WO1996017846A1 - Process for the preparation of intermediates useful in the synthesis of cephalosporins - Google Patents
Process for the preparation of intermediates useful in the synthesis of cephalosporins Download PDFInfo
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- WO1996017846A1 WO1996017846A1 PCT/US1995/015169 US9515169W WO9617846A1 WO 1996017846 A1 WO1996017846 A1 WO 1996017846A1 US 9515169 W US9515169 W US 9515169W WO 9617846 A1 WO9617846 A1 WO 9617846A1
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- 0 *OC(C(N([C@]([C@@]1NC(S)=O)SC2)C1=O)=C2O)=O Chemical compound *OC(C(N([C@]([C@@]1NC(S)=O)SC2)C1=O)=C2O)=O 0.000 description 4
- LYIZAOVRQUBOOK-HWABHILUSA-N CC(N[C@@H]([C@H](N1C2C(O)=O)SCC2=C)C1=O)=O Chemical compound CC(N[C@@H]([C@H](N1C2C(O)=O)SCC2=C)C1=O)=O LYIZAOVRQUBOOK-HWABHILUSA-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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention provides a process for preparing intermediates useful in the synthesis of cephalosporin type antibiotics.
- ceftibuten starting from penicillin G is described in Yoshioka, Pure Appl. Chem.. 59. 1041 (1987). However, this process is costly and inefficient leaving a current need for a more cost effective and efficient process for the commercial scale preparation of ceftibuten.
- EP 082,656 describes the electrochemical reduction of acetoxymethyl compounds of the formula
- n 0 or 1
- R is H or an acyl group, to form the corresponding 3-exomethylene compounds.
- the present invention solves the problems of the prior art processes by providing an efficient electrochemical process for preparing 3-exomethylene cephalosporins while producing very low levels of the 3-methyl tautomer. More specifically the present invention provides a process for preparing compounds of the formula (II) or (III) and esters thereof
- R 1 is H and R is H or NHR 2
- R 2 is H or a protecting group selected from C 6 H 5 CH 2 ⁇ C(0)-, C ⁇ HsCfO)- or C i -C ⁇ alkoxy-C(O)-; or wherein R and R 1 together with the carbon atom to which they are attached comprise -C(O)-.
- Compounds (II) and (III) and the esters thereof are useful as intermediates in the synthesis of ceftibuten (I) .
- the process of the present invention comprises electrochemically reducing a solution of a compound of the formula (IV) wherein: R 3 is CH 3 C(0)-; I ") ' is an optional sulfoxide group; and n.
- R and R 1 are as defined above, at a concentration of 10-50 g/L. at a pH of 7- 10. and at a current density of 10-40 mA/cm 2 , in the presence of a buffer and in a solvent selected from water, an organic solvent, or a mixture of water and a water miscible organic additive, to form a compound of the formula (II) or (III).
- the present invention also provides novel compounds of the formula (II) or (III) as defined above, wherein n is 2 or 3; R 1 is H and R is H or NHR 2 . where R 2 is C 6 H 5 C(0)-; C 6 H 5 CH2 ⁇ C(0)-. or (CH 3 ) 2 CHCH 2 ⁇ C(0)-; or wherein R and R 1 together with the carbon to which they are attached comprise -C(O)-, and esters or salts thereof.
- the present invention provides a process for preparing compounds of the formula (V)
- R 4 is diphenylmethyl, and n. (?) R and R 1 are as defined above;
- step (c ) ozonolyzing the compound (VI) from step (b) to form a compound of the formula (V). as defined above.
