo-acetyl bromide and double-substitution thiourea to prepare the derivant of gamma carbon alkenyl cephalosporin. The prepared product has good antibacterial activity to Gram-positive bacteria.
Description
Technical field
The invention relates to new cynnematin, 3 thiazolinyl types of the carbon that therapeutic activity is arranged cephalosporins derivatives that particularly a class is new, its synthetic method and application.
Background technology
Cephalosporin analog antibiotic has particularly become present serious clinical problem by the streptococcus aureus (MRSA) of Staphcillin resistance, the streptococcus pneumoniae (PRSP) of penicillin resistance and the transmissible disease that the resistance faecalis causes along with clinical its resistance of using widely also produces immediately.
By the structure of modification of cynnematin being transformed, wherein on 7 side chains of cephalo parent nucleus, transform and mainly contain cefotaxime acetic acid side chain series, as cefotaxime, rocephin to obtain novel cynnematin; Phenylglycine series is as Cephalexin Monohydrate Micro/Compacted, Cephradine.And mainly concentrating on the C-3 position, the transformation of pharmacokinetics aspect introduces various functional groups.Current cynnematin structure of modification research field is comparatively active is modification to the C-3 position, cephalosporin 3--group that the OAc group is contained S or N replaces, can improve and widen antibiotic effect, transform the cynnematin of vinyl, propenyl as in the C3 position, can obviously strengthen activity, improve to the stability of β-Nei Xiananmei and to the pharmacokinetics of cynnematin and also make moderate progress gram-positive microorganism and negative bacterium.For example Cefixime Micronized, Cefdinir (3 is vinyl) and Prozef (3 for propenyl).Cefixime Micronized is to Gram-negative bacteria high reactivity and wide antimicrobial spectrum, and is very stable to β-Nei Xiananmei, in vivo not by metabolism, and the bioavailability height, Plasma Concentration is stable, and dosage is few and safe.Cefdinir and Prozef total appraisal have the activity that strengthens resisting gram-positive bacteria and negative bacterium equally, to the high eutherapeutic characteristics of penicillinase stabilised blood concentration.
With cephalosporin mother nucleus 7-ACA or GCLE is raw material, can obtain the cephalo parent nucleus intermediate that the C-3 position is the thiazolinyl type through Witting reaction and deprotection base, is shown below:
Structural formula IV (a) is the intermediate of synthetic Cefixime Micronized, Cefdinir.IV (b) is the intermediate of synthetic Prozef, these two kinds of intermediate commercializations.We are starting raw material with these two kinds of intermediates, and 7 bit aminos and two substituting thioureido condensations are obtained a series of amidine sulphur acetamido cephalosporins derivatives.3 thiazolinyl functional groups of this carbon are not appear in the newspapers with combining of 7 amidine sulfanes of carbon base side company, and this kind bound energy improves the anti-microbial activity of cynnematin, enlarges its antimicrobial spectrum, strengthens the activity to the G+ bacterium, and this purpose of the present invention just.
Summary of the invention
The purpose of this invention is to provide 3 thiazolinyl types of a kind of carbon cephalosporins derivatives.
Another object of the present invention provides the preparation method of 3 thiazolinyl types of carbon cephalosporins derivatives.
A further object of the present invention has provided pharmaceutical composition, the especially injection that 3 thiazolinyl types of carbon cephalosporins derivatives is made activeconstituents.
Of the present inventionly advance a purpose and provided the purposes that 3 thiazolinyl types of carbon cephalosporins derivatives is used for the treatment of gram positive bacteria infection.
The present invention is successfully synthetic a series of to have the salt type Cephem Derivative that unsaturated straight-chain paraffin replaces in 3 in carbon, and its general formula is as follows:
The compound of the preferred following structure of formula of of the present invention (I) compound:
The preparation method of the compound of general formula I may further comprise the steps:
(1), starting material compound IV dissolving or be suspended in the appropriate solvent system, add suitable mineral alkali or organic bases and make its dissolving;
(2), the described solution of step 1 is reacted with bromoacetyl bromide, with mineral alkali or organic bases, regulation system pH is neutral;
(3), with described solution acidifying of step 2 and separation;
(4), with the same N of the described product of step 3, the two substituting thioureidos of N react;
(5), the product that step 4 is obtained separates.
