A method of obtaining a crystalline mono - or dihydrochloride dihydrate 7-[2-(2 - aminothiazol-4-yl) -2-(z)- methoxykynuramine] -3- [(1-methyl-1-pyrrolidino) -methyl] ceph-3-em-4 - carboxylate, essentially free from antihisamine and2isomer


C07D501/06 - Acylation of 7-aminocephalosporanic acid

 

(57) Abstract:

The inventive essentially free from Delta (2)-isomer Siciliano derivative of formula 1, where R and R each represents a hydrogen atom or a silyl protective group, provided that R and R are not simultaneously hydrogen atoms, Xxthe remainder of hydrochloric, itestosterone or sulfuric acid, is subjected to the interaction with the SYN-isomer hydrochloride 2-(2-aminothiazol-4-yl)-2-methoxykynuramine essentially free of anti-isomer in an inert organic solvent in the presence of base, followed by separation of the resulting reaction mixture the desired product in the form of its crystalline mono - or dihydrochloride dihydrate. The structure of the compounds of formula 1: 18 C.p. f-crystals, 4 Il. table 1.

The present invention provides a process of chemical acylation and, in particular, the process of anhydrous acylation to obtain antibiotic, cefpimizole hydrate, which is also known as 7-/2-(2-aminothiazol-4-yl)-2-(Z)-methoxyimino - Mido/-3-/ (1-methyl-1-pyrrolidino)methyl/ceph-3-em-4-carboxylate. The present invention also provides stable crystalline salt of SYN isomer intermediate the substances of a wide range of actions.

There are a number of the cephalosporin-antibiotic, which contain 2-(2-aminothiazol-4-yl)-(Z)-2-methoxyimino acid side chain that is attached to the 7-amino group of zefalosporinovy acid by well-known methods of acylation. In many cases it is necessary to protect the amino-part and activate the carboxylic acid side chain as part of the method of acylation. Therefore, the literature describes a number of aminosidine groups for 2-amino thiazole ring and a number of activating groups for carboxylic acids. The subject of numerous publications still search for better protective groups and activating groups to obtain the desired antibiotic from the point of view of cost and toxicity associated with certain trigger groups. Therefore, there is still a need in obtaining suitable antibiotics of a wide range of actions in a simple, stable, crystalline, economical, non-toxic side chain having the desired geometric (Z)-isomer, which can be easily attached to the 7-amino nucleus of cephalosporin. Below are some typical representatives of the group of the side chain of thiazole.

1represents amino, protected amino, hydroxyl or protected hydroxyl, R5represents a hydroxy or protected hydroxyl, and W represents a hydroxyl,1-C4alkoxy, halogen or OM, where M denotes an alkali metal.

In the patent application UK N GB-2144424, published on March 6, 1985, discloses a number of pyridinium derivatives of cephalosporin using various methods, including the use of the compounds of formula

R4HN or its salts, where R1denotes a hydrogen atom or halogen, R2denotes a hydrogen atom or a radical C1-C6-alkyl and R4denotes a hydrogen atom or aminosidine group, or activated derivative of this compound.

In the application Europatent N ER-160546, published November 6, 1985, discloses a number of cephalosporin compounds in a variety of ways, including the use of substituted oxyiminocephalosporins acetic acid formula

R8HN or their reactive derivatives, where R8denotes a hydrogen atom or a protective group for amino group. Suitable examples of such reactive derivatives of I the water and acid azides.

In U.S. patent N 4385181 in the name of Forge etc. issued may 24, 1983, reveals a complex tilapia formula

RNH where R' denotes a hydrogen atom or a protective radical, Rodenotes a hydrogen atom, alkyl, vinyl, cyanomethyl or a protective radical, and R stands for alkyl, L-2-amino-2-carboxyethyl, phenyl or a number of different heterocyclic radicals listed in columns 4-8, and their SYN - and anti-isomers and mixtures thereof.

In addition to the above references, there are a number of references that disclose various protective groups for 2-aminosalicylates, as well as a number of activating groups/leaving groups part of the carboxylic acid, which can be used in the acylation of 7-amino compounds of the cephalosporin.

However, the definitive reference is a patent Czechoslovakia N 238950, published March 16, 1987 /chemical Abstracts, Volume 110, page 544 (1989)/, which reveals the connection of the present invention, those having the formula:

NH HCl where connection is SYN-configuration. The only evidence present in the patent in respect of a product is a chlorine content equal to from 99% to 100.5 percent of theoretical value.

In connection with attempts developed the ehniki felt the need for a new simple, convenient, economical, crystalline, stable, non-toxic source substances for use in the manufacture of antibiotics. Initial attempts to obtain and use the acid chloride of 2-(2-aminothiazol-yl)-2-methoxyethoxy acid without the use of protecting groups had no success. However, the applicant has found that the compound of the present invention can be obtained by specifically defined reaction conditions. This discovery was later confirmed by the applicant, when he was able to reproduce the doctrine of the above patent Czechoslovakia. The desired SYN-isomer hydrochloric salt of the acid chloride, which is necessary to obtain the desired antibiotic, cannot be repeated. Furthermore, additional experiments confirmed that the doctrine of the opposed patent may not produce hydrochloric salt of the desired SYN-isomer of the acid chloride, essentially free from SYN-isomer and have described in this paper range proton nuclear magnetic resonance (1H NMR).

The antibiotic cefepime broad-spectrum revealed Abenaki and others in the U.S. patent N 4406899, issued September 27, 1983 arousih and deblokiruyuschee groups. In the examples the reaction scheme, the product needs phase chromatographic purification with the aim of separating a mixture of2and3isomers, and therefore, the thus obtained product cefepime is produced in the form zwitterion. However, the form zwitterion connection cefepime is unstable at room and elevated temperatures.

Murray A. Kaplan and others in the U.S. patent N 4910301, issued March 20, 1990, discloses a stable crystalline salt of cefepime in the form of a dry powder having excellent stability at room and much higher temperatures compared with the form zwitterion compounds cefepime, unveiled Abenaki and others in the U.S. patent N 4406899.

In U.S. patent N 4868294, issued September 19, 1990 in the name of Brundidge and other disclosed obtaining salts of 7-amino-3-/(1-methyl-1-pyrrolidino)methyl/ceph-3-em-4-carboxylic acid essentially free from2-isomer, as well as their use in a method of water acylation with the aim of obtaining the antibiotic cefepime in the form of a salt of sulfuric acid (sulfate).

In U.S. patent N 4754031, issued June 28, 1988 in the name of Angerbauer, etc. is disclosed a method of obtaining several antibiotics on the basis of cyclosporine, VM applied anhydride activation in the reaction of aqueous acylation, which provides phase chromatographic purification with getting zwitterion form of cefepime.

In U.S. patent N 4943631, issued July 24, 1990 in the name of Brian E. looker, describes an improved method of producing antibiotic cefepime as idiscovered salt. The method provides control over the formation of undesirable2isomer by using the intermediate sulfoxide cyclosporine. However, as described in the patent, the Method is expensive and inefficient because it uses two additional stages and continues the use of protective groups, which require methods of blocking and release. Furthermore, the method involves the use of column chromatography as a purification method, which is impractical on an industrial scale.

Obtaining a crystalline salt of sulfuric acid (sulfate) in zwitterion of cefepime, which are described in the literature involves the use of essentially the same process water acylation and various blocking and deblokiruyuschee groups and active esters. In all cases, the preferred crystalline form of a hydrate of the dihydrochloride of cefepime should be the simple, direct and effective methods of acylation, which would ensure the elimination reaction stages with the purpose of adding and removal of protective groups, stereochemical control phases and chromatographic techniques and, more importantly, methods of acylation, which would lead to obtaining a hydrate of the dihydrochloride of the antibiotic cefepime, essentially free of anti-isomer and 2isomer.

The present invention provides a process of chemical acylation and, in particular, the process of anhydrous acylation to obtain antibiotic hydrate of the dihydrochloride of cefepime, essentially free of anti-isomer and2isomer. The present invention also provides a stable, crystalline sintomer hydrochloride of 2-(2-amentiies-4-yl)-2-methoxyimino-acetylchloride essentially free of anti-isomer, which is used in the acylation process for obtaining shirokorelsovogo antibiotic cefepime.

Fig.1 shows the spectrum of the proton nuclear magnetic resonance hydrochloride SYN-2-(2-aminothiazol-4-yl)-2-methoxyimino-acetylchloride Example 10 in acetic acid-d4(100 MHz).

Fig.2 shows the spectrum of the proton nuclear magnetic resonance paninaro resonance of the product of Example 13 in acetic acid d4(100 MHz).

Fig.4 shows the spectrum of the proton NMR of the product of Example 14 in acetic acid d4(100 MHz).

The present invention provides a waterless method of acylation for N-acylation of 7-amino-3-/(1-methyl-1-pyrrolidino)methyl/ceph-3-em-4-carboxylate with SYN-isomer hydrochloride 2-(2-aminothiazol-4-yl)-2-methoxyimino-acetylchloride that is essentially free of the anti-isomer, obtaining temperature-stable hydrate of the dihydrochloride of cefepime, essentially free of anti-isomer and2isomer and is represented by the formula Y in which Z represents 1 or 2. H2N 2HClzH2O

The advantages of the proposed method anhydrous acylation become apparent and can be assessed by experts in the field, when all the benefits of the combined and considered as a whole. The formal elimination of the amino - and carboxyl protective groups and the corresponding elimination of additional chemical stages required to lock and unlock, enable you to get obvious advantage in the overall efficiency of the process and the cost of materials before the previously known processes. The proposed method additionally provides and supports the RA cyclosporine without the need for separation of unwanted by-products of cyclosporine and without the use of stereochemical control sulfoxidation, such are described in U.S. patent N 4043631. Another advantage of the present invention is the obtaining and use of unprotected crystalline monohydrochloride salt of SYN isomer of 2-(2-aminothiazol-4-yl)-2-methoxyimino-acetylchloride formula III, which eliminates unusual and sometimes complex organic leaving groups described in the literature. The use of simple chloride ion as a leaving group eliminates the potential toxic leaving groups such as 2-mercaptobenzothiazoles. Another advantage of a preferred variant of this process, anhydrous acylation is getting the required temperature-stable crystalline hydrate of the dihydrochloride of cefepime directly from the reaction mixture method of acylation without the need for obtaining and allocating salt of sulfuric acid or zwitterion of cefepime. This method also allows to obtain a water-soluble crystalline monohydrate cefepime dihydrochloride (or dihydrate), essentially free of anti-isomer and2-isomer, with high yield, directly from the aqueous phase of a two-phase solution.