- the present invention further provides a process for preparing the diphenylmethyl ester of 7-amino-3- desacetoxymethylcephalosporanic acid, i.e. , a compound of the formula (VII)
- R 4 is diphenylmethyl, comprising the steps: (d) reducing a compound of the formula (V) as defined above to form a compound of the formula (VIII)
- R 4 , n, R, and R 1 are as defined above;
- step (e ) reacting the product of step (d) with a compound of the formula P-X, wherein P is a sulfonyl activating group and X is Cl, Br or I, in the presence of a tertiary amine base to form a compound of the formula (IX)
- R 1 are as defined above;
- step (f) (i) treating the product of step (e) with PCI5 in the presence of a tertiary amine base and an alcohol or diol. then with a dialkylamine base; or (ii) treating the product of step (e) with a dialkylamine base or a tertiary amine base, and then with PCI 5 in the presence of a tertiary amine base and an alcohol or diol;
- alkyl means a straight or branched alkyl chains of 1 to 6 carbon atoms;
- aryl means a C ⁇ -C io carbocyclic aromatic group, such as phenyl or naphthyl; and
- substituted aryl means an aryl group having 1 to 3 substituents selected from halogeno, C j -C ⁇ alkyl. NO2 or CF3;
- halogeno means Cl. Br or I
- sulfonyl activating group means a substituent of the formula -SO2R 6 . wherein R 6 is Ci -C ⁇ alkyl, aryl, substituted aryl or -CF3;
- hydride reducing agent means NaBH 4 , BH 4 . NaBH3CN, or a combination of N-1BH 4 and LiCl;
- aqueous acid means an aqueous solution of an acid, such as HC1;
- dialkylamine base means a compound of the formula HN(alkyl)2. such as diethylamine;
- tertiary amine base means bases such as pyridine, DMAP. DMA. Et 3 N or H ⁇ nigs base;
- tetra(alkyl) ammonium salts mean salts comprising a tetra(alkyl) ammonium cation, such as tetraethylammonium, tetramethylammonium. tetrabutylammonium or tetrapropylammonium, and a suitable counterion such as p-toulenesulfonate or sulfate;
- alcohol means a C 1 -C 4 alcohol, such as methanol, ethanol or i-propanol
- diol means a C 2 -C 6 diol, such as ethylene glycol, 1 ,3-propanediol or 1 ,3-butanediol.
- Buffer means one or more buffer compounds which are water soluble acids and/or bases, such as H 2 PO 4 , KH 2 P0 4 . NaH 2 P0 4 , Li 2 HP0 4 . K 2 HP0 4 . Na 2 HP0 4 , Li 3 P0 4 . K3PO 4 , Na 3 P0 4 . HCO 3 , NaHC0 3 . KHCO3, Na 2 C0 3 , K2CO3, 2CO 3 , NaOH, KOH, UOH. HCIO 4 and H3BO3.
- the buffer is an individual buffer compound, or two or more such compounds in combination, and is used to maintain constant pH and to facilitate the course of the eletrochemicai reduction.
- Water miscible organic additives are organic compounds which are soluble in water and relatively unsusceptible to electrochemical reduction under the conditions of the present invention, such as EtOAc, iPrOAc. CH 3 CN, MeOH, EtOH, iPrOH, DMF. formamide. DMSO or urea.
- Adsorbent resin means a polymeric nonionic macroreticular (i.e., porous) adsorbent capable of selectively adsorbing hydrophobic molecules, such as compounds of the formula (II), (III), (XII), (XIII) and (XIV), from a polar solvent, such as water.
- Such resins are typically aromatic polymers. such as styrene and divinylbenzene coplymers, which may be cross-linked.
- Such resins are known and are generally prepared by polymerization of the appropriate monomers. (See, e.g. U.S. Patent Nos.
- a number of such adsorbent resins are readily commercially available, including: Amberlite® XAD-7, XAD- 1180, XAD- 16 and XAD- 1600 (available from Rohm & Haas); XUS-40323.00, XUS- 40285.00 and XUS-40283.00 (available from Dow Chemical Co.); and Diaion HP 10. HP 20, HP 30. HP 40 and HP 50 (available from Mitsubishi Chemical).
- the present invention comprises a process for preparing a compound of the formula (II) or (III) as shown in Reaction Scheme 1
- a solution comprising a compound of the formula (IV), as defined above, a suitable solvent, and a buffer, is electrochemically reduced to form a compound of the formula (II) or (III) as defined above.
