CN103755725B - 7 β-phenylacetylamino-3-is without the preparation method of-3-cephem-4-diphenylmethyl carboxylate - Google Patents
7 β-phenylacetylamino-3-is without the preparation method of-3-cephem-4-diphenylmethyl carboxylate Download PDFInfo
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- CN103755725B CN103755725B CN201310731208.6A CN201310731208A CN103755725B CN 103755725 B CN103755725 B CN 103755725B CN 201310731208 A CN201310731208 A CN 201310731208A CN 103755725 B CN103755725 B CN 103755725B
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- phenylacetylamino
- cephem
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- diphenylmethyl
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- 238000002360 preparation method Methods 0.000 title claims description 33
- 238000000034 method Methods 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 25
- 239000007787 solid Substances 0.000 claims description 16
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- 239000000376 reactant Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 230000006837 decompression Effects 0.000 claims description 9
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 229910021604 Rhodium(III) chloride Inorganic materials 0.000 claims description 7
- -1 methylsulfonyl nitrine Chemical compound 0.000 claims description 7
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- HSVFKFNNMLUVEY-UHFFFAOYSA-N sulfuryl diazide Chemical compound [N-]=[N+]=NS(=O)(=O)N=[N+]=[N-] HSVFKFNNMLUVEY-UHFFFAOYSA-N 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000007832 Na2SO4 Substances 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 150000001540 azides Chemical class 0.000 claims description 6
- 150000008282 halocarbons Chemical class 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- ZKQDCIXGCQPQNV-UHFFFAOYSA-N Calcium hypochlorite Chemical compound [Ca+2].Cl[O-].Cl[O-] ZKQDCIXGCQPQNV-UHFFFAOYSA-N 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 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
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- SONJTKJMTWTJCT-UHFFFAOYSA-K rhodium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Rh+3] SONJTKJMTWTJCT-UHFFFAOYSA-K 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- RVWUHFFPEOKYLB-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1-oxidopiperidin-1-ium Chemical compound CC1(C)CCCC(C)(C)[NH+]1[O-] RVWUHFFPEOKYLB-UHFFFAOYSA-N 0.000 claims description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000872 buffer Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- ONDPGJBEBGWAKI-UHFFFAOYSA-N diphenylphosphane;propane Chemical compound CCC.C=1C=CC=CC=1PC1=CC=CC=C1 ONDPGJBEBGWAKI-UHFFFAOYSA-N 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 8
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims 2
- 235000010290 biphenyl Nutrition 0.000 claims 1
- 239000004305 biphenyl Substances 0.000 claims 1
- 125000006267 biphenyl group Chemical group 0.000 claims 1
- 150000002240 furans Chemical class 0.000 claims 1
- 239000012071 phase Substances 0.000 claims 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 1
- 230000003647 oxidation Effects 0.000 abstract description 4
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 5
- 239000011575 calcium Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229910019093 NaOCl Inorganic materials 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 229960004086 ceftibuten Drugs 0.000 description 2
- UNJFKXSSGBWRBZ-BJCIPQKHSA-N ceftibuten Chemical compound S1C(N)=NC(C(=C\CC(O)=O)\C(=O)N[C@@H]2C(N3C(=CCS[C@@H]32)C(O)=O)=O)=C1 UNJFKXSSGBWRBZ-BJCIPQKHSA-N 0.000 description 2
- 229960000636 ceftizoxime sodium Drugs 0.000 description 2
- ADLFUPFRVXCDMO-LIGXYSTNSA-M ceftizoxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=CCS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 ADLFUPFRVXCDMO-LIGXYSTNSA-M 0.000 description 2
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- NHNUFAASKXPOQA-UHFFFAOYSA-N (3-acetamido-2-hydroxyphenyl)arsonic acid Chemical compound C(C)(=O)NC=1C(=C(C=CC1)[As](O)(=O)O)O NHNUFAASKXPOQA-UHFFFAOYSA-N 0.000 description 1
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- TXLHNFOLHRXMAU-UHFFFAOYSA-N 2-(4-benzylphenoxy)-n,n-diethylethanamine;hydron;chloride Chemical compound Cl.C1=CC(OCCN(CC)CC)=CC=C1CC1=CC=CC=C1 TXLHNFOLHRXMAU-UHFFFAOYSA-N 0.000 description 1
- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- XVASOOUVMJAZNJ-MBNYWOFBSA-N Penicillin K Chemical class S1C(C)(C)[C@H](C(O)=O)N2C(=O)[C@@H](NC(=O)CCCCCCC)[C@H]21 XVASOOUVMJAZNJ-MBNYWOFBSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229960003719 cefdinir Drugs 0.000 description 1
- 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 1
- 229960002129 cefixime Drugs 0.000 description 1
- 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 1
- 229960002580 cefprozil Drugs 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- FSRXIRGQJIHEFB-UHFFFAOYSA-N diphenylphosphane;ethane Chemical compound CC.C=1C=CC=CC=1PC1=CC=CC=C1 FSRXIRGQJIHEFB-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical class C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Inorganic materials O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- XMRSVLCCIJUKDQ-UHFFFAOYSA-N n-diazobenzenesulfonamide Chemical compound [N-]=[N+]=NS(=O)(=O)C1=CC=CC=C1 XMRSVLCCIJUKDQ-UHFFFAOYSA-N 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- RWRDJVNMSZYMDV-UHFFFAOYSA-L radium chloride Chemical compound [Cl-].[Cl-].[Ra+2] RWRDJVNMSZYMDV-UHFFFAOYSA-L 0.000 description 1
- 229910001630 radium chloride Inorganic materials 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention provides and a kind ofly prepare the method for 7 β-phenylacetylamino-3-without-3-cephem-4-diphenylmethyl carboxylate by 7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylate through catalytic oxidation, catalysis piptonychia acidylate two step method; The inventive method has raw material and is easy to get, and reactions steps is short, reaction condition gentleness, and quantity of three wastes is few, and target product purity is good, Atom economy high.
Description
(1) technical field
The preparation method who the present invention relates to a kind of cephalosporins medicine intermediate, is specifically related to 7 β-benzeneAcetylaminohydroxyphenylarsonic acid 3-is without the preparation method of-3-cephem-4-diphenylmethyl carboxylate.
(2) background technology
7 β-phenylacetylamino-3-without-3-cephem-4-diphenylmethyl carboxylate is that one is prepared cephaloThe important intermediate of class medicine, particularly can be used for ceftizoxime sodium (Ceftizoximesodium)And the preparation of Ceftibuten (Ceftibuten). These two medicines all belong to third generation cephalo-typeAntibiotic is current clinical conventional cephalosporins medicine. 7 β-phenylacetylamino-3-is without-3-cephaloBe for No. CAS of alkene-4-diphenylmethyl carboxylate: 36923-19-0, its chemical structural formula is as follows:
Bibliographical information is prepared 7 β-phenylacetylamino-3-without-3-cephem-4-diphenylmethyl carboxylateMethod mainly contains following two kinds.
(1) taking 7 β-phenylacetylamino-3-hydroxyl-3-cephem-4-diphenylmethyl carboxylate as raw material,Pass through NaBH4Reduction, methylsulfonyl and alkali promote the method three-step reaction of eliminating alkylene to obtain7 β-phenylacetylamino-3-without-3-cephem-4-diphenylmethyl carboxylate (CN102617600, US4647658), course of reaction as shown in Figure 1.
Although this technical process yield is higher, the reaction of every step all needs to use greatly excessive anti-Answer reagent. As the NaBH of reduction process needs 2～5 equivalents4, methylsulfonyl process need 4～5The mesyl chloride of equivalent, organic amines more than elimination alkylene process need 10 equivalents is alkali etc.Use these greatly excessive reaction reagents not only to cause course of reaction to produce a large amount of three wastes, alsoMake product separation complexity, need complicated post-processing step. In addition, this technical process is initialThe preparation process of raw material 7 β-phenylacetylamino-3-hydroxyl-3-cephem-4-diphenylmethyl carboxylate is multipleAssorted. This raw material generally needs to obtain through 9 step reactions by penicillin K salt, and course of reaction relates toA large amount of poisonous and harmful reagent, severe reaction conditions (OrganicProcessResearch&Development2002,6,152-157). In a word, just there is reaction step in this technique from sourceRapid long, quantity of three wastes is large, the shortcoming that Atom economy is poor.