The preparation method of described compound, wherein solvent is meant the mixture of alkyl ketone, alkyl alcohol, haloalkane or above-mentioned solvent.
Abovementioned alkyl ketone is meant: acetone, methyl iso-butyl ketone (MIBK)
Alkyl alcohol is meant: methyl alcohol, ethanol, Virahol
Halogenated alkane is meant: methylene dichloride
Above-mentioned organic bases is triethylamine, diethylamine, tetramethyl guanidine;
Mineral alkali is NaHCO
3, Na
2CO
3, NH
3Water, sodium hydroxide solution;
Be used for the acidifying mineral acid in the above-mentioned reaction hydrochloric acid, acetate, dilute sulphuric acid, phosphoric acid are arranged;
Organic acid is tosic acid, formic acid, acetate, trifluoracetic acid or toxilic acid;
The mol ratio of compound IV and bromoacetyl bromide is 1: 3, is preferably 1: 1.3.
It is to adopt the mode of reflux to carry out that the same N of the solution of step in the above-mentioned reaction, the two substituting thioureidos of N react, and reflux temperature is controlled at 38-40 ℃, and the time is 1-8 hour, preferred 2-4 hour.
Among the described preparation method, N, the two substituting thioureidos of N are selected from following thiocarbamide
The method preparation that Chinese style II compound of the present invention is represented with following scheme.
In above-mentioned reaction formula, R
1Such as in the general formula I definition.
Starting raw material formula IV compound is a commercial product in the prior art.
The preparation concrete grammar of intermediate 7-acetobrom amino-3-thiazolinyl-Cephalosporanic acid is:
1, starting raw material formula IV compound mixes stirring with water/organic solvent, is cooled to 0-5 ℃, and add suitable mineral alkali or organic bases and make its dissolving,
2, add the compound bromoacetyl bromide that waits mol ratio at least, drip suitable mineral alkali or organic bases simultaneously, keep the about 6-7 of system pH, reaction, and tell water (heterogeneous) or need not phase-splitting (homogeneous phase);
3, the water that step 2 is told is regulated water pH1.0-1.5, filtration, washing, drying under reduced pressure with mineral acid or organic acid.Obtain compound 7-acetobrom amino-3-thiazolinyl-Cephalosporanic acid
End product (6R, 7R)-(N, N '-diisopropylamidinateand sulphur acetamido)-the 3-thiazolinyl--the preparation method of 4-carboxylate salt II (a), II (b) is specific as follows for 7-:
1, intermediate 7-acetobrom amino-3-thiazolinyl-Cephalosporanic acid is added in the organic solvent, stir, be cooled to 0-5 ℃, slowly add suitable organic bases dissolving fully;
2, add N, the N-di-isopropyl thiourea, temperature rising reflux, reaction is finished the solvent evaporate to dryness, adds after organic solvent grinds, slowly stirs 1 hour filtration, washing, drying under reduced pressure.
3, carry out purifying with conventional solvent crystallization.
In the above-mentioned reaction, available suitable organic solvent has CH
2Cl
2, toluene, acetone, Virahol; Available mineral alkali or organic bases have NaHCO
3Solution, Na
2CO
3Solution, NH
3Water, triethylamine, diethylamine, Tributylamine, tetramethyl guanidine; Available organic acid or mineral acid have hydrochloric acid, acetate, dilute sulphuric acid, phosphoric acid.
The present invention also comprises 7-acetobrom amino-3-thiazolinyl-Cephalosporanic acid intermediate, and its structural formula is:
Its preparation method as mentioned above.
The present invention also comprises a kind of pharmaceutical composition, and the described compound that it comprises general formula I or II is activeconstituents and pharmaceutically acceptable carrier.
