US3749641A - Production of 7-amino-3-methylcephem compounds - Google Patents

Production of 7-amino-3-methylcephem compounds Download PDF

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US3749641A
US3749641A US00210105A US3749641DA US3749641A US 3749641 A US3749641 A US 3749641A US 00210105 A US00210105 A US 00210105A US 3749641D A US3749641D A US 3749641DA US 3749641 A US3749641 A US 3749641A
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methyl
cephem
ifo
carboxylic acid
ester
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M Isono
T Takahashi
K Kawahara
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P35/00—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin
    • C12P35/02—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin by desacylation of the substituent in the 7 position
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/832—Bacillus
    • Y10S435/836—Bacillus licheniformis
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/848—Escherichia
    • Y10S435/849—Escherichia coli
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/872—Nocardia
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/886—Streptomyces
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/911—Microorganisms using fungi
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/911—Microorganisms using fungi
    • Y10S435/929—Fusarium

Definitions

  • the former process involves difiiculties in specifically splitting the terminal acid amide linkage at the 7-position without affecting other parts of the molecule, and particularly when the Compound I is desired, the ester residue is required to be a special radical so as to be easily hydrolyzed. Furthermore, the yield of the desired compound varies with even a slight deviation of the reaction conditions. The latter process gives a still less yield than the former process. As far as the known processes are concerned, therefore, none has been industrially feasible.
  • microorganisms which can produce the desired 7-amino-3-methyl-3-cephem-4-carboxylic acid or its ester from the 7-acylamido-3-methyl-3-cephem-4-carboxylic acid or its ester, and that these microorganisms are widely distributed, in nature or in culture collections, among fungi, yeasts and bacteria inclusive of actinomycetes.
  • microorganisms exist Widely in such genera as Aureobasidium, Anthracobia, Ascotricha, Acremonium, Actinomucor, Alternaria, Aegerita, Beauveria, Botryotinia, Byssachlamys, Botryosphaeria, Corynespora, Cunninghamella, Cylindrocarpon, Cylindrocladium, Colletotrichum, Cylindrocephalum, Cercospora, Ceratocystis, Cephalosporium, Cladosporium, Coniochaeta, Chaetomium, Chrysosporium, Cephaloascus, Diaporthe, Daedaleopsis, Dactylaria, Emericellopsis, Fusarium, Griphosphaeria, Gibberella, Glomerella, Isaria, Microascus, Neurospora, Pestalotiopsis, Pyrenophora, Pse
  • the preferable microorganisms are bacteria, particularly those belonging to the genus Escherichia, Bacillus, Xanthomonas, Pseudomonas, Prot aminobacter, Mycoplana or Aeromonas.
  • 7-phenylacetamidoor 7-phenoxyacetamido-3-methyl-3-cephem-4- carboxylic acid or its ester is brought into contact with either of a culture broth of said microorganism or a processed matter thereof in an aqueous medium.
  • the starting compound used as the substrate is 7 phenylacetamido-3-methyl-3-cephem-4-carboxylic acid, 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid or an ester thereof, and is produced, for example, by conversion from the corresponding 6 acylamidopenicillanic acid esters via their S-oxides as described in U.S. Pat. No. 3,275,626 and Belgian aPt. No. 747,118.
  • the starting compound may be put in use in the form of the free acids or the sodium, potassium, ammonium, amine or other salts.
  • the esters as the starting compound are alkyl esters (e.g. methyl, ethyl, butyl or hexyl ester), substituted alkyl esters (e.g. methylthiomethyl, methylsulfenylmethyl, methylsulfonylmethyl, chloromethyl, bromomethyl or trichloroethyl ester; i.e. the substituent being alkylthio, alkylsulfenyl, alkylsulfonyl, halo and so on), aralkyl esters (e.g. benzyl or phenethyl ester) or other esters.
  • alkyl esters e.g. methyl, ethyl, butyl or hexyl ester
  • substituted alkyl esters e.g. methylthi
  • PROCEDURE A Each of the candidate strains is aerobically cultivated in 20 m1. of an aqueous medium under the respective conditions as illustrated in Table 1 according to Whether the strains are bacteria, actinomycetes, fungi or yeasts.
  • noxyacetie acid as the case may be), p 7.2. for 1 to 2 days.
  • PROCEDURE B (SIMPLIFIED PROCEDURE) In the same way a culture of each of the candidate strains is prepared. To 5 ml. of the culture broth is added a solution of 50 mg. of a substrate (e.g. 7-phenylacetamide-3-methyl-3-cephem-4-carboxylic acid) in 1 ml. of a 0.25 M phosphate buffer (pH 7.0). The mixture is then shaken at 28 C. for 16 hours. As to the resultant mixture the following three tests are applied:
  • a substrate e.g. 7-phenylacetamide-3-methyl-3-cephem-4-carboxylic acid
  • the candidate organisms which gave affirmative answers to all of the three tests can be used for the method of the present invention.
