HU191478B - Process for preparing cefem-carboxylic acid derivatives - Google Patents

Abstract

PURPOSE:To obtan the titled compound useful as an antibacterial agent, in high yield, by reacting a starting compound with a nucleophilic compound and a trivalent or pentavalent cyclic phosphorus compound having specific partial structure, etc. CONSTITUTION:The objective compound of formula IV (R<4> is residue of nucleophilic compound) is prepared by reacting (A) the compound of formulaI(R<1> is H or acyl; R is H or ester residue; the dotted line represents the double bond at the 2- or 3-position of the cephem ring) with (B) a nucleophilic compound (e.g. trialkylamine) and (C) a trivalent or pentavalent cyclic phosphorus compound having the partial structure of formula II (W is O, S or NR<2>; W<1> is O, S or NR<3>; R<2> and R<3> are H or hydrocarbon group) or (C') a reaction product of the compound having the partial structure of formula III with phosphorus oxyhalide, phosphorus trihalide or phosphorus pentahalide, in an organic solvent. The OH group in the hydroxymethyl group at the 3-position of the compound of formulaIcan be substituted with a nucleophilic compound in one step, in a short time, under mild conditions.

Description

The present invention relates to a novel process for the preparation of cephem carboxylic acid derivatives of the formula (I) or their salts

R ¹ is hydrogen; C 1 -C 8 alkanoyl optionally substituted with one or two substituents selected from the group consisting of phenyl, thienyl, aminothiazolyl, carboxyl, (C 1 -C 4) alkyl-oxyimino; benzoyl optionally substituted with a phthalimide or a benzyloxycarbonyl group or an optionally substituted C 1-6 alkyl group, a phenoxycarbonyl group or a C 1-4 alkyl group; - an oxycarbonyl-protected amino group; or a carboxyl group protected by 1 to 4 alkoxy substituted with two C 1 -C 4 alkyl groups,

R is a hydrogen or alkali metal or C 1-4 alkyl group substituted in one or two phenyl groups;

R ⁴ is a nucleophilic group of the formula - S - R * · in which

R ⁴ 'is C 1-4 alkyl, phenyl optionally substituted with carboxyl, substituted or unsubstituted 5-membered. a ring containing nilroene and optionally grease or oxygen, which may be optionally fused with benzene or an optionally substituted 6-membered nitrogen-containing ring, substituents on 5-membered and 6-membered heterocycles containing 1 to 3 carbon atoms, C 1 -C 4 alkylamino-C 1 -C 4 alkyl, carboxy (C 1 -C 4) alkyl, oxo or hydroxy, or a group of formula (6) wherein R ²³ ', R ^23b and R ^{23e are the} same or different and represent C1-C4 alkyl group optionally substituted or R ²³ *, R ^23b and R ²³ 'together with the bind with the nitrogen optionally substituted 5- or 6-membered nitrogen-containing hetero ring to form a cyano or tetrazolyl - the substituents are carbamoyl, cyano, (C 1-3) alkoxycarbonyl, C 1-4 alkyl, or (C 1-4) alkanoylamino, or a 6-membered ring fused to 1 nitrogen atom a dicyclic ring or a 5-membered, 2-nitrogen ring fused 6-membered ring containing 1 or 2 nitrogen atoms or a methylene or ethylene bridged piperidine ring and the dashed line represents the double bond at the 2- or 3-position of the cephem ring.

According to the invention, the compounds of the formula I can be prepared directly from the compounds of the formula II, in which R, R ¹ and the dotted line have the same meaning as in the formula I, or a salt thereof, in one step. The process of the invention is thus suitable for industrial scale implementation.

Not only do the compounds of formula I possess valuable antimicrobial properties, they are also valuable in the preparation of other cephem-carboxylic acid derivatives. Many processes for the preparation of compounds of general formula (I) are known, but to date there is no known process for the satisfactory preparation of compounds of general formula (I) directly from derivatives of general formula (II) as starting materials.

Known processes for the preparation of compounds of formula I include:

(i) processes for reacting a cephem derivative containing an acyloxymethyl group at the 3-position of the cephem ring and a thiol compound: (1) in an aqueous solution or a mixture of water with an organic solvent under acidic or slightly alkaline conditions (1793/1964). and Japanese Patent Publication Nos. 13023/1971, U.S. Patent 3,641,021,

British Patent Nos. 283,811 and 1,321,412; Federal Patent Publication No. 2,262,477, etc.); or (2) heated in an organic solvent (Japanese Patent Application Laid-Open No. 43043/1980, etc.); or (3) is reacted in the presence of an acid or an acid complex in an organic solvent (German Patent Publication No. 2,804,896; 1565,941; 2,027,429; and

British Patent Nos. 048,257; 20724./1980., 49383./1980. and 153790/1980. Japanese Unpublished Patent Applications, etc.);

(ii) the process of reacting the acetoxy group of the 3 acetoxymethyl groups of the cephem ring with a nucleophilic reagent (A.G. Taylor, J. Chem. Soc. 1965, 7020);

(iii) the process of converting a hydroxyl group in the 3-hydroxymethyl group of a cephem ring to a halogen and subjecting the latter to a substitution reaction with a nucleophilic compound (AB Bywood et al., Rccent Advances in Chemistry of β-Laclatn Antibiotics, 1977, 139). );

(iv) the process of converting the 3-hydroxymethyl group of the cephem ring into an acyloxymethyl group by acylation followed by a nucleophilic reagent substitution reaction [Tsushima et al., Chem. Pharm. Bulletin, 27, 696 (1979)].

In variants (I) and (2) of the processes of type (i) the product is of unsatisfactory quality and low yield, for example because the β-lactam ring undergoes hydrolysis under the reaction conditions. In variant (3) of the type (i) processes, side reactions such as the lactone conversion and cleavage of the β-lactam ring may occur. In addition, if Lewis acid or a complex thereof is used as an acid, the equipment required to carry out the reaction and the post-reaction operations become more complicated. Furthermore, after the reaction, the acid is alkalized with alkali! and may cause decomposition and discoloration of the product. The yield of the compound of formula (I) is very low, depending on the starting material and the acid used. When lactonization, β-lactam ring cleavage and discoloration occur, the resulting impurities can be incorporated into the product of formula (I) and the removal of such impurities is time consuming and reduces yield. THE

In variant (3) of the type 191 478_ (i) processes, the moisture content of the starting material ¹ should be low, requiring the introduction of a drying step, and the resulting dry powder may be contaminated by the surrounding environment. For example, since one of the intrinsic properties of 7-aminocephalosporanic acid is that it causes contact dermatitis in humans (Kirk-Othrner, Encyclopedia of Chemical Technology, 3rd Edition, Vol. 907-908, 1978). , this process is disadvantageous for industrial implementation. In process (ii), which requires vigorous reaction conditions, the starting material and the target product are prone to degradation. In carrying out process (iii), in order to avoid lactonization, the 4-carboxylic carboxyl group must be protected in an ester or other form, and in esterified or otherwise protected compounds, the double bond of the cephem ring tends to be isomerized. Although somewhat milder reaction conditions may be used as compared to process (ii), these conditions are not sufficiently mild. Furthermore, except when a special acylating agent is used, an acylation and a substitution reaction must be carried out in separate steps, which will reduce the yield and the quality of the final product. As a result, this process is time consuming and requires additional equipment and is therefore unsatisfactory for industrial purposes.

Compounds for the preparation of the cephem-carboxylic acid derivatives of formula (1) have been extensively investigated using starting compounds of the formula (II), including deacetyl-cephalosporin-C (hereinafter referred to as DCPC), and a compound which may be prepared from DCPC or cephalosporin C by chemical or enzymatic treatment.

Surprisingly, it has been found that a compound of formula II or a salt thereof, a nucleophilic compound or a salt thereof in an organic solvent and as a catalyst (1) in a structural unit of formula (III) containing three or five valent phosphorus or in the presence of a salt thereof or (2) in the presence of a compound of formula IV or a salt thereof with a phosphoryl trihalide, phosphorus trihalide or phosphorus pentahalide, the reaction may be carried out under very mild conditions (i. e. pressure, etc.). The cephem carboxylic acid derivative of formula (I) is obtained in good yield and can be obtained from the anhydrous reaction mixture without isolation and drying step by acylating or deacylating the compound of formula (I) in anhydrous conditions. Therefore, the reaction is suitable for the preparation of the compounds of formula (I) directly from the compounds of formula (II) in a single step, that is to say, in a manner suitable for industrial application. This observation and the detailed examination thereof have led to the present invention, whereby the compounds of the formula I can be produced more cheaply.

In particular, the following compounds are used as catalysts in the process of the present invention:

(a) a trivalent phosphorus containing a cyclic compound of formula (XX11I) or a pentavalent phosphorus of a compound of formula (XXIV): or

Q ¹ * and Q ² *, the same or different, each have a C 1 -C 4 alkyl group or the structural moiety (12) to which they are attached form a benzene or naphthalene group, which rings optionally contain C 1 -C 4 alkyl, halogen, hydroxy or Substituted with (C1-C4) alkoxycarbonyl;

X ', Y and Z * are each halogen, phenyl, (C 1 -C 4) alkylamino, -OQ ³ ' wherein Q ³ is (C 1 -C 6) alkyl optionally substituted with halo or optionally substituted with nitro. phenyl, C3-C7 cycloalkyl or C1-C4 alkyl allyl; or

X ', Y and Z together form an oxo group - or

(b) Phosphorus of a compound of formula (XXV) or a salt thereof wherein Q ¹⁶ and Q ²⁶ together with the moiety 12 form a benzene or naphthalene ring and the rings may be optionally substituted with (C 1 -C 4) alkoxycarbonyl reaction product of oxy halide, trihalide or pentahalide.

In the R * group of the compound of formula (I), C 1-6 alkyl is straight or branched, such as methyl, ethyl, η-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl or isohexyl.

The C 1-4 alkoxy group contains a straight or branched alkyl moiety such as methoxy, ethoxy, η-propoxy, isopropoxy, η-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

Of the acyl groups that are substituted as R ', the compound of formula (1) is often used in the formula

R "represents a phenyl group, a five-membered heterocyclic group containing a nitrogen atom and / or a sulfur atom containing a halogen atom or a heteroatom, or a group of formula (2) wherein R ^c represents an optionally protected amino group and R ' ¹ represents an optionally protected carboxyl group; and

R ^b is C 1 -C 7 alkylene or a group of formula (3) wherein R ^e is C 1 -C 4 alkyl optionally substituted with carboxyl.

More frequently used in the R ^r -R ^g -C0összetételü group - ^R wherein R is phenyl, thienyl, amino-substituted thiazolyl or (2) összetéieiü group wherein R ^c and R ^d are as defined above; and

R ^g is C 1 -C 6 alkylene or a group of formula (4) wherein R ^{h is C} 1 -C 6 alkyl.

Among the acyl groups represented by R 'in the formula (I), the acyl groups represented by the formula (5) are preferred, wherein R' 'represents an amino group which is present in protected form.

191,478

Examples of R ¹ include formyl, acetyl, hexanoyl, benzoyl; D-atanyl, benzyl- ¹ -carbo-benzyloxy-γ-D-glutamyl-D-alanyl

D - Phenylglycyl - D - Alanyl, N - Carbobenzyloxy - D - Alanyl, N - Carbobenzyloxy - D - Phenyl

- glycyl, D - alanyl - D - phenyl - glycyl, γ - D - glutamyl

- D - alanyl; N - [2- (2-amino-4-thiazolyl)

acetyl] - D - phenylglycyl is N - [2- (2 - amino - 4 -

- thiazolyl) - 2 - methoxyiminoacetyl] - d - alanyl -, N - (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl)

- D - phenylglycyl, 2- (2 - amino - 4 - thiazolyl) - 2 - [(2 - amino - 4 - thiazolyl) - 2 - methoxyiminoacetamido] - acetyl, 2 - (2 - amino) (4-thiazolyl) -2-methoxy

- imino - acetyl, 2- (2 - amino - 4 - thiazolyl) - 2 - ethoxy

- imino - acetyl, 2- (2 - amino - 4 - thiazolyl) - 2 - propoxy

- imino - acetyl, 2- (2 - amino - 4 - thiazolyl) - 2 - butoxy

- imino - acetyl, 2 - thienyl - 2 - methoxy - imino - acetyl, 2- (1,2,4 - thiazol - 5 - yl) - 2 - methoxy - imino - acetyl, 2 - phenyl - 2 - methoxyiminoacetyl; phenyl

- acetyl, 5 - amino - 5 - carboxyvalyl, 4 - carboxy

- butir! , thienylacetyl, C 1-4 alkyl groups such as methyl, ethyl, η-propyl, isopropyl, tert-butyl.

In the formula (I), R ^{4 represents} a residue of a nucleophilic compound. These nucleophilic compounds include a diverse group of nucleophilic materials that have been previously reported in the chemical literature on cephalosporins. These nucleophilic compounds are characterized, for example, by having a nucleophilic nitrogen, carbon or sulfur atom. Such a nucleophilic compound is, for example, a compound containing sulfur or containing nitrogen or a nucleophilic carbon atom. Such necleophilic sulfur-containing chemicals, which are represented by the formula R ^4a -SH, may include, inter alia, a (C 1 -C 4) alkylthiol, phenylthiol or a nitrogen-containing 5- or 6-membered heterocyclic thiol, of which the membered ring may contain an oxygen or sulfur heteroatom or heteroatoms. The ring of the heterocyclic thiols may also be ring-linked. Exemplary nitrogen-containing heterocyclic groups include six-membered nitrogen-containing heterocyclic groups such as pyridyl, 1-oxido-pyridyl, pyrimidinyl, pyridazinyl, N-oxido-pyridazinyl and triazinyl; examples of a five-membered nitrogen-containing heterocyclic group include imidazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, and tetrazolyl, and benzene fused to 5-membered rings.

These nitrogen-containing heterocyclic groups may have, for example, the following types of substituents: hydroxy, C 1-3 alkyl (methyl, ethyl, propyl, isopropyl), mono- or di (C 1-3) alkylamino. . One representative of R ⁴ 'is C 1-4 alkyl, phenyl optionally substituted with carboxyl, and substituted or unsubstituted five or six membered nitrogen-containing heterocyclic group or benzene-fused ring system of the 5-membered ring. Thus, in this case, the nucleophilic substituent is C 1 -C 4 alkyl, mono- or di- (C 1 -C 4 alkyl) amino (C 1 -C 4 alkyl), carboxy (C 1 -C 4 alkyl), oxo. or a hydroxyl group.

Representative examples of heterocyclic thiols are pyridinethiol, pyrimidinediol, melylpyridazinethiol, 4,5-dihydro 6-hydroxy-4-methyl-1,2,4-triazine-3-thiol, 2-methyl

- 5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazine-3

- thiol, 2,5 - dihydro - 2 - methyl - 5 - oxo - 1,2,4 - triazine

- 3 - thiol, imidazolol, 1,3,4 - thiadiazolthiol, 1,2,3 thiadiazol - 5 - thiol, 2 - methyl - 1,3,4 - thiadiazolthiol, thiazolol, 5 - methyl - 1,3,4 - oxadiazolthiol, 1,2,3 triazole-5-thiol, I-methyltetrazolthiol, 1- (2-dimethyl)

- aminoethyl) tetrazolethiol is 1 - carboxymethyl

- tetrazolthiol. Aliphatic or aromatic thiols such as methanethiol, ethanethiol and thiophenol may also be used. These sulfur-containing nucleophilic compounds can be reacted in their free form or in the form of a salt of an acidic group with a base or an acid of a basic group thereof.

Nitrogen-containing nucleophiles include, but are not limited to, secondary or tertiary aliphatic, aromatic, aryl aliphatic and cyclic amines such as dialkylamines (such as dimethylamine, diethylamine); trialkylamines (e.g. triethylamine); pyridine bases (e.g., pyridine, alkylpyridine). Among the nitrogen-containing nucleophiles, compounds of formula XI are preferred wherein n ₃ is 0, 1, 2, 3, 4 or 5; and

R ²³ is when n ₃ is 2, 3, 4 or 5 - the same or different and is, for example, C 1-4 alkyl (e.g. methyl, ethyl, n-propyl or isopropyl), carbamoyl - or a cyano group.

One type of commonly used nitrogen-containing nucleophile is represented by Formula (6)

- where

R ²³ ', R ^23b and R ^{23c are the} same or different and are optionally substituted with cyano or telrazolyl; or R ²³ ', R ^23h and R ^{23c taken} together with the adjacent nitrogen atom represent a five or six membered nitrogen-containing heterocyclic group substituted with carbamoyl, cyano, C 1-3 -alkoxycarbonyl or C 1-4 -alkyl.

Representative examples of such nitrogen-containing heterocyclic compounds are pyridine, picoline, pyrazine, 2

carbamoylpyrazine, pyridazine, pyrimidine, imidazole and 1 - methylimidazole.

Examples of compounds containing a nucleophilic carbon include inorganic cyanides, from red and substituted pyrroles such as indole derivatives.

Preferred is the group of nucleophilic compounds of formula (7)

R ^4b is C ^1-4 alkyl, phenyl optionally substituted with carboxyl, or unsubstituted or substituted tetrazolyl, thiadiazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, pyrimidinyl, 1-oxido-pyridyl or triazinyl which may be substituted with C3-alkyl, difi-C3-alkylamino- (C1-C4) alkyloxy, carboxy-C1-4-alkyl, oxo or hydroxy.

Also preferred is the group of nucleophilic compounds of formula (8)

191,478

R ^4c, R ⁴⁴ and R ⁴ 'are the same or different, are hydrogen, 1-4 alkyl, cyano (1-4 szénatomosjalkil- or tetrazolyl (l - 4 alkyl) - group; or R ⁴ ®, R ^4d and R ⁴ 'together with the adjacent nitrogen atom represent unsubstituted or substituted pyridine or pyrrole substituted with carbamoyl, cyano, C 1-3 alkoxycarbonyl or C 1-4 alkyl.

Structural unit (9) having a dashed line in formulas (I) and (II) means structure (10) having a double bond in the 2-helix of the cephem ring, or (11) having a double bond in the 3-position of the cephem ring .

The major part, or at least a part, of the structure of the trivalent or phosphorous cyclic phosphorous compounds useful in the practice of the present invention is represented by formula (III). Accordingly, in formula (111), P represents three or five valent phosphorus atoms.

Such a cyclic compound containing trivalent or pentavalent phosphorus is represented, for example, by Formula XXIII or Formula XXIV, wherein the substituents have the meanings given above.

Generally, it is preferred that Q ¹ and Q ² have the same meanings, or together a cyclic hydrocarbyl group.

Of these types of cyclic compounds containing trivalent or pentavalent phosphorus, it is preferred, for example, to use compounds of formula XV in this formula.

A is a substituent on the benzene ring as defined for Q ¹ * and Q ^2a ;

n * is 0 or 1; and

X ¹ is halogen, phenyl, phenoxy optionally substituted by nitro, C 1-6 alkoxy optionally substituted by halogen, C 1-4 alkylamino.

Of the cyclic compounds containing trivalent or pentavalent phosphorus, it is also preferred to use the compounds of formula XVI wherein A, n * and X ¹ are as defined above.

Of the cyclic compounds containing trivalent or pentavalent phosphorus, the compounds of formula (XVII) are preferred, wherein A and n are as defined above; and X °, Y ° and Z ° are the same or different and are the same as X ¹ .

In the formulas (XV), (XVI) and (XVII), A represents a substituent attached to the benzene ring and may be a C 1-4 alkyl group, a halogen atom, a hydroxy group or a C 1-4 alkoxycarbonyl group. Preferred values for X ¹ , X °, Y ° and Z ° are, for example, halogen, such as chlorine, bromine and fluorine, C 1-5 alkoxy groups which may also contain substituents such as methoxy, ethoxy, β, β, β trichloroethoxy groups; phenoxy and p-nitrophenoxy).

Commonly used groups of ring compounds containing trivalent or pentavalent phosphorus are compounds of formulas XXIII and XXIV, wherein the substituents have the meanings given above.

A preferred group of cyclic compounds containing pentavalent phosphorus are compounds of formula (16)

A 'is hydroxy, (C 1 -C 4) alkyl or (C 4 -C 4) alkoxycarbonyl;

n 'is 0 or 1; and

X ^{b is} phenyl or phenoxy.

