WO2006067803A1 - A novel intermediate for the preparation of cefepime - Google Patents
A novel intermediate for the preparation of cefepime Download PDFInfo
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- WO2006067803A1 WO2006067803A1 PCT/IN2005/000406 IN2005000406W WO2006067803A1 WO 2006067803 A1 WO2006067803 A1 WO 2006067803A1 IN 2005000406 W IN2005000406 W IN 2005000406W WO 2006067803 A1 WO2006067803 A1 WO 2006067803A1
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- WIPO (PCT)
- Prior art keywords
- per
- cefepime
- acetone
- methyl
- carbonate
- Prior art date
Links
- 229960002100 cefepime Drugs 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- HVFLCNVBZFFHBT-ZKDACBOMSA-N cefepime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 HVFLCNVBZFFHBT-ZKDACBOMSA-N 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 15
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000000746 purification Methods 0.000 claims abstract description 6
- STQLBWSBVJOFBE-UHFFFAOYSA-N 4-bromo-2-methoxyimino-3-oxobutanoyl chloride Chemical compound CON=C(C(Cl)=O)C(=O)CBr STQLBWSBVJOFBE-UHFFFAOYSA-N 0.000 claims abstract description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 5
- -1 bromo compound II Chemical compound 0.000 claims abstract description 5
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims abstract description 4
- 230000010933 acylation Effects 0.000 claims abstract description 4
- 238000005917 acylation reaction Methods 0.000 claims abstract description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000011736 potassium bicarbonate Substances 0.000 claims description 11
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 11
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 11
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 9
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 239000001099 ammonium carbonate Substances 0.000 claims description 4
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 229940086542 triethylamine Drugs 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 230000003115 biocidal effect Effects 0.000 abstract description 4
- 229930186147 Cephalosporin Natural products 0.000 abstract description 3
- 229940124587 cephalosporin Drugs 0.000 abstract description 3
- 150000001780 cephalosporins Chemical class 0.000 abstract description 3
- MMRINLZOZVAPDZ-LSGRDSQZSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 MMRINLZOZVAPDZ-LSGRDSQZSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- LRAJHPGSGBRUJN-OMIVUECESA-N cefepime hydrochloride Chemical compound O.Cl.[Cl-].S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 LRAJHPGSGBRUJN-OMIVUECESA-N 0.000 description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- AMTTUPGTZVAKBF-DAXSKMNVSA-N (2z)-4-bromo-2-methoxyimino-3-oxobutanoic acid Chemical compound CO\N=C(/C(O)=O)C(=O)CBr AMTTUPGTZVAKBF-DAXSKMNVSA-N 0.000 description 1
- HSHGZXNAXBPPDL-IOJJLOCKSA-N (6r)-3-(acetyloxymethyl)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C(N)[C@@H]12 HSHGZXNAXBPPDL-IOJJLOCKSA-N 0.000 description 1
- NLARCUDOUOQRPB-UHFFFAOYSA-N 2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetic acid Chemical compound CON=C(C(O)=O)C1=CSC(N)=N1 NLARCUDOUOQRPB-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- STQLBWSBVJOFBE-YWEYNIOJSA-N CO/N=C(/C(CBr)=O)\C(Cl)=O Chemical compound CO/N=C(/C(CBr)=O)\C(Cl)=O STQLBWSBVJOFBE-YWEYNIOJSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction 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
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/48—Methylene radicals, substituted by hetero rings
- C07D501/56—Methylene radicals, substituted by hetero rings with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- 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 is related to provide a novel process for preparation of cefepime of formula I, a cephalosporin antibiotic.
- the present invention further relates to provide a process for preparation of a novel intermediate of formula II which is useful for the preparation of Cefepime of formula I.
- cephalosporin antibiotics A large number of cephalosporin antibiotics are known and are widely used in the treatment of bacterial infection.
- the semi-synthetic antibiotic cefepime is a useful broad- spectrum antibiotic which was first described by Aburaki, et al, in U.S. Pat. No. 4,406,899 wherein the cefepime was synthesized by a multistep process involving protection and deprotection steps thereby making the process lengthy and laborious.
