PL179321B1 - Novel method of obtaining cephalosporin derivatives and novel reactive thiophosphatic derivatives of thia(dia)zoloacetic acid used in that method - Google Patents

Abstract

FIELD: chemical industry. SUBSTANCE: claimed invention describes process for preparing cephem derivatives of general formula (I):wherein Ris carboxy group of protected carboxy group which may form salt -COOMwith alkali metal (M), such as sodium, ion and may form -COOwhen Rhas substituent with positive electric charge such as pyridinium, pyrimidinium or thiazolium; Ris hydrogen, acyloxymethyl, heterocyclic methyl or heterocyclic thiomethyl, each of which may be substituted with suitable substituents; Ris hydrogen or amino protecting group; Ris hydrogen, C-C-alkyl or -C(R)(R)CORwherein Rand Rin -C(R)(R)CORas Rare identical or differ from each other and are hydrogen or C-C-alkyl, or Rand Rtogether with carbon atom to which they are attached may form C-C-cycloalkyl, and Ris hydrogen or carboxy protecting group, and Q is N or CH characterized in that reactive thiophosphate derivative of thia(dia)zoleacetic acid of general formula (II):wherein R, Rand Q are as defined above and Ris C-C-alkyl or phenyl or together with the oxygen or phosphorus atom to which it is attached may form 5- or 6-member heterocyclic ring, is acylated with 7-ACA of general formula (III):wherein Rand Rare as defined above, in the presence of solvent and base, and also novel reactive thiophosphate derivative of thia(dia)zoleacetic acid of formula (II) as defined above, which is used as starting material for preparing cephem derivative of formula (I), and process for preparation thereof. EFFECT: more efficient preparation process.

Description

The subject of the invention is a new method for the preparation of cephem derivatives useful as antibiotics. More specifically, the invention relates to a new process for the preparation of cephemic derivatives having a 2- [aminothia (dia) -zolyl] -2-methoxyiminoacetamide group substituted at the 7-position of the cephem ring. In this process, the novel reactive thia (dia) -zo-acetic acid thiophosphate derivative is acylated with a 7-ACA derivative (7-aminocephalosporanic acid).

This process provides the cephemic derivatives of the general formula I, wherein R ¹ is a carboxy group or a protected carboxyl group that can form a salt with the group -COO'M ⁺ with an alkali metal ion (M +) such as sodium, or can be moiety -COO- when R2 has a substituent having a positive electric charge such as pyridinium group, pirymidyniowa or thiazolyl, R ² represents hydrogen, acyloxymethyl, or heterocyklometylową heterocyklotiometylową in which

The term "heterocycle" denotes a saturated or unsaturated 3- to 7-membered single ring containing at least one heteroatom selected from nitrogen, oxygen and sulfur atoms, or a multi-ring moiety formed by the condensation of two or more individual rings, each of these groups may be substituted with the appropriate substituents, R ³ is hydrogen or an amino protecting group, R ⁵ is hydrogen, C 1-4 alkyl or a group of the formula -C (R ^a ) (R ^b ) CC) ₂ R ^c , in which R ^a and R ^b in the group of formula -C (R ^a ) (R b) CO 2 R c for R are identical or different from any other moiety and are hydrogen or C 1-4 alkyl, or Ra and Rb together with the carbon atom with which they are they bonded may form a C3-7cycloalkyl group, and Rc is hydrogen or a carboxyl protecting group, and Q is N or CH.

In the new process for the preparation of the cephem derivatives of the formula I, which is the subject of the invention, a new reactive thiophosphate derivative of thia (dia) acetic acid is used as a starting compound.

In previous publications and patents, numerous methods for the preparation of antibiotics (4 ldkam antibiotics) have been disclosed. Earlier processes for the preparation of derivatives of β-lactam antibiotics commonly started with an organic acid of the general formula 4, which was converted into its reactive derivative and then acylated with the amino group of the rings. β-lactam compounds of formula 4, wherein R, R5 and Q are as defined above.

Reactive derivatives of the compound of formula IV which were known from the above prior methods include acid chloride, reactive ester, reactive amide, mixed acid anhydride, etc. However, the acid chloride or mixed acid anhydride reactive derivative is prepared under stringent reaction conditions and additionally is unstable such that it would have to be used in situ in the acylation reaction without isolation. This can be a major cause of by-product formation. In addition, the reactive ester and the reactive amide of the compound of formula IV also have the disadvantages that they are produced in a low yield, their reactivity is very low for the required long reaction times and in addition it is very difficult to remove by-products, for example a hydroxy derivative such as such as 1-hydroxybenzotriazole and a thiol derivative such as 2-mercaptobenzothiazole.

In addition, Japanese Patent Laid-open Publication No. (Sho) 57-175196 discloses a compound of formula 6 wherein R-, R5 and Q are as defined above and R4 is C1-4alkU or phenyl, or together with an oxygen or phosphorus atom, to to which it is attached may form a 5- or 6-membered heterocyclic ring. This compound can be prepared from the organic acid of formula IV and the chlorophosphate derivative.

However, the compound of formula 6 is an unstable reactive mixed acid anhydride which cannot be isolated and therefore may cause an unfavorable reaction in the next step.

Thus, a continuous search has been made for a method for the preparation of cephalosporin derivatives which could solve the problems related to the above-described reactive derivatives. Currently, success has been achieved to obtain cephalosporin derivatives in a very convenient way using a new reactive thia (dia) acetic acid thiophosphate derivative with appropriate reactivity and stability, obtained in high yield and with high purity, from the organic acid of the formula 4 and the chlorothiophosphate derivative. Moreover, it has also been found that the cephem derivatives of the formula I, useful as antibiotics, can also be made more economically starting from this novel reactive thia (dia) acetic acid thiophosphate derivative.