The present invention also provides a stable cromogen from antihisamine and represented by formula III:

H2N HCl (III)

Due to the fact that the compound III is essentially free of anti-isomer, it is converted to cephalosporins wide range of actions, which themselves are essentially free of the anti-isomer, with no need for chromatographic separation of SYN and anti-isomers. As a result of increased stability of the compound III can be isolated and stored, and, when necessary, the compound III can be converted into final products in another solvent, which is favorable to obtain the desired antibiotic, essentially free from2isomer. An additional advantage of the intermediate compounds of formula III is that it does not require locking (protecting) amino prior to acylation or unlock (release of security) amino group after acylation, thereby ensures the effectiveness of the method. Another advantage of chloralhydrate formula III is its use in the acylation process of obtaining cephalosporins are broad-spectrum. In contrast to other methods, such as those described in U.S. patent N 4406899 in the name of Abenaki and other intermediate compound of formula III has the chloride ion in the form simply has a place with many other leaving groups, well-known specialists. In addition, some intermediate compounds, which are known to contain other leaving group, it is difficult to obtain, while other intermediate compounds containing such leaving groups as 2-mercaptobenzothiazoles, are toxic /chemical Abstracts, 1989, Volume III (3), / 19243/.

A Reaction scheme I

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SYN-isomer hydrochloride of chlorhydric formula III can be obtained from the SYN-isomer of the acid of formula I, as indicated in the Reaction Scheme I. the Acid of formula I is first converted into the corresponding hydrochloric salt of the formula II with known methods, and then, if necessary, to allocate in the form of anhydrous crystalline compounds of formula II. Education hydrochloric salt mainly carried out using at least one molar equivalent of gaseous hydrogen chloride in an inert organic solvent such as toluene, acetonitrile, dichloromethane, acetone, benzene, xylene, cyclohexane, hexane, dioxane or simple diethyl ether, at a temperature in the range from approximately -10aboutWith up to 50aboutC. Preferably, the reaction is carried out in toluene, dichloromethane or acetonitrile, and thus obtained the hydrochloride Rath formula II, as a rule, retains slightly bound solvent. So beneficial to use the hydrochloride of the acid of formula II from acetonitrile to have time in the next stage, in order to avoid solvate displacement under the action of atmospheric moisture. Most preferably, if the reaction is carried out in toluene or dichloromethane at a temperature from 0aboutWith up to room temperature.

Acid salt of formula II is then favorably to handle gloriouse agent and, most preferably, oxalylamino in combination with dimethylformamide to obtain a stable crystalline SYN-isomer of compound III. As shown in this description, the use of other known gloriously agents can lead to isomerization with the production of undesirable anti-isomer or mixtures of SYN - and anti-isomers. In addition, such gloriouse reagents, as Piatigorsky phosphorus, can lead to chlorination of the 5-position on the thiazole ring, then that will create an undesirable impurity in the antibiotic. The applicant has found that, in addition to obtaining a hydrochloride acid of the formula II, the right choice glorieuses reagent and the reaction conditions such as solvent and temperature, are critical of the Sabbath." >

Methods of chlorination, usually used to activate acids, are well known in the art. Piatigorsky phosphorus, which is the most widely used gloriouse the reagent is not suitable for chlorination of compound (II), because it also leads to isomerization of methoxyimino with unwanted anti-isomer of compound III. This is clearly illustrated in Examples 12, 13, 14, and 16, which are listed below. Another known method of chlorination is the use of oxalicacid in combination with dimethylformamide. However, the applicant has found that the method of oxalicacid in which dimethylformamide is used as a catalyst, not result in significant quantities of the desired SYN-isomer of compound III. This is also clearly demonstrated in Example 15 below. As a result of extensive research, the applicant has found that the use of dimethylformamide in an amount less than the equimolar amount relative to the amount of oxalicacid, has a negative impact on the production of the desired SYN-isomer of the hydrochloride of the acid chloride of the formula III. Most preferably, if the molar amount of dimethylformamide exceeds the molar amount of the also has a negative influence on the reaction, and on the stability of the desired product. Thus, the applicant has discovered a method of controlling the instability of the reaction substances both in relation to the excess of the chloride ion produced by oxalylamino, and in respect of dimethylformamide, each of which is crucial in the production of stable crystalline SYN-isomer of compound III, which is essentially free of anti-isomer. In that case, when the conversion of the compounds of formula II to the compound of formula III is not completed, there remains a small number of the SYN-isomer of the acid of formula II in the selected product of compound III. The presence of a certain amount of unreacted compound (II) in the product, compound III is not affected by the subsequent acylation reaction with respect to the successful production of the desired antibiotic that is essentially free from antisolar specified antibiotic.

The applicant also found that the decisive are the temperature and the reaction solvent chlorination. Preferably, if the reaction is carried out in an inert organic solvent, such as dichloromethane, chloroform or acetonitrile, at a temperature of less than -10aboutC. Most preferably, the Engl is aboutC.

The use of SYN-isomer of the hydrochloride of the acid chloride of the formula III to obtain a useful broad-spectrum antibiotics by means of a common acylation reaction is shown in Reaction Scheme 2. More specifically, a Reaction Scheme 2 illustrates the use of acid chloride of formula III to obtain shirokorelsovogo antibiotic cefepime, which is essentially free of the anti-isomer and2isomer. In addition, chloronitromethane formula III can be used to obtain cephalosporin antibiotics having a SYN-isomer of 2-(2-aminothiazol-4-yl)-2-methoxyaminomethyl attached to the 7-amino nucleus of cephalosporin, for example, cefodizime, cefmenoxime, cefotaxim, cefpirome, cefpodoxime, rethinam, cefteram, ceftiofur, cefetamet and carusona.

In addition, to confirm that the hydrochloride of the acid chloride in accordance with known methods is in the form of anti-isomer, but not in the form of the desired SYN-isomer, the applicant has replaced the product known methods, for example, obtained in Example 14, the SYN-isomer of compounds of formula III in acylation reactions shown in the Reaction Scheme 2 and Example 4. Received cephalosporin product, which was manufactured according to the invention. As you can see from the comparison in Example 19, the anti-cefepime obtained by known methods, is different from the suitable shirokorelsovogo sin-cefepime received in accordance with the present invention.

Defined in the description and in the claims, the term "essentially free" means that the compound contains less than about 5% of the undesired isomer. Preferably, if the compound contains less than about 1% is undesirable isomer.

In accordance with the method of the present invention dihydrochloride hydrate shirokorelsovogo antibiotic cefepime, which is essentially free of the anti-isomer and2isomer, receive N-acylation of compounds of formula IV with SYN-isomer hydrochloride of formula III, as shown in Reaction Scheme 2.

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7-Amino-3-/(1-methyl-1-pyrrolidino)methyl/ceph-3-em-4-carboxylate salt, which is essentially free from2isomer and is represented by formula IV, where NC denotes Hcl, HI or H2SO4can be obtained by the General methods described by C. P. Brundidge and others in the U.S. patent N 4868294.

The intermediate connection of a cephalosporin of the formula IV, where HX preferably denotes HI, may be Siciliano in ineresting formula VI, where R and R1each independently represents H or a silyl group, or their mixture. In one studyIH NMR determined that R1mainly cililitan, and R denotes mainly hydrogen. The specialist must understand that due to the constant changes in the balance of different species in solution is difficult to identify a specific compound of formula VI obtained in situ in the reaction mixture at any particular time. However, it is important to add enough cilleruelo reagent and, if necessary, the base in order to solubilisate intermediate connection of a cephalosporin of the formula IV before anhydrous solution was treated with compound of formula III. Similitude reagents that may be used are well known to experts in the art and include, for example, trimethylchlorosilane, trimethylethylene, hexamethyldisilazane tert-butyldimethylchlorosilane, trimethylsilylacetamide, bis-(trimethylsilyl)urea and the like. Preferably, in the process of acylation can be used trimethylchlorosilane or a mixture of trimethylchlorosilane and hexamethyldisilazane.

Although the interaction requires at least one molar eno, beneficial use about two molar equivalents cilleruelo reagent and about two molar equivalents, or less than, the base, in order to obtain a solution of intermediate compounds of formula VI. However, when similitudine reagent is a mixture of trimethylchlorosilane and hexamethyldisilazane, it is preferable not to add a basis for obtaining a soluble derivative of formula VI. As will be appreciated by person skilled in the art, hexamethyldisilazane as cilleruelo reagent produces a by-product basis, which is sufficient to neutralize a certain amount of acid produced. Because an excessive amount of Foundation has a negative impact on the production of the desired antibiotic, essentially free from2isomer, a mixture of trimethylchlorosilane and hexamethyldisilazane most preferred in accordance with the present invention. The number of3-2isomerization in the nucleus of cephalosporin is sensitive to the used reaction conditions for obtaining soluble similarvideo derivative of formula VI and its N-acylation with acid chloride hydrochloride of the formula III, which leads to poluchennaya, the solvent and temperature used in this way. Most importantly, the basic conditions that result from the use of excess base or as a result of addition of the base before adding cilleruelo reagent or the hydrochloride of the acid chloride of the formula III, increase the isomerization of the double bond cafema from3to2. Therefore, it is most preferable to maintain a minority of the reaction conditions during the process of anhydrous acylation.