Aforementioned pharmaceutical compositions is as antiseptic-germicide.
Antimicrobial pharmacology experimental result of the present invention is as follows: minimum inhibitory concentration MICmg/l
| Compound | Gold Portugal bacterium | Form staph | Faecalis | Streptococcus viridans | Streptococcus pneumoniae | Hemophilus influenzae |
| II(a) | 0.25-2 | 0.0312-1 | 2-8 | 0.125-0.5 | ＞256 | |
| V(a) | 0.25-4 | 4-8 | 0.5-8 | ＞64 | ||
| VI(a) | 0.025-4 | 0.5-4 | ||||
| VII(a) | 0.5-2 | 0.25-2 | 0.05-1 | |||
| VIII(a) | 2-4 | 8-16 | ＞64 | |||
| IX(a) | 0.25-1 | 0.05-2 | ||||
| X(a) | 0.25 | 0.5-4 | ＞256 |
Minimum inhibitory concentration MICmg/l
| Compound | Gold Portugal bacterium | Form staph | Faecalis | Streptococcus viridans | Streptococcus pneumoniae | Hemophilus influenzae |
| II(b) | 0.5-4 | 0.0625-0.5 | 4-64 | 0.0625-2 | ＞64 | |
| V(b) | 0.05-2 | 4-16 | 0.025-1 | |||
| VI(b) | 0.05-2 | 2-8 | 0.5-4 | |||
| VII(b) | 0.05-2 | 0.05-8 | ＞64 | |||
| VIII(b) | 0.5-4 | 4-64 | 0.5-2 | ＞256 | ||
| IX(b) | 0.25-1 | 0.05-4 | 0.5-2 | |||
| X(b) | 0.0625-1 | 2-8 | ＞256 |
Cefixime Micronized is a third generation oral cephalosporin, and it has good anti-microbial effect to streptococcus pneumoniae, micrococcus scarlatinae, intestinal bacteria, gonococcus etc.External kerekou pneumonia uncle faecalis, Salmonella also there is anti-microbial activity.But staphylococcus, green pus bacterium there is not antibiotic effect.Prozef be two generation oral cephalosporin, it has anti-microbial activity to most G+ and G-, and is invalid to methicillin-resistant staphylococcus and faecalis.
The present invention carries out structure of modification to Cefixime Micronized, Prozef, introduces two substituting thioureidos in 7 in carbon, and the series derivates of formation is the cephalosporin derivant of a class inner salt type.Its favorable solubility, clinical injectable administration has changed the route of administration of former Cefixime Micronized, Prozef.In-vitro antibacterial experiment shows Staphylococcus, Streptococcus viridans, Hemolytic streptococcus streptococcus pneumoniae extremely sensitive, the drug-fast faecalis of most of cephalos there is certain anti-microbial activity, strengthened the anti-microbial activity to G+ such as former Cefixime Micronized, Prozef, particularly improved golden Portugal bacterium, form staph, the drug-fast Cefixime Micronized anti-microbial activity of faecalis.
Embodiment
Although the present invention will utilize following examples to be described in more detail, it is not limited only to these embodiment.
(6R, 7R)-preparation of 7-(N, N '-diisopropylamidinateand sulphur acetamido)-3-vinyl-3-cephem-4-carboxylate salt cephalo ethanamidine
Embodiment 1
The preparation of 7-acetobrom amido-3-vinyl-Cephalosporanic acid intermediate III (a)
Earlier 5g7-amino-3-vinyl-3-cephem-4-carboxylic acid is added to 30ml H
2Among the O, add 40mlCH again
2Cl
2Place ice-water bath to stir, when temperature is reduced to 0-5 ℃, slowly drip the 3.14ml tetramethyl guanidine, the 7-amino in the system-3-vinyl-3-cephem-4-carboxylic acid dissolves fully.Dripping bromine acetyl bromide in batches drips the 1.8ml bromoacetyl bromide earlier again, stirs fast, is warming up to 25-30 ℃, drips NaHCO simultaneously
3Solution (5%) to system is clarified fully; After 20 minutes, drip the 0.6ml bromoacetyl bromide again, drip NaHCO simultaneously
3Solution (5%) to system is clarified fully.React after 2 hours, isolate water, regulate water pH to 1.0-1.5 with 6mol/l hydrochloric acid, a large amount of precipitations are separated out.Growing the grain is after 2 hours in the ice-water bath, and filtration, washing, drying under reduced pressure obtain intermediate 7-acetobrom amido-3-vinyl-3-cephem-4-carboxylic acid.
