CN106317079B - A kind of solid-phase synthesis of Ceftriaxone Sodium - Google Patents
A kind of solid-phase synthesis of Ceftriaxone Sodium Download PDFInfo
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- CN106317079B CN106317079B CN201610695428.1A CN201610695428A CN106317079B CN 106317079 B CN106317079 B CN 106317079B CN 201610695428 A CN201610695428 A CN 201610695428A CN 106317079 B CN106317079 B CN 106317079B
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- ceftriaxone sodium
- phase synthesis
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- 229960000479 ceftriaxone sodium Drugs 0.000 title claims abstract description 39
- FDRNWTJTHBSPMW-GNXCPKRQSA-L disodium;(6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-6-oxido-5-oxo-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [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 FDRNWTJTHBSPMW-GNXCPKRQSA-L 0.000 title claims abstract description 39
- 238000010532 solid phase synthesis reaction Methods 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- 238000000034 method Methods 0.000 claims abstract description 35
- 239000002994 raw material Substances 0.000 claims abstract description 30
- 239000007790 solid phase Substances 0.000 claims abstract description 19
- 239000007787 solid Substances 0.000 claims abstract description 12
- -1 triazine heterocyclic compound Chemical class 0.000 claims description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 37
- 239000003960 organic solvent Substances 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 29
- 229920005989 resin Polymers 0.000 claims description 26
- 239000011347 resin Substances 0.000 claims description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000000047 product Substances 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000007789 gas Substances 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 150000007530 organic bases Chemical class 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 125000004185 ester group Chemical group 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 238000007112 amidation reaction Methods 0.000 claims description 6
- 239000004327 boric acid Substances 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 159000000000 sodium salts Chemical class 0.000 claims description 6
- 230000009435 amidation Effects 0.000 claims description 5
- 239000013078 crystal Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
- 125000000777 acyl halide group Chemical group 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 4
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 239000003849 aromatic solvent Substances 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 238000007664 blowing Methods 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- 150000002642 lithium compounds Chemical class 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 2
- 238000007599 discharging Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 3
- 238000005917 acylation reaction Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000012805 post-processing Methods 0.000 abstract 1
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 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 10
- 150000008282 halocarbons Chemical class 0.000 description 8
- 239000003570 air Substances 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000011521 glass Substances 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229910052734 helium Inorganic materials 0.000 description 4
- 239000001307 helium Substances 0.000 description 4
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 3
- 229920003180 amino resin Polymers 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HSHGZXNAXBPPDL-UHFFFAOYSA-N CC(OCC(CSC1C2N)=C(C(O)=O)N1C2=O)=O Chemical compound CC(OCC(CSC1C2N)=C(C(O)=O)N1C2=O)=O HSHGZXNAXBPPDL-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229960004755 ceftriaxone Drugs 0.000 description 2
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound 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 VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000003100 immobilizing effect Effects 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 229920002401 polyacrylamide Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 229920003053 polystyrene-divinylbenzene Polymers 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- UMWWHOXOVPIGFD-UHFFFAOYSA-N 2-methyl-3-sulfanylidene-1,2,4-triazinane-5,6-dione Chemical compound CN1NC(=O)C(=O)N=C1S UMWWHOXOVPIGFD-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 150000007979 thiazole derivatives Chemical class 0.000 description 1
- 229940041007 third-generation cephalosporins Drugs 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of solid-phase synthesis of Ceftriaxone Sodium, it is characterised in that：Raw material A is bridged on solid phase carrier, is substituted, after acylation reaction, solid phase carrier is detached from and Ceftriaxone Sodium is made；The present invention by using synthesis in solid state Ceftriaxone Sodium preparation method, the last handling process after reaction can be omitted, greatly simplify response procedures, product is reduced while post-processing stages are lost, overall yield of reaction can also be increased to 90% or more, purity is increased to 99.5% or more, improves productivity effect.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a solid-phase synthesis method of ceftriaxone sodium.