- the working electrode (cathode) for this reduction is selected from known electrode materials so that hydrogen overpotential is maximized, and includes electrodes made from Ti, In, Cd, Pb. Ga. Zn, Ag, Sn, Bi, Hg. Pt, Mo. Nb, Ta. C, Cu, Fe and Ni, as well as metal alloys such as Pb/Ag, Cu/Hg and steels of various compositions, including those steels described in "Kirk-Othmer Concise Encyclopedia of Chemical Technology", pp.
- cathode materials include Ti, In, Cd. Hg. Pb, Ga. Zn. Ag, Sn, Bi and C (in particular C in the form of graphite, graphite felt or reticulated vitreous carbon). Also preferred are cathodes made from C, Pb, Hg, Sn or Zn, with mercury, tin and lead being most preferred.
- the cathode has a high surface area such that the ratio of electrode area to solution volume is optimized. The reduction is preferably carried out at a current density of 10 mA/cm 2 to 40 mA/cm 2 .
- the solvent is selected from water, a suitable organic solvent, or a mixture of water and a water miscible organic additive, and is preferably water or a mixture of water and a water miscible organic additive.
- the electrochemical reduction is carried out at a temperature of -60° to 80°C, preferably at -20° to 30°C, more preferably at -20° to 20°C, and most preferably at 0° to 10°C, at a pH of 7-10.
- a buffer, or a combination of two or more buffers, is used as needed to maintain the desired pH range.
- the buffer is present at a concentration of 0.1 M to 2 M, preferably at 0.2 M to 1.5 M, and most preferably at 0.5 M to 1.0 M.
- the initial concentration of the starting compound (IV) in the reduction solution is from 1 g/L to 100 g/L, preferably at 5 g/L to 60 g/L and most preferably at 10 g/L to 50 g/L.
- the electrochemical reduction is carried out in a suitable electrochemical cell, a large variety of which are known in the art.
- the cell is a flow cell wherein the solution comprising the compound to be reduced is circulated through the electrochemical cell from an external reservoir.
- a two-chambered cell wherein the cathode and anode are contained in separate chambers.
- the cathode and anode chambers of such cells are constructed such that fluid contained in one chamber is physically separated from the other chamber by a suitable divider while maintaining an electrical connection between the chambers.
- the divider is a porous material, such as sintered glass, or a suitable ion exchange membrane, such as a Nafion ® membrane.
- the chamber containing the anode will also contain a solution of a buffer in water, which buffer can be the same or different as the buffer in the cathode chamber.
- the buffer in the anode chamber i.e., the anolyte, is a phosphate salt, perchloric acid or sulfuric acid, with perchloric acid being preferred.
- the anolyte concentration is preferably 0.2 M to 2 M, and is most preferably about 1 M.
- Compounds of the formula (II), (III) and (IV) contain two carboxylic acid groups and therefore exist as anionic species at the preferred pH used for the electrochemical reduction.
- An ion exchange membrane divider which is permeable to cations but not anions, can therefore be used to prevent migration of compounds (II). (Ill) and (IV) to the anode, thereby preventing the possibility of side reactions from occurring at that electrode.
- the ion exchange membrane is a perfluorinated ionomer membrane, such as the perfluorinated sulfonic acid or perfluorinated carboxylic acid ionomers described in the "Kirk-Othmer Concise Encyclopedia of Chemical Technology", John Wiley & Sons, p. 843-844 (New York, 1985), herein incorporated by reference. Most preferred are Nafion® or Flemion ® membranes, with Nafion ® membranes being especially preferred. Compounds of the formula (IV) are known and can be readily prepared via established methods.
- the product compounds (II) and (III) from the electrochemical reduction of Reaction Scheme 1 typically contain several byproducts as impurities.
- Purified 3-exomethylene products (II) and (III) offer a number of advantages (including superior performance in subsequent steps of the processes described in Reaction Schemes 2 and 3, below).