Examples of cyclic phosphorus compounds are: o-Phenylphosphorus chloride, o-Phenylene Phosphorus Fluoride, Melyl (o-Phenylene) Phosphate, Ethyl (o Phenylene) Phosphate, n-Propyl (o-Phenylene). - phosphate, isopropyl (o - phenylene) phosphate, n - butyl (o - phenylene)

- phosphate, isobutyl (o - phenylene) - phosphate, chair - butyl

- (o - Phenylene) Phosphate, Cyclohexyl (o - Phenylene) Phosphate, Phenyl (o - Phenyl) Phosphate, 2 - Chloroethyl (o)

Phenylene) phosphate, β, β, β - trichloroethyl (o - phenylcn)

- phosphate, ethoxycarbonylmethyl (o-phenylene) phosphate, 1,1-dimethyl-2-propenyl (o-phenylene) phosphate, 2

propenyl (o - phenylene) phosphate, 3 - methyl - 2 - butenyl

- (o - Phenylene) phosphate, 2 - phenyl - 1,3,2 - benzodioxaphosphol - 2 - oxide, 2 - (n - butyl) - 1,3,2 - benzodioxaphosphol - 2 - oxide, 2 - methoxy - 5 - methyl-1,3,2 benzodioxal'phosphole-2-oxide, 2-chloro-5-ethoxycarbonyl-1,3,2-benzodioxoxophosphol-2-oxide, 2-methoxy-5-ethoxycarbonyl-1,3, 2 - Benzodioxoxyphosphol

- 2 - oxide, 5 - ethoxycarbonyl - 2 - phenyl - 1,3,2 - benzodioxoxyphosphol - 2 - oxide, 2,5 - dichloro - 1,3,2 - benzodioxoxyphosphol - 2 - oxide, 2 - methoxy - 4 - chloro 1,3,2-benzodicoxaphosphol-2-oxide, 2-methoxy-4-methyl-1,3,2-benzodioxoxaphosphol-2-oxide, methyl- (2,3

naphthylene) phosphate, 2 - methoxy - 5,6 - dimethyl - 1,3,2

benzodioxoxyphosphol-2-oxide, 2,2-dihydro-4,5,6,7

- tetrachloro-2,2,2-triphenoxy-1,3,2-benzodioxaphosphol, 2,2-dihydro-2,2,2-triphenoxy -1,3,2-benzodioxaphosphol, 2,2-dihydro-2,2 , 2 - trichloro - 1,3,2 - benzodioxaphosphol, o - phentene - phosphorus chloride, o - phenylphenyl phosphorus bromide, o - phenylene phosphorus fluoride, methyl

- (o - Phenylene) Phosphite, n - Butyl (o - Phenylene) Phosphite, Methoxycarbonylmethyl - (o - Phenylene) Phosphite, Phenyl

- (o - Phenylene) Phosphite, p - Nitrophenyl - (o - Phenylene)

- phosphite, 2 - phenyl - 1,3,2 - benzodioxoxaphosphol, 2 - methoxy

5 - methyl - 1,3,2 - benzodioxoxyphosphol, 2 - phenoxy - 5

acetyl - 1,3,2 - benzodioxoxyphosphol, 2 - chloro - 4 - methyl

- 1,3,2 - benzodioxoxyphosphol, 2 - phenyl - 5 - ethoxycarbonyl - 1,3,2 - benzodioxoxyphosphol, 2 - phenoxy - 2 oxo - 1,3,2 - benzodiazaphosphol, 2 - phenoxy - 1,3,2 benzoxazaphosphol, 2,2-dihydro-2-oxo-2-methoxy

4,5-dimethyl-1,3,2-dioxaphosphol, 2,2-dihydro-2

oxo - 2 - chloro - 4,5 - dimethyl - 1,3,2 - dioxaphosphol, 2,2

dihydro - 2,2 - ethylenedioxy - 2 - methoxy - 4,5 - dimethyl

- 1,3,2 - dioxaphosphol, 2,2 - dihydro - 2,2 - dimethoxy - 2 - phenoxy - 4,5 - dimethyl - 1,3,2 - dioxaphosphol, 2,2 - dihydro - 2,2,2 - trimethoxy - 4,5 - dimethyl - 1,3,2 dioxaphosphol, 2,2 - dihydro - 2,2,2 - triphenoxy - 4,5 dimethyl - 1,3,2 - dioxaphosphol, 2,2 - dihydro - 2,2 , 2 trimethoxy-1,3,2-dioxaphosphol, 2,2-dihydro-2,2,2 trimethoxy-4-methyl-1,3,2-dioxaphosphol, and

2,2,4,5,6,7-hexahydro-2,2,2-trimethoxy-1,3,2-benzodioxaphosphol,

The above phosphorus compounds are commercially available or are known compounds [R. S. Edmundson et al., Chem. And Ind. 1962, 1770; K. Darcll Berlin et al., Tetrahedron 20, 2709 (1964); F. Ramirez et al., Tetrahedron 24, 5041 (1968); L. Anschütz et al., Lüebigs Ann. 454, 109 (1927); T. Koizumi and Work5

-5g

191,478 companions: Tetr. Letters, 4763, 1973; P. C. Crofts et al., J. Chem. Soc. 1958, 4520; Marianne, M.C. F. Castelijina et al., J. Org. Chem., 46, 47 (1981)], or can be obtained by methods known per se. They may be used in purified Torma or in the form obtained in their preparation reaction.

In the practice of the invention, the product of the reaction of a compound of formula (XXV) with a phosphoryl trihalide, phosphorus trihalide or phosphorus pentahalide may be used instead of the above-mentioned cyclic compound containing trivalent or pentavalent phosphorus. In the general formula (XXV)

Q ^1b and Q ^{Zb taken} together are benzyl or naphthyl optionally substituted with C 1 -C 4 alkoxycarbonyl.

Representative examples of compounds of formula (XXV) are pyrocalcchine cs, 2,3-dihydroxynaphthalene. In the case of phosphoryl trihalide, phosphorus trihalide and phosphorus pentahalide, the halogen may be, for example, chlorine or bromine. Typical examples of this type of compound are phosphoryl trichloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide and phosphoryl tribromide. Generally, about equimolecular amounts of phosphoryl trihalide or phosphorus per mole of the compound of formula (XXV)

trihalide or about 1/3 to 1.0 molar equivalents of phosphorus pentahalide. This reaction is preferably carried out in a solvent such as dichloromethane, 1,2-dichloroethane, acetonitrile, ethyl acetate, tetrahydrofuran, dioxane, ether, benzene or bromobenzene. Preferred solvents are dichloromethane, acetonitrile and tetrahydrofuran. In some cases, a favorable result is obtained when this reaction is carried out in the presence of a base. Suitable bases include triethylamine, dicyclohexylamine, diisobutylamine, and di (n-butyl) amine. Preferred examples include triethylamine, tri (n-butyl)

amine and di (n - buti!) - amine. This reaction is usually

- 50 ° C to 100 ° C, preferably - 20 ° C to 50 ° C, for 5 to 120 minutes, preferably 10 to 60 minutes. However, the reaction temperature and duration are not limited to the above limits provided that the desired reaction product is obtained. Generally, the reaction mixture is used in the form of a crude product without isolation, but where appropriate, if necessary, the unreacted starting material, i.e., the compound containing the structural unit (IV), the phosphoryl trihalide or phosphorus trihalide or phosphorus pentahalide and / or hydrogen.

the halide formed during the reactions or the base salt thereof may be isolated before carrying out the appropriate reaction of the invention.

Some compounds containing the structural unit of formula (IV) are commercially available, while other compounds of this type may be prepared by known methods or modifications of these methods.

According to the present invention, the target products of formula (1) are prepared by reacting a compound of formula (II) or a salt thereof with a nuclcolyl compound or a salt thereof, as a catalyst (1), in a compound of formula (XXIII) or (XXIV) a reaction product of a pentavalent phosphorus ring or a salt thereof, or (2) a reaction product of a compound of formula XXV with a phosphoryl trihalide or phosphorus trihalide or phosphorus pentahalide (hereinafter referred to as "the reaction product" ) in an organic solvent.

The compound of formula (II) can be used either in its free form, i.e. in the form of its acidic group, i.e. its carboxyl or sulfo group, or in the form of its salt with a non-toxic cation. Examples of such non-toxic cations are sodium or potassium ions or an organic amine such as triethylamine, tri (n-butyl) amine, di (n-butyl)

an amine, dicyclohexylamine, pyridine, collidine or a compound of formula 2.6

- lutidine. If they contain a basic group R and / or R ', this group may also be present in the form of a salt with an organic acid. Examples of such organic acids are acetic acid, tartaric acid, methanesulfonic acid. Inorganic acids such as pcldul hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid are suitable for this salting.

Depending on the chemical nature, the nucleophilic compound may also be present in the form of its basic or acidic salts and these salts may also be used as starting materials in the practice of the invention. The basic and acidic salts are of the same type as those given above for exemplary compounds of Formula II.

The compound of formula (II), the nucleophilic compound and (1) the compound of formula (XXIII) or (XXIV) or (2) the phosphoryl of the compound of formula (XXV)

The reaction product of trihalide or phosphorus trihalide or phosphorus pentahalide may be mixed with the organic solvent in any order. When the compound of formula II, nucleophilic compound, cyclic phosphorus compound and organic solvent are used, the reaction is generally carried out by mixing the compound of formula II with the nucleophilic compound in an organic solvent and subsequently adding the cyclic phosphorus compound, or a solution thereof in an organic solvent, or by mixing the cyclic phosphorus compound in an organic solvent with the nucleophilic compound, and then adding the compound of formula (11) or a solution thereof in an organic solvent. When the reaction product of a compound of formula (XXV) with a phosphoryl trihalide or a phosphorus trihalide or a phosphorus pentahalide is used, the reaction is carried out in the same manner as when a cyclic phosphorus compound is used. In terms of mixing ratio, it is preferred to use the nucleophilic compound in an amount of at least 1.0 mole, preferably 1.0 to 10.0 mole, per mole of the compound of formula (II); it is also preferred to use the ring phosphorus ring in an amount of at least 1.0 mole, preferably 1.0 to 6.0 mole, per mole of the compound of formula (II). When a reaction product of a compound of formula (XXV) with a phosphoryl-6 "-11" -1-trihalide, or a phosphorus trihalide, or a "phosphorus pentahalide" is used, it is preferred to use at least 1.0 mole, more preferably 1 mol. 0 to 0.0 mol of nucleophilic compound, 1.0 to 6.0 mol of compound of formula XXV and 1.0 to 6.0 mol of phosphoryl trihalide or phosphorus trihalide, or 1/3 to 2.0 mol. * moles of phosphorus pentahalide are used per mole of compound (III).

Any acidic solvent which is inert to the reaction may be used to carry out the reaction. Suitable amides are, for example, amides such as formamide, dimethylformamide and dimethylacetamide; halogenated hydrocarbons such as ethyl chloride, isobutyl chloride, dichloromethane, chloroform, 1,2 dichloroethane, carbon tetrachloride, 1,1,1-trichloroethane,

1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, fluorobenzene and dichlorobenzene; ethers such as dimethyl ether, diethyl ether, tetrahydrofuran and dioxane; carboxylic acids such as glacial acetic acid, propionic acid; esters such as methyl acetate, ethyl acetate, isobutyl acetate, methyl propionate, ethylene carbonate; nitriles such as acetonitrile, propionitrile, benzonitrile; nitro compounds such as nitromethane, nitroethane; ketones, such as acetone and methyl-ethyl

ketone; hydrocarbons such as benzene, toluene and mesitylene; and mixtures thereof. Particularly favorable results are obtained when the reaction is carried out in an organic solvent such as a mixture of dichloromethane, acetonitrile, formamide, formamide and acetonitrile, a mixture of dichloromethane and tetrahydrofuran or dichloro

- a mixture of methane and acetonitrile. When a compound of formula (XXV) phosphoryl - trihalide or phosphorus - trihalide or phosphorus - pentahalide reaction product formed is used, then in this reaction mixture can be used itself as a solvent Wed ^r ves. Depending on the chemical nature of any of the starting materials and / or the organic solvent, it may be advantageous to add a base to the reaction mixture. The addition of this base can be conveniently carried out while the starting materials are mixed with the organic solvent. Generally, this base is mixed with the organic solvent and then with the compound of formula (11) or the nucleophilic compound. In general, it is preferred to use 0-5 moles of base per mole of the compound of formula II. The base may be any base which is capable of accelerating the reaction or of neutralizing the acid resulting from the reaction or of dissolving any of the starting materials; this base must be inert to the reaction. Preferred examples include C 1-6 alkyl amines such as triethylamine, tri (n-butyl) amine, di (n-butyl) amine and diisobutyl.

- an amine; and C3-C8 cycloalkylamines such as dicyclohexylamine; cyclic amines such as pyridine or lutidine The reaction temperature and duration may vary depending upon the nature and amount of the compound of formula II, the cyclic phosphorus compound or "reaction product", the nucleophilic compound, the organic solvent and / or the base. In some cases, the reaction is instantaneous at - 60 ° C, but is usually carried out with mild halves, i.e., at a temperature between 80 ° C and 50 ° C, for a few seconds to ten to twenty hours. It is very advantageous if the reaction is carried out at - 40 ° C.

'C over a period of 5 to 120 minutes. Although it is a general rule that the reaction is carried out at a higher reaction temperature in a shorter period of time, it is preferable to carry out the reaction at a low temperature, to avoid, among other things, secondary reactions or secondary reactions.

The resulting cephem carboxylic acid derivative (I) can be isolated and purified by methods well known in the art such as solvent extraction, pH adjustment, phase transfer, salting, crystallization, recrystallization and chromatography. If R ^{1 is a} special type of acyl group, it is possible to convert the compound of formula I without isolation into the corresponding 7-aminocephem derivative (i.e., a compound of formula I in which R ¹ is hydrogen), which is a useful intermediate having antibacterial activity. produce. In such a case, the 7-acyl group is known according to the known method. quench by adding dimethylaniline, trimethylsilyl chloride, phosphorus pentachloride, methanol and water, respectively, to the reaction mixture. If the product of formula (I) is present in free form, it can be converted into its salt in the usual manner. The product of formula (i) also includes salt forms. The salt-forming moiety of this salt form of the compounds of formula (I) may be of the same type as that mentioned above for the starting material of formula (II). Thus, the salt form may be a salt of an acid group of a compound of formula II with an alkali metal such as lithium, sodium or potassium; or alkaline earth metals such as magnesium or calcium; and with amines such as di (n-butyl)

- amine, dicyclohexylamine, diisobutylamine, diphtherc

butyl) amine, triethylamine, pyridine, 2,6 - lutidine and tributylamine. The salt form may also be a salt of a basic group of a compound of formula II with inorganic acids such as hydrochloric acid or sulfuric acid; organic acids such as oxalic acid, formic acid, trichloroacetic acid and trifluoroacetic acid; organic sulfonic acids such as methane, toluene, naphthalene and camphorsulfonic acid; organic phosphoric and phosphonic acids such as methyl, dimethyl, and diphenylphosphoric acid; and phenylphosphonic acid. Some of the products of formula (1) thus obtained can be used alone as antimicrobial agents, while others may be used as starting materials for the preparation of more potent antimicrobial compounds. For example, the cephem of formula (I)

- a carboxylic acid derivative in which R * is 5 - phthalimido - 5 - carboxyvalyl - can be converted to 7 - [2- (2 - aminothiazol - 4 - yl) acetamido] - or 7 - [2 - ( 2-amino-thiazol-4-yl)

A 2-methoxyiminoacetamido] derivative by cleaving the acyl group at the 7-position of the compound of formula (I) in a manner known per se and obtaining the compound with 2- (2-aminothiazole-4-iJ) -acetic acid; 2 - (2 - amino - thiazol - 4 - yl) - 2 - methoxyimino acetic acid! or a reactive derivative of the latter. Thereafter, antibiotic agents such as 7-12- (2-aminothiazole-4-11) acetamido] -3- [1- (2-dimethylaminoethyl) -H

- tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid and 7- [2- (2-aminothiazol-4-yl) -2-methoxy]

-7191478.

imino-acetamido] -3- (1-methyl-1 H -tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid.

Preparation of some catalysts of formula XV (1,3,2-dioxaphosphol derivative)

The following formula (XXVI) is described

The preparation of a 1,3,2-dioxaphosphol derivative wherein the moiety 17 represents an optionally substituted benzene ring; and R is optionally substituted aryl, alkoxy or aralkyloxy.

For example, compounds of Formula XXVI can be used as inert catalysts in the preparation of cephalosporin antibiotics, which are important and valuable agents in the treatment of bacterial diseases; these compounds may also be used in the preparation of compounds which are intermediates for the preparation of cephem carboxylic acid derivatives from penicillin compounds by ring augmentation (Japanese Unexamined Patent Application 4091/1975); they can also be used in the preparation of cephem-carboxylic acid derivatives in which the methyl group attached at the 3-position is replaced by a nuclcolyl group; these latter compounds are important antibiotics or their intermediates. In their use, deacetyl cephalosporin C (DCPC), which may be prepared by fermentation, or cephalosporin C, also obtained by fermentation, or a derivative thereof having a 3-hlyceryl-CH ₂ OH group, is interacted with a nucleophilic reagent as defined above.

Numerous studies have been carried out to prepare the 1,3,2-dioxaphosphol derivatives of the general formula (XXVI). Such known methods are illustrated, for example, in Scheme A.

Method (1) is a sequence of steps; (a) - (E) - (c) (L. Ansehütz. Liebigs Ann. 454, 109 (1927));

According to method (2), the sequence of steps is: (a) - »® © ® [T. A-Khwaja et al., J. Chem. Soc. (C) (1970) 2092];

Method (3) shows the sequence of steps: @ (3) b [H. Gross et al., Chem. Ber., 96, 1387 (1963); German Patent Publication No. 50,606].

In Scheme A, R 'is a residue of an alcohol. The disadvantage of Method (I) is that the starting phosphorus pentachloride sublimates, is difficult to handle and has a low yield and the reaction produces melyl chloride which is a corrosive and hazardous substance. The disadvantage of Method (2) is that the number of steps is low, the yield is low, and the distillation of the intermediates © and (e) results in a large amount of material which tends to solidify and is therefore difficult to handle. Method (3) is also disadvantageous because of the low yield. In addition, for all three of the above methods, the products between (E), (d) and (e) are hygroscopic and decompose upon absorption of moisture and are therefore difficult to handle. For all these reasons, the above methods are not advantageous for the industrial preparation of compounds of formula XXVI. Therefore, it has long been necessary to develop a more advantageous process for the preparation of compounds of formula XXVI.

Various studies have been carried out to prepare the compounds of Formula XXVI, and it has surprisingly been found that these compounds can be prepared in one step, in a very short time, in a very advantageous manner for industrial use, by yielding a compound of Formula XXVII.

wherein the moiety 17 is an optionally substituted benzene ring, with a compound of formula XXVIII wherein X is halogen and R is as defined above at a temperature not exceeding about 30 ° C in the presence of a base.

Compounds of formula (XXVI) are thus prepared by reacting a compound of formula (XXVII) with a compound of formula (XXVIII) at a temperature of up to 30 ° C in the presence of a base.

In the above formulas, the structural unit (17) represents an optionally substituted benzene ring. This benzene ring may have from 1 to 4 substituents which are inert to the reaction conditions and may each be: C 1 -C 4 linear or branched alkyl groups (e.g. methyl, ethyl, n-propyl, isopropyl and n-butyl); An alkoxycarbonyl group containing from 1 to 4 carbon atoms (e.g. methoxycarbonyl, ethoxycarbonyl); halogen (chlorine, bromine, iodine and fluorine); and hydroxyl. Representative examples of compounds of Formula XXVII include pyrocatechin, homopyrocatechin, pyrogallol, methyl 3,4-dihydroxybenzoate, 2-hydroxy-4-propionylphenol, 4-chloro-pyrocatechin, 4-methoxy.

pyrocatechin and 1,2 - dihydroxynaphthalene. For example, pyrocatechin is preferred.

In the above formula (XXVIII), X is a halogen atom such as fluorine, chlorine or bromine. Particularly good results can be obtained when X is a chlorine atom. R is phenyl, C1-C6 alkoxy optionally substituted by halogen, or phenoxy optionally substituted by nitro. Examples of R and preferably include methoxy, ethoxy, propoxy, isopropoxy, butoxy, n-hexyloxy. For example, when R is lower alkoxy such as methoxy or ethoxy, particularly good results can be obtained.

Compounds of formula (XXVI) are prepared by reacting a compound of formula (XXVII) with a compound of formula (XXVIII) at a temperature of up to 30 ° C in the presence of a base.

The compound of formula (XXVII) is reacted either in free form or in the form of a salt with one of the above-mentioned bases. In carrying out this method, the base may be, inter alia, a tertiary amine such as trimethylamine, triethylamine, tri (n

butyl) amine, N - methyl piperidine, cyclohexyl dimethylamine and N - methyl morpholine; or a dialkylamine such as di (n-butyl) amine, diisobutylamine and dicyclohexylamine; or an aromatic amine such as pyridine, lutidine and γ-collidine; or other types of organic amines. Also suitable as bases are alkali metals such as lithium, sodium and potassium; alkaline earth metals such as calcium and magnesium are also contemplated; quaternary ammonium compounds such as tetraethylammonium and tetrabutylammonium hydroxide and other inorganic bases.

-8. 15 - 191

The base may be used in the form of a salt of the phenolic hydroxyl of the compound of formula (XXVII), or may be added to the mixture during the reaction, or may be used in admixture with the compound of formula (XXVII). Preferred bases include tri (C 1-6 alkyl) amines such as trimelylamine, triethylamine and tri (n-butyl) amine, as well as aromatic amines containing a six-membered ring such as pyridine and lutidine. Particularly preferred is tri (n-butyl)

- use of amine and pyridine.

The reaction is preferably carried out by mixing the compound of formula (XXVII) with the compound of formula (XXVIII) and then mixing the mixture with a base at a temperature below 30 ° C; or mixing the compound of formula (XXVII) with a base and mixing the resulting mixture with the compound of formula (XXVIII) at a temperature below 30 ° C; or a salt of a compound of formula (XXVII) and a base mentioned above are mixed with a compound of formula (XXVIH) at a temperature below 30 ° C. The preferred reaction temperature is 0 'C or lower, more preferably from 5' C to 40 'C. More preferably, the reaction is carried out using a solvent. As a solvent, an organic material which is inert to the reaction may be used. Since both the starting compound (XXVIII) and the reaction product (XXVI) are readily hydrolyzed by water, a substantially anhydrous, non-proton solvent is desirable. Examples of solvents that do not react with compound XXVIII include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2-trichloroethane; ethers such as dimethyl ether, methyl ethyl ether, diethyl ether, tetrahydrofuran and dioxane; organic nitriles such as acetonitrile and propionitrile; nitroalkanes such as nitromethane and nitroethane; esters such as methyl acetate, ethyl acetate and methyl propionate; ketones such as acetone and methyl ethyl ketone; aromatic hydrocarbons such as benzene, toluene, chlorobenzene and bromobenzene; aliphatic hydrocarbons such as petroleum ether, hexane and cyclohexane; sulfones such as sulfolane; and mixtures thereof. Suitable solvents include halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether and tetrahydrofuran; and organic nitriles such as acetnitrile and propionitrile. Particularly preferred are diethyl ether, dichloromethane and acetonitrile.

When the aforementioned solvents are used, the reaction is generally carried out by mixing the compound of formula (XXVII) with the compound of formula (XXVIII) in an organic solvent and stirring with a base at a temperature below 30 ° C; or mixing the compound of formula (XXVII) with a base in an organic solvent and mixing the compound of formula (XXVIII) at a temperature below 30 ° C; or a salt of a compound of formula (XXVII) and a base mentioned above in an organic solvent at a temperature below 30 ° C. The compound of formula (XXVIH) is generally used in an amount of 0.8 to 1.2 moles, preferably 0.95 to 1.05 moles, per mole of compound (XXVII). Stoichiometrically, 2 moles of base are required per mole of compound XVII, since 2 moles of hydrogen halide are liberated in the reaction of 1 mole of compound XXVU, which forms a salt with the base.

. 16th

However, unless the reaction adversely affects the reaction, the base is used in an amount of 1.6 to 2.4 moles, preferably 1.8 to 2.2 moles, per mole of compound (XXVII).

