Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-04
2001-08-21
Gerstl, Robert (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06277996
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a new crystalline aminothiazole derivative represented by the following formula (I) and a process of preparing the same, which is very useful as an intermediate for the preparation of cephalosporin antibiotics, including ceftazidime and cefixime:
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., X represents chlorine or bromine, and the acid in the acid addition salt 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.
2. Description of the Prior Art
Many processes for the preparation of cephalosporin antibiotics were disclosed in literatures and patents. In such prior processes, generally, a 2-aminothiazol carboxylic acid compound of the following formula (I-1) is converted into its reactive derivative which is then acylated by reaction with an amino group of a 3-cephem compound to produce a cephem compound:
where R
1
and R
2
have the same meanings as described above, R
3
is a carboxy protecting group which is conventional in the art, R
a
is hydrogen or an amino protecting group.
The reactive derivative of the compound of the formula (I-1) includes, for example, an acid halide, a reactive ester, a reactive amide, or a mixed acid anhydride, etc. However, in the case of employing the acid halide as the reactive derivative, it is disadvantageous in that the preparation of the acid halide must be carried out under strict reaction conditions. In addition to this disadvantage, the compound of the formula (I-1) is first protected on the amino group of its thiazole ring and then converted into its reactive acid halide with an acid halogenating agent. Next, the protected compound is acylated as such with the acylating agent without being subjected to a separation step, such that an unwanted side reaction of the acid halide with the acylating agent is proceeded. For this reason, the use of the acid halide has another problem in that by-products are significantly produced. Moreover, with respect to a further particular problem with the use of the acid halide, as the acid halide is acylated in a state where its functional groups are protected, deprotection of the resulting product must be carried out after the acylation reaction.
On the other hand, in the case of carrying out the acylation with the reactive ester or reactive amide of the compound of the formula (I), the acylation produces a product in low yield. Moreover, as the reactive ester or amide is low in reactivity, the acylation requires a relatively long reaction time. Additionally, the by-products resulted from the acylation are difficult to be removed after the acylation, such that it is difficult for the desired product to be obtained at a high yield and purity.
SUMMARY OF THE INVENTION
We, therefore, have continued to conduct research in an attempt to solve the problems of the prior art. As a result of that, we have found a new intermediate represented by the formula (I) which has not been known up to date. Such a new compound was found to possess a pure crystalline form of acid halide, from which the protecting groups were removed. Thus, where the new compound was used in the acylation with the 3-cephem compound for the preparation of ceftazidime and cefixime, etc., the acylation was completed in a short period of time with little or no production of by-products, thereby allowing the desired compound to be prepared at a high yield and purity. Based on this fact, we have perfected the present invention.
It is therefore an object of the present invention to provide a new aminothiazole compound represented by the following formula (I) and a process of preparing the same, which is useful for the preparation of cephalosporin antibiotics, including ceftazidime, cefixime, and the like:
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., X represents chlorine or bromine, and the acid in the acid addition salt 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.
REFERENCES:
patent: 4258041 (1981-03-01), O'Callaghan et al.
patent: 4433141 (1984-02-01), Jones et al.
patent: 5182383 (1993-01-01), Prager et al.
patent: 2 052 490 (1981-01-01), None
patent: 98/31685 (1998-07-01), None
Lee Myoung Ki
Lee Yoon Seok
Park Mi Soon
Shin Dong Gyun
Song Yoon Seok
Gerstl Robert
Hanmi Fine Chemicals Co., Ltd.
Schmidt Richard D.
Venable
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