US20030135041A1 - Synthesis of ceftiofur intermediate - Google Patents
Synthesis of ceftiofur intermediate Download PDFInfo
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- US20030135041A1 US20030135041A1 US10/035,178 US3517802A US2003135041A1 US 20030135041 A1 US20030135041 A1 US 20030135041A1 US 3517802 A US3517802 A US 3517802A US 2003135041 A1 US2003135041 A1 US 2003135041A1
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- organic solvent
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- furyl
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- ZBHXIWJRIFEVQY-IHMPYVIRSA-N ceftiofur 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=1CSC(=O)C1=CC=CO1 ZBHXIWJRIFEVQY-IHMPYVIRSA-N 0.000 title description 6
- 229960005229 ceftiofur Drugs 0.000 title description 6
- 230000015572 biosynthetic process Effects 0.000 title description 4
- 238000003786 synthesis reaction Methods 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 30
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims abstract description 27
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 claims abstract description 22
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims abstract description 14
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- 229910015900 BF3 Inorganic materials 0.000 claims abstract description 12
- 238000009833 condensation Methods 0.000 claims abstract description 9
- 230000005494 condensation Effects 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 229940093499 ethyl acetate Drugs 0.000 claims description 18
- 235000019439 ethyl acetate Nutrition 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 5
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 5
- 239000000908 ammonium hydroxide Substances 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 5
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 5
- 229940090181 propyl acetate Drugs 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 3
- 238000005406 washing Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- ZMPDMYFTSINIIZ-UHFFFAOYSA-N NC1C(=O)N2C(C(=O)O)=C(CSC(=O)C3=CC=CO3)CSC12 Chemical compound NC1C(=O)N2C(C(=O)O)=C(CSC(=O)C3=CC=CO3)CSC12 ZMPDMYFTSINIIZ-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- ZQULKYXYALHKMU-UHFFFAOYSA-N CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1.II.I[IH]I.O=C(S)C1=CC=CO1 Chemical compound CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1.II.I[IH]I.O=C(S)C1=CC=CO1 ZQULKYXYALHKMU-UHFFFAOYSA-N 0.000 description 3
- -1 amines salts Chemical class 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 229910052979 sodium sulfide Inorganic materials 0.000 description 3
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- LKYIPGJOXSVWPX-UHFFFAOYSA-M sodium;thiophene-2-carboxylate Chemical compound [Na+].[O-]C(=O)C1=CC=CS1 LKYIPGJOXSVWPX-UHFFFAOYSA-M 0.000 description 2
- WTSRRNZHGZJUPW-NHDPSOOVSA-N C/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(=O)C3=CC=CO3)CSC12)C1=CSC(N)=N1 Chemical compound C/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(=O)C3=CC=CO3)CSC12)C1=CSC(N)=N1 WTSRRNZHGZJUPW-NHDPSOOVSA-N 0.000 description 1
- VFAUTVYBJNWIPC-UHFFFAOYSA-N CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1.FB(F)F.I.II.I[IH]I.NC1C(=O)N2C(C(=O)O)=C(CSC(=O)C3=CC=CO3)CSC12.O=C(S)C1=CC=CO1 Chemical compound CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1.FB(F)F.I.II.I[IH]I.NC1C(=O)N2C(C(=O)O)=C(CSC(=O)C3=CC=CO3)CSC12.O=C(S)C1=CC=CO1 VFAUTVYBJNWIPC-UHFFFAOYSA-N 0.000 description 1
- HSHGZXNAXBPPDL-UHFFFAOYSA-N CC(OCC(CSC1C2N)=C(C(O)=O)N1C2=O)=O Chemical compound CC(OCC(CSC1C2N)=C(C(O)=O)N1C2=O)=O HSHGZXNAXBPPDL-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KXXALFSFISKXFX-UHFFFAOYSA-N O=C(c1ccc[o]1)S Chemical compound O=C(c1ccc[o]1)S KXXALFSFISKXFX-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003573 thiols Chemical class 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
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
Definitions
- the present invention discloses an improved process for the preparation of 7-amino-3 -[2-(furylcarbonyl) thiomethyl]-3-cephem-4-carboxylic acid represented by formula (I)
- Ceftiofur is the generic name given to compound of formula (IV)
- ceftiofur acid its alkali metal, alkaline earth metal and amines salts were reported for the first time in U.S. Pat. No. 4,464,367.
