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    • 13. 发明授权
      US3915798A Process for producing 7-amino desacetoxy cephalosphoranic acid 失效
    • Process for producing 7-amino desacetoxy cephalosphoranic acid
    • 制备7-氨基去乙酸基头孢烷酸的方法
    • US3915798A
    • 1975-10-28
    • US37061973
    • 1973-06-18
    • TOYO JOZO KK
    • YAMAGUCHI TSUTOMU , ISHII HIROSHI
    • C12P1/04 , C07D501/18 , C12P1/02 , C12P35/02 , C12D13/06
    • C12P35/02 , Y10S435/813 , Y10S435/815 , Y10S435/83 , Y10S435/873
    • 7-Amino desacetoxy cephalosporanic acid represented by the general formula,

      is produced according to a process in which a 7-acylamino desacetoxy cephalosporanic acid represented by the general formula,


      in which a salt of 7-acylamino desacetoxy cephalosporanic acid represented by the general formula,

      wherein R is a benzyl or phenoxymethyl group, and M is an alkali metal atom capable of forming a water-soluble salt, is treated with a culture filtrate or aqueous medium each containing deacylating enzyme of a microorganism Arthrobacter simplex ATCC 15799, Kluyvera citrophila ATCC 21285, Proteus rettgeri ATCC 9250 or Micrococcus sp. NRRL B-2753. This invention relates to a process for producing 7-amino desacetoxy cephalosporanic acid (herein after designates as 7ADCA) by enzymatically deacylating a 7-acylamino desacetoxy cephalosporanic acid. More particularly, the present invention is concerned with a process for preparing 7-ADCA, i.e. 7-amino-3methyl- Delta 3-cephem-4-carboxylic acid, by use of an enzyme preparation derived from a strain of Arthrobacter simplex ATCC 15799, Kluyvera citraphila ATCC 21285, Proteus rettgeri ATCC 9250 or Micrococcus sp. NRRL B-2753. Heretofore, 7-ADCA has been produced by several procedures including chemical decomposition processes and enzymatic splitting processes. There has not previously been proposed any process for producing 7-ADCA by using microorganism belonging to genus Arthrobacter, Kluyvera, Proteus or Micrococcus. We had found that a strain of Bacillus megaterium produced the enzyme which cleave the 3-methyl-7-acylamido- Delta 3-cephem-4carboxylic acid to form 7-ADCA. The enzymatic process using this strain has, however, according to the conditions employed, the tendency to proceed reversely as acylating reaction. Accordingly, the possibility of enzymatically producing 7-ADCA was considered and various microorganisms capable of deacylating 3-methyl-7acylamido- Delta 3-cephem-4-carboxylic acid without reverse reaction were investigated. It has now been found that a strain Arthrobacter simplex ATCC 15799; Kluyvera citrophila ATCC 21285, Proteus rettgeri ATCC 9250 or Micrococcus sp. NRRL B-2753, which have been obtained from the permanent collection of ATCC and NRRL in U.S.A., produce an enzyme capable of decomposing the amide bonds of 3-methyl-7-phenoxyacetamido- Delta 3-cephem-4-carboxylic acid and 3-methyl-7-phenylacetamido- Delta 3-cephem-4-carboxylic acid. It has also been found that when 3-methyl-7phenylacetamido- Delta 3-cephem-4-carboxylic acid is treated with an enzyme preparation derived from the above-mentioned strains, there is produced the compound known as 7-ADCA. The present invention provides a process for enzymatic production of an intermediate for preparing antibiotic cephalosporins which are useful as chemical therapeutic preparations. According to the invention, there is provided a process for producing 7-amino desacetoxy cephalosporanic acid represented bY the general formula,
      wherein R is a benzyl or phenoxymethyl group, and M is an alkali metal atom forming a water-soluble salt of the compound (I) (hereinafter designates as Ce(I)) is deacylated by treatment with a culture filtrate, cultured microbial cells or enzyme preparation of strain belonging to the genus microorganism hereinbefore which produce an enzyme which can cleave the amide bond of the said compound, said strain being Arthrobacter simplex ATCC 15799, Kluyvera citrophila ATCC 21285, Proteus rettgeri ATCC 9250 or Micrococcus sp. NRRL B-2753. Advantageously, the enzyme is adsorbed on a carrier which does not inactivate said enzyme. The 7-amino desacetoxy cephalosporanic acid can then be recovered from the resulting reaction liquid. The use of an adsorbing carrier avoids the necessity for costly separation of the enzyme from the culture broth. The enzyme is present on the carrier as a solid phase. Thus the enzyme can be repeatedly used without being inactivated. The aqueous solution of the water soluble salt of 7-acylamino desacetoxy cephalosporanic acid can be passed through a column of said carrier, and 7-ADCA emerges in an extremely high yield and, moreover, the enzyme continuously deacylates the 7-acylamino desacetoxy cephalosporanic acid and thus can be used with high efficiency. The enzyme which is used in the present process