Background art:
ceftriaxone sodium, chemical name [6R [6 α,7 β (Z) ] ] -3- [ [ (1,2,5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [ [ (2-amino-4-thiazolyl ] (methoxyimino) acetyl ] amino ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid disodium salt triple hemihydrate, structural formula:
ceftriaxone sodium is a long-acting antibiotic drug in third-generation cephalosporins, has bactericidal effects on a plurality of gram-positive bacteria, gram-negative bacteria and anaerobic bacteria, and is highly stable to most β -lactamase produced by bacteria, so that the antibacterial effect is enhanced.
In the prior literature (CN 103539803A, CN 100335485C, CN 104130273 and the like), 7-aminocephalosporane triazine is a main raw material for synthesizing ceftriaxone sodium (7-ACT), and is acylated with acyl activated 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid compounds to form salt to obtain ceftriaxone sodium, and the total reaction yield is about 60%. The cost of 7-ACT accounts for more than 70% of the cost of ceftriaxone sodium, and the cost of 7-aminocephalosporanic acid (7-ACA) accounts for 80% of the production cost of 7-ACT, so how to improve the yield of 7-ACT and reduce the production cost becomes the key for reducing the cost of ceftriaxone sodium.
Disclosure of Invention
The invention aims to overcome the defects, and provides a preparation method and a solid-phase synthesis method of ceftriaxone sodium, which have the advantages of convenience in post-treatment, simplicity in operation, higher yield and purity of not less than 99.5%, aiming at the technical problems of lower total yield, poor purity and fussy operation in the preparation process of ceftriaxone sodium.
The invention provides a solid-phase synthesis method of ceftriaxone sodium, which is characterized by comprising the following steps: bridging the raw material A on a solid phase carrier, and separating the raw material A from the solid phase carrier after substitution and acylation reaction to obtain ceftriaxone sodium;
wherein the raw material A is a compound shown in the following structure:
the specific reaction equation is as follows:
wherein,represents a solid phase carrier.
Further, the solid-phase synthesis method of ceftriaxone sodium provided by the invention also has the following characteristics: that is, the solid phase carrier is preferably a resin material such as: one or more selected from polystyrene type ion exchange resin and its derivatives, polystyrene divinyl benzene crosslinked resin and its derivatives, polyacrylamide, polyethylene glycol resin and its derivatives, chloromethyl resin and its derivatives, carboxyl resin and its derivatives, amino resin and its derivatives, hydrazide type resin and its derivatives.
Further, the solid-phase synthesis method of ceftriaxone sodium provided by the invention also has the following characteristics: namely, the specific process steps are as follows:
step one, reacting a raw material A with a solid phase carrier in an organic solvent at the temperature of 25-180 ℃ for 0.5-10 hours to obtain a bridging product I;
the reaction is preferably carried out in a container protected from acid and alkali, and in order to quickly realize the quick separation of substances such as solvents in the system, the reaction can also be carried out in a container with a similar structure such as a separation column, and the like, for example: in glazed glass columns and the like, during the reaction, such as: reacting raw material A (namely, 7-ACA) with a solid phase carrier in an organic solvent, selecting a glass column with proper specification, filling the raw material A and the solid carrier with a glaze glass column, tracking the residual quantity of free raw material A by detection means such as TLC, HPLC and the like to determine a reaction end point (namely, when the free raw material A completely disappears or most of the free raw material A disappears and the raw material A is completely bridged on the solid carrier), after the reaction is finished, removing the solvent by flowing with various gases such as nitrogen, air, argon and the like, washing the solid carrier with the organic solvent, removing the reaction solvent, the reaction raw material residues and the like, and directly carrying out the next reaction.
In this step, the solvent for the reaction is preferably one or more selected from halogenated hydrocarbons, amides, and sulfoxide solvents. The organic solvent for washing the solid carrier is preferably selected from halogenated hydrocarbons (e.g., methylene chloride, chloroform, etc.), nitrogen-containing heteroaromatics (e.g., pyridine, etc.), and the like.
Step two, after the triazine heterocyclic compound is added, heating to 40-80 ℃ under the protection of protective gas;
the triazine heterocyclic compound is generally added into a reaction vessel in the form of solution, namely, the triazine heterocyclic compound is added after being dissolved in an organic solvent, wherein the organic solvent can be selected from halogenated hydrocarbon, alkyl nitrile and other organic solvents, and the mass percent concentration of the organic solvent is 25-85%; the shielding gas may be selected from inert gases such as: nitrogen, argon, helium.