- the objective of the present invention is to provide a novel process for preparation of cefepime (I) comprising of (i) acylation of 7-Amino-3-[(l-methyl-l- pyrrolidinium)methyl]-3-cephem-4-carboxylate (7-APC, IV) obtained in step 1 with 4- bromo-2-methoxyimino-3-oxobutyric acid chloride (III) to give provide provide 7-(4-bromo-2- methoxyimino-3-oxobutyramido)-3 ⁇ [(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4- carboxylate (bromo intermediate, II), (ii) cyclisation of bromo compound (II) with thiourea to give cefepime (I) and (iii) purification of cefepime.
- the present invention provides a novel process for the preparation of cefepime of formula (I) as shown in synthetic scheme below.
- the starting material 7-Amino-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4- carboxylate (7-APC, IV) was prepared as per process described in patent US 5,594,131 by reaction of disilylated 7-amino-3-acetoxymethyl-ceph-3-em-4-carboxylate with N- methyl pyrrolidine in cyclohexane.
- the compound 7-APC was isolated as anhydrous or in the form of acid addition salts of HCl, HBr, HI and H 2 SO 4 or hydrates of these salts.
- the preparation of compound of formula II involves condensation of 4-bromo-3 -oxo-2-methoxyimino-butyryl chloride of formula III with 7-amino-3-[(l- methyl 1-pyrolidino) methyl] ceph-3-em-4-carboxylate hydrochloride of formula IV to provide 7-(4-bromo-2-methoxyimmo-3-oxobutyramido)-3--[(l-methyl- l-pyrrolidinium)methyl]-3-cephem-4-carboxylate (bromo intermediate, II) as shown in step 1.
- the starting compound 7-APC (IV) in the step 1 is used as mono-addition salt or as a di-addition salt with HCL, HBr, HI, H 2 SO 4 and H 3 PO 4 .
- These addition salts may additionally be present in solvated form, e. g. as monohydrate or dihydrate, most preferably mono hydrochloride salt of 7-APC is used.
- the another starting material of condensation reaction is 4-bromo-2-methoxyimino-3- oxo-butyric acid chloride (III) is prepared from reaction of ammonium salt of 4-bromo-2- methoxyimino-3-oxo-butyric acid with chlorinating agent such as phosphorous pentachloride, phosphorous oxychloride, oxalyl chloride and thionyl chloride halogenated solvent such as dichloromethane or ethylene dichloride.
- chlorinating agent such as phosphorous pentachloride, phosphorous oxychloride, oxalyl chloride and thionyl chloride halogenated solvent such as dichloromethane or ethylene dichloride.
- the solvent for condensation reaction is selected from dichloromethane, ethylene dichloride, ethyl acetate, methanol, ethanol, propanol, butanol, acetone, ethyl methyl ketone, acetonitrile, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl formamide, water and mixtures thereof.
- the ratio of organic solvent to water in the mixture is in the range of 10:90 to 90: 10, more preferably 50:50.
- the pH is maintained at 5.0-7.0, preferably at 5.4-6.0 by using organic or inorganic base selected from triethyl amine, pyridine, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, ammonia and ammonium carbonate, more preferably potassium hydrogen carbonate.
- organic or inorganic base selected from triethyl amine, pyridine, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, ammonia and ammonium carbonate, more preferably potassium hydrogen carbonate.
- the reaction is performed at temperature-20 to 3O 0 C, preferably at -10 to -15 0 C.
- the compounds of formula II may be isolated in the form free base or as acid addition salts of HCl, HBr, HI and H 2 SO 4 or hydrates of these salts.
- the compound of formula II is treated with thiourea to undergo cyclisation reaction to give cefepime as shown in step 2.
- the solvent used for cyclisation reaction is selected from dichloromethane, ethylene dichloride, ethyl acetate, methanol, ethanol, propanol, butanol, acetone, ethyl methyl ketone, acetonitrile, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl formamide, water and mixtures thereof.
- the ratio of organic solvent to water in the mixture is in the range of 10:90 to 90:10, more preferably 50:50.
- the pH is maintained at 3.5-5.5, preferably at 4.0-4.5 by using organic or inorganic base selected from triethyl amine, pyridine, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, ammonia and ammonium carbonate, more preferably potassium hydrogen carbonate.
