MXPA94009625A

MXPA94009625A - Process for preparing cephalosporin compounds from reactive organic acid derivatives..

Info

Publication number: MXPA94009625A
Application number: MXPA94009625A
Authority: MX
Inventors: Jun Park Bong
Original assignee: Lucky Ltd
Priority date: 1994-03-21
Filing date: 1994-12-13
Publication date: 2005-08-24
Also published as: RO111682B1; RU2097385C1; RU94043775A; PL306199A1; KR950026881A; PL179321B1; RO113245B1; KR0129567B1

Abstract

The present invention provides a process for preparing cephem derivatives having the following general formula (I) : <CHEM> in which R<1> represents a carboxy group or a protected carboxy group which can form the salt of -COO<->M<+> with an alkali metal ion (M<+>) such as sodium, or may represent -COO<-> when R<2> has a substituent having positive electric charge such as pyridinium, pyrimidinium or thiazolium, R<2> represents hydrogen, acyloxymethyl, heterocyclic methyl or heterocyclic thiomethyl, each of which can be substituted with appropriate substituents, R<3> represents hydrogen or an amino-protecting group, R<4> represents C1-C4 alkyl or phenyl, or together with the oxygen or phosphorus atom to which it is attached may form a 5- or 6-membered heterocyclic ring, and Q represents N or CH, characterized in that a reactive thiophosphate derivative of thia(dia)zole acetic acid having the following general formula (II) : <CHEM> wherein R<3>, R<4> and Q are defined as above, is acylated with an 7-ACA derivative having the following general formula (III) : <CHEM> wherein R<1> and R<2> are defined as above, in the presence of a solvent and a base.

Description

NOVEDOSO PROCESS FOR THE PREPARATION OF CEFALOSPORINE COMPOUNDS AND THIOPHOSPHATE DERIVATIVES NOVEDOUS REAGENTS OF TIA ACID (DAY) ZOLACEATICO FOR THE SAME The gentlemen SUNG KYUM KIM, SEONG NYEON KIM, WOO HYUN KIM, JONG CHAN LIM, HEE MYUNG OH, TAE SUK K ON and BONG JUN PARK, of Korean nationality, domiciled, respectively, in Lucky Hana Apt. 101-902, Shinseong , 2 Block, Shinseong-dong Youseong-ku, Daejeon; Lucky Apt. 7-106, 381-42, Doryong-dong, Youseong-ku, Daejeon; Hwangsil Town Apt. 105-1408, 284, Worlpyung-dong, Seo-ku, Daejeon; Lucky Hana Apt. 103-203, Shinseong 2 Block, Shinseong-dong, Youseong-ku, Daejeon; Jookong, Apt. 209-905, 288 Block, Worlpyung-dong, Seo-ku, Daejeon; Lucky dormitory 408, Doryong-dong, Youseong-ku, Daejeon, and Lucky Apt. 7-207, 381-42, Doryong-dong, Youseong-ku, Daejeon; all in the Republic of Korea, inventors, cede, sell and transfer to LUCKY LTD. , Korean society, with address in 20, Yoido-dong, Yongdungpo-ku, Seoul Korea, all the rights to the invention that is described below: SUMMARY OF THE INVENTION The present invention provides a process for the preparation of cephem derivatives having the following general formula (I): wherein: R1 represents a carboxy group or a protected carboxy group which can form the salt of -COO "+, with an alkali metal ion (M +), such as sodium, or can represent -C00" when R2 has a substituent that has a positive electrical charge, such as pyridinium, pyrimidinium or thiazolium, R 2 represents hydrogen, acyloxymethyl, heterocyclic methyl or heterocyclic thiomethyl, each of which may be substituted with appropriate substituents, R3 represents hydrogen or an amino protecting group, R5 represents hydrogen, alkyl of 1 to 4 carbon atoms, or -C (Ra) (Rb) C02Rc, wherein Ra and R in the group -C (Ra) (Rb) C02Rc for R5 are identical or different from each other, and represent hydrogen or alkyl of 1 to 4 carbon atoms, or Ra and Rb, together with a carbon atom to which they are linked, can form a cycloalkyl group of 3 to 7 carbon atoms, and Rc is hydrogen or a carboxy protecting group, and Q represents N or CH, characterized in that a reactive thiophosphate derivative of thia (dia) zolaacetic acid having the following general formula (II): wherein R, R and Q are defined as above, and R represents alkyl of 1 to 4 carbon atoms or phenyl, or together with the oxygen or phosphorus atom with which they are attached can form a heterocyclic ring of 5 or 6 members, acylated with a derivative of 7-ACA having the following general formula (III): (III) wherein R1 and R2 are defined as above, in the presence of a solvent and a base; and further, a novel reactive thiophosphate derivative of thia (day) zolaceutical acid of the formula (II), as defined above, which is used as the starting material in the preparation of the cephe derivative of the formula (I), and a process for its preparation.

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel process for the preparation of cephalosporin compounds useful as antibiotics. More specifically, the present invention relates to a novel process for the preparation of cephem derivatives represented by the following general formula (I), which have the group 2- [aminothia (dia) zolyl] -2-methoxyiminoacetamido on position 7 of the cephem nucleus, characterized in that a thia (dia) zolaacetic acid reactive thiophosphate derivative having the following general formula (II) is acylated with a derivative of 7-ACA (7-aminocephalosporanic acid): wherein: R1 represents a carboxy group or a protected carboxy group that can form the salt of -C00 ~ M +, with an alkali metal ion (M +), such as sodium, or can represent -C00"when R2 has a substituent that has a positive electrical charge, such as pyridinium, pyrimidinium or thiazolium, R 2 represents hydrogen, acyloxymethyl, heterocyclic methyl or heterocyclic thiomethyl, each of which may be substituted with appropriate substituents, R3 represents hydrogen or an amino protecting group, R4 represents alkyl of 1 to 4 carbon atoms or phenyl, or together with the oxygen or phosphorus atom with which it is attached, can form a 5- or 6-membered heterocyclic ring, R5 represents hydrogen, alkyl of 1 to 4 carbon atoms, or -C (Ra) (Rb) C02Rc, wherein Ra and Rb in the group -C (Ra) (Rb) C02Rc for R5 are identical or different from one another , and represent hydrogen or alkyl of 1 to 4 carbon atoms, or Ra and R, together with a carbon atom to which they are bonded, can form a cycloalkyl group of 3 to 7 carbon atoms, and Rc is hydrogen or a protective group of carboxy, and Q represents N or CH. In addition, the present invention relates to a novel reactive thiophosphate derivative of aya (day) zolacetic acid of the formula (II), as defined above, which can be used as the starting material in the process for the preparation of the cephalosporin compounds of the formula (I), and a process for their preparation. 2. Background Technique In general terms, numerous methods have been described for the preparation of ß-lactam antibiotics in publications and specifications of previous patents. These prior methods prepare the β-lactam antibiotic compounds, starting commonly from an organic acid represented by the following general formula of (IV), which is converted to a reactive derivative thereof, and then subjected to the acylation reaction with an amino group of the B-lactam group: wherein R, R and Q are defined as described above. Reactive derivatives of the compound of the formula (IV) which have been known from the above methods, include an acid chloride, a reactive ester, a reactive amide, a mixed acid anhydride and the like. However, the reactive derivative in the form of an acid chloride or a mixed acid anhydride, is prepared under a strict reaction condition, and in addition is unstable, so that it could be used at the site for the acylation reaction without isolation. This may be the main reason for the formation of by-products. In addition, the reactive ester and the reactive amide of the compound of the formula (IV), also have drawbacks, in that they are prepared in a low yield, their reactivity is too low to require the long reaction time, and in addition, the by-products of the reaction, for example, a hydroxy derivative, such as 1-hydroxybenzotriazole and a thiol derivative, such as 2-mercaptobenzotriazole, are difficult to remove. In addition, Japanese Laid Open Patent Publication No. (Sho) 57-175196, discloses a compound of the formula (A), which can be prepared from the organic acid of the formula (IV) and a chlorophosphate derivative: In the above formula (A), R3, R4, R5 and Q are defined as described above. However, the compound of the formula (A) is an unstable reactive mixed acid anhydride, which can not be isolated, and therefore, can adversely affect the reaction in the next step. Accordingly, the present inventors have continuously studied to discover a method that can solve the problems involved in the known reactive derivatives as described above, as a result, we have now succeeded in the preparation of a novel thiophosphate reactive thiophosphate derivative. (dia) zolacético of the formula (II), as defined above, having a suitable reactivity and stability in a high yield and in a high purity, from the organic acid of the formula (IV), and a chlorothiophosphate derivative by means of a convenient method. In addition, we have also discovered that the cephalosporin derivative of the formula (I) useful as an antibiotic, can be prepared in a more economical manner, starting from the novel thia (dia) zolacetic acid reactive thiophosphate derivative and then carried out the present invention. Therefore, it is an object of the present invention to provide a novel process for the preparation of cephem derivatives represented by the general formula (I), as defined above, characterized in that a novel thiaphosphoretic acid thiophosphate derivative of the thia (dia) zolacetic acid of the Formula (II), as defined above, is acylated with a 7-ACA derivative of formula (III), as defined below, in the presence of a solvent and a base. Furthermore, it is an object of the present invention to provide a novel thia (dia) zolacetic acid reactive thiophosphate derivative having the general formula (II), as defined above, which can be used as the starting material in the preparation of the Cephem derivative of the formula (I), as defined above. Furthermore, it is still another object of the present invention to provide a process for the preparation of the novel thia (dia) zolacetic acid reactive thiophosphate derivative of the formula (II), as defined above. The foregoing has illustrated some of the most pertinent objects of the present invention. These objects should be interpreted merely as illustrative of some of the most pertinent features and applications of the present invention. Many other beneficial results can be obtained by applying the described invention in a different manner, or by modifying the invention within the scope of the description. In accordance with the foregoing, other objects, and a more complete understanding of the invention, may be had by refeg to the description of the invention, in addition to the scope of the invention defined by the claims.

