US20040132995A1 - Process for the preparation of cephalosporins - Google Patents
Process for the preparation of cephalosporins Download PDFInfo
- Publication number
- US20040132995A1 US20040132995A1 US10/700,679 US70067903A US2004132995A1 US 20040132995 A1 US20040132995 A1 US 20040132995A1 US 70067903 A US70067903 A US 70067903A US 2004132995 A1 US2004132995 A1 US 2004132995A1
- Authority
- US
- United States
- Prior art keywords
- formula
- compound
- solvent
- xiii
- produce
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 229930186147 Cephalosporin Natural products 0.000 title claims abstract description 15
- 229940124587 cephalosporin Drugs 0.000 title claims abstract description 15
- 150000001780 cephalosporins Chemical class 0.000 title claims abstract description 10
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 5
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 47
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 8
- -1 p-methoxybenzyl Chemical group 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- 239000001632 sodium acetate Substances 0.000 claims description 8
- 235000017281 sodium acetate Nutrition 0.000 claims description 8
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 235000017550 sodium carbonate Nutrition 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- 229940002612 prodrug Drugs 0.000 claims description 6
- 239000000651 prodrug Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 5
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 229910019213 POCl3 Inorganic materials 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 239000012973 diazabicyclooctane Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical class C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 claims description 3
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- ITLHXEGAYQFOHJ-UHFFFAOYSA-N [diazo(phenyl)methyl]benzene Chemical group C=1C=CC=CC=1C(=[N+]=[N-])C1=CC=CC=C1 ITLHXEGAYQFOHJ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 229950003588 axetil Drugs 0.000 claims description 2
- 238000007257 deesterification reaction Methods 0.000 claims description 2
- 150000001983 dialkylethers Chemical class 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- BXBPNSQUZBBTQT-UHFFFAOYSA-N n,n-dimethylacetamide;methylsulfinylmethane Chemical compound CS(C)=O.CN(C)C(C)=O BXBPNSQUZBBTQT-UHFFFAOYSA-N 0.000 claims description 2
- KGCNHWXDPDPSBV-UHFFFAOYSA-N p-nitrobenzyl chloride Chemical compound [O-][N+](=O)C1=CC=C(CCl)C=C1 KGCNHWXDPDPSBV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 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
- 229950009297 pivoxil Drugs 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229950000033 proxetil Drugs 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- ASFAFOSQXBRFMV-LJQANCHMSA-N 3-n-(2-benzyl-1,3-dihydroxypropan-2-yl)-1-n-[(1r)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzene-1,3-dicarboxamide Chemical compound N([C@H](C)C=1C=CC(F)=CC=1)C(=O)C(C=1)=CC(N(C)S(C)(=O)=O)=CC=1C(=O)NC(CO)(CO)CC1=CC=CC=C1 ASFAFOSQXBRFMV-LJQANCHMSA-N 0.000 claims 1
- 0 *C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\C)C3=CSC(N)=N3)C2SC1 Chemical compound *C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\C)C3=CSC(N)=N3)C2SC1 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- GHKGOBUFEGRMJW-FQNRMIAFSA-N (6r)-3-(methoxymethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound C1([C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)NC(=O)CC1=CC=CC=C1 GHKGOBUFEGRMJW-FQNRMIAFSA-N 0.000 description 5
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 5
- WYUSVOMTXWRGEK-WCRCJTMVSA-N (6r)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound C1([C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)NC(=O)C(=NOC)C1=CSC(N)=N1 WYUSVOMTXWRGEK-WCRCJTMVSA-N 0.000 description 4
- BDSDFCVDQUGOFB-XNCJUZBTSA-N (6s,7s)-7-amino-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(COC)=C(C(O)=O)N2C(=O)[C@H](N)[C@H]12 BDSDFCVDQUGOFB-XNCJUZBTSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 4
- LTINZAODLRIQIX-FBXRGJNPSA-N cefpodoxime proxetil Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(=O)OC(C)OC(=O)OC(C)C)C(=O)C(=N/OC)\C1=CSC(N)=N1 LTINZAODLRIQIX-FBXRGJNPSA-N 0.000 description 3
- 229960004797 cefpodoxime proxetil Drugs 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- MASDFXZJIDNRTR-UHFFFAOYSA-N 1,3-bis(trimethylsilyl)urea Chemical compound C[Si](C)(C)NC(=O)N[Si](C)(C)C MASDFXZJIDNRTR-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- RYPRBDZZJFPXLB-UHFFFAOYSA-N N-methylsilylacetamide Chemical compound C[SiH2]NC(C)=O RYPRBDZZJFPXLB-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 150000003585 thioureas Chemical class 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- QWNGESOREPKWTG-DAXSKMNVSA-N (2z)-4-chloro-2-methoxyimino-3-oxobutanoic acid Chemical compound CO\N=C(/C(O)=O)C(=O)CCl QWNGESOREPKWTG-DAXSKMNVSA-N 0.000 description 1
- PPIZNAHHLNIUMJ-YWEYNIOJSA-N (2z)-4-chloro-2-methoxyimino-3-oxobutanoyl chloride Chemical compound CO\N=C(/C(Cl)=O)C(=O)CCl PPIZNAHHLNIUMJ-YWEYNIOJSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- FBCIZEKGBSORCR-UHFFFAOYSA-N CC1=NC(=O)C(=O)NN1C.CC1=NC(=O)C(O)=NN1C Chemical compound CC1=NC(=O)C(=O)NN1C.CC1=NC(=O)C(O)=NN1C FBCIZEKGBSORCR-UHFFFAOYSA-N 0.000 description 1
