JPH0357911B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula [In the formula, R ¹ is a hydrogen atom or an acyl group, R is a hydrogen atom or an ester residue, the dotted line is the double bond at the 2- or 3-position of the cefem ring, and R ⁴ is the residue of a nucleophilic compound. The present invention relates to a method for producing a cephalosporin compound represented by the following formula. The cephalosporin compound of the above formula [] is important as an antibacterial substance or a synthetic intermediate thereof,
As a method for producing [], there has been a method in which a compound having an acyloxymethyl group at the 3-position of the cefem skeleton () and a thiol compound are reacted in water or a mixed solvent of water and an organic solvent under acidic to weakly basic conditions (especially 39-17936, Tokuko 49-45880, Tokuko Sho
46-13023, JP-A-46-3286, JP-A-48-68593, etc.), method of heating in an organic solvent (JP-A-55-1999)
43043, etc.), a method of reacting in the presence of an acid or an acid complex in an organic solvent (Japanese Patent Application Laid-Open No. 53-98987,
JP-A-54-76591, JP-A-55-9048, JP-A-55-
20724, JP-A-55-49383, JP-A-55-139387, JP-A-55-153790, etc.), () Method of substituting the acetoxy group in the acetoxymethyl group at the 3-position of the cefem skeleton with a nucleophile [Taylor ( ABTaylor),
Journal of the Chemical Society, p. 7020 (1965)], () Method of converting the hydroxyl group in the hydroxymethyl group at the 3-position of the cefem skeleton to a halogen and then substituting it with a nucleophile [Biudt (ABBywood), Recent Advances in the Chemistry of Beta-Lactam Antibiotics (ABBywood), etc.
Advances in the Chemistry of β−Lactam
Antibiotics) p. 139 (1977)], () Method of acylating the 3-hydroxymethyl group of the cefem skeleton to convert it into an acyloxymethyl group and then substituting it with a nucleophile [Tsushima et al., Chemical and Pharmaceutical Bulletin (Chemical &
Pharmaceutical Bulletin), vol. 27, p. 696 (1979)]. however,
In method (), the quality and yield of the target product are poor due to hydrolysis of β-lactam under the reaction conditions, and method in () causes side reactions such as lactonization or cleavage of the β-lactam ring. When a Lewis acid or a complex compound is used as the acid, the reaction equipment is limited and it is difficult to handle in the post-treatment process.After the reaction, the acid used may decompose and discolor due to contact with the target product There are problems such as the need to neutralize with a simple alkali before isolation, and depending on the type of raw material and acid, the yield of the target product [ ] is extremely low.
- When decomposition and coloration of lactam occurs, impurities derived from these may be mixed into the target product [], which requires time and effort to remove impurities and causes a decrease in yield. However, this requires a drying process and the dried powder tends to scatter, which worsens the working environment.
-Aminocephalosporanic acid has the property of causing contact dermatitis in humans [Kirk-Othmer, Encyclopedia of Chemical Technology]
Chemical Technology), 3rd edition, 1978,
Volume 2, P.907-908], which is disadvantageous in terms of industrialization.Furthermore, since the reaction conditions in method () are harsh, the raw materials and target products are likely to decompose during the reaction;
In order to avoid lactonization in this method, protection by esterification of the 4-position carboxylic acid is essential;
Cephalosporin compounds in which the carboxylic acid at position is esterified tend to cause isomerization of the double bond in the cefem ring, and although the reaction conditions in method () can be made more relaxed than in method (), it is not sufficient. Furthermore, unless a special acylating agent is used, two steps, acylation reaction and substitution reaction, are generally required, resulting in insufficient yield and quality of the desired product. However, it requires a lot of effort and equipment, and cannot be said to be an industrially advantageous method. Therefore, the present inventors investigated various methods for producing cephalosporin compounds (), and found that deacetylcephalosporin C (DCPC) or DCPC, cephalosporin C, which is produced in high units by fermentation culture.
A compound obtained by chemical or enzymatic reaction of (CPC), i.e. a compound with the formula [Symbols and dotted lines in the formula have the same meanings as above], a nucleophilic compound, and formula (1) A trivalent or pentavalent cyclic phosphorus compound having a partial structure represented by, or formula (2) When a reaction product of a compound having a partial structure represented by and phosphorus oxyhalide, phosphorus trihalide, or phosphorus pentahalide is reacted in an organic solvent,
Surprisingly, 3 of the raw material compounds [] of the present invention
In one step, the hydroxyl group in the position hydroxymethyl group is substituted by a nucleophilic compound under extremely mild conditions, instantaneously or for a short time, even at low temperatures in an organic solvent,
It was discovered that the desired cephalosporin compound of the formula [] could be obtained in good yield, and as a result of further studies based on this, the present invention was completed. That is, the present invention relates to a compound [], a nucleophilic compound, and (1) a trivalent or pentavalent cyclic phosphorus compound having a partial structure [], or (2) a compound having a partial structure [] and an oxyhalogenated phosphorus compound. The present invention relates to a method for producing a cephalosporin compound, which is characterized by reacting a reactant with phosphorus trihalide or phosphorus pentahalide in an organic solvent. In the above formula, R ¹ represents a hydrogen atom or an acyl group. Examples of the acyl group represented by R ¹ include 6 of the conventionally known penicillin derivatives.
An acyl group substituted at the amino group at position, an acyl group substituted at the amino group at position 7 of a cephalosporin derivative, etc. are used. Examples of such acyl groups include, for example, the formula R ⁵ -CO- [wherein R ⁵ represents a hydrogen atom, alkyl, phenyl ^* or a heterocyclic ^* group]. ] Groups and formulas represented by [In the formula, R ⁶ is hydrogen, an amino acid residue, a protecting group for an amino group, or a formula R ⁸ -(CH ₂ )n ₁ -CO- {In the formula, R ⁸
represents a heterocyclic ^* group, and n ₁ represents an integer of 0 to 2, respectively. }, and R ⁷ represents an alkyl, phenyl ^* or heterocyclic ^* group, respectively. ], a group represented by the formula R ⁹ −R ¹⁰ −CO− [] [where R ⁹ is the formula

[Formula] {In the formula, R ¹¹ is alkyl ^* , heterocyclic ^* group, or phenyl ^* , R ¹² is hydrogen, alkyl, or the formula -R ¹³ -R ¹⁴ (In the formula, R ¹³
represents alkylene or alkenylene ^* , R ¹⁴ represents phenyl ^* , carboxyl or its ester, or mono- or dialkylamino, respectively. ) are shown below. }, R ¹⁰ is a simple bond or a formula

[Formula] (in the formula, R ¹⁵ represents an alkyl, phenyl ^* or thiazolyl ^* group). ],
formula [In the formula, R ¹⁶ represents hydroxy, hydroxysulfonyloxy, carboxy, ureido*, sulfamoyl ^* , sulfo ^or phenoxy ^* carbonyl, or formyloxy, and R ¹⁷ represents hydrogen, alkyl, alkoxy, halogen, nitro, or hydroxy, respectively. ], a group represented by the formula R ¹⁸ −R ¹⁹ −CH ₂ −CO [] [wherein R ¹⁸ is cyano, phenyl ^* , phenoxy
^* , alkyl ^* , acyloxy, alkenyl ^* , or heterocyclic ^* group, R ¹⁹ is a simple bond or -
S- is shown respectively. ] etc. are used. In the group represented by the above symbols R ⁵ to R ¹⁹ ,
In the case of a group that "may have a substituent", ^{an *} is attached to the right side of the group. For example, "alkyl which may have a substituent" is expressed as "alkyl ^* ". In this case, the number of substituents is not limited to one, and may have two to several identical or different substituents depending on the group to be substituted. Alkyl is linear or branched and has 1 to 6 carbon atoms.
Lower alkyl is preferred, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, n-
Pentyl, isopentyl, n-hexyl, isohexyl, etc. are used. As an alkenyl,
Straight-chain or branched lower alkenyl having 2 to 6 carbon atoms is preferred, such as vinyl, allyl, isopropenyl, 2-methallyl, 2-butenyl, 3-
Butenyl etc. are used. As a heterocyclic group,
For example, one heteroatom such as a nitrogen atom (which may be oxidized), an oxygen atom, a sulfur atom, etc.
A 5- to 8-membered ring or a condensed ring thereof is used, such as 2- or 3-pyrrolyl, 2-
or 3-furyl, 2- or 3-thienyl, 2
- or 3-pyrrolidinyl, 2-, 3- or 4
-pyridyl, N-oxide-2-, 3- or 4
-pyridyl, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-pyranyl, 2-, 3-
or 4-thiopyranyl, pyrazinyl, 2-,4
- or 5-thiazolyl, 2-, 4- or 5-
oxazolyl, 3-, 4- or 5-isothiazolyl, 3-, 4- or 5-isooxazolyl,
2-, 4- or 5-imidazolyl, 3-, 4-
or 5-pyrazolyl, 3- or 4-pyridazinyl, N-oxide-3- or 4-pyridazinyl, 2-, 4- or 5-pyrimidinyl, N-oxide-2-, 4- or 5-pyrimidinyl, piperazinyl, 4 - or 5-(1,2,3-thiadiazolyl), 3- or 5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 1,
2,5-thiadiazolyl, 4- or 5-(1,
2,3-oxadiazolyl), 3- or 5-
(1,2,4-oxadiazolyl), 1,3,4-
Oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3- or 1,2,4-triazolyl, 1H or 2H-tetrazolyl, pyrido[2,
3-d]pyrimidyl, benzopyranyl, 1,8
-, 1,5-, 1,6-, 1,7-, 2,7- or 2,6-naphthyridyl, quinolyl, thieno[2,3-b]pyridyl and the like are frequently used. As alkoxy, linear or branched carbon number 1
-6 lower alkoxy is preferred, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyl Oxygen etc. are used. As the halogen, fluorine, chlorine, bromine, and iodine are used.
Examples of amino acid residues include glycyl, alanyl, valyl, leucyl, isoleucyl, seryl, threonyl, cysteyl, cystyl, methionyl, α- or β-asparagyl, α- or γ-glutamyl, lysyl, arginyl, phenylalanyl, phenylglycyl, Tyrosyl, histidyl, tryptophanyl, prolyl, etc. are used. The alkylene is preferably a lower alkylene having 1 to 6 carbon atoms, and examples thereof include methylene, ethylene, propylene, isopropylene, and the like. The alkenylene is preferably a linear or branched lower alkenylene having 2 to 4 carbon atoms, such as vinylene, propenylene, etc. As the ester at the carboxyl group, lower alkyl esters having 1 to 6 carbon atoms such as methyl ester, ethyl ester, propylene ester, n-butyl ester, isobutyl ester, and tert-butyl ester are used. As a protecting group for amino group, β
- Those used for this purpose in the field of lactam and peptide synthesis are conveniently employed. For example, phthaloyl, toluoyl, naphthoyl, benzoyl, chlorobenzoyl, p-nitrobenzoyl,
Aromatic acyl groups such as p-tert-butylbenzoyl, p-tert-butylbenzenesulfonyl, benzenesulfonyl, toluenesulfonyl, phenylacetyl, such as formyl, acetyl, propionyl, valeryl, caprylyl, n-decanoyl,
Aliphatic acyl groups such as acryloyl, pivaloyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methanesulfonyl, ethanesulfonyl, camphorsulfonyl, trifluoroacetyl, maleyl, succinyl, for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, Isopropoxycarbonyl, 2-
Cyanoethoxycarbonyl, β, β, β-trichloroethoxycarbonyl, β-trimethylsilylethoxycarbonyl, β-methylsulfonylethoxycarbonyl, benzyloxycarbonyl, p
- esterified carboxyl groups such as nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, e.g. methyl Substituted carbamoyl groups such as carbamoyl, phenylcarbamoyl, naphthylcarbamoyl, and also, for example, trityl, 2-nitrophenylthio, benzylidene, 4-nitrobenzylidene, trialkylsilyl, benzyl, p-nitrobenzyl, such as diethylphosphoryl, dimethylphosphoryl, diphenylphosphoryl, di-isopropylphosphoryl, diisobutylphosphoryl,
Phosphoryl groups such as dibutylphosphoryl, o-hydroxyphenylphosphoryl, methyl(o-hydroxyphenyl)phosphoryl, etc. Phosphinyl groups such as dimethylphosphinyl, diphenylphosphinyl, phosphonyl groups such as phenylphosphonyl, butylphosphonyl, etc. Protecting groups for amino groups other than acyl groups are mentioned. The selection of the protecting group is not particularly limited in the present invention. Among these, alkyl, alkenyl, such as cycloalkyl ^* , cycloalkenyl ^* , aryl
^* , heterocyclic ^* group, alkoxycarbonyl acyl, oxo, halogen, cyano, trifluoromethyl,
Hydroxy, alkoxy, aryl ^* oxy, acyloxy, carbamoyloxy, hydroxysulfonyloxy, alkylsulfonyloxy, aryl ^* sulfonyloxy, nitro, amino, carboxy, aminocarbonyl, alkylthiocarbonyl, mercaptoalkylthio, aminoalkylthio, acylaminoalkylthio, aralkyl
1 to 3 substitutions may be made with ^* thio, aryl ^* thio, heterocycle ^* thio, quaternary ammonium ^* , etc. A substituted alkyl group may be, for example, of the formula [In the formula, n ₂ is an integer from 0 to 3, R ²⁰ and R ²¹ are the same or different hydrogen atoms, and are alkyl, cycloalkyl ^* , aralkyl ^* , aryl ^* , heterocyclic ^* group, alkoxycarbonyl, acyl, or R ²⁰ and R ²¹ together form oxo, R ²² is a hydrogen atom, alkyl, cycloalkyl ^* , aryl ^* , heterocyclic ^* group,
Halogen, cyano, hydroxy, alkoxy, aryl ^* oxy, acyloxy, carbamoyloxy, hydroxysulfonyloxy, alkylsulfonyloxy, aryl ^* sulfonyloxy,
Indicates nitro, amino, carboxy, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, acyl, mercapto, alkylthio, aminoalkylthio, acylaminoalkylthio, aralkyl ^* thio, aryl ^* thio, heterocycle ^* thio, and quaternary ammonium ^* . ] is also used. Here, the cycloalkyl is preferably one having a complex number of 3 to 8, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like. As the aryl, for example, phenyl, α-naphthyl, β-naphthyl, biphenyl, anthryl, etc. are used, and in particular, phenyl, naphthyl, etc. are frequently used. Examples of aralkyl include benzyl, phenethyl, phenylpropyl, naphthylmethyl, and the like. Examples of acyl groups include formyl, alkylcarbonyl, aryl ^* carbonyl,
Aralkyl ^* carbonyl, heterocyclic ^* groups acetyl, etc. are used, inter alia, for example acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl, n-hexanoyl, benzoyl,
-Hydroxybenzoyl, 4-methoxybenzoyl, phenylacetyl, 4-hydroxyphenylacetyl, 4-methoxyphenylacetyl, 2-
thienylcarbonyl, 2-furylcarbonyl, 2
-, 4- or 5-thiazolyl acetyl, 2- or 3-thienyl acetyl, 2- or 3-furylacetyl, 2-amino-4 or 5-thiazolyl acetyl, etc. are used. As the quaternary ammonium group, for example, pyridinium, quinolinium, etc. are used. Substituents for cycloalkyl, cycloalkenyl, aralkyl, aryl, heterocyclic groups, and quaternary ammonium include, for example, alkyl, alkoxy, alkenyl, aryl, aralkyl, mercapto, alkylthio, arylthio, aralkylthio, alkylsulfonyl, and aryl. Sulfonyl, aralkylsulfonyl, trihalogenoalkyl, hydroxy, oxo, thioxo, halogen, nitro, amino, cyano, carbamoyl, carboxy, acyl, acyloxy, acylamino, hydroxyalkyl, carboxyalkyl,
Halogenoalkyl, mono- or dialkylaminoalkyl, etc. are used. (Alkyl, alkoxy, alkenyl, aryl, aralkyl and acyl herein are as defined above). As the substituent for phenoxy ^* , the same substituents for aryl ^* as described above are used.
Furthermore, as substituents of thiazolyl ^* , for example, alkyl, alkoxy, halogen, hydroxy,
Acylamino having 2 to 4 carbon atoms substituted with amino or the like may also be used. As a substituent for a heterocyclic ^group ,
For example, phenyl substituted with alkyl, alkoxy, halogen, nitro, amino, etc. may be used. As the substituent in ureido ^* , for example, sulfo, carbamoyl, sulfamoyl, amidino, alkyl having 1 to 3 carbon atoms, etc., which have appropriately formed a salt with sodium, potassium, etc., are used. As substituents in sulfamoyl ^* ,
For example, lower alkyl having 1 to 3 carbon atoms, amidino, etc. are used. As the substituent for alkenylene ^* , for example, carboxy, cyano, etc. are used. Also, the formula in R ⁹