Suitable bases that can be used in the proposed method, are inorganic and organic bases which are suitable acid acceptors, such as NaHCO3, KHCO3, Na2CO3, K2CO3, ammonia, primary amine, secondary amine, tertiary amine, and so forth. It is most preferable to use such organic bases, such as 1,8-diazabicyclo-/5.4.0/undec-7-ene, N-methylmorpholine, 2,6-lutidine, 2-methyl-6-ethylpyridine, N,N-dimethylaniline, N,N-diethylaniline, triethylamine, diisopropylethylamine and so on. Preferably, and if necessary, in the reactions of sililirovanie and N-acylation can be used N-methylmorpholine or triethylamine, or their mixture. Most preferably LASS="ptx2">

Soluble Siciliano derivative of formula VI, which is obtained in situ, is then treated with acid chloride-hydrochloride of formula III and, preferably, with one molar equivalent, and most preferably with a slight excess of the acid chloride hydrochloride of formula III, followed by addition of an equimolar amount and preferably less than equimolar amount, relative to the base amount of the compounds of formula III, obtaining a mixture containing the desired antibiotic. Preferably, if the amount of the hydrochloride of the acid chloride of the formula III and the base is added slowly in portions. Although the addition of reagents can be carried out immediately in one step, if the temperature and non-core reaction conditions can be controlled favorably to add the reagents in two or three portions in order to ensure full interaction of the reactants.

Suitable solvents that can be used in the proposed method, are inert organic solvents, in which Siciliano derivative of formula VI is soluble and in which the double bond isomerization3minimized, for example, toluene, tetrahydrofuran, acetone, acetonitrile, dig the m method, acetonitrile or dichloromethane. The method of the present invention can be performed at a temperature in the range from -60 to +50aboutWith, preferably about -40aboutWith the room temperature. Getting similarvideo the compounds of formula VI are predominantly carried out at a temperature in the range from approximately -10aboutWith up to room temperature, whereas the N-acylation mainly carried out at a temperature from -40 to 0aboutRoughly.

When N-acylation soluble similarvideo the compounds of formula VI is complete, as evidenced by well-known methods for determining, for example, thin-layer chromatography, liquid chromatography, high pressure and spectroscopic methods, then, in accordance with a preferred variant of the method of the present invention, the reaction mixture was added water in an amount sufficient to dissolve the reaction mixture, if desired, visible solid particles and obtain a two-phase solution of the organic phase and water. The amount to be added to the reaction mixture water is determined on the basis of the choice and amount of the inert organic solvent used in the method, and it should be sufficient to provide, or in order to ensure obtaining the water-rich solution, containing the desired antibiotic. Water rich solution is then treated with a sufficient amount of acid or its soluble non-toxic salts, as for example, hydrochloric acid, sodium chloride, ammonium chloride, potassium chloride, sulfuric acid, sodium sulfate, potassium sulfate, ammonium sulfate, phosphoric acid, sodium phosphate, potassium phosphate, ammonium phosphate, nitric acid, sodium nitrate, potassium nitrate, and so forth, with the receipt of a sufficient number of protovoulia in order to ensure crystallization of the desired of cefepime in the form of a salt, optionally diluted with an appropriate mixed with water with an organic solvent such as methyl ethyl ketone, acetone, isopropanol, butanol, and so forth, in order to induce or to complete the crystallization. Preferably, the water-rich solution is treated with a sufficient amount of sulfuric acid to crystallize salt of sulfuric acid (sulfate) of cefepime, which is essentially free of the anti-isomer and2isomer. Sulphate of cefepime you can then turn into a preferred dihydrochloride monohydrate crystalline cefepime method described by Kaplan and others in the U.S. patent N 4910301. The cefepime sulfate obtained in Kootenai resin, known in this area and, preferably, commercially available, as for example, Amberlite IA-2, Dowex WGR Bio-Rad AG3-X4A, Amberlite IRA 93, Amberlite IRA 35 and so on, to obtain an aqueous or aqueous-organic solution containing zwitterion form of cefepime. The solution is then treated with a sufficient quantity of hydrochloric acid and, optionally mixed with water, an organic solvent, in order to induce crystallization preferably crystalline dihydrochloride of cefepime. Most preferably, if the water-rich solution, the resulting anhydrous acylation in accordance with this method, treated with a sufficient quantity of hydrochloric acid, in order to induce and to ensure crystallization of the specified antibiotic, dihydrochloride hydrate of cefepime, when added miscible with water, an organic solvent, such as acetone. The number miscible with water organiza - ical solvent should be sufficient to obtain complete crystallization of the specified antibiotic and, mainly, in an amount of about 2 to 9 volumes of the aqueous phase in order to obtain a temperature-stable monohydrate or dihydrate crystalline digiteo only get dihydrochloride-monohydrate of cefepime, rich aqueous solution in the anhydrous acylation predominantly treated with a sufficient quantity of hydrochloric acid and diluted with a suitable quantity miscible with water, an organic solvent, as described in this paper, in order to guarantee the desired crystallization monohydrate form. Alternatively, when it is necessary to obtain a stable dihydrochloride-dihydrate of cefepime, rich aqueous solution mainly handle higher equivalent concentration of hydrochloric acid and the amount of mixing water with an organic solvent in order to keep the crystallization point of turbidity before addition of the organic solvent (additional number) to complete the crystallization. However, it should be understood that if the stage of selection of water-rich solution method is not carefully controlled, it is possible that you may receive a mixture of crystalline dihydrochloride-monohydrate and dihydrate of cefepime. In any case, the preparation of only one of the desired hydrate can be done from any hydrate or a mixture of hydrates followed by the technique of recrystallization, episoade invention, can be used to obtain a stable crystalline dihydrochloride-dihydrate of cefepime at regulated concentrations of solvent and hydrochloric acid, and the period of time the cloud point (primary crystallization), as described below. Alternatively, the crystalline dihydrochloride-dihydrate obtained by the proposed method can also be used to get a stable crystalline dihydrochloride-monohydrate of cefepime by recrystallization with excellent controlled conditions, as described below. Thus the method of the present invention can be applied to obtain either monohydrate or dihydrate specified antibiotic.

In contrast to the labile dihydrochloride-dihydrate of cefepime described in U.S. patent N 4910301, which easily loses the second mole of water received in accordance with the invention the crystalline dihydrochloride-dihydrate of cefepime, as found, has a well-defined crystalline structure, which stores a second mole of water. Found that the new crystalline digitately form (needle crystals) are remarkably stable, and the morphology of its crystals is not izmenjevalne with P2O5at a temperature of 50aboutC for 48 h in an oven-dried at a temperature of 70aboutC for 96 h, and in conditions of high and low relative humidity. Crystalline dihydrate has the characteristic absorption peaks in the infrared region of the spectrum when 3574 cm-1and 3432 cm-1as noted in the diffuse reflection infrared spectroscopy with Fourier transform using CVG and 13 mm in the testing Cup and using a spectrometer Nicolet 20SX. This temperature - and moisture-resistant crystal digitata form of cefepime is also characterized by a powder x-ray table.1.

In table.1 "d" refers to the interplanar spacing and I/Io" refers to the relative intensity in percent. Powder x-rays were collected using x-ray diffractometer Rigaku Geigerflex and wavelength Nickel-filtered copper (SC), equal 1,5425 .

Thus, a variant of the present invention provides a method of producing antibiotic, cefepime-dihydrochloride hydrate which is essentially free of the anti-isomer and2isomer, including interaction similarvideo derivative of 7-amino-3-/(1-methyl-1-pyrrolidyl essentially free of anti-isomer, in an inert organic solvent.

A preferred variant of the present invention additionally provides for the SYN-isomer hydrochloride 2(2-amino-thiazol-4-yl)-2-methoxyaminomethyl - chloride solution, essentially free of anti-isomer, by reacting anhydrous hydrochloric acid salt of SYN isomer of 2-(2-aminothiazol-4-yl)-2-methoxyethoxy acid with a mixture containing at least one molar equivalent of oxalicacid and at least one molar equivalent (up to a slight excess) of dimethylformamide (relative to the specified oxalylamino), in an inert organic solvent at a temperature of less than -10aboutC.

Another preferred variant of the present invention provides for similarvideo derived by reacting 7-amino-3-/(1-methyl-1-pyrrolidino)methyl/ceph-3-em-4-carbox - altnoy salt in an inert organic solvent with silylium reagent.

A more preferred variant of the present invention provides a method of producing antibiotic, cefepime-dihydrochloride hydrate which is essentially free of the anti-isomer and2isomer, including interaction silylium national-4-yl)-2-methoxyaminomethyl - chloride in an inert organic solvent, followed by addition of a sufficient amount of water in the reaction mixture to obtain organic water two-phase solution, and with the subsequent addition of sufficient acid or its soluble non-toxic salts and, optionally mixed with water, organic solvent separated aqueous solution.

The most preferred variant of the present invention provides a method of producing antibiotic, cefepime-dihydrochloride-monohydrate and cefepime-dihydrochloride-dihydrate, directly from the rich aqueous solution of the proposed method anhydrous acylation.

The suitability of cefepime (compound V) is shown in Abenaki and other U.S. patent N 4406899. Sustainable digitata form of cefepime produced using the present method, showing the antibiotic properties of the above cefepime for U.S. patent N 4406899 and finds use as an antibiotic in the same way.

It should be understood that the description and examples are merely illustrative and should not be construed as limiting the scope of invention.

P R I m e R 1. Hydrochloric salt of SYN-2-(2-aminothiazol-4-yl)-2-methoxime-noxubee acid. Suspension (25 g, 124,25 mmol) of 2-(2-aminothiazol-4-yl)-2-methoxyethoxy acid in toluene (250 ml) saturated with HCl gas at temperatures which do aliquot additions. After 1 h at a temperature of 20aboutThe product is collected by filtration in a nitrogen atmosphere, washed with toluene (50 ml) and hexane (250 ml) and dried at a temperature of 20-25aboutWith the vacuum obtaining 28,68 g (97%) specified in the connection header.