- IPXLOJANOVAEAK-NPOCFXBGSA-M CCC(=O)/C(=N/OC)C(=O)NC1C(=O)N2C(C)=C(CSC)CSC12.CCC(=O)/C(=N/OC)C(=O)O.CO/N=C(\C(=O)NC1C(=O)N2C(C)=C(CSC)CSC12)C1=CSC(N)=N1.CSCC1=C(C)N2C(=O)C(N)C2SC1.II.I[IH]I.NC(N)=S.[V].[V]I Chemical compound CCC(=O)/C(=N/OC)C(=O)NC1C(=O)N2C(C)=C(CSC)CSC12.CCC(=O)/C(=N/OC)C(=O)O.CO/N=C(\C(=O)NC1C(=O)N2C(C)=C(CSC)CSC12)C1=CSC(N)=N1.CSCC1=C(C)N2C(=O)C(N)C2SC1.II.I[IH]I.NC(N)=S.[V].[V]I IPXLOJANOVAEAK-NPOCFXBGSA-M 0.000 description 1
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- MGCGFOMPXPVARB-UHFFFAOYSA-N CSC1=NC(=O)C(O)=NN1C Chemical compound CSC1=NC(=O)C(O)=NN1C MGCGFOMPXPVARB-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- XCOBLONWWXQEBS-KPKJPENVSA-N N,O-bis(trimethylsilyl)trifluoroacetamide Chemical compound C[Si](C)(C)O\C(C(F)(F)F)=N\[Si](C)(C)C XCOBLONWWXQEBS-KPKJPENVSA-N 0.000 description 1
- MSPCIZMDDUQPGJ-UHFFFAOYSA-N N-methyl-N-(trimethylsilyl)trifluoroacetamide Chemical compound C[Si](C)(C)N(C)C(=O)C(F)(F)F MSPCIZMDDUQPGJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000004133 Sodium thiosulphate Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001734 carboxylic acid salts Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229960005090 cefpodoxime Drugs 0.000 description 1
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000005828 desilylation reaction Methods 0.000 description 1
- OSXYHAQZDCICNX-UHFFFAOYSA-N dichloro(diphenyl)silane Chemical compound C=1C=CC=CC=1[Si](Cl)(Cl)C1=CC=CC=C1 OSXYHAQZDCICNX-UHFFFAOYSA-N 0.000 description 1
- KTQYJQFGNYHXMB-UHFFFAOYSA-N dichloro(methyl)silicon Chemical compound C[Si](Cl)Cl KTQYJQFGNYHXMB-UHFFFAOYSA-N 0.000 description 1
- LIKFHECYJZWXFJ-UHFFFAOYSA-N dimethyldichlorosilane Chemical compound C[Si](C)(Cl)Cl LIKFHECYJZWXFJ-UHFFFAOYSA-N 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000005048 methyldichlorosilane Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 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
Definitions
- the present invention relates to a process for the preparation of cephalosporin antibiotics of the formula (I)
- R 1 represents hydrogen, trityl, CH 3 , CR a R b COOR c where R a and R b independently represent hydrogen or methyl and R c represents hydrogen or (C 1 -C 6 )alkyl;
- R 2 represents CH 3 , CH 2 OCH 3 , CH 2 OCOCH 3 , CH ⁇ CH 2 ,
- EP 0030294 discloses a process for the preparation of compound of cephalosporin antibiotic as given in scheme 1:
- R represents hydrogen atom or a readily hydrolysable ester group and X represents one of the groups
- EP patent 0 842 937 discloses a process for the preparation of compound of cephalosporin antibiotic as given in scheme 2:
- WO 00/63214 discloses a process for the preparation of cephalosporins by condensation of carboxy ester intermediate with silylated thiourea.
- X and R 1 are substituents useful in cephalosporin chemistry and R E is hydrogen, a negative charge or together with the COO— group to which R E is attached is an ester, Y is halogen; R′ is hydrogen or silyl and R′′ is silyl; R′ E is silyl or together with the COO— group to which R E is attached is an ester.
- This patent publication discloses an alternate process, which involves the desilylation of compound of formula (II) and then condensation of desilylated compound with thiourea.
- WO 02/083634 discloses a process for the preparation of cefpodoxime of formula (XII), as shown in scheme 3 below:
- R is hydrogen or silyl group and R′ is silyl group or COOR′ is a carboxylic acid salt; X is halogen.
- the process comprises reacting the compound of formula (IX) with compound of formula (III) and desilylating the compound of formula (X) and cyclizing the desilylated compound with thiourea to produce cefpodoxime acid of formula (XII).
- the primary objective of the invention is to provide a new method for the preparation of cephalosporin antibiotics of the formula (I), which would be easy to implement in commercial scales.
- the present invention provides a process for the preparation of cephalosporin antibiotics of the formula (I) or its esters, which form prodrug or a counter ion which forms salt
- R 1 represents hydrogen, trityl, CH 3 , CR a R b COOR c where R a and R b independently represent hydrogen or methyl and R c represents hydrogen or (C 1 -C 6 )alkyl;
- R 2 represents hydrogen, CH 3 , CH 2 OCH 3 , CH 2 OCOCH 3 , CH ⁇ CH 2 , CH 2 OCONH 2 ,
- the compound of formula (XIII) can be prepared by a process, which comprises esterifying the compound of the formula (XVIII) using an esterifying agent in the presence of a solvent and base.
- R represents lower alkyl, p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group and R 2 is as defined above.
- X represents halogen atom such as chlorine or bromine
- R represents p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group
- R 2 represents hydrogen, CH 3 , CH 2 OCH 3 , CH 2 OCOCH 3 , CH ⁇ CH 2 , CH 2 OCONH 2 ,
- the condensation of compound of formula (III) with (XIII) is performed by using the activated derivative of formula (III) in the presence of a solvent selected from dichloromethane, ethyl acetate, tetrahydrofuran, aromatic hydrocarbon, acetone, dioxane, acetonitrile, DMAc, N,N-dimethylformamide, dialkylethers, water or mixtures thereof.
- a solvent selected from dichloromethane, ethyl acetate, tetrahydrofuran, aromatic hydrocarbon, acetone, dioxane, acetonitrile, DMAc, N,N-dimethylformamide, dialkylethers, water or mixtures thereof.