Embodiment 2
(6R, 7R)-(N, N '-diisopropylamidinateand sulphur acetamido)-3-vinyl-3-cephem-4-carboxylate salt II (a) is the preparation of cephalo ethanamidine to 7-
Get 7-acetobrom amido-3-vinyl-3-cephem-4-carboxylic acid 2.5g that example 1 prepares and add 20mlCH
2Cl
2In, stir, when being cooled to 0-5 ℃, slowly drip the 1.09ml triethylamine, system clarification behind the several minutes.Add 1.37g N again, N '-di-isopropyl thiourea is warming up to 38 ℃, refluxes.After 2 hours, slowly stir 1 hour after, filter, acetone (15ml) washing 3 times, drying under reduced pressure, receive title compound.Product turbidity＜1 (1 gram product is dissolved in 10ml water), about 5.0 (the 1.5g/10ml water) of PH.
Products therefrom nuclear magnetic resonance map (hydrogen spectrum)
HNMR (DMSO-d6,500Hz): 1.17 (m, 12H ,-CH-CH3), 3.03 (q, 2H, J=21.5,7.5Hz ,-S-NH-CH-), 3.51,3.67 (d, 2H, AB type, J=17.0Hz, C2-H), 3.95 (d, 4H, J=11.5Hz,-S-CH2-CO--CH-CH3), 5.10,5.35 (d, 2H, the AB type, J=17.5Hz ,-CH=CH2), 5.10 (d, 1H, J=6.5Hz, C6-H), 5.57 (t, 1H, J=6.5Hz, C7-H), 7.00 (q, 1H, J=29.0,11.0Hz ,-CH=CH2), 9.44 (d, 1H, J=6.5Hz ,-NH-).
Embodiment 3
Intermediate 7-acetobrom amido-3-vinyl-3-cephem-4-carboxylic acid
Earlier 5g 7-amino-3-vinyl-3-cephem-4-carboxylic acid is added to 125ml H
2Among the O, add 50ml toluene again.Place ice-water bath to stir, when temperature is reduced to 0-5 ℃, slowly drip the 3.2ml triethylamine, the 7-amino in the system-3-vinyl-3-cephem-4-carboxylic acid dissolves fully.Dripping bromine acetyl bromide in batches drips the 1.8ml bromoacetyl bromide earlier again, stirs fast, is warming up to 25-30 ℃, drips NaHCO simultaneously
3Solution (5%) to system is clarified fully; After 20 minutes, drip the 0.6ml bromoacetyl bromide again, drip NaHCO simultaneously
3Solution (5%) to system is clarified fully.React after 2 hours, isolate water, regulate water pH to 1.0-1.5 with 6mol/l hydrochloric acid, a large amount of precipitations are separated out.Growing the grain is after 2 hours in the ice-water bath, and filtration, washing, drying under reduced pressure obtain intermediate 7-acetobrom amido-3-vinyl-3-cephem-4-carboxylic acid (5g).
Embodiment 4
(6R, 7R)-preparation of 7-(N, N '-diisopropylamidinateand sulphur acetamido)-3-vinyl-3-cephem-4-carboxylic acid cephalo ethanamidine
Get 7-acetobrom amido-3-vinyl-3-cephem-4-carboxylic acid 2.5g that example 2 prepares and add 25mlCH
2Cl
2In, stir, when being cooled to 0-5 ℃, slowly drip 0.83ml trimethylammonium guanidine, system clarification behind the several minutes.Add 1.17g N again, N '-di-isopropyl thiourea is warming up to 38 ℃, refluxes.After 2 hours, add 50ml acetone, slowly stir 1 hour after, filter, acetone (15ml) washing 3 times, drying under reduced pressure, receive title compound (3.04g).Products therefrom solvability, acidity and nuclear magnetic resonance map (hydrogen spectrum) are with example 2 unanimities.
