KR870002165B1 - Acylamino-3-substituted methyl-3-cephem-4-carboxylic acid derivatives - Google Patents

Abstract

7β-amino-and 7β-acylamino-3-substituted methyl-3-cephem-4carboxylic acids derivatives and 7β-amino-3-substituted-3-cephem-4-carboxylic acid derivatives are prepared by improved deoxygenation process of cephalosporin 1-oxide derivatives. Above method is one-pot process and generally can be applied to derivatives of 7β-acylamino-3- cephem-4-carboxylic 1-oxide derivatives.

Description

[Name of invention]

Single-potted preparation of 7β-amino- and 7β-acylamino-3-substituted methyl-3-cepem-4-carboxylic acid derivatives and 7β-acylamino-3-cepem-4-carboxylic acid mono-oxide derivatives Oxygenation Method

Detailed description of the invention

The present invention relates to a corresponding 7β-amino-3-substituted-3-cefe-4-carboxylic acid derivative (if any) from a 7β-acylamino-3-substituted-3 cefe-4-carboxylic acid 1-oxide derivative. 7α-derivatives), the corresponding 7β-acylamino-3-substituted methyl-3-cepem-4- from 7β-acylamino-3-methyl-3-cepem-4-carboxylic acid 1β-oxide derivatives Method for preparing a carboxylic acid derivative and 7β-amino-3-substituted methyl-3-cepem-4-carboxylic acid derivative from 7β-acylamino-3-methyl-3-cepem-4-carboxylic acid 1β-oxide derivative The present invention relates to a process for the preparation of these compounds, all of which consist of an improved method of deoxygenation of a cephalosporin 1-oxide derivative, which method may be substituted at the 7α-position in a single-pot process. It is generally applicable to carboxylic acid 1-oxide derivatives.

In more detail, the three interrelated single-port methods are interconnected so that the protection of the sepharoserin 4-carboxyl group by silylation introduced in the preliminary step by silylation of the sephalosporin 4-carboxyl group is a preliminary step. Is maintained, and this method does not separate intermediates.

New methods of deoxygenating ordinary cephalosporin 1-oxides are applied to improve the prior art processes by clearly distinguishing them from prior process conditions, or by adding additional reagents and simultaneously or by applying other unequal conditions. This applies broadly to itself in a one-step operation or in a somewhat limited range as a step involving a multi-stage single port. 1-oxides of cephalosporins and cephalosporin derivatives are intermediates in the preparation of cephalosporins with many useful therapeutic activities, for example, because oxidation of sulfur atoms of the dihydrothiazine ring promotes substituents on other parts of the molecule. Used as

In some other syntheses, the double bond of the dihydrothiazine ring is transferred from 3-position to 2-position. In order to restore the biological activity, sulfur atoms are monooxidized and then isomerized back to the 3 position by removing the introduced oxygen atoms.

A particularly interesting application of the sephalosporin 1-oxides to the deoxygenation of the 7β-acylamino-3-substituted methyl-3-cefe-4-carboxylic acid 1β-oxide derivatives is that the resulting 7β-amino compounds are useful antibiotics. Is a direct precursor to the preparation of these compounds, while starting materials are generally converted from penicillin, which can be obtained, for example, by large-scale penicillin enzymes, to the systematic oxidation of these penicillins to 1β-oxide, so-called desacetoxy cephalosporin. From the 7β-acylamino-3-methyl-3-cepem-4-carboxylic acid 10-oxide flow path because it can be obtained in an economical way by expansion and monooxidation to desacetoxy cephalosporin 1β-oxide. It is combined in a multistep preparation of 7β-amino-3-substituted methyl-3-cepem-4-carboxylic acid and ester.

In general, a tunable method of arranging the multistep preparation of 7β-amino sephalosporinic acid derivatives involves a series of next steps.

a) because of the need to protect the carboxyl groups of the cephalosporins, in many cases, from the point of comparatively easy preparation and the very easy removal by subsequent hydrolysis of the ester groups, preferably starting with silyl ester as desacetoxy cephalo Preparation of suitable esters of sporin 1β-oxides, more preferably silyl esters, can be made economically in situ.

b) photoinduced bromination of 3-methyl groups,

c) if required by the nature of the ester group and the properties of the acylamino group, optionally substituted bromine additionally introduced with hydrogen in the methylene group adjacent to the sulfur atom of the dihydrorazine ring;

d) a bromine atom introduced into a 3-methyl group, such as another atom or group, such as a heterocyclic thio group, wherein the heterocyclic moiety is, for example, substituted pyridyl, pyrimidyl, pyridazyl, pyrrolyl, imidazolyl, pyrazolyl, Isoxazolyl, oxazolyl, isozozolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazozolyl, tetrazolyl, etc.)

e) deoxygenation to alcoholic groups,

f) removal of acyl groups from 7β-acylamino substituents to produce free 7β-amino groups.

The main motivation of the present invention is that each step substantially reduces the need to separate intermediates, which in turn makes them compatible with each other by combining them in a single-port process that allows multi-step synthesis, preferably without separating intermediates. The main problem with the other, but related, objects of the present invention in order to reach this goal is to find a suitable deoxygenation method for the sulfoxides involved, particularly with regard to the use of the desired silyl protection in the process.

Preparations are made in comparison to the prior art, which involves substitution reactions applied to 7β-amino-3-acetoxymethyl-3-cepem-4-carboxylic acid (7-ACA) as described in European patent application 0074316. Suitable candidates for the deoxygenation reaction are for the purpose of designing a multi-step preparation of 7β-amino-3-substituted methyl-3-cepem-4-carboxylic acid derivatives from desacetoxycephalosporin 1β-oxide which is sufficiently economical in large scale production. At least the following requirements must be met.

1) A decarbonation process, which is recognized by those skilled in the art, that a good retention of "silicone ester" during a multistage inversion reaction is also a rare phenomenon in the inherently complex field of β-lactam chemistry, preferably contains a femcarboxylic acid. It should be possible equally to the "carbon" ester for the "silium" ester of.

2) Whether or not concurrent with the introduction of the use of the "silicium" ester, the conditions of the technical novel or known suitable deoxygenation process are at least the conditions of the preceding step which require the separation of the decarbonation product and / or It should be possible to smoothly interoperate with the conditions of the final stage containing bromine atoms in the bromethyl group. However, in view of the nature of each of the many sulfoxide reduction methods known in the prior art, none of these methods have previously been predicted by those skilled in the art to meet the requirements of single-port processes, particularly with regard to the use of silylated intermediates. . Moreover, interruptions in the separation of intermediates significantly reduce the benefits associated with using "silicium" esters instead of "carbon" esters.

3) Since all processes contain only one stage, in which the conversion yield is only moderate, that is, step (c), the yield of the deoxygenation reaction should be nearly quantitative.

4) One or more of the preceding processes without unduly detracting from the advantageous point of view of the decarbonization, which is considered to be approximate with respect to the reaction temperature, reaction time and the chemicals used, for example, in a single stage test. It should be possible to apply it in combination with many other steps. The candidate is not suitable if it is deemed necessary to require a significant increase in the energy cost and / or reaction time associated with the use of a suitable drug and / or cooling.

For example, J. Drabowitz et al. [Org. Prep. and Ploc., 9 (2), 63-83 (1977), since the literature clearly explained the nature of the deoxygenation of sulfoxides, it seems to be difficult to find a reasonable discovery and development. However, many of the general and specific methods exemplified in this document do not find economic methods in the field of cephalosporin chemistry. Deoxygenation methods, which are rarely used or never used, are suitable for the development of deoxygenation with suitable conditions, such as zinc and trichlorosilane in acetic acid. The compatibility with the use of silylated intermediates was investigated. However, it is recognized that these methods are not applicable at all or are not sufficiently effective, and of course expensive methods such as reduction with tributyltin hydride cannot be considered.

Next, when considering the possibility of using known methods and procedures known to be effective in cephalosporin chemistry and evaluating that it may correspond to the preparation of a single pot containing at least two successive steps, without separating intermediates, Tried.

ratio. egg. B.R. Crowley et al., Tetrahedron, Vol. 39, pp. 337-342 and 461-467 (1983) describe a slightly similar multistage of 7β-amino-3-substituted methyl-3-cefe-4-carboxylic acid derivatives starting from desacetoxy cephalosporin 1β-oxide derivatives. Although the synthesis has been described, only "carbon" esters have been used for the protection of the 4-carboxylic acid moiety, and further bromination of the methylene groups adjacent to the emulsification as a result of not using a silylated intermediate is not necessarily a significant side reaction and is optional. Bromination should not enter the whole series.

If the acyl group bound to the 7β-amino substituent in this process is not a formyl group, deoxygenation applies only to a single step. The decarbonation method used here contains acetylchloride to activate the sulfur-oxygen bond as a combined reagent and potassium iodine as the reducing agent.

In addition to variations in the yields obtained (ie 60-90% in a single step alone), the process is characterized by all solubility of potassium iodide, the expected reactivity of acetylchloride to "silium" esters at room temperature or above room temperature and the two used. The application of the "silium" ester in terms of the incompatibility of dimethylformamide due to the solvent's reactivity with the solvent, i.e., the solvent itself to the phosphorus pentachloride, which is used in the final step of removing the unacceptable glacial acetic acid and acyl groups from the 7β-substituents. Incompatible

In U.S. Patent No. 4,044,002, a combination of acetylbromide added in excess of at least 100% and a structurally changing bromine complex which removes bromine generated by conversion by addition and / or substitution is used as a reagent. Sulfaside deoxygenation processes have been described that can be applied to various Sepharoseporanic acid 1-oxides and to esters thereof in general. Preferred brominated complexing agents are primarily simple C ₂ -C ₅ monoolefins for economic reasons, but C ₅ -C ₈ cycloolefins are probably equally effective by the second table in column 12.

In at least preferred operation, despite its apparent effectiveness, the method is particularly suitable for use in the more susceptible " silicone " esters indicated in the above patents, in view of the excessively high temperature range, in a suitable general purpose deactivation within the context of the present invention. It cannot be considered an attractive starting point for the development of the oxygenation method.

It is common knowledge in the art that there are various scientific literatures on the use of trivalent phosphorus compounds, in particular phosphorus trichloride and phosphorus tribromide, for the deoxygenation of penicillins and cephalosporins of 1-oxides. It is recognized by those who have [Eg, P. Claes et al, J. Chem. Soc. Perkin I, 932 (1973), I.G. Wright et al, J. Med. Chem., 14, 1420 (1971), G. V. kaiser et al., J. Org. Chem., 35, 2430 (1970).] As well as phosphorus trihalogenide, which is particularly good for deoxygenation to common "carbon" esters of cephalosporin 1-oxides, such as, for example, Belgian Patent 737, 121. There are a number of patents and patent applicants showing use. Even though it is not clear from the prior art that the "silium" ester of Sepharosporin 1-oxide is also capable of the actual valuable deoxygenation by phosphorus trichloride, at least some Sepharosporin 1 during a single step test. It has been recognized that trimethylsilesters of -oxides can be reduced in phosphoric acid chloride in good yield only at temperatures of about -70 ° C or lower.

Moreover, as predicted in the prior art, the activation of its reducing agent with a relatively large amount of dimethylformamide, in particular when applied to "silicium" esters, would instead be bound to conditions without the use of significantly excess phosphorus trichloride. Could not.

In addition, the addition of phosphorus pentachloride at about −50 ° C. during the second step to the reaction mixture containing a large amount of dimethylformamide instead of excess phosphorus trichloride contained strong cooling and a larger amount of phosphorus pentachloride than usual. As such, this view is deoxidized as in a two-stage single-port conversion to 7β-amino-3-cepem-4-carboxylic acid derivatives corresponding to 7β-acylamino-sephalosporin-1-oxide. The use of the extinguishing process has already been made very unattractive.

Remarkably more reagents (in this case, phosphorus trichloride) have been attempted to combine the deoxygenation step and the preceding step of the pre-process into a single-pot preparation, especially in the case of comparatively strong cooling and the presumption of the residual amount of reagents added previously. The consideration of a complete single-port process aimed at not including separation of intermediates has become overly distant.

Finally, one would expect to find a suitable deoxygenation method that could be combined into a two-step or multi-step single-port preparation, but essentially without much suitability for other steps, and its reagents are also preferred for the final sequence of the entire series. Because of the shift in phase, attention has been paid to other methods relating to the use of phosphorus pentachloride as a reducing means in the general sense. According to various descriptions in the prior art, the phosphorus pentachloride in this regard is used repeatedly in two closely related modifications, including removing chlorine forming salts with chlorinated tertiary amines of tertiary amines introduced simultaneously. The equivalent response is formally:

These two correlated reactions are shown separately, as the case may be, but the difference between them is simply chlorine in which Method A uses N, N-dialkylaromatic amines substituted at the para- or ortho position in the aromatic reduction. The atom is bound to an unsaturated aromatic carbon atom, and in method B the chlorine atom is introduced at the saturated allyl position.

According to British Patent Application Nos. 1, 467 and 610, it is also a more general method to use a tertiary amine such as pyridine in terms of good yield when not corrected in the actual content of the finally separated product. It is thought that it is not substituted by chlorine during deoxygenation, and it neutralizes to some extent by formation of the molecular complex between an amine and molecular chlorine.

Method A is for example M. Wakisaka et al. [M. Wakisaka, et al., Synthesis, pp. 67-68 (1980), with some views of possible reactor mechanisms. As already indicated, there is the use of tertiary amines such as dimethylaniline and other preferably weak, pyridine, which is equivalent to the use of the starting material "silium" ester, which is equivalent to 7β-acylamino-3-substituted methyl-3-cefem. Good yields were obtained by a two-step, single-port preparation of 7β-amino-3-substituted methyl-3-cepem-4-carboxylic acid starting from 4-carboxylic acid 1β-oxide derivatives.

Method B using enamines of the same kind as 1-monopolyno-1-cyclohexene and phosphorus pentachloride has become the standard method of deoxygenation for cephalosporin 1-oxides. This method is described in M. above. It was also described by Wakisaka et al. (The same document), and furthermore indicated that enamines are more effective than dialkylanilines for the capture of chlorine due to the lesser involvement of side reactions in the general sense.

Combining these interrelated prior arts suggests possible valuable applications even when using "silicium" esters, so that method A and method B separate two stages, in particular the multistage single-port process of the present invention. It was considered the most suitable candidate. In fact, deoxygenation in the presence of such amines in a single step test using silylated intermediates is particularly well suited when using relatively stable substrates such as phenylacetamido desacetoxy cephalosporin 1β-oxide. Dimethylaniline works better than 1-morpholino-1-cyclohexane in that an optimum yield of at least 90% is obtained in a relatively short time at -45 ° C. The capture of chlorine by such reagents is effective to a lesser extent that is already substantially apparent when the substrate contains heterocyclic thiomethyl groups as substituents in the 3-position. Surprisingly, however, the application of the extended reaction time in deoxygenation and / or the application of excess reagents slightly improved the situation, but the final step of giving the deoxygenation process and the final 7β-amino-3-cepem-4-carboxylic acid. In combination with and it was recognized that the yield of the phone and the yield of separation are low to a level that gives little attention. In the case of using and introducing such complex and more interesting 3-position substituents, the combination in the deoxygenation step comprising the phosphorus pentachloride and such amines or enamines in the multistage single port preparation with the preceding step It is believed that the city does not give sufficient attention in all respects, and in particular could not be achieved on economically attractive criteria when using silylated intermediates.

Since then, cephas have more complex patterns in the 3-position of the cefe nucleus, as well as the relatively stable desacetoxy cephalosporin 1β-oxide, hoping that the new process conditions will be suited for multistage single-port preparation. A novel deoxygenation process that must be at least as effective as any of the known cephalosporin 1-oxide deoxygenation processes in a single step test under practical conditions, using a "silicum" ester for rosporin 1β-oxide. It is a first object of the present invention to develop. In the interest of capturing chlorine because of its interest in the main basic reagents in deoxygenation, i.e. phosphorus pentachloride, other forms of second reagents, preferably acting by substantially different mechanisms, are particularly applicable to multistage preparation. And the use of silylated intermediates was considered. Secondary reagents such as pyridine are thought to absorb chlorine simply by complexing under the conditions involved, while reagents such as dialkylaniline or typical enamines are capable of eliminating chlorine neutralization by possible initial complexation. It reacts with chlorine only by substitution of hydrogen by forming one carbon-chlorine bond for each molecule of chlorine consumed. By addition to the appropriate carbon-carbon double bonds by the formation of two carbon-chlorine bonds per chlorine molecule consumed, it is not thought to be obviously effective to capture chlorine during this kind of deoxygenation reaction and can also be recognized. It was thought to some extent as addition reactions of chlorine with simple non-enamineolefins, i.e. addition and / or substitution, were well known practical conversions as can be inferred from the general enormous amount of literature. .

However, the presence of such a large number of literature on its seemingly simple response indicates that the problem is not comprehensively understood, as is apparent from the content of many comments on this matter. These inherently complicated states are eg S. Sharma et al. [S. Sharma "Halogenation of Olefines", Indian Chemical Manufacturer, 12 (No. 6), pp. 25-35 (1974).

Obviously the rate of conversion, the main process of conversion, ie addition and / or substitution, the range of possible catalysts, the effects of light and oxygen, the influence and involvement of the solvent in the final product, and the structure of the olefin in incomprehensible ways The application of suitable conditions on the surface, as measured by a number of factors, does not give promising results in the early stages of the study leading to the development of the multistage process of the present invention, as attempts with completely ordinary olefins such as cyclohexane Nevertheless, it often happened that attempts made somewhere did not give attractive results.