- An efficient method for removal of all. or at least some, of the byproducts from the desired reduction product (II) or (III) is therefore desirable.
- the instant invention also provides a method for removal of such byproducts comprising chromatography of the crude electrochemical reduction product on a suitable adsorbent resin.
- suitable adsorbent resins include Amberlite ® XAD- 16. Amberlite ® XAD- 1180. Amberlite ® XAD-7. Amberlite ® XAD-1600, Dianon HP-20. SP-825. XUS-40323.00. XUS-40285.00.
- Adsorbent resin chromatography of the electrochemical reduction product is typically carried out at a temperature of 0°C to 25°C at a column load of about 30 g material/L of resin.
- the column is preconditioned by washing with methanol followed by deionized water.
- the electrolytic reduction solution containing the materials to be separated, obtained as described above, is filtered through a filter aid (such as celite ® ) then acidified to a pH of 3.5-4.0, and passed through the column, typically at a rate of about 1 column bed volumes/hour (BV/hr.) to load the column.
- a filter aid such as celite ®
- the column is then eluted using a suitable solvent, such as deionized distilled water or a mixture of deionized distilled water and an alcohol (such as methanol, ethanol or isopropanol), which elution solvent may also contain a buffer to adjust the pH of the solution.
- a suitable solvent such as deionized distilled water or a mixture of deionized distilled water and an alcohol (such as methanol, ethanol or isopropanol), which elution solvent may also contain a buffer to adjust the pH of the solution.
- a suitable solvent such as deionized distilled water or a mixture of deionized distilled water and an alcohol (such as methanol, ethanol or isopropanol)
- an alcohol such as methanol, ethanol or isopropanol
- the present invention also provides a process for preparing compounds of the formula (V) as shown in Reaction Scheme 2.
- Step A of Reaction Scheme 2 the starting compound (IV), as defined above, is eletrochemically reduced to a compound of the formula (II) or (III) via the same procedure described for Reaction Scheme 1.
- the reduction product (II) or (III) is optionally purified by chromatography on an adsorbent resin as described above.
- Step B a compound of the formula (II) or (III) is esterified by treating with a suitable esterifying agent, such as diphenyldiazomethane, in a suitable solvent, such as water or a mixture of water and a polar organic solvent, to form the diester (VI), as defined above.
- a suitable esterifying agent such as diphenyldiazomethane
- a suitable solvent such as water or a mixture of water and a polar organic solvent
- Step C the diester (VI) is treated with ozone in a suitable solvent, such as CH2CI 2 . at a temperature of -100°C to 0°C. preferably at -80° to -20°C, to form an ozonide intermediate, then further treated with a suitable reducing agent, such as P(OC2H 3 )3 to reduce the ozonide intermediate and form a compound of the formula (V), as defined above.
- a suitable solvent such as CH2CI 2 .
- a suitable reducing agent such as P(OC2H 3 )3
- the product (II) or (III) of Step A is treated with ozone, using essentially the same procedure as described for Step C (above), to form a compound of the formula (X)
- step D a compound of the formula (V). as defined above, is treated with a hydride reducing agent, preferably NaBH 4 , in the presence of a suitable solvent to form a compound of the formula (VIII), wherein n, R. R 1 , R 4
- Suitable solvents include Et 2 ⁇ , THF, a C 1 -C 4 alcohol, water, a mixture of CH2CI2 and a C 1 -C 4 alcohol, or a mixture of water and a C 1 -C 4 alcohol.
- the reaction is carried out at a temperature of -100°C to 30°C, preferably at -80°C to 0°C, and the specific solvent or solvent mixture to be used is selected such that the reaction temperature is higher than the freezing point of the mixture.
- the solvent is a mixture of CH2CI2 and a C 1 -C 4 alcohol and the reaction temperature is -80° to -40°C.
- Steps E and F of Reaction Scheme 3 are carried out as a "one pot" process, i.e., the required reagents are sequentially added to the reaction mixture without workup or isolation between steps.