  • Said contact of the substrate with the culture broth or its processed matter may be effected in such a manner that the organism is cultivated in a culture medium containing the substrate if the organism has tolerance against the substrate.
  • it is more generally adopted to cultivate such microorganism in a suitable manner and then make use of the resulting cultured broth or its processed matter.
  • Cultivation may be carried out under stirring with aeration, under shaking or stationarily, but in any way an aerobic cultivation is generally preferable.
  • Culture media are prepared by selecting the components, solely or in combination, according to necessity, from meat extract, yeast extract, peptone, casein hydrolyzate, corn steep liquor, potato juice or any other conventionarily used natural matters; carbon compounds such as sugars, organic acids or normal paraffins; a variety of inorganic and organic nitrogen-containing compounds in a form of amino or nitrate; phosphates, magnesium salts, table salt or other metallic ions and various vitamins.
  • the addition of phenoxyacetic acid or phenylacetic acid, which corresponds to the acyl group of the substrate to be employed, to the culture media at a concentration of 0.05 to 1% may result in enhancing the activity of the resulting culture broth of producing the desired product from the substrate.
  • Suitable pH of the culture media and suitable cultivation temperature varies according to the kind of the microorganisms. But a desirable-pH usually lies in a range of pH 5 to 8 for fungi or yeasts and pH 6 to 9 for bacteria or actinomycetes.
  • the temperature is usually selected from about 10 to about 40 C.
  • the time at which said activity of the culture broth reaches the maximum varies according to the kind of the microorganisms employed, so the optimum time for cultivation is desirably determined as to each of the strains.
  • the culture broth thus obtained or a processed matter thereof is utilized for the production of 7-amino-3-methyl-3-cephem-4-carboxylic acid or its ester.
  • any which has been processed by suitable means for elevating or concentrating said transforming activity can be used.
  • said activity mainly exists intracellularly, for example, 1) a cell suspension of separated cells in a buffer solution, (2) a cell-free extract of the cells obtained by per se conventional means (e.g. as described in Section I, particularly Articles 7 and 9, of Methods in Enzymology, Vol. I, edited by S. P. Colowick and N. 0. Kaplan, published by Academic Press Inc., New York in 1955) or (3) an enzyme solution purified or partially purified from said cell-free extract by per se known means (e.g. as in the subsequent Articles 10 to 13, supra), are suitably utilized.
  • the 7-amino-3-methyl-3-cephem 4 carboxylic acid or its ester can be isolated and purified under mild conditions by combination of per se known means such as extraction with solvents or chromatography. It is particularly recommended to subject the filtrate of the reaction mixture to a column chromatography on Amberlite XAD2 and the elution with water to collect the fractions containing the desired product.
  • the IFO numbers and ATCC number attached to the respective species names are the accession numbers in Institute for Fermentation, Osaka, Japan and in American Type Culture Collection, Maryland, U.S.A. and all strains had been available prior to this invention as listed in lists of cultures published by the respective culture collections, except for the following which are not listed in the publications but have deposited also at the Americal Type Culture Collection under the respective accession numbers:
  • Escherichia coli IFO3210 ATCC-21758 Escherichia coli IFO -3467: ATCC-21753
  • Xanthomonas oryzae IFO-3312 ATCC-21754
  • Protamin-obacter alboflavus TI O-13221: ATCC-21755 Mycoplana sp.
  • IFO-l3240 ATCC-21756 Aeromonas hydrophila
  • IFO-12634 ATCC-21757 As to the Mycoplana sp. IFO-13240, the species has not yet been fixed and thus the characteristics of the strain are described as follows:
  • Agar slant Filiform, light gray, smooth.
  • Broth Turbid.
  • Gelatin stab No liquefaction. Thin surface growth. Casein, starch and cellulose were not hydrolyzed.
  • Nitrites not produced from nitrates.
  • Hydrogen sulfide not produced.
  • Indole not produced.
  • Methyl Red test Negative.
  • Catalase Positive.
  • Litmus milk Unchanged.
  • Potato No growth. No growth or scant, if any, in carbohydrate media.
  • Aromatic compounds such as phenylglycine were utilized. Isolated from soil.
  • EXAMPLE 1 A 2-day inocul-um (5 parts by volume) of Escherichia coli IFO-3210 was inoculated in 200 parts by volume of a culture medium of pH 7.2, comprising 1.0% of meat extract, 1.0% of peptone, 0.5% of sodium glutamate, 0.5 of sodium chloride and 0.05% of phenylacetic acid.
  • the culture medium was incubated at 37 C. under shaking for 48 hours, followed by the addition of a solution of 0.8 part by weight of methyl 7-phenylacetamido- 3 methyl 3 cephem 4 carboxylate in 8 parts by volume of acetone together with 50 parts by volume of a 0.25 M phosphate buffer solution (pH 7.0). The whole mixture was then shaken at 28 C.