Step three, adding a catalyst I, and carrying out catalytic reaction for 1-5 hours to obtain a bridging product II;
after the reaction is finished, various gases such as nitrogen, air, argon and the like are used for removing the solvent, the organic solvent is used for washing and immobilizing, the reaction solvent, the reaction raw material residue and the like are removed, and the next reaction is directly carried out. The organic solvent for washing the solid carrier is preferably selected from halogenated hydrocarbons (e.g., methylene chloride, chloroform, etc.), nitrogen-containing heteroaromatics (e.g., pyridine, etc.), and the like.
Step four, adding a mixed solution of an organic solvent and an organic base, and cooling to below 0 ℃ under the protection of protective gas;
the organic solvent is generally selected from mixed aqueous solutions of halogenated hydrocarbons and alcohols, wherein the ratio of halogenated hydrocarbon: alcohols: the volume ratio of water is 7: 0.1-2: 5-8; the dosage of the organic base is generally 5-10g/150-200ml of solution; the amount of the mixed solution is generally based on the immersion of the solid-carried filler, and the amount of the mixed solution is generally 250ml per 25g of raw material per 100ml of the solution.
Step five, adding an amidation reagent, and reacting for 3-10 hours at the temperature of-15-35 ℃ to obtain a bridging product III;
after the reaction is finished, various gases such as nitrogen, air, argon and the like are used for removing the solvent, the organic solvent is used for washing and immobilizing, the reaction solvent, the reaction raw material residue and the like are removed, and the next reaction is directly carried out. The organic solvent for washing the solid carrier is preferably selected from halogenated hydrocarbons (e.g., methylene chloride, chloroform, etc.), nitrogen-containing heteroaromatics (e.g., pyridine, etc.), and the like.
Step six, adding a mixed solution of an organic solvent and an acid, and reacting for 1-3 hours at the temperature of 10-35 ℃;
the volume ratio of the organic solvent to the acid is preferably 5: 0.5-2;
step seven, cooling the reaction system to below 15 ℃ below zero, adding a catalyst II to react for 1 to 3 hours, and heating to 10 to 35 ℃ to continue the reaction for 3 to 10 hours;
the second catalyst is generally a strong acid catalyst, which is different from the acid contained in the solvent in the sixth step, and the catalyst is used in a catalytic amount, generally 1-10% of the total mass of the reactants.
And step eight, obtaining a target product through post-treatment.
Further, the solid-phase synthesis method of ceftriaxone sodium provided by the invention also has the following characteristics: namely, the triazine heterocyclic compound is a compound represented by the following structure:
wherein R1 is selected from hydrogen, halogen, ester group, alkoxy, acyl halide group, hydroxyl group and other groups easy to leave, wherein the ester group, alkoxy, acyl halide group and other groups are compounds with carbon number not more than 6.
Further, the solid-phase synthesis method of ceftriaxone sodium provided by the invention also has the following characteristics: that is, the amidation agent is a compound represented by the following structure:
wherein R2 is selected from easily leaving groups such as hydrogen, halogen, ester group, alkoxy, nitro, hydroxyl, amino, etc., wherein the ester group, alkoxy, etc. are compounds with no more than 6 carbon atoms.
Further, the solid-phase synthesis method of ceftriaxone sodium provided by the invention also has the following characteristics: namely, after the reaction of the first step, the third step and the fifth step is completed, the solvent in the system is discharged through an air blowing method, and the first bridging product, the second bridging product and the third bridging product are obtained in a mode of at least one time of leaching with the organic solvent.