P R I m m e R 2. Hydrochloride SYN-2-(2-aminothiazol-4-yl)-2-methoxyaminomethyl-reed. To a solution of 0.77 ml, 10 mmol) of dimethylformamide in dichloromethane (40 ml) at a temperature of 5aboutWith add (0,89 ml, 10 mmol) 98% oxalicacid in dichloromethane (4,1 ml). Pocatello addition maintains the temperature at the level of 4-5aboutC. To the resulting suspension cooled to a temperature of -27aboutC, add (2.37 g,10 mmol) of the hydrochloride of 2-(2-aminothiazol-4-yl)-2-methoxyethoxy acid obtained in Example 1. The suspension is stirred for 2.5 hours at a temperature of -25aboutC. Filtration in a nitrogen atmosphere and rinsing with dichloromethane (50 ml) and hexane (100 ml) allow to obtain 1.78 g (69.5 per cent ) specified in the header of the crystalline substance of white color after drying at a temperature of 20aboutWith the vacuum. Specified in the procurement acid chloride Allium hydrochloride complex diphenylmethylene ether 7 aminoacetate-zefalosporinovy acid in a solution of pyridine to obtain a product with one of the omogo complex ester deacetoxy-cephalosporin.

P R I m e R 3. Hydrochloride SYN-2-(2-aminothiazol-4-yl)-2-methoxyimino-acetylcho - reed. To a solution of 1.55 ml, 20 mmol) of dimethylformamide in dichloromethane (80 ml) at a temperature of 5aboutWith add (1,78 ml, 20 mmol) oxalicacid with purity of 98% in dichloromethane (8.2 ml). The time of addition is 5 minutes at a temperature of 5-8aboutC. the resulting suspension is stirred for 10 minutes at a temperature of 5aboutC and then cooled to a temperature of -30aboutC. was Added the hydrochloride of 2-(2-aminothiazol-4-yl)-2-methoxyethoxy acid from Example 1. The suspension is stirred for 2.5 hours at a temperature of from -25 to 30aboutC. Filtration in a nitrogen atmosphere and rinsing with dichloromethane (75 ml) and hexane (100 ml) allow to obtain 3.57 g (69.7 per cent) specified in the header of the crystalline compound after drying at a temperature of 20aboutWith the vacuum.

An aliquot of the solid hydrochloride of chlorhydric Allium hydrochloride complex diphenylmethylene ether 7 aminoacetate - zefalosporinovy acid in a solution of pyridine with obtaining mainly product from one area (thin layer chromatography): consistent with the authentic way (and not separated from it) of the desired ether complex deacetoxycephalosporanic.

P of roxelana (cefepime).

< / BR>
Monohydride 7-amino-3-/(1-methyl-1-pyrrolidino)methyl/-ceph-3-em-4-Carbo - xylota of 0.85 g, 2.0 mmol)/ received in accordance with the method described by C. P. Brundidge and others in the U.S. patent N 4714760/ dissolved in 9 ml of a mixture of acetone-water (2:1) with triethylamine at pH 6.5 and a temperature of 20aboutC. the Hydrochloride of SYN-2-(2-aminothiazol-4-yl)-2-methoxykynuramine (0.56 g; 2.2 mmol) /obtained in Example 3/ added by using triethylamine to pH control in the range of 5-7. The analysis of the obtained solution using liquid chromatography high pressure shows a 58% yield of the desired cephalosporin (cefepime). Acidification with sulfuric acid to a pH of 2.2 allows you to get 0,63 g is specified in the header of the antibiotic in the form of its salt with sulfuric acid (51% yield activity), as described Abenaki and others in the U.S. patent N 4406899, issued September 27, 1983, and Kaplan and others in the U.S. patent N 4910301, issued March 20, 1990.

P R I m e R 5. Hydrochloride SYN-2-(2-aminothiazol-4-yl) -2-methoxykynuramine. To a solution of (9.75 ml, 125,9 mmol) of dimethylformamide in dichloromethane (450 ml) at a temperature of 5aboutWith added dropwise a solution of (11,21 ml, 125,9 mmol) oxalicacid (98%) in dichloromethane (15 ml). Plus complete after 10 min at a temperature of 5-7aboutC. the Yu salt of SYN-2-(2-aminothiazol-4-yl)-2-methoxyethoxy acid in one aliquot. The suspension is stirred for 3.5 hours at a temperature of from -25 to -30aboutWith that filtered in a nitrogen atmosphere, washed with dichloromethane (100 ml) and hexane (400 ml) and dried at a temperature of 20-25aboutWith the vacuum. The output is specified in the header of the crystalline compound is 30.7 g (72,5%).

Specified in the header of the acid chloride Allium hydrochloride complex diphenylmethylene ether 7 aminoacetate-zefalosporinovy acid in a solution of pyridine to obtain essentially the same zone (thin layer chromatography) of the desired ether complex deacetoxycephalosporanic with reference to an authentic sample.

Specified in the header of the acid chloride (200 mg, 0.8 mmol) hydrolyzing in water.IH NMR of the selected product identical to the original Shin-acid.

P R I m e R 6. Hydrochloride SYN-2-(2-aminothiazol-4-yl)-methoxyimino-acetylcho - IDA. To a solution of (8,13 ml, 105 mmol) of dimethylformamide in dichloromethane (350 ml) at a temperature of 5aboutWith added dropwise (9,34 ml, 105 mmol) oxalicacid (purity 98%) in dichloromethane (5 ml). Maximum temperatures during the addition the 7aboutC. the resulting suspension is stirred for 10 minutes at a temperature of 5aboutC and then cooled to -27aboutC. the Hydrochloride what're asked for 2.5 hours at a temperature of from -25 to -30aboutWith that filtered in a nitrogen atmosphere, washed with dichloromethane (25 ml) and hexane (125 ml) and dried at a temperature of 20aboutWith the vacuum. The output is 21,39 g (83.5 per cent) of the crystalline hydrochloride of the acid chloride.

Analytically calculated for C6H7N3O2SCl2:

WITH 28,14, N WAS 2.76, N 16,41, S TO 12.52,

Found: 28,25, N 2,93, N 16,32, S 12,67.

IH NMR (DMSO-d6) : 3,93 (CH3),? 7.04 baby mortality (H5).

P R I m e R 7. Hydrochloric salt of SYN-2-(2-aminothiazol-4-yl)-2-methoxime-noxubee acid. Suspension (87,0 g, 432,4 mmol) of SYN-2-(2-aminothiazol-4-yl)-2-methoxyethoxy acid in toluene (870 ml) at a temperature of 22aboutWith saturates gas using two aliquot of HCl: 17,5 g, 480 mmol for 30 min and 15.0 g, 410 mmol for 20 min at 20-minute periods of mixing between the aliquot. The suspension is stirred for 1.5 hours at a temperature of 25aboutWith that filtered in a nitrogen atmosphere, washed with toluene (100 ml) and hexane (400 ml) and dried at a temperature of 20-25aboutWith the vacuum. The output specified in the procurement of the connection is of 100.2 g (97,5%).

Analytically calculated for C6H8N3O3SCl:

With 30,32, N 3,39, N 17,68, S 13,49, Cl 14,92.

Found: 30,51, N 3,39, Comprised 17.54 N, S 13,37, Cl Of 14.90.

teleformula in dichloromethane (400 ml) at a temperature of 5aboutWith add (or 37.4 ml, 419,7 mmol) dropwise 98% oxalicacid. The resulting suspension is cooled to a temperature of -25aboutWith and added to the suspension (-25aboutC) (95 g, 399,7 mmol) of the hydrochloride of SYN-2-(2-aminothiazol-4-yl)-2-methoxyimino-susei acid from Example 7. The suspension is stirred for 2.5 hours at a temperature of from -25 to -28aboutWith that filtered in a nitrogen atmosphere, washed with dichloromethane (100 ml) and hexane (500 ml) and dried at a temperature of 20-25aboutWith the vacuum. The output is specified in the header of the crystalline compound is 84.3 g (82.3 per cent).

Analytically calculated for C6H7N3O2SCl2:

C 28,14, H WAS 2.76, N 16,41, S TO 12.52,

Found: 27,90, N 3,10, N 16,14, S 12,27.

IH NMR (DMSO-d6) : 3,95 (CH3),? 7.04 baby mortality (N5).

P R I m e R 9. Getting 7-/2-(2-aminothiazol-4-yl)-2-(Z)-methoxykynuramine/ -3-/(1-methyl-1-pyrrolidino)methyl/ceph-3-em-4-carboxylate (cefepime). To a solution of 240 ml of acetone and 80 ml of water was added to 20.0 g of hydroiodide 7-amino-3-/(1-methyl-1-pyrrolidino)methyl/-ceph-3-em-4-carboxylate (0,047 mol) and stirred for curing. Using autotitrator Radiometer ABU80 endpoint is installed on a pH of 6.5, and filled with N-methylmorpholine, hydrochloride SYN-2-(2 - aminothiazol-4-yl)-2-metaxia pH level of 6.5. After adding the thick suspension is stirred for 20 min at room temperature. the pH of the reaction mixture to reduce the pH to 2.65 with 21 ml of a 6 n solution of H2SO4. Is deposited specified in the connection header. The suspension is sieved and stirred at room temperature for 20 minutes. the pH of the suspension was adjusted to 1.8 with 16 ml of a 6 n solution of H2SO4and stirring is continued for another 60 minutes. The suspension is filtered under vacuum and washed with 70 ml of a mixture of water-acetone (1:1), and then 70 ml of acetone, getting 24,09 g (88.5% of the stoichiometric mass) specified in the title compound, which was identical to the compound of Example 4 and cefepime, described Abenaki and others in the U.S. patent N 4406899, issued September 27, 1983, and Kaplan and others in the U.S. patent N 4910301, issued March 20, 1990.

P R I m e R 10. Obtaining hydrochloride SYN-2-(2-aminothiazol-4-yl)-2-methoxime-nacetylmuramic. To a solution of dimethylformamide (8,76 ml, 0,113 mol) in dichloromethane (375 ml) at a temperature of 5aboutWith added oxalicacid (for 9.64 ml, 0,111 mol) dropwise, maintaining the temperature at 5-6aboutC. the Suspension is stirred for 10 min and then cooled to a temperature of -25aboutC. Then add hydrochloric salt of nitrogen. The suspension is stirred for 2.5 hours at a temperature of -25aboutC. the Product is filtered in a dry nitrogen atmosphere and washed filter cake with dichloromethane (80 ml). The product is dried at a temperature of 20-25aboutWith vacuum in the presence of P2O5obtaining 23,88 g (88.6 per cent) indicated in the title compounds as pale yellow crystalline solid.