According to the invention, a new process for the preparation of cephem derivatives of general formula I, in which R ¹ represents a carboxyl group or a protected carboxyl group, which can form a salt with the group -COO'M ⁺ with an alkali metal ion (M +) or can represent the group -COO 'when r2 contains a positively charged substituent, r2 is hydrogen, acyloxymethyl, heterocyclylmethyl or heterocyclylthiomethyl, where the term "heterocyclo" denotes a saturated or unsaturated 3- to 7-membered single ring containing at least one heteroatom

179 321 selected from nitrogen, oxygen and sulfur atoms or a multi-ring moiety formed by fusing two or more single rings, R ³ is hydrogen or an amino protecting group, R ⁵ is hydrogen, C 1-8 -alkyl or a group of the formula - C (R ^a ) (R ' ^b ) CO 2 R ^c , where R ^a and R "in a group of formula -C (R ^a ) (R ^b ) CO R ^C for r 5 are identical or different from any other moiety and are hydrogen or C 1-4 alkyl, or R ^a and R b together with the carbon atom to which they are bonded can form a (C 1-4 cycloalkyl group, and R c is hydrogen or a carboxy protecting group and Q is N or CH, characterized in that the reactive thia (dia) acetic acid phosphorothioate derivative of the general formula 2, in which R ³ , R ^' and Q are as defined above, and R ⁴ is C 1-6 alkyl or phenyl, is acylated with the 7- derivative 7 ACA of the general formula 3 in which R ¹ and R 2 are as defined above, and the reaction is carried out in the presence of a base and an organic solvent, water or a mixture thereof, preferably at 0-30 ° C.

As the solvent, a single solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, tetrahydrofuran dioxane, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, alcohols and water or a mixture of two or more solvents selected therefrom.

Preferably, an alcoholic solvent or an alcohol-water mixture is used as the solvent; more preferably methyl alcohol, ethyl alcohol or isopropyl alcohol.

The base is preferably a base selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, tri- (n-butyl) amine and diisopropylethylamine.

The reaction is preferably carried out at a temperature of 0-30 ° C.

Only a few of the many possible embodiments of the subject matter of the present invention have been sketched above. These variants should only be presented as illustrations for some of the more essential features and applications of the invention. Numerous, equally beneficial, results can be obtained by otherwise applying the disclosed invention or by modifying the invention within the scope of its disclosure. Accordingly, other objects and a more thorough understanding of the present invention may be obtained by referring to the disclosure of the invention and in addition to the scope of the invention as defined in the claims.

The present invention relates to a new process for the preparation of cephem derivatives represented by the general formula 1 above, which consists in that the new thia (dia) soloacetic acid thiophosphate reactive derivative of the above-defined formula 2 is acylated with the 7-ACA derivative of the above-defined formula 3 in the presence of a solvent and a base according to scheme 1 in the drawing.

In the above scheme, the symbols have the following meanings: R ¹ represents a carboxyl group or a protected carboxyl group that can form a salt of the group -COO'M '' with an alkali metal ion (M +) such as sodium, or may be a group -COO ' when R2 carries a positively charged substituent such as a pyridinium, pyrimidinium or thiazolyl group, R2 is hydrogen, acyloxymethyl, heterocyclomethyl or heterocyclylothiomethyl where the term "heterocycle" denotes a saturated or unsaturated 3- to 7-membered single ring containing at least one heteroatom selected from nitrogen, oxygen or sulfur atom or a group of polycyclic formed by condensing two or more of the individual rings, each of which groups may be substituted with appropriate substituents, R3 is hydrogen or an amino protecting group, R ⁴ is Cl alkyl or phenyl, R5 is hydrogen, C1 4alkyl or a group of formula -C (Ra) (Rb) C ^ 2Rc, wherein Rai Rb in the group of formula -C (Ra) (R °) CO2Rc for R5 are identical or different from any other moiety and are hydrogen or Ci -4-alkyl or Ra and R rasem with the carbon atom to which they are bound may form a C3-7cycloalkyl group, Rc is hydrogen or a carboxyl protecting group, and Q is N or CH.

179 321

In the term "acyloxymethyl" as used herein, the term "acyl" includes any acyl group commonly known in the art of β-lactam such as carbamoyl, aliphatic acyl groups, acyl groups containing an aromatic or heterocyclic ring, etc. A preferred example of an acyl group may be include C1-4 alkanoyl such as formyl, acetyl, propionyl, butyryl and the like, preferably C1-2 alkanoyl.

In the terms "heterocyclomethyl" and "heterocyclothiomethyl", the term "heterocyclo" can include a saturated or unsaturated 3- to 7-membered single ring having at least one heteroatom selected from nitrogen, oxygen and sulfur in the ring, or a multi-ring moiety formed by the condensation of two or more individual rings. Typical examples of such heterocycles are pyrrolidinyl, imidazolinyl, piperidinyl, piperazinyl, morpholinyl, thiazolidinyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and: zolyl (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, indolite, benzotriazolyl, tetrazolopyridyl, quinolyl, isoquinolyl, benzoxazolyl, benzothiazolyl and the like, which may be positively charged on the ring, possibly such as in pyridinium, pyrimidine, thiazolyl, etc., and which may be substituted with 1-4 appropriate substituents. Here, a preferred example of such suitable substituents are C14alkyl (e.g. methyl, ethyl, propyl, isopropyl, t-butyl etc.), C2-talcenyl (e.g. ethenyl, 1-propenyl, allyl, 1,3-butaciienyl, , etc.), C2-4alkynyl (e.g., ethynyl, 1- or 2-propynyl, etc.), C3-6cycloalkyl (e.g., cyclopropyl, cyclopentyl, etc.), halogen (e.g., chlorine, fluorine, iodine, etc.), substituted or unsubstituted amino group (e.g. amino, methylamino, ethylamino, N, N-diethylamino, etc.), phenyl substituted or unsubstituted with hydroxy, etc.

The process according to the invention shown in Scheme 1 consists in the use of a new reactive phosphorothioate derivative of the formula 2, showing the appropriate reactivity and stability as a reactive organic acid derivative, and therefore it can be widely used for the synthesis of the currently known cephalosporin derivatives containing the group

2- [aminotia (dia) zoyl] -2-methoxyiminoacetamide at the 7-position of the cephem ring.

In the process according to the invention, the reactive organic acid phosphorothioate derivative of formula II is preferably used in a slight excess to the compound of formula III to terminate the reaction. In general, the reactive organic acid phosphorothioate derivative can be used in an amount of 1.0 to 1.5 weight equivalents with respect to the compound of formula 3. However, for the sake of reaction and economy, the reactive phosphorothioate derivative of formula 2 is preferably used in an amount 1.0 to 1.2 weight equivalents with respect to the compound of formula 3.

In the process of the invention, both an inorganic and an organic base are preferably used as the reaction base. For this purpose, an inorganic base that can be used includes alkali metal carbonates or bicarbonates such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, etc. As the organic base, a tertiary amine such as triethylamine, tri-n can be used. -butylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, and the like. Of these bases, most preferably sodium bicarbonate, triethylamine, tri-n-butylamine, etc. can be used.