- Step E the product (VIII) of step D is reacted with a compound of the formula P-X, wherein P and X are as defined above, in a suitable solvent, such as CH 2 CI2, in the presence of a tertiary amine base, such as Et3N, to form a mixture comprising a compound of the formula (IX), wherein P, / O x
- step F the product mixture from step E is treated sequentially with PCI 5 and a dialkylamine base, such as diethylamine. to form a compound of formula (VII) .
- a dialkylamine base such as diethylamine.
- PCI5 in the presence of the tertiary amine base and a C 1 -C 4 alcohol, preferably methanol, or a C 2 -C 6 diol, preferably 1 ,3- butanediol, serves to cleave the amide side chain to form the free amino group.
- Additional tertiary amine base is added with the PCI5 in step F as necessary.
- Treatment with dialkylamine base results in elimination of the 3-OP group to form the 3.4 double bond.
- the reaction is carried out by adding PCI 5 and an alcohol or diol to the mixture, followed by treatment with a dialkylamine base.
- the mixture is first treated with the dialkylamine base followed by treatment with PCI 5 and alcohol or diol.
- step F further comprises treatment with PCI 3 to reduce the sulfoxide group to the analogous sulfide.
- the product (X) described above is treated with a hydride reducing agent, using essentially the same procedure as described for Step D (above) to form a compound of the formula (XI)
- Electrochemical reductions are carried out in an electrochemical cell with the counter electrode (anode) separated from the working (cathode) and reference electrodes.
- the potential can be controlled using a constant voltage source, such as a Princeton Applied Research Model 273 potentiostat, at from - 1 to -3 volts, preferably from - 1.5 to -2.5 volts.
- Nafion ® membranes for use as dividers are commercially available from a number of sources, e.g. DuPont or Aldrich Chemical Company. The Nafion ® membrane is cleaned prior to use by boiling in 3% H 2 O2 for 30 minutes, followed by immersion in a hot (80°C) solution of 9 M nitric acid for 15 minutes. The membrane is then rinsed in boiling water, sonicated in several aliquots of hot (90°C) water and stored under distilled water until needed.
- the counter electrode is a platinum mesh electrode and the reference electrode is an Ag/AgCl electrode.
- the working electrode is a mercury pool (triple-distilled mercury) electrode; graphite (Johnson Mathey, 99.9995%) electrode; glassy carbon electrode, lead (Johnson Mathey 99.9999%) electrode, tin foil electrode (Aldrich 99.9% pure), or zinc (Johnson Mathey, 99.95%) rod sealed in Teflon ® .
- HPLC analysis is performed on a Brownlee HPLC Analytical Column (RP 18 SPHER 1-5, 250 X 4.6 mm) maintained at a temperature of 35°C.
- the mobile phase is typically 94:6 0.025 M KH 2 P0 4 (aqueous) /CH 3 CN at a flow rate of 1 mL/min., and a UV detector (225 nm) is used.
- Example 1
- Example 1A Dissolve 0.3 g of glutaroyl 7-ACA in 30 mL of an aqueous buffer solution of 1 M H 3 BO 3 and add NaOH to adjust to pH 8.0. Eletrolyze as described for Example 1 at a potential of -2.3 V for a period of 4 hours to give a 6.8: 1 mixture of the same compounds as for Example 1.
- Example 2 Prepare an aqueous electrolysis solution of glutaroyl
- Example 3 Prepare an aqueous electrolysis solution of 5 g/L of glutaroyl 7-ACA and 0.2 M boric acid. Add NaOH to adjust the initial pH of the solution. Using a 2-chambered cell separated by a divider, electrolyze the solution as described for Example 1 at a potential of -2.2 V. Record the final pH and analyze by HPLC, as described above, to determine the yield and the ratio of 3 -exomethylene to 3-methyl compound in the product mixture. At the reaction temperature indicated, the following results are obtained:
- Example 6 Prepare 20 L of an aqueous electrolysis solution of 30 g/L of 7-glutaroyl 7-aminocephalosporanic acid (glutaroyl 7- ACA) and 0.5 M boric acid. Add LiOH to adjust the initial pH of the solution to 9.5. Using a 2-chambered cell separated by a divider, electrolyze the solution at a temperature of 6° to 7°C as described for Example 1 at a current density of 15 mA/cm 2 .