- the compound of formula (III) is activated as acid halides, mixed anhydrides, active esters, active amides.
- the acid halides are acid chlorides or acid bromides.
- the mixed anhydrides are anhydrides of the compounds of formula (III) with pivaloyl chloride, ethyl chloroformate, benzyl chloroformate.
- the silylation of 7-amino cephalosporin of the formula (XIII) is carried out using silylating agent selected from hexamethyldisilazane (HMDS), trimethylchlorosilane (TMCS), trimethylsilyl iodide (TMSI), N,O-bis-(trimethylsilyl)-acetamide (BSA), methyltrimethylsilyltrifluoroacetamide (MSTFA), N,O-bistrimethylsilyltrifiuoroacetamide (BSTFA), methyldichlorosilane, dimethyldichlorosilane, diphenyldichlorosilane, N-methylsilylacetamide (MSA), bistrimethylsilylurea and the like.
- silylating agent selected from hexamethyldisilazane (HMDS), trimethylchlorosilane (TMCS), trimethylsilyl iodide (TMSI), N,O-bis-(tri
- the cyclisation of compound of (XIV) is carried out using solvents selected from water, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C 1 -C 3 )alcohol and the like or mixtures thereof.
- the deesterification of compound of formula (XV) is carried out using anisole/trifluoroacetic acid, phenol/trifluoroacetic acid, formic acid in the absence or presence of dichloromethane, dichloroethane as a solvent.
- the pharmaceutically acceptable salt is sodium or hydrochloride.
- the prodrug ester is proxetil, axetil, hexetil, pivoxil and the like.
- the solvent used for reacting the compound of formula (XVI) in step (i) of scheme-5 is selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C 1 -C 3 )alcohol or mixtures thereof, in the presence of a base selected from sodium acetate, potassium carbonate, triethylamine, 1,4-diazabicyclo-[2,2,2]-octane (DABCO), 1,5-diazabicyclo[4,3,0]-non-5-ene (DBN), 1,8-diaza-bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate.
- a base selected from sodium acetate, potassium carbonate, triethylamine, 1,4-diazabicyclo-[2,2,2]-octane (DABCO), 1,5-diazabic
- the acylation of compound of formula (XVIII) in step (i) of scheme-6 is carried out in the presence of solvent selected from toluene, xylene, benzene, methylene dichloride, chloroform, ethyl acetate and the like.
- the esterification of compound of formula (XIX) in step (ii) of scheme-6 is carried out using esterifying agents such as diphenyl diazomethane, alkyl halide, p-methoxybenzyl chloride, p-nitrobenzyl chloride and a solvent selected from methylene dichloride, chloroform, ethyl acetate, toluene, water, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide N,N-dimethylacetamide, dioxane, (C 1 -C 3 )alcohol or mixtures thereof, in the presence of catalytic quantities of iodine.
- the reaction is carried out in the presence of base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
- the solvent used for reaction in scheme-7 is selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C 1 -C 3 )alcohol or mixtures thereof, in the presence of a base selected from sodium acetate, potassium carbonate, triethylamine, 1,4-diazabicyclo-[2,2,2]-octane (DABCO), 1,5-diazabicyclo[4,3,0]-non-5-ene (DBN), 1,8-diaza-bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate.
- a base selected from sodium acetate, potassium carbonate, triethylamine, 1,4-diazabicyclo-[2,2,2]-octane (DABCO), 1,5-diazabicyclo[4,3,0]-non-5-ene
- R 3 in Scheme-5 is selected from methyl, methoxy, nitro or halogen atom.
- the product obtained in any of the reactions may be used in next step without isolation.
- step V Addition of trifluoro acetic acid (20.75 g) to a stirred solution of phenol (125 mL) and 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid p-methoxy benzyl ester obtained in step V (50 gm) at 40° C. over 20-30 minutes. The reaction mixture was maintained at 40-45° C. for 2-4 hours. Monitored the reaction by HPLC. After completion of the reaction, the reaction mixture was cooled to 25-30° C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The present invention relates to a process for the preparation of cephalosporin antibiotics of the formula (I)
Description
- This application is a continuation in part of pending U.S. application Ser. No. 10/207,103 filed on Jul. 30, 2002.
- The present invention relates to a process for the preparation of cephalosporin antibiotics of the formula (I)
- wherein R 1 represents hydrogen, trityl, CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6)alkyl; R2 represents CH3, CH2OCH3, CH2OCOCH3, CH═CH2,
- EP 0030294 discloses a process for the preparation of compound of cephalosporin antibiotic as given in scheme 1:
- wherein R represents hydrogen atom or a readily hydrolysable ester group and X represents one of the groups
- EP patent 0 842 937 discloses a process for the preparation of compound of cephalosporin antibiotic as given in scheme 2:
- wherein R is
- WO 00/63214 discloses a process for the preparation of cephalosporins by condensation of carboxy ester intermediate with silylated thiourea.
- wherein X and R 1 are substituents useful in cephalosporin chemistry and RE is hydrogen, a negative charge or together with the COO— group to which RE is attached is an ester, Y is halogen; R′ is hydrogen or silyl and R″ is silyl; R′E is silyl or together with the COO— group to which RE is attached is an ester.
- This patent publication discloses an alternate process, which involves the desilylation of compound of formula (II) and then condensation of desilylated compound with thiourea.
- WO 02/083634 discloses a process for the preparation of cefpodoxime of formula (XII), as shown in scheme 3 below:
- wherein R is hydrogen or silyl group and R′ is silyl group or COOR′ is a carboxylic acid salt; X is halogen. The process comprises reacting the compound of formula (IX) with compound of formula (III) and desilylating the compound of formula (X) and cyclizing the desilylated compound with thiourea to produce cefpodoxime acid of formula (XII).
