Abstract:
The present invention relates to a new, simple, and easy process for preparing cephalosporin antibiotics of the following sub-formulas (I), such as cefixime. The process comprises acylating a 7-amino cephalosporanic acid derivative of the following sub-formulas (III) with a crystalline aminothiazole compound of the following sub-formulas (II):  
                         
 
     wherein R 1  and R 2  are the same or different and independently represent H, a C 1-4  alkyl or C 3-5  cycloalkyl group, and the acid in the acid addition salt represents an inorganic acid, such as hydrochloric acid, or an organic acid, such as formic acid or acetic acid.

Description:
CROSS REFERENCE TO RELATED APPLICATION  
       [0001]    This is a continuation-in-part of U.S. patent application Ser. No. 09/564,980, filed May 4, 2000, pending. 
     
    
     
       BACKGROUND OF THE INVENTION  
         [0002]    1. Field of the Invention  
           [0003]    The present invention relates in general to a new, simple, and easy process for preparing cephalosporin antibiotics including ceftazidime. More particularly, the present invention relates to a process for the preparation of cephalosporin antibiotics of the following either Formula 1 or Formula 2, in which a 7-amino cephalosporanic acid derivative depicted by sub-formulas (III) is acylated by reaction with a new crystalline aminothiazole derivative of the sub-formulas (II) in a solvent:  
                         
 
                         
 
           [0004]    wherein R 1  and R 2  are the same or different and independently represent H, an alkyl group of 1 to 4 carbon atoms, or a cycloalkyl group of 3 to 5 carbon atoms, etc., and X represents chlorine, bromine or iodine and n is 1 or 2. Moreover, the acid in the acid addition salt as shown in sub-formulas (II) represents an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, or perchloric acid, etc., or an organic acid, such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, or benzenesulfonic acid, etc.  
           [0005]    2. Description of the Prior Art  
           [0006]    Processes for the preparation of cephalosporin antibiotics of the above Formulas 1 and 2, including ceftazidime and cefixime, were disclosed in several literatures and patents, for example, U.S. Pat. No. 4,258,041; Austrian Patent Publication Nos. 86-2427 and 86-2428;  J. of Antibiotics , Vol.38, pp. 1738, 1985; and Korean Patent Publication Nos. 84-1827, 84-1987, 84-1988, 84-1989, 84-1990, 87-1807, and 93-7810.  
           [0007]    In the above prior processes, an amino group of a 3-cephem compound represented by the following sub-formulas (I-1) is acylated by reaction with a 2-aminothiazol carboxylic acid of the following sub-formulas (I-2) or a salt or reactive derivative thereof to produce the cephalosporin derivative of the sub-formulas (I):  
                         
 
           [0008]    where R 1  and R 2 , have the same meanings as described above, R 3  is a carboxy protecting group, R a  is hydrogen or an amino protecting group, R b  is hydrogen or a carboxy protecting group, such as diphenylmethyl or p-nitrobenzene and R 4  is methylpyridine.  
           [0009]    U.S. Pat. No. 4,258,041, and Korean Patent Publication No. 84-1827, etc. describe processes employing acid chloride of the organic acid (I-2) in the acylation reaction with the 7-amino cephalosporin derivative of the sub-formulas (I-1). According to these processes, the organic acid (I-2) is conventionally protected on an amino group of its thiazole ring, and then converted to its acid chloride with thionyl chloride, phosphorus oxychloride, or phosphorus pentachloride, etc. Thereafter, the resulting acid chloride of the organic acid (I-2) is reacted with the 7-amino cephalosporanic acid derivative, followed by removing the protecting group on the amino group of the thiazole ring. However, these processes have disadvantages in that they are carried out under strict reaction conditions, and further require a step of protecting the amino group of the thiazole ring and a step of removing the protecting group on the amino group. In addition, another drawback with these processes is that the aminothiazole compound activated with unstable acid chloride is acylated as such without being subjected to an isolation step, such that by-products are significantly produced during the acylation reaction owing to the unstable acid chloride.  
           [0010]    Austrian Patent Publication Nos. 86-2427 and 86-2428, and WO No. 98-31685, etc. disclose processes in which a reactive ester of the organic acid (I-2) is prepared and acylated. In this acylation, the reactive ester of the organic acid (I-2) may be reacted with the 7-aminocephalosporin derivative without the protecting group on the amino group of its thiazole ring. However, it is necessary for these processes to remove a protecting group on a carboxy group of the aminothiazole compound (I-2) after the acylation reaction, in order to give the final desired compound.  
           [0011]    In addition, there are also known other processes employing a reactive amide or a mixed acid anhydride, but they have drawbacks similar to those in the above processes.  
           [0012]    Therefore, in the case of carrying out the acylation reaction using the reactive derivative (e.g., the acid chloride) as described above, the amino and carboxyl groups of the compound of the sub-formulas (I-2) must be protected with R a  and R 3 , respectively, before the acylation reaction. On the other hand, in the case of using the reactive ester, the preparation of the reactive ester must be carried out in a state where the amino group is not protected, but the carboxyl group is protected with R 3 . As a result, all the processes according to the prior art have a drawback in that the deprotection must be carried out after the acylation reaction.  
         SUMMARY OF THE INVENTION  
         [0013]    We have discovered that, when an aminothiazole compound represented in Formulas 1 and 2 by the following sub-formulas (II) was acylated by reaction with a 7-amino cephalosporanic acid derivative represented by the following sub-formulas (III) in a solvent as indicated in the following reaction scheme, a desired compound could be directly obtained in a high yield in a simple and easy way without a need of the deprotection after the acylation reaction, whereby we have perfected the present invention based on this discovery:  
                         