- Step A Adsorbent Resin Column preconditioning:
- diphenyldiazomethane from benzophenone hydrazone by oxidation with a mixture of CH 3 CO3H, 1 , 1.3,3- tetramethylguanidine and 1% (w/v) of iodine in CH 2 CI 2 .
- the oxidation is conducted according to the procedure described in Walker, et al., J.C.S. Perkin I. 2030 (1975) to give a 94% yield of diphenyldiazomethane.
- Step D Reduce the 3-hydroxycephem product of Step D by treating with NaBH 4 and HOAc in a mixture of CH2CI2 and MeOH at -50°C for 20 min. Isolate the product to give a 60-70% yield of 7-N-glutaroyl3-hydroxycepham bis-DPM ester.
- the Yoshioka, et al., process is for conversion of a 7-N-phenylacetyl DPM ester to 7-ADMCA DPM ester, and is substantially the same as the process described in Reaction Scheme 3, Steps E and F, shown above.
- H NMR 300 MHz, CDCI3: 7.5-7.4 (m, 2H); 7.38- 7.2 (m. 8H); 6.95 (s. IH); 6.6 (d of d, IH); 4.85 (d of d, 2H); 3.65-3.35 (m, 2H); 1.76 (br s, 2H).
- Example 10 The extractive esterification of Example 9, Step B can be carried out on a 40-50 g/L solution of the 3-exo- methylene starting material. At such higher concentrations the reaction proceeds more rapidly (it is complete in 6 to 7 hours) and requires less diphenyldiazomethane (typically 2.5 equivalents).
- Example 12 Prepare 10 mL of an aqueous electrolysis solution of
- Example 1 at a current density of 30 mA/cm 2 . Analyze by HPLC, as described above, to determine the yield (67%) and the ratio of 3-exomethylene to 3-methyl compound (20: 1) in the product mixture.
- Step A Extractive Esterification
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU43681/96A AU707559B2 (en) | 1994-12-09 | 1995-12-06 | Process for the preparation of intermediates useful in the synthesis of cephalosporins |
EP95942460A EP0796261A1 (en) | 1994-12-09 | 1995-12-06 | Process for the preparation of intermediates useful in the synthesis of cephalosporins |
NZ298241A NZ298241A (en) | 1994-12-09 | 1995-12-06 | Preparation of intermediates in the synthesis of cephalosporins |
KR1019970703933A KR987000310A (en) | 1994-12-09 | 1995-12-06 | Process for the preparation of intermediates useful in the synthesis of cephalosporins |
HU9801181A HUT77976A (en) | 1994-12-09 | 1995-12-06 | Process for the preparation of intermediates useful in the synthesis of cephalosporins |
JP8517620A JPH10507233A (en) | 1994-12-09 | 1995-12-06 | Method for preparing intermediates useful in the synthesis of cephalosporins |
FI972440A FI972440A0 (en) | 1994-12-09 | 1997-06-09 | Process for the preparation of intermediates useful in the synthesis of cephalosporins |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US35303094A | 1994-12-09 | 1994-12-09 | |
US08/353,030 | 1994-12-09 |
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WO1996017846A1 true WO1996017846A1 (en) | 1996-06-13 |
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US (3) | US5571910A (en) |
EP (1) | EP0796261A1 (en) |
JP (1) | JPH10507233A (en) |
KR (1) | KR987000310A (en) |
CN (1) | CN1174555A (en) |
AU (1) | AU707559B2 (en) |
CA (1) | CA2206226A1 (en) |
FI (1) | FI972440A0 (en) |