[Formula] is the expression

Syn isomer and formula represented by [formula]

It represents an anti-isomer of the formula or a mixture thereof. Among the above acyl groups, specific examples of the acyl group represented by the formula R ⁵ -CO- include formyl, acetyl, hexanoyl, benzoyl, p-
Nitrobenzoyl, 3-(2,6-dichlorophenyl)-5-methylisoxazol-4-ylcarbonyl, 5-methyl-3-phenyl-4-isoxazolylcarbonyl, 4-ethyl-2,3 −
Dioxo 1-piperazinocarbonyl and the like are used. formula

Specific examples of the acyl group represented by the formula include D-alanyl, benzyl N-carbobenzoxy-γ-D-glutamyl-D-alanyl, D-phenylglycyl-D-
Alanyl, N-carbobenzoxy-D-alanyl, N-carbobenzoxy-D-phenylglycyl, D-alanyl-D-phenylglycyl, γ-
D-glutamyl-D-alanyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-phenylacetyl, 2-(4-ethyl-2,3-dioxo-1- piperazinocarboxamide)-2-(4-sulfoxyphenyl)acetyl, N-(4-ethyl-2,3-dioxo-1-
piperazinocarbonyl)-D-alanyl, N-(4
-ethyl-2,3-dithiooxo-1-piperazinocarbonyl)-D-phenylglycyl, 2,2
-bis-(4-ethyl-2,3-dioxo-1-
piperazinocarboxamide)acetyl, 2-(2
-amino-4-thiazolyl)-2-(4-ethyl-
2,3-dioxo-1-piperazinocarboxamide)acetyl, 2-(4-hydroxy-6-methylnicotinamide)-2-phenylacetyl, 2
-(4-hydroxy-6-methylnicotinamide)
-2-(4-hydroxyphenyl)acetyl, 2
-{5,8-dihydro-2-(4-formyl-1-
piperazinyl)-5-oxopyrido [2,3-d]
Pyrimidine-6-carboxamide}-2-phenylacetyl, 2-(3,5-dioxo-1,2,
4-triazine-6-carboxamide)-2-(4
-Hydroxyphenyl)acetyl, 2-(3-furfrideneamino-2-oxoimidazolidine-
1-carboxamide)-2-phenylacetyl,
2-(coumarin-3-carboxamide)-2-phenylacetyl, 2-(4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxamide)-2-phenylacetyl, 2-(4-hydroxy -7-trifluoromethylquinoline-3-carboxamide)-2-phenylacetyl, N-[2-
(2-amino-4-thiazolyl)acetyl]-D-
Phenylglycyl, 2-(6-bromo-1-ethyl-1,4-dihydro-4-oxothieno[2,
3-b]Pyridine-3-carboxamide)-2-
Funylacetyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-
thienylacetyl, 2-(4-n-pentyl-2,
3-dioxo-1-piperazinocarboxamide)
-2-thienylacetyl, 2-(4-n-tictyl-2,3-dioxo-1-piperazinocarboxamide)-2-thienylacetyl, 2-(4-cyclohexyl-2,3-dioxo-1-pipe Radinocarboxamide)-2-thienylacetyl, 2-
[4-(2-phenylethyl)-2,3-dioxo-1-piperazinocarboxamide]-2-thienylacetyl, 2-(3-methylsulfonyl-2-
Oxoimidazolidine-1-carboxamide)-
2-phenylacetyl, 2-(3-furfrideneamino-2-oxoimitazolidine-1-carboxamide)-2-(4-hydroxyphenyl)acetyl, 2-(4-ethyl-2,3-dioxo -1
-piperazinocarboxamide)-2-(4-benzyloxyphenyl)acetyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-(4-methoxyphenyl)acetyl ,
2-(8-hydroxy-1,5-naphthyridine-
7-carboxamide)-2-phenylacetyl, etc. are used. As a specific example of the acyl group represented by the formula ^R9 - ^R10 -CO-, for example, 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-(2-amino-4-thiazolyl)-2-methoxyiminoacetamide]acetyl,
2-(2-chloroacetamide-4-thiazolyl)-
2-methoxyiminoacetyl, 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl, 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetyl, 2-(2-amino-4 −
thiazolyl)-2-propoxyiminoacetyl,
2-(2-amino-4-thiazolyl)-2-butoxyiminoacetyl, 2-(2-amino-4-thiazolyl)-2-benzyloxyiminoacetyl,
2-(2-amino-4-thiazolyl)-2-allyloxyiminoacetyl, 2-(2-amino-5-
Chloro-4-thiazolyl)-2-methoxyiminoacetyl, 2-(2-amino-5-bromo-4-
thiazolyl)-2-methoxyiminoacetyl, 2
-(2-amino-4-thiazolyl)-2-oxyiminoacetyl, 2-thienyl-2-methoxyiminoacetyl, 2-furyl-2-methoxyiminoacetyl, 2-(1,2,4-thiadiazole-3
-yl)-2-methoxyiminoacetyl, 2-
(1,2,4,-thiazazol-5-yl)-2
-methoxyiminoacetyl, 2-(1,3,4-
thiadiazolyl)-2-methoxyiminoacetyl,
2-(4-hydroxyphenyl)-2-methoxyiminoacetyl, 2-phenyl-2-methoxyiminoacetyl, 2-phenyl-2-oxyiminoacetyl, 2-[4-(γ-D-glutamyloxy)phenyl ]-2-oxyiminoacetyl, 2
-[4-(3-amino-3-carboxypropoxy)phenyl]-2-oxyiminoacetyl and the like are used. formula

Specific examples of the acyl group represented by the formula include α-sulfophenylacetyl, α-carboxyphenylacetyl,
α-Hydroxyphenylacetyl, α-ureidophenylacetyl, α-sulfouridophenylacetyl, α-sulfamoylphenylacetyl, α-phenoxycarbonylphenylacetyl, α-(p-tolyloxycarbonyl) Phenylacetyl, α-formyloxyphenylacetyl, etc. are used. Specific examples of the acyl group represented by the formula ^R18 - ^R19 - _CH2 -CO- include cyanoacetyl, acetoacetyl, phenylacetyl, phenoxyacetyl, 5-amino-5-carboxyvaleryl, 5-oxo-5-carboxyvaleryl, 4
-carboxybutyryl, trifluoromethylthioacetyl, cyanomethylthioacetyl, 1H-tetrazolyl-1-acetyl, thienylacetyl,
2-(2-amino-4-thiazolyl)acetyl,
4-pyridylthioacetyl, 2-thienylthioacetyl, 3,5-dichloro-1,4-dihydro-
4-oxopyridine-1-acetyl, β-carboxyvinylthioacetyl, 2-(2-aminomethylphenyl)acetyl, etc. are used. The amino group and/or carboxyl group and/or hydroxyl group in the above acyl group are
This also includes cases where it has a protecting group. As the protecting group for the amino group, those similar to the above-mentioned protecting groups for the amino group can be used. In addition, as a protecting group for a carboxyl group, any group that can be normally used as a protecting group for a carboxyl group in the field of β-lactam and organic chemistry can be used, such as methyl, ethyl, n-propyl, isopropyl, tert-butyl, tert-amyl, benzyl, p
-Nitrobenzyl, p-methoxybenzyl, benzhydryl, 1-indanyl, phenacyl, phenyl, p-nitrophenyl, methoxymethyl,
Ethoxymethyl, benzyloxymethyl, acetoxymethyl, pivaloyloxymethyl, β-methylsulfonylethyl, β-trimethylsilylethyl, methylthiomethyl, trityl, β, β, β-
Trichloroethyl, β-iodoethyl, trimethylsilyl, dimethylsilyl, acetylmethyl, p
-Nitrobenzoylmethyl, p-mesylbenzoylmethyl, phthalimidomethyl, propionyloxymethyl, 1,1-dimethylpropyl, 3-methyl-3-butenyl, succinimidomethyl,
3,5-di-tert-butyl-4-hydroxybenzyl, mesylmethyl, benzenesulfonylmethyl,
Ester residues such as phenylthiomethyl, dimethylaminoethyl, pyridine-1-oxide-2-methyl, methylsulfinylmethyl, bis(p-methoxyphenyl)methyl, 2-cyano-1,1-dimethylethyl, etc. , silyl group, etc. are used. As protecting groups for hydroxyl groups, all those that can be used as protecting groups for hydroxyl groups in the field of β-lactams and organic chemistry can be used, such as ester residues such as acetyl, chloroacetyl, β, β, β- Esterified carboxyl groups such as trichloroethoxycarbonyl and β-trimethylsilylethoxycarbonyl,
tert-butyl, benzyl, p-nitrobenzyl,
Ether residues such as trityl, methylthiomethyl, and β-methoxyethoxymethyl, silyl ether residues such as trimethylsilyl and tert-butyldimethylsilyl, and acetal residues such as 2-tetrahydropyranyl and 4-methoxy-4-tetrahydropyranyl. etc. are used. In the present invention, the selection of the protecting group is not particularly limited, as is the case with the protecting groups for amino groups and carboxyl groups. The symbol R in formulas [] and [] represents a hydrogen atom or an ester residue. Examples of the ester residue represented by R include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tertiary-pentyl, hexyl, In addition to lower alkyl groups having 1 to 6 carbon atoms such as isohexyl, aralkyl ^* groups such as benzyl, P-nitrobenzyl, P-methoxybenzyl, diphenylmethyl, and bis(P-methoxyphenyl)methyl, etc. Ester residues that do not cause any problems may be used. The symbol R ⁴ in formula [] represents a residue of a nucleophilic compound. Examples of nucleophilic compounds used here include nucleophilic substances characterized by having nucleophilic nitrogen, carbon, or sulfur, which have been widely described in previous publications on cephalosporin chemistry. It will be done. Examples of such nucleophilic compounds include sulfur nucleophilic compounds, nitrogen nucleophilic compounds, carbon nucleophilic compounds, and the like. Sulfur nucleophilic compounds include, for example, alkyl ^* thiols, aryl ^* thiols, aralkyl
^* Thiols, nitrogen-containing heterocyclic thiols containing 1 to 5 nitrogen atoms that may be oxidized, or containing atoms other than nitrogen, such as oxygen or sulfur, are used. It also includes those having a substituent on the nucleus thereof. Examples of such nitrogen-containing heterocyclic groups include 6-membered nitrogen-containing heterocyclic groups such as pyridyl, N-oxide pyridyl, pyrimidyl, pyridazinyl, N-oxide pyridazinyl, triazinyl, imidazolyl, thiazolyl, thiadiazolyl, oxadiazolyl,
A 5-membered nitrogen-containing heterocyclic group such as triazolyl or tetrazolyl or a fused ring thereof is used.
Substituents on these nitrogen-containing heterocyclic groups include, for example, hydroxyl group, amino group, carboxyl group,
Carbamoyl groups, lower alkyl groups (e.g. methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, isobutyl, etc.), lower alkoxy groups (e.g. methoxy, ethoxy, propoxy, butoxy, etc.), halogen atoms (e.g. chlorine, bromine, etc.) , or lower alkylene group, -
S-,

Those having various substituents via polyvalent groups such as [Formula] are used. When the polyvalent group is a lower alkylene group, this substituent is a mono- or di-lower alkylamino group, a morpholino group,
It may be a carboxyl group, a sulfo group, a carbamoyl group, an alkoxycarbonyl group, a lower alkylcarbamoyl group, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an acyloxy group, a morpholinocarbonyl group, etc., and the polyvalent group may be -S-,

[Formula] When the substituent is a group, the substituent may be a lower alkyl group, a lower alkylene group having the above substituent, or the like. The polyvalent group

In the case of [Formula], an alkoxycarbonyl group, an acyl group, a carbamoyl group, a lower alkylcarbamoyl group, etc. may be directly bonded. in particular,
For example, pyridinethiol, pyrimidinethiol, methylpyridazinethiol, 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, imidazolethiol, 1,3,4-thiadiazolethiol,
1,2,3-thiadiazole-5-thiol, 2
-Methyl-1,3,4-thiadiazolethiol, thiazolethiol, 5-methyl-1,3,
4-oxadiazolethiol, 1,2,3-triazole-5-thiol, 1-methyl-tetrazole-thiol, 1-(2-dimethylaminoethyl)-tetrazolethiol, 1-(2-sulfoethyl)-tetrazolethiol , 1-sulfomethyltetrazolethiol and the like are used. In addition, aliphatic and aromatic thiols such as methanethiol, ethanethiol, and thiophenol, thiourea derivatives such as thiourea and N-methylthiourea, and thioamide derivatives such as thioacetamide and thiobenzamide are used. These sulfur nucleophilic compounds remain in free form;
Alternatively, they can be used in the reaction in the form of a salt of their acidic group with a base or a salt of their basic group with an acid. Nitrogen nucleophilic compounds include, for example, secondary or tertiary aliphatic, aromatic, araliphatic and cyclic amines such as trialkylamines (such as triethylamine), pyridine bases (such as pyridine and alkylpyridines). , heterocyclic amines having more than one heteroatom in which at least one heteroatom is nitrogen, such as pyrimidines, morpholines, purines, pyridazines, pyrazines, pyrazoles, imidazoles, triazoles and thiazoles. Preferred nitrogen nucleophilic compounds include the formula [In the formula, n ₃ is 0 or an integer of 1 to 5, and R ²³ (which may be the same or different when n ₃ is 2 to 5) is an aliphatic group, For example, lower alkyl (methyl, ethyl, n-propyl, iso-
aryl groups such as phenyl, araliphatic groups such as phenyl lower alkyl (benzyl, phenylethyl, etc.), or alkoxymethyl such as methoxymethyl, ethoxymethyl, n-propoxymethyl, iso-propoxymethyl, etc. or acyloxymethyl, such as alkanoyloxymethyl, such as acetoxymethyl, formyl, carbamoyl, acyloxy, such as alkanoyloxy, such as acetoxy, esterified carboxy, alkoxy, such as methoxy, ethoxy, n-propoxy, iso-propoxy, etc., aryloxy, such as phenoxy, Alkoxy such as penzyloxy,
Alkylthio, such as methylthio, ethylthio, arylthio, aralkylthio, cyano,
hydroxy, N-mono-lower alkylcarbamoyl, such as N-methylcarbamoyl, N-ethylcarbamoyl, N.N-di-lower alkylcarbamoyl, such as N.N-dimethylcarbamoyl,
N-(hydroxylower alkyl)carbamoyl, such as N.N-diethylcarbamoyl, e.g.
(Hydroxymethyl)carbamoyl, N-(hydroxyethyl)carbamoyl, etc., or carbamoyl lower alkyl groups, such as carbamoylmethyl, carbamoylethyl, etc., are used. Specifically, nitrogen-containing heterocyclic compounds such as pyridine, picoline, nicotinic acid, nicotinic acid amide, isonicotinic acid amide, pyridine sulfonic acid, pyrazine, 2-carbamoylpyrazine, pyridazine, pyrimidineimidazole, 1-methylimidazole, etc. is used. Carbon nucleophilic compounds include, for example, inorganic cyanides, pyrroles and substituted pyrroles (e.g. indoles), and compounds giving stabilized carbanions, such as acetylenes and compounds with β-diketone groups, such as acetoacetic acid. Esters, malonic acid esters, cyclohexane-1,3-diones, enamines, inamines, enols, etc. are used. For example, the expression [wherein R ²⁴ and R ²⁵ are the same or different, hydrogen, cyano, lower alkyl (such as methyl or ethyl), phenyl, substituted phenyl (such as halo, lower alkyl, lower alkoxy, nitro, amino or (lower alkylaminophenyl, etc.), lower alkoxycarbonyl, mono or diaryl lower alkoxycarbonyl, lower alkylcarbonyl, aryl lower alkyl or _C5
or C ₆ cycloalkyl, and also R ²⁶
is hydrogen, lower alkyl (such as methyl or ethyl), phenyl, substituted phenyl (such as halo, lower alkyl, lower alkoxy, nitro, amino or lower alkylaminophenyl), aryl lower alkyl or C ₅ or C ₆ cycloalkyl Compounds that can introduce a group represented by the following formula into the 3-position substituted portion of the cephalosporin nucleus are used. Also, dotted lines in formulas [] and []