- The primary objective of the invention is to provide a new method for the preparation of cephalosporin antibiotics of the formula (I), which would be easy to implement in commercial scales.
- Accordingly, the present invention provides a process for the preparation of cephalosporin antibiotics of the formula (I) or its esters, which form prodrug or a counter ion which forms salt
- wherein R 1 represents hydrogen, trityl, CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6)alkyl; R2 represents hydrogen, CH3, CH2OCH3, CH2OCOCH3, CH═CH2, CH2OCONH2,
- which comprises:
- (i) condensing the activated derivative of the formula (III) where X represents halogen atom such as chlorine or bromine, with silylated derivative of 7-amino cephalosporin of the formula (XIII) wherein R represents lower alkyl, p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group in the presence of a solvent at a temperature in the range of −50° C. to 0° C. to produce a compound of formula (XIV), where R is as defined earlier,
- (ii) cyclising the compound of formula (XIV) with thiourea in the presence of solvent and sodium acetate at room temperature to produce cephalosporin compound of the formula (XV) wherein R is as defined earlier,
- (iii) deesterifying the compound of formula (XV) using anisole/trifluoroacetic acid, phenol/trifluoroacetic acid, formic acid in the presence or absence of a solvent at a temperature in the range of 0° C. to 60° C. to produce a compound of formula (I) and
- (iv) converting the compound of formula (I), to its pharmaceutically acceptable salt or its esters which form prodrug.
- The process is shown in Scheme-4 below
- In yet another embodiment of the present invention, there is provided a process for the preparation of compound of formula (XIII)
- which comprises:
- (i) reacting the 7-aminocephalosporin derivative of the formula (XVI) wherein R 3 represents hydrogen, (C1-C4)alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy with R2—X, wherein X represents halogen atom and R2 is as defined earlier in the presence in an organic solvent and a base at a temperature in the range of 0° C. to 30° C. to produce 7-aminocephalosporin derivative of the formula (XVII),
- (ii) deacylating the compound formula (XVII) using PCl 5/POCl3/pyridine, PCl5/pyridine, triphenyl phosphite/Cl2 complexes in the presence of an alcohol, at a temperature in the range of −40° C. to 0° C. to produce a compound of the formula (XIII) and
- (iii) isolating the compound of formula (XIII).
- The process is shown in Scheme-5 below
- In yet another embodiment of the present invention, there is provided a process for the preparation of compound of formula (XIII)
- which comprises:
- (i) acylating the 7-aminocephalosporin derivative of the formula (XVIII) phenyl acetyl chloride to produce compound of formula (XIX) in the presence of an organic solvent at a temperature in the range of −20° C. to 30° C.,
- (ii) esterifying the compound of formula (XIX) using an esterifying agent in the presence of a solvent and a base at a temperature in the range of 25° C. to 50° C. to produce a compound of formula (XX)
- (iii) deacylating the compound of formula (XX) using PCl 5/POCl3/pyridine, PCl5/pyridine, triphenyl phosphite/Cl2 complexes in the presence of an alcohol, at a temperature in the range of −40° C. to 0° C. to produce a compound of the formula (XIII) and
- (iv) isolating the compound of formula (XIII).
- The process is shown in Scheme-6 below
- In still another embodiment of the present invention the compound of formula (XIII), can be prepared by a process, which comprises esterifying the compound of the formula (XVIII) using an esterifying agent in the presence of a solvent and base.
- The process is as shown in Scheme-7 below
- wherein R represents lower alkyl, p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group and R 2 is as defined above.
- In another embodiment of the present invention, there is provided a new intermediate of the formula (XIV)
- wherein X represents halogen atom such as chlorine or bromine; R represents p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group; R 2 represents hydrogen, CH3, CH2OCH3, CH2OCOCH3, CH═CH2, CH2OCONH2,
- In yet another embodiment of the present invention, the condensation of compound of formula (III) with (XIII) is performed by using the activated derivative of formula (III) in the presence of a solvent selected from dichloromethane, ethyl acetate, tetrahydrofuran, aromatic hydrocarbon, acetone, dioxane, acetonitrile, DMAc, N,N-dimethylformamide, dialkylethers, water or mixtures thereof.
- The compound of formula (III) is activated as acid halides, mixed anhydrides, active esters, active amides. The acid halides are acid chlorides or acid bromides. The mixed anhydrides are anhydrides of the compounds of formula (III) with pivaloyl chloride, ethyl chloroformate, benzyl chloroformate.
- In yet another embodiment of the present invention, the silylation of 7-amino cephalosporin of the formula (XIII) is carried out using silylating agent selected from hexamethyldisilazane (HMDS), trimethylchlorosilane (TMCS), trimethylsilyl iodide (TMSI), N,O-bis-(trimethylsilyl)-acetamide (BSA), methyltrimethylsilyltrifluoroacetamide (MSTFA), N,O-bistrimethylsilyltrifiuoroacetamide (BSTFA), methyldichlorosilane, dimethyldichlorosilane, diphenyldichlorosilane, N-methylsilylacetamide (MSA), bistrimethylsilylurea and the like.
- In yet another embodiment of the present invention, the cyclisation of compound of (XIV) is carried out using solvents selected from water, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C 1-C3)alcohol and the like or mixtures thereof.
- In still another embodiment of the present invention the deesterification of compound of formula (XV) is carried out using anisole/trifluoroacetic acid, phenol/trifluoroacetic acid, formic acid in the absence or presence of dichloromethane, dichloroethane as a solvent.
- In another embodiment of the present invention, the pharmaceutically acceptable salt is sodium or hydrochloride.
- In yet another embodiment of the present invention the prodrug ester is proxetil, axetil, hexetil, pivoxil and the like.
- In another embodiment of the present invention, the solvent used for reacting the compound of formula (XVI) in step (i) of scheme-5 is selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C 1-C3)alcohol or mixtures thereof, in the presence of a base selected from sodium acetate, potassium carbonate, triethylamine, 1,4-diazabicyclo-[2,2,2]-octane (DABCO), 1,5-diazabicyclo[4,3,0]-non-5-ene (DBN), 1,8-diaza-bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate.