Further, the solid-phase synthesis method of ceftriaxone sodium provided by the invention also has the following characteristics: namely, the organic solvent is selected from one or more of liquid halohydrocarbon, amide, sulfur-containing organic solvent, alkyl nitrile, alcohol, ester, ether, heteroaromatic and aromatic solvent;
the organic solvent is preferably one or more selected from dichloromethane, chloroform, dimethylformamide, dimethyl sulfoxide, acetonitrile, methanol, ethanol, propanol, pyridine, tetrahydrofuran, acetone, diethyl ether, ethyl acetate, methyl acetate, toluene, benzene, and dioxane;
the catalyst one is selected from organic boron catalysts;
the catalyst I is one or more selected from boron trihalide, alkyl boric acid, aromatic boric acid and organic boric acid ester;
the organic base is selected from one or more of organic amine compounds, amide compounds, alkoxide, alkyl metal lithium compounds and nitrogen-containing heterocyclic derivatives;
the organic base is preferably one or more of triethylamine, tetramethylguanidine, urea, sodium methoxide, sodium ethoxide, potassium tert-butoxide and tert-butyllithium;
the acid and the catalyst II are selected from one or more of trifluoroacetic acid, hydrofluoric acid, organic sulfonic acid and silicon-containing reagent.
Further, the solid-phase synthesis method of ceftriaxone sodium provided by the invention also has the following characteristics: that is, the acidity of the acid is stronger than that of the catalyst two.
Further, the solid-phase synthesis method of ceftriaxone sodium provided by the invention also has the following characteristics: namely, the dosage of the raw material A is 5 to 20 percent of the mass of the solid phase carrier;
the molar ratio of the triazine heterocyclic compound to the raw material A is 1-5: 1;
the molar ratio of the first catalyst to the raw material A is 1-3: 1;
the dosage of the organic base is 1 to 20 percent of the total weight of the solvent in the step four;
the amount of the acid is 10-30% of the total volume of the solvent in the sixth step;
the molar ratio of the acylating agent to the raw material A is 1-5: 1.
Further, the solid-phase synthesis method of ceftriaxone sodium provided by the invention also has the following characteristics: namely, the post-treatment process comprises the following steps:
1. filtering the product obtained in the step seven to remove solid insoluble substances, and removing the solvent to obtain a solid crude product;
2. dissolving the crude product in an organic solvent, washing with at least one sodium salt aqueous solution and an extraction liquid, and extracting to obtain a solution layer containing a product;
the organic solvent and the extract are preferably selected from solvents of halogenated hydrocarbons, aromatics, ethers and esters.
The sodium salt is preferably selected from sodium bicarbonate, sodium chloride, sodium carbonate, etc. The sodium salt is generally dissolved in an aqueous solution for use, and the concentration of the sodium salt is different from 25% to 85%.
3. After passing through the acidic column for at least one time, collecting eluent;
the filler of the acid column can be silica gel, sodium alginate, active alumina, acid ion resin and the like.
4. Crystals of the target product are obtained by adding a polar poor solvent to the eluate.
The poor solvent can be selected from ketones, ethers and alcohols.
The invention has the following functions and effects:
by adopting the preparation method for synthesizing ceftriaxone sodium by the solid phase, the post-treatment process after reaction can be omitted, the reaction procedure is greatly simplified, the loss of the product in the post-treatment stage is reduced, the total reaction yield can be improved to more than 90%, the purity can be improved to more than 99.5%, and the production benefit is improved.
In addition, in the synthesis process of the invention, the effects of high yield and high purity are realized by adjusting the conditions of the solvent, the reaction ratio, the reaction temperature and the like of the reaction system.
Detailed Description
The first embodiment is as follows: bridging of 7-ACA with solid phase carriers
Reacting 25g of 7-ACA with 100g of chloromethyl resin in 100ml of DMF in a glazed glass column, detecting by TLC until no raw material remains, sufficiently bridging the raw material with a solid phase carrier, and using N after the reaction is finished2The solvent was removed by a flow of gas (argon, air, helium, etc.), and then the resin was washed with 100ml of dichloromethane and pyridine (or solvents such as chloroform, toluene, etc.) in this order, followed by the next reaction.
In the first embodiment, the chloromethyl resin may be replaced with polystyrene-divinyl benzene crosslinked resin, polyacrylamide, polyethylene-glycol resin, carboxyl resin, amino resin, hydrazide type resin, or the like.
The amount ratio of 7-ACA to resin was adjusted according to the difference in functional groups of the resin. Such as: when polystyrene and polyethylene structural resin is adopted, the dosage of 7-ACA is 5-20 g:100 g of resin. When carboxyl resin, amino resin and hydrazide resin are adopted, the dosage of the 7-ACA is 15-30 g:100 g of resin.