[Formula] is the 2nd position in the Cefem ring double bond

[Formula] or 3-position double bond

[Formula] is shown. As the trivalent or pentavalent cyclic phosphorus compound used in the present invention, a trivalent or pentavalent cyclic phosphorus compound having a partial structure represented by the formula [ ] as the basic part or part of the chemical structural formula is used. Therefore, P in formula [] represents a trivalent or pentavalent phosphorus atom. Such trivalent or pentavalent cyclic phosphorus compounds include, for example, the formula or expression [In the formula, Q ¹ and Q ² are the same or different and are a hydrocarbon group or a ^heterocyclic group, or Q ¹ and Q ² are bonded to each other]

[Formula] together with a cyclic hydrocarbon group or a heterocyclic ^* group, X, Y, Z are the same or different, and the formula -W ² -Q ³ (W ² is an oxygen atom, a sulfur atom, NR ²⁸
(R ²⁸ is a hydrogen atom or a hydrocarbon group) or a bond, Q ³ is a halogen atom, a hydrocarbon group, or a heterocyclic ^* group; however, when Q ³ is a halogen atom, W ² is a bond). the group represented, or X, Y,
Any two of Z are bonded to form an oxo group or the formula -
W ³ −Q ⁴ −W ⁴ − (Q ⁴ is a carbon hydrogen group or a heterocycle ^*
a group, W ³ and W ⁴ are the same or different and are represented by an oxygen atom, a sulfur atom, NR ²⁹ (R ²⁹ is a hydrogen atom or a carbon-hydrogen group) or a bond), and X is a group represented by the formula

[expression] or expression

Cyclic phosphorus compound represented by [Formula] (W ⁵ represents an oxygen atom, a sulfur atom, or a group represented by NR ³⁰ (R ³⁰ is a hydrogen atom or a hydrocarbon group), and the others have the same meanings as above) etc. are used. formula〔〕,
In [], Q ¹ and Q ² are the same or different and represent a carbon hydrogen group or a heterocyclic ^* group. Examples of hydrocarbon groups represented by Q ¹ and Q ² include those mentioned above for R ² and R ³ , and examples of ^heterocyclic groups include those mentioned above for R ⁵ to ^{R 19} . is used. Also, Q ¹ and Q ² are bonded to each other to form a hydrocarbon group to which Q ¹ and Q ² are bonded.

[Formula] may also represent a cyclic hydrocarbon group or a heterocyclic ^* group. As a cyclic hydrocarbon group,
For example, cycloalkenyl ^* , aryl ^* groups, etc. are used. As these cycloalkenyl ^* and aryl groups, those mentioned above for R ⁵ to R ¹⁹ can be used, for example. Usually, it is advantageous to use the case where Q ¹ and Q ² are the same, or when they are bonded to each other to represent a cyclic hydrocarbon group. X, Y, and Z are the same or different and have the formula -W ² -Q ³ [W ² is an oxygen atom,
A sulfur atom, NR ²⁸ (R ²⁸ represents a hydrogen atom or a hydrocarbon group) or a bond, Q ³ is a halogen atom, a carbon hydrogen group, or a heterocyclic ^* group, provided that when Q ² is a halogen atom, W ² indicates a bond]. R ²⁸ of NR ²⁸ represented by W ² represents a hydrogen atom or a hydrocarbon group. Hydrocarbon group represented by R ²⁸ , hydrocarbon group represented by Q ³ , heterocycle ^*
As the group, for example, those mentioned above for Q ¹ and Q ² can be used. As the halogen atom represented by Q ³ , for example, those mentioned above for R ⁵ to R ¹⁹ can be used. Further, X, Y, and Z may represent an oxo group or a group represented by the formula -W ³ -Q ⁴ -W ⁴ -, in which any two of them, such as X and Y or Y and Z, are bonded. Q ⁴ represents a hydrocarbon group, a heterocyclic ^* group,
As such hydrocarbon groups and heterocyclic groups, for example, those mentioned above for Q ¹ and Q ² can be used. W ³ and W ⁴ may be the same or different and represent an oxygen atom, a sulfur atom, NR ²⁹ or a bond. Here, R ²⁹ represents a hydrogen atom or a hydrocarbon group. Examples of the hydrocarbon group represented by R ²⁹ include alkyl ^* , cycloalkyl ^* ,
Alkenyl ^* , cycloalkenyl ^* , alkynyl ^* ,
Aryl ^* , aralkyl ^*, etc. are used. Here, as the alkyl ^* , cycloalkyl ^* , alkenyl ^* , cycloalkenyl ^* , aryl ^* , and aralkyl ^* groups, for example, those mentioned in the explanation of symbols R ⁵ to ^{R 19} are frequently used. The alkynyl group is preferably a linear or branched lower alkynyl group having 2 to 6 carbon atoms, such as ethynyl, 1-
Propynyl, 2-propynyl, etc. are frequently used.
These alkyl groups may have a substituent, for example, the alkyl ^* mentioned in R ⁵ to ^{R 19} above,
It may be substituted with an alkenyl ^* substituent. Furthermore, X is the formula

[Formula] Also is the expression

It may be a group represented by the formula: (Q ¹ and Q ² have the same meanings as above). ^W5 is
It represents an oxygen atom, a sulfur atom or ^NR30 , and ^R30 represents a hydrogen atom or a hydrocarbon group. As the hydrocarbon group represented by R ³⁰ , those mentioned above for R ²⁹ can be used. Among such trivalent or pentavalent cyclic phosphorus compounds, preferable examples include those of the formula [In the formula, A is a substituent on the benzene ring, X ¹ is a halogen atom, alkyl ^* , alkyl ^* oxy, aryl ^* oxy, aralkyl ^* , aralkyl ^* oxy,
Alkyl ^* amino, aryl ^* amino, aralkyl
^* indicates amino or aryl ^* ], formula [A and X ¹ in the formula have the same meanings as above], or the formula A cyclic phosphorus compound represented by the formula [wherein A has the same meaning as above, and X ⁰ , Y ⁰ , and Z ⁰ are the same or different and have the same meaning as X ¹ ] is used. formula〔〕,
A in [] and [] represents a substituent on the benzene ring, and may be any group as long as it does not participate in the reaction. For example, alkyl ^* , alkyl ^* oxy, alkyl ^* thio, halogen atom, nitro, cyano, hydroxy, carboxy, alkyl
^* Oxycarbonyl, alkyl ^* sulfonyl, carbamoyl, alkyl ^* carbamoyl, aliphatic acyl (acetyl, propionyl, etc.), aromatic acyl (benzoyl, p-chlorobenzoyl, etc.), etc. are used. Furthermore, A is, for example, methylenedioxy,