(2) taking 7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylate as formerMaterial, obtains 7 β-phenylacetylamino-3-without-3-by oxidation, de-formylated method two-step reactionCephem-4-diphenylmethyl carboxylate (US4269977, CN101463039), course of reactionAs shown in Figure 2.
This technical process step is short, and required raw material 7 β-phenylacetylamino-3-methylol-3-Cephem-4-diphenylmethyl carboxylate can be by the amino cephalo alkane olefin(e) acid of 7-(7-ACA) through three stepsReaction makes (CN101570544), compared with process route (1), has excellent significantlyGesture. Wherein existing many bibliographical informations 7 β-phenylacetylamino-3-methylol-3-cephem-4-Diphenylmethyl carboxylate is oxidized to intermediate 7 β-phenylacetylamino-3-formoxyl-3-cephem-4-carboxylicThe method of acid benzhydryl ester, as: Anelli method (US5631366), Dess-Martin method (US5510538) and MnO2Methods (CN101463039) etc., yield is between 70～96%.This oxide or the current Cefprozil of preparing, Cefixime, Cefdinir, ME1207The key intermediate of the cephalosporins medicines such as ester. But, existing report remove 7 β-phenylacetyl ammonia3 formoxyls of base-3-formoxyl-3-cephem-4-diphenylmethyl carboxylate are 7 β-phenylacetyl ammoniaThere is significant shortcoming without the method for-3-cephem-4-diphenylmethyl carboxylate in base-3-, greatly restrictionThe actual application value of this technique. As US4269977 uses equivalent costlinessWilkinson reagent (triphenylphosphine radium chloride) removes 3 formoxyls, has greatly increased lifeProduce cost, and the document does not provide yield data. CN101463039 has reported with 0.1The metal of equivalent is catalyst, adopts the method for catalytic hydrogenation to remove 3 formoxyls, but does not haveProvide the kind of concrete metallic catalyst, and the yield of report is only 50%.
In a word, the technique of existing report exists that quantity of three wastes is large, yield is low, production efficiency is low, becomesThe shortcomings such as this is higher, complex operation.
(3) summary of the invention
The object of the invention is to overcome now methodical shortcoming, provide a kind of by 7 β-phenylacetyl ammoniaBase-3-methylol-3-cephem-4-diphenylmethyl carboxylate is through catalytic oxidation, catalysis piptonychia acidylate twoFootwork is prepared the new method of 7 β-phenylacetylamino-3-without-3-cephem-4-diphenylmethyl carboxylate. ThisThe reaction equation that invention relates to is as follows:
The technical solution used in the present invention is:
7 β-phenylacetylamino-3-is without a preparation method for-3-cephem-4-diphenylmethyl carboxylate,Described preparation method is:
7 β-phenylacetylamino shown in modus ponens (II)-3-formoxyl-3-cephem-4-carboxylic acid hexichol firstEster, with anhydrous RhCl3For catalyst, bidentate organic phosphine reagent (P-P) is part, sulphonylAzide compounds (RSO2N3) be CO capturing agent, in absolute ether kind solvent, nitrogenUnder protection, at 20～80 DEG C, carry out piptonychia acylation reaction, HPLC follows the tracks of detection, reactionAfter end, reactant liquor separates and obtains the 7 β-phenylacetylamino-3-shown in target product formula (III)Nothing-3-cephem-4-diphenylmethyl carboxylate, the piptonychia acylation reaction time is 12～24h conventionally; InstituteState 7 β-phenylacetylamino shown in formula (II)-3-formoxyl-3-cephem-4-diphenylmethyl carboxylate withRhCl3, bidentate organic phosphine reagent, sulfonyl azide compounds the amount of substance ratio that feeds intake be 1:0.03～0.1:0.03～0.1:1.0～1.5。
β-phenylacetylamino-3-of the present invention is without the system of-3-cephem-4-diphenylmethyl carboxylatePreparation Method, wherein said bidentate type organic phosphine reagent is selected from (2R, 3S)-2, the two diphenyl phosphines of 2'--1,1'-dinaphthalene (BINAP), 4, two diphenylphosphine-9 of 5-, 9-dimethyl oxa-anthracene (XantPhos),Two [(2-diphenyl phosphine) phenyl] ether (DPEPhos), 1, two (diphenylphosphine) propane (DPPP) of 3-Or two (diphenylphosphine) ethane (DPPE) of 1,3-; Wherein taking XantPhos as best.