Although the used amount of the base may vary depending on the substituent ^R2, the base is used generally in an amount of from 1.5 to 3.5 equivalent weight, preferably from 2.0 to 3.0 equivalent weight with respect to the compound of Formula 3 .

As a solvent in the reaction according to the invention, each polar and non-polylated solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, acetone, N, N-dimethylformamide can be used individually. , alcohols such as methyl alcohol, ethyl alcohol or isopropyl alcohol, water, etc. However, in order to optimize the reactivity and separation of the reaction products, a solvent mixed with two or more solvents selected from the above-mentioned solvents, especially a mixed solvent alcohol can be effectively used ethyl-water.

179 321

Although the amount of solvent used is not critical, the amount of the solvent is generally used in an amount of 8-50 ml, preferably 10-30 ml, based on 10 mmol of starting material.

The reaction temperature in the process of the invention should not be limited, insofar as the temperature selected does not adversely affect the reaction of the invention. However, the reaction can generally be completed in 2-6 hours at 0-30 ° C, especially to rapidly produce the desired compound, more preferably at room temperature 20-25 ° C.

In Reaction Scheme 1, when R ³ is an amino protecting group, if desired, to obtain the desired compound of Formula 1 wherein R 3 is hydrogen, the resulting acyl compound can be subjected to a deprotection reaction.

Typical examples of compounds according to the invention include the following:

3-acetoxymethyl-7- [2- (2-ammo-4-thiazolyl) -2-methoxyimmo] acetamido-3-cephem-4-carboxylic acid (Cefotaxime);

acid ['[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido] -3 - [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2 , 4-triazin-3-yl) thiomethyl] -3-cephem-4-carboxylic acid (Ceftriaxone); acid 7 - [[α- (2-amino-4-thiazolyl) -2- (Z) -methoxyimmo] acettanido] -3 - [[1-methyl-1H-tetrazol-5-yl) -thiom.ethyl] cephem-4 -carboxylic acid (Cefmenoxime);

7- [2-methoxyimino-2- (2-amino-1,3-triazol-4-yl) acetamido-3-cephem-4-carboxylic acid (Ceftizoxime);

7 - [[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino-acetamido-3- (2,3-dicyclopentenopyridinomethyl) -3-cephem-4-carboxylate (Cefpyrome);

7 - [[2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido-3- (1-methylpyrrolidinomethyl) -3-cephem-4-carboxylate (Cefepime);

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido] -3- (4,6-diamino-1,1-dimethylpyrimidim-2-yl) thiomethyl) -3 -cefemo-4-carboxylate;

7 - [[(Z) -2- (2-amino-1,2,4-thiazol-3-yl) -2-methoxyimino-acetamido - 3- (4,6-diamino-1-methylpyrimino- 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-ethylpyrimidinium-2- yl) thiomethyl) -3-cephem-4-carboxylate;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido] -3- (1,4,6-triaminopyrimidin-2-yl) thiomethyl) -3-cephem-4-carboxylate ;

7- [j (Z) -2- (2-ammo-4-thiazclicc) -2-methoxyimino] acetamido] -3- (4,6-di; nnino-1,5-dimethylpyrimidin-2-yl) thiomethyl) -3-cephem-4-carboxylate;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido] -3- (2,6-diamino-1-methylpyrimidinκ] -4-yl) thiomethyl]]) - 3-cfeemo-4-carboxylate;

7 - [[(Z) -2- (2-ammo-4-thiazolyl) -2-methoxyimino-acetamido] -3- (2,6-diamino-1-ethylpyrimidin-4-yl) thiomethyl) -3-cephem -4-carboxylate;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido - 3- (2,6-diamino-3-ethylpyrimidin-4-yl) thiomethyl) -3-ceeemo -4-carboxylate;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimmo] acetamido-3-cephem-4-carboxylate;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido - 3- (4,5,6-triamino-1-methylpyrimidin-2-yl) thiomethyl) -3 -Cfeemo-4-carboxylate;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido] -3- (4-amino-1-methylpyrimidinium-2-yl) thiomethyl) -3-cffemo-4 -carboxylate;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido] ^ 3- (4-a ^^ and ^ (^ -1-methylpyrimidin-2-yl) thi] ] methyl) --- cffemo-4-carboxylate;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido] -3- (4-amino-1-carboxymethylpyrimidinium-2-yl) thiomethyl-3-cefemp-4- k? n -boxylate;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido] -3- (4-amino-1-aminopyrimidin-2-yl) thiomethyl) ^ 3 - ^ (^ efeem (-4J4 ^ و r ^ bc ^ ks ^ yla ^ n;

179 321

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1,4,5-triaminopyimidinium-2-yl) thiomethyl) -3-cephem-4-carboxylate ;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acet: amido] -3- (4-amino-1-methyl-6- (N, N-dimethyl) aminopyrimidinium -2-yl) thiomethyl) -3-cephem-4-carboxylate;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetίanido]] 3- (1,4,5,6-tetraa: minopyrimidinium-2-yl) thiomethyl-3- cephem-4-carboxylate;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetanido] -3- (1,4-diamino-5-methylpyrimidinium-2-yl) thiomethyl) -3-cfeemo -4-kirrboxylam;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetanido] -3- (1,4-diamino-5-ethylpyrimidinium-1-yl} thiomethido-U-cephem-d-cyrroxylate;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetanido] -3- (1,4-diamino-6- (N-methyl) aminopyridin-2-yl) thiomethyl ) -3-cephem-4-carboxylate;

7 - [[(Z) -2- (2-amino-4-thiazoIyl) -2-methoxyimino] acetanido]] 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-methoxyimino] acetamido] -3- (3,4-diamino-3,5,6,7-tetrahydrocySk] pentapiaimidinium-2- yl) thiometic)) - 3-cephem-4-sarboxylan;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (2-amino-1-methyl-1,5,6,7-tetrahydrocyldopentapiaimidim-4-yl) thiomethyl) -3-cephem-4-carboxylate;

7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetiarado] -3- (1,2-dia.mino-1,5,6,7-tetrahydrocyclopentapyrimίdynto-2- yl) thiomethyl) -3-cephem-4-carboxylate;

7i [[(Z) -2i (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (7-amino-1-methyl [1,2,4] triai zolo [1,5iC] pyrimidine] - 5-ylJ-3-cephem-4-carboSykin; or

7 - [[(Z) -2i (2iaminOi4ithiazolyl) i2-methoxyimino] acebaΉido] -3- (1-methyl [1,3] imidazo [1,2-c] and pyrimidIlk] -5-yl) thiometic - 3-cephem (--4-carboxym.