A good addition of bromine to simple olefins during deoxygenation of "carbon" esters of cephalosporin 1-oxide is known from U.S. Pat.No. 4,044,002, which is described in other respects. Since the addition of bromine in the reaction occurs at a fairly high temperature range, the process is not substantially the same and does not show the possibility of using a "silicium" ester in the process and the reaction of bromine with a carbon-carbon double bond Since many of these documents have few problems, it is recognized that sufficient preliminary criteria have been set in this regard.

Trimethylsilyl 7β-phenylacetamido-3- [1-methyl- (1H) -tetrazol-5-yl-thiomethyl] -3-cepem-4- produced by silylation with hexamethyldisilazane Pre-tests containing non-catalytic conditions applied to the carboxylate 1β-oxide and the usual olefins, i.e., cyclohexane, showed disappointing results, which resulted in the application of a rather strange olefin, cis-cyclooctene, as a more stable substrate. Attempts have been made to do well. 7β-phenylacetamide- prepared with a slight excess of phosphorus pentachloride and cis-cyclooctene in dichloromethane in itself in a single step test using several identical excess of trimethylchlorosiltan and N, N-dimethylaniline in 3-Methyl-3-cepem-4-carboxylic acid (relatively stable substrate) and 7β-phenylacetamide-3- [1-methyl- (1H) -tetrazol-5-yl-thiomethyl] -3-cepem The results suitable for the trimethyl silyl ester of 1β-oxide of 4-carboxylic acid (relatively susceptible substrate) were surprising at all. Considering the actual content of this starting and final product, the yield of conversion and separation obtained after 15 minutes at −45 ° C. was excellent and exceeded that reached by other known deoxygenation processes attempted.

Under the above-mentioned conditions constituting only one operation of this decarbonization process, two chlorine consuming second reagents introduced to perform rapid silylation of the substrate sephalosporinic acid 1-oxide and then well-operated by some means Since one of them is a combination of N and N-dimethylaniline, which are known to be effective under the same conditions, part of the chlorine is incidentally consumed by the relative degree of change in the excess size of the reagent by substitution of N and N-dimethylaniline. Can be understood.

However, in contrast to the prior art level in terms of advantages, it can be inferred that dimethylaniline in the modification of the deoxygenation process of the invention is used with at least substantially the equivalent chlorosilanes.

In addition, extensive studies of the properties of deoxygenation processes have revealed a number of important features that must be considered in order to reach many advantageous levels of operation of the flexible novel deoxygenation process of the present invention.

The initial disappointing results of cyclohexane under the conditions shown are not attributable to the relatively susceptible nature of the substrates used, and also under the same conditions that are not particularly suited to the properties of each of these olefins, cyclohexane is usually better than cis-cycloolene. It was thought that not much was caused by unfavorable environment. Certain olefins have proven to be more advantageous than many other olefin compounds having ethylenic bonds in which two or three hydrogen atoms in total are bonded for reasons that cannot be explained at present.

There was little need for a catalyst when using the "carbon" ester of sephalosporinic acid 1-oxide, and the catalyst could be omitted in some cases. However, it was considered almost always necessary when using "silium" esters, at least when trying to make the phone in a short time at the same low temperature.

It is well known from the general art that the reaction of molecular chlorine with an olefinic double bond can be catalyzed in various ways. However, it is very complex because it contains variations due to other conditions such as the nature of the double bond and the composition of the reaction medium. The composition of the final product is also affected by catalysis. Especially with regard to the complexity of the development, the capture of chlorine by the second reagent of the nature of the olefins used in the deoxygenation process can also be catalyzed in various ways.

A clear case of catalysis is recognized in the use of N, N-di (lower) alkyl-formamides such as N, N-dimethylformamide as catalysts, with a relative amount of up to 30 mole% relative to the amount of cephalosporin introduced. It is usually considered to be enough. Catalysts of this type are in particular trimethyl with hexamethyldisilazane described in European Patent Application No. 0043630 which is incorporated herein by reference when starting as a slightly pure ester produced separately or as ester or anhydride produced in the same reactor. It can be advantageously used when the preparation, such as in the case of silylation, does not contain excess catalytic agent, or when the reaction by-product resulting from ester production does not constitute its own catalysis material.

At almost the same relative amounts, any kind of tertiary amine in such a case at the same time provides sufficient catalysis whether or not in combination with at least an equivalent amount of an acid complexing compound such as trimethylchlorosilane. The most preferred amines in this respect are N, N-dialkylanils. Therefore, in the deoxygenation reaction of cephalosporanic acid 1-oxide trimethylsilyl ester prepared by reacting hexamethyldisilazane, addition of about 10 mol% of N and N-dimethylaniline simultaneously plays an important catalytic action. Small amounts of chlorine cannot be explained solely by the environment consumed by nucleophilic substitution of these amines.

Some other forms of tertiary amines, regardless of their tendency to be substituted by chlorine, are catalyzed as described above, but some types of tertiary amines that are virtually unsubstituted by chlorine in the conversion can significantly delay deoxygenation. . This means pyridine and some pyridine-type amines, which are considered to form strong molecular complexes with phosphorus pentachloride, even when applied in equivalent amounts, for example with trimethylchlorosilane. The experimental results on this issue are sharply contrasted with the method of British Patent Application No. 1467610, described above, carrying both pyridine and N, N-dimethylaniline.

Hydrochlorides of pyridine and various tertiary amines in general can be said to impart some degree of catalysis. Such salts are automatically produced upon dissolution of the starting 1-oxide of sephalosporanic acid with halogen containing reagents and tertiary amines.

In addition, relatively strong base aliphatic tertiary amines, such as several kinds of tertiary amines can be used in this regard, but overintroduction of such bases with some pyridine-type bases, for example pyridine and 5 It is recognized that from the disturbances caused by the formation of complexes with phosphorus chlorides, it should be avoided in the context of rapid deoxygenation at relatively low temperatures, even when excess bases are offset by at least equivalent halogen-containing esterification agents, for example trimethylchlorosilane. It became.

Other features that must be considered in order to arrive at the proper application of the deoxygenation process of the present invention are those relevant to the disclosure in the general art. Although several kinds of olefin compounds and many of them may consume molecular chlorine at a relatively low temperature at a high rate, they are not limited to addition reactions by double bonds of carbon-carbon, Since hydrochloric acid is formed at the same time, it is carried out by substitution at one unsaturated carbon atom.

This problem is very complex and the ratio of addition and substitution reactions depends, for example, on the reaction conditions chosen. In the description of a relatively simple olefinic compound, 1-olefins such as 1-hexene having 3 hydrogen atoms bonded to two unsaturated carbon atoms absorb molecular chlorine to a considerable extent by substitution under different conditions. Relative degrees of substitution can be significantly reduced by using generally faster reacting 1-olefins, which are not the same as the hydrogen atoms bonded to the non-terminal unsaturated carbons, and having non-terminal carbon-carbon double bonds such as 2-hexene. If an olefinic compound is used, it is almost negligible.

When using a silyl group that is susceptible to protection of 4-carboxyl groups and thus makes the starch more sensitive, this view is somewhat of a concern for this process, although the process does not contain free molecular chlorine of concern at least at low temperatures. You will experience the same.

In such cases the use of 1-olefins, such as 1-hexene, involves the introduction of suitable tertiary amines, such as but not pyridine, of less than equivalents of triethylamine to mitigate the adverse effects of hydrochloric acid generated during the reaction. At this point, it is generally sufficient to use a smaller amount of base if the relative size of the substitution of about 50 mole% or olefin can be approximated by testing or by information available from the general art. The base can be added slowly at the beginning of deoxygenation or during its conversion. As a result, in view of the excessively high total acidity of the medium as a result of the use of excess tertiary amine bases used in the prior esterification step at least in excess with halogen containing reagents such as trimethylchlorosilane, It was recognized that it might not be suitable enough.

As above, the use of olefins such as 1-hexene, which involves the use of individually adjusted selection conditions, and which also requires relatively long reaction times and / or higher temperatures, makes the deoxygenation step suitable for other steps. It is recognized from the final criterion for the incorporation of the deoxygenation reaction of the invention into the single-port multistage process of the invention, particularly when such a process is concerned with protection silylation.

Thus, in at least a single step test, olefins that vary depending on the nature of the carbon-carbon double bond can be applied as a second reagent for intercalating deoxygenation, which is a pentachloride of several types of sephalosporanic acid 1-oxide, optionally It has been found that the suitability of olefins relates to finding respective suitable conditions for the degree of competition for substitution of olefins, for example, instead of the nature of the esterification, the catalysis and the selective addition of carbon-carbon double bonds.

Therefore, a first object of the present invention is to react the cephalosporin 1β- and / or cephalosporin 1α-oxide of the following general formula (I) with phosphorus pentachloride to the corresponding substituted cephalosporin of the general formula (II) Deoxygenated and optionally R ₁ is introduced to protect the reactive groups in the protecting groups R ₁ and (or optionally in the substituents R ₂ , R ₃ ) in order to obtain a compound of hydrogen or a salt forming cationic formula (II) It relates to a one-step process for eliminating a group.

In the above formula,

X is hydrogen, a (lower) alkyloxy group, or a (lower) alkylthio group, and lower alkyl represents the residue of 1-4 carbon atoms.

R ₁ is a protecting group commonly used in cephalosporin chemistry, e.g., silyl groups such as trimethylsilyl, dimethylchlorosilyl and dimethylsilyl via carboxylate oxygen bound to a part of the cephalosporin of formula (I), t- Benzyl groups such as butyl, pentachlorophenyl, 2, 2, 2, -trichloro-ethyl, benzhydryl or 4-nitrobenzyl and 4-methoxy-benzyl,

R ₂ is a wide variety of atoms or groups, for example hydrogen or chlorine atoms, methoxy, trifluoromethyl, vinyl, methyl and halogen atoms such as chlorine or bromine, protected hydroxy groups such as trialkylsilyloxy groups, (lower) Alkyloxy, (lower) alkyldio, (lower) alkanoyloxy, such as acetoxy, (lower) alkaniorio, 1-pyridinium groups, optionally with heterocyclic groups, having substituents attached to heterocyclic rings, or optionally heterocyclic Containing a methyl group substituted by a heterocyclic thio group substituted in the ring, wherein the heterocyclic group is pyridine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole isoxazole, oxazole, isothiazole, thiazole, 1, 2, 3- (1H) triazole, 1, 2, 4-triazole, 1, 2, 4- and 1, 3, 4-oxadiazole, 1, 2, 4-, 1, 3, 4-, It can be 1, 2, 3- and 1, 2, 5-thiadiazole, 1, 2, 3, 4- tiatiazole and (1H) tetrazole bound to sulfur atoms by ring carbon atoms. In some cases, a substituent bonded to a carbon atom of a heterocyclic ring may optionally include a lower alkyl, cyano, chloro, di (lower) alkylamino, (lower) alkyloxy group such as methoxy, (lower) alkyloxy Carbonyl, di (lower) alkylcarbamoyl, hydroxy, sulfo or carboxyl groups are also included, and the ring-substituted atom of the heterocyclic thio group may have a substituted lower alkyl group depending on the case where it is bonded thereto, and heterocyclic carbon Or a substituent which optionally bonds to the first or second carbon of the lower alkyl group bonded to the nitrogen atom includes di (lower) alkylamino, chloro, cyano, methoxy, (lower) alkyloxycarbonyl, N, N-dimethyl Carbamoyl, hydroxy, carboxyl and sulfo groups may be included, optionally by silylation of hydroxy, carboxy, sulfo and heterocyclic secondary amino groups adjusted in the preceding or in the same reactor or In the last case, if necessary, include protection by acylation,

R ₃ is an acyl group having remarkable reactivity such as formyl, alkane oil, alken oil, aroyl, heterocyclic carbonyl, aryloxyacetyl, cyanoacetyl, halogenoacetyl, phenylacetyl, α-hydroxy-, α-carboxy- and α-sulfo-phenylacetyl, α-carboxy-thienylacetyl, α-acylamino-phenylacetyl, α (substituted) oxyamino-allyl (or-furyl or thiazolyl) acetyl, optionally Secondary amino groups having substituents containing chlorine, fluorine, methoxy, cyano, lower alkyl, hydroxy and carboxy bound to an aromatic or heterocyclic ring and, optionally, by silylation or in an unsaturated ring In the case of acylation, comprising protection capable of easily removing the reactive substituents introduced previously or in the same reactor itself, or R ₃ together with R ₄ and its nitrogen atom to form a phthalamide group,

R ₄ is except that when R ₄ constitutes a phthalamide group,

According to the present invention, a one-step process that is generally deoxygenated by the reaction of cephalosporin-1-oxide with phosphorus pentachloride can be carried out in any case of an organic solvent in which deoxygenation is substantially inert at −7-0 ° C. Is carried out in the presence of an olefinic compound having at least one carbon-carbon double bond to which no more than two hydrogens are bonded, wherein the olefinic compound removes at least a portion of chlorine by an addition reaction to the carbon-carbon double bond Characterized in having a.

Enamines, such as 1-morpholino-1-cyclohexene, are described in the prior art as being effective in use in such cases and are therefore excluded from the present invention. Essentially, instead of phosphorus pentachloride, reagents known in the art to be effective for the deoxygenation of sulfoxides, such as phosphorus pentabromide, may be used more generally, but it is clear that phosphorus pentachloride is an industrially preferred reagent.

Recognition that the ability of olefins to remove chlorine in deoxygenation, which describes phosphorus pentachloride of cephalosporin-1-oxide, corresponds to the ability of the olefin to at least partially absorb molecular chlorine by addition to carbon-carbon double bonds. In principle, olefins capable of absorbing molecular chlorine in rapid reactions below 0 ° C. under similar conditions can be used in the process of the first object of the invention. Thus, the olefinic compound may be a monoolefin, diolefin or monoolefin, diolefin or polyolefin having a carbon-carbon double bond having one or more carbon-carbon double bonds located in a chain or ring. have. If the olefinic compound has one or more carbon-carbon double bonds, the relative amount of olefin used can be reduced depending on the number of double bonds.

In diolefins or polyolefins, the double bonds may be in resonant or non-resonant positions but the benzenoid compounds and aromatic compounds which do not readily add chlorine to the carbon-carbon double bonds are explicitly excluded. In environmental considerations, the polyolefinic compound may also be a polymer compound having carbon-carbon double bonds bonded somewhat regularly to the support frame, especially when using silyl protection of cefem-carboxylic acid.

[alpha], [beta] -unsaturated functional compounds such as [alpha], [beta] -unsaturated nitrile may also be used, but in this case, it is preferable that at least one hydrogen atom is bonded to each carbon atom of the carbon-carbon double bond.

Substituents such as hydroxy, carboxy and carbamoyl that can interact with phosphorus pentachloride are also less compatible. Substituents which may be located at adjacent or distant positions are, for example, alkoxy, alkylthio, bromine or chlorine, and chlorine may already be introduced automatically in about 1/2 equivalents if diolefins are used.

Particularly in terms of the extra cost normally associated with the use of polyolefins and complexly substituted olefin compounds, olefinic compounds of primary application are located in the chain of 3-20 carbon atoms or in the ring of 4-12 carbon atoms. Hydrogen having one or two carbon-carbon double bonds and bonded to non-terminal carbon-carbon double bonds and inner unsaturated carbon atoms with a total number of hydrogen atoms bonded to carbon-carbon double-bonded carbon atoms not greater than two Monoolefins and diolefins including terminal double bonds having no atoms are included.

In general, it is not easy to accurately predict the additional size of chlorine in this process that exceeds the magnitude of substitution by chlorine under normal conditions, but in general, especially when using cephalosporin 1-oxide "silium" esters. In general, monoolefin or di having one or two non-terminal carbon-carbon double bonds can be inferred from the prior art, as it can be inferred from the prior art to increase the size of substitution by placing the double bond in the terminal position. More preferred is the use of olefins. The olefinic compounds included may represent cis-trans isomers, but using trans isomers in place of the corresponding cis-isomers is not suitable or only has minor advantages.

In view of absorbing molecular chlorine faster than known tertiary olefin linkages and quaternary olefin linkages than non-tertiary trisubstituted olefins, they have one or two non-terminal carbon-carbon double bonds well suited for the process of the present invention. And an olefinic compound in which one or both carbon atoms of a double bond are substituted with straight chain lower alkyl groups of 1-4 carbon atoms.

It is generally considered to be very effective and a somewhat preferred olefin for other olefins having non-terminated bisubstituted double bonds is ciscyclooctene. With respect to similar olefins such as cycloheptene and hexene-2, the somewhat preferred state of these olefins differs in this relationship so that the conversion obtained therefrom is not good. Surprisingly, however, in some trials starting with various substrates of general formula (I), it was recognized that the separation rate reached a very good yield and was also easier in cyclooctene. The use of ciscyclooctene under practical conditions reached a separation yield close to the conversion yield measured by high pressure liquid chromatography, so it was thought that the mother liquor no longer needed to be treated.

A generally suitable range for the temperature during deoxygenation is considered to be -60 ° C to -20 ° C. The choice of temperature is mainly selected is determined by the structure and stability of the protecting group R ₁ of the olefin, it is considered to influence the reactivity of the sulfonyl group on the nature or de-oxidation of the protecting group R _1. If R ₁ is a susceptible group such as trimethylsilyl, it is generally advantageous to use a low temperature of -30 ° C. or lower, which leads to a difference in whether the "silicon" ester is produced exactly by itself in the same reactor. . When such esters are prepared in an approximately equivalent amount with a suitable tertiary-amine, such as triethylamine or dimethylaniline, as the chlorosilane, a small amount of 7β-acylamino substituent by phosphorus pentachloride, which is usually introduced due to deoxygenation, is produced. It is desirable to use a temperature of about -40 ° C to completely exclude the possibility of further cleavage.