- In another embodiment of the present invention, the acylation of compound of formula (XVIII) in step (i) of scheme-6 is carried out in the presence of solvent selected from toluene, xylene, benzene, methylene dichloride, chloroform, ethyl acetate and the like.
- In another embodiment of the present invention, the esterification of compound of formula (XIX) in step (ii) of scheme-6 is carried out using esterifying agents such as diphenyl diazomethane, alkyl halide, p-methoxybenzyl chloride, p-nitrobenzyl chloride and a solvent selected from methylene dichloride, chloroform, ethyl acetate, toluene, water, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide N,N-dimethylacetamide, dioxane, (C 1-C3)alcohol or mixtures thereof, in the presence of catalytic quantities of iodine. The reaction is carried out in the presence of base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
- In another embodiment of the present invention, the solvent used for reaction in scheme-7 is selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C 1-C3)alcohol or mixtures thereof, in the presence of a base selected from sodium acetate, potassium carbonate, triethylamine, 1,4-diazabicyclo-[2,2,2]-octane (DABCO), 1,5-diazabicyclo[4,3,0]-non-5-ene (DBN), 1,8-diaza-bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate.
- The substituent on R 3 in Scheme-5 is selected from methyl, methoxy, nitro or halogen atom.
- In yet another embodiment of the present invention, the product obtained in any of the reactions may be used in next step without isolation.
- The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.
- Step I
- Preparation of 7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic Acid
- 7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid (7-AMCA) (100 gm) was reacted with N,O-bis silyl acetamide (103.9 gm) in presence of methylene dichloride (300 mL) at RT for 1 hour under nitrogen atmosphere. The silylated mass was cooled to −10 to −15° C. To this phenyl acetyl chloride (95 gm) was added over 30 minutes, and stirred for 1 hour. After completion of the reaction, chilled water (1000 mL) was added at −10 to −15° C., distilled off methylene chloride under vacuum at 10-12° C. for 30 minutes. Filtered the product and washed with isopropyl ether (1000 mL) and dried under vacuum 40-45° C. till to get the title compound (123 g, purity 95%).
- Step II
- Preparation of 7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic Acid p-methoxy Benzyl Ester
- p-Methoxy benzyl chloride (66 g) was stirred with sodium iodide (41.4 g) in presence of dimethyl sulfoxide (200 mL) for 1 hour at 25-30° C. To this 7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid (100 gm) obtained in step I and sodium bicarbonate (35.3 g) was added and stirred for 25-30° C. for 5-7 hours. After completion of the reaction, the reaction mass was cooled to 20° C. and added DM water (2.5 L) containing sodium thiosulphate (10 gm). The reaction mixture was stirred for 30 min. at 25-30° C., filtered the product and washed with DM water (500 mL). Finally stirred the product with methanol (600 mL) at −5° C. and filtered, dried the product under vacuum 40-45° C. till moisture less than 2% to get the title compound (120 gm, purity 96%).
- Step III
- Preparation of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic Acid p-methoxy Benzyl Ester
- To a suspension of PCl 5 (6.5 gm) in MDC (100 mL), pyridine (2.5 gm) was added under ice cooling and the resulting suspension was stirred at this temperature for 30 minutes. To this 7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid p-methoxy benzyl ester (10 g) obtained in step II was added at below 0° C. After stirring at 0° C. for 90-120 min, the reaction mixture was cooled to −40° C. To the cooled mixture pre-cooled methanol (30 mL, 3 volumes) was added below −10° C. for 30 minutes. After being stirred at 0° C. for 30 minutes, the mixture was concentrated at 45° C. to get residue. This residue was triturated with water (10 mL), EtOAc (40 mL) and isopropyl ether (IPE) (40 mL). The resulting precipitate was collected by filtration, washed with IPE and dried to get the title compound (6.5 gm, >98%).
- Step IV
- Preparation of 7-[(2-(syn)methoxyimino-3-oxo-4-chlorobutyrylamino]-3-methoxymethyl-3-cephem-4-carboxylic Acid p-methoxy Benzyl Ester
- To a suspension of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid p-methoxy benzyl ester (10 g), in MDC (50 mL, 5 volumes) obtained in step III, BSA (10 g) was added at 30° C. for 30 minutes. After stirring at 30° C. for 50-60 minutes solution was cooled to −30° C.
- Meanwhile in another flask to a suspension of PCl 5 (7.89 g) in MDC (50 mL, 5 volumes), 4-chloro-2(Z)-methoxyimino-3-oxo-butyric acid chloride (6.759) was added in four lots at 0 to −10° C. The resulting clear solution was added to the above silylated solution at −30 to −20° C. for 10-15 minutes time. After being stirred for another 15 minutes at same temperature, chilled water (100 ml, 5 volumes) was added for 5 minutes time. Concentrated the separated organic layer at 40-45° C. to get residue, which is triturated, with IPE (100 mL) to get the title compound (9.0 gm, 90%).
- Step V
- Preparation of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3 methoxymethyl-3-cephem-4-carboxylic Acid p-methoxy Benzyl Ester
- To a mixture of THF (50 mL) and water (50 mL), 7-[(2-(syn)methoxyimino-3-oxo-4-chlorobutyrylamino]-3-methoxymethyl-3-cephem-4-carboxylic acid p-methoxy benzyl ester (10 g) obtained in step IV was added at 30° C. To this thiourea (1.74 g) and sodium acetate (7.8 gm) at 30° C. was added and the resulting solution was stirred at 30° C. for 8-10 hours. After extracting the mixture with methylene dichloride (MDC) (100 mL), the resulting MDC layer was concentrated at 40° C. to get residue. This residue was crystallized with MDC-IPE (1:5) mixture to get the title compound (9.5 g, 90%).