The present invention uses a new reactive thiophosphate derivative of thia (dia) zolooctowego of the general formula 2, wherein R3 is hydrogen or an amino protecting group, R ⁴ is C ^ alkyl or phenyl, R ⁵ is a hydrogen atom C14alkil or a of formula -C (Ra) ^(Rb) C0> 2RC, wherein Ra and Rb in the group of formula -C (Ra) (Rb) C0 ₂ R ^ to R5 are identical or different from each other moieties and hydrogen or CM-alkyl or Ra and Rb together with the carbon atom to which they are attached may form a C3-7cycloalkyl group. Rc is a hydrogen atom or a carboxyl protecting group and Q is N or CH. The compound of formula II is used as a starting material in the process for the preparation of the cephem derivatives of the general formula I according to the invention.

The new reactive phosphorothioate derivative represented by the general formula 2, wherein R3, r4, r5 and Q are as defined above, is obtained by the method in which the organic acid of formula 4 wherein R3, r5 and Q are as defined above, is reacted with a chlorothiophosphate derivative of the general formula 5 in which R4 is as defined above, the reactions being carried out in a solvent in the presence of a base and a catalyst.

Preferably, in the compound of formula II, R3 is hydrogen or triphenylmethyl, R is methyl, ethyl or phenyl and R5 is hydrogen, methyl, ethyl or t-butoxySarbOi nylisopropyl.

Compounds of formula II which are preferably used in the process of the present invention are the following compounds: diethylthiophosphoryl (Z) - (2-amino-thiazol-4-yl) methoxyiminoacetate, (Z) and diethylthiophosphoryl (2-triphenylmethyl) amino-thiazol-4-yl) methoxyiminoacetate, (ZjM-aminothia Diethylthiophosphoryl -ylojetoxyiminoacetate, (Z) and diethylthiophosphoryl (2-aminothiazol-4-yl) -ethoxyiminoacetate, (Z) - (2-triphenylmethyl, aminothiophosphoryl-4-yl) ethoxyiminoacetate, (Z) -2-triaminomethyl (2-ylthiophosphoryl) tibutoxycarbonyl) isopyopoxy and diethylthiophosphoryl iminoacetate and diethylthiophosphoryl (Z) and (3-amino-1,2,4-thiadiazolyl) ethoxyiminoacetate.

A process for preparing phosphorothioate reactive derivative of an organic acid of formula 2 is outlined in Scheme 2 of the drawing, in which R3, R4, ^R5 and Q are as defined above.

179 321

In Reaction Scheme 2 the amino protecting group for R ³ is used commonly optionally substituted acyl, optionally substituted aryl (lower) alkyl (eg. Benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, etc.), Halo (lower) alkyl ( e.g., trichloro-methyl, trichioroethyl, etc.), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted arylalkylidene, substituted cycloalkylidene, etc. A suitable acyl as amino protecting group may be an aliphatic acyl group or an acyl group with an aromatic or heterocyclic group . Such an acyl group includes, for example, lower alkanoyl of 1-6 carbon atoms (e.g., formyl, acyl, etc.), alkoxycarbonyl of 2-6 carbon atoms (e.g., methoxycarbonyl, ejoxycarbonyl, etc.), lower alkanesulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.) or aryl (lower) alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.) and the like groups. The above-mentioned acyl group may contain 1-3 substituents selected from the group consisting of halogen atom, hydroxyl, cyano, nitro group, etc. In addition, the product of the action of the amino group with silane, borane, phosphorus compound, etc. may also work. as an amino protecting group.

When in the group of formula -C (Ra) (R ^b ) CC 2 R ^c for R ⁵ , R ^c is a carboxyl protecting group, a suitable example of a carboxyl protecting group is a (lower) alkyl ester (e.g. methyl ester, t ester) -butyl, etc.), (lower) alkenyl ester (e.g., vinyl ester, allic ester, etc.), (lower) alkoxy (lower) alkyl ester (e.g., methoxymethyl ester, etc.), (lower) alkylthio ester (lower) alkyl ester (e.g. methylthiomethyl ester), halo (lower) alkyl ester (e.g. 2,2,2-trichloroethyl ester), optionally substituted arylalkyl ester (e.g. benzyl ester, p-nitrobernzyl ester etc.) or ester silyl, etc.

In the preparation of the reactive phosphorothioate derivative of formula 2 as shown in Scheme 2, the compound of formula 5 is generally used in an amount of C, 5-2, C equivalents by weight, preferably 1.0-1.3 weight equivalents based on the acid. organic compound of formula 4. Furthermore, the reaction can be carried out without any catalyst. However, the catalystless reaction requires a long reaction time, during which by-products can be formed. In contrast, when the reaction is carried out in the presence of a suitable catalyst, the reaction can be carried out in a short reaction time, under mild conditions and without the formation of by-products.

Although a suitable catalyst that can be used in the reaction of Scheme 2 includes tertiary amines, quaternary ammonium or phosphonium compounds, etc., in any case, the catalyst with optimal properties should be selected as the reaction rate may vary with the organic acid used. formula 4, type and amount of catalyst, etc. Examples of tertiary amine catalysts may include 2,4-dimethyl-2,4-diazapentane, 2,5-dimethyl-2,5-diazahexane, N, N, N ', N '-tetramethyl-1,2-diaminocyclohexane, 1,4-dimethyl-1,4-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 ^ 07 ^ 0 ^ 0-2,5,8,11-tetraazadodecane, etc. Suitable examples of quaternary ammonium compounds may include the following: tetra-n-tetramethyl bromide: n-bult ^ 1 ^ oa ^ '^' n ^ ^ ^ ^, tetra-n-butyl ammonium chloride, cetyl trimethyl ammonium bromide, tetra-n- iodide butydoamo sodium chloride, methyltri-2-methylphenylammonium chloride and the like. Furthermore, tetra-n-butylphosphonium bromide is preferably used as the phosphonium compound. The catalyst is generally used in a ratio of C, 1-5C%, preferably C, 5-5% on a molar basis, based on the organic acid of formula 4.