In preparation method of the present invention, described sulfonyl azide compounds (RSO2N3) be selected fromSulfonyl azide, phenyl sulfonyl azide or p-toluene sulfonyt azide that C1～C12 alkyl replaces; ItsIn taking p-toluene sulfonyt azide as best.
In preparation method of the present invention, described ether solvent is selected from ether, isopropyl ether, methyl-tert fourthBase ether, oxolane, dioxane or glycol dimethyl ether; 7 β shown in described formula (II)-The matter that feeds intake of phenylacetylamino-3-formoxyl-3-cephem-4-diphenylmethyl carboxylate and ether solventAmount is than being 1:3～7; Being more preferably this mass ratio that feeds intake is 1:5.
In preparation method of the present invention, particularly preferably 7 β-phenylacetylamino-3-shown in described formula (II)Formoxyl-3-cephem-4-diphenylmethyl carboxylate and RhCl3, bidentate organic phosphine reagent, sulphonyl is foldedThe amount of substance ratio that feeds intake of nitrogen is 1:0.05:0.05:1.1.
In preparation method of the present invention, the separation method of described reactant liquor is: after reaction finishes, anti-Answer liquid to be cooled to room temperature, add water, use CH2Cl2Extraction, the organic phase of merging is successively through HClThe aqueous solution, saturated NaCl solution washing, activated carbon decolorizing, anhydrous Na2SO4Dry, mistakeFilter, filtrate decompression reclaims solvent, and the residue obtained ether/n-hexane that is 1:1 by volume ratio mixesSolvent recrystallization, the solid of recrystallization gained vacuum decompression at 40 DEG C is dry, obtains formula (III)Shown 7 β-phenylacetylamino-3-is without-3-cephem-4-diphenylmethyl carboxylate, through HPLC areaNormalization method is measured, and content is greater than 99%. .
7 β-phenylacetylamino-3-of the present invention is without-3-cephem-4-diphenylmethyl carboxylatePreparation method, 7 β-phenylacetylamino shown in wherein said formula (II)-3-formoxyl-3-cephem-4-diphenylmethyl carboxylate makes as follows: with 7 β-phenylacetylamino-3-shown in formula (I)Methylol-3-cephem-4-diphenylmethyl carboxylate is raw material, and effective chlorine content is 60%Calcium hypochlorite (Ca (OCl)2) be oxidant, 2,2,6,6-tetramethyl piperidine oxide (TEMPO)For catalyst, in the cushioning liquid that is 8.5～11 in pH value and the mixed solvent of halogenated hydrocarbons,At-5～10 DEG C, carry out oxidation reaction 2～4h, HPLC follows the tracks of detection, after reaction finishes, and reactionMixture is isolated to the 7 β-phenylacetylamino shown in formula (II)-3-formoxyl-3-cephem-4-diphenylmethyl carboxylate; 7 β-phenylacetylamino shown in described formula (I)-3-methylol-3-cephaloAlkene-4-diphenylmethyl carboxylate and calcium hypochlorite, 2,2,6, the thing that feeds intake of 6-tetramethyl piperidine oxideThe amount of matter is than being 1:1.1～1.5:0.01～0.1; 7 β-phenylacetylamino-3-shown in described formula (I)The mass ratio that feeds intake of methylol-3-cephem-4-diphenylmethyl carboxylate and cushioning liquid, halogenated hydrocarbonsFor 1:4～10:4～10.
β-phenylacetylamino-3-shown in formula of the present invention (II) is without-3-cephem-4-carboxylic acidThe preparation method of benzhydryl ester, the buffer of wherein said cushioning liquid is selected fromNaHCO3/Na2CO3、NaHCO3/Na2CO3、KHCO3/K2CO3、KHCO3/KOHOr NH4Cl/NH3·H2O; The pH value of preferred described cushioning liquid is 9.5～10; Described haloHydrocarbon is selected from carrene, 1,2-dichloroethanes or chloroform; Particularly preferably described formula (I) instituteShow 7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylate and cushioning liquid, halogenThe mass ratio that feeds intake for hydrocarbon is 1:6:6.