DESCRIPTION OF THE INVENTION In one aspect, the present invention relates to a novel process for the preparation of cephem derivatives represented by the following general formula (I), characterized in that a thiophosphate derivative reactive of aunt (dia) zolacetic acid of the formula (II) , acylated with a 7-ACA derivative of the formula (III) in the presence of a solvent and a base, according to the following reaction scheme I: Reaction Scheme I In the above reaction scheme, R1 represents a carboxy group or a protected carboxy group which can form the salt of -COO "M +, with an alkali metal ion (M +), such as sodium, or can represent -COO" when R2 it has a substituent that has a positive electrical charge, such as pyridinium, pyrimidinium or thiazolium. R2 represents hydrogen, acyloxymethyl, methyl heterocyclic thiomethyl or heterocyclic, each of which may be substituted with appropriate substituents, R3 represents hydrogen or an amino protecting group, R4 represents alkyl of 1 to 4 carbon atoms or phenyl, or together with the oxygen or phosphorus atom with which it is bound can form a 5- or 6-membered heterocyclic ring, R5 represents hydrogen, alkyl of 1 to 4 carbon atoms, or -C (Ra) (Rb) C02Rc, wherein Ra and Rb in the group -C (Ra) (Rb) C02Rc for R5 are identical or different from each other, and represent hydrogen or alkyl of 1 to 4 carbon atoms, or Ra and Rb, together with a carbon atom with which are linked, can form a cycloalkyl group of 3 to 7 carbon atoms, and Rc is hydrogen or a carboxy protecting group, and Q represents N or CH. The term "ac loximetilo" used in the specification of the present invention, the definition of "acyl" includes any acyl group conventionally known in the field of beta-lactam, such as carbamoyl, aliphatic acyl, the acyl groups having aromatic or heterocyclic ring, etc. A preferred example of the acyl group may include alkanoyl of 1 to 4 carbon atoms, such as formyl, acetyl, propionyl, butyryl, etc. , particularly alkanoyl of 1 to 2 carbon atoms. In the terms "heterocyclic methyl" and heterocyclic thiomethyl ", the definition of" heterocyclic "may include a monocyclic 3 to 7 saturated or unsaturated containing at least one heteroatom selected from nitrogen, oxygen and sulfur members in ring or a polycycle which is formed by the merger of two monocycles or as defined above. a typical example of this heterocycle is pyrrolidinyl, imidazolinyl, piperidino, piperazinyl, morpholinyl, thiazolidinyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1, 2, 4-triazolyl, etc.), oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1, 2, 4-oxadiazolyl, etc.), thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4- thiadiazolyl), thienyl, indolyl, isoindolyl, indolinyl, benzotriazolyl, tetrazolopyridyl, quinolyl, isoquinolyl, benzoxazolyl, benzothiazolyl, etc., which may have a positive electric charge in the ring, if possible, as in pyridinium, pyrimidinium, thiazolium, etc. , and may be substituted with one to 4 suitable substituents. In this case, the preferred example of suitable substituents may include alkyl of 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, t-butyl, etc.), alkenyl of 2 to 4 carbon atoms ( for example, ethenyl, 1-propenyl, allyl, 1,3-butadienyl, etc.) »alkynyl of 2 to 4 carbon atoms (eg, ethynyl, 1- or 2-propynyl, etc.), cycloalkyl of 3 to 6 carbon atoms (for example, cyclopropyl, cyclopentyl, etc.), halogen (for example, chlorine, fluorine, iodine, etc.), substituted or unsubstituted amino (for example, amino, methylamino, ethylamino, N, N-dimethylamino) ,?,? - diethylamino, etc.), phenyl which is substituted or unsubstituted with hydroxy, etc. The process according to the present invention, as illustrated in reaction scheme I, is characterized by the use of the reactive thiophosphate derivative of the formula (II), which has a suitable reactivity and stability, such as the organic acid derivative reactant, and therefore, can be broadly applied to the synthesis of currently known cephalosporin compounds having the 2- [amino-thia (dia) zolyl] -2-methoxyiminoacetamido group on the 7-position of the cephem nucleus. In the reaction of the process according to the present invention, the thiophosphate derivative of reactive organic acid of the formula (II), is conveniently used in a slightly excessive amount with respect to the compound of the formula (III) to carry out the reaction. In general terms, the thiophosphate derivative of reactive organic acid of the formula (II) can be used in an amount of 1.0 to 1.5 equivalents by weight with respect to the compound of the formula (5 ??). However, in view of the performance of the reaction and the economy, the reactive thiophosphate derivative of the formula (II) is preferably used in an amount of 1.0 to 1.2 equivalents by weight with respect to the compound of the formula (III) ). As the base in the reaction of the present invention, preferably both an inorganic base and an organic base can be used. For this purpose, the inorganic base that may be used may include carbonates and bicarbonates of an alkaline earth metal, such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, etc. As the organic base, a tertiary amine, such as triethylamine, tri-n-butylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, etc. can be used. Among these bases, sodium carbonate, triethylamine, tri-n-butylamine and the like are more preferably used. Although the amount used of the base can be varied depending on the class of the substituent R2, the base is generally used in an amount of 1.5 to 3.5 equivalents by weight, preferably 2.0 to 3.0 equivalents by weight, with respect to the compound of the formula (III). As the solvent in the reaction of the present invention, any polar or non-polar solvent, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, acetone, can be used individually. N, N-dimethyl formamide, N, N-dimethyl acetamide, alcohols, such as methyl alcohol, ethyl alcohol or isopropyl alcohol, water, etc. However, a mixed solvent of two or more selected from the aforementioned solvents can also be effectively used, for example, a mixed alcohol-water solvent, especially a mixed solvent of ethyl alcohol-water, in order to optimize the reactivity and the separation of the reaction product. Although the amount of solvent used is not critical, the solvent is generally used in an amount of 8 to 50 milliliters, preferably 10 to 30 milliliters, with respect to 10 millimoles of the starting material. The reaction temperature of the present invention should not be restricted, unless the selected temperature adversely affects the reaction of the present invention. However, the reaction can generally be carried out within two to six hours at the temperature of 0 to 30 ° C, particularly inclusive on the ambient temperature scale of 20 to 25 ° C, to easily prepare the desired compound. In reaction scheme I above, when R represents an amino protecting group, if desired, the acyl compound resulting from the reaction can be subjected to the deprotection reaction to remove the protecting group, to obtain the desired compound of the Formula (I), wherein R 3 represents hydrogen. A typical example of the compound that can be prepared in accordance with the process of the present invention, may include the following: 3-Acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamino-3-cephem-4-carboxylic acid (Cefotaxime); 7- [[2- (2-Amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido] -3- [2,5-dihydro-6-hydroxy-2-methi-5-oxo- 1, 2,4-triazin-3-yl) thiomethyl] -3-cephem-4-carboxylic acid (Ceftriaxone); acid 7 - [[α- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido] -3 - [(1-methyl-lH-tetrazol-5-yl) -thiomethyl] -cefem-4 -carboxylic (Cefmenoxime); 7- [2-methoxyimino-2- (2-amino-1, 3-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Ceftizoxime); 7- [[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido] -3- (2,3-dicyclopentenopyr idini omet i lo) -3-cephem-4-carboxylate (Cefpiroma ); 7- [[2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1-methylpyrrolidiniomethyl) -3-cephem-4-carboxylate (Cefepime); 7- [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (4,6-diamino-l, 1-dimethylpyrimidinium-2-yl) thiomethyl-3- cephem-4-carboxylate; 7- [[(Z) -2- (2-amino-1,2,4-thiazol-3-yl) -2-methoxyimino] acetamido] -3- (4,6-diamino-1-methylpyrimidinium-2- il) thiomethyl-3-cephem-4-carboxylate; 7 -. 7 - [[(Z) -2- (2-amino-1,2,4-thiazo-1,3-i 1) -2-methoxyimino] acetamido] -3- (4,6-diamino-1-ethylpyrimidinium-2) il) thiomethyl-3-cef em-4-carboxylate; 7- [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1,4,6-triaminopyrimidinium-2-yl) thiomethyl-3-cef em-4-carboxylate; 7 [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (4,6-diamino-1, 5-dimethylpyrimidinium-2-yl) ti orne t il-3 -cef em-4 carboxylate; 7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (2,6-diamino-l-methylpyrimidinium-4-yl) thiomethyl-1-3-cep 4-carboxylate; 7- [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (2,6-diamino-l-ethylpyrimidinium-4-yl) -thiomethyl-3-cef-4-emf -carboxylate; 7- [[(Z) 2- (2-amino-4-thiazolyl) -2 -methoimino] acetamido] -3- (2,6-diamino-3-ethylpyrimidinium-4-yl) thiomethyl 1-3-zef em-4-carboxylate 7- [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3-2,6 diamino-3-methylpyrimidinium-4-yl) thiomethyl-3 -cephem-4-carboxylate; 7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (4, 5, 6-triamino-l-methylpyrimidinium-2-yl) thiomethyl 1-3-zef em-4-carboxylate; 7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (4-amino-l methylpyrimidinium-2-yl) thiomethyl-3-cef em-4-carboxylate; 7- [[(Z) 2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (4-amino-l methylpyrimidinium-2-yl) thiomethyl-3-cef em-4-carboxylate; 7- [[(Z) 2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (4-amino-l methylpyrimidinium-2-yl) thiomethyl-3-cef em-4-carboxylate; 7- [[(Z) 2 - (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (4-amino-l aminopyrimidinium-2-yl) thiomethyl-3-cef em-4-carboxylate; 7- [[(Z) 2- (2-amino-4-thiazolyl) -2-methoxy imino] acetamido] -3- (1, 4, 5 triaininopyrimidinium-2-yl) thiomethyl-3-cef em-4 carboxylate; 7- [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (4-amino-l-methyl-6- (N, N-dimethyl) aminopyrimidinium-2- il) thiomethyl-3-cef em-4-carboxylate; 7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyim i]] acetamido] -3- (1, 4, 5, 6-tetraaminopyrimidinium-2-yl) thiomethyl-3-zef em-4-carboxylate; 7- [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1,4-diamino-5-methylpyrimidinium-2-yl) thiomethyl-3-cef em-4 -carboxylate; 7- [[(Z) 2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1,4-diamino-5-ethylpyrimidinium-2-yl) thiomethyl-3-cephem-4-carboxylate 7-t [ (Z) ~ 2 ~ (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3 (1,4-diamino-5-N-methyl) aminopyrimidinium-2-yl) thiomethyl-3-cef em 4-carboxylate; 7- [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxy im i] acetamido] -3- (1, 4-diamino-5-methyl-6- (n-methyl) aminopyrimidinium- 2-yl) thiomethyl-3-cephem-4-carboxylate; 7 [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxy imino] acetamido] - (3,4-diamino-3,5,6,7-tetrahydrocyclopentapyrimidinium-2-yl) thiomethyl 3- cef em-4-carboxylate; 7- [[(Z) -2- (2-amino-4-thiazolyl) -2-ethoxyimino] acetamido] -3- (2-amino-l-methyl-1,5,6,7-tetrahydrocyclopentapyrimidinium-4-yl) thiomethyl-3-cephem-4-carboxylate; 7- [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1, 2-diamino-1,5,6,6-tetrahydrocyclopentapyrimidinium-4-yl) thiomethyl- 3-cephem-4-carboxylate; 7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxy-imino] to ketamido] -3- (7-amino-1-methyl [1,2,4] triazolyl [1 , 5-c] pyrimidinium-5-yl) thiomethyl-3-cephem-4-carboxylate; or 7- [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (l-methyl [l, 3] -imidazo [1,2-c] pyrimidinium- 5-yl) thiomethyl-3-cephem-4-carboxylate. In accordance with the second object of the present invention, the present invention also provides a novel reactive thiophosphate derivative of thia (dia) zolacetic acid represented by the following general formula (II), which is used as the starting material in the novel process for the preparation of cephem derivatives of the formula (I) above: where: R represents hydrogen or an amino protecting group, R4 represents alkyl of 1 to 4 carbon atoms or phenyl, or together with the oxygen or phosphorus atom with which it is attached, can form a 5- or 6-membered heterocyclic ring, R5 represents hydrogen, alkyl of 1 to 4 carbon atoms, or -C (Ra) (Rb) C02Rc, wherein Ra and Rb in the group -C (Ra) (R) C02Rc for R5 are identical or different from each other, and represent hydrogen or alkyl of 1 to 4 carbon atoms, or Ra and Rb, together with a carbon atom to which they are bonded, can form a cycloalkyl group of 3 to 7 carbon atoms, and Rc is hydrogen or a carboxy protecting group, and Q represents N or CH. In the third aspect of the present invention, the present invention provides a process for the preparation of a novel reactive thiophosphate derivative represented by the following general formula (II): OR5 (II) wherein R3, R4, R5 and Q are defined as described above, characterized in that an organic acid having the following general formula (IV): wherein R3, R5 and Q are defined as described above, is reacted with a thiochlorophosphate derivative having the following general formula (V): Cl-P (OR4) 2 (V) wherein R is defined as described above, in a solvent, in the presence of a base and a catalyst. Preferably, in the compound of the formula (II) according to the present invention, R3 represents hydrogen or triphenylmethyl, R4 represents methyl, ethyl or phenyl, and R5 represents hydrogen, methyl, ethyl or t-butoxycarbonylisopropyl.