- organic or inorganic base selected from triethyl amine, pyridine, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, ammonia and ammonium carbonate, more preferably potassium hydrogen carbonate.
- the reaction is performed at temperature 10 to 50 0 C, preferably at 25 to 3O 0 C.
- the cefepime is purified by dissolving in alcoholic solvent such as methanol, subjected to carbon treatment, filtering and crystallizing out pure cefepime by addition of ketonic a solvent such as acetone.
- the purification is performed at temperature 10 to 5O 0 C, preferably at 25 to 3O 0 C.
- the cefepime dihydrochloride raonohydrate (I) thus obtained is highly pure (HPLC purity > 99.7%) and stable.
- the process utilizes avoids the use of silylated reagents in step 1, thereby it reduces the load of effluents.
- the process of the present invention is operationally simple and more eco friendly.
- Step 1 7-[4-Bromo-2(Z)-methoxyimino-3-oxobutyramide]- 3-[(l- methyl -1- pyrolidino) methyl] ceph ⁇ 3-em-4-carboxylate hydrochloride (II)
- bromo intermediate (II) The mixture of acetone (500 ml), water (500 ml) and 7-[4-Bromo-2(Z)-methoxyimino-3- oxobutyramide]- 3-[(l- methyl -1-pyrolidino) methyl] ceph-3-em-4-carboxylate hydrochloride (10Og) obtained above was cooled to -1O 0 C. The pH of the mixture was adjusted to 4 to dissolve completely by 25% potassium bicarbonate. Carbon (10 g) was added and mixture was stirred for 30 minutes at 0 to 5°C. Filtered and the pH of filtrate was adjusted by dilute hydrochloric acid to 0.7.
- cefepime (80) g obtained above was dissolved in DM water (400 ml) under stirring. To that acetone (1200 ml) was added slowly in 30 min at 25-28 0 C. Mixture was stirred for 30 min at same temp. Acetone (2000 ml) was added slowly in lhr at 25-28 0 C. Mixture was stirred for lhr, filtered and washed with acetone (400ml), dried under vacuum at 4O 0 C gives pure cefepime dihydrochloride monohydrate 75 g (93% yield, purity 99.7%).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
A novel process is disclosed for preparation of cefepime, a cephalosporin antibiotic in two steps comprising of (i) acylation of 7-Amino-3-[(1-methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate hydrochloride (IV) with 4-bromo-2-methoxyimino-3-oxobutyric acid chloride (III) to give 7-(4-bromo-2-methoxyimino-3-oxobutyramido)-3--[(1-methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate (II), (ii) cyclisation of bromo compound II with thiourea to give cefepime (I) and (iii) purification of cefepime.
Description
A NOVEL INTERMEDIATE FOR THE PREPARATION OF CEFEPIME FIELD OF INVENTION
The present invention is related to provide a novel process for preparation of cefepime of formula I, a cephalosporin antibiotic.
The present invention further relates to provide a process for preparation of a novel intermediate of formula II which is useful for the preparation of Cefepime of formula I.
BACKGROUND OF THE INVENTION
A large number of cephalosporin antibiotics are known and are widely used in the treatment of bacterial infection. The semi-synthetic antibiotic cefepime is a useful broad- spectrum antibiotic which was first described by Aburaki, et al, in U.S. Pat. No. 4,406,899 wherein the cefepime was synthesized by a multistep process involving protection and deprotection steps thereby making the process lengthy and laborious.
The patents US 4,754,031; US 5,594,129 and 5,594,130 disclose synthesis of cefepime as shown below which involves acylation of 7-amino-3-[(l -methyl- 1 - pyrrolidinium)methyl]-3-cephem-4-carboxylate hydrochloride (IV) with 2-(2-amino-4- thiazolyl)-2-methoxyiminoacetic acid that is activated by converting to chloride by
reacting with chlorinating agent such as thionyl chloride or phosphorous pentachloride or to anhydride by reacting with methane sulphonyl chloride.