When an organic solvent is used, it is used in an amount of 0.1 to 20 liters per mole of the compound (XXVII). It is desirable to keep the reaction temperature low, generally at about 30 ° C or lower, because at higher temperatures, by-products can easily form. Depending on the amount of by-products and the degree of cooling that can be achieved in the industry, this reaction is generally carried out at a temperature in the range of 30 ° C to 100 ° C. Taking into account the purity and yield of the desired product and the efficiency of the cooling, it is industrially advantageous to carry out the reaction at a temperature of between 10 ° C and -50 ° C, and more preferably between -10 ° C and -30 ° C. The exothermic reaction is violent at the time when XXVII is mixed with XXVIII in the presence of a base, so this addition must be effected by addition under cooling. The reaction time ranges from a few minutes to several hours, depending on other factors such as the efficiency of cooling. Since the starting material XXVIII and the product XXVI are readily degraded by water, it is preferable that the starting materials and solvent contain up to a minimum amount of water and that the reaction is carried out in the presence of moisture.

The compound of formula (XXVI) obtained in the course of the reaction may be used in the form of a reaction mixture. If necessary, the reaction mixture containing the compound of formula (XXVI) may be stored at low temperature, i.e. below 30 'C, preferably between 10' C and -50 'C, protected from moisture. The compound of formula (XXVI) is unstable at elevated temperatures in the presence of a base or its hydrochloride and reacts readily with water.

If desired, the compound of formula (XXVI) may be isolated from the reaction mixture, for example, by filtration or other removal of the base hydrohalide, which is in the form of a precipitate, or by adding hydrogen halide or a solvent containing the base and the salt of the hydrogen halide has low solubility but the compound of formula XXVI is highly soluble, such as ether, benzene, dichloromethane, acetonitrile, ethyl acetate and then the filtrate is concentrated or otherwise . The compound of formula (XXVI) thus obtained can be further purified by distillation, recrystallization or otherwise.

The starting material of formula (XVIII) used in this process can be readily prepared by reacting a compound of formula R-H, wherein R is as defined above, with a phosphoryl trihalide or a diphosphoryl-tetrahalide def [Mizuma et al., Yakugaku Zasshi, 81; 51 (1961); H. Grunze, Chem. Bcr., 92, 850 (1959)] or a modified form of this method.

Thus, this production process allows the desired product of formula (XXVI) to be prepared very readily, in good yield, in a single step, under mild conditions, from starting materials that are readily commercially available.

-9 ... 17 .. 1 inexpensive to handle. Thus, this production method is very advantageous from the point of view of industrial realization for the production of materials of formula (XXVI).

The following examples illustrate the process of the invention. It is to be understood that the examples are intended to illustrate the invention but are not intended to limit it in any way.

The procedures described in the Examples were performed by column chromatography using TLC (TLC). Merck 60F ₂₅₄ plates were used for TLC, and UV light was used to detect spots.

For the chromatography on silica gel, a column chromatography silica gel 60 manufactured by E. Merck of the Federal Republic of Germany was used. Amberlite XAD-2 is manufactured by Rohm and Haas Co. (USA). The temperatures indicated are not corrected, the term "room temperature" means a temperature of 20 - 25 ° C. The percentages are by weight except for the solvents. In the latter cases, the percentages are percentages by weight. NMR spectra were recorded on a Varian Model Em 390 (90 MHz) or Hitachi Perkin-Elmer R-20/60 MHz instrument with tetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate as internal or external using slandard. All δ values are given in ppm. Notations used in the spectra are as follows: s = singlet; d = doublet, q = quadruplet; ABq = quadruplet type AB; t = triplet; dd = doublet of doublets; m = multiplet; J = switching constant. IR spectra were recorded on a Hitachi EP1-S2 spectrometer. The following additional abbreviations are used in the examples: mmole = millimole; Hz = Herz; DMSO = dimethyl sulfoxide; D ₂ O = heavy water;

THF = tetrahydrofuran; TLC = thin layer chromatography (chromatogram).

Example I

To a mixture of 1.691 g (15.36 mmol) of pyrocatechin and 60 ml of ether is added dropwise 3.109 g (30.72 mmol) of triethylamine. Wash the dropping funnel with 10 ml of ether. Methyl dichlorophosphate (2.287 g, 15.36 mmol) was added dropwise to the mixture with the washing liquid at a temperature between -40 ° C and -35 ° C. The dropping funnel was washed with 10 ml of ether and the mixture was stirred at the same temperature for 10 minutes with the washing liquid. At this time, the cooling bath was removed, the mixture was allowed to warm to room temperature (20-25 ° C), and the mixture was poured onto a sintered glass filter and filtered under nitrogen pressure. The filtered material was washed twice with 15 mL each of ether. The filtrate, together with the washings, was evaporated in vacuo on a water bath at 20 ° C to give 1.847 g (96%) of methyl (o-phenylene) phosphate as a colorless viscous oil which crystallizes in a refrigerator. NMR (CDCl,) 5: 3.82 cs 4.03 (311, each s, _P-OCH3), 7.09 [4H, s, (18) a structural unit of formula]. Trace amounts of ether and triethylamine are also observed in the spectrum.

Vckonyrétcg chromatogram (TLC hereafter) (silica gel 60F-254, development of acetonitrile, water and 99% formic acid 220: 20: 1 as eluent): _Rf = 0.31.

Example 2

Using 1.249 g (11.35 mmol) of pyrocatechin and 42 ml of ether, 2.297 g (22.70 mmol) of triethylamine and 1.849 g (11.35 mmol) of ethyl dichlorophosphate, the reaction is carried out at -40 ° C and - After conducting at 35 ° C and then treating the reaction mixture as in Example 1, 2.159 g (95%) of ethyl o-phenylene phosphate are obtained as a colorless viscous oil. NMR _(CDCl3) δ: 1.42 (3H, 6, J = 7Hz, C-CH _3), 4.23 and 4.40 (2H, each q, J = 7Hz, P - O - CH ₂ ), 7.07 (4H, s, structural unit 18). Trace amounts of ether and triethylamine are also observed in the spectrum.

TLC (under conditions specified in Example 1): _Rf = 0.36.

Example 3

Using 0.993 g (9.02 mmol) of pyrocatechin and 50 ml of ether, 1.825 g (18.04 mmol) of triethylamine and 1.723 g (9.02 mmol) of n-butyl dichlorophosphate were reacted at 5 ° C. and the reaction mixture was treated as in Example 1 to give 1.914 g (93%) of n-butyl (o-phenylene) phosphate as a colorless viscous oil. Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ: 0.7 ~ 2.0 (7H, m, C-CH ₂ CH ₂ CH ₃ ), 4.13 and 4.28 (2H, each t, J = 6.5 Hz) _P-O-CH2), 7.10 [4H, s, (18) a structural unit of formula] observed a trace of ether and triethylamine were also signs in the spectrum.

TLC (under conditions specified in Example 1): _Rf = 0.45.

Example 4

Using 0.856 g (7.77 mmol) of pyrocatechin and 32 mL of ether, followed by 1.573 g (15.50 mmol) of triethylamine and 1.484 g (7.77 mmol) of n-propyl dichlorophosphate, the reaction is carried out at -30 ° C. and - eluting between 25 ° C and then treating the reaction mixture as a slightly cloudy viscous oil 1.695 g (95%) of Example 1. n - propyl - (p - phenylene) - phosphate kapunk.NMRspektrum (CDC1 ₃₎ δ: 0 97 (3H, t, J = 7Hz, C-CH _3), 1.77 (2H, q, J = 7 7.5 Hz, _0-C-CH2). 4.15 and 4.29 (2H, each q, J = 7.5 Hz, P, O - _CH2), 7.08 [4H, s, (18) a structural unit of formula], the spectrum trace amounts of ether and signs suggesting triethylamine are also observed.

TLC (under conditions specified in Example 1): _Rf = 0.41.

Example 5

To a mixture of 1.989 g (10.93 mmol) of ethyl 3,4-dihydroxybenzoate and 30 ml of ether was added 2.211 g (21.86 mmol) of triethylamine and the mixture was stirred at -30 'C and -20' C.

-1019

It was cooled to 191,478 and 1.627 g (10.93 mmol) of methyl was added dropwise with stirring over 10 minutes.

dichlorophosphate and 10 ml ether solution. The reaction mixture was stirred at the same temperature for 5 minutes, then the cooling bath was removed and the temperature was allowed to rise to 20 ° C. Filtration and washing were carried out in the same manner as in Example 1, and then the filtrate was combined with the washing liquid and concentrated in vacuo at 20-25 ° C. This gave 2.877 g (84.6%) of 2-methoxy-2-oxo-5 as a viscous oil

ethoxycarbonyl -1,3,2 - benzodioxaphosphol is obtained.

Nuclear Magnetic Resonance Spectrum (CH 2 Cl 2) δ: 1.26 (3H, t, J = 7Hz, C-CH 3), 3.84 and 4.05 (3H, each s,

Ρ-O-CHJ, 4.34 (2H, q, J = 7Hz, C-CH ₂ ), 7.0 8.0 [3H, m, structural unit (19). Spectra of dichloromethane and trace amounts of ether are observed and observed.

TLC (under conditions specified in Example 1): _Rf = 0.38.

Example 6

1.686 g (13.58 mmol) of 4-methylpyrocatechin and 40 ml of ether, 2.748 g of triethylamine and 2.022 g of methyl

using dichlorophosphate, the reaction mixture is reacted with

Treated according to Example 5 as a viscous oil, 2,400 g (88.4%) of 2-methoxy-2-oxo-5-methyl-1,3,2

- Benzodioxaphosphol is obtained.

Nuclear Magnetic Resonance Spectrum (CH ₂ Cl ₂ ) δ: 2.32 (3H, s, C-CH ₃ ), 3.78 and 3.99 (3H, each s, PO-CH 3, 6.8 ~ 7.1 [ 3H, m, 19] Dichloromethane and trace amounts of ether are also observed in the spectrum.

TLC (under conditions specified in Example 1): _Rf = 0.36.

spectroscopy showed that methyl (o - phenylene) phosphate was present in the filtrate and in the washing liquid together in a yield of 89%. Nuclear Magnetic Resonance Spectrum (CH ₂ Cl ₂ ) δ: 3.81 and 4.02 (3H, each s, P-OCH 3, 7.16] 4H, s, 21). triethylamine hydrochloride, and a weak multiplet signal at 6.2 to 7.6 ppm, attributable to structural unit (18).

The yield of the desired product was calculated by calculating the ratio of the signal corresponding to the structural unit (18) of the desired product (7.16 ppm) to the signal in the range 6.2 to 7.6 ppm (89%).

Example 9

To a solution of 0.710 g (6.45 mmol) of pyrocatechin and 7 ml of dichloromethane was added 0.960 g of methyl dichlorophosphate and 1 ml of dichloromethane, and the mixture was cooled to -15 ° C to -10 ° C with stirring for 8 minutes. 2,390 g of tri (n-butyl) amine are added dropwise. The dropping funnel is rinsed with 3 ml of dichloromethane and the washings are added to the reaction mixture. The mixture was stirred at the same temperature for 5 minutes and then allowed to warm to 10 ° C. NMR analysis of the liquid reaction mixture showed a methyl (- o - phenylene) phosphate yield of 89%. Nuclear Magnetic Resonance Spectrum (CH ₂ Cl ₂ ) δ: 3.81 and 4.02 (3H, s each, P-OCH ₃ ), 7.14 [4H, s, (21). Spectral signals for dichloromethane and triethylamine hydrochloride, as well as a weak multiplet signal at 6.2-7.6 ppm, are attributable to structural unit (18).

The yield of the desired space was determined in the same manner as in Example 8.

Example 7

2,3-dihydroxynaphthalene (1.747 g, 10.91 mmol) and ether (40 mL); triethylamine (2.208 g) and methyl (1.625 g).

using dichlorophosphate, following the procedure of Example 5, 2.20 g (85.4%) of 2-methoxy-2-oxo

- Naphtho (3,2-d) -1,3,2-dioxaphosphol. This product is a white powder.

Nuclear Magnetic Resonance Spectrum (CH ₂ Cl ₂ ) δ: 3.92and4.3 (3H, each s, PO-CH ₃ ), 7.1-7.9 [6H, m (20).

TLC (under conditions specified in Example 1): _Rf = 0.30.

Example 8

To a solution of 1.180 g (10.72 mmol) of pyrocatechin and 11 ml of dichloromethane was added 1.596 g of methyl dichlorophosphate, the mixture was stirred at 20-25 ° C for 20 minutes and then cooled to -30 ° C over 7 minutes, while stirring at -30 ° C to -20 ° C, 2.169 g of triethylamine are added dropwise. The dropping funnel was rinsed with 1 mL of dichloromethane and the mixture was stirred at the same temperature for 15 minutes, then allowed to warm to 10 'C and the triethylamine hydrochloride was filtered off and the precipitate was washed with dichloromethane. The combined filtrate and washings were added by NMR

Example 70

The procedure of Example 9 is followed, but di (n-butyl) amine and pyridine are used instead of lri (n-butyl) amine. The yield of methyl o-phenylene phosphate in the liquid reaction mixture was determined as in Example 9. Yields were 71% and 91%, respectively.

Example 77

To 1.418 g of pyrocatechin, 1.17 g of methyl dichlorophosphate and 11 ml of acetonitrile are added and the mixture is cooled to -25 ° C and stirred at -25 ° C to -20 ° C with stirring at 2.605 g of triethyl as we drip it. The drip funnel was rinsed with 1 mL of acetonitrile. After stirring for 10 minutes at the same temperature, the mixture was allowed to warm to 10 ° C and then filtered. The filtered precipitate was washed with acetonitrile (5 mL, 3 mL), and the washings were combined with the filtrate and concentrated in vacuo in a water bath (15-20 C). 3.102 g of methyl (o-phenylene) phosphate are thus obtained in the form of a slightly cloudy oil. Nuclear Magnetic Resonance Spectrum (CH ₂ Cl ₂ ) δ: 3.81 and 4.01 (3H, each s, P-OCH 3), 7.12 [4H, s, (21)]. The spectrum also shows dichloromethane and triethylamine hydrochloride (0.25 mole per mole of desired product).

-11 _... 21 _

191,478

Example 12

To 0.963 g of pyrocatechin is added 7 ml of dichloromethane and 1.30 g of methyl dichlorophosphate, and the mixture is stirred at 20-25 ° C for 10 minutes, followed by 1.86 g of triethyl at -20 ° C to -15 ° C. as we drop it. The dropping funnel was rinsed with 1 mL of dichloromethane and the mixture was stirred at the same temperature for 5 minutes. A reaction mixture containing methyl (o-phenylcn) phosphate and triethylamine hydrochloride was obtained.

Example 13

To a solution of 3.11 g of phenylphosphonic acid dichloride in 10 ml of ether is added a mixture of 1.76 g of pyrocatechin and 20 ml of ether, the resulting solution is cooled to -25 ° C to -28 ° C and heated for 8 minutes. 3.23 g of triethylamine and 10 ml of ether are added dropwise with stirring. The mixture was then allowed to warm to 20-25 ° C, and the precipitate was filtered off with suction and washed with 30 ml of ether. The washings are combined with the filtrate and the ether is distilled off in vacuo. This gave 3.46 g (94.4%) of 2-phenyl-2-oxo-1,3,2-benzodioxaphosphole as a colorless oil which crystallized overnight in a refrigerator.

NMR (CDC1 ₃₎ δ: 7.11 [4H, s, (18) propen assembly), 7.2 ~ 8, I [5H, m, (22) a structural unit of formula). Trace amounts of ether can also be observed in the spectrum.

TLC (under conditions specified in Example 1): _Rf = 0.35.

Example 14 i, 75 g of bis [tri (n-butyl) amine) salt of 7β - (D - 5 - carboxy - 5 - flalimido - valeramido) - 3 ··hydroxymethyl - 3 - cephem - 4 - carboxylic acid A solution of 0.35 g of 1-methyl-5-mercapto-1H-tetrazole and 20 ml of dichloromethane is cooled to -25 ° C, 0.74 g of methyl (o phenylene) phosphate is added and the mixture is stirred for 2 hours. Stirring is carried out at a temperature between 'C and -20'C. Thereafter, 15 ml of tetrahydrofuran and 15 ml of water were added, stirred and separated. The aqueous phase was extracted with a mixture of tetrahydrofuran (5 mL) and dichloromethane (10 mL). The organic phase and extracts were combined, washed with water (20 mL) and dried over anhydrous magnesium sulfate. The solvents were evaporated in vacuo, the residue was dissolved in a small amount of acetone and ether (100 mL) was added. The precipitate was filtered off, washed with ether and dried in vacuo. There was thus obtained 1.14 g (94.7%) of 7β- (D-5-carboxy-5-phthalimido-valeramido) -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-one. cefem - for 4 carboxylic acids.

IR spectrum (KBr) cm ^-1 : 3340, 2950, 1775, 1715, 1534, 1394.

NMR (DMSO-d ^ δ: 1.40-2.40 [6H, m, - (CH _{2) 3} -), 3.62 (2H, br, 2-CH _z), 3.94 (3H , s, N-CH ₃ ), 4.30 (2H, ABq, J = 15 Hz, 3-CH ₂ ), 4.73 (1 Η, 1, J = 8 Hz,> CH -), 5.01 (1H, d, J = 5Hz, -H), 5.62 (1H, q, J = 5.8Hz, 7H), 7.91 [4H, s, structural unit (23)], 8, 77 (1H, d, J = 8Hz, -CONH-).

Example 75

3.52 g of 7β - (D-5-carboxy-5-phthalimido-valeramido) -3-hydroxymethyl-3-cephem-4-carboxylic acid bis (trictylamine) salt, 1.00 g of 5-mercapto- I - methyl

A solution of 1H-tetrazole and 25 mL of dichloromethane is cooled to 20 'C and 0.25 g of triethylamine is added with stirring. To this solution is added the complete reaction mixture prepared according to Reference Example 12 (reference), cscpcgtctcsscl, with stirring at -20 'Cra cs-15'C. The dropping funnel was washed with dichloromethane (6 mL) and the solution was added to the reaction mixture. The reaction mixture was stirred at the same temperature for 20 minutes and then stirred at -5 ° C to 0 ° C for 60 minutes. Water (10 ml) was added, the solvent was distilled off in vacuo, dichloromethane (30 ml) and tetrahydrofuran (15 ml) were added to the residue and the phases were separated. The organic layer was washed with 1N hydrochloric acid, washed with saturated brine and then dried over magnesium sulfate. The solvents were evaporated in vacuo, the residue was dissolved in a small volume of acetone and the solution was poured into ether. The resulting precipitate was filtered off, washed with ether and dried in vacuo. Yield: 2.82 g (93.8%). The IR and NMR spectra of the product confirm that it is the same as that obtained in the procedure described in Example 14.

Example 76

Dissolve 0.70 g of 1-methyl-5-mercapto-1H-tetrazole in 30 ml of dichloromethane and add 0.65 g of triethylamine followed by 1.14 g of - phenylene phosphorus chloride at 20-25 ° C. temperature. The solution is then brought to -60 'C and 2.12 g of 7β are added at once

- (D - 5 - Carboxy - 5 - phthalimido - valeramido) - 3 hydroxy - inethyl - 3 - cephem - 4 - carboxylic acid bis (triethyl!

(amine) salt in 10 ml of dichloromethane. The mixture was warmed to 15 'C then cooled and a mixture of THF (20 mL) and water (20 mL) was added. After separation, the aqueous layer was extracted with 5 mL of THF and 10 mL of dichloromethane. The organic phase and extract were combined, dried over anhydrous magnesium sulfate, concentrated in vacuo to a volume of about 10 mL, and ether (100 mL) was added. The precipitate was filtered off, washed with ether and dried. Thus 1.33 g (73.7%) of 7β- (D-5-carboxy-5-phthalimido-valeramido) -3

- (I-Methyl-1 H -tetrazol-5-yl) -thiomethyl-3-cephem

- 4 - carboxylic acid.

IR spectrum (KBr) cm ^-1 : 3340, 2950, 1775, 1715, 1534, 1394.

NMR _(DMCO-d6) δ: l, 40 ~ 2.40 [6H, m, - (CH _{2) 3} -), 3.62 (2H, br, _2-CH2), 3.94 ( 3H, s,> N - CH ₃ ), 4.30 (2H, ABq, J = 15 Hz, 3 - CH ₂ ), 4.73 (1H, t, J = 8 Hz,> CH -), δ, 01 (1H, d, J = 5 Hz,

6-H), 5.62 (1H, q, J = 5 and 8 Hz, 7H), 7.91 (4H, s, moiety 23), 8.77 (1H, d, J = 8Hz, -CONH-).

Example 77

1.04 g of 1- (2-dimethylamine-ethyl) -5-mercapto

To a solution of 1H-tetrazole and 60 ml of dichloromethane is added 0.61 g of triethylamine, followed by 1.14 g of o-phenylene

-12 .... 23 .. 1

phosphorus chloride at room temperature. The solution is then cooled to -60 'C and 2.12 g of 7β (D-5-carboxy-5-phthalimido-valeramido) -3-hydroxymethyl-3-cephem-4-carboxylic acid bis (triethyl) are added.

(amine) salt and 10 ml of dichloromethane. The mixture was warmed to 15 ° C, the precipitate was filtered and washed with dichloromethane. The resulting solid was suspended in dichloromethane (30 mL) and triethylamine (0.71 g) was added under ice-water cooling. The suspension is stirred for 30 minutes and the insoluble material is filtered off. To the resulting filtrate was added dropwise 10 ml of 1N ethyl alcoholic hydrogen chloride solution at 0 ° C or less, followed by 20 ml of ether. The precipitate was filtered off, washed with dichloromethane and dried in vacuo. Thus 1.51 g (72.4%) of 7β - (D

- 5 - carboxy - 5 - phthalimido - valeramido) -3 - {1- (2

(dimethylaminoethyl) -1H-tetrazol-5-yl] thio methyl 3-cephem-4-carboxylic acid hydrochloride was obtained.

IR (KBr) cm ^-1: 1775, 1715, 1640; NMR spectrum _(DMSO-d6) δ: 1.30 to 2.40 [6H, m,

- (CH ₂ ) j -], 2.83 [6H, s, structural unit 24], 3.5 ~ 3.8 (4H, m, 2-CH ₂ and -CH ₂ N <), 4 30 (2H, br, 3 - _CH2), 4.5 ~ 4.9 [3H, m, - CH <and (25) formula assembly), 5.03 (lH, d, J = 5 Hz,

C ₆ - H), 5.60 (1H, q, J = 5 and 8 Hz, C ₇ - H), 7.90 [4H, s, structural unit (23)], 8.77 (1H, d) , 8Hz, -CONH-).