Therefore, according to the silylation method used in the process of the present invention, the risk is practically minimized since the excess base put into silylation is usually offset by at least a substantial equivalent of the chlorosilane agent. Deoxygenation according to the invention is carried out substantially in an inert organic solvent. In this respect, various kinds of solvents such as ether type and alkyl ester type solvents can be used. It is obtained from the use of good yield and suitability for the nature of the solvent. In particular, preferred solvents are halogenated hydrocarbons such as chloroform, dichloromethane and 1, 2-dichloroethane. If necessary, it can be used in combination with other solvents, for example, by the solubility of the ester of the general formula (I). As indicated above, the deoxygenation process of the present invention is generally suitably carried out in the presence of a catalyst or additive that promotes rapid conversion at relatively low temperatures. As previously described, the fast inducer is preferably a protective ester group R ₁ by reacting the starting sepharose roric acid 1-oxide with the halogen-containing reagent, such as trimethylchlorosilane, in the presence of a suitable tertiary amine in the reaction itself. It may already exist when you introduce it.

In general, it does not impart catalysis at the next deoxygenation, especially from pre-manufactured rather pure "carbon" esters or by themselves or by their conversion products, such as hydrochloride salts of tertiary amines, during the esterification or anhydride formation procedure. With reagents that do not, the catalyst or the conversion promoter is carefully introduced when starting from other kinds of esters or acid anhydrides, preferably prepared within the reaction itself.

Preferably, such cautious catalysts or inducers are economically used relative amounts not exceeding 30 mole percent relative to the amount of cephalosporin 1-oxide used. In this regard, the compounds include relatively strong complexes with N, N-di (lower) alkyl-formamides such as N, N-dimethyl-formamide and / or phosphorus pentachloride generally used in deoxygenation reactions. It is a tertiary amine which does not form and is consumed by substitution or may not be consumed by a part of chlorine generated in the deoxygenation reaction. Preferred tertiary amines in this respect are N, N-di (lower) alkyl-aniline such as N, N-dimethyl-aniline. Deoxygenation conditions from the above-mentioned point of view, in which the optional olefinic compound used as the second reagent in the deoxygenation process of the present invention in a varying relative range does not consume chlorine by addition to a carbon-carbon double bond, In order to neutralize the generated chlorine, relatively strong basic tertiary aliphatic compounds such as triethylamine or N-dimethyl-molfulin and the like can be added simultaneously or gradually to be captured. At this time, several mole percent of N, N-di (lower) alkylformamide is added if the magnitude of the catalysis imparted by the base and / or its hydrochloride is not sufficient for rapid conversion at low temperatures. The compound of general formula (I) which is a starting material for the process of the first object of the present invention includes a protecting group R ₁ which imparts the properties of mixed anhydrides or esters.

Mixed anhydrides of general formula (I) are generally suitable for preparation in the reaction itself. The protecting group is removed by mild hydrolysis, optionally performed in the reaction itself after deoxygenation, giving R ₁ a compound of formula (II) having hydrogen or a cation for salt formation. Reagents for the preparation of the compounds of the general formula (I) in the form of mixed anhydrides include halogenated carboxylic acids, such as acetyl chloride, chloroacetyl chloride, benzoyl chloride, or chloroform, such as methyl- or ethyl-chloroformmate. Mate, phosphorus pentachloride, phosphorus oxy trichloride, phosphorus trichloride, methoxydichlorophosphine, 2-chloro-1, 3, 2-dioxaphospholane, 5-methyl-2-chloro-1, 3, 2- Compounds containing one or two or more phosphorus-halogen bonds, such as dioxaphospholane, ethoxydichlorophosphate, methoxydibromo phosphate, and the like, and preferred compounds include methoxytrichlorosilane, methyldimethoxychlorosilane, methylmethoxy 1 or 2 or more silium halo such as dichlorosilane, diphenyldichlorosilane, dimethyl tert-butylchlorosilane, triethylchlorosilane, dimethylmethoxychlorosilane, dimethyldichlorosilane Compounds containing gen bonds are particularly preferred are trimethylchlorosilanes. If this reagent contains two or more reactive halogen atoms, the compound of formula (I) still contains one or more halogen atoms bonded to a central atom such as silicon or phosphorus, and ( Or) contains two or more sephalosporanyl moieties bound via a carboxylate oxygen to a central atom, such as silicon or phosphorus. Silyl groups substituted with lower alkoxy groups such as methyl and ethyl can be introduced with the aid of the corresponding disilylamine (disilazane).

The "carbon" esters of general formula (I) are prepared by separate preliminary steps using different hydroxy compounds. After deoxygenation, the compound of formula (II) still having protecting group R ₁ was isolated, treated by known hydrolysis or reduction methods, or a compound of formula (II) having a salt forming cation. The hydroxy carbon compounds derived from the esters of general formula (I) are 2 present in pentachlorophenol, 2-chloro and 2-bromoethanol, 2-methyl imidazole and 1, 2, 3- (1H) triazole. The quat-unsaturated heterocyclic amines may be subjected to acetylation using simple acid chlorides or lower alkylchloroformates, such as acetyl chloride or benzoyl chloride, in view of easy removal of acyl groups by simultaneous silylation or later by mild hydrolysis. Can be protected by.

When the carboxylic acid or carboxylic acid salt of formula (I) is used as starting material, the protection of the cephalosporin-4-carboxylic acid group is preferably carried out by forming a mixed anhydride in the reaction itself. If such starting sephalosporin 1-oxide contains one or more of said reactive second substituents, the protection of the presubstituents which need to be protected is preferably by silylation and, in some cases, by the kind described above. It is introduced in combination with the acylation of the second heterocyclic amine group.

In practice, however, little additional protection of the reactive substituents contained in R ₂ and R ₃ is needed. The process test operation of the first object of the present invention is simple. A solution of the ester of formula (I) or a mixed anhydride in a suitable solvent system is eventually selected after reaction in the reaction itself of the mixed anhydride and after protection of a reactive second substituent, for example by silylation, or It is performed at the originally slightly lower temperature. If desired, the olefinic compound is optionally added in excess of 0-30 mol% if the compound is an olefin during cooling or after reaching the selected low temperature.

If the olefin compound contains one or more "carbon-carbon" double bonds, the relative molar amount of the olefinic compound may be substantially less relative to the number of double bonds, while maintaining 0-30% excess equivalents in some cases. can do.

Disregarding the rather exceptional case where possible, the common conditions for the use of and without the use of catalysts or rapid-promoting compounds are:

When the compound of the general formula (I) mentioned above is a mixed anhydride derived from an ester or a sephalosporanic acid 1-oxide compound, for example, a carboxylic acid, a catalyst of a preferred kind is preferably in the range of 0-30 mol%. Add. Although there are some differences depending on the type and nature of the olefinic compound, the introduction of the catalyst is usually such a mixture as starting material, especially when using "silicium" esters and other types of mixed anhydrides. This is necessary when the anhydride is not produced within the reaction itself by the use of reagents in combination and / or reaction products such as HCl-salts of suitable tertiary amines. If the olefinic compound to be used does not react substantially with the addition of chlorine to the material for chlorination, a suitable tertiary amine, such as 50 mole% or less of triethylamine, may be required if necessary to several mole% of N, N It is added at once or slowly with several mole% of di (lower) alkyl-formamide.

In some cases where the properties of the substituent R ₂ actually impart a relatively high negative effect relative to the reactivity of the sulfoxy group, for example, when R ₂ is a 1-pyridiniummethyl group, a catalytic amount of, for example, N, N-dimethylformamide If used, it may be advantageous for any operation procedure of the carbonation process of the present invention. Phosphorous pentachloride is added to 5-30 mole% of excess phosphorus pentachloride, and then stirred at a low temperature selected, mainly for a time by the selected reaction temperature. Illustrating the reaction time at this time, when using a properly prepared "silium" ester, it is sufficient to stir for about 15 minutes at -45 ℃. The reaction mixture thus obtained is hydrolyzed with care in accordance with known methods. In the deoxygenation process of the most suitable known cephalosporin 1-oxide, despite the difficulties experienced in combination with other steps observed in a single pot, despite the good and indeed good behavior in the single step test, It is unexpected to those of ordinary skill in the art that this deoxygenation process can be inserted without actually or satisfactorily fitting into a single port of two and multiple stages.

Thus, at first glance, the easiest cleavage, namely the selective cleavage of the 7β-acylamino substituent containing phosphorus pentachloride as a reagent by the novel deoxygenation process of the present invention and methods known per se in the prior art ( A two stage single pot process containing iii) was attempted for the first time. Fortunately, the new deoxidation process could be single-ported, since there was virtually no need to combine, and 7β in which at least a substantial part of the compound contained by formula (I) was substituted corresponding to positions 3 and 7 Providing amino-sephalosporin derivatives. Accordingly, a second object of the present invention is to optionally remove the "carbon" ester residue R ₁ of general formula (II) so that R ₁ ′ is 7β-amino of the following general formula (III) having a hydrogen atom or a salting cation It relates to a method for producing a sephalosporan derivative.

In the above formula,

X is as described above,

R ₁ ′ is a hydrogen atom or a salt forming cation or a pentachlorophenyl, benzyl, 4-nitro-benzyl, 4-methoxy benzyl, benzhydryl, 2, 2, 2-trichloroethyl and t-butyl. Carbonyl "ester residues,

R ₂ ′ includes the above-mentioned silyl group for protecting the previously introduced hydroxy, carboxy and sulfo groups and (or) silyl group or acyl group for protecting the unsaturated heterocyclic secondary amine, or a salt thereof. ,

HZ is a salt forming strong acid such as P-tolyl-sulfonic acid or hydrochloric acid commonly used in cephalosporin chemistry,

n is 0 or 1 when X is hydrogen and X is not hydrogen and R ₁ ′ is hydrogen, but n is 1 when X is not hydrogen and R ₁ ′ is a “carbon” ester moiety.

The separation of the compounds of formula (III) in the form of acid addition salts, represented previously as (HZ) n, according to what is known in Sepharoserin chemistry is mainly a matter of separation procedure and stability. Regardless of the R ₁ 'group, n can be 0 or 1 when X is hydrogen. If R ₁ ′ is hydrogen, n is usually 0, but when R ₁ ′ is a carboxylic ester residue such as t-butyl, it may be convenient to separate the compound as acid addition salt (n = 1).

However, if X is hydrogen, then the stability of the final product may be necessary to separate as acid addition salt in the following method known per se, especially when R ₁ ′ is a carboxylic ester residue. In addition, a carboxy, sulfo, unsaturated heterocyclic secondary amino group present in the substituent R _2, as is well known to form internal salts due to the presence of a tertiary dialkylamino group and R ₂ is variable depending on the case of 1-pyridinium group .

According to a second object of the present invention, a two-step process for preparing a compound of formula (II) deoxygenates 7β-acylamino-3-cepem-4-carboxylic acid 1-oxide of formula (Ia). Without separating the product, the next step:

a) Silylation of the cephalosporin 4-carboxyl group and / or optionally included in R ₂ as described above, when R ₁ ′ starts with a compound of formula (Ia) having a hydrogen atom or a salting cation Protection by silylation and / or acylation of reactive reactive residues,

b) in any case in the presence of an olefinic compound which removes chlorine by addition to at least one carbon-carbon double bond having not more than two hydrogen atoms bonded thereto, optionally added or already present catalyst or Deoxygenation in halogenated hydrocarbon solvents using phosphorus pentachloride in the presence of additives.

c) addition of a suitable tertiary amine, such as dimethylaniline and phosphorus pentachloride, to form the corresponding imidechloride in the continuous reaction itself, monohydroxy alcohol such as isobutanol to form the corresponding iminoether Or the 7β-acylamino substituent by known procedure by addition of alkanediol such as 1,3-dihydroxy-protan, and finally water for hydrolysis of the iminoether group and the easily removable protecting group. It is characterized in that the deacylation reaction is performed by dividing in the same reactor in some cases.

In the above formula,

X is as described above,

R ₁ ′ is hydrogen or a salt forming cation or a “carbon” ester moiety as described above,

R ₂ is as described above, and in some cases means protection of a reactive substituent contained in R ₂ before deoxygenation,

R ₃ ′ is a substituted acetyl group R ₅ -CH ₂ -CO similar to a group that can be introduced by phenylsilin fermentation, wherein R ₅ is hydrogen, allyl, alkyl, cycloalkyl, alkenyl, allyloxy, allylthio, Alkylthio) or a benzoyl group.

Thus, it is possible to experimentally carry out all the processes up to the final hydrolysis process in the same reaction tube, and at least some of them may be continuously performed in the same reactor. It is advantageous in some cases to add the reaction mixture of step c) containing imide chloride to a second reaction vessel containing excess hydroxy alkane that has been cooled beforehand.

The final product of formula (III) optionally comprises hydrolysis or reductive cleavage of the "carbon" ester residue R ₁ ′ and is separated basically by known methods.

In the process of the second object of the present invention, other types of solvents may be preferably used in some cases, but it is generally preferred to use halogenated hydrocarbons such as chloroform 1, 2-dichloroethane, in particular dichloromethane. In addition, in view of the appropriate low temperature below -35 ° C for chloride formation step c) containing phosphorus pentachloride, deoxygenation step b) is carried out from -35 ° C to -65 to minimize the cost of additional cooling. Preference is given to performing at a temperature of < RTI ID = 0.0 >

In particular in the chain of 4-12 carbon atoms, optionally substituted with methyl or ethyl groups for one or both unsaturated carbon atoms, in terms of economic reasons and for the most appropriate control of amide bond cleavage, or 5-8 It is preferable to perform deoxygenation with phosphorus pentachloride in the presence of olefin compounds of two reducing agents. Particularly in that the final product in which the separation yield is in close proximity to the conversion yield advantageously separates, it is proved that the effective olefin alone is cis-cyclooctene.

In using the starting material of general formula (Ia), as a preferable protecting group R <_1>', it is a trimethylsilyl group generally. When using the "carbon" ester of general formula (Ia), t-butyl is somewhat preferred over other similar groups R ₁ '. Preferably, R ₃ ′ used is phenylacetyl and phenoxyacetyl.

A third object of the present invention is to synthesize a 7β-acylamino-separosporranic acid derivative using 7β-acylamino-desacetoxycepharosporanic acid 1β-oxide derivative as a starting material, and preferably until the final separation procedure. It relates to a multistage preparation carried out in one and the same reaction vessel, wherein 7β-acylamino substituents are appropriately identical to 6β-acylamino substituents of penicillin, such as phenylacetyl and phenoxyacetylamino, which can be prepared by fermentation, The substituent R ₃ ′ may contain a benzoyl group or formyl. The deoxygenation process of the present invention was applied in the last step. The preceding step leaves the remainder of the various drugs, which generally impedes good deoxygenation by prior art processes and makes such reagents uneconomically and long-lived, even though they can be used at moderate doses. Reaction time was required. Compared with the prior method, it is shown that the novel deoxygenation of the present invention can be applied generally without such non-economic intervention. Even when using silylated intermediates, the suitability in multi-stage single pot manufacturing, fortunately, required little or no change in the relative amounts, reaction time and reaction temperature of the chemical compared to the application in a single test.

Accordingly, a third object of the present invention is to remove the "carbon" ester residues R ₁ ′ according to the case of the 7β-acylami-3-substituted methyl-sephalosporranic acid derivative of formula (IIa), wherein R ₁ ′ The present invention relates to a method for preparing a compound of formula (IIa) having hydrogen or a salt forming cation.

In the above formula,

R ₁ ′ is hydrogen or a salt forming cation or a “carbon” ester moiety as described above,

R ₂ ′ is (lower) alkoxy, (lower) alkylio, (lower) alkanoyloxy, (lower) alkanoylthio, bromo when R ₁ ′ is a “carbon” ester moiety, optionally in a heterocyclic ring. 1-pyridinium groups with bound substituents or, optionally, silyl groups introduced to protect hydroxy, carboxy and sulfo groups and (or) optionally silyl groups introduced to protect unsaturated heterocyclic secondary amine groups. Imparting a free substituent or a salt thereof in which the group or acyl group is removed,

R ₃ ′ is formyl or a group as described above.

According to a third object of the present invention, the multistage process for preparing the compound of formula (IIa) is 7β-acylamino-3-methyl-3-cepem-4-carboxylic acid 1β-oxide of formula (Ib). To derivatives, without separating intermediates, continue to the next step:

a) silyl of a carboxyl group in which a trimethylsilyl or dimethylsilyl group is bonded to an additional part of separosporane of formula (Ib) when R ₁ 'is a starting compound using a compound of formula (Ib) that is not a "carbon" ester group anger,

b) Light-induced bromination of the 3-methyl group of the compound of formula (Ib) using N-bromoamide or N-bromoamide as a brominating agent to give a compound having a 3-bromomethyl group.

c) determined primarily by the nature of the substituents R ₁ ′ and R ₃ ′, if necessary in addition to the methylene group adjacent to the sulfur atom in the dihydrothiazine ring by reaction with trialkyl or triallyl phosphite in step b) Substitution by hydrogen of the introduced bromine atom (s),

d) R, by substitution of bromine introduced in the methyl group in step b), if it is not desirable to prepare a compound of formula (IIa) having a "carbon" ester residue as R ₁ and having bromo as R ₂ ′; ₂ 's introduction,

e) in any case in the presence of an olefinic compound having at least one carbon-carbon double bond to which no more than two hydrogen atoms are bonded and which removes chlorine mainly by addition reactions to carbon-carbon double bonds; It is characterized in that it is optionally carried out in the same reactor and converted by deoxygenation of sulfoxy groups using phosphorus pentachloride in the presence of a catalyst or additive already present or in the presence of an existing catalyst or additive.