)
IV (7-APC) OBJECTIVES OF THE INVENTION
The objective of the present invention is to provide a novel process for preparation of cefepime (I) comprising of (i) acylation of 7-Amino-3-[(l-methyl-l- pyrrolidinium)methyl]-3-cephem-4-carboxylate (7-APC, IV) obtained in step 1 with 4- bromo-2-methoxyimino-3-oxobutyric acid chloride (III) to give provide 7-(4-bromo-2- methoxyimino-3-oxobutyramido)-3~[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4- carboxylate (bromo intermediate, II), (ii) cyclisation of bromo compound (II) with thiourea to give cefepime (I) and (iii) purification of cefepime.
DETAILED DESCRIPTION
The present invention provides a novel process for the preparation of cefepime of formula (I) as shown in synthetic scheme below.
Synthetic Scheme
Pure cefepime (I) Cefepime (I)
The starting material 7-Amino-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4- carboxylate (7-APC, IV) was prepared as per process described in patent US 5,594,131 by reaction of disilylated 7-amino-3-acetoxymethyl-ceph-3-em-4-carboxylate with N- methyl pyrrolidine in cyclohexane. The compound 7-APC was isolated as anhydrous or in the form of acid addition salts of HCl, HBr, HI and H2SO4 or hydrates of these salts.
In an embodiment of the present invention, the preparation of compound of formula II involves condensation of 4-bromo-3 -oxo-2-methoxyimino-butyryl chloride of formula III with 7-amino-3-[(l- methyl 1-pyrolidino) methyl] ceph-3-em-4-carboxylate hydrochloride of formula IV to provide 7-(4-bromo-2-methoxyimmo-3-oxobutyramido)-3--[(l-methyl- l-pyrrolidinium)methyl]-3-cephem-4-carboxylate (bromo intermediate, II) as shown in step 1. The starting compound 7-APC (IV) in the step 1 is used as mono-addition salt or as a di-addition salt with HCL, HBr, HI, H2SO4 and H3PO4. These addition salts may additionally be present in solvated form, e. g. as monohydrate or dihydrate, most preferably mono hydrochloride salt of 7-APC is used.
The another starting material of condensation reaction is 4-bromo-2-methoxyimino-3- oxo-butyric acid chloride (III) is prepared from reaction of ammonium salt of 4-bromo-2- methoxyimino-3-oxo-butyric acid with chlorinating agent such as phosphorous pentachloride, phosphorous oxychloride, oxalyl chloride and thionyl chloride halogenated solvent such as dichloromethane or ethylene dichloride.
The solvent for condensation reaction is selected from dichloromethane, ethylene dichloride, ethyl acetate, methanol, ethanol, propanol, butanol, acetone, ethyl methyl ketone, acetonitrile, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl formamide, water and mixtures thereof. The ratio of organic solvent to water in the mixture is in the range of 10:90 to 90: 10, more preferably 50:50. The pH is maintained at 5.0-7.0, preferably at 5.4-6.0 by using organic or inorganic base selected from triethyl amine, pyridine, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, ammonia and ammonium carbonate, more preferably potassium hydrogen carbonate. The reaction is performed at temperature-20 to 3O0C, preferably at -10 to -150C.
In another embodiment of the present invention the compounds of formula II may be isolated in the form free base or as acid addition salts of HCl, HBr, HI and H2SO4 or hydrates of these salts.
In yet another embodiment of the present invention the compound of formula II is treated with thiourea to undergo cyclisation reaction to give cefepime as shown in step 2. The solvent used for cyclisation reaction is selected from dichloromethane, ethylene dichloride, ethyl acetate, methanol, ethanol, propanol, butanol, acetone, ethyl methyl ketone, acetonitrile, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl formamide, water and mixtures thereof. The ratio of organic solvent to water in the mixture is in the range of 10:90 to 90:10, more preferably 50:50. The pH is maintained at 3.5-5.5, preferably at 4.0-4.5 by using organic or inorganic base selected from triethyl amine, pyridine, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, ammonia and ammonium carbonate, more preferably potassium hydrogen carbonate. The reaction is performed at temperature 10 to 500C, preferably at 25 to 3O0C.