The most preferable compound of the formula (II), according to the present invention, is as follows: (Z) - diethylthiophosphoryl (2-aminothiazol-4-yl) methoxyiminoacetate; (Z) - diethylthiophosphoryl (2-triphenylmethylaminothiazol-4-yl) methoxyiminoacetate; (Z) - diethylthiophosphoryl (2-aminothiazol-4-yl) -2-t-butoxycarbonyl) -isopropoxyiminoacetate; (Z) - diethylthiophosphoryl (2-aminothiazol-4-yl) ethoxyiminoacetate; (Z) - diethylthiophosphoryl (2-triphenylmethylaminothiazol-4-yl) ethoxyaminoacetate; (Z) - (2-tr ifeny lmeti laminotia z ol -4-i l) -2- (t -butoxycarbonyl) isopropoxyiminoacetate diethylthiophosphoryl; or (Z) - diethylphosphoryl (3-amino-1,2,4-thiadiazol-5-yl) ethoxyiminoacetate. The process for the preparation of the reactive organic acid thiophosphate derivative of the formula (II) according to the present invention can be represented by the following reaction scheme in II: Reaction Scheme II (IV) (V) wherein R3, R4 # R5 and Q are defined as described above. In the above reaction scheme, an amino protecting group for R3 denotes a conventional amino protecting group, such as substituted or unsubstituted acyl, substituted (or unsubstituted) aralkyl (eg, benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl) , etc.) / haloalkyl (lower) (eg, trichloromethyl, trichloroethyl, etc.), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene, substituted cycloalkylidene, and the like. A suitable acyl as the amino protecting group can be an aliphatic acyl group, or an acyl group having an aromatic or heterocyclic moiety. This acyl group includes, for example, lower alkanoyl having 1 to 6 carbon atoms (for example, formyl, acetyl, etc.)? alkoxycarbonyl having 2 to 6 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, etc.), lower alkanesulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), or aralkoxycarbonyl (lower) (eg, benzyloxycarbonyl, etc.) , and similar. The acyl group, as mentioned above, may contain from 1 to 3 suitable substituents selected from halogen, hydroxy, cyano, nitro and the like. In addition, the reaction product of the amino group with a silane, borane, phosphorus compound and the like can also act as the amino protecting group. When in the group -C (Ra) (Rb) C02 (Rc) for R5, Rc is a carboxyl protecting group, a suitable example of the carboxyl protecting group includes: (lower) alkyl ester (for example, methyl ester, ester t-butyl, etc.), alkenyl ester (lower) (eg, vinyl ester, allyl ester, etc.), lower alkoxy (lower) alkoxy ester (eg, methyl ester, methyl ester, etc.). ), alkylthio (lower) alkyl ester (lower) (for example, methylthiomethyl ester, etc.), haloalkyl (lower) ester (for example, 2, 2, 2-trichloroethyl ester, etc.), substituted or unsubstituted aralkyl ester ( for example, benzyl ester, p-nitrobenzyl ester, etc.), or silyl ester and the like. In the preparation of the reactive thiophosphate derivative of the formula (II) according to the process of the present invention, as illustrated in reaction scheme II above, the compound of the formula (V) is generally used in an amount of 0.5 to 2.0 equivalents by weight, preferably 1.0 to 1.3 equivalents by weight, with respect to the organic acid of the formula (IV). In addition, the reaction can be practiced in the absence of a catalyst. However, the reaction in the absence of the catalyst requires a long reaction time, and may produce some by-products. On the contrary, when the reaction is carried out in the presence of a suitable catalyst, the reaction can be carried out within a short reaction time under light conditions without the formation of by-products. Although the suitable catalyst that can be used in the reaction according to reaction scheme II includes tertiary amines, quaternary ammonium, or phosphonium compounds and the like, the catalyst having the optimum properties must be selected in any case, since the speed of the reaction can be varied over the organic acid of the formula (IV) as used, the kind and amount of the catalyst and the like. Examples of the tertiary amine catalyst may include 2,4-dimethyl-2,4-diazapentane, 2,5-dimethyl-2,5-diazahexane,?,?,? ',?' - tetramethyl-1,2-diaminocyclohexane , l, 4-dimethyl-l, 4-diazacyclohexane, 2,7-dimethyl-2,7-diaza-4-octane, 1,4-diazabicyclo [2,2,2] octane, 2,6-dimethyl-2 , 6-diazaheptane, 2,9-dimethyl-2, 9-diazadecane, 2,5,8, 11-tetramethyl-2, 5-8,11-tetraazadodecane, and the like. A suitable example of the quaternary ammonium compound may include tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, cetyltrimethylammonium bromide, tetra-n-butylammonium iodide, methyltri-chloride (8 to 10 carbon atoms) alkylammonium, methyltri-2-methylphenylammonium chloride, and the like. In addition, as the phosphonium compound, tetra-n-butylphosphonium bromide is preferably used. The catalyst is generally used in the proportion of 0.1 to 50 percent, preferably 0.5 to 5 percent, based on the molar amount, with respect to the organic acid of the formula (IV). As a solvent in the reaction according to reaction scheme II of the present invention, a polar or non-polar organic solvent, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, acetate, can be used. ethyl, dioxane, tetrahydrofuran, acetone, N, N-dimethyl formamide, acetamide, dimethyl, and the like. However, a mixed solvent of two or more selected from the aforementioned solvents can also be used in order to provide the optimum reactivity and the highest yield of the reaction product. A suitable base that can be used in reaction scheme II includes an inorganic base, for example, alkaline earth metal carbonates or acid carbonates, such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate and the like; and an organic base, for example, tertiary amine, such as triethylenediamine, tri- (n-butyl) amine, diisopropylethylamine, pyridine, pyridine,?,? -dimethylaniline, etc. It is preferred to use more diisopropylethylamine or tri-n-butylamine. In the reaction according to reaction scheme II, the reaction temperature can be varied within a range of -40 ° C to 60 ° C, preferably -15 ° C to 25 ° C. In a particular manner, when the reaction temperature is adjusted from 0 ° C to 20 ° C, the reaction can be carried out within 1 to 3 hours to easily obtain the desired compound of the formula (II) under light conditions. The thiophosphate derivative of reactive organic acid of the formula (II), as prepared in accordance with the process of the present invention, has a unique physicochemical property. In a specific manner, the thiophosphate derivative of reactive organic acid of the formula (II) has a good solubility in a polar or non-polar organic solvent, and also has a good stability, such that it can not be decomposed in the acid organic (IV), even when the thiophosphate derivative of reactive organic acid dissolved in this solvent is washed with acid, basic or neutral water. In addition, when the reactive organic acid thiophosphate derivative of the formula (II) is used in the acylation reaction with the amino group of the B-lactam nucleus, this reaction can be easily practiced, even under light conditions, and the Thiophosphoric acid derivative produced as the by-product is present in the aqueous layer in a dissolved state, and therefore can be easily removed. In addition, in the reaction according to the present invention, although the compound of the formula (II) can be subjected to the acylation reaction after the R3 group is protected with an amino protecting group, the acylation reaction also it can be practiced with the compound of the formula (II) which has no amino protecting group without any restriction. Accordingly, when the process according to the present invention is applied in the preparation of the compound of the formula (I) on an industrial scale, there is a great advantage in that the final β-lactam antibiotics can be easily synthesized in high performance and high purity. Hereinafter, the present invention will be explained more specifically on the basis of the following examples. However, since the main feature of the present invention resides in the thiophosphate derivative of reactive organic acid of the formula (II) and its use in the preparation of the desired compound as described above, the technical scope of the present invention does not it should be limited to the following examples, unless this characteristic constitution of the present invention is altered.