In the above formula,

R ₁ ′ is hydrogen or a salt forming cation, or a “carbon” ester as described above,

R ₃ ′ is as defined above or in the formyl group.

If the process of the third object of the invention is desired to be manipulated without the use of a "carbon" ester for protecting the 4-carboxyl group of the sephalosporin moiety, the protection of this group is preferably carried out in the first step a) It is suitably introduced by silylation carried out by the procedure in the reaction itself. If the starting material is a salt such as sodium salt or triethylamine salt, monohalosilanes such as trimethyl chlorosilane or dimethylmethoxy chlorosilane are added to the salt suspension in a suitable anhydrous organic solvent. Dihalosilanes such as dimethyl dichlorosilane can also be used when the product is exclusively good dicephalosporanyl dimethylsilane. If the starting material is sephalosporanic acid 1β-oxide, it can be carried out in the same chlorosilane by adding a suitable tertiary amine, such as a substantial equivalent of triethylamine. In particular in terms of minimizing the residual amount of drug in relation to the most appropriate and desired operation of step b), but by the process described in EPC No. 0, 043, 630 which is incorporated in substantial reference. Si-NH-Si (UVW) (where UVW is suitably lower alkyl and / or lower alkoxy groups such as methyl and methoxy groups), preferably a balanced amount of a low boiling point 6-substituted disilazane It is preferable to use as a means of sintering and to carry out the silylation by adding a suitable strong silylation catalyst such as saccharin.

This silylation catalyst proved to be good as a first step in the small scale multistage single-port process of the present invention.

However, with regard to the simple operation of the whole process for obvious reasons, the silylation step exactly as shown in EPC Nos. 0, 043, 630 provides sufficient reliability and reproducibility for application of industrial scale under the optionally optimized conditions included. It is admitted. The main problem is that large amounts of ammonia that have not been sufficiently neutralized will interfere with the next bromination step, making it difficult to completely remove and / or neutralize the final residual amount of ammonia that occurs during silylation at large scale. I think it is related. Relatively few problems sometimes arise in the maintenance of painful silyl protection during the whole process, especially when performing limited bromination. By trial and error, the silylation conditions of silylation of mesacetoxy cephalosporranic acid 1β-oxy derivatives with halogenated hydrocarbon solvents such as 6-substituted disilazane in dichloromethane are also silylated. 1-50 mole% of organic compounds in which the mixture tends to be silylated, for example, by hexamethylsilazane, for example under the influence of saccharin, as well as a relative amount of 0.005-5 mole% of a relatively strong silylation catalyst such as saccharin. It has been found that the above problems can be avoided by varying the amount to include relative amounts of. Preferred further organic compounds are added, for example, in greater than the amount of saccharin. Further organic compounds in the first approach are the function of promoting the construction of ammonia in the gas phase form and / or the function of binding ammonia, eg by sufficiently strong complexing or salt formation, to neutralize ammonia.

In the second approach, additional compounds also tend to be silylated and their silylation proceeds to the extent that it removes the slightly excess 6-substituted silazanes normally introduced but impairs the complete silylation of the desacetoxycephalosporin moiety. It was recognized that it was advantageous to remove it to some extent, but not to. The latter means that the silylated derivative of the additional organic compound acts as a silylating agent for the desacetoxy cephalosporin moiety, while it is preferably aired by the silylated desacetoxy cephalosporin 1β-oxide derivative. It is very reactive to moisture in the water, and it is difficult to completely prevent the leakage of moisture in the air during operation on an industrial scale.

Therefore, preferred drugs in this respect are slightly acidic compounds belonging to the following classes, which constitute a relatively weak silylation catalyst substantially in accordance with the invention of EPC Nos. 0, 043, 630:

-3. Known imides such as 3-dimethylglutarimide or saturated cyclic imides such as succinimide,

Saturated cyclic acylureas such as known acylurea or hydanroin such as -3-benzoyl-1-phenyl-urea, and

-Ring-opened or saturated cyclic N-sulfonylcarboamides.

Therefore, such compounds have an NH group between two acyl groups (carbonyl or sulfonyl).

In this respect in particular, the preferred reagent is succinimide.

Attention is directed to lines 6-19 of page 6-19 and page 6-19 of the particularly preferred catalysts, including the enumeration of suitable catalysts of EPCs 0, 043, 630 as indicated by relatively strong silylation catalysts. In the general sense that the compound is a relatively weak silylation catalyst is an example of EPC Nos. 0, 0043, 630, for example shown in the tables attached to Examples 7 and 85.

Normally, silylation is carried out in the presence of saccharin by the disylazane of hexamethyl using relatively strong silylation catalysts such as small to very small amounts of saccharin, for example in combination with substantial amounts of succinimide. Examples of selectable equivalents according to (e.g. Example 1), for example, are not the same as silylation with a mixture of trimethylsilylsuccinimide prepared separately from hexamethylsilazane, in particular the further use of succinimide. As it does not require the use of large amounts of hexamethylsilazane, it will be appreciated by those skilled in the art.

Improvements in the silylation conditions of this nature can be similarly achieved, and in practice also moderately strong silylation catalysts, such as 0.005-5 mole% saccharin, slightly less than 6-substituted silazanes and relatively less equivalents of such equivalents. It can also be appreciated that it can be achieved by introducing a combination of weak silylation catalysts with silyl derivatives, such as N-trimethylsilylsuccinimide.

In other words, when the derivative of the starting material desacetoxy cephalosponin 1β-oxide contains one silylated group that needs protection, ie, generally 4-carboxyl groups, it is about 0.8 to the amount of cephalosporin. To up to 1 equivalent 1 or about 40 to up to 50 mole%) of disilazane is 0.01 to about 50 equivalents (or usually 1 to about 50 mole%) of, for example, N-trimethylsilyl-succinimide in combination, 0.01 An excess of -0.3 silyl equivalents is applied.

Although a good choice may be considered to be less economical as it relates to the use of a second silylating agent that is produced separately, however, its advantage is, in particular, that relatively few succinimide moieties may be present in the mixture.

In principle, sephalosporranic acid 1α-oxides can be used, but the use of corresponding 1β-oxides usually shows a better final yield, and 1β-oxides are generally easier to prepare. By large-scale fermentation, ferricillin having the following group generally can be obtained as the 6β-substituent.

Such penicillins can be converted by means of known methods to equivalent 3-methylsephalosporranic acid (also referred to as desacetoxy cephalosporin) via 1β-oxide in economics and high yield. After conversion to 1β-oxide, such desacetoxy cephalosporonic acid is the most economically suitable starting material, especially when R ₅ is phenyl or phenoxy.

Presumably, the group R ₅ may comprise substituents which in particular require protection, such as hydroxy, and can be easily silylated in step a).

Depending on the nature of the groups R ₅ and R ₁ ′ and the exact conditions of step b), some substances may be damaged by bromination reactions which are somewhat secondary to the methylene groups of substituents R ₅ -CH ₂ , and the bromine substituents in step c) Partially hydrogen substituted.

If you want to eliminate side reactions, you can use other substituents R ₃ ', such as formmill or benzoyl, and the substituents are not brominated to the extent that they are disturbed.

In particular, in view of the fact that the process of the third object of the present invention also does not contain a final step of breaking down the side chains, some variation in the solvent used is possible. In general, however, most suitable are halogenated hydrocarbons, preferably low boiling points such as, for example, chloroform, but more suitably 1, 2-dichloroethane, most suitable dichloromethane. The photoinduced bromination step b) is as described in the EPC 0.034. 394 process incorporated herein by reference. Depending on the scale and configuration of the experiment, the irradiation can be carried out, for example, in one device or a series of devices, and the solution can be pumped from the reservoir to the device by means of a reservoir which can be cooled to give a nearly uniform internal temperature in the entire irradiation device. And take a small sample from the device and, for example, operate the nuclear magnetic resonance spectrum to analytically confirm the progress of bromination, and the nuclear magnetic resonance spectrum is advantageously performed before the silylation reaction.

As described in EPC No. 043. 394, it is generally effective to add an additive which destroys or neutralizes the residual amount used or the small residual amount of its deterioration product before starting the irradiation. Such a suitable additive is sulfamic acid. As set forth in this patent application, reagents known in the art used to heat reactive carbon-hydrogen bonds, peroxide catalysts or photoinduced bromination include, for example, N-bromo-acetamide and N-bromo-capro N-bromo-carboamide, such as lactam, or N-bromo-phthalamide, or N-bromo-carbonamide, such as 1, 3-dibromo-hydanroin, or N-bromosulfonamide And N-bromo sulfonimides such as N-bromosaccharin can be used. Preferred brominating agent is N-bromosuccinimide.

Complete or substantial complete bromination of the methyl group bound to the ring carbon atom 3 position of the dihydrothiazine ring usually involves sulfurization of the sulfur atom to the adjacent methylene group, and the degree of side reactions depends on the exact conditions and substituents R ₃ ′ and R _1. Influenced by the nature of Bromine, which is further introduced in the methylene group, must be replaced with hydrogen in order to reach a relatively good final yield. According to the process described in EPC 0.001.149 which is incorporated by reference, phosphines such as trialkyl and triallyl can be used in step c). Tributyl phosphite has been found to be suitable. Since the 7β-substituted-3-bromomethyl-3-cepem-4-carboxylic acid ester is a flexible and useful means in the Sephasporin chemistry, the third objective process of the present invention is after step c) By omission of d), direct deoxygenation step e) can be applied to the preparation and separation of such compounds. To some extent, this is compatible with the silyl protection of carboxyl groups, but it is difficult to completely prevent 3-bromomethyl-3-cepem-4-carboxylic acid (in the molecule, forming a condensed lactone derivative by cyclization. Preference is given to using protection with "carbon" esters in terms of tendency, and in this regard it is rather preferred to use t-butyl groups as R ₁ '.

In step d), the bromo atom of the 3-bromomethyl group is substituted by residue R ₂ ′ according to generally known procedures. If necessary, the substitution reaction can be carried out with N, N-dimethylformamide, N-methyl-pyrrolidinone and hexamethyl phosphorictriamide to increase the rate and / or to increase the solubility of some R ₂ 'containing reagents. A small amount of the same substantially anhydrous high dipole aprotic solvent can be added, but this relatively small amount of solvent does not significantly impede the rapid and valuable performance of the next deoxygenation process of the present invention, and is also a catalyst for deoxygenation. This is because the action can be given.

In this respect an important collection of the final product of general formula (IIa) contains a heterocyclic thio group which is generally unsaturated as substituent R ₂ ′. Such thiols can be reacted in the presence of nearly equivalents of triethylamine or a suitable tertiary amine such as N, N-dimethylaniline, or a thiol such as a corresponding thiorate such as sodium thiolate or potassium thiolate Acid metals can be added. However, it is possible to carry out the substitution reaction using the corresponding trimethylsilyl thioether as the thiolating agent according to EPC 0047569, incorporated herein by reference, and in view of the manufacturing process of the compound of formula (IIa), In some cases, it is actually useful. If so desired, the reaction time can be shortened, and (or) the 3-bromomethyl-cephalosporin intermediate and trimethyl, as appropriate, using the invention described in EPC No. 091.141, incorporated herein by reference. By adding much less than equivalents of hexamethylphosphate triamide to the reaction between silylthio, the reaction temperature can usually be lowered in the range of -10- + 25 ° C.

Certain forms, including the use of trimethylsilylthioethers, are particularly effective if they contain substituents such as hydroxy, carboxy, etc., which in some cases require protection because the heterocyclic portion of the thiol obtains the highest yield, optionally hexamethyl It will be appreciated that with disilane and catalysts these substituents are silylated with thiol groups.

In step e), the novel deoxygenation process of the present invention is applied with an olefinic compound in the reduced range almost as shown in the application in the process of the second object of the present invention, which is rapid in terms of the preceding step and proper suitability. It is preferable to use an olefinic compound which exclusively predominantly absorbs chlorine by addition reaction. Therefore, under the conditions appropriately developed individually, it is possible to use a terminal olefin which has another substituent on the unsaturated carbon atom inside, and generally reacts rapidly, and also general dienes, but in one or both cases For unsaturated hydrocarbons, non-terminal carbon-carbon wherein 4-12 carbon atom chains substituted with methyl or ethyl groups or optionally 5-8 atoms substituted with methyl or ethyl groups for one unsaturated carbon are located in the carbocyclic ring Preference is given to using monoolefinic compounds having a double bond.

For general capacity and high yields of conversion and separation, cis-cyclooctene is considered to be a particularly suitable olefin. As already explained above, the deoxygenation step is preferably carried out with careful addition of the catalyst. The best catalysts are N, N-dialkylformamides, which do not normally need to be used more than 30 mole% with respect to the amount of sephalosporin introduced.

Careful catalysis may also be imparted by the addition of a similar relative amount of some tertiary amines, in particular N, N-dialkylarylamines, in which some chlorine, for example, of the aromatics of N, N-dimethylaniline It turns out that it is absorbed by substitution. It is also possible to combine such catalyst additives, i.e., add N, N-dimethylformamide and N, N-dimethylaniline. It is also contemplated that the careful catalysis of step e) can optionally be eliminated by the correct conditions relating to the components of one or a number of preceding steps, in particular steps a) and d).

The deoxygenation process of the present invention is primarily concerned with the use of at least equivalent amounts of olefin compounds as chlorine trapping agents, and in fact, it is possible to produce olefins of other forms, such as enamines or N, It is not contemplated that a good combination of N-dialkyl aromatic amines or with pyridine can be developed at all well with similar suitable deoxygenation procedures. These additional reagents consume chlorine by other chemical bonds. Such intervention does not thereby constitute the result of the progressive alignment of independence. As already described at the beginning of the text, the attention of the present invention is preferably several 7β-amino starting from the 7β-acylamino-3-methyl-3-cepem-4-carboxylic acid 1-oxide derivative in the same reactor. To more readily reachable 1-oxides of -3-substituted methyl-3-cepem-4-carboxylic acid derivatives, as well as to starting materials that can be obtained well and economically. Regarding the properties of the 7β-acylamino substituents, the overall preparation thereof can be carried out without separation of the intermediates, furthermore, the continued protection of the cephalosporin 4-carboxyl groups is preferably suitably applied within the same reaction itself. It is to develop various kinds of conversion conditions which are suitable for the multi-step manufacturing which is possible by the silylation, and which can be applied to each other. Char is concerned with the effective and flexible introduction of the sulfoxide deoxygenation step, which allows the development of new processes.

Inventive agent for single-port preparation of 7β-amino-3-substituted-3-cefe-4-carboxylic acid derivatives from 7β-acylamino-3-substituted-3-cefe-4-carboxylic acid 1-oxide derivatives The present invention relates to the preparation of 7β-acylamino-3-substituted methyl-3-cepem-4-carboxylic acid derivatives for 2 purposes and from 7β-acylamino-3-methyl-cepem-4-carboxylic acid 1β-oxide derivatives. Combining the results of both objectives preceding the valuable application of the novel deoxygenation process in the third object of the invention to confer the fourth object of the invention, i.e., 7β-acylamino-3-methyl-3-cepem Is there an impression that the total synthesis of the 7β-amino-3-substituted methyl-3-cepem-4-carboxylic acid derivatives performed without separating intermediates from the 4-carboxylic acid 1β-oxide derivatives does not involve progressive steps? I do not know.

However, many of the drugs remaining from the first stage of the invention in the third object of the invention, such as succinimide, trimethylsilylsuccinimide, phosphite and step c, which have been used in substantial excess in the third object of the invention From the fact that there is a fundamentally unknown, disturbing relative amount of byproducts from the consumption of phosphites, improperly performing without impediment or economic attraction of the last stage cannot be expected otherwise. Was recognized.

Therefore, the fourth object of the present invention is the addition of an acid using a strong inorganic or organic acid, which is usually used, in the case of the 7β-amino-3-substituted methyl-cephalosporinic acid derivative represented by the following general formula (IIIa) The final product in the form of a salt is isolated, and the residue residue R ₁ ′ in the “carbon” is removed to produce a compound of formula IIIa wherein R ₁ ′ is hydrogen or a salt forming cation.

In the above formula,

R ₁ ′ is hydrogen or a salt forming cation, or a “carbon” ester moiety as described above,

R ₂ ′ is as described above.

According to the fourth object of the present invention, the multistage process for preparing the compound of general formula (IIIa) is a 7β-acylamino-3-methyl-3-cepem-4-carboxylic acid 1β-oxide derivative of general formula (Ib). (Wherein R ₁ ′ and R ₂ ′ are the same as described above and R ₃ ′ does not contain a formyl group). It is characterized by continuous execution:

a) silylation of a carboxyl group, optionally carried out in the same reaction itself, starting from a compound of formula (Ib) having hydrogen or a salt forming cation as R ₁ ′,

b) mineral induction bromination process as described above,

c) selective debromination using triorganic phosphite, if necessary, as described above;

d) introduction of substituent R ₂ ′ [offer when using “carbon” ester residue R ₁ ′ selected to maintain bromine as substituent R ₂ ′ in the final product of formula (IIIa);

e) deoxygenation of the sulfoxy groups described above, and

f) Desylation reaction which cleaves a 7β-acylamino group substituent according to a well-known procedure using phosphorus pentachloride as mentioned above.