【formula】

[Formula] etc., and these may be substituted with, for example, a halogen atom such as chlorine or bromine, or a nitro or cyano group. A and X ¹ , X ⁰ , Y ⁰ , Z ⁰
In, halogen atom, alkyl ^* , aryl
As the ^* , aralkyl ^* group, those mentioned in the symbols R ⁵ to R ¹⁹ are used. Preferred examples of X ¹ , X ⁰ , Y ⁰ , and Z ⁰ include halogen atoms such as chlorine, bromine, and fluorine, methoxy, ethoxy, 2,
an optionally substituted C ₁ to C ₅ lower alkyloxy group such as 2,2-trichloroethoxy, 2-cyanoethoxy, 2-methylsulfonylethoxy;
Optionally substituted aryloxy groups such as phenoxy, 4-chlorophenoxy, 4-nitrophenoxy, benzyloxy, aryloxy, p
-Nitrobenzyloxy, optionally substituted aralkyloxy groups such as 1,1-dimethylaryloxy, alkyl ^* , aryl ^* groups, etc. are used. Also, two of X ⁰ , Y ⁰ , and Z ^{0 ,} for example, X ⁰ and Y ⁰ , Y ⁰ and Z ^{0 ,} are connected to each other, for example, 0-
It may also represent phenylenedioxy, ethylenedioxy, etc. In the case of a cyclic phosphorus compound represented by formula [] or formula [], X ¹ is -O-
may represent a linking group and form a dimer with each other. Specific examples of cyclic phosphorus compounds include 0
-phenylene phosphorochlorideate, 0-phenylene phosphorofluorideate, methyl 0-phenylene phosphate, ethyl 0-phenylene phosphate, n-propyl 0-phenylene phosphate, iso-propyl 0-phenylene phosphate Nylene phosphate, n-butyl 0-phenylene phosphate, isobutyl 0-phenylene phosphate, sec-butyl 0-phenylene phosphate, cyclohexyl 0-phenylene phosphate, p- Chlorophenyl 0-phenylene phosphate, p-acetylphenyl 0
-phenylene phosphate, 2-chloroethyl 0
-phenylene phosphate, 2,2,2-trichloroethyl 0-phenylene phosphate, ethoxycarbonylmethyl 0-phenylene phosphate, carbamoylmethyl 0-phenylene phosphate, 2-cyanoethyl 0-phenylene phosphate, 2-methylsulfonylethyl 0-phenylene phosphate, benzyl 0-phenylene phosphate 1,1-dimethyl-2-propenyl 0-phenylene phosphate, 2-propenyl 0-phenylene phosphate, 3-methyl-2 -butenyl 0-phenylene phosphate, 2-thienylmethyl 0-phenylene phosphate, 2-furfurylmethyl 0-phenylene phosphate, bis-0-
Phenylene pyrophosphate, 2-phenyl-
1,3,2-benzodioxaphosphole-2-oxide, 2-(p-chlorophenyl)-1,3,2
-benzodioxaphosphole-2-oxide, 2
-(n-butyl)-1,3,2-benzodioxaphosphole-2-oxide, 2-anilino-1,
3,2-benzodioxaphosphole-2-oxide, 2-phenylthio-1,3,2-benzodioxaphosphole-2-oxide, 2-methoxy-
5-Methyl-1,3,2-benzodioxaphosphole-2-oxide, 2-chloro-5-ethoxycarbonyl-1,3,2-benzodioxaphosphole-2-oxide, 2-methoxy-5 -Ethoxycarbonyl-1,3,2-benzodioxaphosphole 2-oxide, 5-ethoxycarbonyl-
2-phenyl-1,3,2-benzodioxaphosphole-2-oxide, 2,5-dichloro-1,
3,2-benzodioxaphosphole-2-oxide, 4-chloro-2-methoxy-1,3,2-benzodioxaphosphole 2-oxide, 2-methoxy-4-methyl-1,3,2 -Benzodioxaphosphole-2-oxide, 2,3-naphthalenemethyl phosphate, 5,6-dimethyl 2-methoxy-1,3,2-benzodioxaphosphole-
2-oxide, 2,2-dihydro-4,5,6,
7-tetrachloro-2,2,2-trimethoxy-
1,3,2-benzodioxaphosphole, 2,2
-dihydro-4,5,6,7-tetrachloro-
2,2,2-triphenoxy-1,3,2-benzodioxaphosphole, 2,2-dihydro-2,
2-ethylenedioxy-2-methoxy-1,3,
2-Benzodioxaphosphole, 2,2-dihydro-2-benzyl-2,2-dimethoxy-1,
3,2-benzodioxaphosphole, 2,2-dihydro-4,5-benzo-2,2,2-trimethoxy-1,3,2-benzodioxaphosphole,
2,2-dihydro-2,2,2-triphenoxy-1,3,2-benzodioxaphosphole, 2,
2-dihydro-2,2-(0-phenylenedioxy)-2-phenoxy-1,3,2-benzodioxaphosphole, 2-chloro-2,2-dihydro-2,2-(0- phenylenedioxy)-1,3,
2-Benzodioxaphosphole, 2,2-dihydro-2-methoxy-2,2-(0-phenylenedioxy)-1,3,2-benzodioxaphosphole, 2,2-dihydro-2 ,2,2-trichloro-1,3,2-benzodioxaphosphole, 9,
10-phenanthenedioxytrimethoxyphosphorus, 0-phenylenephosphochloridite, 0-
Phenylene phosphorobromidite, 0-phenylene phosphorofloridite, methyl 0-phenylene phosphite, n-butyl 0-phenylene phosphite, methoxycarbonylmethyl 0-phenylene phosphite, phenyl 0-phenylene phosphite p-chloro(or p-nitro)phenyl 0-phenylene phosphite, 2-phenyl-
1,3,2-benzodioxaphosphole, bis0
-phenylene pyrophosphite, 2-methoxy-
5-methyl-1,3,2-benzodioxaphosphole, 5-acetyl-2-phenoxy-1,3,
2-Benzodioxaphosphole, 9,10-phenanthrene phosphorochloridite, 2-chloro-4
-Methyl-1,3,2-benzodioxaphosphole, 5-ethoxycarbonyl-2-phenyl-
1,3,2-benzodioxaphosphole, 2-chloro-2-thioxo-1,3,2-benzodioxaphosphole, 2,2-dihydro-2-oxo-
2-methoxy-4,5-dimethyl-1,3,2-
Dioxaphosphole, 2,2-dihydro-2-oxo-2-chloro-4,5-dimethyl-1,3,
2-dioxaphosphole, 2,2-dihydro-2
-oxo-2-(1-imidazolyl)-4,5-dimethyl-1,3,2-dioxaphosphole, 2,
2-dihydro-2,2-ethylenedioxy-2-
Methoxy-4,5-dimethyl-1,3,2-dioxaphosphole, 2,2-dihydro-2,2-dimethoxy-2-phenoxy-4,5-dimethyl-
1,3,2-dioxaphosphole, 2,2-dihydro-2,2,2-trimethoxy-4,5-dimethyl-1,3,2-dioxaphosphole, 2,2
-dihydro-2,2,2-triphenoxy-4,
5-dimethyl-1,3,2-dioxaphosphole, 2,2-dihydro-2,2,2-triethoxy-4,5-diphenyl-1,3,2-dioxaphosphole, 2,2- dihydro-2,2,2-trimethoxy-4,5-diphenyl-1,3,2-dioxaphosphole, 2,2-dihydro-2-oxo-2-methoxy-4,5-diphenyl-1,
3,2-dioxaphosphole, 2,2-dihydro-2,2,2-trimethoxy-1,3,2-dioxaphosphole, 2,2-dihydro-2,2,2
-trimethoxy-4-phenyl-1,3,2-dioxaphosphole, 2,2-dihydro-2,2,
2-trimethoxy-4-methyl-1,3,2-dioxaphosphole, 2,2-dihydro-2,2,
2-trimethoxy-4-methyl-phenylcarbamoyl-1,3,2-dioxaphosphole, 2,
2,4,5,6,7-hexahydro-2,2,2
-trimethoxy-1,3,2-benzodioxaphosphole, 2,2'-oxybis(4,5-dimethyl-2,2-dihydro-1,3,2-dioxaphosphole), 2,2' -oxybis(4,5-dimethyl-2,2-dihydro-1,3,2-dioxaphosphole-2-oxide) and the like are used.
These cyclic phosphorus compounds are commercially available or are known compounds [RS Edmundson
etc. Chemistry and Industry pp. 1770-1778. 1962
Year; K. Darell Berlin et al. Tetrahedron 1964, 20 volumes
pp. 2709-2716; F. Ramirez et al. Tetrahedron
1968, Vol. 24, pp. 5041-5051; L. Anschu¨tz et al.
Annalen1927 Vol. 454, pp. 109-120; T. Koizumi
Tetrahedron Letters 1973, pp. 4763-4766;
PCCrofts et al. J.Chem.Soc., 1958 4250-4254
Page; Marianne MCFCastelijins et al. J.Org.
Chem. 1981, Vol. 46, pp. 47-53] or according to known methods, and purified products or products produced by reaction can be used in the present invention as they are. In the present invention, instead of the above trivalent or pentavalent cyclic phosphorus compound, the partial structure []
A reaction product of a compound having the formula and phosphorus oxyhalide, phosphorus trihalide, or phosphorus pentahalide may be used. As a compound having a partial structure [], for example, the formula Compounds represented by [the symbols in the formula have the same meanings as above] are used. A preferred example is, for example, the formula Compounds represented by [the symbols in the formula have the same meanings as above] are used. Specific examples include catechol, 3,4-dihydroxybenzoic acid ethyl ester, 2,3-dihydroxynaphthalene,
3,4-dihydroxytoluene, 2,3-dihydroxytoluene, 3,4-dihydroxychlorobenzene, etc. are used. As the halogen of phosphorus oxyhalide, phosphorus trihalide, and phosphorus pentahalide, for example, chlorine, bromine, etc. are used. Specifically, for example, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus oxybromide, etc. are used. As a reaction product of a compound having partial structure [] and phosphorus oxyhalide, phosphorus trihalide or phosphorus pentahalide,
For example, a reaction mixture obtained by reacting the two may be used. Usually, about an equivalent mole of phosphorus oxyhalide or phosphorus trihalide, or about 1/3 to 1.0 equivalent mole of phosphorus pentahalide is reacted with 1 mole of a compound having the partial structure [ ].
The reaction is preferably carried out in a solvent, and examples of such solvents include methylene chloride, 1,2-dichloroethane, acetonitrile, ethyl acetate, tetrahydrofuran, dioxane, ether, benzene, and bromobenzene. In particular, methylene chloride, acetonitrile, tetrahydrofuran and the like are frequently used. Good results may be obtained when the reaction is carried out in the presence of a base. The base used is, for example, triethylamine, tributylamine, dicyclohexylamine, diisobutylamine, di-n-butylamine, etc., and preferably, for example, triethylamine, tri-n-butylamine, di-n-butylamine, etc. Usually -50~100℃ Preferably -20~50℃
Perform the reaction. The reaction time is 5 to 120 minutes, preferably 10 to 60 minutes, but the reaction temperature and time are not limited as long as the desired reactant is obtained. The obtained reactant is usually used as a raw material for the main reaction without being isolated. However, if necessary, unreacted raw materials, that is, compounds having a partial structure [ ], phosphorus oxyhalide, phosphorus trihalide, or phosphorus pentahalide, or a reaction mixture of hydrogen halide generated in the reaction or a salt thereof with a base. After removal, it can also be supplied as a raw material for the present invention. Note that the compound having the partial structure [ ] is commercially available, or can be produced by a known method or a method analogous thereto. In the method of the present invention, a compound [], a nucleophilic compound, and (1) a trivalent or pentavalent cyclic phosphorus compound having a partial structure [], or (2) a compound having a partial structure [] and an oxyhalogenated phosphorus compound are combined. The desired product [ ] can be produced by reacting a reaction product (sometimes simply referred to as a "reactant") with phosphorus trihalide or phosphorus pentahalide in an organic solvent. In the compound [], acidic groups such as carboxyl groups and sulfo groups contained in R and R ¹ may be used as they are, but, for example, non-toxic cations such as sodium and potassium, triethylamine, tri-n- Butylamine, di-n-butylamine, dicyclohexylamine, pyridine, collidine,
It may be used by forming a salt with an organic amine such as 2,6-lutidine. In addition, when R and R ¹ contain a basic group, salts with organic acids such as acetic acid, tartaric acid, methanesulfonic acid, etc., and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. It may also be used by forming a salt with. Nucleophilic compounds can take the form of basic salts or acidic salts depending on the type, and both basic salts and acidic salts are included in the raw materials of the present invention. As such basic salts and acidic salts, for example, basic salts and acidic salts as described in the compound [] can be used. A compound [], a nucleophilic compound, and (1) a trivalent or pentavalent cyclic phosphorus compound having a partial structure [], or (2) a compound having a partial structure [] and a phosphorus oxyhalide, phosphorus trihalide, or The organic solvents of the reactants with the phosphorus halide may be mixed in any order. When mixing the compound [], a nucleophilic compound, a cyclic phosphorus compound, and an organic solvent, the compound [] and the nucleophilic compound are usually mixed in an organic solvent, and then the cyclic phosphorus compound or its organic solvent solution is added, or It is carried out by mixing a cyclic phosphorus compound and a nucleophilic compound in an organic solvent, and then adding the compound [ ] or its solution in an organic solvent. Further, when using a reaction component of a compound having the partial structure [] and phosphorus oxyhalide, phosphorus trihalide, or phosphorus pentahalide, the reaction is carried out in the same manner as in the case of a cyclic phosphorus compound. As for the mixing ratio, the molar ratio of the nucleophilic compound to the compound [] is preferably 1.0 times or more, more preferably 1.0 to 10.0 times, and the molar ratio of the cyclic phosphorus compound is preferably 1.0 times or more, more preferably 1.0 times. ~6.0 times. When using a reactant of a compound having the partial structure [] and phosphorus oxyhalide, phosphorus trihalide, or phosphorus pentahalide, the mixing ratio is such that the molar ratio of the nucleophilic compound to the compound [] is 1.0 times or more. is good, more preferably 1.0 to 10.0 times, and the partial structure []
1.0 to 6.0 times the amount of phosphorus oxyhalide or trihalide, and 1/3 to 2.0 times the amount of phosphorus pentahalide. The organic solvent used in this reaction may be any solvent that does not participate in the reaction, such as formamide,
Amides such as dimethylformamide and dimethylacetamide, chloroethane, isobutyl chloride, methylene chloride, chloroform, 1,2-
Dichloroethane, carbon tetrachloride, 1,1,1-trichloroethane, 1,1,2-trichloroethane,
Halogenated hydrocarbons such as 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 and propionic acid, methyl acetate, ethyl acetate, isobutyl acetate,
Esters such as methyl propionate and ethylene carbonate; nitriles such as acetonitrile, propionitrile, and benzonitrile; nitro compounds such as nitromethane and nitroethane; ketones such as acetone and methyl ethyl ketone; hydrocarbons such as benzene, toluene, and mesitylene. etc., and these may be used in combination. In particular, good results are obtained when the reaction is carried out in an organic solvent such as methylene chloride, acetonitrile, formamide, a mixed solvent of formamide and acetonitrile, a mixed solution of methylene chloride and acetonitrile or tetrahydrofuran. Partial structure []
When using a reaction product of a compound having the above and phosphorus oxyhalide, phosphorus trihalide, or phosphorus pentahalide, the reaction product itself can also serve as an organic solvent. Depending on the type of raw material and organic solvent used, the reaction can be advantageously advanced by adding a base. Such a base can be added as appropriate when mixing the raw materials and the organic solvent, but is usually mixed into the organic solvent together with the compound [] or the nucleophilic compound. The amount of the base added is preferably 0 to 5 times the molar amount of the compound []. Any base may be used as long as it does not affect the reaction by accelerating the reaction, neutralizing the acid produced by the reaction, or making it easier to dissolve the raw materials, such as triethylamine, Tri-n-butylamine, di-n-butylamine, diisobutylamine, dicyclohexylamine, pyridine, 2,6-lutidine and the like are frequently used. The reaction temperature and time vary depending on the amount and type of the compound used, cyclic phosphorus compound or reactant, nucleophilic compound, organic solvent, base, etc., but the reaction completes instantaneously at a low temperature of -60℃. However, the reaction is usually completed under mild conditions at -80 to 50°C for several seconds to over ten hours. In particular, −
Preferably, the reaction is carried out at 40 to 40°C for 5 to 120 minutes.
However, in general, the reaction time can be shortened by raising the reaction temperature, but in order to suppress side reactions etc., the reaction is carried out at a low temperature. The thus obtained cephalosporin compound [] can be isolated and purified by known means such as solvent extraction, liquid conversion, dissolution transfer, salting out, crystallization, recrystallization, chromatography, etc. Depending on the type of acyl group represented by ^R1 , dimethylaniline, trimethylsilyl chloride, phosphorus pentachloride, methanol, and water may be sequentially added to the reaction mixture without isolating [] from the reaction mixture, as known in the art. It is also possible to cleave the acyl group at the 7-position by the method described above to lead to a 7-aminocephem compound (in which R ¹ represents a hydrogen atom in the compound []), which is a useful intermediate for the production of antibacterial substances. When the obtained target product [] is free, it may be converted into a salt according to a conventional method, and such salts are also included in the target product of the formula []. The salt for the purpose [] is as described for the raw material compound [], such as alkali metals such as lithium, sodium, potassium, and magnesium, alkaline earth metals such as calcium, di-n-butylamine, dicyclohexyl, etc. Amine, diisobutylamine, di-tert-butylamine, triethylamine, pyridine, 2,6-lutidine, tributylamine and other amines and acidic group salts, hydrochloric acid,
Mineral acids such as sulfuric acid, organic acids such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, sulfonic acids such as methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid,
Salts of phosphoric acids such as methyl phosphoric acid, dimethyl phosphoric acid, and diphenyl phosphoric acid, and phosphonic acids such as phenylphosphonic acid with basic groups are used. The target product obtained in this way may be used as an antibacterial substance in itself, but it is also useful as a raw material compound for producing better antibacterial substances. For example, as R ¹ 5-phthalimide
The acyl group at the 7-position of a cephalosporin compound [] having a 5-carboxybarrel group was cleaved by a method known per se, and the acyl group at the 7-position was cleaved to give (2-aminothiazol-4-yl)acetic acid and 2-(2-aminothiazol-4-yl). - 7-[2-(2-aminothiazol-4-yl)acetamide], 7-[2-(2-(2-aminothiazol-4-yl)acetamide)]
-aminothiazol-4-yl)-2-methoxyiminoacetamide], for example, the antibiotic 7-[2-(2-aminothiazole-
4-yl)acetamide]-3-[1-(2-N,N
-dimethylaminoethyl)-1H-tetrazole-
5-yl]thiomethyl-3-cephem-4-carboxylic acid, 7-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3-
(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid can also be produced. Example 1 30 ml of methylene chloride and 0.61 g of triethylamine are added to 0.70 g of 5-mercapto-1-methyl-1H-tetrazole, and 1.14 g of 0-phenylene phosphorochlorideate is added at room temperature. Add this solution to -60
After cooling to ℃, 2.12 g of the ditriethylamine salt of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-CEFM-4-carboxylic acid was added to 10 methylene chloride.
Add the solution dissolved in ml all at once. After that, 15
Raise the temperature to ℃, cool it again, add 20 ml of tetrahydrofuran (THF) and 20 ml of water, and separate the liquid.
The aqueous layer is extracted with 5 ml of THF and 10 ml of methylene chloride, and the organic layers are combined and dried over anhydrous magnesium sulfate.
Concentrate to approximately 10 ml under reduced pressure, then add 100 ml of ether.
ml and remove the precipitate. After washing with ether and vacuum drying, 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-
(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-CFM-4-carboxylic acid 1.33
g (yield 73.7%) was obtained. IR (KBr) cm ^-1 ; 3340, 2950, 1775, 1715,
1534, 1394 NMR (DMSO-d ₆ ); δ1.40-2.40 (6H, m, -
(CH ₂ ) ₃ −), 3.62 (2H, br, 2−CH ₂ ) 3.94
(3H, s, >N-CH ₃ ), 4.30 (2H, ABq, J=
15Hz, 3-CH ₂ ), 4.73 (1H, t, J = 8Hz,

[Formula]), 5.01 (1H, d, J=5Hz, 6-H), 5.62 (1H, q, J=5&8Hz, 7-H),
7.91 (4H, S,

[Formula]), 8.77 (1H, d, J = 8Hz, -CONH-) Example 2 1.04 g of 1-(2-dimethylaminoethyl)-5-mercapto-1H-tetrazole and methylene chloride
Add 60ml and 0.61g of triethylamine, and let it cool to 0 at room temperature.
- Add 1.14 g of phenylene phosphorochlorideate. After cooling this solution to −60°C,
Ditriethylamine salt of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-CFM-4-carboxylic acid
Add a solution of 2.12 g dissolved in 10 ml of methyl chloride all at once. Thereafter, the temperature was raised to 15°C, and the precipitate was collected and washed with methylene chloride. The obtained solid substance was suspended in 30 ml of methylene chloride, 0.71 g of triethylamine was added under ice cooling, and the mixture was stirred for 30 minutes, and insoluble matter was removed by filtration. 1N ethanol hydrochloric acid 10
ml and 20 ml of ether are added dropwise at below 0°C. The precipitate was collected, washed with methylene chloride, and dried in vacuum to give 7β-(D-5-carboxy-5-
phthalimidovaleramide)-3-[1-(2-dimethylaminoethyl)-1H-tetrazole-5-
1.51 g (yield: 72.4%) of hydrochloride of yl]thiomethyl]-3-FM-4-carboxylic acid was obtained. IR (KBr) cm ^-1 ; 1775, 1715, 1640 NMR (DMSO-d ₆ ); δ1.30-2.40 (6H, m, -
(CH ₂ ) ₃ −), 2.83 (6H, S,

[Formula]), 3.5-3.8 (4H, m, 2-CH ₂ &-CH ₂ N),
4.30 (2H, br, 3-CH ₂ ), 4.5-4.9 (3H, m,

[Formula]), 5.03 (1H, d, J=5Hz, C ₆ −H), 5.60 (1H, q, J=5and
8Hz, _C7 -H), 7.90(4H, s,