EXAMPLE 1 Synthesis of diethylphosphoryl (Z) - (2-aminothiazol-4-yl) -methoxyiminoacetate (Z) - (2-aminothiazol-4-yl) methoxyiminoacetic acid (20.1 grams), tri-n-butylamine (24.10 grams), and 1,4-diazabicyl [2, 2, 2] octane (0.11 grams) were suspended. in dry dichloromethane (200 milliliters), and then diethylchlorothiophosphate (24.52 grams) was added dropwise thereto for 20 minutes, while maintaining the reaction mixture from 0 ° C to 5 ° C in the cooling bath under one atmosphere of nitrogen. The reaction mixture was stirred for another 2 hours. After the reaction was finished, distilled water (300 milliliters) was added to the reaction solution, and then the mixture was stirred for 5 minutes. The organic layer was separated, washed successively with a 5 percent aqueous solution of sodium bicarbonate (300 milliliters) and saturated serum (300 milliliters), dried with magnesium sulfate, filtered, and then concentrated under reduced pressure. . Normal hexane (400 milliliters) was added to the concentrated solution to solidify the product, which was then filtered, washed with normal hexane (100 milliliters) and dried to obtain 33.2 grams (94.0 percent yield) of the title compound as a pale yellow solid. Melting point: 87 to 88 ° C. NMR (< S, CDC13): 1.38 (t, 6H), 4.05 (s, 3H), 4.31 (m, 4H), 5.49 (bs, 2H), 6.87 (s, 1H).