In yet another embodiment of the present invention the cefepime is purified by dissolving in alcoholic solvent such as methanol, subjected to carbon treatment, filtering and crystallizing out pure cefepime by addition of ketonic a solvent such as acetone. The purification is performed at temperature 10 to 5O0C, preferably at 25 to 3O0C.
The cefepime dihydrochloride raonohydrate (I) thus obtained is highly pure (HPLC purity > 99.7%) and stable.
The present invention has following advantages:
(i) the process provides highly pure and stable cefepime dihydrochloride monohydrate in good yield,
(ii) the process utilizes avoids the use of silylated reagents in step 1, thereby it reduces the load of effluents. Thus, the process of the present invention is operationally simple and more eco friendly.
(iii) the process is commercially viable as there are no protection and deprotection steps involved.
The present invention is illustrated in the following examples without limiting the scope of the invention.
Example 1
Step 1 7-[4-Bromo-2(Z)-methoxyimino-3-oxobutyramide]- 3-[(l- methyl -1- pyrolidino) methyl] ceph~3-em-4-carboxylate hydrochloride (II)
A mixture of phosphorous pentachloride (74.5 g, 0.3573 mol.), dichloromethane (500ml) was cooled to -100C. Ammonium salt of 4-bromo-2-oxyimino-3-oxo butyric acid was added in lots at -10 to-15°C. Mixture was stirred at 3O0C for 30 min. and 0 to 50C for 30 min. Dichloromethane was evaporated completely. To this acetone (250 ml) was added. In another flask the mixture of acetone (500 ml), water (500 ml) and 7-amino-3-[(l- methyll-pyrolidino) methyl] ceph-3-em-4-carboxylate hydrochloride (10Og) was cooled to -100C. pH was adjusted to 6.5 by 25% potassium bicarbonate solution. Acid chloride was added slowly by maintaining pH 5.4 to 5.8 at -5 to -1O0C. Mixture was stirred for 20 minute. pH was adjusted to 0.7 slowly by concentrated hydrochloric acid at 0 to -50C. Mixture was stirred for 2 hr at same temperature, filtered washed with (1:1) acetone- water (400ml) and acetone (400ml). Drying under vacuum at 4O0C affords 7-[4-Bromo-
2(Z)-methoxyimino-3-oxobutyramide]- 3-[(l- methyl -1-pyrolidino) methyl] ceph-3-em- 4-carboxylate hydrochloride (bromo intermediate, II) (12Og, 74.4%).
Purification of bromo intermediate (II) The mixture of acetone (500 ml), water (500 ml) and 7-[4-Bromo-2(Z)-methoxyimino-3- oxobutyramide]- 3-[(l- methyl -1-pyrolidino) methyl] ceph-3-em-4-carboxylate hydrochloride (10Og) obtained above was cooled to -1O0C. The pH of the mixture was adjusted to 4 to dissolve completely by 25% potassium bicarbonate. Carbon (10 g) was added and mixture was stirred for 30 minutes at 0 to 5°C. Filtered and the pH of filtrate was adjusted by dilute hydrochloric acid to 0.7. Slurry was stirred for 2 hr at 0 to-5°C, filtered washed with water and acetone, drying under vacuum at 400C affords (85g) pure 7-[4-bromo-2(Z)-methoxyimino-3-oxobutyramide]- 3-[(l- methyl -1-pyrolidino) methyl] ceph-3-em-4-carboxylate hydrochloride (85g)
Step 2
Preparation of 7-[2-(2-aminotiazol-4yl)-2-(z)-methoxy-iminoacetamido]-3-[(l-methyl-l- pyrolidino)-methyl] ceph-3-em-4carboxylate dihydrochloride monohydrate (cefepime, I).