 
           [0014]    wherein R 1  and R 2 , and the acid addition salt have the same meaning as defined above.  
           [0015]    It is therefore an object of the present invention to provide a process for preparing cephalosporin antibiotics including ceftazidime, using a new aminothiazole compound represented by the sub-formulas (II).  
         DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
         [0016]    The foregoing and other objects, features and advantages of the invention will be apparent to those skilled in the art to which the present invention relates from reading the following specification.  
           [0017]    The aminothiazole compound of the sub-formulas (II) used as the starting material in the practice of the present invention is a new material and a reactive derivative in the form of a crystalline acid chloride. Thus, this is more stable and can be stored over a lengthy period of time at a low temperature and room temperature, as compared with the conventional acid chloride. Moreover, the process of the present invention produces little or no by-products in the acylation reaction of the 7-aminocephalosporin derivative with the compound of the sub-formulas (II), and is also relatively short in reaction time. Additionally, the process of the present invention employing this compound of the sub-formulas (II) does not require the removal of the protecting group after the acylation, and allows the desired compound to be directly obtained after the acylation. As a result, the process of the present invention makes the acylation reaction more economical and also simple and easy.  
           [0018]    The new aminothiazole derivative of the sub-formulas (II) is described in detail in Korean Patent Application No.2000-11127______ (Filing date: Mar. 6, 2000; Name of Applicant: HANMI FINE CHEMICALS, CO., LTD; and Title: New thiazole compounds and a process thereof), the disclosure of which is incorporated herein by reference. Moreover, among the derivatives of the sub-formulas (III), a 3-vinyl-7-aminocephalosporanic acid mentioned herein are known compounds and described in detail in several literatures, for example, U.S. Pat. No. 4,423,213, Korean Patent No. 127,113, and British Patent No. 2,052,490, the disclosure of which is incorporated herein by reference.  
           [0019]    In the acylation reaction according to the present invention, the compound of the sub-formulas (II) is used in the amount of 1.0 to 2.0 equivalents, and preferably 1.2 to 1.4 equivalents, relative to the compound of the sub-formulas (III). The solvent which can be used in the practice of the present invention includes, for example, dichloromethane, dichloroethane, chloroform, acetonitrile, tetrahydrofuran, N,N-dimethylacetamide, N,N-dimethylformamide, methanol, ethanol, or a combination thereof. However, a solution adjuvant, such as N,O-bistrimethylsilylacetamide, trimethylchlorosilane, or trimethyliodosilane, etc., may also be used in combination with the solvent in the present invention depending on the kind of the 7-cephalosporin derivative.  
           [0020]    The solvent is used in the amount of 5 ml to 30 ml, and preferably 10 ml to 15 ml, relative to 1 g of the compound of the sub-formulas (II). The acylation reaction according to the present invention is preferably carried out at a temperature of −10° C. to 30° C.  
           [0021]    The acylation reaction of the present invention is generally carried out without the use of a base, although an organic or inorganic base may also be used depending on the 7-aminocephalosporin derivative. If used, the base is used in the amount of 1.0 to 3.0 equivalents. Examples of the organic base which can be used in the present invention include tri-(n-butyl)amine, diisopropylethylamine, pyridine, dicyclohexylamine, and the like. Moreover, the acylation reaction may also be carried out in a mixed solution of a basic aqueous solution and the organic solvent, with the basic aqueous solution being preferably an aqueous solution of sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, or sodium hydroxide, etc.  
           [0022]    In this acylation reaction, water and the organic solvent are preferably used in the volume of 10 times to 20 times relative to the compound of the sub-formulas (II), with the volume ratio of water to the organic solvent being ¼ to {fraction (1/10)}.  
           [0023]    As described above, the process for the preparation of the cephalosporin derivative is characterized in that the compound of the sub-formulas (III) is reacted with the new thiazole compound of the sub-formulas (II), as the reactive organic acid derivative, to give the cephalosporin derivative of the sub-formulas (I). Such a process does not require the deprotection step and is reduced in production step, as compared with the processes according to the prior art. Furthermore, as the reactive acid derivative used in the process of the present invention is the acid chloride of the stable crystalline form, the acylation reaction with the compound of the sub-formulas (II) can be completed clean in a quantitative view with little or no production of by-products. In addition, the compound of the sub-formulas (II) can be stored in the form of acid chloride and is thus easy to use. As a result, the present invention provides the more inexpensive and new acylation process for the preparation of the cephalosporin derivatives having the compound of the sub-formulas (II) at a 7-position.  
           [0024]    The following examples are for illustration purposes only and in no way limit the scope of this invention. 
       