EXAMPLE 2 Synthesis of diethylphosphoryl (Z) - (2-aminothiazol-4-yl) -2-t-butoxycarbonyl) isopropoxyiminoacetate (Z) - (2-aminothiazol-4-yl) -2-t-butoxycarbonyl) isopropoxyiminoacetic acid (32.9 grams), tri-n-butylamine (22.25 grams), and 1,4-diazabicyclo [2, 2, 2] octane (0.11 grams) in dry N, N-dimethyl acetamide (100 milliliters), and then diethylchlorothiophosphate (22.63 grams) was added dropwise over 20 minutes, while the 0 ° reaction solution was maintained. C at 5 ° C in the cooling bath. The reaction mixture was stirred for another 2 hours. Ethyl acetate (300 milliliters) and distilled water (300 milliliters) were added to the reaction solution, and then the mixture was stirred for 5 minutes. The organic layer was separated, washed successively with a 5 percent aqueous solution of sodium bicarbonate (300 milliliters) and saturated serum (300 milliliters), dried with magnesium sulfate, filtered and then concentrated under reduced pressure. Cyclohexane (100 milliliters) was added to the concentrated solution to solidify the product, which was then filtered, washed with cyclohexane (50 milliliters) and dried to obtain 44.26 grams (92% yield) of the title compound as a pale white solid. Melting point: 114 to 115 ° C. NR (< S, CDC13): 1.39 (t, 6H), 1.46 (s, 9H), 1.50 (s, 6H), 4.32 (m, 4H), 6.74 (s, 1H), 6.79 (bs, 2H) .

EXAMPLE 3 Synthesis of diethylthiophosphoryl (Z) - (2-aminothiazol-4-yl) -ethoxyimiiioacetate 33.04 grams (90 percent yield) of the title compound were prepared, starting from (Z) - (2-aminothiazol-4-yl) ethoxyiminoacetic acid (21.5 grams) in accordance with the procedure analogous to EXAMPLE 2. of fusion: 118 to 119 ° C. NMR (5, CDC13): 1.35 (m, 9H), 4.32 (m, 6H), 5.67 (bs, 2H), 6.82 (S, 1H).

EXAMPLE 4 Synthesis of diethylthiophosphoryl (Z) - (2-trifenylaminothiazol-4-yl) -ethoxyaminoacetate 57.2 grams of the title compound were prepared starting from (Z) - (2-triphenylaminothiazol-4-yl) -ethoxyaminoacetic acid (45.7 grams) in accordance with the procedure analogous to EXAMPLE 1. Melting point: 98 to 99 ° C. NMR (£, CDCl 3): 1.35 (m, 9H), 4.32 (m, 6H), 6.62 (s, 1H), 7.02 (bs, 2H), 7.32 (m, 15H).

EXAMPLE 5 Synthesis of diethylthiophosphoryl (Z) - (2-trifenylaminothiazol-4-yl) -methoxyaminoacetate 57.4 grams of the title compound were prepared, starting from (Z) - (2-triphenylaminothiazol-4-yl) -methoxyaminoacetic acid (44.3 grams) in accordance with the procedure analogous to EXAMPLE 1. Melting point:, 101 a 103 ° C. NMR (6, CDC13): 1.32 (m, 6H), 4.02 (S, 3H), 4.28 (ltl, 4H), 6.62 (s, 1H), 7.00 (bs, 1H), 7.28 (m, 15H).

EXAMPLE 6 Synthesis of diethylthiophosphoryl (Z) - (2-triphenylaminothiazol-4-yl) -2- (t-butoxycarbonyl) isopropoxyiminoacetate 68.46 grams of the title compound were prepared, starting from (Z) - (2-triphenylaminothiazol-4-yl) -2- (t-butoxycarbonyl) isopropoxyiminoacetic acid (57.1 grams) in accordance with the procedure analogous to EXAMPLE 1. Melting point: 101 to 103 ° C. NMR (£, CDCI3): 1.33 (t, 6H), 1.41 (3.9H), 1.52 (s, 6H), 4.30 (m, 4H), 6.63 (s, 1H), 6.80 (bs, 1H), 7.25 (m, 15H).

EXAMPLE 7 Synthesis of diethylthiophosphoryl (Z) - (3-amino-1,2,4-thiadiazol-5-yl) ethoxyiminoacetate 33 grams of the title compound were prepared, starting from (Z) - (3-amino-1,2,4-thiadiazol-5-yl) ethoxyiminoacetic acid (21.6 grams) in accordance with the procedure analogous to EXAMPLE 1. Melting point: 132 to 133 ° C. NR (< S, CDC13): 1.37 (m, 9H), 4.36 (m, 6H), 6.49 (bs, 2H).

EXAMPLE 8 Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino-3-acetamido-3-cephem-4-carboxylic acid (Cefotaxime) To distilled water (200 milliliters) and tetrahydrofuran (200 milliliters) in a one-liter round flask, 7-aminocephalosporanic acid (54.46 grams) and diethylphosphorus were added in succession i 1 - (Z) - (2-aminotia) -4-yl) methoxyiminoacetate (77.74 grams) with stirring. After adding tri-n-butylamine (74.15 grams), the reaction mixture was stirred for 3 hours, while maintaining the temperature at 20 to 25 ° C, and then extracted with a 12 percent aqueous solution of carbonate of sodium (453 grams), and ethyl acetate (100 milliliters) to remove the organic layer. The separated aqueous layer was extracted again with ethyl acetate (100 milliliters) to remove the organic layer. Then the aqueous layer was neutralized with a 20 percent aqueous solution of sulfuric acid to a pH of 6. To the neutralized aqueous solution was added active carbon (10 grams) and then the mixture was stirred for 30 minutes and filtered. The filtrate was saturated with sodium chloride. The saturated aqueous solution was adjusted to a pH of 4 by the addition of a 20 percent aqueous solution of sulfuric acid. After adding the small amount of the title compound, the mixture was then adjusted to a pH of 2.5 by another addition of a 20 percent aqueous solution of sulfuric acid. The crystal was completely precipitated, filtered, washed with water, and then dried to obtain 83.8 grams (92 percent Yield) of the title compound as a pale yellow solid. HPLC purity; 98.5 percent.