β-phenylacetylamino-3-shown in formula of the present invention (II) is without-3-cephem-4-carboxylic acidThe preparation method of benzhydryl ester, particularly preferably 7 β-phenylacetylamino-3-shown in described formula (I)Methylol-3-cephem-4-diphenylmethyl carboxylate and calcium hypochlorite, 2,2,6,6-tetramethyl piperidine oxygenThe amount of substance ratio that feeds intake of compound is 1:1.1:0.03; And, preferably at 0～5 DEG C, react 2～4h.
β-phenylacetylamino-3-shown in formula of the present invention (II) is without-3-cephem-4-carboxylic acidThe preparation method of benzhydryl ester, the method that wherein said reactant mixture separates is: reaction finishesAfter, in reactant mixture, dripping the HCl aqueous solution to pH value is 6～7, separates organic layer,Water layer is used when reacting halogenated hydrocarbon solvent extraction identical in mixed solvent, merges organic phase, hasMachine is used the 5wt% sodium hydrosulfite aqueous solution (being hydrosulfurous acid sodium water solution), saturated NaCl mutually successivelySolution washing, anhydrous Na2SO4Dry, to filter, filtrate decompression reclaims solvent, obtainsResidue is recrystallized with acetonitrile, and the solid of recrystallization gained vacuum decompression at 40 DEG C is dry,Obtain the 7 β-phenylacetylamino-3-formoxyl-3-cephem-4-diphenylmethyl carboxylate shown in formula (II).
Beneficial effect of the present invention is mainly reflected in:
1, this technique is with 7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylateFor initiation material, adopt oxidation, de-formylated method to prepare 7 β-phenylacetylamino-3-Nothing-3-cephalo-4-diphenylmethyl carboxylate, has raw material and is easy to get, and reactions steps is short, reaction conditionGentleness, quantity of three wastes is few, and target product purity is high, Atom economy high.
2, this technique is at 7 β-phenylacetylamino-3-formoxyl-3-cephem-4-diphenylmethyl carboxylatePiptonychia acylation process in, taking cheap sulfonyl azide reagent as CO capturing agent, greatly reduceNoble metal RhCl3Consumption, make reaction under catalytic condition, can carry out, thereby greatlyReduce production cost; Under the effect of bidentate organophosphorus ligand, greatly improved catalysis simultaneouslyAgent RhCl3Activity, make reaction under relatively lower temp, carry out, thereby improved reactionThe purity of selective and product.
3, this technique is at 7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylateOxidizing process in, with solid Ca (OCl)2For oxidant, accurate measurement, easy and simple to handle,Safe to use. The NaOCl aqueous solution with bibliographical information taking mass concentration as 17.9g/mlCompare for the reaction condition of oxidant, not needing to add KBr is cocatalyst, simultaneously canAvoid owing to adding the NaOCl aqueous solution, the dilution effect of generation causes the variation of system pH,Thereby the carrying out of impact reaction.
(4) brief description of the drawings
Fig. 1 is CN102617600, the 7 β-phenylacetylamino-3-reporting in US4647658The synthetic route chart of nothing-3-cephem-4-diphenylmethyl carboxylate;
Fig. 2 is US4269977, the 7 β-phenylacetylamino-3-reporting in CN101463039The synthetic route chart of nothing-3-cephem-4-diphenylmethyl carboxylate.