Analytically calculated for C6H7N3O2SCl2:

C 28,14, H was 2.76, N 16,41, to 12.52 S, Cl 27,68

Found: C 28,06, H 2,71, N 16,26, S 12,30, Cl 27,23.

The product of the previous experiment is characterized by a spectrum of proton nuclear magnetic resonance in acetic acid d4(IH NMR, shown in Fig.1.

IH NMR (CD4CO2D) : 4,14 (CH3), 7,10 (H5). The level of residual hydrochloride acid of CH3(4,11) is 5.1% Insignificant level isomeric H5 visible when to 7.67 ppm.

P R I m e R 11. Hydrochloride SYN-2-(2-aminothiazol-4-yl)-2-methoxyimino-acetylcho - reed. To a solution of dimethylformamide (17,92 ml, 231,9 mmol) in dichloromethane (375 ml) at a temperature of 5aboutWith added oxalicacid (19,76 ml, 220,8 mmol). The time of addition is 15 minutes at a temperature of 5-6aboutC. the resulting suspension permesigita 2-(2-aminothiazol-4-yl)-2-methoxyethoxy acid (25,0 g, of 105.2 mmol). The resulting solution tatrallyay specified in the header connection with obtaining a product suspensie. The suspension is stirred for 3.5 hours at a temperature of -25aboutWith that filtered in a dry nitrogen atmosphere, washed with dichloromethane (150 ml) and dried at a temperature of 20-25aboutWith the vacuum. The output is specified in the header of the crystalline compound is being 9.61 g (35,7%).

An aliquot of the solid product of the hydrochloride of the acid chloride Allium hydrochloride complex diphenylmethylene ester of 7-amino-deacetoxycephalosporanic acid in a solution of pyridine with the product, essentially with a single zone (thin layer chromatography), which is consistent with an authentic sample (and not separated from it) of the desired ether complex deacetoxycephalosporanic.

P R I m e R 12. Obtaining hydrochloride 2-(2-aminothiazol-4-yl)-2-methoxyimino - acetylchloride. Experimental part example 1 in the patent Czechoslovakia N 238950 repeat as follows:

A sample of SYN-2-(2-aminothiazol-4-yl)-2-methoxyethoxy acid (4.0 g), with a coefficient of McKinney 0,06% are suspended in 30 ml of benzene at a temperature of 21aboutC. Add one drop of dimethylformamide, followed by addition of 5 g of the powder is increased to 40aboutWith one minute, resulting in a complete solution. The solution is cooled, and the temperature 36aboutWith a precipitate. After stirring for 30 min the temperature is 22aboutC. Solid light yellow color is collected by filtration in a dry nitrogen atmosphere and washed with 30 ml of benzene and 20 ml of heptane. The product yield is 2,88 g after drying under vacuum in the presence of P2O5at a temperature of 20-25aboutWith over 18 PM

The product of the above experiment is characterized by a spectrum of proton nuclear magnetic resonance in acetic acid do4(IH NMR), as shown in Fig.2, where N5 is the value when 7,56 ppm and CH3when 4,34 ppm. This range is consistent with the product specified in the title compound, having the configuration of the anti-isomer and not SYN-isomer, as disclosed in the opposed patent Czechoslovakia.

P R I m e p 13. Obtaining hydrochloride 2-(2-aminothiazol-4-yl)-2-methoxyimino-AC - ethylchloride. Experimental part Example 2 in patent Czechoslovakia N 238950 repeat as follows:

A sample of SYN-2-(2-aminothiazol-4-yl)-2-methoxyethoxy acid (4.0 g), with a coefficient of McKinney 0,06% are suspended in 20 ml azet the screens 20aboutC. After addition of 6.0 g of powdered petaluridae phosphorus the temperature was raised to 40aboutWith and get a complete solution. The solution is cooled to a temperature of 20aboutC, and the precipitate formed when the temperature of the 33aboutC. After stirring for 30 min the product is collected in a dry nitrogen atmosphere and washed with 30 ml of benzene and 20 ml of heptane. The output is 1.86 g after drying for 18 hours at a temperature of 20-25aboutWith vacuum in the presence of P2O5.

The product of the above experiment is characterized by a spectrum of proton nuclear magnetic resonance in acetic acid d4(IH NMR), as shown in Fig.3, where N5 is the value when 7,56 ppm and CH3when or 4.31 ppm.IH NMR spectrum is consistent with the product specified in the title compound, having the configuration of the anti-isomer and not SYN-isomer, as disclosed in the opposed patent Czechoslovakia.

P R I m e R 14. Obtaining hydrochloride 2-(2-aminothiazol-4-yl)-2-methoxyimino - acetylchloride. Experimental Example 3 of the patent Czechoslovakia N 238950 repeat as follows:

Concentrated hydrochloric acid (0.16 ml) was added to 30 ml of dichloromethane. After cooling, atory 0aboutWith added in one aliquot 4.0 g of SYN-2-(2-aminothiazol-4-yl)-2-methoxyethoxy acid, with a coefficient of McKinney 0,06% Temperature increase to 2aboutC. Complete solution get in 9 minutes at a temperature of 0aboutC. After 40 min, the precipitate begins to form. The product suspension is stirred for 2.8 h at a temperature of 2-3aboutWith filtered in a dry nitrogen atmosphere, washed with 30 ml of benzene and 20 ml of heptane and dried in a vacuum at a temperature of 20-25aboutIn the presence of P2O5within 18 hours, the Output is of 3.42 g of powder of light yellow color.

The product of the above experiment is characterized by a spectrum of proton nuclear magnetic resonance in acetic acid d4(IH NMR), as shown in Fig.4, where N4 is manifested when 7,56 ppm and CH3when or 4.31 ppm.IH NMR spectrum is consistent with the product specified in the title compound, having the configuration of the anti-isomer and not SYN-isomer, as disclosed in the opposed patent Czechoslovakia.

P R I m e R 15. Taken receipt of the hydrochloride of 2-(2-aminothiazol-4-yl)-2-methoxykynuramine.

The General technique described in Example 7 of U.S. patent N 4203899 to convert protected aminodiol acid as follows:

A sample of hydrochloric salt of SYN-2-(2-aminothiazol-4-yl)-2-methoxyimino Noi acid (2.38 g, 0.01 mol) are suspended in 30,5 ml of benzene and cooled to a temperature of 20aboutC. Add oxalicacid (2,09 ml, 0,024 mol) followed by addition of dimethylformamide (0,50 ml, 0,0065 mol). The temperature increases to 22aboutWith vigorous evolution of gas. Within 20 minutes at a temperature of 20aboutC is oblagorazhivanie gas, and the suspension is stirred at a temperature of 20 2aboutC for 2 h, the Suspension was concentrated in vacuo to remove the solvent, and the resulting yellow product is dried under vacuum in the presence of P2O5at a temperature of 20-25aboutC for 16 h Output is 2.59,

The product resulting from the above experiment is characterized by a spectrum of proton nuclear magnetic resonance (IH NMR) in acetic acid (d4that shows H5 when 7,60 ppm and CH3at 4.37 ppm. Product spectrum is consistent with that stated in the title compound, having the configuration of antihisamine.

P R I m e R 16. Taken receipt of the hydrochloride of 2-(2-aminothiazol-4-yl)2-methoxykynuramine.

The General procedure described in Example 59 patent € against unprotected aminocaproate acid as follows:

A sample of hydrochloric salt of SYN 2-(2-aminothiazol-4-yl)-2-methoxyimino Noi acid (2.38 g, 0.01 mol) are suspended in 25 ml of dichloromethane. After cooling to a temperature of 4aboutWith a gain of 2.08 g (0.01 mol) petaluridae phosphorus. While cooling on ice, the temperature was raised to 6aboutC, and after cooling to 4aboutWith the suspension stirred for 1 h the Precipitate is collected by filtration in a dry nitrogen atmosphere, washed with dichloromethane (10 ml) and dried in vacuum at a temperature of 20-25aboutWith obtain 1.4 g of pale yellow solid.

The product of the above experiment is characterized by a spectrum of proton nuclear magnetic resonance (IH NMR) in acetic acid (d4that shows H5 when to 7.61 ppm and CH3when 4,34 ppm. Product spectrum is consistent with that stated in the title compound, having the anti-isomer configuration. In addition, the product is contaminated with non-convertible acid (IH NMR with H5 when 7,07 ppm and CH3when 4,06 ppm), which further confirmed by the surge of the original acid.

P R I m e R 17. The acylation of salt N1 7-amino-3-/(1-methyl-1-pyrrolidino)-meth - yl/-ceph-3-em-4-carboxylate using the hydrochloride of 2-(2-AMI thiazol-4-yl)-2-methoxyimino is at a temperature of 10aboutWith add N1 salt of 7-amino-3-/(1-methyl-1-pyrrolidino)methyl/ceph-3-em-4-carboxylate (1.13 g, of 2.66 mmol). Hydrochloride of 2-(2-aminothiazol-4-yl)-2-methoxykynuramine-Yes (1,09 g is 4.21 mmol) /obtained in Example 14/ added in 5 portions at a temperature of 0aboutWith together with triethylamine (0,37 ml of 2.66 mmol), in order to maintain a pH level of 6.0-7.0mm. The reaction mixture was stirred at ambient temperature for 15 minutes. The analysis of the obtained solution liquid chromatography high-pressure gradient column WITH a18from 2 to 25% acetonitrile in a 0.005 M solution of NH4H2PO4shows 72,4% of the area of anti-cefepime on 13,08 min and the complete absence of sin-cefepime, which, as expected, has a retention time of about 8.5 minutes Acidification with sulfuric acid to pH of 1.9 leads to obtain 1.48 g of anticipate in the form of a salt of sulfuric acid (sulfate). The product identification is confirmedIH NMR spectroscopy (DMSO-d6), and shown that it contains of 0.58 mol of the salt of triethylamine.