EXAMPLE 9 Synthesis of 3-acetoxymethyl-7-r2- (2-amino-4-thiazolyl) -2-methoxyimino "! -acetamido-3-cephem-4-carboxylic acid (Cefotaxime) Distilled water (200 milliliters), 7-aminocephalosporanic acid (54.46 grams), and sodium acid carbonate (33.6 grams) were introduced into a one liter round flask, and then allowed to fully dissolve by stirring at room temperature. To this reaction solution were added tetrahydrofuran (200 milliliters) and diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate (77.74 grams), and the mixture was stirred for 5 hours at the temperature of 20 25 ° C. The reaction solution was extracted with ethyl acetate (100 milliliters), to remove the organic layer, and the separated aqueous layer was extracted again with ethyl acetate (100 milliliters), and then neutralized to a pH of 6 by addition of a 20 percent aqueous solution of sulfuric acid. Activated carbon (10 grams) was added to the neutralized aqueous solution, and then the mixture was stirred for 30 minutes and filtered. The filtrate was saturated with sodium chloride. This saturated aqueous solution was adjusted to a pH of 4 by the addition of a 20 percent aqueous solution of sulfuric acid. After adding the small amount of the title compound, the mixture was again adjusted to a pH of 2.5 by another addition of a 20 percent aqueous solution of sulfuric acid. After the crystal was completely precipitated, it was filtered, washed with water, and then dried to obtain 81.07 grams (89 percent Yield) of the title compound as a pale yellow solid. HPLC purity: 98.6 percent.

EXAMPLE 10 Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyiminol-acetamido-3-cephem-4-carboxylic acid (Cefotaxime) In accordance with the same procedure as that of EXAMPLE 9, except that triethylamine (40.48 grams) was used in place of sodium acid carbonate, 77.43 grams (85 percent yield) of the title compound were obtained. HPLC purity: 98.4 percent.

EXAMPLE 11 Synthesis of 3-acetoxymethyl-7- \ 2- (2-amino-4-thiazolyl) -2-methoxyiminol-acetamido-3-cephem-4-carboxylic acid (Cefotaxime) In accordance with the same procedure as in EXAMPLE 8, except that acetamide N, N-dimethyl (100 milliliters) and dichloromethane (400 milliliters) were used, instead of distilled water and tetrahydrofuran, and dichloromethane (100 milliliters) was used in Place of ethyl acetate as an extraction solvent, 82.0 grams (90 percent yield) of the title compound were obtained. HPLC purity: 98.6 percent.

EXAMPLE 12 Synthesis of 3-acetoxymethyl-7-r2- (2-amino-4-thiazolyl) -2-methoxyimino-T-acetamido-3-cephem-4-carboxylic acid (Cefotaxime) To 95 percent ethyl alcohol (400 milliliters) in a one-liter round flask, 7-aminocephalosporanic acid (54.46 grams) and diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate were added sequentially (77.74). grams) with agitation. After adding triethylamine (40.48 grams), the reaction mixture was stirred for 3 hours, while maintaining the temperature at 20 to 25 ° C, and then concentrated hydrochloric acid (31.25 grams) diluted with ethyl alcohol was added thereto. to 95 percent (200 milliliters). The mixture was stirred vigorously for about one hour to completely precipitate the crystals. The precipitated crystals were filtered, washed with water, and then dried to obtain 83.8 grams (92 percent Yield) of the title compound as a white solid. HPLC purity: 98.6 percent.

EXAMPLE 13 Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino-3-acetamido-3-cephem-4-carboxylic acid (Cefotaxime) In accordance with the same procedure with EXAMPLE 12, except that distilled water (100 milliliters) and isopropyl alcohol (400 milliliters) were used, instead of ethyl alcohol, 82.0 grams (90 percent yield) of the title compound were obtained. . Purity of HPCL: 98.4 percent.

EXAMPLE 14 Synthesis of 7- [\ 2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] -acetamido-3-f2,5-dihydro-6-hydroxy-2-methyl-5- acid oxo-1,2,4-triazin-3-yl) -thiomethyl-3-cephem-4-carboxylic acid (Ceftriáxone) To distilled water (200 milliliters) and tetrahydrofuran (200 milliliters) in a one-liter round flask, 7-amino-3- [(2,5-dihydro-6-hydroxy-2-methyl-5- oxo-l, 2,4-triazin-3-yl) thio ethyl] -3-cephem-4-carboxylic acid (37.1 grams), diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 grams) and tri-n-butylamine (55.7 grams) with stirring. This solution of the reaction was stirred for 3 hours while maintaining the temperature of 20 to 25 ° C, and then toluene (200 milliliters) was added thereto, to remove the organic layer. The aqueous layer was adjusted to a pH of 3 with a 20 percent aqueous solution of sulfuric acid. The solution containing the precipitated product was stirred thoroughly for one hour under cooling with ice. The resulting product was filtered, washed with water and then dried to obtain 50.7 grams (91.5% yield) of the title compound. HPLC purity: 99.3 percent.

EXAMPLE 15 Synthesis of 7-f \ 2 - (2-amino-4-thiazolyl) -2- IZ) -methoxyiminol-acetamido-3-r2,5-dihydro-6-hydroxy-2-methyl-5-oxo-acid l, 2,4-triazin-3-yl) -thiomethyl-3-cephem-4-carboxylic acid (Ceftriáxone) To 95 percent ethyl alcohol (400 milliliters) in a one-liter round flask, 7-amino-3- [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1) acid was added sequentially., 2, 4-triazin-3-yl) thiomethyl] -3-cephem-4-carboxylic acid (37.1 grams), diet i 11 iofos f or i 1- (Z) - (2-aminotia zo 1 - 4 -il ) methoxyiminoacetate (38.8 grams) and triethylamine (30.36 grams) with stirring. This solution of the reaction was stirred for 3 hours while maintaining the temperature of 20 to 25 ° C, and then concentrated hydrochloric acid (26.04 grams) diluted with 95 percent ethyl alcohol (200 milliliters) was added thereto. The solution containing the precipitated product was stirred thoroughly for one hour under cooling with ice. The resulting product was filtered, washed with water and then dried to obtain 50.7 grams (91.5% yield) of the title compound. HPLC purity: 99.3 percent.