As a solvent for the reaction of Scheme 2, polar or non-polar organic solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, acetone, N, N-dimethylformamide, N, N- dimethylacetamide and the like. However, a solvent mixed with two or more of the above-mentioned solvents may also be used to ensure optimal reactivity and high yield of the reaction product.

Suitable bases that can be used in the reaction of Scheme 2 include inorganic bases, for example, alkali metal carbonates or bicarbonates such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate and the like;

Organic bases, for example a tertiary amine such as tri (n-butyl) amine. Most preferably, diisopropylethylamine or tri-n-butylamine is used.

In the reaction of Scheme 2, a reaction temperature ranging from -40 ° C to 60 ° C, preferably -15 ° C to 25 ° C can be used. Especially when using a reaction temperature in the range of 0 ° C to 20 ° C, the reaction can be carried out under mild conditions, within 1 to 3 hours, easily obtaining the desired compound of formula 2.

The reactive organic acid phosphorothioate derivative of formula II, prepared by the method according to scheme 2, has unique physico-chemical properties. Namely, the reactive organic acid phosphorothioate derivative of formula II has good stability in a polar or non-polar organic solvent such that the derivative cannot decompose into the organic acid of formula IV, even when the phosphorothioate is reactive. the derivative of the organic acid is dissolved in such a solvent which is washed with acidified, basic or neutral water. Moreover, when a reactive organic acid thiophosphate derivative is used in the acylation reaction with the amino group of the β-lactam ring, this reaction can be carried out quickly even under mild conditions, and the phosphorothioic acid derivative that is formed as a by-product is contained in the aqueous layer in the form of dissolved and can therefore be removed quickly.

Further, in the reaction of Scheme 2, although the compound of Formula 2 may be acylated after protection of the R3 group with an amino protecting group, the acylation reaction can also be carried out without any limitation with a compound of Formula 2 which has no group. an amino protecting group. Thus, when the process of the invention is used industrially for the preparation of the compound of formula 1, it is of great advantage that the final antibiotics [i-lactam can be synthesized quickly with high yield and a high purity product is obtained.

In the following, the invention will be explained in detail in the following examples. However, since the main characteristic of the present invention resides in the previously described novel process for the preparation of cephalosporin derivatives using the novel reactive phosphorothioate derivative of an organic acid of formula 2, the technical scope of the present invention should not be limited to the examples below, unless such a system is maintained. .

Example 1 Synthesis of (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate of diethylthiophosphoryl.

(Z) - (2-aminothiazol-4-yl) methoxyiminoacetic acid (20.1 g), tri-n-butylamine (24.1 [mu] g) and 1,4-diazabicyclo [2.2.2] octal and ( 0.11 g) was suspended in anhydrous dichloromethane (200 ml) and then diethyl chlorothiophosphate (24.52 g) was added dropwise thereto over 20 minutes while maintaining the reaction mixture under nitrogen at 0-5 ° C in a cooling bath. The mixture was stirred for an additional 2 hours. After completion of the reaction, distilled water (300 mL) was added to the reaction solution, followed by stirring for 5 minutes. The organic phase was separated, washed sequentially with 5% aqueous sodium bicarbonate (300 mL) and saturated brine (300 mL), dried with magnesium sulfate, filtered and then concentrated under reduced pressure. Normal hexane (400 mL) was added to the concentrated solution until the product solidified, which was then filtered, washed with normal hexane (100 mL), and dried. 33.2 g (94.0% yield) of the title compound was obtained as a light yellow solid.

Melting point: 87-88 ° C.

NMR (δ, CDCl,): 1.38 (t, 6H), 4.05 (s, 3H), 4.31 (m, 4H), 5.49 (bs, 2H), 6.87 (s , 1H).

Example II. Synthesis of diethylthiophosphoryl (Z) - (2-aminothiazol-4-yl) -2- (t-butoxycarbonyl) isopropoxyiminoacetate.

(Z) - (2-Aminothiazol-4-yl) -2- (t-butoxycartonyl) isopropoxyiminoacetic acid (32.9 g). tri-n-butylamine (22.25 g) yl, 4-diaazabicyclo [2.2.2] octane (0.11 g) was dissolved in anhydrous N, N-dimethylacetamide (100 ml) and then chlorothiophosphate was added dropwise over 20 minutes diethyl (22.63 g) while keeping the reaction solution in a cooling bath at 0-5 ° C. The mixture was stirred for an additional 2 hours. Ethyl acetate (300 ml) and distilled water (300 ml) were added to the reaction mixture, followed by stirring for 5 minutes. The organic phase was separated, washed successively with 5% aqueous sodium bicarbonate (300 ml) and saturated brine (300 ml), dried with magnesium sulfate, filtered and then concentrated under reduced pressure. Cyclohexane (100 ml) was added to the concentrated solution until the product solidified, which was then filtered, washed with cyclohexane (50 ml) and dried.

44.26 g (92% yield) of the title compound were obtained as a light white solid.

Melting point: 114-115 ° C.

NMR (δ, CDClj): 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 III. Synthesis of (Z) - (2-aminothiazol-4-yl) ethoxyiminooetaiudiethylthiophosphoryl.

Using a procedure analogous to that of Example 2 and starting from (Z) - (2-aminothiazole. 2 -N ^ ^ ^: ^ o) et ^ l ^; yim ^ acetic acid (21.5 g) 33.04 g (90% yield) were prepared the title compound.

Melting point: 118-119 ° C.

NMR (δ, CDCl3): 1.35 (m, 9H), 4.32 (m, 6H), 5.67 (bs, 2H), 6.82 (s, 1H).

Example IV. Synthesis of diethylthiophosphoryl (Z) - (2-triphenylmethylaminothiazol-4-yl) ethoxyiminoacetate.

Using an analogous procedure to Example 1 starting from (Z) - (2-triphenylmethylaninotet! Az) 1-4-yl) ethoxyiminoacetic acid (45.7 g), 57.2 g of the title compound were prepared.

Melting point: 98-99 ° C.

NMR (δ, CDClj): 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-triphenylmethylaminothiazol-4-yl) methoxyiminoacetate.

Using an analogous procedure to Example 1 starting from (Z) - (2-triphenylmethylaminotazol-4-yl) methoxyiminoacetic acid (44.3 g), 57.4 g of the title compound were prepared.

Melting point: 101-103 ° C.