- Step VI
- Preparation of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic Acid (Cefpodoxime Acid)
- Addition of trifluoro acetic acid (20.75 g) to a stirred solution of phenol (125 mL) and 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid p-methoxy benzyl ester obtained in step V (50 gm) at 40° C. over 20-30 minutes. The reaction mixture was maintained at 40-45° C. for 2-4 hours. Monitored the reaction by HPLC. After completion of the reaction, the reaction mixture was cooled to 25-30° C. and chilled water (250 mL), ethyl acetate (250 mL) was added and adjusted the pH to 7.3-7.5 with 25% Na 2CO3 solution (90 mL) at 20° C. Stirred and separated the layers and extracted the aqueous layer with ethyl acetate (250 mL) and separated the layers. Adjusted the pH to 5.8 with 10% H2SO4 solution and charged carbon (10 gm), sodium dithionite (0.35 gm), and stirred the reaction mixture for 1 hour. Filtered and washed with water (50 mL). Adjusted the pH to 2.8 with 10% H2SO4 solution at 20-25° C. and stirred the reaction mixture at 5° C. for 3 hours. Filtered the product and washed with chilled acetone (−5 to −10° C., 100 mL) and suck dried to get the title compound (20 gm, purity>98%).
- Step I
- Preparation of 7-[(2-(syn)methoxyimino-3-oxo-4-chlorobutyrylamino]-3-methoxymethyl-3-cephem-4-carboxylic Acid p-methoxy Benzyl Ester
- To a suspension of PCl 5 (6.5 gm) in MDC (100 mL), pyridine (2.5 gm) was added under ice cooling and the resulting suspension was stirred at this temperature for 30 minutes. To this 7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid p-methoxy benzyl ester (10 g) obtained in step II was added at below 0° C. After stirring at 0° C. for 90-120 min, the reaction mixture was cooled to −40° C. To the cooled mixture pre-cooled methanol (30 mL, 3 volumes) was added below −10° C. for 30 minutes. After being stirred at 0° C. for 60 minutes, the mixture temperature was taken to −20° C. and charged 20 ml of water below −10° C. The pH of the mass is adjusted to 4-4.5 by adding 25% of sodium carbonate solution (40 ml) keeping the temperature below −5° C. The temperature of the reaction mass is raised to 30° C. in 30-40 min. The layers were separated and to the organic layer was added Bis-(trimethylsilyl)urea (BSU) 8.5 g. The mass was stirred for 2-3 Hrs at 30° C.
- The mixture was cooled to −30° C. Meanwhile in another flask to a suspension of PCl 5 (6.5 g) in MDC (50 mL, 5 volumes), 4-chloro-2(Z)-methoxyimino-3-oxo-butyric acid (5.6 g) was added in four lots at 0 to −10° C. The resulting clear solution was added to the above silylated solution at −30 to −20° C. for 10-15 minutes time. After being stirred for another 15 minutes at same temperature, chilled water (100 m, 10 volumes) was added in 5-10 minutes. The temperature of the mass was raised to 30° C. over a period of 30-40 min. The layers were separated and the organic layer was treated with sodium carbonate solution to bring its pH to 5.8-6.2. Again the layers were separated and the organic layer was concentrated at 40-45° C. under vacuum to get residue, which is triturated, with IPE (100 mL) to get the title compound (8.0 gm, purity>85%)
- Step II
- Preparation of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic Acid (Cefpodoxime Acid)
- To a mixture of THF (50 mL) and water (50 mL), 7-[(2-(syn)methoxyimino-3-oxo-4-chlorobutyrylamino]-3-methoxymethyl-3-cephem-4-carboxylic acid p-methoxy benzyl ester (10 g) obtained in step III was added at 30° C. To this thiourea (1.74 g) and sodium acetate (7.8 gm) at 30° C. was added and the resulting solution was stirred at 30° C. for 8-10 hours. After extracting the mixture with methylene dichloride (MDC) (100 mL), the resulting MDC layer was concentrated at 40° C. to get residue. To this residue was added phenol (25 mL) at 40-45° C. Trifluoro acetic acid (4.2 g) was added to the above mixture in 20-25 min at 40-45° C. The reaction mass was stirred for 4-5 Hrs and finally poured into a mixture of ethyl acetate (50 ml) and water (50 ml). The pH of the reaction mass was adjusted to 8.5 with 25% sodium carbonate solution at 30° C. The layers were separated. The aqueous layer was again washed with 50 ml of ethyl acetate. Finally the aqueous layer is treated with charcoal (1.0 g), charcoal is filtered off and to the clear filtrate dilute sulfuric acid is added to bring the pH to 2.6-2.8. The mixture was cooled to 5° C. and product was collected by filtration and washed with acetone (3.0 g, purity>98%).
Claims (19)
1. A process for the preparation of cephalosporin antibiotics of the formula (I) or its esters, which form prodrug or a counter ion which forms salt
wherein R1 represents hydrogen, trityl, CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6)alkyl; R2 represents hydrogen, CH3, CH2OCH3, CH2OCOCH3, CH═CH2, CH2OCONH2,
which comprises:
(i) condensing the activated derivative of the formula (III)
where X represents halogen atom such as chlorine or bromine, with silylated derivative of 7-amino cephalosporin of the formula (XIII)
wherein R represents lower alkyl, p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group and R2 is as defined above in the presence of a solvent at a temperature in the range of −50° C. to 0° C. to produce a compound of formula (XIV),
where R1 is as defined above,
(ii) cyclising the compound of formula (XIV) with thiourea in the presence of solvent and sodium acetate at room temperature to produce cephalosporin compound of the formula (XV)
wherein all symbols are as defined above,
(iii) deesterifying the compound of formula (XV) using anisole/trifluoroacetic acid, phenol/trifluoroacetic acid, formic acid in the presence or absence of a solvent at a temperature in the range of 0° C. to 60° C. to produce a compound of formula (I) and
(iv) converting the compound of formula (I) to its pharmaceutically acceptable salt or its esters which form prodrug.