EXAMPLE 16 Synthesis of 7- [~ G2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino-1-acetamido-3-ri-methyl-lH-tetrazol-5-yl) -thiomethyl-3- acid cefem-4-carboxylic (Cefmenoxima) To a one-liter round flask was added distilled water (100 milliliters), 7-amino-3- [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid ( 32.8 grams), and sodium acid carbonate (16.8 grams), and the mixture was allowed to dissolve completely with stirring at room temperature. Then diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 grams) dissolved in tetrahydrofuran (100 milliliters) was added thereto, and the reaction mixture was stirred at 20 to 25 ° C for 5 hours. . Ethyl acetate (2 x 100 milliliters) was added to the reaction solution to separate the organic layer. The aqueous layer was then adjusted to a pH of 3.1 with an aqueous 2N hydrochloric acid solution, and stirred for one hour under ice-cooling. The resulting precipitate was filtered, washed with water and then dried to obtain 46.3 grams (90.6 percent yield) of the title compound. HPLC purity: 99.4 percent EXAMPLE 17 Synthesis of 7-G 2 - (2-amino-4-thiazolyl) -2- (Z) -methoxyiminol-acetamido-3-f-l-methyl-lH-tetrazole-5 acid il) -tiom til] -3-cefem-4-carboxilico (Cefmenoxima) To 95 percent ethyl alcohol (400 milliliters) in a one liter round flask, 7-amino-3- [l-methyl-lH-tetrazol-5-yl) thiomethyl] -3-cephem- was added sequentially. 4-carboxylic acid (32.8 grams), diethylthiophosphoryl- (Z) -2- (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 grams), and triethylamine (20.24 grams) with stirring. The reaction mixture was then stirred at 20 to 25 ° C for 5 hours, and concentrated hydrochloric acid (15.63 grams) diluted with 95 percent ethyl alcohol (200 milliliters) was added thereto. The reaction mixture was stirred for one hour under cooling with ice. The resulting precipitate was filtered, washed with water, and then dried to obtain 46.3 grams (90.6 percent yield) of the title compound. HPLC purity: 99.4 percent.

EXAMPLE 18 Synthesis of 7-f r 2 -methoxyimino-2- (2-amino-1,3-thiazole-yl) acid? -acetamido ") -3-cephem-4-carboxylic acid (Ceftizoxime) To a one-liter round flask, were added . ,. ^ J¾- fcl > ..- ^ til¾Mwti¾; distilled water (100 milliliters), 7-amino-3-cephem-4-carboxylic acid (20 grams), and sodium acid carbonate (16.8 grams), and the mixture was allowed to completely dissolve with stirring at room temperature. Then diethylthiophosphoryl- (Z) -2- (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 grams) dissolved in tetrahydrofuran (100 milliliters) was added, and the reaction mixture was stirred at 20 to 25 ° C for 5 hours. Ethyl acetate (2 x 100 milliliters) was added to the reaction solution to separate the organic layer. Then the aqueous layer was adjusted to a pH of 3 with an aqueous 2N hydrochloric acid solution, and stirred for one hour under cooling with ice. The resulting precipitate was filtered, washed with water, and then dried to obtain 35.8 grams (Yield 93.4 percent) of the title compound. HPLC purity: 98.4 percent.

EXAMPLE 19 Synthesis of 7- f2-methoxyimino-2- (2-amino-1,3-thiazol-yl) - acetamidc-T-3-cephem-4-carboxylic acid (Ceftizoxime) To 95 percent ethyl alcohol (400 milliliters) in a one-liter round flask, 7-amino-3-cephem-4-carboxylic acid (20 grams), diethylthiophosphoryl- (Z) -2- (2) were added sequentially. -aminothiazol-4-yl) methoxyiminoacetate (38.8 grams) and triethylamine (20.24 grams) with stirring.

Then the reaction mixture was stirred at 20 to 25 ° C for 5 hours, and concentrated hydrochloric acid (15.63 grams) diluted with 95 percent ethyl alcohol (200 milliliters) was added thereto. The reaction mixture was stirred for one hour under cooling with ice. The resulting precipitate was filtered, washed with water, and then dried to obtain 35.8 grams (Yield 93.4 percent) of the title compound. HPLC purity: 98.4 percent EXAMPLE 20 Synthesis of sulfate 7-f [2- (2-amino-4-thiazolyl) -2- (Z) -methoxyiminoTacetamidol -3- (2,3-cyclopentenopyridinomethyl) -3-cephem-4-carboxylate (Cefpiroma) To distilled water (100 milliliters) and tetrahydrofuran (100 milliliters) in a one liter round flask were added successively 7-amino-3- (2,3-cyclopentenopyridiniumomethyl) -3-cephem-4-carboxylate hydroiodide (45.9). grams), diet i 11 iofos f or i 1- (Z) - (2-aminotia zo-4-yl) methoxyiminoacetate (38.8 grams) and tri-n-butylamine (37.2 grams) with stirring. This solution of the reaction was stirred for 3 hours while maintaining the temperature of 20 to 25 ° C, and then ethyl acetate (2 x 200 milliliters) was added thereto to remove the organic layer. The aqueous layer was adjusted to a pH of 1.2 with a 20 percent aqueous solution of sulfuric acid. To this solution was slowly added ethyl alcohol (300 milliliters) while maintaining the temperature from 0 to 5 ° C, and then the mixture was stirred completely for one hour. The resulting precipitate was filtered, washed with water, and then dried to obtain 47.1 grams (Yield of 76.9 percent) of the title compound. HPLC purity: 98.1 percent.

EXAMPLE 21 Synthesis of sulfate 7-f 2 - (2-amino-4-thiazolyl) -2- (2) -methoxyimino-acetamido] -3- (2,3-cyclopenteno-pyridinimethyl) -3-cephem-4-carboxylate (Cefpiroma) To 95 percent ethyl alcohol (400 milliliters) in a one liter round flask, 7-amino-3- (2,3-cyclopentenopyridiniumomethyl) -3-cephem-4-carboxylate (45.9 grams) was added in succession. , d iet i 11 i of os f or i 1 - (Z) - (2-aminot iazo 1 - 4 -il) methoxyiminoacetato (38.8 grams) and triethylamine (20.2 grams) with agitation. This solution of the reaction was stirred for 3 hours while maintaining the temperature of 20 to 25 ° C, and then concentrated sulfuric acid (12.25 grains) diluted with 95 percent ethyl alcohol (300 milliliters) was added thereto. . The mixture was stirred for one hour while maintaining the temperature of 0 to 5 ° C. The resulting precipitate was filtered, washed with water and then dried to obtain 47.1 grams (Yield 76.9 percent) of the title compound. HPLC purity: 98.1 percent.

EXAMPLE 22 Synthesis of sulphate 7-f \ 2 - (2-amino-4-thiazolyl) -2-methoxyiminolacetamidol-3- (i-methylpyrrolidiniomethyl) -3-cephem-4-carboxylate (Cefepime) To distilled water (100 milliliters) and tetrahydrofuran (100 milliliters) in a one liter round flask were added successively 7-amino-3- (1-methylpyrrolidiniomethyl) -3-cephem-4-carboxylate hydroiodide (43.4 grams). , diethylphosphoryl- (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 grams), and triethylamine (20.2 grams) with stirring. This solution of the reaction was stirred for 4 hours while maintaining the temperature of 20 to 25 ° C, and then ethyl acetate (2 x 100 milliliters) was added thereto to remove the organic layer. Active carbon (5 grams) was added to the aqueous layer and the mixture was stirred for 30 minutes, and then filtered. The filtrate was adjusted to a pH of 1.2 with a 20 percent aqueous solution of sulfuric acid, and then acetone (400 milliliters) was added slowly. The mixture was stirred for one hour. The resulting precipitate was filtered, washed with water and then dried to obtain 45.1 grams (78 percent yield) of the title compound. HPLC purity: 97.1 percent.

EXAMPLE 23 Synthesis of sulfate 7-f [2 - (2-amino-4-thiazolyl) -2-methoxyiminolacetamidol-3- (l-methylpyrrolidiniomethyl) -3-cephem-4-carboxylate (Cefepime) To 95 percent ethyl alcohol (400 milliliters) in a one-liter round flask, 7-am ino-3 - (1-methylpyrrolidiniomethyl) -3-cephem-4-carboxylate hydodium (43.4 grams) was added in succession, diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 grams) and triethylamine (20.2 grams) with stirring. This solution of the reaction was stirred for 4 hours while maintaining the temperature of 20 to 25 ° C, and then activated carbon (5 grams) was added thereto. Then, the mixture was stirred for 30 minutes, and then filtered. To the filtrate was added concentrated sulfuric acid (12.25 grams) diluted with 95 percent ethyl alcohol (400 milliliters) and the mixture was stirred for one hour while maintaining the temperature from 0 to 5 ° C. The resulting precipitate was filtered,

Claims

Was washed with water and then dried to obtain 45.1 grams (78% yield) of the title compound. HPLC purity: 97.1 percent.