NMR (δ, CDClj): 1.32 (m, 6H), 4.02 (s, 3H), 4.28 (m, 4H), 6.62 (s, 1H), 7.00 (bs, 1H ). 7.28 (m, 15H).

Example VI. Synthesis of diethylthiophosphoryl (Z) - (2-triphenylmethylaminothiazol-4-yl) -2- (t-butoxycarbonyl) isopropoxyiminoacetate.

Using an analogous procedure to Example 1, starting from (Z) - (2-triphenylmethylaminoticaol-4-yl) -2- (t-butoxycarbonyl) isopropoxyiminoacetic acid (57.1 g), 68.46 g (90% yield) of the title compound were prepared.

Melting point: 101-103 ° C.

NMR (δ, CDClj): 1.33 (t, 6H), 1.41 (s, 9H), 1.52 (s, 6H), 4.30 (m, 4H), 6.63 (s, 1H ), 6.80 (bs, 1H), 7.25 (m, 15H).

Example VII. Synthesis of diethylthiophosphoryl (Z) - (3-amino-1,2,4-thiadiazol-5-yl) ethoxyiminoacetate.

Using an analogous procedure to Example 1 starting from (Z) - (3-amino-1,2,4-thiadiiaol-5-yl) ethoxyiminoacetic acid (21.6 g), 33 g of the title compound were prepared.

Melting point: 132-133 ° C.

NMR (δ, CDCl3): 1.37 (m, 9H), 4.36 (m, 6H), 6.49 (bs, 2H).

Example VIII. Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido-3-cephem-4-carboxylic acid (Cefotaxime).

7-Aminocephalosporanic acid (54.46 g) and (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate were added successively to distilled water (200 mL) and tetrahydrofuran (200 mL) in a 1 L round bottom flask with stirring. diethylthiophosphoryl (77.7 g). After addition of tri-n-butylamine (74.15 g), the reaction mixture was stirred for 3 hours maintaining the temperature at 20-25 ° C and then extracted with 12% aqueous sodium carbonate (453 g) and ethyl acetate (100 ml) to remove organic phase. The separated organic phase was back-extracted with ethyl acetate (100 mL) to remove the organic phase. The aqueous phase was then neutralized with a 20% aqueous sulfuric acid solution to pH 6. Activated charcoal (10 g) was added to the neutralized aqueous solution, followed by stirring for 30 minutes and filtering. The filtrate was saturated

179 321 with sodium chloride. The saturated aqueous solution was adjusted to pH 4 by adding 20% aqueous sulfuric acid. After adding a small amount of the title compound, the mixture was then adjusted to pH 2.5 by further adding 20% aqueous sulfuric acid. The crystals precipitated completely, filtered, washed with water and then dried to give 83.8 g (92% yield) of the title compound as a light yellow solid.

HPLC purity: 98.5%.

Example IX. Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetanido-3-cephem-4-carboxylic acid (Cefotaxime).

Distilled water (200 mL), 7-aminocephalosporanic acid (54.46 g) and sodium bicarbonate (33.6 g) were added to a 1 L round bottom flask and then completely dissolved by stirring at room temperature. To this reaction solution were added tetrahydrofuran (200 ml) and diethylthiophosphoryl (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate (77.74 g), and the mixture was stirred for 5 hours at 20-25 ° C. The reaction solution was extracted with ethyl acetate (100 ml) to remove the organic phase and the separated aqueous phase was extracted again with ethyl acetate (100 ml) and then neutralized to pH 6 by adding 20% aqueous sulfuric acid. Activated charcoal (10 g) was added to the neutralized aqueous solution, followed by stirring for 30 minutes and filtering. The filtrate was saturated with sodium chloride. This saturated aqueous solution was adjusted to pH 4 by the addition of 20% aqueous sulfuric acid. After addition of a small amount of the title compound, the mixture was re-adjusted to pH 2.5 by additional addition of 20% aqueous sulfuric acid. After the crystals had completely precipitated, they were filtered off, washed with water, and then dried to obtain 81.07 g (89% yield) of the title compound as a light yellow solid.

HPLC purity: 98.6%.

Example X. Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino | -acetamido-3-cephem-4-carboxylic acid (Cefotaxime).

Using an analogous procedure to Example 9 except that triethylamine (40.48 g) was used in place of sodium bicarbonate, afforded 77.43 g (85% yield) of the title compound.

HPLC purity: 98.4%.

Example XI. Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thi & zolyl) -2-methoxyimino] -acetianido-3-cephem-4-carboxylic acid (Cefotaxime).

Using an analogous procedure to Example 8 except that N, N-dimethylacetamide (100 ml) and dichloromethane (400 ml) were used instead of distilled water and tetrahydrofuran and dichloromethane (100 ml) were used instead of ethyl acetate as the extraction solvent (100 ml). (90% yield) of the title compound.

HPLC purity: 98.6%.

Example XII. Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino | -acetaimi ^ (^^^^^^ cephem-4-carboxylic acid (Cefotaxime).

While stirring, 7-aminocephalosporanic acid (54.46 g) and (Z) - (2-aminothi ^ <^ i-4-) were added successively to 95% ethyl alcohol (400 ml) in a 1 liter round bottom flask. il) diethylthiophosphoryl methoxyiminoacetate (77.74 g). After adding triethylamine (40.48 g), the reaction mixture was stirred for 3 hours maintaining the temperature at 20-25 ° C and then concentrated hydrochloric acid (31.25 g) diluted with 95% ethyl alcohol (200 ml) was added. The mixture was vigorously stirred for about one hour until crystals precipitated. The precipitated crystals were filtered, washed with water and then dried to obtain 83.3 g (92% yield) of the title compound as a white solid.

HPLC purity: 98.6%.

Example XIII. Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido-3-cephem-4-carboxylic acid (Cefotaxime).

Using an analogous procedure to Example 12 except distilled water (100 ml) and isopropyl alcohol (400 ml) were used instead of ethyl alcohol, to obtain 82.0 g (90% yield) of the title compound.

HPLC purity: 98.4%.

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Example XIV. Synthesis of 7 - [[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido] -3 - [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo -1,2,4-triazin-3-yl) -thiomethyl] -3-cephem-4-carboxylic acid (Ceftriaxone).