[Formula]), 8.77 (1H, d, 8Hz, -CONH-) Example 3 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-CFM, -4-carboxylic acid 2.12 g of ditriethylamine salt of and 5-mercapto-1-methyl-1H
-Add 30 ml of methylene chloride and 0.61 g of triethylamine to 0.52 g of tetrazole, dissolve and cool to -15°C. Add 1.67 g of methyl 0-phenylene phosphate to this solution and react at -15 to -10°C for 30 minutes. Add 20 ml of THF and 20 ml of water to the reaction solution, adjust the pH to 2 with 6N-hydrochloric acid, and separate the layers. The aqueous layer is extracted with 5 ml of THF and 10 ml of methylene chloride, and the organic layers are combined and dried over anhydrous magnesium sulfate. The following treatment was carried out in the same manner as in Example 1, and 1.64 g of the target product was obtained.
(yield 90.9%). The IR and NMR values of this product were consistent with those obtained in Example 1. Example 4 Methyl 0-phenylene phosphate in Example 3
1.71 g of 0-phenylene phosphorochlorideate instead of using 1.67 g of methylene chloride (15 ml)
Add 0.91 g of triethylamine to the solution, add 0.29 g of methanol to this at room temperature, and react for 10 minutes at room temperature. Using a solution of methyl 0-phenylene phosphate, the reaction and post-treatment were carried out in the same manner to obtain the desired product. 1.62g (yield 89.8%) was obtained. The IR value of this product matched that obtained in Example 1. Example 5 1.75 g of ditri-n-butylamine salt of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-CFM-4-carboxylic acid and 5-mercapto-1-methyl-
A solution of 0.35 g of 1H-tetrazole in 20 ml of methylene chloride is cooled to -25°C, 0.74 g of methyl 0-phenylene phosphate is added, and the mixture is reacted at -25 to -20°C for 2 hours. Add 15 ml of THA and 15 ml of water to the reaction solution, stir well, and separate the liquid. THA5ml of aqueous layer
and CH ₂ Cl ₂ (10 ml), and the organic layers were combined, washed with 20 ml of water, and dried over anhydrous magnesium sulfate.
After distilling off the solvent under reduced pressure, dissolve in a small amount of acetone and add to 100 ml of ether. The deposited precipitate was collected, washed with ether, and then dried under vacuum to obtain 1.14 g (yield: 94.7%) of the desired product. The IR value of this product matched that obtained in Example 1. Example 6 0.52 g of 1-(2-dimethylaminoethyl)-5-mercapto-1H-tetrazole and methylene chloride
Add 40ml and 0.40g of triethylamine, and add 7β
-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-CFM-4-carboxylic acid ditriethylamine salt
Add 1.14g. Add 1.12 g of methyl 0-phenylene phosphate to this solution and react at 20-25°C for 10 minutes. The reaction solution was cooled, and 5 ml of 1N ethereal hydrochloric acid was added dropwise at 0° C. or lower, and the precipitate was collected and washed with methylene chloride. The obtained solid was suspended in 20 ml of methylene chloride, and triethylamine was added under ice cooling.
Add 0.47 g, stir for 30 minutes, and remove insoluble matter by filtration. 6.7 ml of 1N alcohol-hydrochloric acid and 10 ml of ether are added dropwise to the solution at below 0°C. The deposited precipitate was collected, washed with methylene chloride, and vacuum dried to obtain 1.00 g (yield: 71.9%) of the desired product. This product
IR and NMR values were consistent with those obtained in Example 2. Example 7 0-phenylene phosphorochlorideate 0.76g
Dissolve in 10ml of methylene chloride and add triethylamine.
Add 0.40g then P-nitrophenol 0.56
Add g little by little at room temperature and react at room temperature for 10 minutes. This reaction solution was cooled to -20°C and 7β-(D-5
-carboxy-5-phthalimide valeramide)
-3-Hydroxymethyl-3-CFM-4-
1.41 g of ditriethylamine salt of carboxylic acid, 5-
Mercapto-1-methyl-1H-tetrazole
0.35g and triethylamine 0.20g methylene chloride
Add to 20 ml of solution and react at -20±2°C for 20 minutes.
The following post-processing was carried out in the same manner as in Example 3, and the target product was 0.911
g (yield 75.7%). The IR value of this product is Example 1
It was consistent with what I got. Example 8 Dissolve 0.74 g of 2,2,2-trichloro-1,3,2-benzodioxaphosphole in 10 ml of methylene chloride, add 0.30 g of triethylamine, then add 0.10 g of methanol at room temperature, and dissolve at room temperature for 10 minutes. react. This reaction solution was cooled on ice, and triethylamine was added.
0.20 g, 0.17 g of 5-mercapto-1-methyl-1H-tetrazole and the ditriethylamine salt of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-CFM-4-carboxylic acid. Add 0.71 g in sequence and react for 30 minutes under ice cooling. Thereafter, post-treatment was carried out in the same manner as in Example 3 to obtain 0.404 g (yield: 66.8%) of the same desired product.
The IR value of this product matched that obtained in Example 1. Example 9 Dissolve 0.74 g of 2,2,2-trichloro-1,3,2-benzodioxaphosphole in 10 ml of methylene chloride, add 0.4 g of triethylamine, and then add 0.51 g of p-chlorophenol little by little at room temperature. To this solution, 0.2 g of triethylamine and 0.17 g of 5-mercapto-1-methyl-1H-tetrazole were added.
g and 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-
0.71 g of ditriethylamine salt of 3-CFM-4-carboxylic acid was sequentially added and reacted at room temperature for 40 minutes. The following post-treatment was carried out in the same manner as in Example 3, and the target product was obtained.
0.436g (yield 72.0%) was obtained. The IR value of this product matched that obtained in Example 1. Example 10 1.13 g of bis(0-phenylene dioxo)chlorophosphorus was dissolved in 10 ml of methylene chloride, and 0.2 g of triethylamine, 0.17 g of 5-mercapto-1-methyl-1H-tetrazole and 0.17 g of 5-mercapto-1-methyl-1H-tetrazole were added to the solution under ice cooling.
Ditriethylamine salt of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-CFM-4-carboxylic acid
Add 0.71 g in sequence and react for 30 minutes under ice cooling. Thereafter, post-treatment was carried out in the same manner as in Example 3 to obtain 0.43 g of the target product. The IR value of this product matched that obtained in Example 1. Example 11 0.71 g of ditriethylamine salt of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-CEFM-4-carboxylic acid and 5-mercapto-1-methyl-1H-
Dissolve 0.17 g of tetrazole in 5 ml of methylene chloride. 0.2 g of triethylamine and 0.51 g of methyl 0-phenylene phosphite are added to this solution, and the mixture is reacted at room temperature for 22 hours. Thereafter, post-treatment was carried out in the same manner as in Example 3 to obtain 0.40 g (yield: 67.7%) of the same desired product.
The IR and NMR values of this product were consistent with those obtained in Example 1. Example 12 874 mg of ditri-n-butylamine salt of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid and 2-mercaptobenzothiazole
A solution of 251 mg of methylene chloride in 10 ml was cooled to -10°C, 400 mg of ethyl 0-phenylene phosphate was added thereto, and the mixture was stirred at -10 to -5°C for 2 hours. to the reaction solution
Add 8 ml of THF and 8 ml of water, stir, and separate the liquids. The aqueous layer was extracted with 3 ml of THF and 5 ml of methylene chloride, the organic layers were combined, 10 ml of water was added to separate the layers, and anhydrous magnesium sulfate was added to the organic layer for drying. The solvent was distilled off under reduced pressure, dissolved in a small amount of a mixed solvent of acetonitrile, water, and formic acid (20:2:0.1), and subjected to silica gel column chromatography. The compartments containing the target product were collected, concentrated under reduced pressure, and the resulting powder was obtained by adding ether to the residual oil, washing with ether and drying to obtain 7β-(D-5-carboxy-5-phthalimidovaleramide)-3- [(benzothiazol-2-yl)thiomethyl]-3-cephem-
555 mg (yield 85.0%) of 4-carboxylic acid was obtained. IR (KBr): cm ^-1 3320, 1775, 1715 NMR (DMSO-d ₆ ); δ1.30-2.40 (6H, m, -
CH ₂ CH ₂ CH ₂ −), 3.62 (2H, ABq, J=18Hz,
2-CH ₂ ), 4.38 (2H, ABq, J=14Hz, 3-
_CH2 ), 4.73 (1H, t, J=7Hz, CH-),
5.04 (1H, d, J = 5Hz, C ₆ −H), 5.63 (1H,
q, J=5&8Hz, C ₇ −H) 7.86 (4H, s,

[Formula]), 8.80 (1H, d, J=8Hz, -CONH-) Example 13 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carvone 874 mg of ditri-n-butylamine salt of acid and 5-mercapto-2-methyl-1,
3,4-thiadiazole 198 mg methylene chloride 1
ml of the solution was cooled to -20 to -15°C, 372 mg of methyl 0-phenylene phosphate was added, and the mixture was stirred for 1.5 hours under ice cooling. The reaction solution was treated in the same manner as in Example 12,
7β-(D-5-carboxy-5-phthalimidovaleramide)-3-[(2-methyl-1,3,4-
Thiadiazol-5-yl)thiomethyl]-3-
Cefem-4-carboxylic acid 502 mg (yield 81.3%)
I got it. IR (KBr): cm ^-1 3300, 1775, 1715 NMR (DMSO-d ₆ ): δ1.30-2.40 (6H, m, -
CH ₂ CH ₂ CH ₂ −), 2.71 (3H, s, −CH ₃ ), 3.62
(2H, ABq, J=19Hz, 2-CH ₂ ), 4.37 (2H,
ABq, J=13Hz, 3-CH ₂ ), 4.76 (1H, t,
J=7Hz, CH-), 5.06 (1H, d, J=5
Hz, _C6 -H), 5.65 (1H, q, J=5&8Hz,
C ₇ −H), 7.92 (4H, s,

[Formula]), 8.81 (1H, d, J=8Hz, CONH) Example 14 0-phenylene phosphorochlorideate 477 mg
A 5 ml solution of methylene chloride was cooled to -20 to -10°C, and 463 mg of tri-n-butylamine and phenol were added.
Add 235 mg and stir at the same temperature for 5 minutes to remove phenyl 0.
- A solution of phenylene phosphate was prepared.
7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditri-n-butylamine salt 874 mg, 2-carboxymethylthio-5-mercapto-1,3 , 312 mg of 4-thiadiazole was stirred in 5 ml of methylene chloride, and 278 mg of tri-n-butylamine was added under ice cooling, and the mixture was heated to -10 to -5°C.
The mixture was cooled to 100 mL, and the above solution of phenyl 0-phenylene phosphate was added thereto, followed by stirring at the same temperature for 2 hours. The reaction solution was treated according to Example 12 to give 7β-(D-5-carboxy-5-phthalimidovalerylamide)-
3-[(2-carboxymethylthio-1,3,4-
Thiadiazol-5-yl)thiomethyl]-3-
Cefem-4-carboxylic acid 501 mg (yield 72.2%)
I got it. IR (KBr): cm ^-1 3300, 1775, 1713 NMR (DMSO-d ₆ ): δ1.30-2.40 (6H, m, -
CH ₂ CH ₂ CH ₂ −), 3.59 (2H, br, 2−CH ₂ ),
4.13 (2H, s, -SCH ₂ COO-), 4.33 (2H,
ABq, J = 13Hz, 3-CH ₂ ), 4.72 (1H, t,
J = 6Hz, CH), 5.04 (1H, d, J = 5Hz,
_C6 -H), 5.40-5.80 (1H, br, C7 _- H), 7.90
(4H, s,

[Formula]), 8.78 (1H, d, J = 8Hz, -CONH-) Example 15 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carvone 874 mg of acid ditri-n-butylamine salt and 312 mg of 1-carboxymethyl-5-mercapto-1H-tetrazole were mixed, 10 ml of methylene chloride was added, the mixture was cooled on ice, and 278 mg of tri-n-butylamine was added. After stirring for 10 minutes, add 372 mg of methyl 0-phenylene phosphate to −25 to −
It was added at 20℃ and stirred at the same temperature for 2 hours. The reaction solution was treated in the same manner as in Example 12 to obtain 7β-(D-5-carboxy-5-phthalimidovaleramide)-3.
-[(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-
476 mg (yield 73.7%) of carboxylic acid was obtained. IR (KBr): cm ^-1 3300, 1775, 1713 NMR (DMSO-d ₆ ): δ1.40-2.40 (6H, m, -
CH ₂ CH ₂ CH ₂ −), 3.62 (2H, br, 2−CH ₂ ),
4.33 (2H, ABq, J=14Hz, 3-CH ₂ ), 4.71
(1H, t, J=6Hz, CH), 4.99 (1H, d,
J=5Hz, C ₆ −H), 5.28(2H, s,
NCH ₂ CO−), 5.62 (1H, q, J=5&8Hz,
C ₇ −H), 7.89 (4H, s,

[Formula]), 8.77 (1H, d, J=8Hz, -CONH-) Example 16 In Example 12, 2-ethoxycarbonylmethylthio-5-mercapto-1,3,4 was used instead of 2-mercabutobenzothiazole. -thiadiazole
The same procedure was carried out using 354 mg of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-
[(2-ethoxycarbonylmethylthio-1,3,
4-thiadiazol-5-yl)thiomethyl]-
3-cephem-4-carboxylic acid 600 mg (yield 83.2
%) was obtained. IR (KBr): cm ^-1 3320, 1775, 1715 NMR (DMSO-d ₆ ): δ1.00-2.40 (9H, m, -
CH ₃ & −CH ₂ CH ₂ CH ₂ −), 2.9 to 4.5 (8H, m,
2- _CH2 , 3- _CH2 , -S- _CH2CO- ,
CO ₂ CH ₂ ), 4.75 (1H, t, J=6Hz, CH),
5.06 (1H, d, J=5Hz, _C6 -H), 5.40-5.90
(1H, br, C ₇ −H), 7.90 (4H, s,

[Formula]), 8.60-9.10 (1H, br, -CONH -) Example 17 7β-[D-5-carboxy-5-(benzamide)valeramide]-3-hydroxymethyl-3
- Dissolve 874 mg of ditri-n-butylamine salt of cefem-4-carboxylic acid in 10 ml of methylene chloride, -
At 50 to -40°C, add 198 mg of pyridine followed by 372 mg of methyl 0-phenylene phosphate and 3 ml of methylene chloride.
After adding the solution, raise the temperature to -10 to 0℃ and incubate at the same temperature for 2 hours.
I stirred the time. Add 15ml of water to the reaction solution and adjust the pH to 7.0.
The aqueous layer was washed twice with 5 ml of methylene chloride, the pH was adjusted to 6.0 again, and the residue was concentrated under reduced pressure. The residue was subjected to Amberlite XAD-2 column chromatography and mixed with water and water-methanol. The compartments containing the target product were sequentially eluted and concentrated, and N-[7β-{D-5
410 mg (yield 73.1%) of monosodium salt of -(benzamide)adipinamide}-3-cephem-3-ylmethyl]pyridinio-4-carboxylic acid was obtained. IR (KBr): cm ^-1 3360, 3250, 1765, 1645, 1630,
1605 NMR ( _D2O ): δ1.50-2.60 (6H, m, -( _CH2 ) ₃
-), 3.14 (2H, ABq, J=19Hz, 2-CH ₂ ),
4.36 (1H, m, CH), 5.05 (1H, d, J=5
Hz, _C6 -H), 5.32 (2H, ABq, J=15Hz, 3
_-CH2 ), 5.60 (1H, d, J=5Hz, _C7 -H),
7.0~9.0 (10H, m,

[Formula]) Example 18 0-phenylene phosphorochlorideate 286 mg
5-mercapto-1- in 3 ml of methylene chloride solution of
Add 174 mg of methyl-1H-tetrazole and -20~-
The mixture was cooled to 10° C. and a solution of 152 mg of triethylamine in 1 ml of methylene chloride was added with stirring. After returning this solution to room temperature, 7-[D-5-carboxy-5-(benzyloxycarbonylamino)valeramide]-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt 710
mg of methylene chloride was added to a 7 ml solution of methylene chloride while cooling and stirring at -30 to -20°C. Stir at the same temperature for 5 minutes, then add 2N-HCl 15ml tetrahydrofuran 10
The organic layer was washed twice with 5 ml of saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then added to ether to collect the resulting powder. This powder was dissolved in a mixture of acetonitrile and water, subjected to silica gel chromatography, and eluted with acetonitrile-water-formic acid (20:2:0.1).
The compartment containing the target product was concentrated, ether was added, and the resulting powder was dried to yield 7β-[D-5-carboxy-5-(benzyloxycarbonylamino)valeramide]-3-[(1-methyl-1H-tetrazole). -5-yl)thiomethyl-3-cephem-4
-370 mg (yield 61.1%) of carboxylic acid was obtained. IR (KBr) cm ^-1 : 3300, 1775, 1715 NMR (DMSO- _d6 ): δ1.30-1.90 (4H, m, _CH2
×2), 2.00 to 2.30 (2H, m, CH ₂ ), 3.67 (2H,
br, 2-CH ₂ ), 3.93 (3H, s, N-CH ₃ ),
4.30 (2H, br, 3- _CH2 ), 4.80~5.20 (4H, m,
−CH ₂ O−,