Experiments have shown that the entire series of steps can be carried out in one and the same reactor in the final hydrolysis, which can also be carried out in the same reactor for at least some, and as will be appreciated by those skilled in the art, It may be technically advantageous to recycle the reaction vessel and use it as a central supply for light irradiation bromination that operates in a series of irradiation devices. This final product of formula (IIIa) is optionally hydrolyzed to "carbon" ester residues R ₁ 'or separated by known procedures involving reductive cleavage. It is preferred for the fourth object of the present invention to operate on “carbon” esters when preserving bromine as substituent R ₂ ′ as in the third object.

The description of the process for steps a) -e) is analogous to that given to these steps of the third object of the present invention and is suitably applied by preferred methods of operation and eg by solvent, temperature and deoxygenation step e). Very similar or the same by the choices indicated in the drug, such as olefinic compounds. Since the fitting of the final step f) does not involve surprisingly specially applied criteria, this step can be carried out as step c) of the second object of the present invention applying a method known in the art. Preferably starting from 7β-phenylacetamide (or phenoxyacetamide) -3-methyl-3-cepem-4-carboxylic acid 1β-oxide derivative, the preferably prepared compound of formula (IIIa) 7β-amino-3- ancetoxymethyl-3-cepem-4-carboxylic acid (7-ACA), and R ₁ 'is a "silyl group" or t-butyl ester instead of a "carbon" ester group Since it is preferable to operate, the mainly separated final compound is suitably a salt containing t-butylester of 7-ACA or a strong inorganic or organic acid thereof. However, in general, it is preferable to manipulate the process in "silyl" protection, for example using trimethylsilyl groups, for the carboxyl group of cephalosporin. Preference is given to using “silyl” protection throughout all procedures, most preferably when prepared starting from desacetoxy oxycephalosporin 1β-oxide with 7β-phenylacet amido groups or 7β-phenoxyacetamido groups The final compound of formula (IIIa) comprising the separation of the salt form according to

7β-amino-3- [1-methyl- (1H) tenerazol-5-yl-thiomethyl] -3-cepem-4-carboxylic acid,

7β-amino-3- [1- (2-dimethylamino) ethyl- (1H) tetrazol-5-yl-thiomethyl] -3-cepem-4-carboxylic acid,

7β-amino-3- [sulfomethyl- (1H) -tetrazol-5-yl-thiomethyl] -3-cepem-4-carboxylic acid,

7β-amino-3- [1-carboxymethyl- (1H) tetrizol-5-yl-thiomethyl] -3-cefe-4-carboxylic acid,

7β-amino-3- [1, 2, 3- (1H) triazol-5-yl-thiomethyl] -3-cefe-4-carboxylic acid,

7β-amino-3- (5-methyl-1, 3, 4-thiadiazol-3-yl-thiomethyl) -3-cepem-4-carboxylic acid,

7β-amino-3- (1, 3, 4-thiadiazol-2-yl-thiomethyl) -3-cefe-4-carboxylic acid,

7β-amino-3- (2, 5-dihydro-6-hydroxy-2-methyl-5-oxo-1, 2, 4-triazine-3-3-cepem-4-carboxylic acid,

Also, preferably the most preferred final product with “silyl” protection in the process is 7β-amino-3- (1-methyl)-(1H) tetrazol-5-yl-thiomethyl-3-cepem-4- Carboxylic acid.

The present invention, which is a method of the four purposes described above, will be described below by way of examples, but the present invention is not limited to these examples.

Example I

Deoxygenation of 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid 1β-oxide with cychloroheptene.

Trimethyl while stirring at 0 ° C. in a suspension of 3.48 g (purity 96%; 9.59 mmol) of 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid 1β-oxide in 40 mL of dichlorotitanium under nitrogen. Chloro silane and 2.3 ml (18.09 mmol) and 2.3 ml (17.75 mmol) N, N-dimethylanilyl are added. The temperature is raised to about 20 ° C. and stirred for 30 minutes. The mixture is cooled to −60 ° C., then 1.3 ml (11 mmol) of cycloheptene and 2.4 g (11.5 mmol) of phosphorus pentachloride are added successively, and then the mixture is stirred again at −45 ° C. for 15 minutes. Carefully add 10 ml of water, then stir at −10 ° C. for 15 minutes. 30 ml of toluene are added and stirred at -5 ° C. for 3 hours to form a precipitate which is collected by filtration, washed with toluene and water and dried under vacuum until a constant volume, 2.92 g of 7β-phenyl Acetamido-3-methyl-3-cepem-4-carboxylic acid is obtained. Identification of the separation product is confirmed by TLC and PMR. HPLC analysis showed a purity of 97% by weight, corresponding to a separation of 8.52 mmol.

The yield is 88.9%, calculated from the purity of the starting material. According to HPLC analysis, the combined filtrates contained 7.1% of the desired product. Therefore, the total call yield was 96%.

PMR (pyridin-d ₅ , δ-values in ppm, 60 MC, TMS):

2.12 (s, 3 H); 3.01, 3.32, 3.41 and

3.72 (AB-q, J = 18 Hz, 2H); 3.83 (s, 2 H);

5.18 (d, J = 4.5 Hz, 1H); 6.19 (dd, J = 4.5

Hz, J = 8 35 Hz, 1H); 7.13 to 7.58 (m, 5 H);

10.06 (d, J = 8 Hz, about 1H); 10.16 (s, about 1 H).

IR (KBr-disc, values in cm ^-1 ): 3270,

3060, 1760, 1700, 1665, 1626, and 1545.

Example II

Deoxygenation of 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid 1β-oxide with cis-ciclooctene.

a) It is carried out as in the method described in Example I, except that 10 mmol (1.3 mL) of cis-cyclooctene is used instead of 11 millimoles of cycloheptene. The separated weight was 2.98 g, which was a yield of 89.7% based on the 96% purity by HPLC analysis. The combined filtration by HPLC analysis also contained 9.4% of the desired product. Therefore, the total conversion yield considering the starting material (96 wt% purity) is 99.1%.

b) Repeat in the same manner as a).

The separated amount was 3.02 g. Direct separation, taking into account purity (HPLC analysis: 97.5%) and starting material purity (96%), yields a yield of 92.4%.

c) The experiment was repeated with all the same conditions except that the sulfoxide was doubled (6.96 g). The direct separation yield considering the purity (97.5% by HPLC analysis) and the starting material purity was 5.91 g, 91.2%. The filtrate also contained the desired 3%. The filling yield is therefore 94.2%.

d) Only one change was made in experiment c), and the same amount was repeated. 40 ml of n-hexane was added instead of 40 ml of toluene, followed by stirring at 0 ° C. for 3 hours. The precipitate was collected by filtration, washed with -hexane and water and dried in vacuo. The separated amount was 6.42 g. The yield of the direct separation is 97.1% in view of the purity of 97.5% by HPLC analysis.

Example III

Deoxygenation of 7β-phenylacetamido-3-acetoxymethyl-3-cepem-4-carboxylic acid 1β-oxide with cis-cyclooctene.

In the same manner as in Example I, experiments were carried out at about the same scale. 4.06 g of starting sulfoxide (8.59 mmol from 86% purity by HPLC analysis), 2.4 mL (18.9 mmol) of trimethylchlorosilane, 2.4 mL (18.5 mmol) dichloromethane, N, N-dimethylaniline 40 mL, cis-cyclooctene 1.3 ml (10 mmol), 10 ml of water and 30 ml of toluene were used. The weight of the isolate of the substantially dry product was 3.48 g. A purity of 90.5% by weight, as determined by HPLC analysis, showed that the isolated product contained 8.07 mmol of 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid. Therefore, the actual yield is 94%. The combined filtrate by HPLC analysis contained 3.9% of the desired compound. Therefore, the termination rate is 97.9%. The product was identified using TLC, PMR and IR.

PMR (DMSO-d ₆ , δ-values in ppm, 60 Mc, TMS):

2.04 (s, 3 H); about 3.6 (4H); 4.59, 4.80, 4.95 and 5.16 (AB-q, J = 13 Hz, 2H); 5.08 (d, J = 4.5 Hz, 1H); 5.69 (dd, J = 4.5 Hz, J = 8 Hz, 1H); 7.27 (s, 5 H); 9.04 (d, J = 8 Hz, about 1 H).

IR (KBr-disc, values in cm ^-1 ): 3265, 3050, 1785, 1752, 1740, 1715, 1662, 1230.

Example IV

Of 7β-phenylacetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid 1β-oxide with cis-cyclooctene Deoxygenation.

HPLC analysis confirmed the purity of the starting material was 85% by weight. To a suspension of 8.00 g (14.21 mmol) of sulfoxide in 80 mL of dichloromethane under nitrogen, 4.6 mL (36.2 mmol) of trimethylchlorosiltan and 4.5 mL (35.5 mmol) of N, N-dimethyl-aniline are added with stirring at 0 ° C. . The temperature is raised to 20 ° C. and stirred for 30 minutes. After cooling the mixture to -66 ° C, 3.9 g (18.7 mmol) of 2.6 mL (20 mmol) of ciscyclooctene pentachloride are added continuously, and the mixture is further stirred at -45 ° C for 10 minutes. 5 ml of N, N-dimethyl-formamide are added, followed by continued stirring, and carefully 20 ml of water. The cold bath is removed, the mixture is brought to -5 ° C and the layers are separated.

Dilute ammonia is added to adjust the pH to 7, and the organic layer is extracted several times with 60 ml of water. The organic layer was discarded and the combined water layers were diluted with 50 ml of cold methanol. On the other hand, 4N hydrochloric acid is added while adjusting to maintain pH 2, and the adjusted solution is gradually added to the mixed solution of 20 ml of water and 20 ml of methanol with little stirring. After standing at 0 ° C., the precipitate is collected by filtration, washed with cool water and dried until it is content in the major. It was isolated as a crude product of 7β-phenylacetamido-3- (5-methyl-1, 3, 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid. HPLC analysis showed 87.5 weight% purity of the separation product.

Thus, the yield was 12.48 mmol, i.e. 89%. The filtrate also contained 2% of the desired product. Thus, the total telephone yield was 91%.

PMR (d ₆ -DMSO, δ-values in ppm, 60 Mc, TMS):

2.67 (s, 3 H); 3.52 (s, 2 H); 3.35, 3.65, 3.68 and 3.98 (AB-q, J = 18 Hz, 2H); 4.10, 4.30, 4.43 and 4.63 (AB-q, J = 12.5 Hz, 2H); 5.06 (d, J = 8.5 Hz, 1H); 5.70 (dd, J = 4.5 Hz, J = 8.5 Hz, 1H); 7.28 (5 H); 9.14 (d, J = 8.5 Hz, about 1 H).

IR (KBr-disc, values in cm ^-1 ): 3280, 3035, 1777, 1720, 1661, 1535, 1500 and 1458.

Example V

Carbonation of 7β-phenylacetamido-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid 1β-oxide with cis-cyclooctene.

a) Starting material was converted using the same method as Example IV. 5.24 g of crude starting material containing 9.99 mmol (sample purity of 88.2% by weight), 2 ml (15.5 mmol) trimethyl chlorosilane, N, 2 ml (15.4 mmol) N, N-dimethylaniline and dichloromethane 40 by HPLC analysis The resulting mixture was cooled to -60 ° C. and 1.4 ml (10.8 mmol) of cis-cyclooctene and 2.4 g (11.5 mmol) of phosphorus pentachloride were added successively, followed by stirring at −50 ° C. for 15 minutes, followed by water. Carefully add 10 ml. After addition of 2 ml of N, N-dimethylformamide, the mixture is stirred at -10 占 폚 for 15 minutes. 30 ml of toluene is added and then stirred at -5 ° C for 3 hours. The resulting precipitate was filtered off, washed with cold water and toluene and then dried in vacuo. The product was 4.76 g. HPLC analysis showed that 85% of this product is 7β-phenylacetamido-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid and the yield is 90.8. It corresponded to%. HPLC-analysis of the filtrate showed that the filtrate contained 6.3% of the desired product. Therefore, the total call yield was 97.1%.

PMR (mixture of CDCI ₃ and d ₆ -DMSO, δ-values in ppm, 300Mc, TMS): 3.56, 3.60, 3.62 and 3.66 (AB-1, J = 14 Hz, 2H): 3.67 (s, 2H): 3.94 (s, 3 H); 4.28, 4.32, 4.34 and 4.38 (AB-q, J = 13.5 Hz, 2H): 4.96 (d, J = 5 Hz, 1H); 5.74 (dd, J = 5 Hz, J = 8.5 Hz, 1H); 7.21-7.34 (m, 5H); 8.27 (d, J = 8.5 Hz, about 1 H).

IR (KBr-disc, values in cm ^-1 ): 3260, 1780, 1725, 1657, 1619, 1535, 1492, 1155, 1085.

b) The above example was repeated using N, N-dimethylaniline (10.8 mmol) instead of cis-cyclooctene in order to compare the known process with the process of the present invention. HPLC-analysis of the sample obtained after stirring for 15 minutes further showed that the desired compound was formed in inverted yield of 86.6%. Stirring at −5 ° C. for 3 hours in the separation procedure did not yield a crystalline precipitate. Add 10 ml of water and 10 ml of dichloromethane to form an oily precipitate. This supernatant layer was poured out, and the residual oil was dissolved in 15 ml of dichloromethane to obtain a solid. At this time, 10 ml of toluene was added while stirring at 0 degreeC. After filtration, the resultant was washed with 1: 1 dichloromethane-toluene and dried in vacuo to obtain 4.92 g of a desired product having a purity of only 66.5% by weight. This filtrate also contained about 13% of the product. The total telephone yield was about 86.5%.

Example VI

Deoxygenation of t-butyl 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylate 1β-oxide with cis-cyclooctene.

408 g of t-butyl 7β-phenylacetamido-3-methyl-cefe-4-carboxylate 1β-oxide in 80 ml of dichloromethane (90% purity according to HPLC analysis, 9.08 mmol) was stirred at -20 ° C. 1.3 ml (10 mmol) of cyclooctene and 2.4 g (11.5 mmol) of phosphorus pentachloride were added. The temperature was lowered to -40 ° C and stirred for further 15 minutes. After 10 ml of water was noted, the mixture was stirred at 0 ° C. for 15 minutes. The layers were separated, the organic layer washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a volume of about 25 ml. A little addition of light petroleum forms a precipitate. The solid was collected by filtration, washed with light petroleum and dried in vacuo. This gave 4.1 g of t-butyl 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylate. Purity is 80.5% by HPLC-analysis, corresponding to a yield of 93%.

PMR (CDCI ₃ , δ-values in ppm, 60Mc, TMS):

1.50 (s, 9 H); 2.06 (s, 3H; 2.93, 3.23, 3.36, 3.66 (AB-q, J = 18.5 Hz, 2H); 3.61 (s, 2H); 4.90 (d, J = 4.5 Hz, 1H); 5.75 (dd, J = 4.5 Hz and J = 9 Hz, 1H) +6.85 (d, J = 9 Hz, about 1H); 7.31 (s, 5H).

IR (KBr-disc, values in cm ^-1 ): 3260, 1780, 1725, 1657, 1619, 1535, 1492, 1155 and 1085.

EXAMPLE VII

7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid 1α-oxide deoxygenation with cis-cyclooctene.

It carried out in the same procedure as Example I. 0.245 g (up to 0.70 mmol) of phenylacetamido-desacetoxy cephalosporin 1α-oxide of unknown quality, 0.14 mL (1.10 mmol) of trimethylchlorosilane, 0.14 mL (1.10 mmol) dichloromethane of N, N-dimethylaniline 2.8 ml, 1.103 ml (0.79 mmol) of cis-cyclooctene and 0.175 g (0.84 mmol) of phosphorus pentachloride were used, and 1.4 ml of toluene was used in the separation method. Reaction conditions in the reduction series were carried out for 15 minutes at -45 ℃ as usual. Thus, 0.1579 g of the desired product, phenylacetamido desacetoxy cephalosporin, was isolated in solid form. This is about 84.0% pure by HPLC-analysis, so the direct yield corresponds to 57%. HPLC-analysis confirmed that the filtrate contained about 15% of the same compound. Thus, the total telephone yield is at least about 72%.

EXAMPLE VII

Variation of deoxygenated olefinic compound via 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid 1β-oxide.

Many olefinic compounds used in the present invention were carried out according to the same standard procedure. The results of this experiment are shown in Table 1, which also shows experiments (final) using a second reagent for recruitment of chlorine, and two experiments using a second reagent known in the prior art, namely N, N-dimethylaniline. . Therefore, the procedure is the procedure of Example 1 description. The amount and dose used are as follows.

6.96 g (substantially 19.38 mmol) of 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid 1β-oxide having a purity of 97% by HPLC-analysis.

Dichloromethane 80ml

4.6 ml (36.2 mmol) trimethylchlorosilane

4.6 ml (35.5 mmol) N, N-dimethylaniline

Olefins or compounds of the prior art 22 mmol phosphate 4.8 g (23 mmol)

During the workup of the reaction mixture, a reaction mixture of 20 ml of water and 40 ml of toluene was added. Deoxygenation was all performed at -45 ° C for 15 minutes unless otherwise specified. 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid was corrected to actual content by HPLC-analysis.