A mixture of 7-[4-bromo-2(Z)-methoxyimino-3-oxobutyramide]- 3-[(l - methyl -1 - pyrolidino) methyl] ceph-3-em-4-carboxylate hydrochloride (II) (8Og, 0.1481mol), acetone (400ml), water (400ml) was cooled to 10°C. pH of mixture was adjusted to 4 by 25% potassium bicarbonate , thiourea (15.68g, 0.2063 mol) was added. Mixture was stirred for 90 min at pH 4.2 to4.5 at 250C. Carbon (12 g) was added and stirred for 1 hr, filtered washed with water (80ml). pH of filtrate was adjusted to 0.5 by concentrated hydrochloric acid at 8-1O0C. Acetone (3440ml) was added slowly in 2 hr at 8-1O0C. After stirring for 1 hr at 8-1O0C mixture was filtered, washed with acetone (400 ml) gives cefepime dihydrochloride monohydrate 88 g (94.5% yield, purity 99.3%).
Purification of cefepime dihydrochloride monohydrate:
Cefepime (80) g obtained above was dissolved in DM water (400 ml) under stirring. To that acetone (1200 ml) was added slowly in 30 min at 25-280C. Mixture was stirred for 30 min at same temp. Acetone (2000 ml) was added slowly in lhr at 25-280C. Mixture was stirred for lhr, filtered and washed with acetone (400ml), dried under vacuum at 4O0C gives pure cefepime dihydrochloride monohydrate 75 g (93% yield, purity 99.7%).
Claims
1. A process for preparation of cefepime of formula (I)
comprising the steps:
(i) acylation of 7-Amino-3 -[( 1 -methyl- 1 -pyrrolidinium)rnethyl] -3 -cephem-4- carboxylate (7-APC, IV) with 4-bromo-2-methoxyimino-3-oxobutyric acid chloride (III) to give provide 7-(4-bromo-2-methoxyimino-3- oxobutyramido)-3~[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4- carboxylate (bromo intermediate, II)
(ii) cyclisation of bromo compound (II) with thiourea to give cefepime (I) and (iii) purification of cefepime.
A process as per claim 1 wherein, the step 1 is carried out in solvent selected from dichloromethane, ethylene dichloride, ethyl acetate, methanol, ethanol, propanol, butanol, acetone, ethyl methyl ketone, acetonitrile, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl formamide, water and mixtures thereof, preferably mixture of acetone and water.
A process as per claim 2 wherein, the ratio of acetone and water in the step 1 is in the range of 10:90 to 90:10, more preferably 50:50.
A process as per claim 1 wherein, step 1 is carried out at pH 5.0-7.0, preferably at 5.4-6.0.
5. A process as per claim 1 wherein, the pH 5.4-6.0 in step 1 is maintained by using organic or inorganic base selected from triethyl amine, pyridine, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium
hydroxide, potassium hydrogen carbonate, potassium carbonate, ammonia and ammonium carbonate, most preferably potassium hydrogen carbonate.
6. A process as per claim 1 wherein, the step 1 is performed at temperature-20 to 3O0C, preferably at -10 to -150C.
7. A process as per claim 1 wherein, the step 2 is carried out in solvent selected from dichloromethane, ethylene dichloride, ethyl acetate, methanol, ethanol, propanol, butanol, acetone, ethyl methyl ketone, acetonitrile, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl formamide, water and mixtures thereof, preferably mixture of acetone and water.
8. A process as per claim 2 wherein, the ratio of acetone and water in the step 2 is in the range of 10:90 to 90:10, more preferably 50:50.
9. A process as per claim 1 wherein, step 2 is carried out at pH 3.3 to 5.5, preferably at 4.0 to 4.5.
10. A process as per claim 1 wherein, the pH in step 2 is maintained by using organic or inorganic base selected from triethyl amine, pyridine, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, ammonia and ammonium carbonate, most preferably potassium hydrogen carbonate.
11. A process as per claim 1 wherein, the step 1 is performed at temperature 10-
5O0C, preferably at 25-3O0C.
12. A process as per claim 1 wherein, the step 3 is carried out by dissolving cefepime in alcoholic solvent such as methanol and crystallizing out pure cefepime by addition of ketonic a solvent such as acetone.