[Formula]), 5.63 (1H, q, J=5&8Hz, C ₇ -H), 7.10~7.60 (m,
6H,

[Formula]), 8.78 (1H, d, J=8Hz, -CONH-) Example 19 In Example 5, 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cepheme -4-carboxylic acid ditri-n
-7β-[D-5- instead of 1.75 g of butylamine salt
(pt-butylbenzamide)-5-carboxyvalerylamide]-3-hydroxymethyl-3-
The same procedure was carried out using 1.81 g of ditri-n-butylamine salt of cefem-4-carboxylic acid, and 7-[D-
5-(pt-butylbenzamide)-5-carboxyvalerylamide]-3-(1-methyl-1H-
1.18 g (yield 93.4%) of thiomethyl-3-cephem-4-carboxylic acid (tetrazol-5-yl) was obtained. IR (KBr) cm ^-1 : 1776, 1727, 1640 NMR ( _d6 -DMSO): δ1.28 (9H, s, _CH3 × 3),
1.70 & 2.21 (6H, CH ₂ × 3), 3.54 & 3.77 (2H,
ABq, J = 18Hz, 2-CH ₂ ), 3.91 (3H, s, -
N- _CH3 ), 4.20 & 4.37 (2H, ABq, J=13
Hz, 3- _CH2 ), 4,39 (1H,-CH), 5.20
(1H, d, J=5Hz, C ₆ −H), 5.64 (1H, q,
J=5&8Hz, _C7 -H), 7.43&7.81(4H,

[Formula]), 8.42 (1H, d, J = 8Hz,

[Formula]), 8.79 (1H, d, J=8Hz, -CONH-) Example 20 0-phenylene phosphorochlorideate 0.450
Dissolve 0.437 g of tri-n-butylamine in 1 ml of methylene chloride at 0-5℃.
After adding the solution, a solution of 76.0 mg of methanol in 2 ml of methylene chloride was added and stirred at room temperature for 20 minutes to prepare a solution of methyl 0-phenylene phosphate.
1.032 g of ditri-n-butylamine salt of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid and 0.267 g of 2-mercaptobenzoxazole in 5 ml of methylene chloride. -20 to -25
Cool to ℃, add the above methyl 0-phenylene phosphate solution while stirring, and cool at -20 to -10℃.
React for 80 minutes, add 15 ml of water to the reaction solution and separate the liquid.
15 ml of water was added to the organic layer, and the pH was adjusted to 9.0 with N-NaOH and the layers were separated. The organic layer was further extracted twice with 5 ml of water, the combined aqueous layers were washed with 5 ml of methylene chloride, and the aqueous layer was diluted with 2N-
The organic layer was adjusted to pH 2 with HCl and extracted with a mixture of methylene chloride and THF (1:1). The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and ether was added to remove the resulting powder. , when dry
7β-(D-5-carboxy-5-phthalimidovaleramide)-3-(benzoxazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid
588 mg (yield 78.2%) was obtained. IR (KBr) cm ^-1 : 3310, 2930, 1775, 1715,
1530, 1500 NMR (d ₆ -DMSO: δ1.30-2.40 (6H, m, -
CH ₂ CH ₂ CH ₂ −), 3.68 (2H, ABq, 2−
CH ₂ ), 4.23 & 4.66 (2H, ABq, J = 14Hz, 3-
CH ₂ ), 4.73 (1H, t, J = 7Hz,

[Formula]), 5.04 (1H, d, J=5Hz, C ₆ −H) 5.63 (1H,
q, J=5&8Hz, C7 _- H), 7.20-7.77 (4H,
m,

[Formula]), 7.87 (4Hz, s,

[Formula]), 8.78 (1H, d, J=8Hz, -CONH-) Example 21 0-phenylene phosphorochlorideate 376 mg
A solution of 57.0 mg of methanol and 365 mg of tri-n-butylamine in 6 ml of methylene chloride.
The solution was added with stirring at -20-10°C, and then returned to room temperature and stirred for 1 hour to prepare a solution of methyl 0-phenylene phosphate. 7β-(D-5-carboxy-5-phthalimidovaleramide)-3
-Dissolve 874 mg of ditri-n-butylamine salt of hydroxymethyl-3-cephem-4-carboxylic acid in 5 ml of methylene chloride, add a solution of 158 mg of pyridine in 2 ml of methylene chloride at 5 to 0°C, and then -40 to
The above methyl 0-
Add phenylene phosphate solution, -30 to -10
The precipitated powder was stirred for 45 minutes at 0-10℃ for 30 minutes, washed with methylene chloride, and dried.
-(D-5-carboxy-5-phthalimidovaleramide)-3-cephem-3-pyridiniomethyl-4-carboxylate 456 mg (yield 82.4%)
was gotten. IR (KBr) cm ^-1 : 3375, 3020, 2920, 1772,
1710, 1390 NMR (D ₂ O + NaOD: δ1.30-2.60 (6H, m, -
CH ₂ CH ₂ CH ₂ −), 2,90 & 3,55 (2H, ABq,
J = 18Hz, 2-CH ₂ ), 5.10 (1H, d, J = 5
Hz, _C6 -H), 5.32 & 5.66 (2H, ABq, J=17
Hz, 3- _CH2 ), 5.63 (1H, d, J=5Hz, _C7 -H), 7.78 (4H,
s,

[Formula]), 8.03~9.06 (5H, m,

[Formula]) Example 22 646 mg of 2,6-lutidine was added to a solution of 528 mg of 0-phenylene phosphorochloridite in 3 ml of methylene chloride.
A solution of 96.8 mg of methanol and 7 ml of methylene chloride was added under ice cooling while stirring, and reacted for 5 minutes.
A solution of methyl 0-phenylene phosphite was prepared. Add 376 mg of isonicotinamide to this solution, stir for 10 minutes, and then add 2,6-lutidine of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid. After adding 923 mg of salt and reacting under ice cooling for 2 hours and stirring at room temperature for 5 hours, -20 ~
It was kept at −10°C overnight. Add 15 ml of water to the reaction solution and
After adjusting the pH to 7.0 with NaOH and washing the aqueous layer with methylene chloride, the pH was adjusted to 6.0 and concentrated under reduced pressure, and the concentrated solution was subjected to column chromatography using Amberlite XAD-2. It eluted. When the compartments that mainly contain the target substance are collected, concentrated, and freeze-dried,
560 mg (yield 63.1%) of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-cephem-3-(4-carbamoylpyridinio)methyl-4-carboxylate sodium salt was obtained. IR (KBr) cm ^-1 : 3350, 1773, 1708, 1613, 1463 NMR (D ₂ O): δ1.30-2.60 (6H, m, -
CH ₂ CH ₂ CH ₂ −), 2.90 & 3.55 (2H, ABq, J=
18Hz, 2-CH ₂ ), 5.10 (1H, d, J = 5Hz,
C ₆ −H), 5.34 & 5.68 (2H, ABq, J=14Hz,
3- _CH2 ), 5.60 (1H, d, J=5Hz, _C7-
H), 7.79 (4H, s,

[Formula]), 8.41 & 9.14 (4H, dd,

[Formula] Example 23 0-phenylene phosphorochlorideate 0.469
A solution of 5 ml of methylene chloride of 0.3 g was cooled to -50 to -40°C, and a solution of 0.455 g of tri-n-butylamine and 78.8 mg of methanol in 5 ml of methylene chloride was added with stirring, and the temperature was returned to room temperature and reacted for 20 minutes to form methyl 0-phenylene. A solution of phosphate was prepared. 7β−
(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditri-n-butylamine salt
Add 0.339 g of tri-n-butylamine to a suspension of 1.066 g of 4,6-dimethyl-2-mercaptopyrimidine hydrochloride and 0.322 g of 4,6-dimethyl-2-mercaptopyrimidine hydrochloride in 5 ml of methylene chloride, dissolve the solution, and cool to -30 to -35°C while stirring. After adding a solution of methyl 0-phenylene phosphate, the temperature was returned to 0 to 5°C and the mixture was reacted for 1 hour. Add 15 ml of water to the reaction solution, separate the layers, and add 15 ml of water to the organic layer.
The pH was adjusted to 6.0 and the layers were separated again, 20 ml of water was added to the organic layer, the pH was adjusted to 9.0 with N-NaOH and the layers were separated, and the aqueous layer was washed twice with 5 ml of methylene chloride. Add 45 ml of methylene chloride-tetrahydrofuran (1:1) to the aqueous layer, and
The organic layer was washed with saturated brine, dried over magnesium sulfate, the solvent was distilled off, ether was added to the residue, the resulting powder was taken and dried, and 7β-(D-5- Carboxy-5-phthalimidovaleramide)-3-(4,6-dimethylpyrimidin-2-yl)thiomethyl-3-cephem-
0.630 g (yield 82.5%) of 4-carboxylic acid was obtained. IR (KBr) cm ^-1 : 3290, 2930, 2560, 1773,
1710, 1580, 1530 NMR ( _d6 -DMSO): δ1.30-2.40 (6H, m, -
CH ₂ CH ₂ CH ₂ −), 2.35 (6H, s, CH ₃ ×2),
3.55 (2H, 2-CH ₂ ), 3.93 & 4.36 (2H, ABq,
J = 14Hz, 2-CH ₂ ), 4.78 (1H, t, J = 7
Hz,

[Formula]), 4.99 (1H, d, J=5Hz, C ₆ −H), 5.56 (1H, d, J=5×8Hz, C ₇ −
H), 6.93 (1H, s,

[Formula]), 7.87 (4H, s,

[Formula]), 8.22 (1H, d, J=8Hz, - CONH-) Example 24 (1) Dissolve 0.195 g of 5-mercapto-1-methyl-1H-tetrazole in 5 ml of methylene chloride, -
Cool to 10°C, add a solution of 0.268 g of 0-phenylene phosphorochlorideate in 5 ml of methylene chloride,
Cool to -20~-25℃ and diphenylmethyl 7β-(5
-diphenylmethyloxycarbonyl-5-phthalimidovalerylamide)-3-hydroxymethyl-3-cephem-4-carboxylate
A solution of 1.170 g of methylene chloride in 8 ml was added dropwise and stirred at the same temperature for 20 minutes to react. 10ml of water to the reaction solution
was added, the temperature was returned to room temperature, the layers were separated, the organic layer was washed with water, dried over Glauber's salt, concentrated, and added to 80 ml of ether to collect the resulting powder. This product was subjected to silica gel chromatography and ethyl acetate:n-hexane (4:
Elute with the mixed solvent of 1), collect the sections containing the target product, concentrate, and add ether to obtain diphenylmethyl 7β-(5-diphenylmethyloxycarbonyl-5-phthalimidovalerylamide)-3-
(1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylate was obtained. IR (KBr) cm ^-1 : 3350, 3030, 2930, 1780,
1717 NMR ( _d6 -DMSO): δ1.30-2.40 (6H, m, -
CH ₂ CH ₂ CH ₂ −), 3.68 (2H, broad s, 2
−CH ₂ ), 3.88 (3H, s,

[Formula]), 4.24 (2H, broad s, 3-CH ₂ ), 4.90-5.20
(2H, m,

[Formula]), 5.73 (1H, q, J = 5 & 8Hz), 6.83 & 6.90 (2H, s, -
COOCH x 2), 7.10-7.60 (20H, m,

[Formula]), 7.91 (4H, s,

[Formula]), 8.87 (1H, d, J=8Hz, -CONH-) (2) 5-mercapto-1-methyl-1H-tetrazole 0.182g, tri-n-butylamine 0.485
Dissolve g in 5 ml of methylene chloride, cool to -10℃,
0-phenylene phosphorochlorideate 0.250
Add 5 ml of methylene chloride solution of -20 to -25℃
Cool and diphenylmethyl-7β-(5-diphenylmethyloxycarbonyl-5-phthalimidovalerylamide)-3-hydroxymethyl-
Adding 1.09 g of 3-cephem-4-carboxylate and reacting and post-treating in the same manner as in (1) yields (1) and IR,
A target product with the same NMR value was obtained. Example 25 (1) 7β-(2-thienyl acetamide)-3-hydroxymethyl-3-cephem-4-carboxylic acid tri-n-butylamine salt 0.540 g, 5-mercapto-1-methyl-1H-tetrazole 0.175
Add g to 10 ml of ethyl acetate and add -20 g while stirring.
The mixture was cooled to 0.degree. C. and a solution of 0.370 g of methyl 0-phenylene phosphorideate in 5 ml of ethyl acetate was added.
After stirring and reacting for 1.5 hours under ice-cooling, add water 10
ml, separate the liquids, add 20ml of water to the organic layer, and make the pH 9.0.
The layers were separated and the aqueous layer was washed with 5 ml of ethyl acetate. Add 20ml of ethyl acetate to the aqueous layer to adjust the pH to 2.0, separate the layers, wash the organic layer with saturated brine, dry with Glauber's salt, distill off the ethyl acetate under reduced pressure, add ether, and remove the resulting powder.7β-( 2-Thienylacetamide)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-
0.380 g (yield 84.1%) of 4-carboxylic acid was obtained. The IR and NMR of this product matched the standard. (2) Using 0.477 g of 7β-phenylacetamide-3-hydroxymethyl-3-cephem-4-carboxylic acid di-n-butylamine salt in (1),
After the reaction treatment according to (1) above, 7-phenylacetamide-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-
0.361 g (yield 80.9%) of 4-carboxylic acid was obtained. The IR and NMR of this product matched the standard. Example 26 To 180 mg of 5-mercapto-1-methyl-1H-tetrazole was added a solution of 271 mg of 0-phenylene phosphorochloridite in 4 ml of methylene chloride, then a solution of 157 mg of triethylamine in 3 ml of methylene chloride was added, and the mixture was cooled to -5°C. While stirring, add 7β-(D-5
-carboxy-5-phthalimide valeramide)
732 mg of ditriethylamine salt of -3-hydroxymethyl-3-cephem-4-carboxylic acid was added and stirred at the same temperature for 5 minutes to react. 10% water to reaction solution
ml, add 7 ml of tetrahydrofuran, adjust the pH to 2.0, separate the layers, add 20 ml of water to the organic layer to adjust the pH to 7.0, distill off methylene chloride and tetrahydrofuran under reduced pressure, add 10 ml of fresh methylene chloride, and add N-NaOH to remove the methylene chloride and tetrahydrofuran. PH
After separating the layers and washing the aqueous layer with 10 ml of methylene chloride, methylene chloride-tetrahydrofuran (1:
1) Added 20ml. Adjust the pH to 2.0 with 2N-HCl, separate the layers, wash the organic layer with saturated saline, dry it with sodium chloride, concentrate, add ether to the residue, take the resulting powder, and dry it to obtain 7β-(D-5-carboxy-5 410 mg (yield: 65.7%) of -phthalimidovaleramide)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid was obtained. The IR and NMR spectra of this product matched those obtained in Example 1. Example 27 (1) 0-phenylene phosphorochlorideate 762
mg (4mM) in 10ml methylene chloride solution.
741 mg (4 mM) of n-butylamine was added, and then a solution of 128 mg (4 mM) methanol in 5 ml of methylene chloride was added dropwise to prepare a solution of methyl 0-phenylene phosphate. 7β-(D-5-carboxy-5-phthalimidovaleramide)-3
-Hydroxymethyl-3-cephem-4-carboxylic acid ditri-n-butylamine 874 mg and 5-
Mercapto-1-methyl-1H-tetrazole
174 mg was dissolved in 5 ml of methylene chloride and added dropwise to the above solution at -15 to -10°C. After stirring and reacting at the same temperature for 40 minutes, methylene chloride was distilled off under reduced pressure, and the residue was dissolved in water:acetonitrile (3:
2V/V). 7β in this solution
The amount of -(D-5-carboxy-5-phthalimidovaleramide)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid was determined by high performance liquid chromatography. 537mg (yield)
89.3%). (2) to (18) In the reaction of (1), instead of 128 mg of methanol,
A solution in which 0-phenylene phosphorochlorideate was esterified according to (1) using 4 mM of various hydroxy compounds described in (1) was prepared, and using this solution, ( Reaction and quantification were performed according to method 1). Reaction time and 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-(1-methyl-1H-
Table 1 shows the results obtained regarding the yield of tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.