To distilled water (200 mL) and tetrahydrofuran (200 mL) in a 1 L round bottom flask, 7-amino-3 - [(2,5-dihydro-6-hy (dOxy-2-methyl-5- oxo-1,2,4-triazin-3-yl) thiomethyl] -3-cephem-4-carboxylic acid (37.1 g), (Z) - (2-ammothiazol-4-yl) metoS; diethylthiophosphoryl siminoacetate (38 , 8 g) and trin-butylamine (55.7 g). This reaction solution was stirred for 3 hours maintaining the temperature at 20-25 ° C, and then toluene (200 ml) was added thereto to remove the organic phase. The aqueous phase was adjusted to pH 3. by adding 20% aqueous sulfuric acid solution While cooling with ice, the solution containing the precipitated product was thoroughly stirred for one hour The obtained product was filtered, washed with water and then dried to obtain 50.7 g (91.5% yield) of the title product.

HPLC purity: 99.3%.

Example XV. Synthesis of the acid 7 - [[2- (2-ammo-4-thiazolyl) -2- (Z) -methoxyimmo] acttamido] -3- [2,5-dihydro-6-hydroxy-2-methyl-5-oxo- 1,2,4-tri-zin-3-yl) -thiomethyl] -3-cephem-4-carboxylic acid (Ceftriaxone).

7-Amino-3 - [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-L2,4-) acid was sequentially added to 95% ethyl alcohol (400 mL) in a 1 L round bottom flask with stirring. triazin-3-yl) thiomethyl] -3-ceftmo-4-carboxylic acid (37.1 g), (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate diethylthiophosphoryl (38.8 g) and triethylamine (30.36 g). While maintaining the temperature at 20-25 ° C, the reaction solution was stirred for 3 hours, and then concentrated hydrochloric acid (26.04 g) diluted with 95% ethyl alcohol (200 ml) was added. The solution containing the precipitated product was stirred for one hour while cooling with ice. The obtained product was filtered, washed with water and then dried to obtain 50.7 g (yield 91.5%) of the title product.

HPLC purity: 99.3%.

Example XVI. Synthesis of 7 - [[2- (2-amino-4-thiazolyl) -2- (Z) -mttoxyimino] acetamido] -3 - [(1-methyl-1H-tetrazol-5-yl-phthiomethyl] -3-cephemcM carboxylic acid (Cefmenoxime).

To a 1 L round bottom flask was charged distilled water (100 mL), 7-amino-3 - [(1-methyl-1H-terrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid (32.8 g) and sodium bicarbonate (16.8 g) and complete dissolution by stirring at room temperature. Then dieththiophosphoryl (Z) - (2-aminothiazoL4-yl) methoxyiminoacetate (38.8 g) dissolved in tetrahydrofuran (100 ml) was added and the mixture was stirred at 20-25 ° C for 5 hours. Ethyl acetate (2 x 100 mL) was added to the reaction solution to separate the organic phase. The aqueous phase was then adjusted to pH 3.1 with 2N aqueous hydrochloric acid and stirred for one hour while cooling with ice. The resulting precipitate was filtered, washed with water and then dried to afford 46.3 g (yield 90.6%) of the title compound.

HPLC purity: 99.4%.

Example XVII. Synthesis of the acid 7 - [[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetαmdo] -3 - [(1-methyl-1H-tttriα; ol-5-yl) -thiometh- lo] -3-ceftmo-4-carboxylic acid (Cefmenoxime).

7-Amino-3 - [(1-methyl-1H-telrazol-5-yl) thiomethyl] -3-cephem 4-carboxylic acid (32.8) was successively added to 95% ethyl alcohol (400 ml) in a round bottom flask with stirring. g), diethylthiophosphoryl (Z) -2- (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 g) and triethylamine (20.24 g). The mixture was stirred at 20-25 ° C for 5 hours, and concentrated hydrochloric acid (15.63 g) diluted with 95% ethyl alcohol (200 ml) was added thereto. The reaction mixture was stirred for one hour while cooling with ice. The resulting precipitate was filtered, washed with water and then dried to afford 46.3 g (yield 90.6%) of the title compound.

HPLC purity: 99.4%.

179 321

Example XVIII. Synthesis of 7 - [[2-methoxyimino-2- (2-amino-1,3-triazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Ceftizoxime).

Distilled water (100 mL), 7-amino-3-cephem-4-carboxylic acid (20 g) and sodium bicarbonate (16.8 g) were added to a 1 L round bottom flask and brought to room temperature while stirring at room temperature. completely dissolved. Then dieththiophosphoryl (Z) -2- (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 g) dissolved in tetrahydrofuran (100 ml) was added and the mixture was stirred at 20-25 ° C for 5 hours. Ethyl acetate (2 x 100 mL) was added to the reaction solution to separate the organic phase. The aqueous phase was then adjusted to pH 3.1 with 2N aqueous hydrochloric acid and stirred for one hour while cooling with ice. The obtained precipitate was filtered, washed with water and then dried to obtain 35.8 g (yield 93.4%) of the title compound.

HPLC purity: 98.4%.

Example XIX. Synthesis of Y-l'-methoxyimino-l-l-amino-lJ-triazoM-yl) aeetamido] -3-cephem-4-carboxylic acid (Ceftizoxime).

7-Amino-3-cephem-4-carboxylic acid (20 g), (Z) -2- (2-aminothiazol-4-yl) methoxyiminoacetate was successively added to 95% ethyl alcohol (400 ml) placed in a round bottom flask with stirring. diethylthiophosphoryl (38.8 g) and triethylamine (20.24 g). The mixture was stirred at 20-25 ° C for 5 hours, and concentrated hydrochloric acid (15.63 g) diluted with 95% ethyl alcohol (200 ml) was added thereto. The reaction mixture was stirred for one hour while cooling with ice. The obtained precipitate was filtered, washed with water and then dried to obtain 35.8 g (yield 93.4%) of the title compound.

HPLC purity: 98.4%.

Example XX. Synthesis of 7 - [[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido] -3- (2,3-cyclopentenopyridinomethyl) -3-cephem-4-carboxylate (Cefpyrome) sulfate.