  • reaction mixture was filtered to remove the cells, and the filtrate was subjected to a column chromatography on Amberlite XAD-Z (vide supra) with the use of distilled water as the eluant, to give 0.35 part by weight of 7-amino 3 methyl 3 cephem 4 carboxylic acid, melting at 240 to 242 C. with decomposition.
  • EXAMPLE 2 In the same manner as in Example 1, the respective 2-day cultures of the bacterial strains listed in Table 2 were prepared. To 200 ml. of the respective culture broths were added a solution of 800 mg. of methyl 7-phenylacetamido 3 methyl 3 cephem 4 carboxylate (Substrate 1) in 8 ml. of acetone and 50 ml. of a 0.25 M phosphate buffer solution (pH 7.0). Alternatively, to another 200 ml. of each of the culture broths was added a solution of 800 mg. of 7-phenylacetamido 3 methyl- 3-cephem 4 carboxylic acid (Substrate 2) in 50 ml. of a 0.25 M phosphate buffer (pH 7.0).
  • the reaction mixture was filtered to remove the cells, and the filtrate was combined with the washing of the cells.
  • the combined solution was chromatographed on Amberlite XAD-Z, and the column was eluted with distilled water. Lyophilization of the eluates gave 1.0 part by weight of pure 7-amino-3-methyl-3-cephem-4-carboxyli: acid as powder showing good accord with an authentic sample with respect to melting point, specific rotation, infrared spectrum, nuclear magnetic resonance spectrum and ultraviolet spectrum.
  • EXAMPLE 5 A loopful of the respective 7-day slant cultures of the microorganisms listed below was inoculated into ml. each of a culture medium of pH 6, comprising 3% of sucrose, 0.2% of sodium nitrate, 0.1% of dipotassium hydrogenphosphate, 0.05% of potassium chloride, 0.05% of magnesium sulfate, 0.001% of ferrous sulfate, 0.5% of yeast extract, 0.5% of peptone, 0.5% of corn steep liquor and 0.05% of phenoxyacetic acid. The culture media were incubated under shaking at 28 C. for 4 days, followed by the addition of a solution of 100 mg.
  • Cylindrocarpon willkom'rm'i IFO5995.
  • Cladosporium cladosporioides IFO6371 Coniochaeta teiraspora IFO8526..
  • Dactylaria mycophila IFO-6785-..
  • a 4-day seed culture (30 parts by volume) of Griphosplzaeria nivalis IFO-7436 was inoculated into 1,000 parts by volume of a culture medium of pH 6, which comprised 3% of sucrose, 0.2% of sodium nitrate, 0.1% of dipotassium hydrogenphosphate, 0.05 of potassium chloride, 0.05 of magnesium sulfate, 0.001% of ferrous sulfate and 0.05% of phenoxyacetic acid.
  • the culture medium was incubated under shaking at 28 C.
  • reaction mixture was subjected to thin layer chromatography with the use of methanohacetone 1:1) as the solvent, to find that the substrate methyl 7- phenoxyacetamido-3-methyl-3-cephem-4-carboxylate (Rf 0.95) had disappeared and that there had been instead produced 7 amino-3-methyl-3-cephem-4-carboxylic acid with an almost quantitative yield.
  • reaction mixture was filtered to remove the mycelia, and the filtrate was concentrated and purified by column chromatography to give 1.9 part by weight of the product, melting at 240 to 242 C. with decomposition.
  • EXAMPLE 7 A loopful of a 4-day agar slant culture of each of the yeast strains listed in Table 5 was inoculated into 30 ml. of a culture medium of pH 6, consisting of 5% of sucrose, 0.025% of potassium dihydrogenphosphate, 0.1% of calcium nitrate, 0.025% of magnesium sulfate, 0.012% of potassium chloride and tap water. Cultivation was conducted at 28 C. under shaking for 48 hours. To the culture medium were added a solution of mg. of methyl 7-phenoxyacetamido-3-methyl-3-cephem 4 carboxylate in 1 ml. of acetone and 7 ml.
  • EXAMPLE 8 To 30 ml. of a 4-day culture broth of each of the strains listed in Table 6, prepared in the same manner as in Example 5, there were added 7 ml. of a 0.25 M phosphate buffer solution (pH 7.0) and a solution of 100 mg. of benzyl 7 phenoxyacetamido-3-rnethyl-3-cephem-4-carboxylate in 1 ml. of acetone. The mixture was shaken at 28 C. for 16 hours to allow the reaction to take place. The yields of the resulting 7-amino-3-methyl-3cephem-4- carboxylic acid (Product I) and its benzyl ester (Product II), in terms of respective turnovers are shown in Table 6.
  • EXAMPLE 9 To 30 ml. of a 4-day culture broth of each of the strains listed in Table 7, each prepared in the same manner as in Example 5, there were added 7 ml. of a 0.25 M phosphate buffer solution (pH 7.0) and a solution of 100 mg. of methylthiomethyl 7 phenoxyacetamido 3 methyl-3- cephem-4-carboxylate.
  • Escherichia coli IFO-3210 was cultivated in the same manner as in Example 1 for 24 hours.
  • the cultured broth in an amount of 200 parts by volume was centrifuged to collect cells.
  • the cells were suspended in 20 parts by volume of a 0.05 M phosphate buffer solution (pH 7.0) and then subjected to a sonication of 10 kilocycles per second at C. for 20 minutes.
  • the resultant sonicates were centrifuged to obtain 17 parts by volume of a cellfree supernatant.
  • microorganism is a bacterium belonging to the genus Escherichia, Bacillus, Xanthomonas, Pseudomonas, Protaminobacter, Mycoplana or Aeromonas.