- the ceftiofur is a condensation product of 7-ACA with furyl-2-carbonylthiol and 2-(2-amino thiazol-4-yl)-2-methoxyimino) acetic acid at its 3 and 7 positions respectively.
- 7-amino-3-[2-furylcarbonyl) thiomethyl]-3-cephem-4-carboxylic acid represented by formula (I) is the key intermediate which decides the quality and overall yield of the process for making ceftiofur.
- the primary object of the invention is to provide an improved and commercially viable efficient process for preparing 7-amino-3-[2-(furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid (I), as an intermediate for ceftiofur.
- Another object of the invention is to use furyl-2-carbonylthiol in situ without isolating it.
- Yet another objective of this invention is to provide a process which will give high yield and purity of the required product.
- Still another object of the invention is to provide the use of boron trifluoride in gaseous state or its solution in an organic solvent for carrying out the condensation reaction at low temperature which are convenient for commercial production.
- the present invention provides a process for the preparation of 3-[2-(furylcarbonyl) thiomethyl]-3-cephem-4-carboxylic acid (I) by the condensation of 7-aminocephalosporanic acid (II) with furyl-2-carbonylthiol (III) in the presence of borontrifluoride at a temperature range of 20°-50° C. in an organic solvent.
- This process gives high yields and excellent purity.
- the present invention provides a process for the preparation of 3-[2-(furylcarbonyl) thiomethyl]-3-cephem4-carboxylic acid represented by formula (I),
- the said process comprising the steps of condensing 7-aminocephalosporanic acid (II) with furyl-2-carbonylthiol (III) in the presence of borontrifluoride at 20°-50° C. in an organic solvent and isolating the compound of formula (I).
- An embodiment of the present invention provides a temperature range of 30°-35° C. for performing the condensation reaction.
- Another embodiment of the present invention provides a pH range of 3-4 and preferably 3.45-3.55 for the precipitation of the solid from the solution.
- Yet another embodiment of the present invention provides the drying of the precipitated solid at a temperature range of 40°-45° C. under vacuum.
- One embodiment of the present invention provides the use of furyl-2-carbonylthiol in situ as a solution in an organic solvent.
- Another embodiment of the present invention provides the use of organic solvent in the condensation reaction selected from group consisting of ethyl acetate, methyl acetate, propyl acetate, dichloromethane, toluene, diethyl ether, diisopropyl ether and/or mixture thereof.
- One another embodiment of the present invention provides the use of base to adjust the pH of the reaction mixture is selected from a group consisting of ammonium hydroxide, sodium hydroxide or sodium carbonate.
- Yet another embodiment of the present invention provides use of condensing agent borontriflouride in its gaseous form or its solution in an organic solvent.
- the required product is obtained by precipitation and followed by filtration.
Abstract
The present invention provides an improved process for the preparation of 7-amino-3-[2-(furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid represented by formula (I)
by the condensation of 7-amino cephalosporanic acid (7-ACA) represented by formula (II) with furyl-2-carbonylthiol represented by formula (III) using borontrifluoride as condensing agent in an organic solvent at a temperature range of 20°-50°C.
Description
- The present invention discloses an improved process for the preparation of 7-amino-3 -[2-(furylcarbonyl) thiomethyl]-3-cephem-4-carboxylic acid represented by formula (I)
- by the condensation of 7-amino cephalosporanic acid (7-ACA) represented by formula (II) with furyl-2-carbonylthiol represented by formula (III) using borontrifluoride as condensing agent.
- Ceftiofur is the generic name given to compound of formula (IV)
- Ceftiofur acid, its alkali metal, alkaline earth metal and amines salts were reported for the first time in U.S. Pat. No. 4,464,367. The ceftiofur is a condensation product of 7-ACA with furyl-2-carbonylthiol and 2-(2-amino thiazol-4-yl)-2-methoxyimino) acetic acid at its 3 and 7 positions respectively. 7-amino-3-[2-furylcarbonyl) thiomethyl]-3-cephem-4-carboxylic acid represented by formula (I) is the key intermediate which decides the quality and overall yield of the process for making ceftiofur.