(5) detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described further, but protection of the present inventionScope is not limited in this:
The preparation of embodiment 1:7 β-phenylacetylamino-3-formoxyl-3-cephem-4-diphenylmethyl carboxylate
In 150mL four-hole boiling flask, add successively 30gCH2Cl2, 30g unsaturated carbonate hydrogenThe cushioning liquid (pH=9.5) of sodium and sodium carbonate, 0.047gTEMPO(0.3mmol) and5.14g7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylate (10Mmol). At 0 DEG C, in 10min, adding 2.62g effective chlorine content is 60%Ca(OCl)2(11mmol) solid, finishes, and continues stirring reaction 2h. After reaction finishes,It is 6.5 that reactant liquor is adjusted to pH by the hydrochloric acid solution that is 10% with mass fraction, separates organicLayer, water CH2Cl2(15mL × 2) extraction. The organic phase obtaining is used mass fraction successivelyBe 5% safety powder solution, saturated NaCl solution washing, anhydrous Na2SO4Dry. CrossFilter drier, decompression and solvent recovery, the solid obtaining is recrystallized with acetonitrile, true at 40 DEG CEmpty drying under reduced pressure. Finally obtain faint yellow solid 4.73g, yield 92.4%. HPLC detectsPurity 98.6%(HPLC area normalization method). M.p.143-144 DEG C (dec.);1HNMR(DMSO-d6)δ3.35(s,2H),3.39-3.61(m,2H),4.61-4.64(m,1H),4.77-4.4.80(m,1H),7.70(s,1H),7.18-7.51(m,15H),9.22(s,1H),13.18(s,1H);13CNMR(125Hz,DMSO-d6)δ21.7,41.6,59.4,60.0,80.0,122.8,126.52,126.63,127.12,128.11,128.21,128.23,128.50,128.56,128.98,135.60,138.20,138.91,139.15,159.8,165.7,170.9,187.6.ESI-MS(m/z):535.1[M+Na]+。
Embodiment 2:
The preparation of 7 β-phenylacetylamino-3-formoxyl-3-cephem-4-diphenylmethyl carboxylate: exceptThe pH value of saturated sodium bicarbonate and sodium carbonate cushioning liquid is outside 8.5, other operating conditionAll identical with embodiment 1, obtain faint yellow solid 4.35g, yield 85.0%, purity 98.0%.Embodiment 3:
The preparation of 7 β-phenylacetylamino-3-formoxyl-3-cephem-4-diphenylmethyl carboxylate: exceptReplace outside carrene with 1,2-dichloroethanes, other operating condition is all identical with embodiment 1,Obtain faint yellow solid 4.62g, yield 90.4%, purity 98.8%.
Embodiment 4:
The preparation of 7 β-phenylacetylamino-3-formoxyl-3-cephem-4-diphenylmethyl carboxylate: exceptReplace sodium acid carbonate and sodium carbonate buffering taking pH value as 9.5 ammonium chloride and ammoniacal liquor cushioning liquidOutside solution, other operating condition is all identical with embodiment 1, obtains faint yellow solid 4.58g,Yield 89.5%, purity 98.0%.
Embodiment 5:
The preparation of 7 β-phenylacetylamino-3-formoxyl-3-cephem-4-diphenylmethyl carboxylate: raw materialInventory and the enforcement of 7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylateExample 1 is identical, except 7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylate,Ca(OCl)2With the ratio of the amount of substance that feeds intake of TEMPO be outside 1:1.3:0.02, other behaviourMake condition all identical with embodiment 1, obtain faint yellow solid 4.12g, yield 80.5%, purity98.1%。
Embodiment 6:7 β-phenylacetylamino-3-is without the preparation of-3-cephalo-4-diphenylmethyl carboxylate
In tri-mouthfuls of reaction flasks of 50mL, under nitrogen protection, add successively 0.10g anhydrousRhCl3(0.5mmol), 0.29gXantPhos(0.5mmol) and the anhydrous tetrahydrochysene furan of 25gMutter, N2Under protection, after stirring at room temperature 10min, then add 5.12g7 β-phenylacetylamino-3-Formoxyl-3-cephem-4-diphenylmethyl carboxylate (10mmol) and 2.17g tolysulfonyl are foldedNitrogen (11mmol). Reactant liquor is warming up to 45 DEG C, stirring reaction 12h. After reaction finishes, anti-Answer liquid to be cooled to room temperature, add 50mL water, water CH2Cl2(25mL × 2) extraction.The salt acid elution that the organic phase merging is 5% through mass fraction successively, the saturated NaCl aqueous solutionWashing, activated carbon decolorizing, anhydrous Na2SO4Dry. Remove by filter drier, recovered under reduced pressureSolvent, ether that the dope obtaining is 1:1 by volume ratio/n-hexane recrystallization, true at 40 DEG CEmpty drying under reduced pressure. Finally obtain white solid 4.22g, yield 87.2%. HPLC detects pureDegree 99.2%(HPLC area normalization method). M.p.169-170℃(dec.);1HNMR(500Hz,DMSO-d6)δ3.51-3.61(m,2H),3.64-3.71(m,2H),5.09(d,J=5.5Hz),5.11(d,J=5.0Hz,1H),5.18(t,J=5.5Hz,1H),5.81(dd,J1=5.0Hz,J2=8.5Hz1H),6.78(dd,J1=3.5Hz,J2=6.0Hz1H),6.92(s,1H),7.23-7.58(m,15H),9.17(d,J=8.5Hz,1H);13CNMR(125Hz,DMSO-d6)δ23.7,41.6,57.1,59.3,78.1,122.6,126.21,126.44,126.62,126.77,127.69,127.91,128.18,128.43,128.54,128.98,135.8,139.9, 140.5,160.2,164.7,170.9.ESI-MS(m/z):507.2[M+Na]+。
Embodiment 7:
7 β-phenylacetylamino-3-is without the preparation of-3-cephalo-4-diphenylmethyl carboxylate: except withBINAP replaces outside XantPhos, and other operating condition is all identical with embodiment 6, obtains whiteLook solid 3.15g, yield 65.1%, purity 98.2%.