Example 18

2.12g7β- (D-5-Carboxy-5-phthalimido-valeramido) -3-hydroxymethyl-3-cephem-4-carboxylic acid bis (triethylamine) salt, 0.52 g of 5-mercapto-1 - To a mixture of methyl 1H-tetrazole and 30 ml of dichloromethane was added 0.61 g of triethylamine, the solution was cooled to -15 ° C, 1.67 g of methyl (o-phenylene) phosphate was added, followed by 30 minutes The temperature is maintained between -15 ° C and -10 ° C so that the reaction is complete. The reaction mixture was quenched with THF (20 mL) and water (20 mL) and adjusted to pH 2 with 6N hydrochloric acid. After separation of the phases, the aqueous solution was extracted with 5 ml of THF and 10 ml of dichloromethane. The organic phase and the extract obtained were combined and dried over anhydrous magnesium sulfate. Following the procedure of Example 16, 1.64 g (90.9%) of the product of Example 16 are obtained. The two products have the same IR and NMR spectra.

__ 24th

Example 20

1.75 g of bis [tri (n-butyl) amine] salt of 7β - (D-5-carboxy-5-phthalimido-valeramido) -3-hydroxymethyl-3-cephem-4-carboxylic acid, 0.35 g A solution of 1-methyl-5-mercapto-1H-tetrazole (g) in dichloromethane (20 ml) was cooled to -20 ° C, 0.74 g of methyl (o-phenylene) phosphate was added and Allow to stand at 20 ° C for complete reaction. Thereafter, 15 ml of THF and 15 ml of water were added and the mixture was thoroughly worked up and allowed to stand to separate the phases. The aqueous layer was extracted with a mixture of THF (5 mL) and dichloromethane (10 mL), the organic layer and this extract were combined, washed with water (20 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was dissolved in a small amount of acetone, and ether (100 mL) was added. The precipitate was filtered off, washed with ether and dried in vacuo. 1.14 g (94.7%) of product is obtained which is identical with the product prepared according to Example 16 by IR spectrum.

Example 21

0.52 g of 1- (2-dimethylaminoethyl) -5-mercapto

- To a solution of 1H-tetrazole and 40 ml of dichloromethane, 0.40 g of triethylamine followed by 1.41 g of 7β- (D-5-carboxy-5)

phthalimido - valeramido) - 3 - hydroxymethyl - 3 - cephem

Add the bis (triethylamine) salt of 4 - carboxylic acid, add 1.12 g of methyl (o - phenylene) phosphate and leave to stand at room temperature for 10 minutes to complete the reaction. It is then cooled and 5 ml of a 1N ethereal hydrogen chloride solution are added dropwise at 0 ° C or lower. The precipitate was filtered off and washed with dichloromethane, then suspended in dichloromethane (20 ml) and triethylamine (0.47 g) was added under ice-cooling. The mixture was mechanically stirred for 30 minutes and the insoluble material was filtered off. To the filtrate was added dropwise a solution of 1N ethyl alcoholic hydrogen chloride (6.7 mL) at 0 ° C or lower, followed by ether (10 mL). The precipitate was filtered off, washed with dichloromethane and dried in vacuo. 1.00 g (71.9%) of product are obtained which is identical with the product prepared according to Example 17 by IR and NMR.

Example 19

To a solution of 1.71 gophenylene phosphorus chloride and 15 mL of dichloromethane was added 0.91 g of triethylamine at room temperature, 0.29 g of methyl alcohol was added and the reaction was allowed to stand at room temperature for 10 minutes to complete the reaction. The resulting methyl (o-phenylene) phosphate solution was used in place of 1.67 g of methyl o-phenylene phosphate used in the above example (Example 18) and 1.62 g (89) in the following Example 18. (8%) to give the same product as in Example 16. The two products have the same IR and NMR spectra.

Example 22 To a solution of dichloromethane and 0.76 g of phenylene-phosphorus chloride in 0.40 g of trielylamine was added 0.56 gp-nitro phenol at room temperature, and the mixture was allowed to stand at room temperature for 10 minutes. to complete the reaction. To the resulting mixture was added 1.41 g of 7β - (D - 5 - carboxy - 5 - phthalimido - valeramido) - 3.

hydroxy - methyl - 3 - cephem - 4 - carboxylic acid bis (triethyl

- amine) - salt, 0.35 g of 1-methyl-5-mercapto-1H-tetrazole, 0.20 g of triethylamine in 20 ml of dichloromethane

Cooled to 20 'C and the resulting mixture was allowed to stand for 20 minutes at -20 ± 2' C for 20 minutes. The reaction mixture was then13

-13 .... 25. 1 is treated as in FIG. Example 9 gave 0.911 g (75.7%) of product, which was identical to the product of Example 16 by IR spectrum.

Example 23

To a solution of 0.74 g of 2,2,2-trichloro-1,3,2-benzodioxaphosphol in 10 ml of dichloromethane was added 0.30 g of triethylamine followed by 0.10 g of methanol at room temperature and the mixture was allowed to stand for 10 minutes at room temperature. leave for the complete reaction. Then, under ice-cooling, 0.20 g of triethylamine, 0.17 g of 1-methyl-5-mercapto-1H-tetrazole and 0.71 g of 7β- (D-5-carboxy)

5 - phthalimido - valeramido) - 3 - hydroxymethyl - 3

Add the bis (triethylamine) salt of cephem - 4 - carboxylic acid in the order indicated. The mixture was allowed to stand under ice-cooling for 30 minutes and then treated as described in Example 18 below. 0.404 g (66.8%) of product is obtained which is identical with the product of Example 16 on the IR spectrum.

Example 24

To a mixture of 0.74 g of 2,2,2-trichloro-1,3,2-benzodioxaphosphole and 10 ml of dichloromethane was added 0.4 g of triethylamine, followed by dropwise addition of 0.51 gp-chlorophenol, 0, at room temperature. 2 g of triethylamine, 0.17 g of I-methyl-5-mercapto-1H-tetrazole and 0.71 g of 7β - (D - 5 - carboxy - 5 - phthalimido - valeramido) - 3 - hydroxymethyl - 3 - bis (triethylamine) salt of cephem - 4 - carboxylic acid. The mixture was kept at room temperature for 40 minutes to complete the reaction and then treated as described in Example 18 below. 0.436 g (72%) of product is obtained which is identical with the product prepared according to Example 16 by IR spectrum.

0.41 g (67.7%) of product is obtained which is identical with the product of Example 16 by IR and BNR.

Example 27

874 mg of bis [tri (n-butyl) amine] salt of 7β - (D - 5 - carboxy - 5 - phthalimido valeramido) - 3 - cephem - 4 - carboxylic acid and 251 mg of 2 - mercapto - benzothiazole in 10 ml of dichloromethane The solution was cooled to -10 ° C and 400 mg of ethyl (o-phenylene) phosphate was added. After stirring at -10 ° C to -5 ° C for 2 hours, THF (8 mL) and water (8 mL) were added and the mixture was stirred and allowed to stand to separate. The aqueous phase was extracted with dichloromethane (5 mL), the extract was combined with the organic phase, water (10 mL) was added and the organic layer was dried over anhydrous magnesium sulfate after separation of the lyases. The solvent was evaporated in vacuo and the residue was dissolved in a small amount of acetonitrile / water / formic acid (20: 2: 0.1) on a silica gel column. The _Rf value of about 0.43 The fractions containing the desired product were collected and concentrated in vacuo. Ether was added to the oily residue and the resulting powdered precipitate was filtered off, washed with ether and dried. Yield: 555 mg (85%) of 7β- (D-5-carboxy-5-phthalimido-valeramido) -3 - [(benzothiazol-2-yl) thio]

- methyl] - 3 - cephem - 4 - carboxylic acid.

IR spectrum (KBr) cm ^-1 . ^- 3320, 1775, 1715.

NMR _(DMSO-d6) δ: l, 30 ~ 2.40 (6H, m, - CHjCHjCHj -), 3.62 (2H, ABq, J = 18Hz, _2-CH2), 4.38 ( 2Η, ABq, J = 14 Hz, 3-CH ₂ ), 4.73 (1H, t, J = 7 Hz,> CH-), 5.04 (1H, d, J = 5 Hz, C ₆ - Η ), 5.63 (1H, q, J = 5 & 8 Hz, C ₇ - H), 7.86 [4H, s, (18) wherein the structural unit] 8.80 (IH, d, J = 8 Hz , -CONH-).

Example 25

To a solution of 1.13 g of bis (o-phenylene dioxy) chlorophosphorus in 10 ml of dichloromethane under ice-cooling are added 0.2 g of triethylamine, 0.17 g of 1-methyl-5-mercapto

- 1H - tetrazole and 0.71 g of 7β - (D - 5 - carboxy - 5 - phthalimido - valeramido) - 3 - hydroxymethyl - 3 - cephem

Bis (triethylamine) salt of 4 - carboxylic acid is added. The mixture was then allowed to stand for 30 minutes under ice-cooling to complete the reaction and then treated as in Example 18 below. 0.43 g of product is obtained which is identical with the product prepared in Example 16 on the basis of the IR sequence.

Example 26

0.71 g of 7β- (D-5-carboxy-5-phthalimido-valcramido) -3-hydroxymethyl-3-cephem-4-carboxylic acid bis (triethylamine) salt and 0.17 g of 1-methyl-5 mercapto-1H-tetrazole is dissolved in 5 ml of dichloromethane, 0.2 g of triethylamine and 0.51 g of methyl (o-phenylene) phosphite are added and the solution is left to stand at room temperature for 22 hours to complete the reaction, and then treated as in Example 18.

Example 28

874 g of bis [tri (n-butyl) amine] salt of 7β - (D - 5 - carboxy - 5 - phthalimido - valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 - carboxylic acid and 198 mg of 2 - methyl A solution of 5-mercapto-1,3,4-thiadiazole in 10 ml of dichloromethane was cooled to -20 ° C to -15 ° C and 375 mg of methyl (o-phenylene) phosphate was added under ice-cooling 1, Stir for 5 hours. The mixture was then treated as in Example 27. Thus, 502 mg (81.3%) of 7β - (D-5-carboxy-5-phthalimido-valeramido) -3 - [(2-methyl-1,3,4 thiadiazol-5-yl) thiomethyl] -3 - cefem - 4 - carboxylic acid is obtained.

IR spectrum (KBr) cm ^-1 : 3300, 1775, 1715.

NMR _(DMSO-d6) δ: l, 30 ~ 2.40 (6H, m, _{-CH2 CH2 CH2} -), 2.71 (3H, s, CH,), 3.62 (2H , ABq, 19 Hz, _2-CH2), 4.37 (2H, AB quartet, J = 13 Hz, 3 - CH _2), 4.76 (1H, t, J = 7Hz,> CH -), 5 , 06 (1H, d, J = 4Hz, C ₆ -H), 5.65 (1H, q, J = 5 and 8Hz, C 1 -H), 7.92 [4H, s, (18) structural unit], 8.81 (1H, d, J = 8Hz, -CONH-).

-1 428

Example 29

^A solution of 47 ^Ί mg of ο-phenylene-phosphoric chloride and 5 ml of dichloromethane is cooled to -20 ° C to -10 ° C, 463 mg of tri (n-butyl) are added.

amine and 235 mg of phenol and stirred for 5 minutes at the same temperature. A solution containing phenyl (o - phenylene) phosphate is thus formed. Meanwhile, under stirring and ice-cooling, 278 mg of tri (n-butyl) amine were added 874 mg of 7β - (D - 5 - carboxy - 5 - flalimido - valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 - carboxylic acid bis [tri (n-butyl) amine] salt and 312 mg of 2-carboxymethylthio-5-mercapto-1,3,4-thiadiazole in 5 ml of dichloromethane. The resulting mixture was cooled to -10 ° C to -5 ° C and a solution of phenyl (o-phenylene) phosphate prepared as described above was added and the whole was stirred at room temperature for 2 hours. Further treatment and work-up as described in Example 27 gave 501 mg (72.2%) of 7β - (D - 5 - carboxy - 5 - phthalimido - valeramido) - 3 - [(2 - carboxymethylthio).

- 1,3,4 - thiadiazol - 5 - yl) - thiomethyl] - 3 - cephem - 4

- Carboxylic acid is obtained.

IR spectrum (KBr) cm ^-1 : 3300, 1775, 1713.

NMR _(DMS0-d6) δ: 30 ~ 2.40 (6H, m, _{-CH2 CH2 CH2} -), 3.59 (2H, br, _2-CH2), 4.13 ( 2H, s, -SCH ₂ COO-), 4.33 (2H, ABq, J = 13Hz,

3-CHJ, 4.72 (IH, t, J = 6Hz,> CH), 5.04 (IH, d, J = 5Hz, C _e -H), 5.40 ~ 5.80 (H , broad, C ₇ -H), 7.90 [4H, s, (18)], 8.78 (1H, d, J = 8Hz, -CONH-).

Example 30

874 mg bis [tri (n-butyl) amine] salt of 7β - (D-5-carboxy-5-phthalimido valermido) -3-hydroxymethyl-3-cephem-4 carboxylic acid, 312 mg 1 carboxymethyl- To a solution of 5-mercapto-1H-tetrazole and 10 ml of dichloromethane under ice-cooling, 278 mg of tri (n

(butyl) amine was added and the mixture was stirred for 10 minutes, followed by the addition of 372 mg of methyl (o-phenylene) phosphate at -25 ° C to -20 ° C, and the resulting mixture was heated at the same temperature for 2 hours. stir. Further treatment and work-up as described in Example 27 gave 476 mg (73.7%) of 7β - (D - 5 - carboxy - 5 - phthalimido - valeramido) - 3 - [(1 - carboxymethyl - 1H - tetrazole). 5)

thiomethyl] -3 - cephem - 4 - carboxylic acid is obtained. IR spectrum (KBr) an ¹ : 3300, 1773, 1713.

NMR _(DMS0-d6) δ: 1.40 ~ 2.40 (6H, m, _{-CH2 CH2 CH2} -), 3.62 (2H, br, 2-CHJ, 4.33 (2H, AB quartet, J = 14 Hz, 3 - CH _2), 4.71 (IH, t, J = 6Hz,> CH-), 4.99 (IH d, J = 5Hz, C ₆ -H), 5 28 (2H, s,> _NCH2 CO -), 5.62 (IH, q, J = 5 and 8 Hz, C ₇ - H), 7.89 [4H, s, (18) a structural unit of formula] , 8.77 (1H, d, J = 8 Hz, + CONH-).

31. ' example

- Using 354 mg of 2-ethoxycarbonylmethylthio-5-mercapto -1,3,4-thiadiazole instead of mercapto-benzothiazole, 600 mg (83.2%) of 7β - (D -) was used as in Example 27. 5-Carboxy-5-phthalimido-valeramido) -3 - ((2-ethoxycarbonylmethyl-thio-1,3,4-thiadiazol-5-yl) -thiomethyl] -3-cephem-4-carboxylic acid is obtained. .

IR spectrum (KBr) cm ^-1 : 3320, 1775, 1715.

NMR _(DMSO-d6) δ: l, 00 ~ 2.40 (9H, m, CH ₂ and CH ₂ CH ₂ CH ₂ -), 2.9 ~ 4.5 (8H, m, 2- CH ₂ , 3 -CH ₂ , -S-CH ₂ CO-, CO ₂ CH ₂ ), 4.75 (1H, t, J = 6Hz,> CH-), 5.06 (1H, d, J = 5 Hz, C 1 - H), 5.40 - 5.90 (1H, broad, C ₇ - H), 7.90 [4H, s, structural unit (18)], 8.60 ~ 9.10 (1H, broad, -C0NH-).

Example 32

874 mg of a mixture of 7β - (D-5-carboxy-5-benzamido valeramido) -3-hydroxymethyl-3-cephem-4 carboxylic acid bis [tri- (n-butyl) amino] salt and 10 ml dichloromethane After cooling to -50 ° C to 40 ° C, 198 mg of pyridine is added followed by 372 mg of methyl (o-phenylene) phosphate and 3 ml of dichloromethane. The mixture was then stirred at -10 ° C to 0 ° C for 2 hours. Water (15 mL) was added to adjust the pH to 7.0 and the mixture was allowed to stand to separate the layers. The aqueous phase was washed twice with dichloromethane (5 mL each), adjusted to pH 6.0, and concentrated in vacuo. The residue was chromatographed on an Amberlite XAD-2 column (XAD-2 fineness 100-200 mesh, 100 mL, column height 32 cm) eluting with water followed by 10: 2 water / methanol. Each fraction was checked using TLC (developing solvent: 15: 5: 0.25 acetonitrile / water / 99% formic acid). The desired product (the _Rf value of about 0.24) containing fractions were collected and concentrated to give 410 mg (73.1%) of N - [7β - (D - 5 - benzamido - adipinamido)

- 3 - cephem - 3 - ylmethyl] - pyridinium - 4 - carboxylic acid

- monosodium salt is obtained.

IR spectrum (KBr) cm ^-1 : 3360, 3250, 1765, 1645, 1630, 1605.

Nuclear Magnetic Resonance Spectrum (D ₂ O) δ: 1.50 - 2.60 (6H, m,

- (CH ₂ ) ₃ -), 3.14 (2H, ABq, J = 19 Hz, 2 - CH ₂ ), 4.36 (1H, m, > CH -), 5.05 (1H, d, J = 5 Hz, C ₆ - H), 5.32 (2H, ABq, J = 15 Hz, 3 - CH ₂ ), 5.60 (1H, d, J = 5 Hz, C ₇ - Η), 7, 0 ~ 9.0 [10H, in, units 26 and 22].

Example 33

To a solution of 286 mg of o-phenylene phosphoric chloride and 3 ml of dichloromethane is added 174 mg of 1-methyl-5-mercapto-1H-tetrazole, the mixture is cooled to -20 ° C and -10 ° C, and 152 mg of triethyl are added. amine and 1 ml of dichloromethane, allowed to stand under stirring and then at room temperature, followed by 710 mg of 7β - [D-5-carboxylic acid

- 5 - (Benzyloxycarbonylamino) - valeramido] 3 - hydroxymethyl - 3 - [alpha] - 4 - carboxylic acid bis (trictyl)

(amine) salt and dichloromethane (7 ml) which was cooled with stirring at -30 ° C to -20 ° C. The mixture was stirred for 6 minutes at this temperature

-15- 29

After stirring at 191,478, 15 ml of 2N hydrochloric acid and 10 ml of THF were added. The organic layer was separated, washed twice, dried with brine (5 mL each), anhydrous magnesium sulfate, concentrated in vacuo, and ether was added to the residue. The resulting powdery precipitate was filtered off, dissolved in a mixture of acetonitrile and water and chromatographed on a column of silica gel (20 g, 24 cm column height) using a 20: 2: 0.1 mixture of acetonitrile, water and formic acid. . Each fraction was checked by TLC (solvent mixture as described in the previous example). Fractions of about 0.24 R _r containing the desired product were collected, evaporated and ether was added to the residue. The precipitated powder was collected by filtration and dried to give 370 mg (611%) of 7β - [D - 5 - carboxy - 5 - (benzyloxycarbonylamino) valeramido] - 3 - [(I - methyl - 1H - tetrazole - 5). (Ü) thiomethyl] -3-cephem-4-carboxylic acid.

IR (KBr) cm- ¹ : 3300, 1775, 1715.

NMR (DMSO-d δ: l, 30 ~ 1.90 (4H, m, 2 x CH), 2.00 2.30 (2H, m, _CH2), 3.67 (2H, br,

2-CH ₂ ), 3.93 (3H, s, N-CH 3, 4.30 (2H, broad,

3-CH 3, 4.80-5.20 (4H, m, -CH ₂ O-,> CH- and

C _e - H), 5.63 (IH, q, J = 5 and 8 Hz, C - H), 7.10 to 7.60 [m, 6H, (22) and the structural unit kcplctű

-OCONH-], 8.78 (1H, d, J = 8 Hz, -CONH-).

Example 34

1.75 g of 7β - (D - 5 - carboxy - 5 - phthalimido - valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 - carboxylic acid instead of the bis [tri (n - butyl) amine] salt 1.81 g g of 7β - [D5- (p-tert-butylbenzamido) -5-carboxy valeramido] -3-hydroxymethyl-3-cephem-4 carboxylic acid using bis [tn (n-butyl) amine] salt , and more, following the procedure of Example 20, 1.18 g (93.4%) of 7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvaleramido] -3- (1-methyl). 1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid is obtained.

IR spectrum (KBr cm ^{-1 -1} : 1776, 1727, 1640).

NMR (DMSO-d _e) δ: 1.28 (9H, s, _CH3 x 3), 1.70 and 2.21 (6H, CH _2, CH ₂ x 3), 3.54 and 3.77 (2H, ABq, J = 18 Hz, 2-CH3, 3.91 (3H, s,> N-CH3, 4.20 and 4.37 (2H, ABq, J = 13 Hz, 3-CH3, 4, 39 (lH,> CH-), 5.02 (IH, d, J = 5Hz, C _e H) m 5.64 (IH, q, J = 5 and 8 Hz, C - H), 7 , 43 and 7.81 [4H, moiety (38)], 8.42 [1H, d, J = 8 Hz, moiety (39)], 8.79 (1H, d, J = 8 Hz) , - CONH -).

Example 35

A solution of 0.450 g of o-phenylene phosphoric chloride and 2 ml of dichloromethane is cooled to 0-5 ° C and 0.437 g of tri (n-butyl) are added first.

a mixture of amine and 1 ml of dichloromethane followed by a solution of 76 mg of methanol and 2 ml of dichloromethane. This mixture was stirred at room temperature for 20 minutes to give a solution of methyl (o phenylene) phosphate. This solution is treated with stirring at -20 ° C to -25'C with 1.032 g of 7β- (D-5-carboxy-5).

phthalimido - valeramido) - 3 - hydroxymethyl - 3 - cephem

A solution of 4 - carboxylic acid bis [tri (n - butyl) amine] salt and 0.267 g of 2 - mercapto - benzoxazole in 5 ml of dichloromethane. The mixture was allowed to stand for 80 minutes at -20 ° C to -10 ° C to complete the reaction, then water (15 ml) was added and, after separation of the phases, water (15 ml) was added to the organic phase. The pH was adjusted to 9.0 with 1N sodium hydroxide solution and, after separation of the phases, the organic layer was extracted twice more with 5 ml of water each time. The aqueous solutions were combined and washed with dichloromethane (5 mL), then the pH of the aqueous phase was adjusted to 2 with 2N hydrochloric acid and extracted with dichloromethane: THF (1: 1). The organic layer was washed twice with brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, ether was added, and the resulting powdery precipitate was filtered off and dried, yielding 588 mg (78.2%) of 7β- (D-5-carboxy-5-phthalimido).