- There are very few methods reported in the literature for the synthesis of 7-amino-3-[2-(furylcarbonyl) thiomethyl]-3-cephem-4-carboxylic acid (I). The first report for the synthesis of this intermediate appeared in the U.S. Pat. No. 4,464,367, wherein the method used for the preparation of the compound of Formula (I) was followed from a reference from the journal of Antibiotics 27,573- 8,(1974). This reference is about the condensation of 7-aminocephalosporanic acid and sodium thiofuroate carried out at a pH of 6.4 using phosphate buffer. The reaction time is very long by following this tedious method and a yield is of 47% is reported for the final product. These limitations make this process unfavorable for commercial exploitation. Another method was disclosed in WO patent 87/01117 which is also merely an extension of the above-mentioned US patent. The condensation was effected by reaction of sodium thiofuroate and 7-ACA at a temperature of 65° C. in an aqueous medium at a pH of 6.4. Cephalosporins are known to decompose at high temperature and moreover using this process, the reaction is not completed and yields are also very poor (about 45% and in addition, the reaction takes longer time, for example, even after several hours the reaction is incomplete).
- Looking at all these problems, a method for the condensation under non-aqueous conditions was reported in U.S. Pat. No. 5,387,679, where condensation of 7-ACA with heterocyclic thiols in the presence of complex of borontriflouride with dialkyl carbonate was carried out to provide intermediates which are used in the synthesis of cephalosporin antibiotics.
- When the process of U.S. Pat. No. 5,387,679 is applied for the condensation of 7-ACA and furyl-2-carbonylthiol, the reaction mixture obtained is associated with several impurities, which could not be separated even during the final purification step. Later on, after several experimentation, the applicant found that the stability of furyl-2-carbonylthiol isolated in solid form is not encouraging. Further, this problem is encountered because furyl-2-carbonylthiol belongs to the class of heterocyclic thioacids and not heterocyclic thiol. The behavior of the reaction is not similar for the thioacids as it was for thiols thereby disallowing the conditions of the U.S. Pat. No. 5,387,679 to be used in the present invention to achieve the final result.
- In order to overcome this problem, the applicant provides for the first time an improved process for condensing 7-ACA with furyl-2-carbonylthiol which is generated and used in situ in the presence of borontriflouride in a gaseous state or its solution in an organic solvent to obtain compound of formula (I). This process gives desired product of formula (I) in excellent yield (90-95%) and high purity (98-99%).
- The primary object of the invention is to provide an improved and commercially viable efficient process for preparing 7-amino-3-[2-(furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid (I), as an intermediate for ceftiofur.
- Another object of the invention is to use furyl-2-carbonylthiol in situ without isolating it.
- Yet another objective of this invention is to provide a process which will give high yield and purity of the required product.
- Still another object of the invention is to provide the use of boron trifluoride in gaseous state or its solution in an organic solvent for carrying out the condensation reaction at low temperature which are convenient for commercial production.
- To meet the above objectives, the present invention provides a process for the preparation of 3-[2-(furylcarbonyl) thiomethyl]-3-cephem-4-carboxylic acid (I) by the condensation of 7-aminocephalosporanic acid (II) with furyl-2-carbonylthiol (III) in the presence of borontrifluoride at a temperature range of 20°-50° C. in an organic solvent. This process gives high yields and excellent purity.
- The present invention provides a process for the preparation of 3-[2-(furylcarbonyl) thiomethyl]-3-cephem4-carboxylic acid represented by formula (I),
- the said process comprising the steps of condensing 7-aminocephalosporanic acid (II) with furyl-2-carbonylthiol (III) in the presence of borontrifluoride at 20°-50° C. in an organic solvent and isolating the compound of formula (I).
- In an embodiment of the present invention, the sequence of the present reaction is shown herebelow:
- An embodiment of the present invention provides a temperature range of 30°-35° C. for performing the condensation reaction.
- Another embodiment of the present invention provides a pH range of 3-4 and preferably 3.45-3.55 for the precipitation of the solid from the solution.
- Yet another embodiment of the present invention provides the drying of the precipitated solid at a temperature range of 40°-45° C. under vacuum.
- One embodiment of the present invention provides the use of furyl-2-carbonylthiol in situ as a solution in an organic solvent.
- Another embodiment of the present invention provides the use of organic solvent in the condensation reaction selected from group consisting of ethyl acetate, methyl acetate, propyl acetate, dichloromethane, toluene, diethyl ether, diisopropyl ether and/or mixture thereof.