13. A process as per claim 1 wherein, the step 3 is performed at temperature 10 to 5O0C, preferably at 25 to 3O0C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1382/MUM/2004 | 2004-12-21 | ||
| IN1382MU2004 | 2004-12-21 |
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| Publication Number | Publication Date |
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| WO2006067803A1 true WO2006067803A1 (en) | 2006-06-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2005/000406 WO2006067803A1 (en) | 2004-12-21 | 2005-12-09 | A novel intermediate for the preparation of cefepime |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1832593A1 (en) * | 2006-03-09 | 2007-09-12 | Harvest Lodge Limited | Direct process for the production of sterile Cefepime dihydrochloride monohydrate |
| US7479556B2 (en) * | 2004-11-08 | 2009-01-20 | Acs Dobfar S.P.A. | Process for producing Cefepime and cephalosporin analogues |
| CN101200473B (en) * | 2007-06-07 | 2010-06-30 | 深圳信立泰药业股份有限公司 | Method for preparing cefepime dihydrochloride monohydrate crystal |
| US7847093B2 (en) * | 2003-04-16 | 2010-12-07 | Sandoz Ag | Processes for the preparations of cefepime |
| CN104610283A (en) * | 2015-01-30 | 2015-05-13 | 悦康药业集团有限公司 | Cefepime dihydrochloride compound and pharmaceutical composition thereof |
| CN114539289A (en) * | 2021-10-15 | 2022-05-27 | 广州艾奇西医药科技有限公司 | Cefepime arginine polymer and preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0324418A2 (en) * | 1988-01-14 | 1989-07-19 | Takeda Chemical Industries, Ltd. | Method for production of t-butyl- 3-oxobutyrates and their use |
| WO2002083634A2 (en) * | 2001-04-17 | 2002-10-24 | Ranbaxy Laboratories Limited | Process for the preparation of cefpodoxime acid |
| WO2004092183A2 (en) * | 2003-04-16 | 2004-10-28 | Sandoz Ag | Processes for the preparations of cefepime |
| US20050043531A1 (en) * | 2003-08-21 | 2005-02-24 | Handa Vijay Kumar | Process for preparing cefepime |
| WO2005019227A1 (en) * | 2003-08-22 | 2005-03-03 | Orchid Chemicals & Pharmaceuticals Ltd | Process for the preparation of cephalosporin antibiotic |
-
2005
- 2005-12-09 WO PCT/IN2005/000406 patent/WO2006067803A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0324418A2 (en) * | 1988-01-14 | 1989-07-19 | Takeda Chemical Industries, Ltd. | Method for production of t-butyl- 3-oxobutyrates and their use |
| WO2002083634A2 (en) * | 2001-04-17 | 2002-10-24 | Ranbaxy Laboratories Limited | Process for the preparation of cefpodoxime acid |
| WO2004092183A2 (en) * | 2003-04-16 | 2004-10-28 | Sandoz Ag | Processes for the preparations of cefepime |
| US20050043531A1 (en) * | 2003-08-21 | 2005-02-24 | Handa Vijay Kumar | Process for preparing cefepime |
| WO2005019227A1 (en) * | 2003-08-22 | 2005-03-03 | Orchid Chemicals & Pharmaceuticals Ltd | Process for the preparation of cephalosporin antibiotic |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7847093B2 (en) * | 2003-04-16 | 2010-12-07 | Sandoz Ag | Processes for the preparations of cefepime |
| US7479556B2 (en) * | 2004-11-08 | 2009-01-20 | Acs Dobfar S.P.A. | Process for producing Cefepime and cephalosporin analogues |
| EP1832593A1 (en) * | 2006-03-09 | 2007-09-12 | Harvest Lodge Limited | Direct process for the production of sterile Cefepime dihydrochloride monohydrate |
| CN101200473B (en) * | 2007-06-07 | 2010-06-30 | 深圳信立泰药业股份有限公司 | Method for preparing cefepime dihydrochloride monohydrate crystal |
| CN104610283A (en) * | 2015-01-30 | 2015-05-13 | 悦康药业集团有限公司 | Cefepime dihydrochloride compound and pharmaceutical composition thereof |
| CN104610283B (en) * | 2015-01-30 | 2019-01-11 | 悦康药业集团有限公司 | A kind of cefepime hydrochloride compound and its pharmaceutical composition |
| CN114539289A (en) * | 2021-10-15 | 2022-05-27 | 广州艾奇西医药科技有限公司 | Cefepime arginine polymer and preparation method and application thereof |
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