The solvent may also be dichloromethane, DMSO, chloroform: DMF (50/50), DMSO: DMF (10/90), and the like, in amounts to immerse the resin.
The bridging reaction may be performed by room temperature reaction, stirring reaction, heating reflux reaction, microwave reaction, ultrasonic reaction, etc.
Example two: preparation of solid phase bridged ceftriaxone
A. Adding 30g of acetonitrile (in a state of being completely dissolved) solution of 6-hydroxy-3-mercapto-2-methyl-1, 2, 4-triazine-5-ketone into a glazed glass column, heating to 50 ℃ under the protection of nitrogen, adding 56g of catalyst boron trifluoride, reacting for 2 hours under stirring, and reacting with N after the reaction is finished2The solvent was removed by a flow of gas (argon, air, helium, etc.), and then the resin was washed with 100ml of dichloromethane and pyridine (or solvents such as chloroform, toluene, etc.) in this order, followed by the next reaction.
In this step, the 6-hydroxy-3-mercapto-2-methyl-1, 2, 4-triazin-5-one may also be replaced with a triazine compound with other sulfur-containing leaving groups in position 3, such as:
x: is leaving group with structures of chlorine, iodine, bromine, ester group, acyl halide group, etc.
The triazine compound is used in the following amount: the molar ratio of 7-ACA to triazine compound is 1:1 or 1:2 or 1:2.5 or 1:3 or 1:3.5 or 1:4 or 1:5, and the concentration of the added solution of triazine compound may vary from 35 to 90% depending on the solubility of triazine compound in various solvents, and when the solubility of triazine compound is high, the concentration is higher at 75 to 90%, and when the solubility of triazine compound is low, the concentration is lower at 35 to 74%.
According to the difference of system environment and reaction conditions, the reaction can be carried out under the following conditions: 40 ℃ for 5 hours (s: DMF, X: CH)3COO-); 4 hours at 40 ℃ (s: TCM, X: H); 50 ℃ for 3 hours (s: DMSO, X: H); 60 ℃ for 2 hours (s: THF, X: H); 70 ℃ for 1.5 hours (s: ACN, X: ClCO-); 80 ℃ for 1h (s: DCM, X: I).
B. S1[ dichloromethane (75ml) -ethanol (10ml) -triethylamine (8g) -water (70ml) was added to the column]The solution is stirred and cooled under the protection of nitrogen, 25g of 2- (2-amino-4-thiazolyl) -2- (methoxyimino) thiothiazole acetate is added at the temperature of minus 5 ℃ (-15 ℃ -0 ℃), and the reaction is kept at the temperature of minus 5 ℃ for 6 hours. After the reaction is finished, N is used2The solvent was removed by a flow of gas (argon, air, helium, etc.), and then the resin was washed with 100ml of dichloromethane and pyridine (or solvents such as chloroform, toluene, etc.) in this order, followed by the next reaction.
The reaction solvent may also be S2[50ml DCM: 5ml THF 10g TMG 100ml H2O]Or S3[70ml TCM: 15ml DEE 15g Urea 50ml H2O]Or S4[50ml DMF: 2ml DMK 20gTEA 70ml H2O]Or S5[80ml TCM: 5ml EtOH 30g Urea 40ml H2O]Or S6[50ml DMSO: 2ml EA 20g TEA 70ml H2O]Or S7[80ml DCE: 5ml MeOH 25gPy:5g TMG 80ml H2O]Etc.;
in this step, thiothiazole 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetate may also be replaced by thiazole derivatives of other leaving groups, such as:
y: is chlorine, iodine, bromine, -OR (R is an alkyl group having not more than 4 carbon atoms), nitreAnd leaving groups with structures of cyano, amino, hydroxyl and the like.
The amount of the acylating agent is as follows: the molar ratio of 7-ACA to acylating agent varies from 1:1 or 1:2 or 1:2.5 or 1:3 or 1:3.5 or 1:4 or 1: 5.