- One another embodiment of the present invention provides the use of base to adjust the pH of the reaction mixture is selected from a group consisting of ammonium hydroxide, sodium hydroxide or sodium carbonate.
- Yet another embodiment of the present invention provides use of condensing agent borontriflouride in its gaseous form or its solution in an organic solvent.
- Still yet another embodiment of the present invention the required product is obtained by precipitation and followed by filtration.
- The invention is illustrated with following examples, which should not be construed as limiting the scope of the invention.
- Charge sodium sulfide (54.6 g) in water (600 ml) and furyl-2-carbonylchloride (50.0 g) is added over a period of 60 minutes at a temperature of 20° C. Ethyl acetate is added to it and pH of the reaction mixture mass is adjusted to 1.0. The organic layer is separated, dried over anhydrous sodium sulphate, filtered to get furyl-2-carbonylthiol in ethyl acetate.
- In an another flask ethylacetate (350 ml) is charged, boron trifluoride (124.0 g) gas is purged into it. 7-Amino-cephalosporanic acid (91.0 g ) is added at 10.0° C. into the solution of borontrifluoride followed by the addition of furyl-2-carbonylthiol solution in ethylacetate (prepared above). The reaction is completed by stirring for 4 -5 hr at 30-40° C. After completion of the reaction, the mixture is poured into ice cold water. The pH of the solution is adjusted to 3.45-3.55 by addition of ammonium hydroxide. The solid precipitated is filtered and washed with mixture of water and ethylacetate to get 7-amino -3-(2-furylcarbonyl) thiomethyl]-3-cephem-4-carboxylic acid (I, 110.0 g) with a purity of 98-99% by HPLC.
- Charge sodium sulfide (36.4 g) in water (400 ml) and furyl-2-carbonylchloride (33.3.0 g) is added to it over a period of 60 minutes at a temperature of 20° C. Ethyl acetate is added to it and pH of the reaction mixture is adjusted to 1.0. The organic layer is separated, dried over anhydrous sodium sulphate, filtered to get furyl-2-carbonylthiol in ethyl acetate.
- In an another flask acetonitrile (350 ml) is charged, boron trifluoride gas (85.0 g) is purged into it. 7-Amino-cephalosporanic acid (60.6 g ) is added at 10.0° C. into the solution of borontrifluoride, followed by the addition of furyl-2-carbonylthiol solution in ethylacetate (prepared above). The reaction is completed by stirring for 5 -6 hr at 30-40° C. After completion of the reaction, the mixture is poured into ice cold water. The pH of the solution is adjusted to 3.45-3.55 by addition ammonium hydroxide. The solid precipitated is filtered and washed with mixture of water and acetonitrile to get 7-amino -3-(2-furylcarbonyl) thiomethyl]-3-cephem-4-carboxylic acid (I, 69.0 g) with a purity of 97-98 % by HPLC.
- Charge sodium sulfide (54.6 g) in water (600 ml) and furyl-2-carbonylchloride (50.0 g) is added to it over a period of 60 minutes at a temperature of 20° C. Ethyl acetate is added to it and pH of the mixture is adjusted to 1.0 by adding hydrochloric acid. The organic layer is separated, dried over anhydrous sodium sulphate, filtered to get furyl-2-carbonylthiol in ethyl acetate.
- In an another flask containing acetonitrile (350 ml) is added 7-Amino-cephalosporanic acid (91.0 g) at room temperature followed by addition of 45-48% solution of boron trifluoride etherate (275.5 ml) at a temperature of 10.0° C. To this added furyl-2-carbonylthiol solution in ethylacetate (prepared above) and the reaction is completed by stirring for 4 -5 hr at 40-50° C. After completion of the reaction, the mixture is poured into ice cold water. The pH of the solution is adjusted to 3.45-3.55 by addition of sodium carbonate solution. The solid precipitated is filtered and washed with mixture of water and ethylacetate to get 7-amino-3-(2-furylcarbonyl) thiomethyl]-3-cephem-4-carboxylic acid (I, 104.0 g) with a purity of 97-98 % by HPLC.