Embodiment 5
The preparation of intermediate 7-acetobrom amido-3-vinyl-3-cephem-4-carboxylic acid
Earlier 5g7-amino-3-vinyl-3-cephem-4-carboxylic acid is added to 40ml H
2Among the O, add 40ml acetone again.Place ice-water bath to stir, when temperature is reduced to 0-5 ℃, add 5gNaHCO
3Solid, the 7-amino in the system-3-vinyl-3-cephem-4-carboxylic acid dissolves fully.Dripping bromine acetyl bromide in batches drips the 1.8ml bromoacetyl bromide earlier again, stirs fast, is warming up to 25-30 ℃, drips triethylamine to system simultaneously and clarifies fully; After 20 minutes, drip the 0.6ml bromoacetyl bromide again, drip triethylamine to system simultaneously and clarify fully.React after 2 hours, isolate water, regulate water pH to 1.0-1.5 with 6mol/l hydrochloric acid, a large amount of precipitations are separated out.Growing the grain is after 2 hours in the ice-water bath, and filtration, washing, drying under reduced pressure obtain intermediate 7-acetobrom amido-3-vinyl-3-cephem-4-carboxylic acid (7.16g).
Embodiment 6
(6R, 7R)-preparation of 7-(N, N '-diisopropylamidinateand sulphur acetamido)-3-vinyl-3-cephem-4-carboxylic acid cephalo ethanamidine
Get 7-acetobrom amido-3-vinyl-3-cephem-4-carboxylic acid 5g that example 5 prepares and add 50mlCH
2Cl
2In, place ice-water bath to stir, when being cooled to 0-5 ℃, slowly drip the 2.0ml triethylamine, system clarification behind the several minutes.Add 2.4g N again, N '-di-isopropyl thiourea is warming up to 38 ℃, refluxes.After 2 hours, basic evaporate to dryness CH
2Cl
2, add 50ml acetone, slowly stir 1 hour after, filter, acetone (15ml) washing 3 times, drying under reduced pressure, receive title compound (3.8g).
Products therefrom solvability, acidity and nuclear magnetic resonance map (hydrogen spectrum) are with example 2 unanimities.
Embodiment 7
Intermediate 7-acetobrom amido-3-allyl group-3-cephem-4-carboxylic acid III (b)
Earlier 4.8g7-amino-3-allyl group-3-cephem-4-carboxylic acid is added to 24ml H
2Among the O, add 48ml toluene again.Place ice-water bath to stir, when temperature is reduced to 0-5 ℃, slowly drip the 2.8ml triethylamine, the 7-amino in the system-3-allyl group-3-cephem-4-carboxylic acid dissolves fully.Dripping bromine acetyl bromide in batches drips the 1.5ml bromoacetyl bromide earlier again, stirs fast, is warming up to 25-30 ℃, drips NaHCO simultaneously
3Solution (5%) to system is clarified fully; After 20 minutes, drip the 0.8ml bromoacetyl bromide again, drip NaHCO simultaneously
3Solution (5%) to system is clarified fully.React after 2 hours, isolate water, regulate water pH to 1.0-1.5 with 6mol/l hydrochloric acid, a large amount of precipitations are separated out.Growing the grain is after 2 hours in the ice-water bath, and filtration, washing, drying under reduced pressure obtain intermediate 7-acetobrom amido-3-allyl group-3-cephem-4-carboxylic acid (4.8g).
