Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-14
2002-09-10
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S224000
Reexamination Certificate
active
06448393
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for preparing 3-halogenated methylcephem compound of high reactivity which can be used in place of 7-aminocephalosporanic acid (7-ACA) generally used as a conventional starting material. The invention also relates to a process for preparing 3-thiomethylcephem compound which is an important intermediate of various antibiotic substances.
3-Thiomethylcephem compounds prepared in the present invention are useful intermediates of antibiotic substances represented by cefazolin and ceftriaxone. These antibiotic substances are excellent antibacterial agents having a wide range antibacterial spectrum as disclosed in, for example, Handbook of Latest Antibiotics, 9th ed., Katsuji Sakai, P. 59 and P. 73.
BACKGROUND ART
As a process for preparing 3-halogenated methylcephem compounds, there has been usually employed a process in which, by utilizing 7-aminocephalosporanic acid (7-ACA) generally used in preparing cephalosporanic antibiotic substances, amino group and carboxylic acid are protected with silyl group, and the acetoxy group is halogenated, followed by deprotection of the silyl protecting groups at the 7-position and 4-position. In this process, however, an expensive silyl reagent of not less than 2 equivalents is required, and a very expensive reagent such as trimethylsilyl iodide is needed in the conversion of acetoxy group into halogen atom. Since these reagents are highly sensitive to water, it is necessary to maintain the reaction system free from water. This process is therefore unsuitable industrially.
As a process for preparing 3-thiomethylcephem compounds, there has been usually employed a process in which 7-aminocephalosporanic acid (7-ACA) is directly reacted with thiol or its salt. This process, however, constrains the reaction at high temperatures, because the reactivity of acetoxy group is low. In this event, not only a decrease in reaction yield and an increase in by-product are unavoidable, but also isolation and purification operation is complicated. That is, this process is not always advantageous industrially. Accordingly, there has been a desire for a process for preparing 3-halogenomethylcephem compounds or 3-thiomethylcephem compounds, which is industrially feasible with ease, and is highly practical.
An object of the present invention is to establish an industrially feasible process for preparing 3-halogenomethylcephem compounds, and provide a process for preparing 3-thiomethylcephem compounds by using 3-halogenomethylcephem compound as a starting material.
DISCLOSURE OF THE INVENTION
The present invention provides a process for preparing 3-halogenomethylcephem compound of the formula (2) or its salt, comprising a carboxylic acid protecting group at the 4-position of 7-amino-3-halogenomethylcephem compound of the formula (1) or its salt is deprotected with phenol derivative
wherein X
1
is halogen atom; and R
1
is benzyl group which has on a phenyl ring an electron-donating group as a substituent, or diphenylmethyl group which may have an electron-donating group on a phenyl ring
wherein X
1
is halogen atom.
The present invention also provides a process for preparing 3-thiomethylcephem compound of the formula (4) or its salt, comprising 3-halogenomethylcephem compound of the formula (2) or its salt is reacted with thiol compound or its salt of the formula (3)
wherein X
1
is halogen atom
R
2
S—M (3)
wherein R
2
is nitrogen-containing aromatic heterocyclic group which may have a substituent; and M is hydrogen atom, alkali metal or alkaline earth metal
The present invention further provides a process for preparing 3-thiomethylcephem compound or its salt, comprising a carboxylic acid protecting group at the 4-position of 7-amino-3-halogenomethylcephem compound of the formula (1) is deprotected with phenol derivative and, without isolation, reacted with thiol compound or its salt of the formula (3), thereby obtaining 3-thiomethylcephem compound of the formula (4) or its salt.
The conventional process for preparing 3-thiomethylcephem compounds by employing 7-ACA as a starting material, suffers from the drawbacks of the low reaction yield and the formation of by-product, resulting in an unsatisfactory process. To establish an industrially feasible process, the inventors regarded that these drawbacks were due to the low reactivity of the acetoxy group at the C-3′ position, and employed 3-halogenomethylcephem compounds which have at the C-3′ position a halogen atom having a higher reactivity, as a starting material. However, any practical process for preparing these compounds were not known. Therefore, by utilizing a deprotection reaction in which phenol derivative is used for the carboxyl group at the 4-position of 7-amino-3-halogenomethylcephem compound, the inventors established an industrially feasible process for preparing 3-halogenomethylcephem compounds, as well as a process with which 3-thiomethylcephem compound is prepared from 7-amino-3-halogenomethylcephem compound at high purity and high yield.
The process of the invention enables to smoothly proceed the reaction at environmental temperature, minimize by-product, and facilitate the isolation and purification of a desired product. That is, this process has a higher industrial practicality than the conventional reaction using the 7-ACA as a starting material.
Also, the process of the invention enables to prepare 3-halogenomethylcephem compounds and 3-thiomethylcephem compounds at high purity and high yield, in such a manner as to be industrially feasible with ease.
Examples of the groups mentioned in the specification are as follows. Exemplary of the halogen atom are fluorine atom, chlorine atom, bromine atom and iodine atom. Examples of lower alkyl group are straight-chain or branched-chain C
1
-C
4
alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Exemplary of aryl group are phenyl and naphthyl.
Examples of electron-donating group substituted on the phenyl ring of benzyl group or diphenylmethyl group represented by R
1
are hydroxy; methyl, ethyl, tert-butyl and like lower alkyl groups; and methoxy, ethoxy and like lower alkoxy groups. The diphenylmethyl group includes a type of the group which is a substituted or unsubstituted phenyl group bonded in the molecule via methylene chain or hetero-atom. There are, for example, p-methoxybenzyl, diphenylmethyl, 3,4,5-trimethoxybenzyl, 3,5-dimethoxy-4-hydroxybenzyl, 2,4,6-trimethylbenzyl and ditolylmethyl.
Examples of nitrogen-containing aromatic heterocyclic group which may have a substituent represented by R
2
are triazolyl, triazinyl, thiadiazolyl, tetrazolyl and benzothiazolyl. Examples of substituent which can substitute for the heterocyclic group are lower alkyl group, sulfo lower alkyl group, carboxy lower alkyl group, amino lower alkyl group, lower alkyl substituted amino lower alkyl group and hydroxy lower alkyl group.
Examples of thio group represented by R
2
S— are thio substituents among the known substituents at the 3-position of cephalosporin as described in USAN and the USP dictionary of drugs names. There are, for example, 1,2,3-triazol-4-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio, 1-methyltetrazol-5-ylthio, 1-sulfomethyltetrazol-5-ylthio, 1-carboxymethyltetrazol-5-ylthio, 1-(2-dimethylaminoethyl)tetrazol-5-ylthio, 1,3,4-thiadiazol-5-ylthio, 1-(2-hydroxyethyl)tetrazol-5-ylthio, 3-methyl-1,3,4-triazine-5,6-dione-2-thio, and benzothiazol-2-thio.
Examples of alkali metal or alkaline earth metal represented by M are lithium, sodium, potassium, calcium and magnesium.
The 3-halogenomethylcephem compounds (1) used as a starting material in the invention can be easily prepared in the following manner that 7-phenylacetamide-3-chloromethylcephem-4-carboxylate prepared by a process as described in the literature of Torii et al., Tetrahedron Lett., 23, 2187 (1982), is subjected to deprotection of the 7-position amide side chain, by a process as described in RECENT ADVANCES IN THE CHEMISTRY OF &bgr;-Lactam Antiobiotics
Berch Mark L.
Otsuka Kagaku Kabushiki Kaisha
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