Although the present invention has been described in its preferred form with some degree of particularity, it is appreciated by those skilled in the art that the present description of the preferred form has been made only by way of example, and that numerous changes can be resorted to. in the details of the construction, combination and configuration of parts, without departing from the spirit and scope of the invention.
NOVELTY OF THE INVENTION
Having described the foregoing invention, it is considered as a novelty and, therefore, the content of the following is claimed as property:
R E I V I N D I C A C I O N S 1. A process for the preparation of cephem derivatives of the following general formula (I): wherein: R1 represents a carboxy group or a protected carboxy group which can form the salt of -COO ~ M +, with an alkali metal ion (M +), or can represent -C00- when R2 has a substituent having an electrical charge positive, R 2 represents hydrogen, acyloxymethyl, heterocyclic methyl or heterocyclic thiomethyl, each of which may be substituted with appropriate substituents,
R3 represents hydrogen or an amino protecting group, R5 represents hydrogen, alkyl of 1 to 4 carbon atoms, or -C (Ra) (Rb) C02Rc, wherein Ra and Rb in the group -C (Ra) (Rb) ) C02Rc for R5 are identical or different from each other, and represent hydrogen or alkyl of 1 to 4 carbon atoms, or Ra and R, together with a carbon atom with which they are bonded, can form a cycloalkyl group of 3 to 7 carbon atoms, and Rc is hydrogen or a carboxy-protecting group, and Q represents N or CH, characterized in that a reactive thiophosphate derivative of tia (day) zolacetic acid having the following general formula (II): wherein R, R5 and Q are defined as above, and R4 represents alkyl of 1 to 4 carbon atoms or phenyl, or together with the oxygen or phosphorus atom with which they are attached can form a heterocyclic ring of 5 or 6 members, is attached with a derivative of 7-ACA having the following general formula (III):
(III) wherein 1 and R2 are defined as above, in the presence of a solvent and a base. 2. The process according to claim 1, characterized in that the solvent is one selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, acetone, for amide?,? - dimethyl, acetamide N, N-dimethyl, alcohols and water, or a mixture of two or more solvents selected therefrom. 3. The process according to claim 2, characterized in that the solvent is an alcohol solvent or a mixed alcohol-water solvent. 4. The process according to claim 3, characterized in that the alcohol is methyl alcohol, ethyl alcohol or isopropyl alcohol. 5. The process according to claim 1, characterized in that the base is selected from the group consisting of sodium carbonate, sodium acid carbonate, potassium carbonate, potassium hydrogen carbonate, triethylamine, tri- ( n-butyl) amine and diisopropylethylamine. 6. The process according to claim 1 in any of claims 1 to 5, characterized in that the temperature of the reaction is from 0 to 30 ° C.
7. A novel reactive thiophosphate derivative of thia (dia) zolacetic acid represented by the following general formula (II): wherein: R3 represents hydrogen or an amino protecting group, R4 represents alkyl of 1 to 4 carbon atoms or phenyl, or together with the oxygen or phosphorus atom to which it is attached, can form a heterocyclic ring of 5 or 6 members, R5 represents hydrogen, alkyl of 1 to 4 carbon atoms, or -C (Ra) (Rb) C02Rc, wherein Ra and Rb in the group -C (Ra) (Rb) C02Rc for R5 are identical or different from each other, and represent hydrogen or alkyl of 1 to 4 carbon atoms. carbon, or Ra and Rb, together with a carbon atom to which they are linked, can form a cycloalkyl group of 3 to 7 carbon atoms, and Rc is hydrogen or a carboxy protecting group, and Q represents N or CH.
8. The compound of formula (II) according to claim 7, characterized in that R3 represents hydrogen or triphenylmethyl; R 4 represents methyl, ethyl or phenyl and R 5 represents hydrogen, methyl, ethyl or t-butoxycarbonyl isopropyl.
9. The compound of (II) as claimed in claim 8, wherein the compound is selected from the group consisting of: (Z) - diethylthiophosphoryl (2-aminothiazol-4-yl) methoxyiminioacetate, (Z) - diethylthiophosphoryl (2-triphenylmethylaminothiazol-4-yl) methoxyiminoacetate, diethylthiophosphoryl (Z) - (2-aminothiazol-4-yl) -2 - (t-butoxycarbonyl) isopropoxyiminoacetate, (Z) - (2-aminothiazole) Diethylthiophosphoryl-4-yl) ethoxyiminoacetate, diethylthiophosphoryl (Z) - (2-triphenylmethylmethiazol-4-yl) ethoxyiminoacetate, (Z) - (2-triphenylmethylathiazol-4-yl) -2- (t-butoxycarbonyl) ) diethylphosphoryl isopropoxyiminoacetate, and (Z) - (3-amino-1,2,4-thiadiazol-5-yl) ethoxyiminoacetate diethylphosphoryl.
10. A process for the preparation of a novel thia (dia) zolacetic acid reactive thiophosphate derivative having the following general formula (II): N R3HN wherein: R3 represents hydrogen or an amino protecting group, R4 represents alkyl of 1 to 4 carbon atoms or phenyl, or together with the oxygen or phosphorus atom to which it is attached, can form a heterocyclic ring of 5 or 6 members, R5 represents hydrogen, alkyl of 1 to 4 carbon atoms, or -C (Ra) (Rb) C02Rc, wherein Ra and Rb in the group -C (Ra) (Rb) C02R ° for R5 are identical or different from each other, and represent hydrogen or alkyl of 1 to 4 carbon atoms, or Ra and Rb, together with a carbon atom to which they are bonded, can form a cycloalkyl group of 3 to 7 carbon atoms, and Rc is hydrogen or a carboxy protecting group, and Q represents N or CH, characterized in that an organic acid having the following general formula (IV): wherein R3, R5 and Q are defined as described above, is reacted with a thiochlorophosphate derivative having the following general formula (V): C1-P (0R4) 2 wherein R is defined as described above, in a solvent, in the presence of a base and a catalyst.
11. The process according to claim 10, wherein the solvent is a single solvent selected from dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, acetone. , formamide N, N-dimethyl and acetamide?,? - dimethyl, or a mixture consisting of two or more solvents selected from them.
12. The process according to claim 10, wherein the base is selected from the group consisting of sodium carbonate, sodium acid carbonate, potassium carbonate, potassium acid carbonate, triethylamine, tri ( n-butyl) amine and diisopropylethylamine.
13. The process according to claim 10, wherein the catalyst is tertiary amines, quaternary ammonium or phosphonium compounds.
14. The process according to claim 13, wherein the catalyst is 1,4-diazabicyclo [2.2.2] octane, tetra-n-butylammonium bromide, or tetra-n-butylphosphonium bromide.
15. The process according to claim 10, 13 or 14, wherein the catalyst is used in an amount of 0.1 to 50 percent, based on the molar amount, with respect to the organic acid of the formula ( IV).
16. The process according to claim 10, wherein the temperature of the reaction is -40 to 60 ° C. IN WITNESS WHEREOVER, I have signed the above description and novelty of the Invention, as attorney of LUCKY LTD., In the city of Mexico, D.F., on the 13th day of the month of December of 1994. P-P- LUCKY LTD.