P R I m e R 18. The acylation N1 salt of 7-amino-3-/(1-methyl-1-pyrrolidino)-meth - Il/ceph-3-em-4-carboxylate using the hydrochloride of 2-(2-aminothiazol-4-yl)-2-methoxykynuramine (antisolar from Example 14). To pre-cooled rmetal/ceph-3-em-4-carboxylate (13.5 g, 0,0317 mol). the pH of the suspension was adjusted to 7.0 using 2,7 ml of a 14% solution of NH4OH. At a temperature of 10aboutWith portions within 60 minutes add the hydrochloride of 2-(2-aminothiazol-4-yl)-2-methoxyimino - tallarida (13.5 g, 0,015 mol) /obtained by the method of Example 14/ using a 14% solution of NH4OH (27 ml) to maintain the pH at 6.3-7,0 during the first half of the time, addition and pH of 6.1 and 6.6 during the second half. The reaction mixture was stirred at ambient temperature for 30 minutes, the Reaction mixture was filtered to final cleaning and washed with 6 ml of 2:1 acetone-water, after which the filtrate is slowly added 6 n solution of H2SO4(15 ml) to adjust pH to the level of 1.87-1,90. After stirring for one hour, the insoluble matter is filtered and the cake washed with 21 ml of 2:1 acetone/water, and then 30 ml of acetone. To the filtrate add 1 liter of acetone for 30 min and the mixture is stirred at a temperature of 5-8aboutWith over 40 minutes, the Product is collected by filtration, washed twice 24 ml of 4:1 acetone/water, 60 ml of acetone and dried in vacuum to obtain 20,64 g (116% of the stoichiometric mass) anti-cefepime in the form of a salt of sulfuric acid (95.4 percent purity in liquid chromatography high pressure CLASS="ptx2">

P R I m e R 19. Comparison of the product of Example 9 (SYN-isomer of cefepime) and the product of Example 17 (anti-isomer of cefepime) shows the following differences in physical characteristics. Liquid chromatography high pressure isomers of cefepime carried out on a column of Water M Bondapack C18(3,h ml) using a solvent system 1000 ml of water containing 2,88 g (0,013 mol) of sodium salt of heptanesulfonate, and the pH was adjusted to 4.0 with acetic acid and 100 ml of acetonitrile with the spreading rate of the solvent front, equal to 2.0 ml/min Products observed visually using a detector with variable wavelength Water Model 450 installed at 254, to obtain the following results.

Retention time, min

The SYN-isomer of cefepime (example 9) 10,5

Anti-isomer of cefepime (example 17) of 37.8

Spectra proton NMR SYN - and anti-metoxi-isomers of cefepime in the form dogloesvgoderbd salts define spectrometer Bruker AMX-400 F T nuclear magnetic resonance using deuterated dimethyl sulfoxide as a solvent. Described chemical shifts are referred to in relation to DMSO at 2,49 ppm. The notation below in the formula and the table is given for convenience only.

A table comparing the chemical shifts of the proton NMR (ppm)

Job SYN-cefepime Anti-cefepime

C2-H2 4.04, 3.65 4.02, 3.65

C6-H 5.33 5.31

C7-H 5.88 5.85

C11-N2 4.60, 4.31 4.59, 4.30

C12 H4 2.93 2.93

C13-H4 3.7, 3.4 and 3.6, 3.3

C14-H4 2.10 2.10

C18-H4 to 6.88 7.57

C20-H3 3.92 4.05

NH 9.83 9.56

NH2 8.60 8.70

SpectraIH NMR two metoxi-isomers of cefepime, as shown above, differ significantly from each other. Diatlovo ring CH(18) SYN-(Z) metoxi-isomer when to 6.88 ppm reduced by the height field of anti-(E) metoxi-isomer of CH(18) in EUR 7.57.

P R I m e R 20. Anhydrous acylation N1 salt of 7-amino-3-/(1-methyl-1-pyrrolidino)methyl/ceph-3-em-carboxylate using the hydrochloride of 2-(2-aminothiazol - 4-yl)-2-methoxykynuramine (SYN-isomer). In the atmosphere of nitrogen N1 salt of 7-amino-3-/(1-methyl-1-pyrrolidino)-methyl/ceph-3-em-4-carboxylate (50 g, 0,1176 mol) is cooled to a temperature of -20aboutWith 500 ml of acetonitrile. Add trimethylchlorosilane (39 ml, 2.5 equivalents) and triethylamine (38 ml, 2.3 equivalents), keeping the temperature below -10aboutC. After stirring silloway mixture for 1.5 hours at a temperature of -10aboutWith the hydrochloride of 2-(2-aminothiazol-4-yl)-2-methoxyaminomethyl - chloride (SYN-isomer obtained in Example 5) is (0.25 equivalent) of the hydrochloride of 2-(2-aminothiazol-4-yl)-2-methoxyimino-acetylchloride - Yes (SYN-isomer). The suspension is stirred at a temperature of -10aboutC for 15 min, then add 150 ml of water and stirring is continued at ambient temperature to dissolve all solids. The acetonitrile layer is separated from the rich aqueous layer, which was added 6 n Hcl solution (2.5 equivalent) with 400 ml of acetone. The solution tatrallyay and crystallized within 15 minutes. To complete the crystallization add another 1000 ml of acetone. The suspension is stirred for one hour and then filtered, washed with 400 ml of acetone and dried at a temperature of approximately 40aboutC. the product Yield is 56,51 g (84,1% stoichiometric mass) cefepime (98,6% purity, as determined by the analysis of liquid chromatography high pressure in the form of cefepime 2hcl H2O), which is identical to cefepime. 2hcl H2O described by Kaplan and others in the U.S. patent N 4910301, issued March 20, 1990.

P R I m e R 21. Anhydrous acylation N1 salt of 7-amino-3-/(1-methyl-1-pyrrolidino)methyl/ceph-3-em-4-carboxylate using the hydrochloride of 2-(2-aminothiazol - 4-yl)-2-methoxyimino-acetylchloride (SYN-isomer). In the atmosphere of nitrogen N1 salt of 7-amino-3-/(1-methyl-1-pyrrolidino)methyl/ceph-3-em-4-carboxylate (5.0 g, 0,01176 mol) is cooled to a temperature of 0-5aboutFrom in maintaining the temperature of the 5aboutC. Silloway the mixture is stirred for 1.5 hours at a temperature of 0-5aboutC. 2-(2-Aminothiazol-4-yl)-2-methoxyimino-acetylchloride-hydrochloride (1.5 g, 0.5 equivalent) was added in two aliquots, and then stirred for 10 minutes the Other two aliquots of the hydrochloride of 2-(aminothiazol-4-yl)-2-methoxyimino-acetylchloride (1.5 g, 0.5 equivalent) was added with triethylamine (0.8 ml, 0.5 equivalent of each). The suspension is stirred at a temperature of 0-5aboutC for one hour, then add 15 ml of water and the mixture was stirred at ambient temperature to dissolve all solid phone the Organic layer is separated from the rich aqueous layer, the aqueous layer was added 6 n HCl (5 ml, 2.5 equivalents) and 60 ml of acetone and stirred for 15 min before the start of crystallization. To complete the crystallization add 80 ml of acetone. The suspension is stirred for 1 h and then filtered, washed with 50 ml of acetone and dried at a temperature of approximately 40aboutC. the Yield of the dihydrochloride monohydrate of cefepime is 5,78 g (86,0% stoichiometric mass).

P R I m e R 22. Anhydrous acylation N1 salt of 7-amino-3-/(1-methyl-1-pyrrolidino)methyl/ceph-3-em-4-carboxylate using the hydrochloride of 2-(2-aminothiazol - 4-yl)-2-methoxyimino-ATA (5.0 g, 0,01176 mol) is cooled to a temperature of 0-5aboutWith 50 ml of acetonitrile. Add trimethylchlorosilane (of 1.34 ml, 0.90 equivalent) and hexamethyldisilazane (1.8 ml, 0.75 equivalent), maintaining the temperature of the 5aboutC. Silloway the mixture is stirred for 1 h at a temperature of 0-5aboutC. Then added in two aliquots hydrochloride 2-(2-aminothiazol-4-yl)-2-methoxyimino-acetylchloride (1.8 g, 0.59 each equivalent) and stirring is continued for 10 minutes Then add two more aliquots of the hydrochloride of 2-(aminothiazol-4-yl)-2-methoxyimino-acetyl chloride (1.5 g, 0.5 equivalent of each) with triethylamine (0.8 ml, 0.5 equivalent of each). The suspension is stirred at a temperature of 0-5aboutC for 1.5 h, followed by addition of 15 ml of water and stirring at ambient temperature to dissolve all solids. The organic layer is separated from the rich in water, the aqueous layer was added 6 n Hcl solution (5 ml, 2.5 equivalents) and 30 ml of acetone and stirring is continued for 10 minutes to crystallization of the product. To complete the crystallization add another 110 ml of acetone. The suspension is stirred for one hour, then filtered, washed with 75 ml of acetone and dried at a temperature of approximately 40aboutC. Output monohydratemeridia N1 salt of 7-amino-3-/(1-methyl-1-pyrrolidino)methyl/ceph-3-em-4-carboxylate using the hydrochloride of 2-(2-aminothiazol - 4-yl)-2-methoxyimino-acetylchloride (anti-isomer from Example 12. In the atmosphere of nitrogen N1 salt of 7-amino-3-/(1-methyl-1-pyrrolidino)methyl/ceph-3-em-4-carboxylate (2.0 g 4,70 mmol) cooled to a temperature of -20aboutWith in 20 ml of acetonitrile. Add trimethylchlorosilane (1,26 ml, 2.1 equivalents) and triethylamine (1,32 ml, 2.05 equivalents), keeping the temperature at or below -10aboutAfter stirring silloway mixture for 1.5 hours at a temperature of -10aboutTo give the hydrochloride of 2-(2-aminothiazol-4-yl)-2-methoxyimino-acetylchloride (anti-isomer obtained in Example 12) (1.2 g, 1.49 equivalent) and the reaction mixture stirred for 1 h at a temperature of -10aboutC.