Valeramido) -3- (benzoxazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid is obtained.

IR spectrum (KBr) cm ^-1 : 3310, 2930, 1775, 1715, 1530, 1500.

NMR _(DMSO-d6) δ: l, 30 ~ 2.40 (6H, m, _{-CH2 CH2 CH2} -), 3.68 (2H, AB q, 2 CHJ, 4.23 and 4, 66 (2H, ABq, J = 14 Hz, 3-CH3, 4.73 (1H, t, J = 7Hz,> CH-), 5.04 (1H, d, J = 5 L, C ₆ -H), 5.63 (1H, q, J = 5 and 8 Hz, C 1 -H), 7.20-7.77 14H, m, structural unit 40], 7.87 [4H, s, (18)], 8.78 (1H, d, J = 8Hz, -CONH +).

Example 36

To a stirred solution of 56.0 mg of methanol, 365 mg of tri (n-butyl) amine and 6 ml of dichloromethane at -20 ° C to -10 ° C was stirred 376 mg o phenylene phosphorus chloride and 5 ml dichloromethane. methane was added and the mixture was stirred at room temperature for one hour to complete the formation of methyl o-phenylene phosphate. In another apparatus, 874 mg of 7β - (D - 5 - carboxy - 5 - phthalimido - valeramido) - 3

- hydroxymethyl - 3 - cephem - 4 - carboxylic acid bis [tri (n

(butyl) amine] salt and 5 ml of dichloromethane at 0-5'C is added a mixture of 158 mg of pyridine and 2 ml of dichloromethane. The mixture is cooled to -40 ° C to -30 ° C and the methyl (o-phenylene) phosphate solution prepared above in another apparatus is added with stirring, and the mixture is then stirred at -30 ° C and -10 ° C. After stirring at 45 ° C for 45 minutes and then at 0-10 ° C for 30 minutes, the powder was filtered off, washed with dichloromethane and dried. Thus, 465 mg (83.4%) of 7β- (D-5-carboxy-5)

phthalimido - valeramido) - 3 - pyridinio - methyl - 3 cephem - 4 - carboxylate is obtained.

IR spectrum (KBr) cm ^-1 : 3375, 3020, 2920, 1772, 1710, 1390.

Nuclear Magnetic Resonance Spectrum (D ₂ O + NaOD) δ: 1.30 - 2.60 (6H, m, -CH ₂ CH ₂ CH ₂ -), 2.90 and 3.55 (2H, Abq. J = 18 Hz, 2 -CH 2, 5.10 (1H, d, J = 5Hz, C ₆ -H), 5.32 and 5.66 (2H, ABq. J = 17Hz, 3-CH 3, 5.63 (1H, d) , J = 5 Hz, C ₆ -H), 7.78 [4H, s, structural unit 18], 8.03-9.06 [5H, m, structural unit 26].

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Example 37

A mixture of 646 mg of 2,6-lutidine, 96.8 mg of methanol and 7 ml of dichloromethane was added to a solution of 528 mg of o-phenylene-phosphoric chloride and 3 ml of dichloromethane in ice-cooled stirring and stirred for 5 minutes. Formation of (o - phenylene) - phosphate should be completed. To this solution was added 376 mg of isonicotinic acid amide, and the mixture was stirred for 10 minutes, followed by 923 mg of 7β - (D - 5 - carboxy - 5 - phthalimido - valeramido) - 3.

2,6-Lutidine salt of hydroxymethyl-3-cephem-4-carboxylic acid was added and the mixture was stirred under ice-cooling for 2 hours and then at room temperature for 5 hours. The reaction mixture was then stirred at -20'C overnight

Allow to stand at a temperature between 10 ° C. Water (15 mL) was added and the pH was adjusted to 7.0 with 1 N sodium hydroxide. The aqueous phase was washed with dichloromethane, adjusted to pH 6.0, and evaporated in vacuo. The residue was chromatographed on a column of Amberlite XAD-2 eluting with water followed by water / methanol. The active fractions were collected, evaporated and lyophilized. There was thus obtained 560 mg (63.1%) of 7β- (D-5-carboxy)

The sodium salt of 5-phthalimido-valeramido) -3- (4-carbamoylpyridinium) methyl 4-carboxylate is obtained. IR spectrum (KBr) cm ^-1 : 3350, 1773, 1708, 1613, 1463.

Nuclear Magnetic Resonance Spectrum (D ₂ O) δ: 1.30 2.60 (6H, m, -CH ₂ CH ₂ CH ₂ -), 2.90 and 3.55 (2H, Abq, J = 18 Hz, 2-CH _2), 5.10 (IH, d, J = 5Hz, Ce-H), 5.34 and 5.68 (2H, ABq, J = 14Hz, _3-CH2), 5.60 (IH, d, J = 5 Hz, C ₇ -H), 7.79 [4H, s, (18) [alpha]), 8.41 and 9.14 (4H, dd, 4-carbonylpyridinium moiety).

Example 38

To a solution of 0.469 g of - phenylene phosphoric chloride and 5 ml of dichloromethane cooled to -50 ° C to -40 ° C is added a solution of 0.455 g of tri (n-butyl) amine, 78.8 mg of methanol and dichloromethane, and the mixture was then heated to room temperature for 20 minutes. Stir at moderate temperature to complete formation of methyl (o - phenylene) phosphate. In another apparatus, 0.339 g of tri (n-butyl) amine were added to 1.066 g of 7β (D-5-carboxy-5-phthalimido-valeramido) -3-hydroxymethyl-3-cephem-4-carboxylic acid bis (tri (n-butyl) amine salt, a suspension of 0.322 g of 4,6-dimethyl-2-mercapto-pyrimidine hydrochloride in 5 ml of dichloromethane. The resulting solution was cooled to -30 ° C to -35 ° C and added with stirring. The solution of methyl (o-phenylene) phosphate prepared above was then completed for 1 hour at 0-5 ° C. Then 15 ml of water was added and the layers were again allowed to separate. water is added and the pH is adjusted to 6.0 After separation of the phases, 20 ml of water is added to the organic phase and the pH of the mixture is adjusted to 9.0 with 1N sodium hydroxide solution. , and washed twice with 5 ml of dichloromethane each To the phase was added 45 mL of a mixture of THF and dichloromethane (F) and the pH of the mixture was adjusted to 2.0 with 2N hydrochloric acid. After separation of the phases, the organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off and ether was added to the residue. The resulting powdery precipitate was filtered off and dried. Thus 0.6.30 g (82.5%) of 7β- (D5-carboxy-5)

phthalimido - valeramido) - 3- (4,6 - dimethylpyrimidine)

2- (yl) -thiomethyl-3-cephem-4-carboxylic acid is obtained.

IR spectrum (KBr) cm- ¹ : 3290, 2930, 2560, 1773, 1710, 1580, 1530.

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ ) δ: 1.30 - 2.40 (6H, m, -CH ₂ CH ₂ CH ₂ -), 2.35 (6H, s, CH ₃ x 2), 3.55 ( 2H, 2-CH ₂ ), 3.93 and 4.36 (2H, ABq, J = 14 Hz, 2-CH ₂ ), 4.78 - (Η, 1.1, J = 7 Hz,> CH) , 4.99 (1H, d, J = 5Hz, C 1 -H), 5.56 (1H, d _t J = 5 and 8Hz, C ₇ -H), 6.93 [1H, s, ( 27), 7.87 (4H, s, 18), 8.22 (1H, d, J = 8Hz, -CONH-).

Example 39

Method 1:

A solution of 0.195 g of 1-methyl-5-mercapto-1H-tetrazole and 5 ml of dichloromethane was cooled to -10 ° C and 0.268 g of phenylene-phosphorus chloride in 5 ml of dichloromethane was added, followed by -20 ° C. cool to -25 ° C and add dropwise 1,170 g of 7β- (5-diphenylmethyloxycarbonyl-5-phthalimido-valeramido) -3-hydroxymethyl-3-cephem.

A mixture of diphenylmethyl ester of 4 - carboxylic acid and 8 ml of dichloromethane. stirring was maintained for 20 minutes, water (10 mL) was added and the mixture was allowed to stand at room temperature until the phases were separated. The organic layer was washed with water, dried over anhydrous sodium sulfate, evaporated and the residue was poured into 80 mL of ether. The precipitated powder was filtered off and chromatographed on a silica gel column (30 g, 36 cm height) eluting with ethyl acetate / n-hexane (4: 1). Each fraction was monitored by TLC (eluent was applied to the aforementioned developed), and the fractions with _Rf of about 0.71, containing the desired product were collected and evaporated. Add ether to the evaporation residue to give 7β - (5

- diphenylmethyloxycarbonyl-5-phthalimido valeramido) -3- (1-methyl-1H-tetrazol-5-yl) thio

diphenylmethyl ester of methyl 3 - cephem - 4 - carboxylic acid is obtained.

IR spectrum (KBr) cm- ¹ : 3350, 3030, 2930, 1780, 1717.

NMR (DMSO-d _e) δ: 1.30 to 2.40 (6H, m, _{-CH2 CH2 CH2} -), 3.68 (2H, br, s, 2-CH ₂₎ 3, 88 (3H, s,> N-CH ₃ ), 4.24 (2H, broad, s, 3-CH ₂ ), 4.90-5.20 (2H, m, C ₆ -H and> CH-). , 5.73 (1H, q, J = 5 and 8 Hz), 6.83 and 6.90 (2H, s, - COOCH λ x 2), 7.10 7.60 [20H, m, (C H _{S 2} C ₂ x 2], 7.91 [4H, s, (18)), 8.87 (1H, d, J = 8Hz, -CONH-).

Method 2:

A solution of 0.182 g of 1-methyl-5-mercapto-1H-tetrazole, 0.485 g of tri (n-butyl) amine and 5 ml of dichloromethane is cooled to -10 ° C, 0.250 g of phenylene phosphorus chloride and 5 ml of dichloromethane, then

-17. 33 ....

191,478.

the mixture was cooled to -20 ° C to -25 ° C, and 1.09 g of 7β- (5-diphenylmethyloxy) was added.

- carbonyl - 5 - flalimido - valeramido) - 3 - hydroxy

diphenyl methyl ester of 3-cephem-4-carboxylic acid, and this mixture is treated in the same manner as in Method 1. This gives the desired product which is identical with the product obtained according to Method 1 by IR and NMR.

Example 40

1. 0.540 g of 7β - (2-thienylacetamido) -3-hydroxymethyl-3-cephem-4-carboxylic acid tri (n-butyl) amine

- salt, 0.375 g of methyl o-phenylene phosphate and 5 ml of ethyl acetate are added to a mixture of 0.175 g of I-methyl-5-mercapto-1H-tetrazole and 10 ml of ethyl acetate at -20 ° C, then stirred under ice-cooling for 1.5 hours, and then 10 ml of water were added. After separation of the phases, water (20 mL) was added to the organic layer and the pH of the mixture was adjusted to 9.0. The aqueous layer was separated and washed with ethyl acetate (5 mL). To the aqueous phase was added 20 mL of Clil-accl and the pH of the mixture was adjusted to 2.0. After separation, the organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated in vacuo and ether was added to the residue. The powdery precipitate thus formed is filtered off. Thus 0.380 g (84.1%) of 7β- (2-thienylacetamide)

- 3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3

- cefem - 4 - carboxylic acid is obtained. The IR and NMR spectra of this product are identical to those of an authentic product.

2. Using the procedure described under 1, using 0.477 g of di (n-butyl) amine salt of 7β-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylic acid 0.361 g (80.9%) 7

- phenylacetamido - 3- (1 - methyl - 1H - tetrazole - 5

- yl) - thio - inethyl - 3 - cephem - 4 - carboxylic acid having IR and NMR spectra identical to that of an authentic product.

Example 41

To a solution of 271 mg of o-phenylene phosphoric chloride and 4 ml of dichloromethane was added 180 mg of 1-methyl-5-mercapto-1H-tetrazole, followed by the addition of 157 mg of triethylamine and 3 ml of dichloromethane. To the resulting mixture was added 732 mg of the bis (triethylamine) salt of 7β - (D-5-carboxy-5-flalimido valeramido) -3-hydroxymethyl-3-cephem-4 carboxylic acid at -5 ° C with stirring. and stirring is maintained for 5 minutes while maintaining the temperature. Water (10 mL) and THF (7 mL) were added and the pH was adjusted to 2. After separation of the phases, water (20 ml) was added to the organic layer and the pH of the mixture was adjusted to 7.0. Dichloromethane and THF were distilled off in vacuo, and dichloromethane (10 mL) was added to the residue and the pH of the mixture was adjusted to 9.0 with 1N sodium hydroxide solution. The aqueous layer was separated, washed with dichloromethane (10 mL), a 1: 1 mixture of dichloromethane and THF (20 mL) was added, the pH was adjusted to 2.0 with 2N hydrochloric acid, and the layers were separated. The organic layer was washed with saturated brine, dried over sodium sulfate, and evaporated. Ether was added to the residue and the precipitated powder was filtered and dried to give 410 mg (65.7%) of 7β- (D-5-carboxy-5-phthalimido-valeramido) -3- (1-methyl-1H-tetrazole). (5-yl) thiomethyl-3-cephem-4-carboxylic acid is obtained which is identical with the product (rt) in Example 16 by IR and NMR.

Example 42 (1) To a solution of o-phenylene phosphoric chloride (762 mg, 4 mmol) in dichloromethane (10 mL) was added tri (n-butyl) amine (741 mg, 4 mmol) followed by methyl (128 mg, 4 mmol). alcohol and 5 ml of dichloromethane are added dropwise. This gives a solution of methyl (o-phenylene) phosphate. In another apparatus, 874 mg of 7β - (D - 5

- carboxy - 5 - flalimido - valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 - carboxylic acid bis [tri (n - butyl) amine] - salt, 174 mg of 1 - methyl - 5 - mercapto - 1H - tetrazole and 5 ml. the dichloromethane mixture is cooled to -15 ° C to -10 ° C and a solution of methyl (o-phenylene) phosphate prepared above is added dropwise to this side. The mixture was stirred at the same temperature for 40 minutes and then dichloromethane was evaporated in vacuo. The residue was dissolved in water / acetonitrile 3: 2 (v / v). The solution contains 7β - (D - 5 - carboxy)

- 5-Phthalimido-valeramido) -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid as determined by high performance liquid chromatography to yield 537 mg (89, 3%).

(2) - (18)

Instead of 128 mg of methyl alcohol used in the procedure described in (1), 4 mmol of each hydroxyl environment in Table I were used to prepare a solution containing the appropriate o-phenylene phosphate. Following the procedure described in (1), this solution was carried out at a temperature between -15 ° C and -10 ° C, and the reaction mixture was tested for 7β- (D-5-carboxy-5-phthalimido-valeramido) -3 - (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3

- amount of cephem - 4 - carboxylic acid. This yield and reaction time are also shown in Table 1.

/. Spreadsheet

THE

Row- song hydroxy reaction time-: duration minute Yield mg % (2) Methanol 35 493 82.0 (3) Methanol 40 511 . 84.9 (4) Methanol 60 505 84.0 (5) Ethyl alcohol 120 507 84.3 (6) 2,2,2-trichloro-CLIL alcohol 5 493 84.9 (7) 2-Bromo-ethyl alcohol 20 509 84.6

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191,478

Continuation of Table 7

Row- song Hidroxivcgyület THE reaction time- duration minute Yield mg % (8) n-Propyl Alcohol 140 531 88.3 ' (9) Isopropyl alcohol 180 434 72.1 (10) 2,3-dibromo-propyl alcohol 20 475 79.0 (II) n-Butyl alcohol 150 493 82.0 (12) Isobutyl alcohol 150 502 83.5 (13) sec-Butyl Alcohol 210 513 85.3 (14) cyclohexanol 270 505 83.9 (15) Phenol 10 495 82.3 (16) Phenol 5 509 84.6 (17) Allyl alcohol 40 ' 498 82.8 (18) 2-methylallyl alcohol 40 490 81.5

Example 43

A mixture of 762 mg of o-phenylene phosphoric chloride and 12 ml of dichloromethane was cooled to 10 ° C to 0 ° C and 741 mg of tri (n-butyl) -amine was added, followed by 236 mg of this solution at room temperature. n-propylamine is added. The reaction was allowed to proceed for 10 minutes at the same temperature to give a solution of 2-oxo-2-propylamino-1,3,2-benzodioxaphosphol. 874 mg of 7β- (D-5-carboxy-5-phthalimido valeramido) -3-hydroxymethyl-3-cephem-4 carboxylic acid bis [tri ( n - butyl) amine] salt, 174 mg of a mixture of 1-methyl-5-mercapto-1H-tetrazole and 5 ml of dichloromethane. The reaction was completed at the same temperature for an additional 150 minutes and then dichloromethane was removed in vacuo. The residue was further treated according to Example 42 (1) and the yield determined according to the method disclosed therein. 454 mg (75.5%) of 7β - (D-5-carboxy-5-phthalimido-valeramido) -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid we get.

Example 44 (1) 5.5 g of pyrocatechin are dissolved in 110 ml of dichloromethane, 15.2 g of triethylamine are added, and 7.29 g of phosphoryl trichloride is added dropwise at 10 to 20 ° C with stirring. The reaction mixture was filtered under nitrogen and washed with a small amount of dichloromethane. 124 ml of a substantially pure filtrate are thus obtained.

(2) A solution of 9.4 ml of the filtrate obtained in (1) is added dropwise at -10 ° C to 0 ° C with 7β- (D-5-carboxy-5-phthalimido valeramido) -3-hydroxy- bis (triethylamine) salt of methyl 3-cephem-4 carboxylic acid, 168 mg of 1-methyl-5-mercapto-1H-tetrazole and 6 ml of dichloromethane elcgycliez, and the mixture is kept at the same temperature for 2 hours. then the mixture was heated at 0-5 ° C overnight. At this time 10 ml of 2N hydrochloric acid was added under ice-cooling and the pH of the mixture was adjusted to 2. To the mixture was added 18 ml of a 1: 1 (v / v) THF-water mixture, the insoluble material was filtered off and washed with 2 ml of a 1: 1 mixture of THF-water. The filtrate and washings were combined, the layers separated, the organic layer washed with water (10 mL) and the aqueous layer extracted with dichloromethane (2 mL). This extract was combined with the organic phase obtained previously, dried over anhydrous magnesium sulfate, concentrated to a volume of about 5 ml, and poured into 70 ml of ether. The precipitate formed on the powder is filtered off, washed with ether and dried. Thus, 514 mg (71%) of 7β

- (D - 5 - Carboxy - 5 - phthalimido - valeramido) - 3 - (1

- methyl - 1H - tetrazol - 5 - yl) - thio - methyl! 3-cephem-4-carboxylic acid is obtained having an IR cs NMR spectrum identical to that of an authentic sample.

Example 45

849 mg of bis (trictylamine) salt of 7β - (D - 5 - carboxy - 5 - phthalimido valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 carboxylic acid, 194 mg of 2 - mercapto - benzothiazole and 6 ml of dichloro - 9.4 ml of the filtrate obtained in Example 44 (1) are added dropwise to a mixture of methane at -10 ° C to 0 ° C. The mixture was then allowed to stand at room temperature for 40 minutes to complete the reaction and then kept at 0-5 ° C overnight. Subsequently, the mixture was treated according to Example 44 (2) with 467 mg (59.6%) of 7β - (D - 5 - carboxy - 5 - phthalimido - valeramido) - 3 - {(benzothiazol - 2 - yl) thio -. methyl] -3-cephem-4 carboxylic acid having IR and NMR spectra similar to that of Example 27.

Example 46 (1) 3.64 g of ethyl 3,4-dihydroxybenzoate are dissolved in 44 ml of dichloromethane and 6.06 g of triethylamine are added. Then 2.92 g of phosphoryl trichloride are added dropwise at 10-20 ° C over 10 minutes. The mixture was filtered under nitrogen and the filter cake washed with dichloromethane (20 mL). The wash was combined with the filtrate to give a volume of 62 ml.

(2) To a solution of 17.6 ml of the solution obtained in (1) is added 168 mg of I-mcyl-5-mercapto-1H-tetrazole and then cooled to 0-5 ° C, 849 mg of 7β - ( D-5-carboxy-5-phthalimido-valeramido) -3-hydroxymethyl-3-cephem-4-carboxylic acid bis (triethylamine) salt was added and the reaction mixture was allowed to stand at the same temperature for 2 hours. to make it. Water (10 mL) and dichloromethane (10 mL) were added and the pH was adjusted to 2. After separation of the phases, the organic layer is washed with 5 ml of water, 20 ml of water are added to the organic phase and the pH of the mixture is adjusted to 8.5 with 1 N sodium hydroxide solution. The phases were again separated and the organic phase was separated

-1 937

Wash with 191,478 ml of water. The aqueous layers were combined and washed twice with dichloromethane (5 mL each). Dichloromethane (15 mL) and THF (15 mL) were added to the aqueous phase, and the mixture was adjusted to pH 2 with 4N hydrochloric acid and allowed to stand to separate the phases. The aqueous layer was washed with 10 mL of a 1: 1 (v / v) dichloromethane-THF mixture, the organic layers were combined, washed twice with 10 mL each of saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent, ether was added and the precipitated powder was filtered off with ether. wash, dry. There was thus obtained 510 mg (70.5%) of 7β- (D-5-phthalimido-valeramido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid. The IR spectrum is identical to that of an authentic sample IR. spectrum.

Example 47 (1) 3.27 g of 2,3-dihydroxynaphthalene are dissolved in 44 ml of dichloromethane, 6.06 g of triethylamine are added, and 2.92 g of phosphoryl is added to this solution with stirring at 10-20C. trichloride is added dropwise. The mixture was filtered under nitrogen and the residue was washed with dichloromethane (20 mL). The filtrate and washings were combined to give a volume of 56 ml.

(2) The filtrate obtained in (l). To 15.9 ml was added 168 mg of 1-methyl-5-mercapto-1H-tetrazole, followed by stirring at 0-5 ° C with stirring 849 mg of 7β- (D-5 carboxy-5-phthalimido-valeramido) -3 (hydroxy methyl - 3 - cephem - 4 · carboxylic acid (bis-triethylamine) salt). The reaction was completed at the same temperature for 2 hours and then at room temperature for 5 hours, then allowed to stand at 0-5 ° C overnight, followed by the procedure of Example 46 (2). This gives 7β- (D-5-carboxy-5-phthalimido-valeramido) -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid, which has the same NMR spectrum. NMR spectrum of an authentic sample.