2. The process as claimed in claim 1 , wherein the solvent used for condensation is selected from dichloromethane, ethyl acetate, tetrahydrofuran, aromatic hydrocarbon, acetone, dioxane, acetonitrile, DMAc, N,N-dimethylformamide, dialkylethers, water or mixtures thereof.
3. The process as claimed in claim 1 , wherein the activated derivative of the compound of formula (III) is an acid halide, a mixed anhydride, an active ester or an active amide
4. The process as claimed in claim 1 , wherein solvent used for cyclisation in step (ii) is selected from water, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C1-C3)alcohol or mixtures thereof.
5. The process as claimed in claim 1 , wherein the solvent used for deesterification in step (iii) is selected from dichloromethane or dichloroethane.
6. The process as claimed in claim 1 , wherein the pharmaceutically acceptable salt is sodium or hydrochloride.
7. The process as claimed in claim 1 , wherein the prodrug ester is proxetil, axetil, hexetil or pivoxil.
8. A process for the preparation of compound of formula (XIII)
which comprises;
(i) reacting the 7-aminocephalosporin derivative of the formula (XVI)
wherein R3 represents hydrogen, (C1-C4)alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy with R2—X, wherein X represents halogen atom and R2 represents hydrogen, CH3, CH2OCH3, CH2OCOCH3, CH═CH2, CH2OCONH2,
in the presence in an organic solvent and a base at a temperature in the range of 0° C. to 30° C. to produce 7-aminocephalosporin derivative of the formula (XVII),
(ii) deacylating the compound formula (XVII) using PCl5/POCl3/pyridine, PCl5/pyridine, triphenyl phosphite/Cl2 complexes in the presence of an alcohol, at a temperature in the range of −40° C. to 0° C. to produce a compound of the formula (XIII) and
(iii) isolating the compound of formula (XIII).
9. The process as claimed in claim 8 , wherein the solvent used in step (i) is selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C1-C3)alcohol or mixtures thereof
10. The process as claimed in claim 8 , wherein the base used in step (i) is selected from sodium acetate, potassium carbonate, triethylamine, 1,4-diazabicyclo-[2,2,2]-octane (DABCO), 1,5-diaza-bicyclo[4,3,0]-non-5-ene (DBN), 1,8-diazabicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate.
11. A process for the preparation of compound of formula (XIII)
wherein R2 represents hydrogen, CH3, CH2OCH3, CH2OCOCH3, CH═CH2, CH2OCONH2,
which comprises;
(i) acylating the 7-aminocephalosporin derivative of the formula (XVIII)
phenyl acetyl chloride to produce compound of formula (XIX)
in the presence of an organic solvent at a temperature in the range of −20° C. to 30° C.,
(ii) esterifying the compound of formula (XIX) using an esterifying agent in the presence of a solvent and a base at a temperature in the range of 25° C. to 50° C. to produce a compound of formula (XX)
(iii) deacylating the compound of formula (XX) using PCl5/POCl3/pyridine, PCl5/pyridine, triphenyl phosphite/Cl2 complexes in the presence of an alcohol, at a temperature in the range of −40° C. to 0° C. to produce a compound of the formula (XIII) and
(iv) isolating the compound of formula (XIII).
12. The process as claimed in claim 11 , wherein the solvent used in step (i) is selected from toluene, xylene, benzene, methylene dichloride, chloroform, ethyl acetate and the like.
13. The process as claimed in claim 11 , wherein the base used in step (ii) is selected from sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
14. The process as claimed in claim 11 , wherein the esterifying agent is selected from diphenyl diazomethane, alkyl halide, p-methoxybenzyl chloride, p-nitrobenzyl chloride.
15. The process as claimed in claim 11 , wherein the solvent used for esterification is selected from methylene dichloride, chloroform, ethyl acetate, toluene, water, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide N,N-dimethylacetamide, dioxane, (C1-C3)alcohol or mixtures thereof.
16. A process for the preparation of compound of formula (XIII)
wherein R2 represents hydrogen, CH3, CH2OCH3, CH2OCOCH3, CH═CH2, CH2OCONH2,
comprising esterifying the compound of the formula (XVIII)
using an esterifying agent in the presence of a solvent and base.
17. The process as claimed in claim 16 , wherein the solvent used is selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C1-C3)alcohol or mixtures thereof.
18. The process as claimed in claim 16 , wherein the base used is selected from sodium acetate, potassium carbonate, triethylamine, 1,4-diazabicyclo-[2,2,2]-octane (DABCO), 1,5-diazabicyclo[4,3,0]-non-5-ene (DBN), 1,8-diaza-bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate.