HU (1) | HUT77976A (en) |
NZ (1) | NZ298241A (en) |
WO (1) | WO1996017846A1 (en) |
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EP0720611A1 (en) * | 1994-07-22 | 1996-07-10 | Antibioticos S.P.A. | Glutaryl 7-aca derivatives and processes for obtaining them |
CN1308141C (en) | 1996-05-15 | 2007-04-04 | 松下电器产业株式会社 | Method for controlling screen printer |
JP4418043B2 (en) * | 1998-10-07 | 2010-02-17 | 大塚化学株式会社 | Process for producing β-hydroxyester |
JP4215132B2 (en) * | 2007-03-05 | 2009-01-28 | 学校法人慶應義塾 | Electrochemical analysis method using boron-doped conductive diamond electrode |
CN102617600A (en) * | 2012-02-23 | 2012-08-01 | 苏州中联化学制药有限公司 | Synthesizing method of 7-amino-3-nor-3-cephem-4-carboxylic acid |
CN103374018A (en) * | 2012-04-26 | 2013-10-30 | 黄山市歙县宏辉化工有限公司 | Novel method for preparing ceftibuten parent nucleus 7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (7-NACABH) |
CN103588791A (en) * | 2013-11-29 | 2014-02-19 | 中国科学院长春应用化学研究所 | Preparation method of p-nitrobenzyl-7-phenoxyacetamido-3-hydroxycephem-4-carboxylate-1-beta-oxide |
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AU575854B2 (en) * | 1983-10-04 | 1988-08-11 | Shionogi & Co., Ltd. | 7beta-(carboxyalkenamido) cephalosporins |
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US5126446A (en) * | 1991-01-04 | 1992-06-30 | Eli Lilly And Company | Process for 3-exomethylenecepham sulfoxide esters |
GB9203327D0 (en) * | 1992-02-17 | 1992-04-01 | Erba Carlo Spa | Process for the synthesis of exomethylenecephams |
-
1995
- 1995-05-26 US US08/451,287 patent/US5571910A/en not_active Expired - Fee Related
- 1995-12-06 WO PCT/US1995/015169 patent/WO1996017846A1/en not_active Application Discontinuation
- 1995-12-06 KR KR1019970703933A patent/KR987000310A/en active IP Right Grant
- 1995-12-06 CA CA002206226A patent/CA2206226A1/en not_active Abandoned
- 1995-12-06 NZ NZ298241A patent/NZ298241A/en unknown
- 1995-12-06 HU HU9801181A patent/HUT77976A/en unknown
- 1995-12-06 CN CN95197495A patent/CN1174555A/en active Pending
- 1995-12-06 EP EP95942460A patent/EP0796261A1/en not_active Withdrawn
- 1995-12-06 AU AU43681/96A patent/AU707559B2/en not_active Ceased
- 1995-12-06 JP JP8517620A patent/JPH10507233A/en active Pending
- 1995-12-08 US US08/569,631 patent/US5660711A/en not_active Expired - Fee Related
-
1996
- 1996-12-13 US US08/767,268 patent/US5847116A/en not_active Expired - Fee Related
-
1997
- 1997-06-09 FI FI972440A patent/FI972440A0/en unknown
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Also Published As
Publication number | Publication date |
---|---|
US5847116A (en) | 1998-12-08 |
US5571910A (en) | 1996-11-05 |
HUT77976A (en) | 1999-01-28 |
JPH10507233A (en) | 1998-07-14 |
CA2206226A1 (en) | 1996-06-13 |
AU4368196A (en) | 1996-06-26 |
CN1174555A (en) | 1998-02-25 |
KR987000310A (en) | 1998-03-30 |
US5660711A (en) | 1997-08-26 |
NZ298241A (en) | 1999-05-28 |
FI972440A (en) | 1997-06-09 |
EP0796261A1 (en) | 1997-09-24 |
FI972440A0 (en) | 1997-06-09 |
AU707559B2 (en) | 1999-07-15 |
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