Claims (11)
1. A process for preparation of 3-[2-(furylcarbonyl) thiomethyl]-3-cephem-4-carboxylic acid represented by formula (I),
the said process comprising the steps of condensing 7-aminocephalosporanic acid (II) with furyl-2-carbonylthiol (III) in the presence of borontrifluoride at 20-50° C. in an organic solvent and isolating the compound of formula (I)
2. A process as claimed in claim 1 , wherein the condensation reaction is performed at a temperature range of 30°-35° C.
3. A process as claimed in claim 1 , wherein the reaction mixture of condensation is poured into ice cold water, adjusting the pH of the solution to 3-4 with a base to precipitate the solid.
4. A process as claimed in claim 3 , wherein the pH of the solution lies/is in the range of 3.45-3.55.
5. A process as claimed in claim 2 , wherein the solid obtained by precipitation is washed with a mixture of water and organic solvent, drying the solid at a temperature range of 40°-45° C. under vacuum.
6. A process as claimed in claim 1 , wherein furyl-2-carbonylthiol of formula (III) without isolating is used as its solution in an organic solvent selected from a group consisting of ethylacetate, methyl acetate, propyl acetate, dichloromethane, toluene, diethyl ether,di-isopropyl ether and/or mixture thereof.
7. A process as claimed in claim 1 , wherein the organic solvent used in the condensation reaction is selected from a group consisting of ethylacetate, methyl acetate, propyl acetate, dichloromethane, toluene, diethyl ether, di-isopropyl ether, acetonitrile, acetic acid or mixture thereof, most preferably ethyl acetate.
8. A process as claimed in claim 1 , wherein the condensing agent borontrifluoride is used in a gaseous form or its solution in an organic solvent selected from ethyl acetate, acetonitrile, methyl acetate, propyl acetate, dichloromethane, toluene, diethyl ether, di-isopropyl ether and/or mixture thereof, most preferably in gaseous form.
9. A process as claimed in claim 1 , wherein 3-8 moles of borontrifluoride is used with respect to 7-aminocephalosporanic acid, the preferred molar ratio being 4.5:1.
10. A process as claimed in claim 3 , wherein the base used is selected from a group consisting of ammonium hydroxide, sodium hydroxide, or sodium carbonate and most preferably ammonium hydroxide.
11. A process as claimed in claim 5 , wherein the organic solvent used for washing the final product is selected from a group consisting of acetonitrile, ethylacetate, acetone, methyl acetate, propyl acetate, dichloromethane, toluene, diethyl ether,di-isopropyl ether and/or mixture thereof.
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/035,178 US20030135041A1 (en) | 2002-01-04 | 2002-01-04 | Synthesis of ceftiofur intermediate |
| US10/208,879 US6803461B2 (en) | 2002-01-04 | 2002-08-01 | Synthesis of ceftiofur intermediate |
| EP02751578A EP1463734B1 (en) | 2002-01-04 | 2002-08-13 | An improved synthesis of ceftiofur intermediate |
| CNB028266498A CN1310923C (en) | 2002-01-04 | 2002-08-13 | An improved synthesis of ceftiofur intermediate |
| ES02751578T ES2242044T3 (en) | 2002-01-04 | 2002-08-13 | IMPROVED SYNTHESIS OF A CEFTIOFUR INTERMEDIATE. |
| CA2471310A CA2471310C (en) | 2002-01-04 | 2002-08-13 | An improved synthesis of ceftiofur intermediate |
| DE60203944T DE60203944T2 (en) | 2002-01-04 | 2002-08-13 | IMPROVED MANUFACTURE OF CEFTIOFUR INTERMEDIATE PRODUCTS |
| BR0215473-0A BR0215473A (en) | 2002-01-04 | 2002-08-13 | Improved synthesis of ceftiofur intermediate |
| PCT/IB2002/003268 WO2003055893A1 (en) | 2002-01-04 | 2002-08-13 | An improved synthesis of ceftiofur intermediate |