Embodiment 8:
7 β-phenylacetylamino-3-is without the preparation of-3-cephalo-4-diphenylmethyl carboxylate: except withDPEPhos replaces outside XantPhos, and other operating condition is all identical with embodiment 6, obtainsWhite solid 3.48g, yield 71.9%, purity 98.0%.
Embodiment 9:
7 β-phenylacetylamino-3-is without the preparation of-3-cephalo-4-diphenylmethyl carboxylate: except withDPPP replaces outside XantPhos, and other operating condition is all identical with embodiment 6, obtains whiteSolid 4.02g, yield 83.1%, purity 98.7%.
Embodiment 10:
7 β-phenylacetylamino-3-is without the preparation of-3-cephalo-4-diphenylmethyl carboxylate: except with first sulphurAcyl azide replaces outside p-toluene sulfonyt azide, and other operating condition is all identical with embodiment 6,To white solid 4.10g, yield 84.7%, purity 98.2%.
Embodiment 11:
7 β-phenylacetylamino-3-is without the preparation of-3-cephalo-4-diphenylmethyl carboxylate: raw material 7 β-benzeneIn the inventory and embodiment 6 of acetylaminohydroxyphenylarsonic acid 3-formoxyl-3-cephem-4-diphenylmethyl carboxylateIdentical, except 7 β-phenylacetylamino-3-formoxyl-3-cephem-4-diphenylmethyl carboxylate,RhCl3, bidentate organophosphorus ligand, sulfonyl azide the ratio of the amount of substance that feeds intake beOutside 1:0.03:0.03:1.2, other operating condition is all identical with embodiment 6, obtains white solid3.52g, yield 72.8%, purity 97.0%.
Claims (6)
1. a 7 β-phenylacetylamino-3-is without the preparation side of-3-cephem-4-diphenylmethyl carboxylateMethod, is characterized in that described preparation method is:
7 β-phenylacetylamino shown in modus ponens (II)-3-formoxyl-3-cephem-4-carboxylic acid hexichol firstEster, with anhydrous RhCl3For catalyst, bidentate organic phosphine reagent is part, sulfonyl azide classCompound is CO capturing agent, in absolute ether kind solvent, and under nitrogen protection, at 20～80 DEG C,Carry out piptonychia acylation reaction, HPLC follows the tracks of detection, and after reaction finishes, reactant liquor separates and obtains7 β-phenylacetylamino-3-shown in target product formula (III) is without-3-cephem-4-carboxylic acid hexichol firstEster; 7 β-phenylacetylamino shown in described formula (II)-3-formoxyl-3-cephem-4-carboxylic acid hexicholMethyl esters and RhCl3, bidentate organic phosphine reagent, sulfonyl azide compounds the amount of substance that feeds intakeThan being 1:0.03～0.1:0.03～0.1:1.0～1.5; Described bidentate organic phosphine reagent is selected from(2R, 3S)-2, two diphenyl phosphine-1 of 2'-, 1'-dinaphthalene, 4, two diphenylphosphine-9 of 5-, 9-dimethyl oxa-Two (diphenylphosphine) propane of anthracene, two [(2-diphenyl phosphine) phenyl] ether or 1,3-; Described sulphonyl is foldedNitrogen compound is selected from methylsulfonyl nitrine or p-toluene sulfonyt azide; Described ether solvent is selected from fourHydrogen furans;
2. 7 β-phenylacetylamino-3-as claimed in claim 1 is without-3-cephem-4-carboxylic acid twoThe preparation method of benzene methyl, is characterized in that 7 β-phenylacetylamino-3-shown in described formula (II)The mass ratio that feeds intake of formoxyl-3-cephem-4-diphenylmethyl carboxylate and ether solvent is 1:3～7.