To distilled water (100 mL) and tetrahydrofuran (100 mL) in a 1 L round bottom flask, 7-amino-3- (2,3-cyclopentenopyridinomethyl) -3-cephem-4-carboxylate (45.9 g) hydroiodide was added sequentially with stirring. ), (Z) - (2-aminothiazol-4-yl) -methoxyiminoacetate diethylthiophosphoryl acetate (38.8 g) and tri-n-butylamine (37.2 g). The reaction mixture was stirred for 3 hours maintaining the temperature at 20-25 ° C and then ethyl acetate (2 x 100 ml) was added to remove the organic phase. The aqueous phase was adjusted to pH 1.2 with 20% aqueous sulfuric acid. Ethyl alcohol (300 ml) was slowly added to this solution while maintaining the temperature at 0-5 ° C, followed by thorough stirring for one hour. The obtained precipitate was filtered off, washed with water and then dried to obtain 47.1 g (76.9% yield) of the title compound.

HPLC purity: 98.1%.

Example XXI. Synthesis of 7 - [[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido] -3- (2.3-cyclopentenopyridinomethyl) -3-c.efem-4-carboxylate (Cefpyrome) sulfate.

7-Amino-3- (2,3-cyclopentenopyridinomethyl) -3-cephem-4-carboxylate (45.9 g) hydroiodide was sequentially added to 95% ethyl alcohol (400 mL) in a 1 L round bottom flask with stirring. Diethylthiophosphoryl (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 g) and triethylamine (20.2 g). While maintaining the temperature at 20-25 ° C, the reaction solution was stirred for 3 hours and then concentrated sulfuric acid (12.25 g) diluted with 95% ethyl alcohol (300 ml) was added. The temperature was kept at 0-5 ° C and stirred for one hour. The obtained precipitate was filtered, washed with water and then dried to obtain 47.1 g (76.9% yield) of the title product.

HPLC purity: 98.1%.

Example XXII. Synthesis of 7 - [[2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1-methylpyrrolidinomethyl) -3-cephem-4-carboxylate (Cefepime) sulfate.

To distilled water (100 ml) and tetrahydrofuran (100 ml) placed in a 1 liter round bottom flask, 7-amino-3- (1-methylpyrrolidinomethyl) -3-cephem-4-carboxylate hydroiodide (43.4 g) was added sequentially with stirring. Diethylthiophosphoryl (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 g) and triethylamine (20.2 g). Reaction mixture 14

The mixture was stirred for 4 hours maintaining the temperature at 20-25 ° C and then ethyl acetate (2 x 100 ml) was added to remove the organic phase. Activated charcoal (5 g) was added to the aqueous phase and the mixture was stirred for 30 minutes and then filtered. The filtrate was adjusted to pH 1.2 with aqueous sulfuric acid and then acetone (400 ml) was added slowly. The mixture was stirred for one hour. The resulting precipitate was filtered, washed with water and then dried to give 45.1 g (78% yield) of the title compound.

HPLC purity: 97.1%.

Example XXIII. Synthesis of 7 - [[2- (2-amino-4-thiazolyl) -2-methoxyimino] acetainido '] - 3- (1-methylpyrrolidinomethyl) -3-cephem-4-carboxylate (Cefepime) sulfate.

7-Amino-3- (1-methylpyrrolidinomethyl) -3-ceiem-4-carboxylate (43.4 g) hydroiodide (43.4 g) was sequentially added to 95% ethyl alcohol (400 mL) in a 1 L round bottom flask with stirring. ) - (2-aminothi & zol-4-yl) methoxyiminoacetate diethylthiophosphoryl (38.8 g) and triethylamine (20.2 g). While maintaining the temperature at 20-25 ° C, the reaction solution was stirred for 4 hours, and then activated charcoal (5 g) was added. It was then stirred for 30 minutes and filtered. Concentrated sulfuric acid (12.25 g) diluted with 95% ethyl alcohol (400 ml) was added to the filtrate and stirred for one hour while maintaining the temperature at 0-5 ° C. The resulting precipitate was filtered, washed with water and then dried to give 45.1 g (78% yield) of the title compound.

HPLC purity: 97%.

While the invention has been described in its preferred form with some degree of detail, it will be appreciated by those skilled in the art that the preferred form of the disclosure was made to illustrate an exemplary embodiment and that numerous changes to details of construction, connection and arrangement of parts can be made without prejudice the nature and scope of the invention.

179 321

179 321

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179 321

Principle

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Formula 2

Scheme 1

179 321

F ^ HN © R ⁵ s' ir u _z , ccop (or% o

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Publishing Department of the UP RP. Nakiad 70 copies. Price PLN 4.00.

Claims (5)

Patent claims 1. A new process for the preparation of cephem derivatives of general formula I, in which R ¹ is a carboxy group, or a protected carboxyl group which can form a salt of the group -COO'M + with an alkali metal ion (M +) or can be a group of -COO 'when R ² has a positively charged substituent, R ² is a hydrogen atom , acyloxymethyl, or heterocyclothiomethyl, where the term "heterocyclo" denotes a saturated or unsaturated 3- to 7-membered single ring containing at least one heteroatom selected from nitrogen, oxygen and sulfur atoms, or a polycyclic moiety formed by fusing two or more individual rings , R ³ is hydrogen or an amino protecting group, R ⁵ is hydrogen, C 1-6 alkyl or a group of the formula -C (R ^a ) (R ^b ) CO 2 R ^c , where R ^a and R ^b in the group o of the formula -C (R ^a ) (R ^b ) CO 2 R ^c for R 5 are identical or different from any other moiety and represent a hydrogen atom or a C 1 -alkyl or Ra and Rb together with the carbon atom to which they are bonded ne may form a 3-7 cycloalkyl, and R c is hydrogen or a carboxyl protecting group and Q represents N or CH, characterized in that a reactive thiophosphate derivative of thia (dia) zolooctowego of the general formula 2, wherein R ^3, R ⁵ and Q are as defined above, and R ⁴ is C ¹ -alkyl or phenyl, is acylated with the 7-ACA derivative of the general formula 3 in which R 1 and R 2 are as defined above, in the presence of a base and a solvent organic, water or their mixture, preferably at a temperature of 0-30 ^o C. 2. The method according to p. The process of claim 1, characterized in that a single solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, acetone, N, N-dimethylformamide, N, is used as the solvent. N-dimethylacetamide, alcohols and water or a mixture of two or more solvents selected therefrom. 3. The method according to p. The process of claim 2, wherein the solvent is an alcohol solvent or an alcohol-water mixture. 4. The method according to p. The process of claim 3, wherein the alcohol solvent is methyl alcohol, ethyl alcohol or isopropyl alcohol. 5. The method according to p. The process of claim 1, wherein the base is a base selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, tri- (n-butyl) amine and diisopropylethylamine.