| KR1020047010492A KR100847339B1 (en) | 2002-01-04 | 2002-08-13 | An improved synthesis of ceftiofur intermediate |
| AT02751578T ATE294183T1 (en) | 2002-01-04 | 2002-08-13 | IMPROVED PRODUCTION OF CEFTIOFUR INTERMEDIATE PRODUCTS |
| MXPA04006587A MXPA04006587A (en) | 2002-01-04 | 2002-08-13 | An improved synthesis of ceftiofur intermediate. |
| AU2002367103A AU2002367103A1 (en) | 2002-01-04 | 2002-08-13 | An improved synthesis of ceftiofur intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/035,178 US20030135041A1 (en) | 2002-01-04 | 2002-01-04 | Synthesis of ceftiofur intermediate |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US10/208,879 Continuation-In-Part US6803461B2 (en) | 2002-01-04 | 2002-08-01 | Synthesis of ceftiofur intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US20030135041A1 true US20030135041A1 (en) | 2003-07-17 |
Family
ID=21881126
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US10/035,178 Abandoned US20030135041A1 (en) | 2002-01-04 | 2002-01-04 | Synthesis of ceftiofur intermediate |
| US10/208,879 Expired - Fee Related US6803461B2 (en) | 2002-01-04 | 2002-08-01 | Synthesis of ceftiofur intermediate |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US10/208,879 Expired - Fee Related US6803461B2 (en) | 2002-01-04 | 2002-08-01 | Synthesis of ceftiofur intermediate |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US20030135041A1 (en) |
| EP (1) | EP1463734B1 (en) |
| KR (1) | KR100847339B1 (en) |
| CN (1) | CN1310923C (en) |
| AT (1) | ATE294183T1 (en) |
| AU (1) | AU2002367103A1 (en) |
| BR (1) | BR0215473A (en) |
| CA (1) | CA2471310C (en) |
| DE (1) | DE60203944T2 (en) |
| ES (1) | ES2242044T3 (en) |
| MX (1) | MXPA04006587A (en) |
| WO (1) | WO2003055893A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112645965A (en) * | 2020-12-22 | 2021-04-13 | 浙江华尔成生物药业股份有限公司 | Preparation process of ceftiofur sodium for vacuum freeze-drying injection |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100502390B1 (en) * | 2001-09-07 | 2005-07-19 | 주식회사 엘지생명과학 | Process for preparing cephalosporinic acid |
| ATE373667T1 (en) * | 2002-10-29 | 2007-10-15 | Lupin Ltd | METHOD FOR PRODUCING CEFTIOFUR |
| US8470809B2 (en) * | 2005-10-12 | 2013-06-25 | Orchid Chemicals & Pharmaceuticals Limited | Crystalline sodium salt of cephalosporin antibiotic |
| JP2009511563A (en) * | 2005-10-12 | 2009-03-19 | オーキッド ケミカルズ アンド ファーマシューティカルズ リミテッド | Crystalline sodium salt of cephalosporin antibiotics |
| EP2324034A4 (en) * | 2008-08-22 | 2012-05-16 | Orchid Chemicals & Pharm Ltd | Crystalline sodium salt of cephalosporin antibiotic |
| CN102234289B (en) * | 2010-05-02 | 2013-07-10 | 青岛科技大学 | Novel method for preparing ceftiofur intermediate |
| CN103804394A (en) * | 2014-01-24 | 2014-05-21 | 瑞普（天津）生物药业有限公司 | Preparation method of ceftiofur intermediate |
| CN108623617B (en) * | 2017-03-22 | 2021-04-02 | 蒋辉 | Preparation method of ceftiofur intermediate |
| CN114409676A (en) * | 2021-12-24 | 2022-04-29 | 河南立诺制药有限公司 | Preparation method of 7-ACF |
| CN116535421A (en) * | 2023-07-04 | 2023-08-04 | 齐鲁晟华制药有限公司 | Synthesis method of ceftiofur sodium |
Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4115645A (en) * | 1977-05-10 | 1978-09-19 | Eli Lilly And Company | Decolorizing process for 7-amino-3-(((2-methyl-1,3,4-thiadiazol-5-yl)thio)methyl)-3-cephem-4-carboxylic acid |
| US4144391A (en) * | 1977-03-07 | 1979-03-13 | Eli Lilly And Company | Cephalosporin displacement reaction |