3. 7 β-phenylacetylamino-3-as claimed in claim 1 is without-3-cephem-4-carboxylic acid twoThe preparation method of benzene methyl, is characterized in that the separation method of described reactant liquor is: reaction finishesAfter, reactant liquor is cooled to room temperature, adds water, uses CH2Cl2Extraction, the organic phase of merging is complied withInferior to the HCl aqueous solution, saturated NaCl solution washing, activated carbon decolorizing, anhydrous Na2SO4Dry, to filter, filtrate decompression reclaims solvent, the residue obtained ether that is 1:1 by volume ratio/N-hexane mixed solvent recrystallization, the solid of recrystallization gained vacuum decompression at 40 DEG C is dry,Obtain the 7 β-phenylacetylamino-3-shown in formula (III) without-3-cephem-4-diphenylmethyl carboxylate.
4. 7 β-phenylacetylamino-3-as claimed in claim 1 is without-3-cephem-4-carboxylic acid twoThe preparation method of benzene methyl, is characterized in that 7 β-phenylacetylamino-3-shown in described formula (II)Formoxyl-3-cephem-4-diphenylmethyl carboxylate makes as follows: with 7 β shown in formula (I)-Phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylate is raw material, effective chlorine qualityMark is that 60% calcium hypochlorite is oxidant, and 2,2,6,6-tetramethyl piperidine oxide is catalysisAgent, in the cushioning liquid that is 8.5～11 in pH value and the mixed solvent of halogenated hydrocarbons, at-5～10 DEG CUnder carry out oxidation reaction, HPLC follows the tracks of detection, reaction finish after, reactant mixture through separateObtain the 7 β-phenylacetylamino shown in formula (II)-3-formoxyl-3-cephem-4-carboxylic acid hexichol firstEster; 7 β-phenylacetylamino shown in described formula (I)-3-methylol-3-cephem-4-carboxylic acid hexicholMethyl esters and calcium hypochlorite, 2,2,6, the amount of substance ratio that feeds intake of 6-tetramethyl piperidine oxide is1:1.1～1.5:0.01～0.1; 7 β-phenylacetylamino shown in described formula (I)-3-methylol-3-cephaloThe mass ratio that feeds intake of alkene-4-diphenylmethyl carboxylate and cushioning liquid, halogenated hydrocarbons is 1:4～10:4～10;Described halogenated hydrocarbons is selected from carrene or 1,2-dichloroethanes;
5. 7 β-phenylacetylamino-3-as claimed in claim 4 is without-3-cephem-4-carboxylic acid twoThe preparation method of benzene methyl, is characterized in that the buffer of described cushioning liquid is selected fromNaHCO3/Na2CO3、NaHCO3/Na2CO3、KHCO3/K2CO3、KHCO3/KOHOr NH4Cl/NH3·H2O。
6. the 7 β-phenylacetylamino-3-as described in claim 4 or 5 is without-3-cephem-4-carboxylicThe preparation method of acid benzhydryl ester, is characterized in that the method that described reactant mixture separates is:After reaction finishes, in reactant mixture, dripping the HCl aqueous solution to pH value is 6～7, separatesOrganic layer, water layer is used when reacting halogenated hydrocarbon solvent extraction identical in mixed solvent, is associated withMachine phase, organic phase is used the 5wt% sodium hydrosulfite aqueous solution, saturated NaCl solution washing successively,Anhydrous Na2SO4Dry, to filter, filtrate decompression reclaims solvent, the residue obtaining acetonitrile weightCrystallization, the solid of recrystallization gained vacuum decompression at 40 DEG C is dry, obtains shown in formula (II)7 β-phenylacetylamino-3-formoxyl-3-cephem-4-diphenylmethyl carboxylate.
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