The product of the above acylated mixture compared with a similar product of a mixture of anhydrous acylation using hydrochloride SYN-2-(2-aminothiazol-4-yl)-2-methoxyimino-acetyl - chloride, as in example 20. The main peak of the product under liquid chromatography high pressure above acylation reaction does not correspond to the peak of the desired antibiotic cefepime. A sample of the product in the above reaction acylation allocate chromatography, and dataIH NMR and liquid chromatography high pressure relative to a given sample are consistent with the anti-isomer of cefepime as op is/ceph-3-em-4-carboxylate using the hydrochloride of 2-(2-aminothiazol - 4-yl)-2-methoxyimino-acetylchloride (SYN-isomer). In the atmosphere of nitrogen N1 salt of 7-amino-3-/(1-methyl-1-pyrrolidino)methyl/ceph-3-em-4-carboxylate (10.0 g, 0,02252 mol) is stirred with 100 ml of dichloromethane at a temperature of 20aboutC. Add trimethylchlorosilane (2.35 ml, 0.82 equivalent) and hexamethyldisilazane (of 3.85 ml, 1,62 equivalent), and temperature silloway mixture was raised to 25aboutWith and retain for 1.5 hours at a temperature of from 25 to 30aboutC. Then silloway the mixture is cooled to a temperature of -40aboutWith and within 40 minutes add the hydrochloride of 2-(2-aminothiazol-4-yl)-2-methoxyimino-AC - ethylchloride (6,04 g 0,93 equivalent) at a temperature of from -40 to 20aboutC. Added triethylamine (1.65 ml, 0.5 equivalent) hydrochloride and 2-(2-aminothiazol-4-yl)-2-methoxyimino-ACET - inflorida (1,21 g 0,19 equivalent) and the suspension is maintained at a temperature of from -20 to 25aboutWith over 65 minutes

Then, the suspension is added to water (50 ml) for 10 min and stirred at ambient temperature for 1 h to dissolve most of the solids. Added celite (brownmillerite) (0.5 g), the mixture is filtered and the cake washed with dichloromethane (10 ml). The organic layer is separated from the rich aqueous layer, which was added concentrated sulfuric acid (5,9 ml, 0,111 mol) for 5 min at the rate the AI product. Suspension keep for 20 min at ambient temperature and then cooled to 0-5aboutC for one hour. The suspension is filtered, washed with acetone (150 ml) and the solid is dried at a temperature of approximately 40aboutC. the Yield of sulphate of cefepime is 11,54 g (84,9 stoichiometric mass).

P R I m e R 25. Anhydrous acylation N1 salt of 7-amino-3-/(1-methyl-1-pyrrolidino)methyl/ceph-3-em-4-carboxylate using the hydrochloride of 2-(2-aminothiazol - 4-yl)-2-methoxyimino-acetylchloride (SYN-isomer). In the atmosphere of nitrogen N1 salt of 7-amino-3-/(1-methyl-1-pyrrolidino)methyl/ceph - 3-em-4-carboxylate (10.0 g, 0,02252 mol) is stirred with 100 ml of dichloromethane at a temperature of 20aboutC. Add trimethylchlorosilane (2.35 ml, 0.82 equivalent) and hexamethyldisilazane (of 3.85 ml, 1,62 equivalent), and temperature silloway mixture was raised to 25aboutWith and retain for 1.5 hours at a temperature of from 25 to 30aboutC. Silloway the mixture is cooled to a temperature of -40aboutAnd for 40 minutes at a temperature of from -40 to -20aboutTo give the hydrochloride of 2-(2-aminothiazol-4-yl)-2-methoxyimino-acetylchloride. Added triethylamine (1.65 ml, 0.5 equivalent) hydrochloride and 2-(2-aminothiazol-4-yl)-2-methoxyimino-acetylchloride (1,21 g 0,19 equivalent) and the suspension support was stirred at ambient temperature for one hour to dissolve most of the solids. Add brownmillerite (0.5 g) and the mixture filtered through brownmillerite (1.0 g) gasket. The organic layer is separated from the rich aqueous layer twice stirred with carbon (1.0 g each time) and filtered. United carbon cake was washed with a solution of water (10.5 ml), 12 N. HCl (5 ml, 2.5 equivalents) and acetone (20.5 ml). Then, the combined filtrate was added acetone (320 ml) and washed for 35 min for crystallization of the product. Suspension retain 30 min at ambient temperature and then cooled to a temperature of 0aboutC for 1 h, the Suspension was filtered, washed with 80 ml of acetone and the solid is dried at a temperature of approximately 40aboutC. the Output of the dihydrochloride monohydrate of cefepime is of 10.25 g (76,3% of the stoichiometric mass).

P R I m e R 26. Hydrochloric salt of SYN 2-(2-aminothiazol-4-yl)-2-methoxyethoxy acid. SYN 2-(2-aminothiazol-4-yl)-2-methoxyimino acid (85,3 g, 424 mmol) in dichloromethane (570 ml) crushed under nitrogen for 15 minutes in the mixer. Received micronized suspension was diluted with dichloromethane (100 ml) and transferred under nitrogen into the reactor with jacket Buchi volume of 1 liter reactor create an increased pressure with nitrogen (5 pounds per square guyabera introducing hydrogen chloride (15,4 g, 424 mmol) at a rate of 0.2 g per minute. The temperature is increased to 2aboutC. the Mixture is stirred for another 30 min at a temperature of 0aboutC, filtered and washed with dichloromethane (350 ml) under nitrogen. The solid is dried in vacuum at a temperature of 45aboutC for 18 hours Specified in the header of the connection takes the form of a powder is not quite white (110,9 g, uncorrected output 111%).

Analytically calculated for C6H8N3O3SCl:

C 30,32, H 3,39, N 17,68, S 13,49, Cl 14,91.

Found: 29,37, N 3,17, N 16,34, 12,70 S, Cl 16,99.

IH NMR (DMSO-d6) : of 4.05 (s, 3H, CH3), 5,9 (15 C. mol. residual CH2CL2), and 7.1 (s, IH, C-5 H). Signals are visible when 4,18 (s, 3H, CH3) and 7.7 (s, 1H, C-5 H), which corresponds to approximately 2% of the anti-isomer.

P R I m e R 27. Hydrochloric salt of SYN 2-(2-aminothiazol-4-yl)-2-methoxyethoxy acid. SYN 2-(2-aminothiazol-4-yl)-2-methoxyimino acid (25 g, 124 mmol) in acetonitrile (125 ml) under nitrogen titrated, 1,39 m solution of Hcl in acetonitrile (89,2 ml, 123,9 mmol) and keep the temperature at 10-15aboutC. the Mixture is stirred for 30 minutes at a temperature of 10-15aboutC, filtered and washed with acetonitrile (200 ml) under nitrogen. The solid is dried in vacuume completely white (29.5 g, uncorrected yield of 97.4%).

IH NMR (CD3OD) : 2,05 (c, 13% of the mass. residual acetonitrile),

4,1 (s, 3H, CH3), and 7.1 (s, 1H, C-5 H). The signals are also visible at 4.2 (s, 3H, CH3) and 7.8 (s, 1H, C-5 H), which corresponds to approximately 0.5% of the anti-isomer.

P R I m e R 28. Hydrochloride SYN 2-(2-aminothiazol-4-yl)-2-methoxyaminomethyl-reed. Hydrochloride SYN 2-(2-aminothiazol-4-yl)-2-methoxyethoxy acid (56,24 g, 210 mmol), containing about 11 wt. residual acetonitrile in dichloromethane (450 ml) crushed under nitrogen for 3 minutes in the mixer, then cooled to a temperature of -35aboutWith and transferred under nitrogen for 5 min in a well-mixed suspension of reagent Vilsmaier, also at a temperature of -35aboutC. Suspension of reagent Vilsmaier, obtained by addition of oxalicacid (28,2 g, 221 mmol) in portions into a solution of dimethylformamide (16,89 g, 231 mmol) in dichloromethane (330 ml) at a temperature of 0aboutC, followed by cooling to a temperature of -35aboutC. During the addition, the reaction temperature is increased up to -28aboutC. After addition, the reaction mixture tatrallyay product. After 2.5 h at temperatures from -28 to -35aboutThe mixture is filtered and the filter cake prom who shat in vacuum at room temperature for 12 hours Specified in the header connection receive in the form of a powder is not quite white (42.9 g, yield 72%).

IH NMR (CD3OD) : 4,06 (s, 3H, CH3), 7,12 (s, 1H, C-5 H). Signals are visible when 7,18, which corresponds to approximately 5% hydrochloric acid salt, and when 7,80 (s, C-5 H), which corresponds to approximately 0.5% of the anti-isomer. After derivatization with diethylamine in acetonitrile analysis of liquid chromatography high pressure shows mentioned in the title compound (SYN-isomer as Diethylaminoethanol) with a retention time of 9.6 min, hydrochloric acid salt with a retention time of 2.8 min and anti-isomer (as Diethylaminoethanol) with a retention time of 16.4 minutes the ratio of the SYN-isomer: hydrochloric acid salt: anti-isomer is 90:5:<1.

SYN-2-(aminothiazol-4-yl)-2-methoxy - imino-acetic acid (84,7 g, 421 mmol) in dichloromethane (570 ml) crushed under nitrogen for 20 minutes in the mixer. Received micronized suspension was diluted with dichloromethane (100 ml) and transferred under nitrogen into the reactor with jacket Buchi volume of 1 liter reactor created with the help of nitrogen overpressure (5 head part of the reactor is injected hydrogen chloride (15.3 g, 421 mmol) at a rate of 0.2 g per minute. The temperature is increased to 2aboutC. the Mixture is stirred for 30 minutes at a temperature of 0aboutWith milled for 3 minutes in the mixer, then cooled to a temperature of -35aboutWith and transferred under nitrogen for 5 min in a well-mixed suspension of reagent Vilsmaier, also at a temperature of -35aboutC. Suspension of reagent Vilsmeier get by adding oxalicacid (56,1 g, 439 mmol) in portions into a solution of dimethylformamide (33,8 g, 462 mmol) in dichloromethane (880 ml) at a temperature of 0aboutWith subsequent cooling to a temperature of -35aboutC. During the addition the reaction temperature increases to -28aboutC. After addition, the reaction mixture tatrallyay product. After 2.5 h at temperatures from -28 to -35aboutThe mixture is filtered and the filter cake washed with dichloromethane (350 ml) under nitrogen. Nitrogen is passed through the pellet for 30 min, after which the solid is dried in vacuum at room temperature for 12 hours Specified in the header connection receive in the form of a powder is not quite white (95,2 g, 89% uncorrected yield). Analytically calculated for C6H7N3O2SCl2:

C 28,14, H Was 2.76, N 16,41, To 12.52 S, Cl 27,6 C-5, N).