| US4317907A (en) * | 1977-02-08 | 1982-03-02 | Toyama Chemical Co., Ltd. | Process for producing 7-(substituted)amino-3-substituted thiomethyl cephem carboxylic acids |
| US4472574A (en) * | 1981-05-22 | 1984-09-18 | Hoffman-La Roche Inc. | Process for the manufacture of a cephem carboxylic acid derivative |
| US5580978A (en) * | 1985-06-03 | 1996-12-03 | Biochemie Gesellschaft M.B.H. | Process for the production of 7-ACA derivatives |
| US5597914A (en) * | 1993-10-22 | 1997-01-28 | Biochemie Gesellschaft M.B.H. | Process for the production of cephalosporins |
| US5700932A (en) * | 1996-07-19 | 1997-12-23 | Cheil Jedang Co. | Process for preparing cephem derivative |
| US5869649A (en) * | 1996-03-18 | 1999-02-09 | Ranbaxy Laboratories Ltd. | Process for producing cephalosporin antibiotics |
| US6191123B1 (en) * | 1999-03-19 | 2001-02-20 | Parker Hughes Institute | Organic-arsenic compounds |
| US6214997B1 (en) * | 1998-06-01 | 2001-04-10 | Ranbaxy Laboratories Limited | Process for the preparation of crystalline (Z)-2-(2-tert.-butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl) acetic acid in association with N,N-dimethylformamide |
| US6235896B1 (en) * | 1998-03-30 | 2001-05-22 | Ranbaxy Laboratories Limited | Process for the preparation of cefuroxime |
| US6384213B1 (en) * | 1998-10-23 | 2002-05-07 | Ranbaxy Laboratories Limited | Process for preparing a pure, pharmacopoeial grade amorphous form of cefuroxime axetil |
| US6458949B1 (en) * | 2000-08-14 | 2002-10-01 | Aurobindo Pharma Limited | Ceftiofur, its intermediate and a process for the preparation of the same |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2472574A1 (en) | 1979-12-24 | 1981-07-03 | Ici Pharma | CEPHALOSPORINE DERIVATIVES AND PHARMACEUTICAL COMPOSITION CONTAINING SAME |
| FR2479229B1 (en) | 1980-03-26 | 1986-01-17 | Clin Midy | NOVEL CEPHALOSPORIN DERIVATIVES, PROCESS FOR THEIR PREPARATION AND MEDICAMENTS FOR USE AS ANTIBIOTICS CONTAINING SAID DERIVATIVES |
| EP0233255B1 (en) | 1985-08-12 | 1996-05-29 | The Upjohn Company | Conversion of cephalosporin hydrohalide salt to alkali metal salt |
| GB9115287D0 (en) | 1991-07-15 | 1991-08-28 | Antibioticos Spa | Process for the preparation of cephalosporins intermediates |
| AU5839000A (en) | 1999-07-30 | 2001-02-19 | Ranbaxy Laboratories Limited | An improved form of form i celiprolol hydrochloride |
| IN190849B (en) | 2000-07-17 | 2003-08-23 | Ranbaxy Lab Ltd | |
| US6476220B2 (en) | 2000-11-27 | 2002-11-05 | Aurobindo Pharma Limited | Process for the preparation of furaca |
| EP1294712A1 (en) | 2001-05-18 | 2003-03-26 | Aurobindo Pharma Limited | Process for the crystallization of losartan potassium |
-
2002
- 2002-01-04 US US10/035,178 patent/US20030135041A1/en not_active Abandoned
- 2002-08-01 US US10/208,879 patent/US6803461B2/en not_active Expired - Fee Related
- 2002-08-13 BR BR0215473-0A patent/BR0215473A/en not_active IP Right Cessation
- 2002-08-13 AT AT02751578T patent/ATE294183T1/en not_active IP Right Cessation
- 2002-08-13 EP EP02751578A patent/EP1463734B1/en not_active Expired - Lifetime
- 2002-08-13 CA CA2471310A patent/CA2471310C/en not_active Expired - Fee Related
- 2002-08-13 DE DE60203944T patent/DE60203944T2/en not_active Expired - Lifetime
- 2002-08-13 MX MXPA04006587A patent/MXPA04006587A/en active IP Right Grant
- 2002-08-13 ES ES02751578T patent/ES2242044T3/en not_active Expired - Lifetime
- 2002-08-13 WO PCT/IB2002/003268 patent/WO2003055893A1/en not_active Application Discontinuation
- 2002-08-13 KR KR1020047010492A patent/KR100847339B1/en not_active IP Right Cessation
- 2002-08-13 CN CNB028266498A patent/CN1310923C/en not_active Expired - Fee Related