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US00210105A 1970-12-25 1971-12-20 Production of 7-amino-3-methylcephem compounds Expired - Lifetime US3749641A (en)

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3915798A (en) * 1972-06-17 1975-10-28 Toyo Jozo Kk Process for producing 7-amino desacetoxy cephalosphoranic acid
US3960662A (en) * 1974-01-23 1976-06-01 Toyo Jozo Kabushiki Kaisha Process for the production of 7-amino-cephem compounds
US3972774A (en) * 1975-07-28 1976-08-03 Eli Lilly And Company Enzymatic de-esterification of cephalosporin para-nitrobenzyl esters
US4001600A (en) * 1975-06-02 1977-01-04 Watkins-Johnson Company Interconnecting circuit for ebs diodes and method
US4059573A (en) * 1973-08-01 1977-11-22 Glaxo Laboratories Limited Extraction of N-blocked amino acids from aqueous media
US4141790A (en) * 1976-05-24 1979-02-27 Meiji Seika Kaisha Ltd. Process for the preparation of 7-amino-cephem compounds using mold fungi
US4230799A (en) * 1977-02-09 1980-10-28 Schering Corporation Process for the preparation of antibiotic W-10 complex and for the isolation of Antibiotic 20561 and Antibiotic 20562 therefrom
US4316955A (en) * 1980-11-10 1982-02-23 Eli Lilly And Company Enzymatic deesterification of cephalosporin methyl esters
US4316958A (en) * 1979-02-10 1982-02-23 Kyowa Hakko Kogyo Co., Ltd. Process for producing optically active cephalosporin analogs
US4414328A (en) * 1980-07-21 1983-11-08 Fujisawa Pharmaceutical Co., Ltd. Process for the preparation of deacetylcephalosporin C
US4618583A (en) * 1984-11-19 1986-10-21 E. R. Squibb & Sons, Inc. Method of preparing L-(+)-β-hydroxyisobutyric acid by fermentation
US4981789A (en) * 1987-03-18 1991-01-01 Merck & Co., Inc. One-step enzymatic conversion of cephalosporin C and derivatives to 7-aminocephalosporanic acid and derivatives
US5104800A (en) * 1989-06-27 1992-04-14 Merck & Co., Inc. One-step cephalosporin c amidase enzyme
US5229274A (en) * 1989-06-27 1993-07-20 Merck & Co., Inc. Gene encoding one step cephalosporin C amidase and expression thereof in recombinant bacillus
US5441874A (en) * 1992-08-07 1995-08-15 Finpael S.P.A. Method for the acylation of the 7-amino group of the cephalosporanic ring