Example 48 (1) To a mixture of dichloromethane (44 ml) and triethylamine (6.06 g) was added pyrocathelene (2.20 g) and 2.61 g of phosphoryl trichloride was added dropwise under ice-cooling. Following the procedure of Example 47 (1), 52 ml of filtrate were obtained.

(2) With the filtrate obtained in 14.8 ml (1), the reaction was carried out as in Example 47 (2) for 30 minutes. The reaction mixture was treated in the same manner as in Example 47 (2) below to afford 433 mg (60%) of 7β- (D-5-carboxy-5-phthalimido-valeramido) -3- (1-methyl-1H) - Tetrazol - 5 - yl) thiomethyl - 3 - [alpha] - cm - 4 - carboxylic acid having IR and NMR spectra identical to that of an authentic sample.

Example 49 (1) 2.20 g of pyrocatechin are dissolved in 44 ml of dichloromethane and 10.1 g of triethylamine, and 3.96 g of phosphorus pentachloridol is added under ice-cooling and stirring. The mixture is further treated as in Example 47 (1) to give 48 ml of the filtrate.

(2) Using the solution obtained in (7.7) in Example 46 (2), 7β- (D-5-carboxy-5-phthalimido valeramido) -3- (1-methyl-1 H -tetrazole-5) - yl) - thiomethyl - 3 - cephem - 4 - carboxylic acid having an IR spectrum identical to that of an authentic sample.

Example 50 (1) 2.20 g of pyrocatechin are dissolved in a mixture of 40 ml of dichloromethane and 7.76 g of diisobutylamine, and 2.92 g of phosphoryl trichloride is added dropwise to this solution under ice-cooling. The mixture was stirred at room temperature for 10 minutes. The volume of the resulting reddish brown solution was 50 ml.

(2) The reaction mixture obtained in (14) (14.2 ml) was treated as in Example 46 (2) for 50 minutes under ice-cooling and the resulting mixture was stirred at room temperature for 2.5 hours. The mixture was further treated according to Example 46 (2) with 471 mg (65.2%) of 7β- (D-5-carboxy-5-phthalimido-valeramido) -3- (1-methyl-1 H -tetrazo-5-one). il) - thiomethyl - 3 - cephem - 4 - carboxylic acid, which has the same NMR spectrum as an authentic sample.

Example 51 (1) In a mixture of 40 ml of dichloromethane and 6.06 g of triethylamine, 2.20 g of pyrocatechin is added dropwise to this solution while cooling with ice, 2.61 g of phosphorus trichloride is added, followed by 4 ml of dichloroethane. . After stirring at room temperature for 10 minutes, the mixture was cooled to 5 ° C and 0.64 g of methanol was added. The temperature of the solution then rises to 18 ° C. The mixture was stirred at room temperature for 10 minutes and then filtered under nitrogen. The precipitate on the filter was dichloromethane! wash and combine the washings with the filtrate. The resulting solution had a volume of 55 mL.

(2) To a solution of 15.6 ml of (l) is 168 mg of 1-methyl

- 5-Mercapto-1H-tetrazole was added and after dissolution, 849 mg of 7β (D-5-carboxy-5-phthalimido-valeramido) -3-hydroxymethyl-3-cephem-4-carboxylic acid bis (triethyl) was added under ice-cooling and stirring.

(amine) salt and the mixture was stirred at the same temperature for 1.5 hours and then at room temperature for 2 hours. The mixture was then allowed to stand overnight at 0-5 'Con and the reaction was completed for 6 hours at room temperature. Subsequently, the mixture was treated according to Example 46 (2) with 482 mg (66.8%) of 7β - (D - 5 - carboxy - 5 - phthalimido - valeramido) - 3.

- (1 - methyl! - 1H - tetrazol - 5 - yl) - thio - methyl - 3 - cephem

4-Carboxylic acid is obtained which has an IR spectrum identical to the IR spectrum of an authentic sample.

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Example 191 478 '52 52 ml 1-methyl-5-mercapto-1H-tetrazole and 437 mg 7β- (D-5-carboxy) in dichloromethane

5 - phthalimido - valeramido) - 3 - hydroxymethyl - 3

Dissolve the bis (tributylamine) salt of cephem carboxylic acid and add to this solution 0.5 ml of 2,2-dihydro-4,5-dimethyl-2,2 in 5 minutes at -25 ° C to -20 ° C. , 2 - trimethoxy - 1,3,2 - dioxaphosphol is added dropwise. After stirring at the same temperature for 5 minutes, water (15 ml) was added. After separation of the phases, the aqueous layer was washed with dichloromethane (5 mL) and the organic layers were combined. Water (15 mL) was added and the pH of the mixture was adjusted to 1N with caustic soda. Set to 8.5 again to separate the phases. The aqueous layer was washed with dichloromethane (5 mL) and THF (10 mL) and dichloromethane (15 mL) was added. The pH of the mixture was adjusted to 2.8 with 2N hydrochloric acid and the phases were again separated. The organic layer was washed with water (5 mL) followed by brine (5 mL) and dried over anhydrous magnesium sulfate. The solvent was distilled off and a little acetone was added to the residue. To the resulting solution was added ether and the precipitate which was in powder form was filtered, washed with ether and dried. There was thus obtained 2.15 mg (71.5%) of 7β- (D-5-carboxy-5-phthalimido)

- valeramido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid having IR and NMR spectra identical to that of an authentic sample.

Example 53 (1) A solution of 1,86 gt triphenylphosphite in 12 ml dichloromethane was added at room temperature to a mixture of 1.476 gchloroanil and 10 ml dichloromethane. A solution of 2,2-dihydro-4,5,6,7-tetrachloro-2,2,2-triphenoxy-1,3,2-benzodioxaphosphol in dichloromethane (23 ml) was obtained.

(2) using 3.0 mL of the solution of (1) in place of 0.5 mL of 2,2-dihydro-4,5-dimethyl-2,2,2-trimethoxy-1,3,2-dioxaphosphol, and otherwise Following the procedure described in Example 52, 220 mg (73.1%) of 7β - (D-5 carboxy-5-phthalimido-valeramido) -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3- cephem - 4 is a carboxylic acid having the same IR and NMR spectra as an authentic sample.

Example 54 0.173 g of 1- (2-dimethylaminoethyl) -5-mercapto-1H-etetrazole are suspended in acetonitrile and 0.152 g of triethylamine are added. To this solution was added 0.874 g of the bis [tri (n-butyl) amine] salt of 7β - (D - 5 - carboxy - 5 - phthalimido -. Valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 carboxylic acid. The resulting solution was cooled to -25 ° C and a mixture of 0.744 g of methyl (o-phenylphenyl) phosphate in 5 ml of dichloromethane was added dropwise at -25 ° C to -20 ° C and the resulting mixture was stirred at the same temperature for 20 minutes. stir for a minute. At this time, 5 ml of water was added to the mixture and concentrated in vacuo. The residue was diluted with water / acetonitrile 3: 2 (v / v) to exactly 50 mL and determined in this solution by high performance liquid chromatography to determine 7β - (D - 5).

- carboxy-5-phthalimido-valeramido) -3- [1- (2-dimethylaminomethyl) -1H-tetrazol-5-yl] thio-methyl-3-cephem-4-carboxylic acid. Yield: 0.593 g (90%). To 45.0 ml of the 50 ml solution was added 4.0 ml of 1 N hydrochloric acid,

1θ of the resulting solution was concentrated and lyophilized. The syrupy material thus obtained was dissolved in ethyl alcohol and ether was added. The precipitate, which is in powder form, is filtered off, washed with ether and dried. Thus, 0.54 g of the hydrochloride of the compound described above is obtained, which has the same NMR spectrum.

Spectrum obtained in Example 17.

Example 55 1.75 g of 7β - (D - 5 - carboxy - 5 - phthalimido - valeramido) - 3 in a mixture of 1 ml of formamide and 6 ml of acetonitrile

- hydroxymethyl - 3 - cephem - 4 - carboxylic acid bis [lri (n

(butyl) amine] salt and 0.293 g of isonicolinic acid amide were cooled to -20 ° C and 0.74 g of methyl (o-) was added dropwise with stirring at -20 ° C to -15 ° C. phenylene) phosphate and 2 ml of dichloromethane, and the reaction is then completed at the same temperature for 30 minutes. The reaction mixture was then allowed to warm to 10 ° C. 50 ml of acetonitrile and 50 ml of ether are added. The precipitated powder was filtered off, washed with acetonitrile and dried. Thus 1.04 g (85.5%) of 7β

- (D-5-Carboxy-5-phthalimido-valeramido) -3,3-cephem -3- (4-carbamoylpyridinium) -methyl-4-carboxylic acid.

Nuclear Magnetic Resonance Spectrum (D ₂ O + K ₂ CO ₃ ) identical to that of Example 37.

Example 56

0.74 g instead of 0.74 g of methyl o-phenylene phosphate 2

using a mixture of phenyl-1,3,2-benzodioxaphosphol and 4 ml of dichloromethane and following the procedure of Example 20, the reaction was carried out for 10 minutes. Thereafter, the reaction mixture was treated as in Example 20 to give 1.22 g (93.1%) of product having IR and NMR spectrum.

5q is identical to the corresponding spectra of the product prepared in Example 16.

Example 57 Dissolve 0.670 g of 7β- (D-5-carboxy) in 1 ml of water

5 - phthalimido - valeramido) - 3 - hydroxymethyl - 3

- cephem - 4 - carboxylic acid - dipotassium salt - pentahydrate and 5 mL of THF is added. The pH of the mixture is adjusted to 2.5 with θθ 4N hydrochloric acid at 5 ° C or lower and 10 ml of dichloromethane are added. After separation of the Λ phases, the aqueous layer was extracted with 2.5 ml of TI IF and 5 ml of dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate and evaporated under reduced pressure.

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Concentrate at 191,478 ounces. To the residue was added THF (10 mL) and dichloromethane (50 mL) and the mixture was concentrated again. The residue was dissolved in THF (10 mL) and 0.174 g of 1-methyl-5-mercapto-1H-tetrazole was added. Then a mixture of 0.744 g of methyl (o-phenylene) phosphate and 4 ml of THF is added at -15 'to -10' C with stirring, and the mixture is stirred for a further 50 minutes and then concentrated in vacuo. The residue was dissolved in a small amount of THF and 100mL. is poured into ether. The precipitated powder was filtered off, washed with ether and dried. Thus 0.560 g (93.1%) of 7β- (D-5-carboxy-5-phthalimido-valeramido) -3- (1-methyl-1 H -tetrazol-5-yl) -thiomethyl-3-cfem-4 - a carboxylic acid having the same NMR and IR spectra of the compound obtained in Example 16 is obtained.

Example 58

0.74 g instead of 0.74 g methyl o-phenylene phosphate 2

- oxo-2,2-dihydro-2-methoxy-4,5-dimethyl-1,3,2

using a mixture of dioxaphosphol and 4 ml of dichloromethane and following the procedure of Example 20, the reaction was carried out for 30 minutes and then treated as described in Example 20. 0.95 g (79%) of product is obtained which has the same IR and NMR spectra as the product of Example 16.

Example 59 (I) To 8.78 g of sodium salt of deacetyl cephalosporin C (90.1% by weight thereof) is added 24 ml of water and after complete dissolution 8 ml of THF are added. 3.76 g of phenyl (chloroformate) and 40% aqueous potassium carbonate solution are added dropwise at 15-20 ° C, maintaining the pH between 9.5 and 10.0. After the addition, the mixture was stirred for 10 minutes, then THF (40 mL) was added and concentrated hydrochloric acid was added dropwise at 3-5 ° C to pH 2.5. Dichloromethane (65 mL) was added and the phases were separated. The aqueous layer was extracted with THF (17 mL) and dichloromethane (34 mL), the combined organic extracts were dried over anhydrous magnesium sulfate, and 8.16 g of tri (n-butyl) amine were added, followed by evaporation to dryness in vacuo. Dichloromethane was added to the residue and evaporation was repeated. At this time, the residue was dissolved in dichloromethane and this solution was poured into ether. The precipitated powder was filtered. so

16.2 g of the bis [tri (n-butyl) amine] salt of 7β - (D-5-carboxy-5-phenoxycarbonylamino-valeramido) -3-hydroxymethyl-3-cephem-4-carboxylic acid are obtained. . IR spectrum (KBr) cm ^-1 : 3250, 2930, 1760, 1735, 1660, 1600;

NMR (DMSO-d _e) 5: 0.7 to 2.4 and 2.6 to 3.1 m, (CH ₃ CH ₂ CH ₂ CH _{2) 1} N- and - (CH _{2) 3} CO-] 3.45 (br, _2-CH2), 3.95 (m,> CH-), 4.15 (br, _3-CH2), 4.94 (d, J = 5Hz, _C6 - H) , 5.52 (q, J = 5 and 8 Hz, C ₇ -H), 6.9, 7.6 [m, structural unit (22)], 7.7-8.9 (m, -O). -CONH-), (C-CONH, -COOH).

(2) 8.64 g of 7β - (D - 5 - carboxy - 5 - phenoxycarbonyl

- amino - valeramido) - 3 - hydroxymethyl! - 3 - cefem

To a solution of the bis [tri (n-butyl) amine] salt of 4-carboxylic acid and 100 ml of dichloromethane was added 1.74 g of 1-methyl-5-mercapto-1H-tetrazole and after dissolution, 20 ° C was added. and - 3.72 g of methyl (o-phenylene) are added over a period of 5 minutes at a temperature between 25 ° C and

- a mixture of phosphate and 10 ml of dichloromethane, followed by stirring at 0-5 ° C for 60 minutes. 80 ml of cold water are added, the pH is adjusted to 8.5 with 1 N sodium hydroxide solution, and the aqueous layer is washed twice with 20 ml of dichloromethane each time. To the aqueous layer was added 50 mL of THF and 50 mL of dichloromethane, adjusting the pH of the mixture to conc. Hydrochloric acid. Set to 1.5. After separation of the phases, the aqueous layer was extracted with a mixture of 15 ml of THF and 15 ml of dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate and evaporated to leave only a small amount of solvent. 300 ml of ether are added dropwise to the residue, the precipitated substance is filtered off, washed with ether and dried in vacuo. Thus, 5.41 g (91.4%) of 7β- (D-5-carboxy-5-phenoxy)

- carbonylamino - valeramide) -3 - (1 - methyl - 1H

- tetrazol - 5 - yl) - thiomethyl - 3 - cephem - 4 carboxylic acid.

IR spectrum (KBr) cm ^-1 : 3270, 3020, 2920, 1780, 1725, 1530.

NMR (DMSO-d _e) δ: 1.4-2.4 [6H, m, - (CH _{2) 3} -], 3.69) 2H, br, _2-CH2), 3.94 (3H , s, N-CH ₃ ), 4.30 (2H, broad, 3-CH ₂ ), 5.05 (1H, d, J = 5Hz, C ₇ -H), 5.65 (1H, q, J = 5 and 8 Hz, C ₇ -H), 6.9-7.6 (5H, m, structural unit 22), 8.03 (1H, d, J = 8 Hz, -OCONH-) .

Example 60 (1) 10.95 g of sodium salt of deacetyl cephalosporin C (90.1% active ingredient) are dissolved in 25 ml of water and 7 ml of acetonitrile are added. Thereafter, 40% aqueous potassium carbonate solution and 3.38 g ethyl

(chloroformate) was added dropwise to the solution to a pH of 9.5-10, and the reaction mixture was concentrated in vacuo and acetonitrile was distilled off. The residue was cooled to 0-5 ° C and the pH was adjusted to 2.5 with concentrated hydrochloric acid. The precipitate formed is filtered off, washed with cold water and suspended in 200 ml of water. To the slurry was added 8 mL of triethylamine and stirred until dissolved and the mixture was concentrated in vacuo. The residue is lyophilized and in a desiccator _; dried over phosphorus pentoxide in vacuo. Thus 15.2 g of 7β - (D - 5 - carboxy)

- 5 - ethoxycarbonylamino - valeramido) - 3 - hydroxy

- methyl 3 - cephem - 4 - carboxylic acid bis (triethylamine)

- we get salt.

IR spectrum (KBr) cm ^-1 : 3550-3150, 2930, 2840, 2670, 2480, 1762, 1710-1660, 1600, 1535;

Nuclear Magnetic Resonance Spectrum (D ₂ O) δ: 1.14 (3H, t, J = 7Hz, -CH 2), 1.26 (18H, t, J = 7Hz, CH, x 6), 1.5-1.9 (4H, m, _{-CH2 CH2} -), 2.2 2.5 (2H, m, CH ~ CO ~ _2), 3.19 (I2H, q, J = 7Hz, CH ₂ x 6), 3.54 (2H, ABq, 2-CH ₂ ), 4.08 (2H, q, J = 7Hz, - CO ₂ CH ₂ ), 4.26 (2H, s, 3-CH ₂ ), δ, 08 (1H, d, J = 5Hz, C ₆ -H), 5.59 (1H, d, J = 5Hz, C ₇ -H).

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191 478 (2) A mixture of 15 ml of dichloromethane, 5 ml of acetonitrile, 0.35 g of methyl 5-mercapto-1H-tetrazole and 0.2 ml of tri (n-butyl) amine is added 1.30 g of 7β - ( D-5-carboxy

- 5 - ethoxycarbonylamino - valeramido) - 3 - hydroxy

- Methyl 3 - Cephem - 4 - Carboxylic acid bis (trictylamine)

- salt. A solution of 0.74 g of methyl (o-phenylene) phosphate in 2 ml of dichloromethane was added dropwise to the resulting solution at -15 to -10 ° C with stirring for 5 minutes, followed by 30 minutes. stirred at 0-5 ° C and then concentrated in vacuo. To the residue was added dichloromethane (20 ml) and water (15 ml), the mixture was cooled to 0-5'C, adjusted to pH 9.0 with 1N sodium hydroxide solution and the organic layer was washed with water (3 ml). The aqueous phase and extract were combined and washed with dichloromethane (5 mL). To the resulting aqueous phase was added 10 ml of THF and 20 ml of dichloromethane, the mixture was cooled to 0-5 ° C and the pH was adjusted to 2 with 2N hydrochloric acid. The organic layer was separated, the aqueous phase was treated with 5 mL of THF and 10 mL of dichloromethane and the mixture was allowed to stand to separate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated. Ether was added to the residue and the precipitated powder was filtered off. Thus 0.97 g (89.2%) of 7β- (D-5-carboxy)

- 5-ethoxycarbonylamino-valeramido) -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem

- 4 - carboxylic acid.

IR spectrum (KBr) cm ^-1 : 3350, 2950, 1775, 1710, 1530;

NMR _(DMS0-d6) δ: 1.18 (3H, t, J = 7Hz,

- CH _a ), 1.4 ~ 2.4 (6H, m, -CH ₂ CH ₂ CH ₂ -), 3.93 (3H, s, N-CH 3), 3.68 (2H, ABq, 2- CH ₂ ), 3.97 (2H, q, J = 7Hz, -O-CH ₂ -), 4.29 (2H, ABq, 3-CH ₂ ), 5.06 (1H, d, J = 5 Hz, C _e -H), 5.66 (IH, q, J = 5 and 8 Hz, C ₇ -H), 7.25 (1H, d, J = 8Hz, - OCONH -), 8.79 (1H, d, J = 8Hz, -CONH-).

Example 61 (1) 3.53 g of the bis (triethylamine) salt of 7β - (D - 5 - carboxy - 5 - phthalimido valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 carboxylic acid and 0.87 g. 1 - methyl

Dissolve 5-mercapto-1H-letrazole in 20 ml of dichloromethane and add dropwise with stirring at -25 ° C to -20 ° C 1,50 g of ethyl (o-phenylene) phosphate and 3,8 dichloromethane and stirred at -5 ° C to 0 ° C for one hour. At this time, 50 ml of water, 20 ml of THF and 20 ml of dichloromethane were added to the reaction mixture and the mixture was adjusted to pH 2 with 4N hydrochloric acid. After separation of the phases, the aqueous layer was extracted with a mixture of dichloromethane (20 mL) and THF (10 mL). The organic phase and extract were combined, washed with water (20 mL), dried over anhydrous magnesium sulfate, concentrated in vacuo, and the residue was dissolved in acetone (20 mL). This solution was added dropwise to 300 mL of ether Thus, 2.86 g (95.1%) of 7β- (D-5-carboxy-5-phthalimido-valeramido) -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl

3-cephem-4-carboxylic acid is obtained which has the same IR and NMR spectra as the product of Example 16.

(2) A solution of ethyl (o phenylene) phosphate in dichloromethane (1) was added dropwise at 23-27 ° C and the mixture was stirred for 5 minutes at about 39 ° C and cooled to 0 ° C. is treated as described below for (l) -bcn. 2.72 g (90.4%) of a white powder are obtained which has the same IR spectrum as the product of (1).

Example 62 (1) To a mixture of 1.10 g of pyrogallol and 1.30 g of methyl (phosphorus dichloride) is added 8 ml of dichloromethane, followed by 1.86 g of this mixture at -35 to -30 ° C. triethylamine was added dropwise with stirring and the mixture was stirred at 0-5 ° C for an additional 2 hours to give 2-methoxy-2-oxo

A mixture containing 4-hydroxy-1,3,2-benzodioxalosulfonate is obtained.

(2) 3.53 g of the bis (triethylamine) salt of 7β - (D - 5 - carboxy - 5 - phthalimido valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 carboxylic acid and 0.87 g of 1 - methyl

5-Mercapto-1H-tetrazole is dissolved in 20 ml of dichloromethane and to this solution is added, with stirring, the reaction mixture (1), which is rinsed with 6 ml of dichloromethane. The resulting slurry was stirred at -5'C to 0'C for 1 hour and then proceeded as in Example 61 (1). Thus 2.76 g (91.8%) of 7β- (D-5-carboxy)

- 5 - phthalimido - valeramido) - 3- (I - methyl - 1H - tetrazol - 5 - yl) - thiomethyl - 3 - cephem - 4 - carboxylic acid, the structure of which is confirmed by IR spectra · (3) According to (1) but using 1.59 g of ethyl 3,4-dihydroxybenzoate instead of pyrogallol 2

A reaction mixture containing methoxy - 2 - oxo - 5 - ethoxycarbonyl - 1,3,2 - benzodioxaphosphol was prepared. The following procedure (2) gave 2.85 g (1) (94.7%) of the product described in (2), the structure of which is supported by the IR sequence.