【table】

[Table] Example 28 0-phenylene phosphorochlorideate 762 mg
To a 12 ml solution of methylene chloride was added 741 mg of tri-n-butylamine at -10 to 0°C, then 236 mg of n-propylamine was added at room temperature, and the mixture was reacted for 10 minutes at the same temperature to form 2-oxo-2-propylamino- 1, 3,
A solution of 2-benzodioxaphosphole was prepared. Add 7β-(D-5-carboxy-5-
Phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditri-
874 mg of n-butylamine salt and 5-mercapto-1
- A solution of 174 mg of methyl-1H-tetrazole in 5 ml of methylene chloride was added dropwise at -15 to -10°C and reacted at the same temperature for 150 minutes. Then, the methylene chloride was distilled off under reduced pressure. When treated and quantified in the same manner as 27(1), 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-(1-
Content of methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
The amount was 454 mg (yield 75.5%). Example 29 (1) 110 ml of methylene chloride and 15.2 g of triethylamine were added to 5.5 g of pyrocatechol and dissolved. Phosphorus oxychloride with stirring at 10-20℃
7.29 g was dropped over about 10 minutes. The reaction solution was filtered under a nitrogen stream and washed with a small amount of methylene chloride to obtain 124 ml of an almost clear solution. (2) 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3
-849 mg of ditriethylamine salt of cefem-4-carboxylic acid and 5-mercapto-1-methyl-
A solution of 168 mg of 1H-tetrazole in 6 ml of methylene chloride was stirred, and while cooling to -10 to 0°C, 9.4 ml of the solution obtained in step (1) was added dropwise to the solution, reacted at the same temperature for 2 hours, and then kept at 0 to 5°C overnight. . 2N under ice cooling
Add 10 ml of HCl to adjust the pH to 2, add 18 ml of a mixture of tetrahydrofuran and water (1:1, V/V) to remove insoluble matter, and wash with 2 ml of the same mixture. Separate the washing liquid, wash the organic layer with 10 ml of water, extract the aqueous layer with 2 ml of methylene chloride, combine with the organic layer, dry over anhydrous magnesium sulfate, concentrate to about 5 ml, and add 70 ml of ether.
ml and the precipitated powder was washed with ether and dried to give 7β-(D-5-carboxy-5-
514 mg (yield
71.0%) was obtained. The NMR and IR values of this product matched those of the standard product. Example 30 Ditriethylamine salt of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid
Dissolve 849 mg and 194 mg of 2-mercaptobenzothiazole in 6 ml of methylene chloride, and add -10 while stirring.
9.4 ml of the solution obtained in Example 29(1) was added dropwise at ~0°C, reacted at the same temperature for 40 minutes, and then kept at 0-5°C overnight. After the reaction is treated in the same manner as in Example 29(2),
467 mg (yield 59.6%) of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-[(benzothiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid was obtained. The IR and NMR values of this product matched those obtained in Example 12. Example 31 (1) 44 ml of methylene chloride and 6.06 g of triethylamine were added to and dissolved in 36.4 g of 3,4-dihydroxybenzoic acid ethyl ester, and 2.92 g of phosphorus oxychloride was added dropwise at 10 to 20°C over about 10 minutes. The reaction solution was filtered under a nitrogen stream, and the residue was dissolved in methylene chloride.
It was washed with 20ml. The total amount of liquid and washing liquid is 62
ml of solution was obtained. (2) Add and dissolve 17.6 ml of the solution obtained in (1) to 168 mg of 5-mercapto-1-methyl-1H-tetrazole, and dissolve 7β-(D
Ditriethylamine salt of -5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid 849
mg was added and reacted at the same temperature for 2 hours. water in reaction solution
10 ml and methylene chloride were added, the pH was adjusted to 2, the layers were separated, and the organic layer was washed with 5 ml of water. 20 ml of water was added to the organic layer, the pH was adjusted to 8.5 with N-NaOH water, and the layers were separated. The organic layer was washed with 10 ml of water, and the aqueous layers were combined and washed twice with 5 ml of methylene chloride. Methylene chloride in the aqueous layer
Add 15ml and 15ml of tetrahydrofuran and add 4N−
Adjust the pH to 2 with HCl, separate the layers, and separate the aqueous layer with a mixture of methylene chloride and tetrahydrofuran (1:1, V/
V) Wash with 10ml, combine the organic layer and add 10ml of saturated saline.
ml twice, dried over magnesium sulfate, and the solvent was distilled off. Add ether to the residue, take the resulting powder, wash it with ether and dry it to obtain 7β-
(D-5-carboxy-5-phthalimidovaleramide)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-
510 mg (70.5%) of 4-carboxylic acid were obtained.
The IR value of this product matched that of the standard product. Example 32 (1) 44 ml of methylene chloride and 6.06 g of triethylamine were added and dissolved in 3.27 g of 2,3-dihydroxynaphthalene, and 2.92 g of phosphorus oxychloride was added dropwise while stirring and cooling to 10 to 20°C. The reaction solution was filtered under a nitrogen stream, and the residue was diluted with methylene chloride 20
ml and the washing liquid was combined to obtain 56 ml of solution. (2) Add and dissolve 15.9 ml of the solution obtained in (1) to 168 mg of 5-mercapto-1-methyl-1H-tetrazole, stir and cool to 0 to 5°C to dissolve 7β-
(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt
849mg was added and reacted at the same temperature for 2 hours and at room temperature for 5 hours, then kept at 0-5℃ overnight and treated in the same manner as in Example 31(2) to give 7β-(D-5-carboxy-5-
Phthalimidovaleramide)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid was obtained.
The NMR value of this product matched that of the standard product. Example 33 (1) Add 44 ml of methylene chloride and 6.06 g of triethylamine to 2.20 g of pyrocatechol, dissolve it, add 2.61 g of phosphorus trichloride dropwise under ice cooling, process in the same manner as in Example 32 (1), and dissolve 52 ml of pyrocatechol. A solution was obtained. (2) Using 14.8ml of the solution obtained in (1), Example 32(2)
After reacting for 30 minutes according to
433 mg (60.0%) of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid was obtained. . The IR and NMR values of this product matched those of the standard product. Example 34 (1) Dissolve 2.20 g of pyrocatechol in 44 ml of methylene chloride and 10.1 g of triethylamine, add 3.96 g of phosphorus pentachloride little by little while stirring under ice cooling,
It was treated in the same manner as in Example 32(1) to obtain 48 ml of solution. (2) Using 13.7 ml of the solution obtained in (1), Example 31
The reaction and post-treatment were carried out in the same manner as in (2), and 7β-(D-5
-carboxy-5-phthalimidovaleramide)-3-(1-methyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid was obtained. The IR value of this product matched that of the standard product. Example 35 (1) Dissolve 2.20 g of pyrocatechol in 40 ml of methylene chloride and 7.76 g of diiso-butylamine, dropwise add 2.92 g of phosphorus oxychloride over 10 minutes under ice cooling, and stir for 10 minutes at room temperature.
ml was obtained. (2) Using 14.2 ml of the reaction solution of (1), the reaction was carried out under ice cooling for 50 minutes and then at room temperature for 2.5 hours according to Example 31 (2). When the reaction solution is post-treated in the same manner as in Example 31(2),
471 mg (65.2%) of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid was obtained. . The NMR value of this product matched that of the standard product. Example 36 (1) 2.20 g of pyrocatechol was dissolved in 40 ml of methylene chloride and 6.06 g of triethylamine, and 2.61 g of phosphorus trichloride was added dropwise under ice cooling, followed by washing with 4 ml of methylene chloride. Stir for 10 minutes at room temperature and then return to 5°C.
When cooled to
The temperature rose to ℃. After stirring at room temperature for 10 minutes, the reaction solution was filtered under a stream of nitrogen gas, the residue was washed with methylene chloride, and the washings were combined to obtain 55 ml of a solution. (2) Add and dissolve 15.6 ml of the solution obtained in (1) to 168 mg of 5-mercapto-1-methyl-1H-tetrazole, and dissolve 7β-(D-5-carboxy-
Add 849 mg of ditriethylamine salt of (5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid, stir at the same temperature for 1.5 hours, and react at room temperature for 2.0 hours.
It was kept overnight at ℃. After further reacting at room temperature for 6 hours, the reaction solution was post-treated in the same manner as in Example 31(2) to obtain 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-(1-methyl-1H- 482 mg (66.8%) of tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid were obtained. The IR value of this product matched that of the standard product. Example 37 450 mg of 5-mercapto-1-methyl-1H-tetrazole and 437 mg of ditributylamine salt of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid Dissolve in 10ml of methylene chloride -
2,2-dihydro- while cooling to 25~-20℃
4,5-dimethyl-2,2,2-trimethoxy-
0.5 ml of 1,3,2-dioxaphosphole was added dropwise over about 5 minutes. After stirring at the same temperature for 5 minutes, add 15 ml of water to separate the layers, wash the aqueous layer with 5 ml of methylene chloride, combine the organic layers, add 15 ml of water, adjust the pH to 8.5 with N-NaOH water, separate the layers, and add the aqueous layer to methylene chloride. I washed it with 5ml. 10 ml of tetrahydrofuran and 15 ml of methylene chloride in the aqueous layer.
The organic layer was washed with 5 ml of water and 5 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Add a small amount of acetone to the residue, dissolve it, add ether, take the resulting powder, wash with ether and dry to obtain 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-(1-methyl-1H -tetrazol-5-yl)thiomethyl-3-cephem-
215 mg (71.5%) of 4-carboxylic acid were obtained. The IR and NMR values of this product matched those of the standard product. Example 38 (1) A solution of 1.476 g of 0-chloranil in 10 ml of methylene chloride was added to a solution of 1.86 g of triphenyl phosphite in 12 ml of methylene chloride at room temperature, and 2,2-dihydro-4,5,6,7-tetrachloro- 2,
23 ml of a methylene chloride solution of 2,2-triphenoxy-1,3,2-benzodioxaphosphole was obtained. (2) In Example 37, 2,2-dihydro-4,
5-dimethyl-2,2,2-trimethoxy-
7β-(D-5-carboxy-5-phthalimide valeramide)-3
220 mg (73.1%) of -(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid was obtained. IR of this product,
The NMR value was consistent with the standard. Example 39 Suspend 0.173 g of 1-(2-dimethylaminoethyl)-5-mercapto-1H-tetrazole in 15 ml of acetonitrile, add and dissolve 0.152 g of triethylamine, and dissolve 7β-(D-5-carboxy-5-phthalimide barrel). ditri-n of amido)-3-hydroxymethyl-3-cephem-4-carboxylic acid
-Add 0.874g of butylamine salt and dissolve at -25℃
Cool to methyl 0-phenylene phosphate
0.744g methylene chloride 5ml solution at -25~-20℃
It was dripped. The reaction was allowed to proceed at the same temperature for 20 minutes with stirring, then 50 ml of water was added to the reaction solution, concentrated under reduced pressure, and the resulting residue was mixed with a mixture of water and acetonitrile (3:
2, V/V) to exactly 50 ml, and the target product 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-[1-(2-dimethylaminoethyl)-1H -tetrazol-5-yl]
The content of [thiomethyl]-3-cephem-4-carboxylic acid was determined by high performance liquid chromatography.
It contained 0.593g (yield 90.0%). Take 45.0ml of the above 50ml diluted solution and add N-HCl4.0
ml was added, concentrated, and lyophilized to obtain a candy-like solid. This solid was dissolved in ethanol, ether was added, and the resulting powder was washed with ether and dried to obtain 0.54 g of the hydrochloride of the above-mentioned target product. The NMR value of this product matched that obtained in Example 2. Example 40 1.75 g of ditri-n-butylamine salt of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid and 0.293 g of isonicotinamide were dissolved in formamide. 4 ml and 6 ml of acetonitrile, and cooled to -20°C. While stirring -20~-
Methyl 0-phenylene phosphate 0.74g at 15℃
A 2 ml solution of methylene chloride was added dropwise thereto, and the mixture was allowed to react at the same temperature for 30 minutes. The reaction solution was heated to 10°C, 50 ml of acetonitrile and 50 ml of ether were added, and the precipitated powder was collected, washed with acetonitrile, and dried to obtain 7β.
-(D-5-carboxy-5-phthalimidovaleramide)-3-cephem-3-(4-carbomoylpyridinium)methyl-4-carboxylate
1.04 g (yield 85.5%) was obtained. NMR ( _D2O + _K2CO3 ): Same value as that obtained in Example ₂₂ . Example 41 In Example 5, 2-phenyl-1,3,2 was used instead of 0.74 g of methyl 0-phenylene phosphate.
-Benzodioxaphosphole-2-oxide 0.93
After reacting for 10 minutes using 4 ml of methylene chloride solution of
g (yield 93.1%). IR and NMR of this product
The values were consistent with those obtained in Example 1. Example 42 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid dipotassium salt pentahydrate
Dissolve 0.670g in 5ml of water, add 5ml of tetrahydrofuran, and then adjust the pH to 2.5 with 4N-NCl at 5°C or below.
Then, 10 ml of methylene chloride was added to separate the layers. Add 2.5 ml of tetrahydrofuran and 5 ml of methylene chloride to the aqueous layer.
The organic layers were combined, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and again diluted with tetrahydrofuran 10
ml and 50 ml of methylene chloride were added and concentrated. The residue was dissolved in 10 ml of tetrahydrofuran, 0.174 g of 5-mercapto-1-methyl-1H-tetrazole was added, and a solution of 0.744 g of methyl 0-phenylene phosphate dissolved in 4 ml of tetrahydrofuran was added at -15 to -10°C. . After stirring at the same temperature for 50 minutes, the residue was concentrated under reduced pressure, dissolved in a small amount of tetrahydrofuran, added to 100 ml of ether, and the precipitated powder was washed with ether and dried.
5-carboxy-5-phthalimidovaleramide)-3-(1-methyl-1H-tetrazole-5
0.560 g (93.1%) of thiomethyl-3-cephem-4-carboxylic acid was obtained. This product
The NMR and IR spectra were consistent with those obtained in Example 1. Example 43 In Example 5, 2-oxo-4,5-dimethyl-2,2-dihydro-2-methoxy-1, instead of 0.74 g of methyl 0-phenylene phosphate
Example 5 After reacting for 30 minutes using a solution of 0.65 g of 3,2-dioxaphosphole in 4 ml of methylene chloride.
After treatment in the same manner as above, 0.95 g (79.0%) of the target product was obtained. The IR and NMR values of this product matched those obtained in Example 1. Example 44 (1) Add 24 ml of water to 8.78 g of deacetylcephalosporin C sodium (purity 90.1%) and dissolve it.
Add 8 ml of tetrahydrofuran (THF).
40% potassium carbonate aqueous solution and phenyl chlorocarbonate 3.76
Alternately add 1.5 g of the solution dropwise at a pH of 9.5 to 10.0 and a temperature of 15 to 20°C.
After dropping, stir for 10 minutes, add 40ml of THF, and add agricultural hydrochloric acid dropwise while cooling to 3-5°C, pH 2.5.
Then, 65 ml of methylene chloride was added to separate the layers, and the aqueous layer was further extracted with a mixture of 17 ml of THF and 34 ml of methylene chloride. The organic layers were combined and dried over anhydrous magnesium sulfate, 8.16 g of tri-n-butylamine was added, and the mixture was dried under reduced pressure. Methylene chloride was added to the residue and the mixture was dried again. When the residue is dissolved in methylene chloride and dropped into ether, the precipitated powder is removed.
16.2 g of ditri-n-butylamine salt of 7β-[D-5-carboxy-5-phenoxycarbonylaminovaleramide]-3-hydroxymethyl-3-cephem-4-carboxylic acid was obtained. IR (KBr) cm ^-1 ; 3250, 2930, 1760, 1735,
1660, 1600 NMR ( _d6 -DMSO); δ0.7~2.4 and 2.6~3.1
(m, (CH ₃ CH ₂ CH ₂ CH ₂ ) ₃ N&-(CH ₂ ) ₃ CO
-), 3.45 (br, 2-CH ₂ ), 3.95 (m,