According to the difference of system environment and reaction conditions, the reaction can be carried out under the following conditions: 10 hours at-15 ℃ (S2, Y: CH)3O-); 8 hours at-10 ℃ (S3, Y: I); 7 hours at-5 ℃ (S4, Y: NO)2) (ii) a 0 ℃ for 6 hours (S5, Y: Cl); 5.5 hours at 10 ℃ (S6, Y: C)2H5O-); 15 ℃ for 5 hours (S1, X: -OH); 4 hours at 20 ℃ (S7, X: CN); at 25 ℃ for 3 hours (S1, X: NH)2)。
Example three: separation reaction of ceftriaxone and solid phase
The resin was transferred to a reaction flask, 100ml dichloromethane and 20ml trifluoroacetic acid solution were added, after stirring for 2h at room temperature (depending on the solvent the reaction temperature could also be 1h or 1.5 h or 2.5 h or 3 h), the reaction mixture was cooled to-20 ℃, 5ml trifluoromethanesulfonic acid was added with stirring, after 2h of reaction, the temperature was raised to room temperature and stirring continued for 6h, filtration and the organic solvent was removed in vacuo.
Dissolving the obtained solid in 100ml tetrahydrofuran and ethyl acetate solution, extracting with sodium acetate (organic sodium salt such as sodium formate) water solution, washing the obtained water layer with ethyl acetate, separating and purifying with active alumina column chromatography, and collecting eluate containing the target compound. Adding acetone into the eluent, cooling to 15 ℃, growing the crystals for 1h, continuously and slowly dripping acetone solution, cooling to 0 ℃, stirring, growing the crystals for 1h, filtering, washing and drying. Obtaining the ceftriaxone sodium crystal. The total yield of the reaction is 90%, and the purity is 99.5%.
The reaction system can also be: DMSO, DMSO: HF (10:3) or TCM: TFA (10:2.5) or Tol: TFA (10:1.5) or DMF: TFA (10: 1), and the like.
Claims (11)
1. A solid phase synthesis method of ceftriaxone sodium is characterized in that:
bridging the raw material A on a solid phase carrier, and separating the raw material A from the solid phase carrier after substitution and amidation reactions to obtain ceftriaxone sodium;
wherein the raw material A is a compound shown in the following structure:
the solid phase carrier is chloromethyl resin;
the specific process steps are as follows:
step one, reacting a raw material A with a solid phase carrier in an organic solvent at the temperature of 25-180 ℃ for 0.5-10 hours to obtain a bridging product I;
step two, after the triazine heterocyclic compound is added, heating to 40-80 ℃ under the protection of protective gas;
step three, adding a catalyst I, and carrying out catalytic reaction for 1-5 hours to obtain a bridging product II;
step four, adding a mixed solution of an organic solvent and an organic base, and cooling to below 0 ℃ under the protection of protective gas;
step five, adding an amidation reagent, and reacting for 3-10 hours at the temperature of-15-35 ℃ to obtain a bridging product III;
step six, adding a mixed solution of an organic solvent and an acid, and reacting for 1-3 hours at the temperature of 10-35 ℃;
step seven, cooling the reaction system to below 15 ℃ below zero, adding a catalyst II to react for 1 to 3 hours, and heating to 10 to 35 ℃ to continue the reaction for 3 to 10 hours;
and step eight, obtaining a target product through post-treatment.
2. The solid-phase synthesis method of ceftriaxone sodium according to claim 1, characterized in that:
the triazine heterocyclic compound is a compound shown in the following structure:
wherein R1 is selected from hydrogen, halogen, ester group, alkoxy, acyl halide group and hydroxyl.
3. The solid-phase synthesis method of ceftriaxone sodium according to claim 1, characterized in that:
the amidation reagent is a compound shown in the following structure:
wherein R2 is selected from hydrogen, halogen, ester group, alkoxy, nitro, hydroxyl and amino.
4. The solid-phase synthesis method of ceftriaxone sodium according to claim 1, characterized in that:
and after the reactions of the first step, the third step and the fifth step are finished, discharging the solvent in the system by an air blowing method, and obtaining a first bridging product, a second bridging product and a third bridging product by at least one-time organic solvent leaching mode.