(4) Using the method of (1), but using 1.09 g of 4-pyrocatechin instead of pyrogallol, a reaction mixture containing 2-methoxy-2-oxo-5-methyl-1,3,2-benzodioxaphosphol is prepared. The following procedure (2) gave 2.83 g (94.1%) of the product described in (2) having the same IR spectrum as the product of (2).

Example 63 mg 1-methyl-5-mercapto-1H-tetrazole and 216 mg 7β- [2- (2-aminothiazol-4-yl) -2-color methoxy

- imino - acetamido] - 3 - hydroxymethyl - 3 - cephem

To the mixture of the sodium salt of 4 - carboxylic acid is added 1 ml of formamide and 1 ml of acetonitrile and stir until it becomes a clear solution. To this side, a solution of 280 mg of methyl (o phenylene) phosphate and 0.75 ml of dichloromethane was added with stirring and ice-cooling, and the mixture was stirred under ice-cooling for half an hour. At this time, 1 ml of cold water was added and the reaction mixture was concentrated in vacuo. To the remaining solution was added 2 mL of water and the solution was adjusted to pH 2.5

-2 345

191,478. The precipitate thus formed is filtered off, washed with 1 ml of cold water and dried in vacuo. Thus, 210 mg (82.6%) of 7β - [2- (2-aminoliazol-4-yl)

2 - color - methoxyimino - acclamido] - 3 - (I - methyl

1H-tclrazol-5-yl) -thiomethyl-3-ecfem-4-carboxylic acid is obtained.

NMR _(DMS0-d6) δ: 3.67 (2H, br, 2CHj). 3,8.3, .3,93 (6H, two singlets, N-CH _2, O-CHJ, 4.27 (2H, br, _3-CH2), 5.09 (IH, d, J = 5 Hz, C ₆ -H), 5.76 (1H, q, J = 5 and 8 Hz, C-H), 6.73 (1H, s, moiety 28), 9.55 (1H, d) , J = 8 Hz, -CONH-).

Example 64

230 mg of 7β-amino-3-hydroxymethyl-3-ccfcm

- 4 - Carboxylic acid, 174 mg I - methyl - 5 - mercapto - 1H

- Tclrazole, 4 ml formamide and 1 ml acetonitrile were added under ice-cooling with stirring, and 253 mg of triethylamine were added thereto, and 650 mg of methyl was added to the resulting solution at -10 ° C to 0 ° C with stirring.

A solution of (o-phenylene) ibsal, 2 mL of dichloromethane and 5 mL of acetonitrile is added and stirring is continued for 1 hour at 0-5. The precipitate was filtered off, washed with 5 ml of acetonitrile and suspended in a mixture of 6 ml of water and 2 ml of acetonitrile and 0.1 ml of 35% hydrochloric acid was added to give a clear solution. The pH was adjusted to 4 by addition of 25% aqueous ammonium hydroxide solution under ice-cooling, the precipitated crystals were filtered off, washed with 2 ml of cold water and dried in vacuo. There was thus obtained 280 mg (85.3%) of 7β-amino-3- (1-methyl-1H-tetrazole-5)

- yl) - thiomethyl - 3 - cephem - 4 - carboxylic acid is obtained. IR (KBr) ν max 1790, 1615, 1535, 1410. Nuclear Magnetic Resonance Spectrum (L) ₂ O 1 CE, COOD) δ: 3.71 (2H, s, 2-CH ₂ ), 3.96 (3H, s) , N-CH ₃ ), 4.22 (2H, s, 3-CH ₂ ), 5.06 (1H, d, J = 5Hz, C ₆ -H), 5.17 (1H, d, J = 5 Hz, C ₇ -H).

Example 65

To a mixture of 0.954 g of 7β - (D - 5 - carboxy - 5 - benzoamido valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 carboxylic acid and 0.244 g of 1 - methylpyridine was added 2 ml of formamide and 4 ml of acetonitrile. 0.744 g of methyl (o-phenylcene) is added to the resulting solution at -5 ° C to 0 ° C with stirring.

a mixture of phosphate and 2 ml of dichloromethane, and the resulting solution is stirred for a further half an hour at the same temperature. To the reaction mixture was added dichloromethane (24 mL), THF (12 mL) and water (20 mL), and the pH was adjusted to 2 by addition of 4N hydrochloric acid. After separation of the phases, the aqueous layer was extracted with 15 ml of a 2: 1 mixture of dichloromethane and THF. The organic phase will be treated in the same manner as in the following

Example 61 in (l). Thus 0.944 g (87.3%) of 7β- (D-5 carboxy-5-benzamido-valeramido) -3- (1-methyl)

- from red - 2 - yl) - methyl - 3 - cephem - 4 - carboxylic acid.

IR spectrum (KBr) cm- ¹ : 1770, 1725, 1645, 1530. NMR Spectrum ( ₂ ) ₂ · 1Nalit · O, · δ: 1.5-2.7 [611, m, - (CH ₂ ) ₃ - J, 2.80, 3.16 (2H, ABq, J = 18Hz, 2-CH _2), 3.44, 3.90 (2H, ABq, J = 14Hz, _3-CH2), 3.46 ( 3H, s, N-CH3), 4.42 (1H, in,> CH-), 4.96 (1H, d, J = 5Hz, _C6- H), 5.53 (1H, d, .1 = 5Hz, C ₇ -H), 5.8-6.2, 6.6-6.8 [3H, m, (29) a structural unit of formula], 7.2-8.0 [5H, m, structural unit 22].

Example 66 (1) To a mixture of 0.430 g of 2-methyl-3-thioxo-5-oxo-2,3,4,5-tetrahydro-aza-triazine, 4 ml of Ibrmamide and 4 ml of alanylryl is added 0.416 ml of triethylamine and to the solution 1.16 g of 7β - (D - 5 - carboxy - 5 - phthalimido

- valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 carboxylic acid dipotassium salt. To the resulting mixture was added a solution of 1.12 g of methyl (p.o.) phosphate and 3 ml of dichloromethane at -2 () C to -15 ° C with stirring, followed by 0-5 Stir at C. The reaction mixture was concentrated in vacuo and cold water (80 mL) was added. The precipitate formed is filtered off, washed with 10 ml of cold water and dried in vacuo. Thus 1.14 g (90.7%) of 7β- (D-5-carboxy-5-phthalimido valeramido) -3- (2-methyl-3-thioxo-5-oxo-2.5)

- dihydro - as - triazin - 3 - yl) - thiomethyl - 3 - cephem

- 4 - Carboxylic acid is obtained.

IR spectrum (KBr) cm ^-1 : 1775, 1715, 1645.

Nuclear Magnetic Resonance Spectrum (D ₂ O + NaOD) δ: 1.3 - 2.6 [6H, m, - (CH ₂ ) ₃ -1, 3.04, 3.60 [2H, ABq, .1 = 18 Hz, 3-CH ₂ ), 3.86 (3H, s, N-CH 2), 4,02,4,39 (2H, ABq, J = 13 Hz, 3-CH ₂ ), 4.99 (1H, d , J = 5Hz, C _f H), 5.55 (1H, d, J = 5Hz, C ₇ -H), 7.75 (lH, s, triazine-Η), 7.80 [4H, s, structural unit (18)].

(2) Using 0.384 g of 2-thio uracil in place of the triazine derivative and otherwise following the procedure of (1), 1.10 g (89.6%) of 7β- (D-5-carboxy-5-phthalimido valeramido) -3- ( 4 - Hydroxy - pyrimidin - 2 - yl) - thio

methyl 3 - cephem - 4 - carboxylic acid is obtained.

IR spectrum (KBr) cm ^-1 : 1770, 1710, 1530.

Nuclear Magnetic Resonance Spectrum (D ₂ O + NaOD) δ: 1.3 - 2.6 [6H, m, - (CH 2) -, 3.02, 3.50 (2H, ABq, J = 18 Hz, 2-CH ₂ ), 3.97, 4.33 (2H, ABq, J = 13 Hz, 3-CH ₂ ), 5.01 (1H, d, J = 5 Hz, C ₆ -H), 5, 54 (1H, d, J = 5Hz, C ₇ -H), 6.23, 7.84 {2H, dd, .1 = 7 Hz, (30) a structural unit kcpletű], 7.82 [4H, s, Structural unit (18)].

Example 67

0.195 g of 2-mercaptobenzimidazole and 0.580 g of 7β

To a mixture of the dipotassium salt of (D - 5 - carboxy - 5 - phthalimido - valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 - carboxylic acid is added 2 ml of formamide and 2 ml of acetonitrile and the resulting solution is kept at - 10 ° C. - with stirring at 5 ° C, 0.558 g of methyl

A solution of (o-phenylene) phosphate and 1.5 ml of dichloromethane is added and the mixture is stirred at 0-5C for 1 hour. The reaction mixture was further treated and worked up according to Example 66 (I) and treated with 0.560 g (88.1%) of 7β- (D-5-carboxy-5-Ralimido-valcramido) -3- (benzimidazol-2-yl) thio. - methyl - 3 - cephem

- 4 - carboxylic acid.

IR spectrum (KBr) cin ' ¹ : 1785, 1770, 1710, 1640, 1390;

-24191 478.

Nuclear Magnetic Resonance Spectrum (D ₂ O-SoHCO 3) δ: 1.3-2.6 [6H, m, - (CH ₂ ) ₃ -J, 2.96 3.23 (2H, ABq, J = 18 Hz, 2CH ₂ ), 3.84, 4.40 (2H, ABq, J = 13Hz, 3-CH2), 4.57 (1H, m,> CH-), 4.92 (1H, d, J = 5 Hz, C ₆ -H), 5.52 (1H, d, J = 5Hz, C ₇ -H), 6.9-7.8 [8H, m, structural unit of formula (23), structural unit].

Example 68 (1) 1.637 g of bis (triethylamine) salt of 7β - (D - 5 - carboxy - 5 - phthalic acid valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 carboxylic acid and 0.53 g of 2 - to the mixture of mercapto-benzoic acid were added 14 ml of dichloromethane and 7 ml of THF, and to the resulting solution at -20 ° C to -15 ° C, while stirring, 0.863 g of methyl (o-phenylene) phosphate and 2 A solution of dichloromethane (3 ml) was added and the mixture was stirred at 0-5 ° C for half an hour. Subsequently, by treating the reaction mixture according to Example 61 (1), 1.36 g (91.7%) of 7β- (D-5-carboxy-5-phthalimido-valeramido) -3

- (2-Carboxyphenyl) -thiomethyl-3-cephem-4 carboxylic acid is obtained.

IR spectrum (KBr) cm ^-1 : 1770, 1710, 1535, 1465, 1390.

NMR _(DMSO-d6) δ: 1.2-2.4 [6H, m,

- (CH ₂ ) ₃ -], 3.55 (2H, broad, 2-CH ₂ ), 4.06 (2H, broad, 3-CH 2), 4.75 (1H, t, J = 7Hz,> CH-), 5.06 (1H, d, J = 5Hz, C ₆ -H), 5.61 (1H, q, J = 5 and 8Hz, C ₇ -H), 7.0-7, 7 [4H, m, structural unit 32], 7.89 [4H, m, structural unit 23], 8.79 (1H, d, J = 8 J 2, -CONH).

(2) Proceed according to (1), but 2 - mercapto

0.443 g of 2 - mercapto - pyridine instead of benzoic acid!

- using oxide. The reaction mixture was concentrated in vacuo and the residue was dissolved in 50 mL of a 1: 1 mixture of water and acetonitrile. After evaporation of the acetonitrile, the precipitate is filtered off, washed with 10 ml of cold water and dried under vacuum. so 1.3! g (92.3%) of 7β - (D - 5 - carboxy - 5 - phthalimido - valeramido) - 3

- (1-Oxido-pyridin-2-yl) -thiomethyl-3-cephem

- 4 - Carboxylic acid is obtained.

IR spectrum (KBr) cin- ¹ : 1775, 1715, 1530, 1470, 1390.

Nuclear Magnetic Resonance Spectrum (D ₂ O + NaOH) δ 1.3-2.6 [6H, m

- (CH ₂ ) j -], 2.99, 3.53 (2H, ABq, J = 18 Hz, 2-CH ₂ ), 3.90, 4.25 (2H, ABq, J = 14 Hz, 3 -CH ₂ ), 4.95 (1H, d, J = 5Hz, C ₆ -H), 5.53 (1H, d, J = 5Hz, C 1 -H), 7.1-8.5 [8H, m, structural unit (18), structural unit (33)].

Example 69

0.288 g of 1 - carboxymethyl - 5 - mercapto - 1H - Tetrazole and 0.363 g of triethylamine are dissolved in 6 ml of dichloromethane and 0.847 g of 7β - (D - 5 carboxy - 5 - phthalimido - valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 - carboxylic acid bis (triethyl) is added. (amine) is added and a solution of 0.450 mg of methyl (o-phenylene) phosphate in 1.2 ml of dichloromethane is added dropwise at -20 to -15. The mixture was stirred at -5 'C to 1' C for 1 hour and was then stirred at 61 ° C for 1 hour.

Example I (I) was followed by cl. Thus 0.711 g (91.8%) of 7β (D-5-carboxy-5-phthalimido-valeramido) -3- (1

- carboxymethyl - 1H - tetrazol - 5 - yl) - thiomethyl

3-cephem-4-carboxylic acid is obtained.

IR spectrum (KBr) cm ^-1 : 1770, 1710, 1530.

NMR _(DMSO-d6) δ: 1.3-2.4 [6H, m, - (CH _{2) 3} -], 3.62 (2H, br, _2-CH2), 4.17, 4 47 (2H, ABq, J = 14Hz, _3-CH2), 4.71 (IH, t, J = 6Hz,> CH-), 4.99 (IH, d, J = 5 Hz, C _e- H), 5.28 (2H, s, NCH 2 COO), 5.62 (1H, q, J = 5 and 8 Hz, C ₆ -), 7.89 [4H, s, structural unit 18]. ], 8.77 (1H, d, J = 8Hz, CONH).

Example 70 (1) 0.975 g of bis (trictylamine) salt of 7β - (D - 5 - carboxy - 5 - phthalimido valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 carboxylic acid, 0.172 g of ctanethiol and 10 ml. to a mixture of dichloromethane, with cooling and stirring, at -20 to -15 ° C, is added a mixture of 0.514 g of methyl (o-phenylene) phosphate and 1.39 ml of dichloromethane, and the mixture is stirred at 0 - 5 for 1 hour. 'Con stir. At this time, water (20 mL) and THF (20 mL) were added and the pH was adjusted to 2 with 35% aqueous hydrochloric acid. Dichloromethane (30 ml) was added to the mixture, the layers were separated and the aqueous layer was extracted with 15 ml (v / v) dichloromethane in THF. The organic phase and the latter extract are combined, washed twice with 10 ml of water each and 10 ml of water are added. The pH of this mixture was adjusted to 7 and, after separation, the organic phase was extracted with 5 ml of water. The aqueous phase and extract were combined and concentrated in vacuo. The concentrated solution was chromatographed on an Amberlite XAD-2 column (XAD-2 fineness 100-200 mesh; column height 40 cm, volume 70 mL) eluting with water and then 20: 1 water / acetone (v / v). mixture. The individual fractions were checked by TLC (40: 2: 0.1 aclonitrile / water / 99% formic acid was used for development) and the fractions containing the desired product ₍ Rf = 0.16) were combined and concentrated in vacuo. and lyophilize. There was thus obtained 0.515 g (63%) of 7β- (D-5-carboxy-5-phthalimido)

- valeramido) - 3 - ethylthiomethyl - 3 - cephem - 4 carboxylic acid, disodium salt.

IR spectrum (KBrjcnT ¹ : 1760, 1710, 1610, 1390) NMR spectrum (D ₂ O) δ: 1.18 (3H, t, CH ₃ ), 1.4-2.7 (80, _m , - (CH ₂ ) ₃ -, - CH ₂ CH ₃ T 2.93, 3.55 (2H, ABq, J = 18 Hz, 2-CH ₂ ) 3.23, 3.81 (2H, ABq, J = 14 Hz, _3-CH2), 4.98 (1H, d, J = 5Hz, C _e -H), 5.48 (1H, d, J = 5Hz, C ₇ -H), 7.88 [4H, s, structural unit 18], (2) To a mixture of 0.580 g of dipotassium salt of 7β - (D - 5 - carboxy - 5 - phthalimido valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 carboxylic acid and 0.165 g of thiophenol. formamide and 2 ml of acetonitrile are added to this solution, while stirring and cooling, at -30 ° C to -20 ° C, a mixture of 0.558 g of methyl (o-tnenylene) phosphate and 1.5 ml of dichloromethane is added, followed by the mixture was stirred for 45 minutes at 0-5 ° C. The mixture was concentrated in vacuo and the residue was added with cold water (40 mL). The precipitate was filtered, washed with cold water (10 mL, 20 mL).

-2 549

Dissolve in 191,478% aqueous acetonitrile. The solution was adjusted to pH 7 and the acetonitrile was evaporated in vacuo. The concentrated residue was chromatographed on XAD-2 column chromatography _(Rf value of the desired product, about 0.36), it is in (I) above. 0.397 g (62.1%) of the disodium salt of 7β - (D - 5 - carboxy - 5 - phthalimido - valcramido) - 3 - phenylthiomethyl - 3 - cephem - 4 - carboxylic acid are obtained.

IR (KBr) cm ^-1 : 1765, 1710, 1605, 1390. NMR (DMSO-d ₆ + D ₂ O) δ: 1.2-2.5] 6H, m, ~ (CH ₂ ) ₃ -. ], 3.11, 3.49 (2H, ABq, J = 18Hz, 2-CH _2), 4.36 (IH, m,> CH-), 4.81 (IH, d, J = 5 Hz, C _6- H), 5.42 (1H, d, J = 5 Hz, C ₇ -H), 7.34 [5H, windy unit (22)], 7.84 [s, (18) structural unit]. ;

Example 71 3.53 g of 7β- (D-5-carboxy) in dichloromethane

5 - phthalimido - valeramido) - 3 - hydroxymethyl - 3

Dissolve cefem-4-carboxylic acid (bis-triethylamine) salt and 0.76 g of triethylamine and add 2.79 g of methyl (o -) dropwise with stirring at - 45 ° C to - 40 ° C. phenylene) phosphate and 7.5 mL of dichloromethane and then stirred at the same temperature. At this time, 50 ml of ether were added to the reaction mixture, which was allowed to stand for 20 minutes at 20-25 ° C. The precipitated powder was filtered off, washed with ether, dried and then dissolved in a mixture of 10 ml of water and 20 ml of acetonitrile, the pH of the mixture was adjusted to 7.0 with 1N sodium hydroxide solution and the acetonitrile was distilled off in vacuo. The concentrated residue was chromatographed on an Amberlite XAD-2 column (XAD-2 fineness 100-200 mesh; volume 150 mL; column height 45 cm) eluting with water. The eluate was checked by TLC (80: 15: 2 acetonitrile: water: 99% formic acid) to develop the fractions containing the desired lenses - containing material displaced by 0.12 R _r . The resulting solution was concentrated, adjusted to pH 6.0 with 1 N sodium hydroxide solution and lyophilized. Thus 2.76 g (90.7%) of 7β- (D-5-carboxylate)

Sodium salt of 5 - phthalimido - valeramido) - 3 - cephem - 3- (triethylammonio - methyl) - 4 - carboxylate is obtained. IR Spectrum (KBr) cm ^-1 ': 3450, 1775, 1710, 1612, 1465th

Nuclear Magnetic Resonance Spectrum (D ₂ O) δ: 1.34 [9H, t, J = 7Hz, (-CH 2 x 3), 1.30-2.60 [6H, m, ~ (CH ₂ ) ₃ -J, 2.9 to 4.3 [10H, m, 2-CH _{2-3-CH 2} N (CH ₂ CH _{3) 3],} 5.13 (IH, d, J = 5Hz, C ₆ -H) 5.6! (IH, d, J = 5Hz, C _e -H), 7.88 [4H, s, (18) a structural unit of formula].

Example 72

3.53 g of 7 (1- (D-5-carboxy-5-phthalimido-valcramido) -3-hydroxymethyl-3-cephem-4-carboxylic acid bis (trictylamine) salt, 1.33 g of 1- (2-Dimethylaminoethyl) -1H-tetrazole and 0.76 g of triethylamine are dissolved in 25 ml of dichloromethane and 2.79 g of methyl- is added dropwise with stirring at -45 ° C to -40 ° C. (o-Phenylene) phosphate and 7.5 ml of dichloromethane, then stirred at the same temperature for 30 minutes, allowed to stand at 20 to 25 ° C for 20 minutes, and the resulting powder was filtered off, washed with dichloromethane and vacuum dried.

The product thus obtained, having an R _f of about 0.17, is treated with 2.67 g (82.3%) of 7β- (D-5-carboxylate-5-phthalimido-valeramido) -3-cephem, following Example 71. - 3 - (dimethyl - [2

- (1,2,3,4-Tetrazol-1-yl)] - ethylammonio) methyl

- 4 - Carboxylate sodium salt is obtained.

IR spectrum (KBr) cm ^-1 : 3450, 1770, 1710, 1613, 1390.

Nuclear Magnetic Resonance Spectrum (D ₂ O) δ: 1.30 - 2.60 [6 H, m, - (CH ₂ ) ₃ -], 3.00-4.30 [10 H, m,> N '(CH ₃ ) ₂ , 2CH ₂ , -NCHJ. 4.90-5.40 (3H, m, -NCH ₂ , C ₆ -H),

5.53 (1H, d, J = 5Hz, C 1 -H), 7.82] 4H, s, moiety (18)], 9.37 [1H, s, (34) moiety ].

Example 73 In a mixture of ml of formamide and 8 ml of acetonitrile, 1.20 g of 7β - (D-5-carboxylate-5-phthalimido-valeramido)

Dihydrate salt of 3-hydroxymethyl-3-cephem-4-carboxylate monohydral is dissolved in 312 mg of 4-cyanopyridine, dropwise with stirring at 0-5 ° C, and 1.12 g of methyl (o-phenylene) phosphate is added dropwise. and 3 ml of dichloromethane and stirred for 30 minutes at the same temperature. At this time, 3.5 ml of 1 N sodium hydroxide were added to the reaction mixture, and dichloromethane and acetonitrile were distilled off in vacuo. The concentrated residue was chromatographed on a silica gel column (50 g silica gel, 38 cm height, 80: 15: 2 acetonitrile: water: formic acid) eluted with 2.5: 1 acetonitrile: water. The eluate was monitored by TLC (80: 15: 2 acetonitrile: water: 99% formic acid) and the fractions containing the desired product - Rf = 0.22 - were collected. This solution was concentrated and the residue was adjusted to pH 6.0 with 1N sodium hydroxide and lyophilized. This gives 1.08 g (88.3%) of the sodium salt of 7β- (D-5-carboxylalo-5-phthalimido-valeramido) -3-cyclone -3- (4-cyano-pyridinio) methyl-4-carboxylate.