19. An intermediate of the formula (XIV)
wherein X represents halogen atom such as chlorine or bromine; R represents p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group; R2 represents hydrogen, CH3, CH2OCH3, CH2OCOCH3, CH═CH2, CH2OCONH2,
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/700,679 US20040132995A1 (en) | 2002-05-03 | 2003-11-05 | Process for the preparation of cephalosporins |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN338/MAS/2002 | 2002-05-03 | ||
| IN338CH2002 | 2002-05-03 | ||
| US10/207,103 US6800756B2 (en) | 2002-05-03 | 2002-07-30 | Method for the preparation of ceftiofur sodium and its intermediates |
| US10/700,679 US20040132995A1 (en) | 2002-05-03 | 2003-11-05 | Process for the preparation of cephalosporins |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US10/207,103 Continuation US6800756B2 (en) | 2002-05-03 | 2002-07-30 | Method for the preparation of ceftiofur sodium and its intermediates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US20040132995A1 true US20040132995A1 (en) | 2004-07-08 |
Family
ID=29287798
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US10/207,103 Expired - Fee Related US6800756B2 (en) | 2002-05-03 | 2002-07-30 | Method for the preparation of ceftiofur sodium and its intermediates |
| US10/700,679 Abandoned US20040132995A1 (en) | 2002-05-03 | 2003-11-05 | Process for the preparation of cephalosporins |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US10/207,103 Expired - Fee Related US6800756B2 (en) | 2002-05-03 | 2002-07-30 | Method for the preparation of ceftiofur sodium and its intermediates |
Country Status (4)
| Country | Link |
|---|---|
| US (2) | US6800756B2 (en) |
| EP (1) | EP1501839A2 (en) |
| AU (1) | AU2002367896A1 (en) |
| WO (1) | WO2003093278A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050020561A1 (en) * | 2001-04-17 | 2005-01-27 | Yatendra Kumar | Process for the preparation of cefpodoxime acid |
| US20050027118A1 (en) * | 2003-06-19 | 2005-02-03 | Orchid Chemicals & Pharmaceuticals, Ltd. | Process for the preparation of a cephalosporin antibiotic |
| US8445715B2 (en) * | 2007-07-02 | 2013-05-21 | Synkem | Method of synthesizing fenofibrate |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005019227A1 (en) * | 2003-08-22 | 2005-03-03 | Orchid Chemicals & Pharmaceuticals Ltd | Process for the preparation of cephalosporin antibiotic |
| US20060094872A1 (en) * | 2003-08-22 | 2006-05-04 | Orchid Chemicals & Pharmaceuticals Ltd. | Process for the preparation of cephalosporin antibiotic |
| CN102234289B (en) * | 2010-05-02 | 2013-07-10 | 青岛科技大学 | Novel method for preparing ceftiofur intermediate |
| CN102268020B (en) * | 2011-06-10 | 2013-12-04 | 洛阳惠中兽药有限公司 | Ceftiofur acetoxy ethyl ester and preparation method thereof |
| CN102993216A (en) * | 2013-01-06 | 2013-03-27 | 瑞普（天津）生物药业有限公司 | Preparation method of ceftiofur hydrochloride |
| CN104496937B (en) * | 2014-11-21 | 2016-09-28 | 山东金城医药股份有限公司 | The synthetic method of BPTA |
| CN110372631B (en) * | 2019-07-24 | 2021-03-02 | 东南大学成贤学院 | Preparation method of aminothiazoly loximate acetaldehyde |
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| US4902683A (en) * | 1984-10-25 | 1990-02-20 | The Upjohn Company | Crystalline cephalosporin hydrohalide salts |
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| FI67385C (en) | 1979-11-21 | 1985-03-11 | Hoffmann La Roche | PROCEDURE FOR FRAMSTATION OF AV (6R 7R) -7- (2- (2-AMINO-4-THIAZOLYL) -2- (Z-METHOXYIMINO) ACETAMIDO) -3-CEFEM-4-CARBOXYL SYRATER DERIVATIVES |
| IT1286494B1 (en) | 1996-11-19 | 1998-07-15 | Hichem Pharma S P A | PROCEDURE FOR THE PREPARATION OF CEPHALOSPORANIC DERIVATIVES |
-
2002
- 2002-07-30 US US10/207,103 patent/US6800756B2/en not_active Expired - Fee Related
- 2002-08-02 EP EP02751515A patent/EP1501839A2/en not_active Withdrawn
- 2002-08-02 WO PCT/IB2002/003065 patent/WO2003093278A2/en not_active Application Discontinuation
- 2002-08-02 AU AU2002367896A patent/AU2002367896A1/en not_active Abandoned
-
2003
- 2003-11-05 US US10/700,679 patent/US20040132995A1/en not_active Abandoned
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| US4242510A (en) * | 1976-12-27 | 1980-12-30 | Fujisawa Pharmaceutical Co., Ltd. | Cephalosporin compounds and processes for the preparation thereof |
| US4487927A (en) * | 1979-11-19 | 1984-12-11 | Fujisawa Pharmaceutical Co., Ltd. | 3-Phosphonium and 3-phosphoranylidenecephems |
| US4464367A (en) * | 1980-03-26 | 1984-08-07 | Sanofi | Cephalosporin derivatives, process for preparation thereof and drugs containing said derivatives usable as antibiotics |
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| US4935507A (en) * | 1987-08-19 | 1990-06-19 | Fujisawa Pharmaceutical Co., Ltd. | Crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) |
| US4877782A (en) * | 1988-02-16 | 1989-10-31 | The Upjohn Company | Zinc ceftiofur complexes |
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| US6458949B1 (en) * | 2000-08-14 | 2002-10-01 | Aurobindo Pharma Limited | Ceftiofur, its intermediate and a process for the preparation of the same |
| US6388070B1 (en) * | 2001-01-05 | 2002-05-14 | Orchid Chemicals & Pharmaceuticals Ltd. | Thioester derivatives of thiazolyl acetic acid and their use in the preparation of cephalosporin compounds |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050020561A1 (en) * | 2001-04-17 | 2005-01-27 | Yatendra Kumar | Process for the preparation of cefpodoxime acid |
| US20050027118A1 (en) * | 2003-06-19 | 2005-02-03 | Orchid Chemicals & Pharmaceuticals, Ltd. | Process for the preparation of a cephalosporin antibiotic |
| US7098329B2 (en) * | 2003-06-19 | 2006-08-29 | Orchid Chemicals & Pharmaceuticals Ltd. | Process for the preparation of a cephalosporin antibiotic |
| US8445715B2 (en) * | 2007-07-02 | 2013-05-21 | Synkem | Method of synthesizing fenofibrate |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003093278A3 (en) | 2004-04-08 |
| EP1501839A2 (en) | 2005-02-02 |
| US6800756B2 (en) | 2004-10-05 |
| US20030216567A1 (en) | 2003-11-20 |
| WO2003093278A2 (en) | 2003-11-13 |
| AU2002367896A1 (en) | 2003-11-17 |
| AU2002367896A8 (en) | 2003-11-17 |
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