TABLE I

Deoxygenation via trimethyl ester of 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid 1β-oxide with phosphorus pentachloride in dichloromethane in the presence of an olefinic compound (45 ° C., 15 minutes) ).

TABLE 1

a) Commercial 2-hexenes contain trans-2-hexene and large amounts of cis-2-hexene.

b) After 75 minutes at -45 ° C the results are as follows:

5.74 g, 99.5%, 88.7%, 3.2% and 91.9%

EXAMPLE VII

T-butyl 7β-phenylacetamido-3-bromomethyl-3-cepem-4-carboxylate 1β-oxide deoxygenation with cis-cyclooctene.

At 25 C, 0.325 mL (12.5 mmol) of cis-cyclooctene and 0.6 g (2.9 mmol) of phosphorus pentachloride were dissolved in 25 mL of dichloromethane in t-butyl 7β-phenylacetamido-3-bromomethyl-3-cepem- 1.21 g of 4-carboxylate 1β-oxide (93% purity, 2.33 mmol by HPLC analysis) was added continuously with stirring. After cooling to -40 [deg.] C., further stirring for 15 minutes, then 3 ml of water were carefully added and stirred at 0 [deg.] C. for 15 minutes. The layers are separated, the organic layer is washed twice with 3 ml of ice water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a volume of about 51 .. When light petroleum (boiling point 40-60 ° C.) is added to this, a precipitate is formed. The precipitates were collected by filtration, washed with n-hexane and dried in vacuo. 1.0 g of t-butyl 7β-phenylacetamido-3-bromomethyl-3-cepem-4-carboxylate was obtained, and the yield was 85% because the purity was 92.5% by HPLC analysis.

PMR (CDCI ₃ , δ-values in ppm, 60Mc, TMS):

1.52 (S, 9 H); 3.15, 3.45, 3.53 and 3.83 (AB-q, 2H, J = 18 Hz, 2H); 3.60 (s, 2 H); 4.33 (s, 2 H); 4.89 (d, J = 4.5 Hz, 1H); 5.76 (dd, J = 4.5 Hz and J = 9 Hz); 6.46 (d, J = 9 Hz, about 1 H); 7.27 (s, 5 H).

IR (KBr-disc, values in cm ^-1 ): 3345, 1765, 1705, 1655, 1610, 1500, 1360, 1300, 1260, 1200, 1140, 1080, 1000, 835, 710, 690 and 600.

EXAMPLE VII

7β-phenoxyacetamido-3-methyl-3-cepem-4-carboxylic acid 1β-oxide deoxygenation with cis-cyclooctene.

7.29 g of 7β-phenoxyacetamido-3-methyl-cefe-4-carboxylate in 80 ml of dichloromethane (purity is 98.6% by HPLC analysis, so 19.7 mmol corresponds to 19.7 mmol of trimethyl chloro 4.6 mL (36 mmol) of silane and 4.6 mL (35.5 mmol) of N, N-dimethylaniline were added with stirring at 0 ° C. After 30 minutes of further stirring at room temperature, the reaction mixture was cooled to −50 ° C. and cis- 2.86 mL (22 mmol) of cyclooctene and 4.8 g (23 mmol) of phosphorus pentachloride are added continuously, stirring at -45 [deg.] C. for 15 minutes, carefully adding 20 mL of water and stirring at about -15 [deg.] C. for 15 minutes. do.

80 ml of toluene is added and stirring is continued at 0 ° C. for 3.5 hours. The precipitate thus formed is collected by filtration, washed with water and toluene and dried in vacuo. The separated amount was 6.37 g of 7β-phenoxyacetamido-3-methyl-cefe-4-carboxylic acid, and the yield was 91.7% because the purity was 98.8% by HPLC-analysis.

PMR (pyridine-d ₅ , δ-values in ppm, 60Mc, TMS):

2.14 (s, 3 H); 3.02, 3.32, 3.39, 3.69 (AB-q, J = 18 Hz, 2H); 5.23 (d, J = 4.5 Hz, 1H), 6.19 (dd, J = 4.5 Hz, J = 8.5 Hz, 1H); 4.81 (s, 2 H); 6.78-7.50 (m, 5H); about 9.1 (broad, about 1H); 9.82 d, J = 8.5 Hz, about 1 H).

IR (KBs-disc, values in cm ^-1 ): 3400, 1755, 1730, 1670, 1592, 1585, 1520, 1492, 1225, 754 and 683.

[Example XI]

Deoxygenation of 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid 1β-oxide with dienes.

The following experiment was carried out under the same conditions as in Example I.

In this experiment

Title compound (19.40 mmol, since 97.5% purity by HPLC-analysis): 6.93 g

Dichloromethane 80ml

4.6 ml (36.2 mmol) trimethylchlorosilane

4.6 ml (35.5 mmol) N, N-dimethylaniline

4.8 g (23 mmol) phosphorus pentachloride

20 ml of water and

Toluene 40ml

Was used. Only the identity and amount of dienes changed. All yields were calculated based on the content of desired product by HPL analysis.

a) The reaction with phosphorus pentachloride was carried out in the presence of 1.36 ml (11 mmol) of 1, 3-cyclo-octadiene. The isolated amount of 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid was 4.27 g. The separation yield is 61.9% since the purity by HPLC-analysis is 93.5% by weight. The mother liquor also contained 8.6% of the same compound. Therefore, the total telephone yield was 70.5%.

b) The deoxygenation reaction was carried out in the presence of 2.72 ml (22 mmol) of 1, 3-cyclooctadiene. The separated amount is 4.80 g. The yield is 71.5% since the separated compound is 96% weight%. The mother liquor contained 5.6% of the same desired compound. Total phone yield is 77.1%.

c) The reaction with phosphorus pentachloride was carried out in the presence of 1.26 ml (11 mmol) of trans-2-trans-4-hexadiene. The isolated amount of the desired compound was 5.86 g. Since the purity is 95.5% by weight, the separation yield was 86.8%. The mother liquor contained the desired compound 6.75. Therefore, the total telephone yield was 93.5%.

d) The deoxygenation reaction was carried out in the presence of 2.51 ml (22 mmol) of trans-2-trans-4-hexadiene. The separated amount was 5.75 g. As 98% purity by HPLC-analysis, the separation yield was 87.4%. The mother liquor also contained 4.1% of the desired compound. Thus, the total telephone yield is 91.5%.

e) The deoxygenation reaction was carried out in the presence of 1.24 mL (10 mmol) of 1, 5-cyclooctadiene. The separated amount was 4.92 g. As the purity by HPLC-analysis was 95.5% by weight, the separation yield was 74%. The mother liquor contained 4.7% of the desired compound. Thus, the total phone yield is 78.7%.

[Example II]

Deoxygenation of 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid 1β-oxide in acetonitrile with cysi-cyclooctene.

To a suspension maintained under nitrogen of 6.93 g (19.4 mmol) of 1β-oxide in 160 mL of acetonitrile, 4.6 mL (36.2 mmol) of trimethylchlorosilane and 2.3 mL (35.5 mmol) of N, N-dimethylaniline were added with stirring. Raise the temperature to about 20 ° C. and stir for another 30 minutes. After cooling the mixture to −40 ° C. or lower, 2.86 mL (22 mmol) of cis-cyclooctene and 4.8 g (23 mmol) of phosphorus pentachloride are continuously added, followed by further stirring at −45 ° C. for 15 minutes. 20 ml of cold water is carefully added with continued stirring and stirred at −10 ° C. for 15 minutes.

Acetonitrile was azeotropically removed by vacuum concentration at about 0 ° C. Add 40 ml of toluene and 10 ml of cold water to form a crystalline precipitate. After stirring for 1 hour at 0 ° C, the product is collected by filtration, washed with cold water and toluene, and then dried in vacuo until a constant volume is obtained. The amount of the isolated 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid was 5.45 g. The separation yield is 83% since the purity by HPLC-analysis is 97% by weight. The mother liquor contains 2.7% of the desired product, so the total conversion yield is 84.7%.

[Example III]

7β-amino-3 from 7β-phenylacetamido-3- (5-methyl-1, 3, 4-thiadiazol-2-yl-thiomethyl) -3-cef-4-carboxylic acid 1β-oxide Preparation of-(5-methyl-1, 3, 4-thiadiazol-2-yl-thiomethyl) -3-cepem-4-carboxylic acid.

a) 7β-phenylacetamido-3- (5-methyl-1) in 3.6 ml (28.3 mmol) of trimethyl chlorosilane 3.6 ml (28.3 mmol) and 3.55 ml (28.0 mmol) dichlorometal 60 ml under nitrogen atmosphere 8.0 g (84% by weight of purity, 14.04 mmol) of 3,4-thiadiazol-2-yl-thiomethyl) -3-cepem-4-carboxylic acid (14% by weight) was stirred at 20 ° C. for 30 hours, and then Lower to −60 ° C. and continue to add 2.25 mL (16.3 mmol) of cis-chlorooctene and 3.9 g (17.3 mmol) of phosphorus pentachloride. The final reaction mixture was stirred at -45 ° C for 10 minutes, then the temperature was lowered to -55 ° C and 5.5 g (26.4 mmol) phosphorus pentachloride and 3.7 ml (29.2 mmol) N, N-dimethylaniline were added continuously. The mixture is stirred at -45 ° C for 3 hours. The temperature is brought to −60 ° C., and then 25 ml of cold isobutalol are added and stirring is continued at −45 ° C. for 1 hour. After adding 25 ml of 4N sulfuric acid, the mixture was stirred for 10 minutes at −10 ° C., the final two layers were separated, and the organic layer was extracted with 20 ml of 2N sulfuric acid. The organic layer was discarded and the mixed aqueous solution layer was treated with 2 g of activated carbon. After removing the sulfurous charcoal by filtration, it was made PH1 by adding 25% ammonia dissolved in water. The precipitate formed by cooling for 1 hour with ice was collected by filtration, washed with water and acetone, and dried until a constant volume was obtained. The isolated amount is 4.47 g of 7β-amino-3- (5-methyl-1, 3, 4-thiadiazol-2-yl-thiomethyl) -3-cepem-4-carboxylic acid, and analyzed by HPLC-analysis. Purity was 92.5 weight%. Total phone yield was 86%.

b) a batch of significantly higher purity 7β-phenylacetamido-3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid 1β-oxide A great deal of effort has been made to make a relatively most desirable improvement method for synthesizing the same final product using a two-stage deoxygenation process with the proper starting material and appropriate combination of known phosphorus trichloride / N, N-dimethylformamide. Incidentally performed.

The procedure was carried out in the same manner as described above, except that 19.8 mmol of the starting material (which corresponds to 10.0 g since the purity was 95% by weight by HPLC-analysis) was determined using dichloromethane using 39.9 mmol of trimethylchlorosilane and 39.5 mmol of N and N-dimethylaniline. Silylation was performed in 70 ml of methane if necessary using continuous cooling from -75 to -70 [deg.] C. and deoxygenation with 13 mmol of N, N-dimethylformamide and 31.4 mmol of trichloride (dropwise added in 5 minutes). 20 ml of N, N-dimethylaniline and 48 mmol of phosphorus pentachloride were used, and amide chloride was added at a temperature from the first -70 ° C to the last -45 ° C for 2.5 hours. Is generated.

Then treated with isobutanol and water in a conventional manner to give 5.82 g of isolated product having a purity of 94.0% by weight by HPLC analysis. The overall yield is 80.3% compared to Table II attached to Example XIV for the comparison of the most important contents of the two methods described above, where the amount of different types of drugs used in Example a was 19.8 mmol Instead of using it as a proportional increase.

c) Only one change was made, and the experiment described above was repeated and repeated. In other words, in order to avoid using a second reducing agent in the deoxygenation process, only the use of cis-cyclooctene was omitted. According to HPLC fractions, the hydrolyzed reaction mixture contained an amount of 7β-amino derivative equal to 32% conversion yield. The final isolate was 1.0 g.

d) Only one change was made and the experiment described in a) was repeated. Instead of 17.3 mmol of cis-cyclooctene, 17.3 mmol of N, N-dimethylaniline was used.

The final product isolated was 4.05 g with a purity of 89.0 wt% according to HPLC analysis. The overall yield was therefore 75%. This difference is not due to the relatively low separation effect, because the mixed filtrate contains 2.5% of the residual product.

[Example IV]

7β-amino-3- [1- from 7β-phenylacetamido-3- [1-methyl- (1H) tetrazol-5-yl-thiomethyl] -3-cepem-4-carboxylic acid 1β-oxide Preparation of Methyl- (1H) Tetrazol-5-yl-thiomethyl] -3-cepem-4-carboxylic acid.

a) 7β-phenylacetamido-3- [1-methyl- (1H) tetrazol-5-yl-thiomethyl] -3-cepem-4-carboxylic acid 1β-oxide in 60 mL under 0 ° C. nitrogen. To 7.8 g (83 mmol by purity, 14 mmol) of suspension, 3 mL (23.5 mmol) of trimethylchlorosilane and 2.95 mL (23.1 mmol) of N, N-dimethylaniline are added with stirring.

The mixture is then stirred at about 20 ° C. for 30 minutes and then cooled to -60 ° C. 2.05 mL (15.7 mmol) of cis-cyclooctene and 3.6 g (17.3 mmol) of phosphorus pentachloride are continuously added, followed by stirring at −45 ° C. for 10 minutes and then cooling to −60 ° C. 4.0 g (19.2 mmol) of phosphorus pentachloride and 3.45 mL (27.2 mmol) of N, N-dimethylaniline are added and stirred at -45 ° C for 3 hours. The temperature was lowered to -60 ° C and 25 ml of pre-cooled isobutane was added, followed by continuous stirring at -45 ° C for 1 hour. 25 ml of 4N sulfuric acid is added and stirred at -15 ° C for 10 minutes, and then the two layers formed are separated and the organic layer is extracted with 30 ml of 6N sulfuric acid. 70 ml of water is added during the extraction process to dissolve the precipitate. Then the organic layer was discarded. 2 g of activated carbon was added to the extract, followed by stirring. The clear acidic solution obtained by filtration was treated with 25% aqueous ammonia to pH 1.5 at 0 ° C. After a while, the precipitated product was collected by filtration, washed with cold water and acetone, and dried until a constant volume was obtained. The separated 7β-amino-3- [1-methyl- (1H) tetrazol-5-yl-thiomethyl] -3-cefe-4-carboxylic acid was 4.46 g and the purity by PHLC analysis was 93.0 wt%. . Overall yield was 90.2%.

b) This experiment was carried out in the same manner as in Example XIII b), except that 7β-phenylacetamido-3- [1-methyl- (1H) with higher purity of phosphorus trichloride / N, N-dimethyl formamide deoxygenation method. Starting from tetrazol-5-yl-thiomethyl] -3-cepem-4-carboxylic acid 1β-oxide, the maximum utilization is carried out to obtain a relatively most suitable method for the synthesis of the title compound.

This experiment is carried out with 3.83 g (7.33 mmol) of starting compound having a purity of 88.5 wt%. Other substances 25 ml of dichloromethane, 12.3 mmol of trimethylchlorosilane, 14.6 mmol of N, N-dimethylaniline, 5.8 mmol of N, N-dimethylformamide 12.6 mmol of phosphorus trichloride, 19.2 mmol of phosphorus pentachloride and N, N-dimethylaniline Using 25.8 mmol, imidechloride is obtained and the solution is treated with isobutanol as described in a). The deoxygenation step is carried out at -75 to -70 ° C using quenching. The final product was isolated was 2.15g, its purity was 86% by weight. Therefore, the total yield was 76.4%.

The most important contents of these two preparation methods are listed in Table II below as well as in Example XIII. The amount of all reagents used in Examples a) and b) is based on the use of 19.8 mmol of the starting material. Raised in proportion.

(A) Deoxygenation start temperature is shown in parentheses.

7β-amino- of XIII and IV, starting from 19.8 mmol of the corresponding 7β-tenylacetamido 1β-oxide derivative, comprising novel PCl ₅ / olefin method a) or known PCl ₅ / DMF method b) as deoxygenation method Details of Two-Step Single-Port Preparation of 3-Substituted Methyl-3-cepem-4-carboxylic Acid (All in Millimol)

Example IV

7β-amino-3- (5-methyl-1, 3, 4-thiadiazol-2-yl-thiomethyl) starting with 7β-phenylacetamido-3-cefe-4-carboxylic acid 1β-oxide Single-Port Formulation of 3-Cefem-4-carboxylic Acid.

According to the method described in EPC Application No. 0,043,630, 7β-phenylacetamido-3 was continuously operated under nitrogen atmosphere using dichloromethane 21, hexamethyldisilazane 35.5 ml, succinimide (0 g and 0.075 g saccharin). 102.6 g of -methyl-3-cepem-4-carboxylic acid 1β-oxide (97.5 wt.% Purity by HPLC analysis) were converted to the corresponding trimethylsilyl ester, as shown in EPC applications 0,034,394 and 0,015 629. According to the method, 74 g of N-bromo-succinimide and 2.64 g of sulfamic acid were used to investigate and bromine the resulting reaction mixture, according to the method set forth in EPC Application No. 0,001,149. The reaction mixture obtained using phosphate was selectively brominated, using the method of EPC Patent Application No. 0,043,630 using 200 ml of dichloromethane, 50 ml of hexamethyldisilazane and 0.1 g of saccharin. , 4-thiadia 40 g of -2-yl-thiol were converted to the corresponding trimethylsilylthioether The latter solution containing silylated thiol was added to the former solution at 5 ° C. by the method of EPC Patent Application No. 0,047,560 and at 5 ° C. Stir for 5.5 hours The reaction mixture thus obtained is cooled to −52 ° C., and 6 ml of N, N-diethylformamide, 42 ml of cis-cyclooctene and 68 g of phosphorus pentachloride are continuously added. Stir at 15 ° C. to −52 ° C. for 15 minutes, then add 64 ml of N, N-dimethylaniline and 60 g of phosphorus pentachloride at −50 ° C. and stir for 2 hours Stirring 200 ml of pre-cooled isobutanol at up to −45 ° C. Add slowly and stir for 1 hour, add 400 ml of water to the reaction mixture, stir for 15 minutes at -5 ° C. Separate organic layer and aqueous layer, extract organic layer with 100 ml of water. Dilute 400 ml of acetone in the mixed aqueous solution layer , A sodium hydroxide solution of 25% concentration 30 minutes to ensure that the gradually cheomgahyeong pH.