Embodiment 8
(6R, 7R)-7-(N, N '-diisopropylamidinateand sulfur acetyl)-3-allyl group-3-cephem-4-carboxylic acid II (b) is cephalo third amidine
Get 7-acetobrom amido-3-allyl group-3-cephem-4-carboxylic acid 4.2g that example 7 prepares and add 50mlCH
2Cl
2In, place ice-water bath to stir, when being cooled to 0-5 ℃, slowly drip the 1.6ml triethylamine, system clarification behind the several minutes.Add 2.8g N again, N '-di-isopropyl thiourea is warming up to 38 ℃, refluxes.After 2 hours, slowly stir 1 hour after, filter, acetone (15ml) washing 3 times, drying under reduced pressure, receive title compound (4.4g).HNMR (DMSO-d6,500Hz): 1.17 (m, 12H ,-CH-CH3), 1.67 (q, 3H, J=9.0,6.0Hz ,-CH=CH-CH3), 3.02 (q, 2H, J=21.5,7.5Hz ,-S-NH-CH-), 3.45,3.65 (d, 2H, AB types, J=16.5Hz, C2-H), 3.94 (t, 4H, J=6.0Hz ,-S-CH2-CO-,-CH-CH3), 5.11 (d, 1H, J=5.0Hz, C6-H), 5.54 (dt, 1H, C7-H ,-CH=CH-CH3) 9.43 (S, 1H ,-NH-).
Embodiment 9
Intermediate 7-acetobrom amido-3-allyl group-3-cephem-4-carboxylic acid
Earlier 2.4g7-amino-3 allyl groups-3-cephem-4-carboxylic acid is added to 20ml H
2Among the O, add 40ml acetone again.Place ice-water bath to stir, when temperature is reduced to 0-5 ℃, add the ml tetramethyl guanidine, the 7-amino in the system-3-allyl group-3-cephem-4-carboxylic acid dissolves fully.Dripping bromine acetyl bromide in batches drips the 0.8ml bromoacetyl bromide earlier again, stirs fast, is warming up to 25-30 ℃, drips triethylamine to system simultaneously and clarifies fully; After 20 minutes, drip the 0.3ml bromoacetyl bromide again, drip triethylamine to system simultaneously and clarify fully.React after 2 hours, isolate water, regulate water pH to 1.0-1.5 with 6mol/l hydrochloric acid, a large amount of precipitations are separated out.Growing the grain is after 2 hours in the ice-water bath, and filtration, washing, drying under reduced pressure obtain intermediate 7-acetobrom amido-3-allyl group-3-cephem-4-carboxylic acid (2.5g).
Embodiment 10
(6R, 7R)-preparation of 7-(N, N '-diisopropylamidinateand sulfur acetyl)-3-allyl group-3-cephem-4-carboxylic acid II (b) cephalo third amidine
Get 7-acetobrom amido-3-allyl group-3-cephem-4-carboxylic acid 2.3g that example 9 prepares and add 30mlCH
2Cl
2In, place ice-water bath to stir, when being cooled to 0-5 ℃, slowly drip the 0.9ml triethylamine, system clarification behind the several minutes.Add 1.6g N again, N '-di-isopropyl thiourea is warming up to 38 ℃, refluxes.After 2 hours, slowly stir 1 hour after, filter, acetone (15ml) washing 3 times, drying under reduced pressure, receive title compound (2.4g).HNMR result is with example 8.
Embodiment 11
(6R, 7R)-preparation of 7-(N, N '-diisopropylamidinateand sulfur acetyl)-3-allyl group-3-cephem-4-carboxylic acid cephalo ethanamidine
Earlier 2.4g 7-amino-3-allyl group-3-cephem-4-carboxylic acid is added to 20ml H
2Among the O, add 40mlCH again
2Cl
2Place ice-water bath to stir, when temperature is reduced to 0-5 ℃, slowly add NaHCO
3Solid, the 7-amino in the system-3-allyl group-3-cephem-4-carboxylic acid dissolves fully.Dripping bromine acetyl bromide in batches drips the 0.8ml bromoacetyl bromide earlier again, stirs fast, is warming up to 25-30 ℃, drips NaHCO simultaneously
3(5% clarifies to system solution fully; After 20 minutes, drip the 0.3ml bromoacetyl bromide again, drip NaHCO simultaneously
3Solution (5%) to system is clarified fully.React after 2 hours, isolate water, regulate water pH to 1.0-1.5 with 6mol/l hydrochloric acid, a large amount of precipitations are separated out.Growing the grain is after 2 hours in the ice-water bath, and filtration, washing, drying under reduced pressure obtain intermediate 7-acetobrom amido-3-allyl group-3-cephem-4-carboxylic acid.