    
    
     EXAMPLE 1  
     Preparation of 7-{2-(2-aminothiazol-4-yl)-2-(Z)-(2-carboxyprop-2-oxyimino)acetamidol}-3-(1-pyridiniummethyl)-ceph-3-em-4-carboxylate dihydrochloride (ceftazidime dihydrochloride)  
       [0025]    To 100 ml of acetonitrile which was cooled down to 0 to 5° C., 10 g of 7-amino-3-(1-pyridiniummethyl) -ceph-3-em-carboxylate dihydrochloride was added, and 5 ml of N,O-bistrimethylsilylacetamide was then slowly added dropwise over 30 minutes. After adding 9.4g of (Z)-(2-carboxyprop-2-oxyimino)-2-aminothiazole-4-yl)-acetylchloride monohydrochloride, the resulting solution was stirred for 30 minutes, and 20 ml of 35% concentrated hydrochloric acid was then added to the stirred solution, followed by adding 50 ml of diethylether. Next, the solution was stirred for 10 minutes, and an aqueous layer was then separated and collected. After 100 ml of acetone was added to the aqueous layer and the mixture was stirred at room temperature for 5 to 6 hours, the deposited crystal was filtered. The filtered crystal was washed with 50 ml of isopropyl alcohol, and then with 20 ml of acetone, and dried, thereby giving 12.4 g (84% yield) of the title compound as a white solid.  1 NHR:(d, DMSO-d 6 ):9.6(d, 1H, —CONH—), 9.0(d, 2H, pyridinium proton), 8.6(t, 2H, pyridinium proton), 8.2(t, 2H, pyridinium proton), 6.8(s, 1H, aminothiazole proton), 5.9(dd, 1H, C 7 -H), 5.6(ABq, 2H, —CH 2 —), 5.2(d, 1H, C 6 -H), 3.5(ABq, 2H, C 2 -H), 1.4(s, 6H, —C(CH 3 ) 2 )  
       EXAMPLE 2  
     Preparation of 7-{2-(2-aminothiazole-4-yl)-2-(Z)-(2-carboxyprop-2-oxyimino)acetamido}-3-(1-pyridiniummethyl)-ceph-3-em-4-carboxylate pentahydrate (ceftazidime pentahydrate)  
       [0026]    To 100 ml of dichloromethane, 10 g of 7-amino-3-(1-pyridiniummethyl)-ceph-3-em-4-carboxylate hydroiodide was added, and 4 ml of triethylamine was then added dropwise at a temperature of 0 to 10° C. to ensure the dissolution of the hydroiodide. To which, (Z)-(2-carboxyprop-2-oxyimino)-2-(2-aminothiazole-4-yl)-acetylchloride monohydrochloride was added three or four times for 30 minutes in such a fashion that the totally added amount thereof corresponds to 9.4 g. The resulting mixture was then stirred at a temperature of 0 to 10° C. for 30 minutes. The stirred solution was added with 50 ml of water to be separated into two layers. Next, an aqueous layer was collected, to which 2 g of activated carbon was added. The solution was stirred for 30 minutes, and the stirred solution was filtered by a siliceous earth to remove the activated carbon. The resulting solution was adjusted to pH 3.8 with a 2N-hydrochloric acid solution, and left to stand at 5° C. for 12 hours. The resulting crystal was filtered, and washed with ice-water and acetone, in sequence, and then dried, thereby giving 11.8 g (80% yield) of the title compound as a white solid.  1 NHR:(d, DMSO-d 6 ):9.5 (d, 1H, —CONH—), 9.4 (d, 2H, pyridinium proton), 8.6 (t, 2H, pyridinium proton), 8.2 (t, 2H, pyridinium proton), 7.3(s, 2H, —NH 2 ), 6.7(s, 1H, amino-thiazole proton), 5.7(dd, 1H, C 7 -H), 5.5(ABq, 2H, —CH 2 —), 5.1(d, 1H, C 6 -H), 3.3(ABq, 2H, C 2 -H), 1.4(s, 6H, —C(CH 3 ) 2 )  
         [0027]    As apparent from the above description and Examples, the present invention provides the process for the preparation of the cephalosporin derivative, wherein the compound of the sub-formulas (III) is reacted with the new thiazole compound of the sub-formulas (II), as the reactive organic acid derivative, to give the cephalosporin derivative of the sub-formulas (I). Such a process does not require the deprotection step and is reduced in production step, as compared with the processes according to the prior art. Furthermore, as the reactive organic acid derivative used in the process of the present invention is the acid chloride of the stable crystalline form, it allows the acylation reaction with the compound of the sub-formulas (III) to be completed clean in a quantitative view with little or no production of by-products. In addition, the compound of the sub-formulas (II) can be stored in the form of acid chloride and is thus easy to use. As a result, the present invention provides the more inexpensive and new acylation process for the preparation of the cephalosporin derivatives having the compound of the sub-formulas (II) at a 7-position.  
         [0028]    Although the preferred embodiments of the invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.