- 2002-08-13 AU AU2002367103A patent/AU2002367103A1/en not_active Abandoned
Patent Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4317907A (en) * | 1977-02-08 | 1982-03-02 | Toyama Chemical Co., Ltd. | Process for producing 7-(substituted)amino-3-substituted thiomethyl cephem carboxylic acids |
| US4385178A (en) * | 1977-02-08 | 1983-05-24 | Toyama Chemical Co., Ltd. | Process for producing 7-(substituted)amino-3-substituted thiomethyl cephem carboxylic acids |
| US4144391A (en) * | 1977-03-07 | 1979-03-13 | Eli Lilly And Company | Cephalosporin displacement reaction |
| US4115645A (en) * | 1977-05-10 | 1978-09-19 | Eli Lilly And Company | Decolorizing process for 7-amino-3-(((2-methyl-1,3,4-thiadiazol-5-yl)thio)methyl)-3-cephem-4-carboxylic acid |
| US4472574A (en) * | 1981-05-22 | 1984-09-18 | Hoffman-La Roche Inc. | Process for the manufacture of a cephem carboxylic acid derivative |
| US5580978A (en) * | 1985-06-03 | 1996-12-03 | Biochemie Gesellschaft M.B.H. | Process for the production of 7-ACA derivatives |
| US5597914A (en) * | 1993-10-22 | 1997-01-28 | Biochemie Gesellschaft M.B.H. | Process for the production of cephalosporins |
| US5869649A (en) * | 1996-03-18 | 1999-02-09 | Ranbaxy Laboratories Ltd. | Process for producing cephalosporin antibiotics |
| US5700932A (en) * | 1996-07-19 | 1997-12-23 | Cheil Jedang Co. | Process for preparing cephem derivative |
| US6235896B1 (en) * | 1998-03-30 | 2001-05-22 | Ranbaxy Laboratories Limited | Process for the preparation of cefuroxime |
| US6214997B1 (en) * | 1998-06-01 | 2001-04-10 | Ranbaxy Laboratories Limited | Process for the preparation of crystalline (Z)-2-(2-tert.-butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl) acetic acid in association with N,N-dimethylformamide |
| US6384213B1 (en) * | 1998-10-23 | 2002-05-07 | Ranbaxy Laboratories Limited | Process for preparing a pure, pharmacopoeial grade amorphous form of cefuroxime axetil |
| US6191123B1 (en) * | 1999-03-19 | 2001-02-20 | Parker Hughes Institute | Organic-arsenic compounds |
| US6458949B1 (en) * | 2000-08-14 | 2002-10-01 | Aurobindo Pharma Limited | Ceftiofur, its intermediate and a process for the preparation of the same |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112645965A (en) * | 2020-12-22 | 2021-04-13 | 浙江华尔成生物药业股份有限公司 | Preparation process of ceftiofur sodium for vacuum freeze-drying injection |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1639169A (en) | 2005-07-13 |
| CA2471310A1 (en) | 2003-07-10 |
| WO2003055893A1 (en) | 2003-07-10 |
| DE60203944D1 (en) | 2005-06-02 |
| KR20040098628A (en) | 2004-11-20 |
| CN1310923C (en) | 2007-04-18 |
| KR100847339B1 (en) | 2008-07-21 |
| ES2242044T3 (en) | 2005-11-01 |
| CA2471310C (en) | 2011-02-22 |
| US6803461B2 (en) | 2004-10-12 |
| MXPA04006587A (en) | 2005-07-13 |
| AU2002367103A1 (en) | 2003-07-15 |
| EP1463734A1 (en) | 2004-10-06 |
| ATE294183T1 (en) | 2005-05-15 |
| US20030130502A1 (en) | 2003-07-10 |
| DE60203944T2 (en) | 2006-02-23 |
| BR0215473A (en) | 2004-11-30 |
| EP1463734B1 (en) | 2005-04-27 |
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Owner name: ORCHID CHEMICALS & PHARMACEUTICALS LIMITED, INDIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DESHPANDE, PRAMOD NARAYAN;KHADANGALE, BHAUSAHEB PANDHARINATH;KUMAR, SURULICHAMY SENTHIL;AND OTHERS;REEL/FRAME:012870/0595;SIGNING DATES FROM 20020211 TO 20020404 |
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| STCB | Information on status: application discontinuation |
Free format text: EXPRESSLY ABANDONED -- DURING EXAMINATION |