can be obtained by aerobically culturing Arthrobacter simplex ATCC 15799, Kluyvera citrophila ATCC 21285, Proteus rettgeri ATCC 9250 or Micrococcus sp. NRRL B-2753 at 28* to 35*C. for 18 to 72 hours in a medium which is ordinarily used for the cultivation of microorganism, e.g. a nutrient medium containing proper amounts of a nitrogen source such as peptone, meat extract, corn steep liquor, yeast extract, dry yeast, soybean protein hydrolysate or soybean lixiviate; a carbon source such as molasses, glucose or glycerin; and inorganic salts; and, in some cases, other growthpromoting materials. Generally, aeration is effected by stirring the culture liquid. The above-mentioned enzyme is ordinarily an exo- or endo-enzyme and is present in a culture filtrate or cultured nicrobial cells. In the enzyme reaction, therefore, the enzyme is used in the form of a culture filtrate or cultured broth, or of an enzyme preparation prepared from the culture filtrate or microbial cells. The enzyme preparation is obtained by subjecting the enzyme to a conventional method. The enzyme solution obtained according to the conventional procedures may be subjected to reduced pressure concentration, freeze-drying or the like operation to obtain a solid product, or may be used as it is for the treatment of Ce(I). In case of endo-enzyme, cultured broth or microbial cells collected therefrom, suspension of microbial cells, freeze dried cells, acetone dried cells or the like may be used as the enzyme preparation for the enzyme reaction. The enzyme reaction may be carrieid out by dissolving Ce(I) in water or a buffer solution and then treating the solution with the above-mentioned enzyme preparation. The Ce(I) is converted into a water-soluble sodium or potassium salt, and may be used at a concentration within the range from 0.1 to 2.0% W/V, preferably from about 0.5 to 1% W/V. The pH of the reaction liquid is preferably maintained within the range from about 7 to 8. The reaction temperature is from 20* to 45*C., preferably from about 30* to 37*C., whereby favorable results can be obtained. The reaction time varies depending on the reaction conditions, but is ordinarily from about 3 to 30 hours, and the reaction may be terminated when the yield of the 7-ADCA represented by the formula (II) becomes maximum. The carrier used in the present process must be able to adsorb the deacylating enzyme without inactivating it; should not release the enzyme even when washed with water; it should have no detrimental influence on the Ce(I)-deacylating reation; and should not substantially adsorb the resulting 7-ADCA. For example, when an inorganic carrier such as diatomaceous earth (''''Celite'''' (trade mark)), or an ion exchanger such as CMCellulose, or an ion-exchange resin such as ''''Amberlite'''' (trade mark) CG-50 is used as the carrier, the Ce(I)-deacylating enzyme produced by the microorganism hereinbefore is adsorbed well without being inactivated. In adsorbing the Ce(I)-deacylating enzyme on the carrier, it is desirable that the pH of the cultured broth of Ce(I)-deacylating enzyme-producing strain is previously adjusted to the stable pH for the deacylating enzyme. The adsorbtion of the deacylating enzyme on the carrier may be carried out batches or in a column. The amount of the carrier to be used varies depending on the amount and activity of enzyme and on the adsorbability of the deacylating enzyme on the carrier. In adsorbing the enzyme according to the batch-wise procedure, however, the amount of the carrier used may be about 5 to 15 W/V% based on the amount of the culture filtrate or 5 to 20 excess amount based on the amount of the cultured microbial cells, and a mixture of the culture filtrate and the carrier is stirred, and then the carrier is separated and washed with water. In the case of adsorption according to the columnwise procedure, a carrier packed in a column is wetted with water or with a buffer solution adjusted to the stable pH of the deacylating enzyme, the cultured broth or enzyme solution is passed through the column, and then the column is washed with water. When the thus obtained solid preparation is dried, the deacylating enzyme tends to be inactivated. Accordingly, it is desirable that the preparation is kept in a wet state. The Ce(I) used in the present invention may be prepared according to a known process. However, the inventive Ce(I)deacylating reaction is carried out in aqueous solution so that the Ce(I) should be in the form of a water-soluble alkali metal salt, e.g. a sodium or potassium salt.
    • 由通式表示的7-氨基脱乙酰氧基头孢菌素酸，根据通式R-CO-NH-（CH 3）2表示的7-酰基氨基脱乙酰氧基头孢菌素酸的方法制备H 2 N - - | PARALLEL -| OCHCH 3 COOM其中R为苄基或苯氧基甲基，M为能够形成水溶性盐的碱金属原子，用含有微生物的脱酰基酶的培养滤液或含水培养基处理 单克罗杆菌ATCC 15799，克鲁维酵母ATCC 21285，变形杆菌ATCC 9250或Micrococcus sp。 NRRL B-2753。
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