IR spectrum (KBr) cm- ¹ : 3420, 1770, 1710, 1613, 1395.

Nuclear Magnetic Resonance Spectrum (D ₂ O) δ: 1.40-2.70 [6H, m, - (CH ₂ ) ₃ -]. 3.04 and 3.68 (2H, ABq, J = 18 Hz, 2CH ₂ ), 5.13 (1H, d, J = 5 Hz. C ₆ -H), 5.44 and 5.70 (2H, AB q, .1 = 15Hz. _3-CH2), 5.63 (1H, d, J = 5Hz, C ₇ -H), 7.82 [4H, s, (18) a structural unit of formula], 8 , 57 and 9.36 [4H, dd, structural unit 35].

Example 74 1.20 g of 7β - (D-5-carboxylate-5-phthalimido-valeramido) in a mixture of 1 ml of lormamide and 8 ml of acetonitrile

Dipotassium salt of 3-hydroxymethyl-3-cephem-4-carboxylate monohydral and 411 mg of methyl nicotinate were dissolved and the resulting solution was stirred with stirring at -10 to -5. A mixture of methyl 49- (o-phenylene) phosphate (1.49 g) and dichloromethane (4 ml) was stirred at the same temperature for an additional 30 minutes. The reaction mixture is further treated as described in Example 73 (the desired product R _f = about 0.23), 1.18 g (91.5%) 7β - (D - 5 - carboxylato - 5 - phthalimido phenoxycarbonylaminovaleramido) - 3 - The sodium salt of cephem -3- (3-methoxycarbonylpyridinio) methyl-4-carboxylate is used.

IR spectrum (KBr) cm ^-1 : 3445, 1770, 1708, 1613, 1395.

Nuclear Magnetic Resonance Spectrum (D ₂ O) δ: 1.30 - 2.60 (6H, m, - (CH ₂ ) ₃ -], 2.95 and 3.62 (2H, ABq, J = 18 Hz, 2CH ₂ ). 4.10 (3H, s, CH _3), 5.12 (IH, d, J = 5 Hz, C H _o), 5.36 and 5.72 (2H, AB quartet, J = 15 Hz, 3-CH 3, 5.62 (1H, d, J = 5Hz, C 1 -H), 7.79 (4H, s, moiety 18), 8.0-9.8 [4H, m , Structural unit (36)].

Example 75 In 7 mL of dichloromethane 7.06 g of 7β- (D-5-carboxy)

5 - phthalimido - valeramido) - 3 - hydroxymethyl - 3

- cephem - 4 - carboxylic acid bis (triethylamine) salt and 1.47 g of 4 - dimethylaminopropionitrile are dissolved and 3.72 g of methyl (o) are added dropwise with stirring at - 45 ° C to - 40 ° C. (above) phosphate / dichloromethane (10 ml) and stirred at the same temperature for a further 30 minutes. The mixture was allowed to warm to room temperature and stirred again for 20 minutes. The precipitated powder was filtered and washed with dichloromethane. The resulting powder was dissolved in a mixture of 12 ml of water and 24 ml of acetonitrile and the pH of the mixture was adjusted to 3.4 with 4N hydrochloric acid. This solution was poured into 310 ml of acetonitrile, with stirring, cooled to about 5'C, decanting the solvent! removed and 90 ml of acetonitrile was added with stirring to the remaining viscous oil product. The precipitated powder was filtered, washed with acetonitrile and dried in vacuo. Thus, 4.78 g (81.9%) of 7β- (D-5-carboxy-5-phthalimido valeramido) -3- (2-cyanoethyldimethylammonio)

yielding methyl 3-cephem-4-carboxylate.

IR spectrum (KBr) cm ^-1 : 3400, 2247, 1777, 1715, 1617, 1392.

Nuclear Magnetic Resonance Spectrum (D ₂ O + NaOD) δ: 1.30 - 2.60 [6H, m, - (CH ₂ ) _{3 -} J, 2.8 - 4.4 [14H, m,> N ⁺ (CH _3). ) _2, CH ₂ CH _2, CH ₂ CH _2, CH 3, - CH ₂ CH ₂ CNJ, 5.20 (IH, d, J = 5Hz, C _e -H), 5.61 (IH, d, J = 5 Hz, C ₇ -H), 7.86 [4H, s, (18)].

Example 76 6.70 g of dipotassium salt of 7β - (D - 5 - carboxylate - 5 - phthalimido - valeramido) - 3 - hydroxymethyl - 3 - cephem - 4 - carboxylate in water are added, 30 ml of THF are added and The mixture was adjusted to pH 2.5 with 4N hydrochloric acid at 0-5 C and 35 mL of dichloromethane was added and the phases were separated. The aqueous layer was extracted twice with 6 mL of THF and 10 mL of dichloromethane each. This extract and the organic phase were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was taken up in 10 ml of formide and 40 ml of aceto52.

and 2.93 g of diethylamine are added.

A solution of 3.72 g of methyl (o-phenylene) phosphate in 10 ml of dichloromethane is added dropwise to the resulting solution at -35 ° C to -30 ° C, followed by stirring at the same temperature for 10 minutes, and then stir at -5 ° C to 0 ° C for 30 minutes. Ether (100 mL) was added to the reaction mixture, the solvent was removed by decantation, and the resulting viscous oil was dissolved in a mixture of water (7 mL) and acetonitrile (14 mL) and adjusted to pH 2.5 with 4N hydrochloric acid at 0-5C. The resulting solution was adjusted to pH 6.0 with 4N sodium hydroxide solution at 0-5 ° C and the acetonitrile was removed in vacuo. The concentrated residue was chromatographed on a silica gel column (250 g silica gel was charged into a column at 63 cm height with 80: 15: 2 acetonitrile: water: formic acid) and eluted with 3: 1 acetonitrile: water. The eluate was monitored by TLC (80: 15: 2 acetonitrile / water / 99% formic acid) and the fractions containing the desired product containing about 0.25 R _{f were} collected. The resulting solution was concentrated in vacuo, adjusted to pH 6.0 with 1 N sodium hydroxide solution and lyophilized. Thus, 4.81 g (82.8%) of 7β- (D-5-carboxy)

- 5 - phthalimido - valeramido) - 3- (dictylaminomethyl)

The sodium salt of 3-cephem-4-carboxylate is obtained.

IR (KBr) tnf ¹ : 1766, 1705, 1607, 1391; Nuclear Magnetic Resonance Spectrum (D ₂ O) δ: 1.2 - 2.7 [12H, m, - CH ₃ x 2, - (CH ₂ ) _{3 -} j, 2.8 - 3.6 (OH, ni, -CH ₂ CH ₃ x 2, 2-CH 3, 3.75 and 4.08 (2H, ABq, J = 14 Hz, 3-CH 3, 5.07 (1H, d, J = 5 Hz, C 1 -H), 5.58 (1H, d, J = 5Hz, C ₇ -H), 7.86 (4H, s, structural unit 18)].

Example 77

279 mg o-picoline and 435 mg sodium 7β - [2 - (2

- Amino-thiazole-4-yl) -2- (color) -methoxyimino-acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate in 2 ml of formamide was added 2 ml of acetonitrile, and the mixture was stirred at 0 ° C. They are hyphae to 'C'.

Ethyl o-phenylene phosphate (400 mg) was added and the mixture was stirred at 0 ° C for 30 minutes until the reaction was complete. 70 ml of water are added and the pH is adjusted to 6.5 by addition of 10% sodium carbonate. The resulting solution was washed with methylene chloride (20 mL) and concentrated to about 50 mL. The solution was chromatographed on an Amberlite XAD-2 column (XAD-2, 100-200 mesh, 70 mL, column height 40 cm), eluting with water followed by 10: 1 water / acelonitrile. The fractions containing the desired product were combined, concentrated in vacuo and lyophilized. In this way, 305 mg of 7β was obtained in 60% yield

- [2- (2-Aminothiazol-4-yl) -2- (syn) methoxy

- Iminoacetamido] -3- (2-methyl-1-pyridine) methyl-3-cephem-4-carboxylate is obtained. Physical characteristics of the product obtained:

IR spectrum (KBr) cm ^-1 : 3350, 1770, 1660, 1620 NMR (D ₂ O + NaHCO 3 δ: 2.81 (3H, s, CH ₃ ), 3.17 and 3.50 (2H, ABq, J = 18 Hz, 2-CH 3, 3.95

-2 753

191,478 (311, s, OCH 2), 5.22 (1H, d, J-5Hz, C 1 -H), 5.28 cs

5.53 (2H, AB q, .1 = 15 Hz, 3-CHJ, 5.81 (IH, d, .1 = 5Hz, C _r H), 6.90 (lH, s, thiazole), 7. 6-7.95, 8.15-8.45 and 8.55-8.75 (3H, m, pyridine) ppm

Example 78

Example 77 was followed, but 278 mg quinuclidine was used instead of 279 mg a-picoline. In this way, 324 mg of 7β - [2- (2-aminothiazole) were obtained in a yield of 64%

- 4 - yl) - 2 - (syn) methoxyimino - acetamido] - 3

- (I - Quinuctidine) methyl 3 - cephem - 4 - carboxylate is obtained. Physical characteristics of the received rooms:

NMR (I) ₂₀₎ His: 2.03 (6H, br, CH ₂ x 3), 3.42 (6H, br, CH ₂ x 3), 3.92 (2H, dd), 3.98 ( 3H, s, CH 3, 5.35 (1H, d, C 7 -H), 5.85 (1H, d, C ₇ -H), 7.01 (1H, s, thiazole) ppm

Example 79

The procedure was as in Example 77, but using 366 mg of 3-formamidopyridine instead of 279 mg of picoline, giving 373 mg of 7β- [2- (aminothiazol-4-yl) -2 (-) Synthesis of methoxyimino acetamido] -3- (3-formamido-l-pyridinio) - incl-3-cephem-4-carboxylate is obtained. Product Features:

NMR (d _s -DMSO) δ: 3.13 and 3.53 (2H, dd, S-CHJ, 3.78 (3H, s, CHJ, 5.06 (IH, d, C ₆ -H); 5.23 and 5.73 (2H, dd, C ₃ -CH ₂ ), 6.70 (5H, s, thiazole), 7.22 (2H, bs, NH ₂ ), 8.1 -9.7 ( 4H, m, pyridine), 8.52 (1H, s, CHO), 9.56 (1H, d, CONH)

Example 80

Example 77 was used, but the 279 mg a-picoline sites were obtained using the following nitrogen nuclofilcc:

(a) 357 mg of 2,3-cyclopenylcno-pyridine nitrogen nucleophile were used. There was thus obtained 365 mg of 7β - [2- (2-aminothiazol-4-yl) -2- (syn) in a yield of 71%.

- methoxyimino - acetamide] - 3- (2,3 - cyclopenten

1- (pyridine) methyl 3-cephem-4-carboxylate is obtained. Product Features:

IR spectrum (KBr): 3350, 1765, 1665, 1615 cm -1 ¹ H NMR (D ₂ O + NaHCO 3): 2.0-2.5 (2H, m, -CH ₂ CH ₂ CH ₂ -), 3.0 -3.5 (4H, m,

-CH ₂ CH ₂ CH ₂ -), 3.16 and 3.46 (2H, ABq, J = 18 Hz, 2-CH 3, 3.94 (3H, s, OCH ₃ ), 5.20 (1H, d , J = 5Hz, C, _fi-H), 5.23 and 5.47 (2H, ABq, J = 15Hz, 3-CHJ, 5.79 (IH, d, J = 5Hz, C ₇ -H ), 6.84 (1H, s, thiazole), 7.5-7.8 and 8.05-8.55 (3H, m, pyridinio) ppm.

b) 400 mg of imidazoic 1,2-ayperpyridine nitrogen nucleophile. 133 mg of 7β - [2- (2-aminothiazol-4-yl) -2- (syn) methoxy] were obtained in a yield of 26%.

- Iminoacetamido] -3- (imidazo [1,2-a] pyridinium -1-yl) methyl-3- [alpha] -carbonyl-4-carboxylate is obtained. Product Features:

¹ H NMR (KBr): 3375, 1765, 1610 cm -1 ¹ H NMR (DMSO-d ₆ ) δ: 2.97 and 3.44 (2H, ABq, J = 17 Hz, 2-CH 3, 3.77 (3H) , s, OCH 3, 4.97 (1H, d, J = 5Hz, C ₆ -H), 5.22 and 5.35 (2H, ABq, J = 14Hz,

3-CH 3, 5.58 (111, dd, J = 5 x 8 Hz, C ₇ -H), 6.65 (III, s, thiazole), 7.13 (211, broad, N 11 ₂ ), 7 , 35 - 7.6,

7.8-8.1.8.25-8.7 cs 8.8-8.95 (6H, m, Jinidazopyridinium), 9.41 (1H, d, J = 8Hz, CONH) ppm

c) 295 mg of imidazo [1,5-a] pyridine nitrogen nucleophile were used. In 35% yield 180 mg of 7β - [2 - (2

- aminothiazol-4-yl) -2- (syn) methoxyimino acetamido] -3- (imidazo [1,5-a] pyridinium-2-yl) methyl 3-cetem-4-carboxylate is obtained. The resulting product features:

IRISH. Nuclear Magnetic Resonance Spectrum (KBr) 3375, 1765, 1655, 1610 cm -1 ¹ H NMR (DMSO-d6 δ: 3.13 and 3.54 (2H, ABq, J = 18 Hz, 2-CH3, 3.77 (3H, s, OCH3, 5.00 (1H, d, J = 5Hz, _C6- H), 5.04 and 5.51 (2H, ABq, J = 15Hz, 3-CH3, 5.59 (1H, dd, J = 5 x 8Hz, C ₇ -H), 6.66 (lH, s, thiazole), 7.13 (2H, br, NH, 6.9 to 7.4, 7, 7.9 7,

8.4-8.7, 8.47 and 10.03 (6H, imidazopyridinium), 9.37 (1H, d, J = 8Hz, CONH) ppm.

d) 357 mg of iinidazo [1,2-b] pyridazine nitclolid. In this way, 242 g of 7β - (2- (2-aminothiazol-4-yl) -2- (syn) methoxy) were obtained in a yield of 47%.

- Iminoacetamido] -3- (imidazole-1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate is obtained. Product Features:

Nuclear Magnetic Resonance Spectrum (DMSO-d6 δ: 3.03 and 3.48 (2H, ABq, J = 18Hz, 2-CH3), 3.77 (3H, s, OCH3), 4.98 (1H, d, J = 5 Hz, C ₆ -H), 5.25 and 5.51 (2H, ABq. J = 14 Hz, 3-CH 3, 5.59 (1H, dd, J = 5 * 8 Hz, C ₇ -H ), 6.65 (1H, s, thiazole), 7.13 (2H, broad, NH ₂ ), 7.90 (1H, dd, J = 4 χ 9 Hz), 8.70 (2H, broad), 8.99 (1H, d, J = 4Hz) and 9.27 (5H, imidazopyridazinium), 8.42 (1H, d, J = 8Hz, CONH) ppm.

Claims (15)

Claims A process for the preparation of cephem carboxylic acid derivatives of the formula (I) and their salts wherein R ¹ is hydrogen; C 1 -C 8 alkanoyl optionally substituted with one or two substituents selected from the group consisting of phenyl, thienyl, aminothiazolyl, carbexyl, (C 1 -C 4) alkyl-oxyimino; an amino group protected as a phthalimide or a benzoyl group optionally substituted with a benzyloxycarbonyl group or a C 1 -C 6 alkyl group, a phenoxycarbonyl group or a C 1 -C 4 alkyloxycarbonyl group; or a carboxyl group protected by a C1-C4 alkoxy substituted with a C1-C4 alkyl group; R is hydrogen or alkali metal or C 1-4 alkyl substituted by one or more phenyl groups; R ⁴ is a nucleophilic group of the formula - S - R ⁴ 'in which R ^4a is C 1 -C 4 alkyl, C 1 -C 4 alkyl, optionally substituted phenyl by carboxyl, substituted or unsubstituted 5-membered ring containing nitrogen and optionally sulfur or oxygen, which may be optionally fused to benzene or optionally substituted 6-membered nit-2855 191,478-containing ring, substituents on 5- and 6-membered heterocycles containing 1-3 carbon atoms, mono- or di (1-3 carbon atoms) alkylamino (1-4 carbon atoms), carboxy (1-4) scnyl) alkyl, oxo or hydroxy, or a group of Formula 6 wherein R ^23a , R ^23b and R ^{23c are the} same or different and are C 1 -C 4 alkyl optionally substituted with cyano or tetrazoyl or R ^23a , R ^23b and R ^23c together with the nitrogen atom to which they are attached form an optionally substituted 5- or 6-membered nitrogen-containing heterocycle - the substituents being carbamoyl, cyano, (C 1 -C 3) alkoxycarbonyl, (C 1 -C 4) alkyl or (C 1 -C 4) alkyl; C 4 -C 4 alkanoylamino - or a 6-membered 4- to 6-membered cycloalkyl group fused to a 1 nitrogen atom or a 6-membered ring containing 1 or 2 nitrogen atoms fused to a 5-membered ring containing 2 nitrogen atoms; forms a piperidine ring ring bridged with an ethylene or ethylene group and the dashed line represents the double bond at the 2- or 3-position of the cephem ring - R ', R and the dashed line have the meaning of formula (1) with a nucleophilic compound or a salt thereof, the nucleophilic compounds have the meanings given for R ⁴ of the compound of formula (I), characterized in that (a) a cyclic compound of formula XXII1 containing a trivalent phosphorus or a cyclic compound of formula XXIV containing a divalent phosphorus or a salt thereof Q '' and Q ^{2a, the} same or different, are C 1 -C 4 alkyl or, together with the moiety to which they are attached, form a benzene or naphthalene group, which rings optionally contain C 1 -C 4 alkyl, halogen, hydroxy or Substituted with (C1-C4) alkoxycarbonyl; X, Y ^is cs Z 'are each halogen, phenyl, (C 1 -C 4) alkylamino, -OQ ^3a wherein Q ^3a is (C 1 -C 6) alkyl optionally substituted with halo or optionally substituted phenyl (nitro). C3-C7 cycloalkyl or C1-C4 alkyl allyl; ^{X, Y} and Z both together form oxo ^groups - or (b) phosphorus of a compound of formula (XXV) or a salt thereof wherein Q ⁵ and Q ²⁶ together with the moiety 12 form a benzene or naphthalene ring and the rings may be optionally substituted with (C 1 -C 4) alkoxycarbonyl; - oxy - halide, -trihalide! or its pentahalide reaction product as catalyst and optionally in a basic medium. 2. A process according to claim I wherein the catalyst is a cyclic phosphorus compound of formula (16) wherein A 'is hydroxy, (C 1 -C 3) alkyl or (C 1 -C 4) alkoxycarbonyl; n ^b is 0 or I and X ^b is C 1-6 alkoxy, phenyl, phenoxy or (C 1-6) alkylamino. 3. The method of claim 2 wherein the substituent X ^b 1 -6 is used as the compound containing carbon atoms (16) - A 'and U ^b are as defined in claim 2. t A process for the preparation of compounds of formula (I) wherein R ¹ , R ⁴ and the dashed line are as defined in claim 1, wherein the appropriately substituted compound of formula (II) is compound. A process for the preparation of a compound of formula (I) according to claim 1 wherein the dashed line represents a double bond at the 3-position of the cephem ring - R, R ⁴ cs R 'are as defined in claim I - the corresponding compound of formula (U) is used. 6. The process of claim 1, wherein the heterocycle is a tetrazolyl, thiadiazolyl, pyridyl, pyrimidinyl or triazinyl group. for preparing compounds of formula (I) - wherein using the corresponding formula (II) kcpletű starting material - wherein R and R ¹ of the first claim. The process for the preparation of compounds of formula I according to claim 1, wherein R ⁴ is a group of formula (6) wherein R ²³ *, R ^23b and R ^23e together with the nitrogen atom to which they are attached are optionally carbamoyl, pyridinium or pyrrolinium substituted with cyano or (C 1-3) alkoxycarbonyl; A process according to claim 1, characterized in that the appropriately substituted compound of formula (II) is used. 8. The process of claim I wherein the nucleophilic compound comprises a tetrazolylthio-nucleophilic moiety substituted with a C 1-3 alkyl group. 9. The method of claim 1 wherein the nucleophilic compound comprises a 1-methyl-1 H -tetrazol-5-yl group as the nucleophilic residue. A process according to claim I, wherein R 'is a 5-membered heterocyclic ring containing a nitrogen and / or sulfur atom optionally substituted with an amino group or a compound of formula (I) as a substituent of R 1; wherein R ^c is an optionally protected amino group and R ^d is an optionally protected carboxyl group; R ^b is a C 1 -C 5 alkylene group or a group of formula 3 wherein R ^c is a ^C 1 -C 3 alkyl group optionally substituted with a carboxyl group; for preparing compounds of formula (I) - wherein R and ^R4 are as defined. The compound of claim 1, wherein the appropriately substituted starting reagent of formula (II) is used. -2 957 191,478 A process according to claim I for the preparation of compounds of formula I containing a substituent R ¹ - wherein R ^a is an aromatic acyl protected amino group or an esterified carboxyl group, wherein the protecting or esterification groups as defined in claim 1, characterized in that the appropriately substituted starting compound of formula (II) is used. 12. A process for the preparation of compounds of general formula (I) according to claim I, wherein R 'is 2- (2-aminothiazol-4-yl) -2- (sin) methoxyiminoacetyl, - R ⁴ , R and the dashed line are as defined in claim 1, characterized in that the appropriately substituted compound of formula (II) is used. 13. The process of claim I, wherein the reaction is carried out in the presence of a base. A process for the preparation of a compound of formula (I) according to claim 1 wherein R ¹ is R ^c -CH (COOH) - (CH ₂ ) j -CO-, wherein R ^{c is} optionally as defined in claim 1. an amino group as defined in claim 1; R is hydrogen, R ⁴ is a 1-methyl-1H-tetrazol-5-yl group and the dashed line is a 3-licyl bond, wherein the appropriately substituted compound of formula II is used and the catalyst of formula 16a is X ^b is methoxy or ethoxy - or one thereof 15 salts.