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD74282A (is") *
FR1357977A (fr) * 1963-05-20 1964-04-10 Merck & Co Inc Procédé de production d'acide 7-aminocéphalosphalosporanique par voie enzymatique
US3284451A (en) * 1965-07-22 1966-11-08 Bristol Myers Co Activated esters of 7-amino-cephalosporanic acid
NL150798B (nl) * 1967-08-07 1976-09-15 Koninklijke Gist Spiritus Werkwijze voor de bereiding van 7-aminocefalosoranzuur en derivaten daarvan.
US3522250A (en) * 1968-10-15 1970-07-28 American Home Prod Derivatives of 7-aminocephalosporanic acid

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3915798A (en) * 1972-06-17 1975-10-28 Toyo Jozo Kk Process for producing 7-amino desacetoxy cephalosphoranic acid
US4059573A (en) * 1973-08-01 1977-11-22 Glaxo Laboratories Limited Extraction of N-blocked amino acids from aqueous media
US3960662A (en) * 1974-01-23 1976-06-01 Toyo Jozo Kabushiki Kaisha Process for the production of 7-amino-cephem compounds
US4001600A (en) * 1975-06-02 1977-01-04 Watkins-Johnson Company Interconnecting circuit for ebs diodes and method
US3972774A (en) * 1975-07-28 1976-08-03 Eli Lilly And Company Enzymatic de-esterification of cephalosporin para-nitrobenzyl esters
US4141790A (en) * 1976-05-24 1979-02-27 Meiji Seika Kaisha Ltd. Process for the preparation of 7-amino-cephem compounds using mold fungi
US4230799A (en) * 1977-02-09 1980-10-28 Schering Corporation Process for the preparation of antibiotic W-10 complex and for the isolation of Antibiotic 20561 and Antibiotic 20562 therefrom
US4316958A (en) * 1979-02-10 1982-02-23 Kyowa Hakko Kogyo Co., Ltd. Process for producing optically active cephalosporin analogs
US4414328A (en) * 1980-07-21 1983-11-08 Fujisawa Pharmaceutical Co., Ltd. Process for the preparation of deacetylcephalosporin C
US4517299A (en) * 1980-07-21 1985-05-14 Fujisawa Pharmaceutical Co., Ltd. Acetylesterases
US4316955A (en) * 1980-11-10 1982-02-23 Eli Lilly And Company Enzymatic deesterification of cephalosporin methyl esters
US4618583A (en) * 1984-11-19 1986-10-21 E. R. Squibb & Sons, Inc. Method of preparing L-(+)-β-hydroxyisobutyric acid by fermentation
US4981789A (en) * 1987-03-18 1991-01-01 Merck & Co., Inc. One-step enzymatic conversion of cephalosporin C and derivatives to 7-aminocephalosporanic acid and derivatives
US5104800A (en) * 1989-06-27 1992-04-14 Merck & Co., Inc. One-step cephalosporin c amidase enzyme
US5229274A (en) * 1989-06-27 1993-07-20 Merck & Co., Inc. Gene encoding one step cephalosporin C amidase and expression thereof in recombinant bacillus
US5441874A (en) * 1992-08-07 1995-08-15 Finpael S.P.A. Method for the acylation of the 7-amino group of the cephalosporanic ring

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NL7117696A (is") 1972-06-27
DE2163791C2 (de) 1985-02-21
AT320144B (de) 1975-01-27
AU3737171A (en) 1973-06-28
FR2120839A5 (is") 1972-08-18
NL175642B (nl) 1984-07-02
BE777261A (fr) 1972-04-17
DE2163791A1 (de) 1972-07-20
CH565186A5 (is") 1975-08-15
JPS4948760B1 (is") 1974-12-23
HU166646B (is") 1975-04-28
NL175642C (nl) 1984-12-03
CA1013692A (en) 1977-07-12
SE402123B (sv) 1978-06-19
AU467458B2 (en) 1975-12-04
GB1377379A (en) 1974-12-11

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