Then stored at 0-5 ° C. for 1 hour. The final precipitate was collected by filtration and washed continuously with 100 mL of ice water, 100 mL of 1: 1 acetone-water and 200 mL of acetone. Drying in vacuo gave 55.5 g of product. HPLC-analysis showed that 85.5% by weight of this product 7β-amino-3- (5-methyl-1, 2, 4-thiadiazol-2-yl-thiomethyl) -3-cefe-4-carboxylic acid Contained. Among the impurities, 0.5 wt% of 7β-amino-3-methyl-4-cepem-4-carboxylic acid was contained. The overall yield was therefore 48%.

[Example VI]

7β-amino-3- [1-methyl- (1H) tetrazol-5-yl-thiomethyl] starting from 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid 1β-oxide Single Port Formulation of 3-Cefe-4-carboxylic Acid.

In a dry atmosphere, a mixture of dichloromethane 612 1, saccharin 2.3 g, succinimide 0.3 kg, and sulfoliside 3.078 kg (purity 97.5 wt%) is boiled, dichloromethane 51. is added and reflux boiling is continued until a clear solution is obtained. 80 g of sulfamic acid and 2.225 kg of N-bromo-succinimide were added, and the mixture was then irradiated for 2 hours at -5 ° C according to the method of EPC Patent Application No. 0,034,394. Stirring was allowed to recycle. Tributylphosphite 0.61. Was then added at -10 ° C and stirred at -5 ° C for 15 minutes.

Anhydrous sodium 1-methyl- (5H) tetrazol-5-yl-thiolate is added and then the mixture is stirred at 0-5 ° C. for 1 hour. After cooling to −53 ° C., 180 ml of N, N-dimethylformamide and 1.26 L of cis-cyclooctene are added to the mixture, and 1.8 kg of phosphorus pentachloride is stirred for about 15 minutes while maintaining the temperature at −53 ° C. Add slowly. And this mixture was stirred for 30 minutes at -48-52 degreeC. 1.92 L of N, N-dimethylaniline and 1.8 kg of phosphorus pentachloride are added in about 15 minutes and stirred at -47 to -45 ° C for 2 hours. The reaction temperature was maintained at -42 to -40 [deg.] C., and 6 l of previously cooled isobutanol was added in about 10 minutes and stirred for 1 hour. The reaction mixture was transferred to another vessel and treated with 12 liters of water for 10 minutes to bring the final temperature to -5 ° C. The aqueous solution was separated from the organic layer. The organic layer is extracted with cold water of about 3 L in total. The combined aqueous layers are diluted with 6 L of acetone. The solution was slowly added to a mixture of 6 L of water and 6 L of acetone with stirring at 25 ° C, and maintained at pH 3 by addition of 25% aqueous sodium hydroxide solution. The mixture was further stirred at 10 ° C. for 1 hour and then left at about 10 ° C. for 1.5 hours. The crystal product was collected by filtration and washed successively with 6 L of ice water, 3 L of acetone 1: 1 with acetone 1: 1 and 6 L of acetone. It was then dried in a ventilated shelf to yield 1.704 kg of product. HPLC-analysis showed that the product contained 89.2% by weight of 7β-amino-3- [1-methyl- (1H) tetrazol-5-yl-thiomethyl] -3-cefe-4-carboxylic acid. The total yield was 53.7% when calculated from the purity of starting material sulfoxide and final product. Among the impurities, 7β-amino-3-methyl-3-cepem-4-carboxylic acid and 7β-amino-3- [1-methyl- (1H) tetrazol-5-yl-thiomethyl] -3-cepem-4 -1.5 weight% of carboxylic acid 1 (beta) -oxides were contained.

EXAMPLE VII

7β-amino-3- (pyridinium-1-yl-methyl)-from 7β-phenyl acetamido-3- (pyridinol-1-yl-methyl) -3-cepem-4-carboxylate 1β-oxide Preparation of 3-cefe-4-carboxylate dihydrochloride.

A crude starting material was obtained by stopping the method similar to that of Example XV, using an appropriate amount of excess pyridine in place of the thiol silylated used in Example 15. Since the purity is 82.52% by weight, a product containing 33 mmol of 17.0 g of compound is added to 200 ml of dichloromethane and suspended. Since water and a hydroxy-type impurity were contained in a large amount, 16.9 ml (132 mmol) of N, N-dimethylaniline and 17.0 ml (133 mmol) of trimethyl chlorosilane were added and 90 minutes at 30-32 캜 under a nitrogen atmosphere. Stir to dissolve the product. The solution is cooled to -40 [deg.] C. and 4.7 ml (36.3 mmol) cis-cyclooctene, 0.6 ml N, N-dimethylformamide and 8.61 g (41.3 mmol) phosphorus pentachloride are added successively. After stirring for 20 minutes, 4 ml (31.5 mmol) of N, N-dimethylaniline and 12.9 g (62 mmol) of phosphorus pentachloride were added and stirred at -35 ° C for 70 minutes. Lower the temperature to −55 ° C. and add 50 ml of 1, 3-dihydroxy propane. Continue stirring at −10 ° C. for 60 minutes. The resulting mixture is diluted with 50 ml of toluene and then evaporated in vacuo at the final 1 mm Hg. The residue was dissolved in methanol and then 500 ml of ethyl acetate was added gradually under vigorous stirring.

It was cooled in a cooling bath for 1 hour to form a precipitate, which was collected by filtration, and then ground and washed with 100 ml of ethyl acetate. The solvent was removed by filtration and the solid was dissolved in methanol. 200 ml of isopropanol was added and then concentrated in vacuo to about 100 ml. Centrifuge the obtained suspension. The remaining solids are centrifuged and washed twice with 50 ml of isobutanol. Drying in vacuo gave the final product. Product 12.5 with 81% content of 7β-amino-3- (pyridinium-1-yl-methyl) -3-cepem-4-carboxylate dihydrochloride in view of 78% purity by HPLC-analysis g was obtained. PMR spectra revealed a significant amount of impurities in the final product by isopropanol and 1,3-dihydroxypropane.

PMR (D ₂ O, δ-values in ppm, 60 Mc, int. Ref.

2, 2-dimethylsilapentane-5-sulphonate): 3.21, 3.52, 3.66 and 3.96 (AB-q, J = 18.5 Hz, 2H): 5.20 and 5.29 (d, J = 5.2 Hz, 1H): 5.34 and 5.42 (d , J = 5.2Hz, 1H): 5.29, 5.54, 5.75 and 5.90 (AB-q, J = 14.7Hz, 2H): 7.97 to 9.14 (m, 5H.)

IR (KBr-disc, value in cm ^-1 ): 3400, 1785, 1715, 1630, 1485, 1400, 1210.

EXAMPLE VII

7β-amino-3 [1- (2-dimethylamino) ethyl- (1H) tetrazole from trimethylsilyl 7β-phenylacetamido-3-bromomethyl-3-cepem-4-carboxylate 1β-oxide solution Preparation of -5-yl-thiomethyl] -3-cepem-4-carboxylic acid hydrochloride.

A solution of 5.59 mmol of trimethylsilyl phenylacetamido-3-bromomethyl-3-cepem-7β-4-carboxylic acid 1β-oxide in 65 mL of dichloromethane after the debromination reaction was carried out by the method described in Example XV. Got. 0.12 ml of N, N-dimethylformamide and 1.88 g (9.9 mmol) of ammonium 1- (2-dimethylamino) ethyl- (1H) tetrazol-5-yl-thioleate were stirred under nitrogen at -10 ° C. After the addition, the mixture was stirred for 45 minutes to raise the temperature of the mixture to about 10 ° C. The reaction mixture was cooled to −55 ° C., and then 0.94 mL (7.26 mmol) of cis-cyclooctene, 0.14 mL (1.1 mmol) of N and N-dimethylaniline, and 2.0 g (9.5 mmol) of phosphorus pentachloride were added successively. . The mixture was stirred at -48 [deg.] C. for 30 minutes and then 2.0 mL (15.8 mmol) of N, N-dimethylaniline and 2.0 g (9.5 mmol) of phosphorus pentachloride were added.

The mixture was stirred at −45 ° C. for 135 minutes, and then 6.7 ml of isobutanol was added dropwise at −40 ° C. for 90 minutes. Then 25 ml of water was added. After stirring at −5 ° C. for 10 minutes, the layers were separated and the organic layer was extracted with 15 mL of water. The extracts were combined and washed with 15 ml of dichloromethane. The organic layer was decanted and 25 mL of ethyl acetate was added to the extract, followed by addition of triethylamine to pH 6.0. After separating the layers, the organic layer was poured out and the aqueous layer was made to pH 3.2 by adding 6N hydrochloric acid, and then activated carbon was added, stirred at 0 to 5 ° C, and filtered. The filtrate was concentrated in vacuo until precipitation formed. About 100 ml of ethanol was slowly added to form a precipitate, and the mixture was stirred for 30 minutes at 3 ° C. The solids were collected by filtration, washed with ethanol and acetone, respectively, and dried in vacuo. The isolated product was purified by HPLC-analysis of 7β-amino-3- [1- (2-dimethylamino) ethyl- (1H) tetrazol-5-yl-thiomethyl-3-cepem-4-carboxylic acid hydrochloride. 87.3% by weight and content was 1.70 g. Therefore, the overall yield of the three steps was 63%, while the yield of all the processes performed continuously starting from 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylate 1β-oxide Was about 40%.

PMR (D ₂ O, δ-values in ppm, 60Mc int, ref. 2, 2-dimethylsilapentane-5-sulphonate): 3.07 (s, 6H): 3.86 (t, J = 6 Hz, 2H): 3.83 (s, 2H): 4.32 (s, 2H): 5.02 (t, J = 6 Hz, 2H): 5.17 (d, J = 5.2 Hz): 5.31 (d, J = 5.2 Hz, 1H).

IR (KBr-disc, values in cm ^-1 ): 3360, 1802, 1618, 1530, 1410, 1345, 1285.

EXAMPLE VII

7β-amino-3- [1-sulfomethyl- (1H) tetrazol-5-yl- from a crude solution of trimethylsilyl 7β-phenylacetamido-3-bromomethyl-3-cepem-4-carboxylate Preparation of Thiomethyl] -3-cepem-4-carboxylic acid monosodium salt.

It carried out similarly to the method of Example XV. Silylation, bromination and debromination were carried out, and HPLC analysis showed that 323 g of 20.24 mmol of trimethylsilyl 7β-phenylacetamido-3-bromomethyl-3-cefe-4-carboxylate 1β-oxide were contained. Got. To the mixture under a nitrogen atmosphere, 7.8 g (31.85 mmol) of dry disodium of 1-sulfomethyl- (1H) tetrazol-5-yl-thiol was added at 5 ° C. for 2 minutes and stirred at -10 to 0 ° C. for 60 minutes. It was.

While cooling the mixture to −60 ° C., 0.3 mL (2.3 mmol) of N, N-dimethylaniline and 3.4 mL (26.1 mmol) of cis-cyclooctene were added. 7.2 g (34.6 mmol) of phosphorus pentachloride was added and stirred at −60 ° C. for 40 minutes, followed by successively adding 7.2 mL (56.8 mmol) of N, N-dimethylaniline and 7.2 g (34.6 mmol) of phosphorus pentachloride. The resulting mixture was stirred at -40 ° C to -50 ° C for 2 hours, then 24 ml of isobutanol was slowly added and stirred at -40 ° C for 1 hour. 45 ml of water was added to the mixture and stirred vigorously for 15 minutes at -9 to -15 占 폚. At a temperature slightly lower than 0 ° C., about 25 mL of 4N NaOH was added and stirred to bring the pH to 0.2 at 0 ° C. The slightly cloudy solution was filtered through a filter bath to make it clear. The layers were separated and the organic layer was extracted with 12 ml of cold water. The aqueous layer was separated and the same volume (25 mL) was washed with dichloromethane. The organic layer was poured out and treated with an aqueous solution of 0.5 g of cooled sodium hydrogen sulfite dissolved in a combined aqueous solution (approximately 90 ml), followed by addition of 200 ml of methanol with stirring. The pH was brought to pH 0.5-4.0. The resulting mixture was left at 30 ° C. for 16 minutes, and the formed precipitate was collected by filtration, washed with 70% methanol and acetone, and dried in vacuo. The obtained product was obtained by PHLC analysis, the purity of 7β-amino-3- [1-sulfomethyl- (1H) tetrazol-5-ylthiothio] -3-cefe-4-carboxylic acid monosodium was 76% by weight. And yield was 7.73 g. The overall yield of this three-step method was 67.5%.

PMR (D ₂ O + NaHCO ₃ , δ-values in ppm.60Mc. Int.ref. 2, 2-dimethylsilapentane-5-sulphonate): 3.21, 3.51, 3.64 and 3.93 (AB-q, J = 18Hz, 2H) ; 3.95, 4.18, 4.32 and 4.54 (AB-q, J = 13.5 Hz, 2H); 4.71 (d, J = 4.5 Hz, 1H); 4.99 (d, J = 4.5 Hz, 1H); 5.51 (s, 2 H).

IR (KBr-disc, values in cm ^-1 ): 1800, 1615, 1530, 1405, 1340, 1220, 1040, 955 and 590.

EXAMPLE VII

Deoxygenation of 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid 1β-oxide trimethylsilyl ester performed under various conditions.

The experimental results under these various conditions are shown in the following Table III, and among them, the yield and the effect of the catalyst are shown. Most experiments, namely experiments 1-12 and 18, include the following standard silylation and the following reduction procedure. 15 ml of dichloromethane was distilled from a mixture of 6.93 g of starting material (which is 19.40 mmol, since the purity of the HPLC assay was 97.5%, 19.40 mmol) to azeotropically remove water. Successively under a nitrogen blanket, 2.42 mL (11.6 mmol or trimethylsilyl equivalent 1.29 equivalents) of hexamethyldisilazane was mixed for 15 minutes and added dropwise to the boiling suspension. The temperature boiled for 205 minutes was cooled to -60 DEG C, 22 mmol of olefin (38.8 mmol in Experiment No. 4) was added, and silyl No. 18 which was finally added to the catalyst of Table III and succinimide at the beginning of the silylation procedure was excluded. 4.8 g (23 mmol) of phosphorus pentachloride was added. After stirring at -45 ° C, 20 ml of water was slowly added carefully and stirred at -10 ° C for 15 minutes. 40 ml of toluene was added and then stirred at 0 ° C. for 3 hours. The precipitate formed was filtered off, washed with water and toluene and then dried in vacuo.

The separation yield of the substantial phase was confirmed by HPLC-analysis.

In the same manner, it was determined whether 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid was present in the mother liquor. The silylation process chosen to confirm the effectiveness of the catalysis was not ideal in terms of optimal conversion rate because of the presence of overlying silylating agents that interfered with the reaction with phosphorus pentachloride or because of excess ammonia neutralized by amidosulfonic acid ( Except experiment # 18).

In the result of Experiment 18, the excess silylating agent was removed to show a good effect. Also, non-ideal silylation processes occur when the amount of product present in the mother liquor or even cis-cyclooctene is used. The fact that cis-cyclooctene, the agent of choice under actual conditions is not always the best and / or fastest reaction agent, on the one hand, together with the results of Experiments 3 and 4, and on the other hand, the results of the repeated experiments of Experiment 1-2 In addition, the results of 12 and 12 were shown by experiments 1-2 comparing the teeth of repeated experiments. Compared with Experiment 1-2, Experiment 5-9 shows that the catalytic action is limited by N, N-dimethylformamide, N, N-dimethylaniline and a small amount of trimethylamine. And experiment No. 5 indicates that the possible pyridine catalysis is not obstructed through the formation of a complex with phosphorus pentachloride, but the formation of a complex of this material with quinoline does not completely prevent the catalysis of this base. The experimental conditions of Experiment No. 13-17 are as follows:

When the silylation process with pyridine and trimethylchlorosilane is carried out, these compounds are added at intervals of 5 minutes at 0 ° C., and a suspension of 19.4 mmol of starting material and 80 ml of dichloromethane is added continuously, followed by stirring at room temperature for 30 minutes. It was. Triethylamine was used instead of pyridine, and the formulation was added in the same manner at -10 ° C, and then stirred at -10 ° C for 60 minutes. The following operation was carried out as described above. The results of Experiment Nos. 13-17 clearly show that even with an excess of trimethylchlorosilane, pyridine can be advantageously used in small excess.

Good results of Experiment No. 16 indicate the catalysis of the optional pyridine hydrochloride.