5. The solid-phase synthesis method of ceftriaxone sodium according to claim 1, characterized in that:
the organic solvent is selected from one or more of liquid halohydrocarbon, amide, sulfur-containing organic solvent, alkyl nitrile, alcohol, ester, ether, heteroaromatic and aromatic solvent;
the catalyst one is selected from organic boron catalysts;
the organic base is selected from one or more of organic amine compounds, amide compounds, alkoxide, alkyl metal lithium compounds and nitrogen-containing heterocyclic derivatives;
the acid and the catalyst II are selected from one or more of trifluoroacetic acid, hydrofluoric acid, organic sulfonic acid and silicon-containing reagent.
6. The solid-phase synthesis method of ceftriaxone sodium according to claim 1, characterized in that:
the organic solvent is selected from one or more of dichloromethane, chloroform, dimethylformamide, dimethyl sulfoxide, acetonitrile, methanol, ethanol, propanol, pyridine, tetrahydrofuran, acetone, diethyl ether, ethyl acetate, methyl acetate, toluene, benzene and dioxane.
7. The solid-phase synthesis method of ceftriaxone sodium according to claim 1, characterized in that:
the catalyst I is one or more selected from boron trihalide, alkyl boric acid, aromatic boric acid and organic boric acid ester.
8. The solid-phase synthesis method of ceftriaxone sodium according to claim 1, characterized in that:
the organic base is selected from one or more of triethylamine, tetramethylguanidine, urea, sodium methoxide, sodium ethoxide, potassium tert-butoxide and tert-butyllithium.
9. The solid-phase synthesis method of ceftriaxone sodium according to claim 1, characterized in that:
the acidity of the acid is stronger than that of the catalyst II.
10. The solid-phase synthesis method of ceftriaxone sodium according to claim 1, characterized in that:
the dosage of the raw material A is 5-30% of the mass of the solid phase carrier;
the molar ratio of the triazine heterocyclic compound to the raw material A is 1-5: 1;
the molar ratio of the first catalyst to the raw material A is 1-3: 1;
the dosage of the organic base is 1 to 20 percent of the total weight of the solvent in the step four;
the amount of the acid is 10-30% of the total volume of the solvent in the sixth step;
the molar ratio of the amidation reagent to the raw material A is 1-5: 1.
11. The solid-phase synthesis method of ceftriaxone sodium according to claim 1, characterized in that:
the post-treatment process comprises the following steps:
1. filtering the product obtained in the step seven to remove solid insoluble substances, and removing the solvent to obtain a solid crude product;
2. dissolving the crude product in an organic solvent, washing with at least one sodium salt aqueous solution and an extraction liquid, and extracting to obtain a solution layer containing a product;
3. after passing through the acidic column for at least one time, collecting eluent;
4. crystals of the target product are obtained by adding a polar poor solvent to the eluate.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000063214A1 (en) * | 1999-04-15 | 2000-10-26 | Biochemie Gesellschaft M B H | Beta-lactam production |
| WO2002085914A2 (en) * | 2001-04-19 | 2002-10-31 | Bioferma Murcia, S.A. | ENZYMATIC PROCESS FOR PREPARING CEPHALOSPORANIC ACID DERIVATIVES USING α-KETOACID DERIVATIVES |
| CN102559829A (en) * | 2011-12-27 | 2012-07-11 | 山东鑫泉医药有限公司 | Synthetic method of ceftriaxone sodium crude salt |
| CN105061472A (en) * | 2015-08-18 | 2015-11-18 | 齐鲁安替（临邑）制药有限公司 | One-pot synthesis method of ceftriaxone sodium |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000063214A1 (en) * | 1999-04-15 | 2000-10-26 | Biochemie Gesellschaft M B H | Beta-lactam production |
| WO2002085914A2 (en) * | 2001-04-19 | 2002-10-31 | Bioferma Murcia, S.A. | ENZYMATIC PROCESS FOR PREPARING CEPHALOSPORANIC ACID DERIVATIVES USING α-KETOACID DERIVATIVES |
| CN102559829A (en) * | 2011-12-27 | 2012-07-11 | 山东鑫泉医药有限公司 | Synthetic method of ceftriaxone sodium crude salt |
| CN105061472A (en) * | 2015-08-18 | 2015-11-18 | 齐鲁安替（临邑）制药有限公司 | One-pot synthesis method of ceftriaxone sodium |
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