Get 7-acetobrom amido-3-vinyl-3-cephem-4-carboxylic acid 2.3g of preparing of step and add 20mlCH
2Cl
2In, stir, when being cooled to 0-5 ℃, slowly drip the 1.09ml triethylamine, system clarification behind the several minutes.Add 1.6gN again, N '-di-isopropyl thiourea is warming up to 38 ℃, refluxes after 2 hours, slowly stir 1 hour after, filter, acetone (15ml) washing 3 times, drying under reduced pressure, receive title compound.HNMR result is with example 8.
The result of embodiment 12～22 is as shown in the table, method reference example 1,2,7,8,11.
Claims (10)
1,3 thiazolinyl types of carbon cephalosporins derivatives, its feature is represented with following general formula:
R1：-CH＝CH
2 -CH＝CH-CH
3
2,3 thiazolinyl types of the described carbon of claim 1 cephalosporins derivatives is characterized in that chemical structural formula is:
R
1：-CH＝CH
2，-CH＝CHCH
3。
3, the preparation method of 3 thiazolinyl types of the described carbon of claim 1 cephalosporins derivatives may further comprise the steps:
(1), with starting material compound IV dissolving or be suspended in the appropriate solvent system; Adding organic bases or mineral alkali makes solid molten fully clear;
(2), the settled solution with step 1 reacts with bromoacetyl bromide;
(3), the solution acidifying with step 2 gained also separates;
(4), with the same N of the product of step 3 gained, the two substituting thioureidos of N carry out condensation reaction;
(5), the product that step 4 is obtained separates.
4, the preparation method of 3 thiazolinyl types of the described carbon of claim 3 cephalosporins derivatives, wherein solvent is meant the mixture of alkyl ketone, alkyl alcohol, halogenated alkane, ester class or above-mentioned solvent.
5, the preparation method of 3 thiazolinyl types of the described carbon of claim 4 cephalosporins derivatives, wherein said alkyl ketone is meant acetone, methyl iso-butyl ketone (MIBK); Alkyl alcohol is meant methyl alcohol, ethanol, Virahol etc.; Halogenated alkane is meant methylene dichloride; Nitrile is meant acetonitrile; The ester class is meant ethyl acetate, butylacetate etc.
6, the preparation method of 3 thiazolinyl types of the described carbon of claim 3 cephalosporins derivatives, wherein organic bases is triethylamine, diethylamine, tetramethyl guanidine, Tributylamine etc.;
Mineral alkali is NaHCO
3, Na
2CO
3, NH
3Water, sodium hydroxide solution;
The mineral acid that acidifying is adopted has hydrochloric acid, acetate, dilute sulphuric acid, phosphoric acid;
Organic acid is: toluenesulphonic acids, methylsulfonic acid, formic acid, trifluoroacetic acid or toxilic acid.
7, the preparation method of 3 thiazolinyl types of the described carbon of claim 3 cephalosporins derivatives, wherein same N, it is to adopt the mode of reflux to carry out that the two substituting thioureidos of N carry out condensation reaction.
8, the preparation method of 3 thiazolinyl types of the described carbon of claim 2 cephalosporins derivatives may further comprise the steps:
9, a kind of 7-acetobrom amino-3-thiazolinyl-Cephalosporanic acid structural formula is:
R1：-CH＝CH
2 -CH＝CH-CH
3
10, a kind of antibacterial combination, it comprises each described compound and pharmaceutically acceptable carrier according to claim 1-2.
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