The signals are also visible when 7,18 (S, C-5 H), which corresponds to approximately 4% hydrochloric acid salt, and when 7,80 (s, C-5 H), which corresponds to approximately 2% of the anti-isomer. After derivatization with diethylamine in acetonitrile analysis using liquid chromatography high pressure shows specified in the header of the connection (as it diethylamide-derived) with a retention time of 9.6 min, initial acid with a retention time of 2.8 min and anti-isomer (as its diethylamide-derived) with a retention time of 16.4 minutes the ratio of the SYN-isomer: original acid anti-isomer is 90:4:2.

P R I m e R 30. The transformation of the dihydrochloride monohydrate of cefepime in the dihydrochloride dihydrate of cefepime. Monohydrate cefepime-dihydrochloride (300 g, the degree of purity of 99.9% with liquid chromatography high-pressure coefficient McKinney 3,8%) dissolved in deionized water (1200 ml). Add 6 N. hydrochloric acid solution (132 ml, 1.5 equivalents). The solution is filtered and washed with deionized water (300 ml).

To the filtered solution was added acetone (1500 ml). Then within 20 minutes added dropwise additional amount of acetone (4000 ml). Solution save askapache.com analysis; the seed for choice when turbidity). Within 25 min add additional acetone (8000 ml). The thick suspension is stirred at a temperature of 25aboutC for 1 h

The shape of the crystals confirmed as dihydrates (acicular) microscopic analysis, comparing with authentic crystals. The suspension is filtered and washed with acetone (CH ml). The cake is dried at a temperature of 40aboutC in vacuum for 15 h Output dihydrate cefepime-dihydrochloride is 305,10 g (98,6%) degree of purity 99,0% for liquid chromatography high-pressure coefficient McKinney 6,5%

P R I m e R 31. The conversion of dihydrate cefepime-dihydrochloride monohydrate in cefepime-dihydrochloride. Dehydrate cefepime-dihydrochloride (15.0 g, the degree of purity of 99.2% for liquid chromatography high-pressure coefficient McKinney 6,4% ) dissolved in deionized water (75 ml). Added 6 n hydrochloric acid (0.9 ml, 0.2 equivalent). The solution is filtered through a filter with a size of 0.45 µm sieve. To the filtered solution for 20 min added dropwise acetone (200 ml) to give a hazy solution (optional introduction of the seed at this point). Not hold at a given point, etc>TheC for one hour. The shape of the crystals confirmed as monohydrate microscopic analysis, comparing crystals with authentic sample. The suspension is filtered and washed with acetone (CH ml). The cake is dried at a temperature of 40aboutC in vacuum for 15 h Output monohydrate cefepime-dihydrochloride is 13,28 g (91,8%), and the crystal structure confirms similar as described by Kaplan and others in the U.S. patent N 4910301.

P R I m e R 32. Getting hydrates 7-/2-(2-aminothiazol-4-yl)-2-(Z)-methoxyimino-acetamido/-3- (1-methyl-1-pyrrolidino)methyl/ceph-3-em-4 - carboxylate-dihydrochloride. In an inert atmosphere at room temperature hydroiodide 7-amino-3-(1-methyl-1-pyrrolidino)methyl/ceph-3-em-carboxylate (14,67 g, 0,0345 mol) is suspended in dichloromethane (150 ml). To the suspension was added trimethylchlorosilane (4,7 ml) and hexamethyldisilazane (7.7 ml) and the mixture is heated to a temperature of 25-30aboutC for 1.5 hours Then the reaction mixture is cooled to a temperature of about -50aboutWith, and in three receptions for 35 minutes, add the hydrochloride of SYN-2-(2-aminothiazol-4-yl)-2-methoxyimino-acetylchloride (7,24 g, 0,0283 mol), while the temperature is gradually raised to -30aboutC. Added triethylamine (1,47 ml) and 1.78 g (0,0069 mol) charged the 25aboutWith approximately one hour. Upon completion of the reaction (according to the analysis of liquid chromatography high pressure), the mixture is heated to a temperature of -5aboutWith, then add 56 ml of water and 10 ml of dimethylacetamide. The reaction suspension is stirred at a temperature of 25aboutWith to dissolve the solids. The phases are separated and the aqueous phase is finally filtered. The aqueous phase discolor activated carbon (3 g), filtered and the filtrate is divided into two equal portions.

Method AND

One portion of the rich aqueous filtrate is acidified with 12 N. a solution of hydrochloric acid (11.7 ml, 0.14 mol) and the Suspension tatrallyay dihydrate cefepime-dihydrochloride (0.5 g) and the suspension is heated at a temperature of 40aboutC for one hour, and then maintained at room temperature during the night. The mixture is diluted with acetone (126 ml), stirred at room temperature for 0.5 h, then cooled at room temperature 0-5aboutC for one hour. The product is collected by filtration, washed with acetone and dried in a vacuum at a temperature of 45aboutC. Digitalnow the form of the dihydrochloride specified in the connection header (needle crystals) are obtained with purity of 96,3% (9,11 g, 8 is asnau spectroscopy with Fourier transform (diffusion reflection coefficient with CVG) shows peaks of absorbance at 3574 cm-1and 3432 cm-1.

Method C.

The second portion of the rich aqueous filtrate is acidified with 6 N. a solution of hydrochloric acid (15 ml, 0.09 mol), diluted with acetone (280 ml) for 20 min and then cooled to a temperature of 0-5aboutC for one hour. The suspension is filtered, washed with acetone and dried in a vacuum at a temperature of 45aboutC. Monohydrate form dihydrochloride (granular crystals) specified in the connection header get-purity 95.5% of (scored 8.38 g, 83.1% of the stoichiometric mass). The water content in the analysis of Karl Fischer is 3.9%

1. The method of obtaining crystalline mono or dihydrochloride dihydrate 7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxykynuramine] -3-[ (1-methyl-1-pyrrolidino) -methyl]ceph-3-em-4-carboxylate, essentially free from antihisamine and2isomer, wherein said essentially free from2isomer Siciliano derivative of General formula I

< / BR>
where R and R1each hydrogen or a silyl protective group, provided that R and R1are not simultaneously hydrogen;

X-the remainder of hydrochloric, itestosterone or sulfuric acid,

subjected to interaction with the SYN-isomer GM organic solvent, in the presence of base, followed by separation of the resulting reaction mixture the desired product in the form of its crystalline mono-or dihydrochloride dihydrate.

2. The method according to p. 1, characterized in that the SYN-isomer hydrochloride 2-(2-aminothiazol-4-yl)-2 methoxykynuramine essentially free of anti-isomer, is obtained by interaction of anhydrous hydrochloride SYN-isomer of 2-(2-aminothiazol-4-yl)-2-methoxyethoxy acid with a mixture containing at least 1 molar equivalent of oxalicacid and at least 1 molar equivalent to a small excess of dimethylformamide in relation to a specified number of oxalicacid, in an inert organic solvent at a temperature below 10oC.

3. The method according to p. 2, characterized in that the number of oxalicacid is 1 to 2 molar equivalents relative to the anhydrous hydrochloride SYN-isomer of 2-(2-aminothiazol-4-yl)-2-methoxyethoxy acid, and the number of dimethylformamide is insignificant equimolar excess relative oxalicacid.

4. The method according to p. 3, characterized in that the number of oxalicacid is 1.05 molar equivalents, and the number of dimethylformamide methoxykynuramine acid.

5. The method according to p. 2, characterized in that the interaction is carried out at a temperature of 15 to 40oC.

6. The method according to p. 1, wherein said essentially free from2isomer Siciliano derivative of General formula I are obtained by processing essentially free from2isomer of 7-amino-3-[(1-methyl-1-pyrrolidinium)methyl] -ceph-3-em-4-carboxylate in the form of additive salts with chloride-hydrogen, iodine hydrogen or sulfuric acid silylium agent in an inert organic solvent.

7. The method according to p. 6, characterized in that similitude reagent is a mixture of trimethylchlorosilane with hexamethyldisilazane.

8. The method according to p. 7, characterized in that the number cilleruelo agent is 2.0 to 2.5 molar equivalents.

9. The method according to p. 1, characterized in that use is less than 1 molar equivalent of base with respect hydrochloride 2-(2-aminothiazol-4-yl)-2-methoxykynuramine.

10. The method according to p. 9, wherein the base is N-methylmorpholine or triethylamine.

11. The method according to p. 1, characterized in that the reaction mixture was added a sufficient amount of water for the formation of aqueous and organic phases, separating the slots.

12. The method according to p. 11, characterized in that the use of chloride-hydrogen acid to obtain the target product.

13. The method according to p. 11, characterized in that use sulfuric acid.

14. The method according to p. 13, characterized in that obtained by treating the acid salt of sulfuric acid is neutralized with base, followed by addition of a sufficient amount of chloride-hydrogen acid to obtain the target product.

15. The method according to p. 14, wherein the base is a weakly basic ion exchange resin.

16. The method according to PP. 1, 2 or 6, characterized in that the inert organic solvent is acetonitrile or dichloromethane.

17. The method according to p. 1, characterized in that the target product contains 2.5 to 7.0 wt. water.

18. The method according to p. 1, characterized in that the target product is a dihydrochloride monohydrate of 7-[2-(2-aminothiazol-4-yl)-2-(Z) -methoxykynuramine] 3 -[(1-methyl-1 pyrrolidino) -methyl]-ceph-3-em-4-carboxylate.

19. The method according to p. 1, characterized in that the target product is a dihydrochloride dihydrate 7-[2-(2-aminothiazol-4-yl)-2-(Z)

methoxykynuramine] -3-[(1 - methyl-1 - the feast of the Sabbath.

 

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