The olefin compound in dichloromethane and 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid 1β-oxide via its trimethyl ester by phosphorus pentachloride using various conditions at −45 ° C. Deoxygenation method of A).

a) Although it was somewhat difficult to experiment to obtain the exact total conversion of the reaction mixture by HPLC analysis, the percentages shown here (not shown in the table) were within 3% of the absolute value calculated after separation.

(Abbreviated name: HMDS: hexamethyldisilazane, pyr: pyridine),

Quin: quinoline, TEA: triethylamine,

DMA: N, N-methylaniline,

DMF: N, N-dimethylformamide,

TMCS: trimethylchlorosilane).

TABLE III

[Example XI]

7β-amino-3- [1-carboxymethyl- (1H) tetrazol-5-yl-thiomethyl] starting with 7β-phenylacetamido-3-methyl-cepem-4carboxylic acid 1β-oxide Single Port Preparation of 3-Cefe-4-carboxylic Acid.

It carried out similarly to the method of Example XV.

325 ml of a solution containing 26.6 mmol of trimethylsilyl 7β-phenylacetamido-3-bromomethyl-3-cef-4-carboxylate 1β-oxide in dichloromethane by carrying out silylation, bromination and debromination reactions Got r. Apart from the above procedure, 7.2 g (45 mmol) of 1-carboxymethyl- (1H) tetrazol-5-yl-thiol, 80 ml of 1, 2-dichloroethane, 80 mg of saccharin and 13.6 of hexamethyldisilazane The ml mixture was refluxed for 3.5 h. Then vacuum evaporation gave trimethylsilyl-5-trimethylsilylio- (1H) tetrazol-1-yl-acetate as a viscous oil. To the silylated 3-bromomethyl-cephalosporin intermediate solution, 0.9 ml of N, N-dimethylformamide and silylated thiol were added to several ml of dry dichloromethane at 5 ° C. The mixture was stirred at 5 ° C. for 5.5 h in nitrogen. The reaction mixture was cooled to -52 ° C, 0.4 mL of N, N-dimethylaniline, 5.2 mL of cis-cyclooctene, and 9.9 g of phosphorus pentachloride were added successively, followed by stirring at 45 ° C for 30 minutes. Then 10.2 ml of N, N-dimethylaniline and 9.9 g of phosphorus pentachloride were added and stirred at -45 ° C for 1 hour.

In the temperature range of -45 ° C to -35 ° C, 31.5 ml of pre-cooled isobutanol is added, followed by stirring the mixture at -40 ° C for 1 hour. 50 ml of water are added and stirred at 0 ° C. for 15 minutes.

The aqueous layer is separated from the organic layer and then the organic layer is extracted twice with 40 ml of water. The combined aqueous layers were washed twice with dichloromethane and diluted by adding 300 ml of methanol. 4N sodium hydroxide solution was added to make pH 3.4 and then left at 0 ° C. overnight to form a precipitate. The precipitate was collected by filtration. The precipitates collected at 0 ° C. were polished, washed with 12 ml of a 1: 1 methanol-water solution, collected by filtration, washed with the same mixture, washed with acetone and dried under vacuum until constant weight. The amount of product thus obtained was 7.4 g. According to the PMR-analysis, the product is composed of 7β-amino-3- [1-carboxymethyl- (1H) tetrazol-5-yl-thiomethyl] -3-cepem-4-carboxylic acid and its mono-nathium salt. It was a mixture of 1: 3. Therefore, the yield of the present compound is 59.7% based on the brominated sephalosporin derivative and the present compound is calculated on the basis of 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid 1β-oxide. The yield is 36.8%. The purity of this compound is 84% by weight. The title compound, with no residual monosodium salt, has a total yield of about 30%, with a purity of 95% by weight by PMR-analysis, which gives the crude product with hydrochloric acid in the least amount of water. The mixture was made to pH 1.4, and then added with 3 times the amount of methanol, filtered, and sodium hydroxide to obtain a pH of 2.6. The precipitate was collected by filtration, washed and dried as described above.

PMR (DCO ₂ D, δ-values in ppm. 250Mc, int. Ref. TMS): 3.83, 3.90, 3.90, 3.97 (AB-q, J = 18 Hz, 2H); 4.50, 4.55, 4.64, 4.69 (AB-q, J = 14 Hz, 2H); 5.43, 5.45, 5.47, 5.49 (AB-q, 2H, J about 5 Hz, 2H); 5.50 (s, 2 H).

IR (KBr-disc, values in cm ^-1 ): 1820, 1635, 1550, 1370, 1130, 1080.

Claims (40)

Sepharoseporin 1β- and Sepharoseporin 1α-oxides of the following general formula (I) are reacted with phosphorus pentachloride to deoxygenate to the corresponding substituted cephalosporin of the following general formula (II), and the substituents R ₂ and in the R ₃ retain the groups introduced to protect reactive groups present in that to remove the protecting group R ₁ R ₁ a method of manufacturing the general formula (ⅱ) compound is hydrogen or a salt forming cation, a de-oxidation are -70 ℃ Carried out in the presence of an olefinic compound having at least one carbon-carbon double bond to which no more than three hydrogen atoms in the organic solvent are substantially inert at −0 ° C., with the addition of the olefin compound to the carbon-carbon double bond Having a function of removing at least part of the chlorine by

In the above formula, R ₁ represents a tri (lower) alkyl silyl group or (lower) alkyl group, R ₂ represents a hydrogen atom, a methyl group, a substituted methyl group, wherein the substituent represents a halogen atom, (lower) alkoxy, (lower) alkylthio group, (lower) alkanoyloxy or (lower) alkanoylthio group) 1-pyridi A nium group, a heterocyclic thio group, wherein the heterocyclic group is a thiadiazole or tetrazole group bonded to a carbon atom and substituted by an unsubstituted or di (lower) alkylamino, carboxy or sulfo group, R ₃ represents a phenylacetamido or phenoxy acetamido group. The method of claim 1, wherein the number of hydrogen atoms bonded to one or two carbon-carbon double bond carbon atoms in the chain of 3-20 carbon atoms or in a ring of 4-12 carbon atoms is not greater than two. How to be. 3. Process according to claim 1 or 2, characterized in that the compound uses a monoolefin or diolefin compound having one or two non-terminal carbon-carbon double bonds. The monoolefin or diolefin compound according to claim 1 or 2, which is substituted with a linear lower alkyl group having 1 to 4 carbon atoms of one or both carbon atoms of non-terminal carbon-carbon double bond in the chain or ring. It is characterized by being. The process according to claim 2, wherein the deoxygenation reaction is carried out in the presence of cis-cyclooctene. The method of claim 1, wherein the deoxygenation reaction is carried out at -60 ~ -20 ℃. The method according to claim 1, wherein the substantially inert organic solvent used is dichloromethane, chloroform, 1, 2-dichloromethane or acetonitrile. The method according to claim 1, wherein the deoxygenation reaction is carried out in the presence of a catalyst or an additive which promotes the chlorine consumption of the olefin compound. 9. The process according to claim 8, wherein the catalyst or additive used is N, N-dimethylformamide N, N-dialkyl-aniline or trialkylamine. In the method for producing 7β-amino-3-sephalosporranic acid represented by the following general formula (III), the 7β-acylamino-3-cefe-4-carboxylic acid 1β-oxide derivative of the following general formula (Ia) is deoxidized. Without ingesting the digestion product, in succession by the following steps. a) for introducing a silyl group in the case of carboxylate oxygen bound to an additional separosporanyl moiety of formula (Ia) starting from a compound of formula (Ia) having hydrogen or a salting cation as R ₁ ; Silylation of Separosporin 4-carboxyl Group. b) in any case using phosphorus pentachloride in the presence of an olefinic compound having at least one carbon-carbon atom having not more than two hydrogen atoms bonded and having chlorine removed mainly by carbon-carbon double bonds by addition reactions; Deoxygenation. c) successive addition of a suitable tertiary amine such as N, N-dimethylaniline and phosphorus pentachloride to form the corresponding imide chloride within the same reaction itself, isobutanol to form the corresponding imino ether 7β-acyl by known procedures by the addition of suitable monohydroxy alkanes such as or alkanediols such as 1,3-dihydroxypropane, and finally water for the hydrolysis of the imino ester and the easily removed protecting groups Deacylation reaction which cleaves an amino substituent.

In the above formula, R ₁ is a hydrogen atom, a salt forming cation or a (lower) alkyl group, R ₂ is a hydrogen atom, a methyl group, a substituted methyl group, wherein the substituent is a halogen atom (lower) alkoxy, (lower) alkylthio group, (lower) alkanoyloxy, or (lower) alkanoylthio group], 1-pyri Dinium groups, heterocyclic thio groups, wherein the heterocyclic groups are bonded to sulfur atoms by carbon atoms and are unsubstituted or di (lower) alkylamino, carboxy or sulfoxy groups substituted thiadiazoles or tetrazole groups Is, R ₃ phenylacetamido or phenoxyacetamido group; Hz is a salt forming acid, n represents 0 or 1. The following general formula (Ⅱa) of 7β- acylamino-3-substituted methyl-formula as "carboxyl", R ₁ to remove the "ester residue R ₁ of a cephalosporin derivative having a Sefar hydrogen atom or a salt forming cation (Ⅱa In the method for preparing a compound, the following steps are continuously carried out without separating the 7β-acylamino-3-methyl-3-cepem-4-carboxylic acid 1β-oxide derivative of general formula (Ib), a) silylation of a carboxyl group which introduces a silyl group carried out in the reaction itself, when R ₁ ′ starts with a compound of formula (Ib), which is not a lower alkyl ester group, b) photoinduced bromination of the 3-methyl group of the compound of formula (Ib) using a brominating agent with N-bromo-amide or N-bromoamide to obtain a compound having a 3-bromomethyl group, c) introduction of a substituent R ₂ ′ by substitution of bromine introduced in the methyl group in step b) d) conversion by deoxygenation of sulfoxy groups using phosphorus pentachloride in the presence of an olefinic compound.

In the above formula, R ₁ ′ is a hydrogen atom, a salt forming cation or a (lower) alkyl, R ₂ ′ is (lower) alkoxy, (lower) alkylthio, (lower) alkanoyloxy, (lower) alkanoylthio, or when R ₂ ′ is a (lower) alkyl ester moiety, bromo, pyridinium group, heterocycle Thio group, wherein the heterocyclic group is a thiadiazole or tetrazole group which is bonded to a sulfur atom by a carbon atom and is unsubstituted or substituted by di (lower) alkylamino, carboxy or sulfoxy group) Include free groups or salts thereof by removing acyl groups introduced to protect the silyl, silyl or unsaturated heterocyclic secondary amine groups derived to protect the hydroxy, carboxy or sulfo groups, R ₃ represents a phenylacetamido or phenoxyacetamido group. 2. The process of claim 1, wherein R ₁ ′ is hydrogen or a salt forming cation converting the compound to the corresponding trimethylsilyl ester in the first step when using a compound of formula (Ia). The process according to claim 10, wherein the multistage preparation is carried out in halogenated hydrocarbons as solvent. The method of claim 13, wherein the solvent is dichloromethane. The method of claim 10, wherein the deoxygenation step is carried out at -65 ~ -35 ℃. 12. The amount of strong silylation catalyst of 0.005 to 5 mole percent of residual ammonia according to claim 11 when using the six-substituted silazane in the silylation step a) for the protection silylation of the acetoxysepharosporanic acid 1β-oxide derivative. Characterized in that it is used in combination with an amount of 1 to 50 mole% of the silylated organic compound to remove and to neutralize. 17. The process according to claim 16, wherein the silylated organic compound added during the silylation step of removing residual ammonia and forming inorganicization is used in an amount exceeding the amount of strong silylation catalyst. 17. The weak silyl of claim 16 wherein the silylated organic compound is selected from the group consisting of ring-opened or saturated cyclic acylurea containing NH between two acyl-type groups and ring-opened or saturated cyclic N-sulfonylcarbonamide A process characterized in that the oxidation catalyst. 19. The method of claim 18, wherein the silylated carbon compound is succinimide. The method according to claim 10, wherein the monoolefin during the deoxygenation step is a compound having a non-terminal carbon-carbon double bond on 4-12 carbon atoms or 5-8 membered carbocyclic ring. The method of claim 20, wherein the monoolefin compound is cis-cyclooctene. The method of claim 10, wherein in performing the deoxygenation step, N, N-dimethylformamide is added. 23. The process according to claim 22, wherein N, N-dimethyl-formamide used in the deoxygenation step is used at 30 mole% or less based on the amount of the compound of general formula (Ib) introduced. The method of claim 11, wherein the formula is the method of FIG characterized amino-phenyl acetamido-phenoxy or cyano set 'R ₃ when used as a trimethylsilyl group' (Ⅰb) compound is a protecting group of R _1. 12. The method according to claim 11, wherein a t-butyl group is used as a protecting group for R ₁ 'when preparing the general formula (IIa) in which the substituent R ₂ ' is a bromine atom or an acetoxy group. The process according to claim 10, wherein the conversion reaction is carried out in the same reactor without separating intermediates. The method according to claim 11, wherein the conversion reaction is carried out without separating the intermediate. The process according to claim 10, wherein the deoxygenation step is carried out in the presence of a catalyst or additive. The method of claim 10, wherein in step a) the R ₂ reactive substituents are protected from silylation or acylation. 12. The process according to claim 11, wherein the bromine atom introduced in step b) in the methylene group adjacent to the sulfur atom in the dihydrothiazine ring is reacted with trialkyl phosphite or trialkyl phosphite to be replaced with hydrogen. In the process for preparing a compound of formula (IIIa) wherein the final product in the form of acid addition salt using a strong inorganic or organic acid is separated and the carbon ester residue R ₁ ′ is removed, wherein R ₁ ′ is hydrogen or a salt forming cation. The following 7β-acylamino-3-methyl-3-cepem-4-carboxylic acid 1β-oxide derivative of the general formula (Ib) was subjected to subsequent steps without separating intermediates: In other words, a) silylation of a carboxyl group carried out in the reaction itself, starting with a compound of formula (Ib) having hydrogen or a salt forming cation as R ₁ ′, b) photoinduced bromination of the methyl group, c) introduction of a substituent R ₂ ′ by substitution of bromine introduced in the methyl group in step b) d) deoxygenation of sulfoxy groups using phosphorus pentachloride in the presence of an olefinic compound which removes chlorine by addition reaction for one or more carbon-carbon double bonds bonded to not more than two hydrogen atoms, e) a method of converting by using a phosphorus pentachloride by a deacylation reaction which cleaves the 7β-acylamino substituent according to a known procedure.

In the above formula, R ₁ is a hydrogen atom, a salt forming cation or a (lower) alkyl group, R ₃ ′ is (lower) alkoxy, (lower) alkylthio, (lower) alkanoyloxy, (lower) alkanoylthio, bromo, 1-pyridinium group, compound when R ₁ ′ is a (lower) alkylester moiety A monocyclic thio group, wherein the heterocyclic group is a thiadiazole or tetrazol group unsubstituted or substituted by di (lower) alkylamino, carboxy or sulfoxy groups, bonded to a sulfur atom by a carbon atom, or Include free groups or salts thereof by removing the acyl groups introduced to protect the silyl, silyl, or acyclic heterocyclic secondary amine groups derived to protect hydroxy, carboxy or sulfo groups, R ₃ represents a phenylacetamido or phenoxyacetamido group. 32. The process of claim 31 wherein the inversion reaction is carried out in the same reactor without separation of intermediates. 33. The process according to claim 31 or 32, wherein R ₁ is converted to the corresponding trimethyl silyl ester in the first step when a hydrogen atom or a salt forming cation uses a compound of formula (Ib). . 33. The process according to claim 31 or 32, wherein the multistage synthesis is carried out in halogenated hydrocarbons as a solvent. 33. The method of claim 31 or 32, wherein the deoxygenation reaction is carried out at -65 to -35 ° C. 33. The method according to claim 31 or 32, characterized in that in the deoxygenation step the monoolefin compound is of a non-terminal carbon-carbon double bond located in the chain of 4-12 carbon atoms or in the ring of 5-8 carbon atoms. Way. 33. The process according to claim 31 or 32, wherein N, N-dimethylformamide is added when the deoxygenation step is carried out. 33. The method of claim 31 or 32, a) t-butyl 7β-amino-3-acetoxymethyl-cepem-4- from t-butyl 7β-phenylacetamido-3-methyl-3-cepem-4-carboxylate 1β-oxide, omitting step a) Carboxylate and acid addition salts thereof. 33. The compound of claim 31 or 32, wherein R ₁ ′ is hydrogen or a salt cation and R ₂ ′ is 1-methyl- (1H) tetrazol-5-yl-thiomethyl, 1- (2-dimethylamino) -Ethyl- (1H) tetrazol-5-yl-thiomethyl, 1-sulfomethyl- (1H) tetrazol-5-yl-thiomethyl, 1-carboxymethyl- (1H) tetrazol-5-yl- Thiomethyl, 1, 2, 3- (1H) triazol-5-yl-thiomethyl, 5-methyl-1, 3, 4-thiadiazol-2-yl-thiomethyl, 1, 3, 4-thia Diazol-2-yl thiomethyl and 2, 5-dihydro-6-hydroxy-2-methyl-5-oxo-1, 2, 4-triazyl-3-yl-thiomethyl, sodium, potassium or Salt forming an addition carboxy or sulfo group having an anion derived from an amine such as magnesium or an external salt of an additional dimethylamino group together with a 7β-amino group or a strong inorganic or organic acid. 38. The method of claim 37, wherein 7β-amino-3- (1-methyl- (1H) tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid is prepared and isolated.