[Formula]), 4.15 (br, 3-CH ₂ ), 4.94 (d, J=5Hz, C ₆ -H), 5.52 (q, J=5×8
Hz, _C7 -H), 6.9-7.6 (m,

[Formula]), 7.7-8.9 (m, -O-CONH -, C-CONH, -COOH) (2) 7β-[D-5-carboxy-5-phenoxycarbonylaminovaleramide]-3-hydroxy Dissolve 8.64 g of ditri-n-butylamine salt of methyl-3-cephem-4-carboxylic acid in 100 ml of methylene chloride, add and dissolve 1.74 g of 5-mercapto-1-methyl-1H-tetrazole, and heat to -20 to -25°C. While cooling, a solution of 3.72 g of methyl O-phenylene phosphate in 10 ml of methylene chloride was added dropwise over 5 minutes, followed by stirring at 0 to -5°C for 60 minutes. Add 80 ml of cold water to the reaction solution, and
Adjust the pH to 8.5 with NaOH water, separate the layers, wash the aqueous layer twice with 20 ml of methylene chloride, add 50 ml of THF and 50 ml of methylene chloride to the aqueous layer, add agricultural hydrochloric acid dropwise to adjust the pH to 1.5, separate the layers, remove the organic layer, and remove the aqueous layer. The mixture was further extracted with a mixture of 15 ml of THF and 15 ml of methylene chloride, the organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was concentrated to a small amount. The residual liquid was dropped into 300 ml of ether, and the precipitated powder was washed with ether and dried in vacuum to give 7β-(D-5-carboxy-5
-Phenoxycarbonylaminovaleramide)
-3-(1-methyl-1H-tetrazole-5-
5.41 g (yield 91.4%) of thiomethyl-3-cephem-4-carboxylic acid (yield: 91.4%) was obtained. IR (KBr) cm ^-1 ; 3270, 3020, 2920, 1780,
1725, 1530 NMR ( _d6 -DMSO); δ1.4-2.4 (6H, m, -
(CH ₂ ) ₃ −), 3.69 (2H, br, 2−CH ₂ ), 3.94
(3H, s, N-CH ₃ ), 4.30 (2H, br, 3-
_CH2 ), 5.05 (1H, d, J=5Hz, _C6 -H),
5.65 (1H, q, J = 5 x 8Hz, C ₇ -H), 6.9
~7.6 (5H, m,

[Formula]), 8.03 (1H, d, J=8Hz, -OCONH-), 8.83 (1H,
d, J = 8 Hz, -CONH-) Example 45 (1) Add 25 ml of water to 10.95 g of deacetylcephalosporin C sodium (purity 90.1%) to dissolve it, and add 7 ml of acetonitrile. While cooling to 15-20°C, 40% potassium carbonate aqueous solution and 3.38 g of ethyl chlorocarbonate are alternately added dropwise at pH 9.5-10 and stirred to react. The reaction solution was concentrated under reduced pressure to remove acetonitrile, cooled to 0 to 5°C, and pHed with concentrated hydrochloric acid.
2.5, remove the precipitate, wash with cold water, then add 200 ml of water.
ml of triethylamine while stirring.
ml of 7β-(D-5-carboxy-5-ethoxycarbonylaminovaleramide)-3-hydroxymethyl-3. -Cefem-4-carboxylic acid ditriethylamine salt 15.2g was obtained. IR (KBr) cm ^-1 ; 3550~3150, 2930, 2840,
2670, 2480, 1762, 1710-1660, 1600, 1535 NMR ( _D2O ); δ1.41 (3H, t, J=7Hz, -
CH ₃ ), 1.26 (18H, t, J = 7Hz, CH ₃ ×
6), 1.5 to 1.9 (4H, m, -CH ₂ CH ₂ -), 2.2
~2.5 (2H, m, _-CH2CO- ), 3.19 (12H,
q, J=7Hz, CH ₂ ×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 ),
5.08 (1H, d, J=5Hz, _C6 -H), 5.59
(1H, d, J = 5Hz, C ₇ -H) (2) 7β-(D-5-carboxy-5-ethoxycarbonylaminovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine 1.30 g of salt, 15 ml of methylene chloride, 5 ml of acetonitrile, 0.35 g of 5-mercapto-1-methyl-1H-tetrazole and tri-
0.2 ml of n-butylamine was added and dissolved. The solution was cooled to -15 to -10°C, and while stirring, a solution of 0.74 g of methyl O-phenylene phosphate in 2 ml of methylene chloride was added dropwise over 5 minutes.
Stir for 30 minutes at 5°C. Concentrate the reaction solution under reduced pressure, add 20 ml of methylene chloride and 15 ml of water to the residue, cool it to 0-5°C, adjust the pH to 9.0 with N-NaOH water, separate the layers, take the aqueous layer, and wash the organic layer with 3 ml of water. The aqueous layers were combined and washed with 5 ml of methylene chloride. To the aqueous layer were added 10 ml of tetrahydrofuran and 20 ml of methylene chloride, cooled to 0 to 5°C, adjusted to pH 2 with 2N-HCl water, and separated. Take the organic layer, add 5 ml of tetrahydrofuran and 10 ml of methylene chloride to the aqueous layer, separate the layers, combine the organic layers, dry over anhydrous magnesium sulfate, concentrate, add ether, take the resulting powder, and dry it to obtain 7β-(D- 5-carboxy-5-ethoxycarbonylaminovaleramide)-3-(1-
Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid 0.97g
(yield 89.2%). IR (KBr) cm ^-1 ; 3350, 2950, 1775, 1710,
1530 NMR ( _d6 -DMSO); δ1.18 (3H, t, J=7
Hz, _-CH3 ), 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- _CH2 ), 5.06 (1H, d, J=5Hz, _C6-
H), 5.66 (1H, q, J=5×8Hz, C ₇ −
H), 7.25 (1H, d, J=8Hz, -OCONH
-), 8.79 (1H, d, J = 8 Hz, -CONH-) Example 46 (1) 7β-(D-5-carboxy-5-phthalimidovaleramide)-3- in 20 ml of methylene chloride
Hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt 3.53g and 5-mercapto-1-methyl-1H-tetrazole 0.87g
melted. Add this solution to −25℃−−20℃ under stirring.
While cooling, a solution of 1.50 g of ethyl O-phenylene phosphate in 3.8 ml of methylene chloride was added dropwise, and the mixture was stirred at -5°C to 0°C for 1 hour. Add 50 ml of water, 20 ml of tetrahydrofuran (THF), and 20 ml of methylene chloride to this reaction mixture, and add 4N
-Adjust the pH to 2 with hydrochloric acid. After separation, the aqueous layer was extracted with a mixture of 20 ml of methylene chloride and 20 ml of THF.
The organic layer and extract were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 20 ml of acetone and added dropwise to 300 ml of ether. The resulting precipitate was collected, washed with ether, and dried under vacuum to obtain 7β-(D
-5-carboxy-5-phthalimidovaleramide)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-
2.86 g (yield 95.1%) of carboxylic acid was obtained.
The IR and NMR spectra of this product matched those obtained in Example 1. (2) In (1) above, add the methylene chloride solution of ethyl O-phenylene phosphate dropwise at 23-27°C, stir the mixture at about 39°C for 5 minutes, cool it to 0°C, and then add (1) above. ), white powder 2.72
g (yield 90.4%) was obtained. The IR spectrum of this product matched that obtained in (1) above. Example 47 (1) 1.10 g of pyrogallol and 1.30 g of methylphosphorodichlorideate were mixed, and 8 ml of methylene chloride was added. Add this mixture to −35℃−−30℃ under stirring.
1.86 g of triethylamine was added dropwise while cooling to 4-hydroxy-2-methoxy-2-oxo-1,3,2- by stirring at 0-5°C for 2 hours.
A reaction mixture containing benzodioxaphosphole was obtained. (2) 3.53 g of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt and 5-mercapto-1-methyl- in 20 ml of methylene chloride. 0.87 g of 1H-tetrazole was dissolved. Add this solution to −25°C to −20°C while stirring.
While cooling, the entire amount of the reaction mixture obtained in (1) was added, and the reaction mixture adhering to the reactor was washed with 6 ml of methylene chloride and added. This suspension was stirred at -5-0°C for 1 hour and the reaction mixture was treated as in Example 46-(1), resulting in 7β-(D-5-
carboxy-5-phthalimide valeramide)
-3-(1-methyl-1H-tetrazole-5-
2.76 g (yield: 91.8%) of yl)thiomethyl-3-cephem-4-carboxylic acid was obtained. The product was identified by IR spectrum. (3) 5-ethoxycarbonyl-2-methoxy-2-oxo-1,3, obtained by the same method as (1) using 1.59 g of 3,4-dihydroxybenzoic acid ethyl ester instead of pyrogallol. 2-
Proceeding in the same manner as (2) using a reaction mixture of benzoshioxaphosphole yields the same product as (2) 2.85
g (yield 94.7%) was obtained. The identification of this product is IR
I did it with a spectrum. (4) 2-Methoxy-5-methyl-2-oxo-1,3,2-benzo obtained by carrying out the same method as (1) using 1.09 g of 3,4-dihydroxytoluene instead of pyrogallol. Using the reaction mixture of dioxaphosphole, the same method as (2) was carried out to obtain 2.83 g of product (yield 94.1%). The IR spectrum of this product matched that obtained in (2). Example 48 87 mg of 5-mercapto-1-methyl-1H-tetrazole and 7β-[2-(2-ami)thiazole-
4-yl)-2-(syn)-methoxyiminoacetamide]-3-hydroxymethyl-3-cephem-
216 mg of 4-carboxylic acid sodium salt was mixed, 1 ml of formamide and 1 ml of acetonitrile were added, and the mixture was stirred to dissolve. A solution of 280 mg of methyl O-phenylene phosphate in 0.75 ml of methylene chloride was added to this solution while stirring and cooling with an ice bath, and the mixture was stirred for 0.5 hour while cooling with an ice bath. 1 ml of cold water was added and the reaction solution was concentrated under reduced pressure. Add 2 ml of water to the residue and adjust the pH to N-
Adjusted to 2.5 with HCl. Remove the formed precipitate and rinse with cold water.
When washed with 0.5ml and vacuum dried, 7β-[2-(2-ami)
thiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid 210 mg (yield 82.6 %)was gotten. NMR (DMSO-d ₆ ) δ; 3.67 (2H, br, 2-
CH ₂ ), 3.83, 3.93 (6H, 2 s, N-CH ₃ ,
O- _CH3 ), 4.27 (2H, br, 3- _CH2 ), 5.09
(1H, d, J = 5Hz, C ₆ −H), 5.76 (1H, q,
J=5&8Hz, C7 _- H), 6.73(1H, s,

[Formula]), 9.55 (1H, d, J=8Hz, CONH) Example 49 230 mg of 7β-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid, 5-mercapto-1-methyl-1H-tetrazole To a mixture of 174 mg of triethylamine, 4 ml of formamide, and 1 ml of acetonitrile was added 253 mg of triethylamine while stirring and cooling in an ice bath. A solution of 650 mg of methyl O-phenylene phosphate in 2 ml of methylene chloride and 5 ml of acetonitrile were added to the resulting solution with stirring and cooling to -10°C to 0°C, followed by stirring at 0-5°C for 0.5 hour. Collect the resulting precipitate and wash with 5 ml of acetonitrile.
It was suspended in a mixture of 6 ml of water and 2 ml of acetonitrile. Approximately 0.1 ml of 35% hydrochloric acid was added to the suspension to dissolve it. Adjust the pH to 4 with 25% ammonia water under ice-cooling, remove the formed crystals, wash with 2 ml of cold water, and dry under vacuum.
7β-Amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-
280 mg (yield 85.3%) of carboxylic acid was obtained. IR (KBr) cm ^-1 ; 1790, 1615, 1535, 1410 NMR (D ₂ O + CF ₃ COOD) δ; 3.71 (2H, s, 2
-CH ₂ ), 3.96 (3H, s, N-CH ₃ ), 4.22 (2H,
s, 3- _CH2 ), 5.06 (1H, d, J=5Hz, _C6
-H), 5.17 (1H, d, J=5Hz, _C7 -H) Example 50 7β-(D-5-carboxy-5-benzamidovaleramide)-3-hydroxymethyl-3-cephem-4-carvone 0.954 g of acid and 0.244 g of 1-methylpyrrole were mixed, and 2 ml of formamide and 4 ml of acetonitrile were added. Add methyl O- to this solution.
A solution of 0.744 g of phenylene phosphate in 2 ml of methylene chloride was added with stirring and cooling to -5-0°C, and the mixture was stirred at -5-0°C for 0.5 hour. 24 ml of methylene chloride, 12 ml of THF, and 20 ml of water were added to the reaction mixture, and the pH was adjusted to 2 with 4N hydrochloric acid. The layers were separated, and the aqueous layer was extracted with 15 ml of methylene chloride-THF (2:1). The organic layer and extract were combined and treated according to the method of Example 46-(1) to give 7β-(D-5-carboxy-5-benzamidovaleramide)-3-(1-methylpyrrol-2-yl)methyl- 0.944 g (yield 87.3%) of 3-cephem-4-carboxylic acid was obtained. IR (KBr) cm ^-1 ; 1770, 1725, 1645, 1530 NMR (D ₂ O + NaHCO ₃ ) δ; 1.5-2.7 (6H, m,
−(CH ₂ ) ₃ −), 2.80, 3.16 (2H, ABq, J=18
Hz, 2- _CH2 ), 3.44, 3.90 (2H, ABq, J=14
Hz, 3-CH ₂ ), 3.46 (3H, s, N-CH ₃ ),
4.42 (1H, m, CH-), 4.96 (1H, d, J=
5Hz, C ₆ −H), 5.53 (1H, d, J = 5Hz, C ₇
-H), 5.8-6.2, 6.6-6.8 (3H, m,

[Formula]), 7.2−8.0 (5H, m,

[Formula]) Example 51 (1) 2-methyl-5-oxo-3-thioxo-
0.416 ml of triethylamine was added to a mixture of 0.430 g of 2,3,4,5-tetrahydro-as-triazine, 4 ml of formamide, and 4 ml of acetonitrile. 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-
1.16 g of hydroxymethyl-3-cephem-4-carboxylic acid dipotassium salt was added. A solution of 1.12 g of methyl O-phenylene phosphate in 3 ml of methylene chloride was added to the mixture while stirring and cooling to -20 to -15°C, followed by stirring at 0 to 5°C for 0.5 hour. Concentrate the reaction mixture under reduced pressure and add cold water to the residual liquid.
Added 80ml. The resulting precipitate was washed with 10 ml of cold water and dried under vacuum to give 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-
(2,5-dihydro-2-methyl-5-oxo-as-triazin-3-yl)thiomethyl-3
-Cefem-4-carboxylic acid 1.14g (yield 90.7
%)was gotten. IR (KBr) cm ⁻¹ ; 1775, 1715, 1645 NMR (D ₂ O + NaOD) δ; 1.3−2.6 (6H, m, −
(CH ₂ ) ₃ −), 3.04, 3.60 (2H, ABq, J=18
Hz, 2-CH ₂ ), 3.86 (3H, s, N-CH ₃ ),
4.02, 4.39 (2H, ABq, J=13Hz, 3-
_CH2 ), 4.99 (1H, d, J=5Hz, _C6 -H),
5.55 (1H, d, J=5Hz, C7 _- H), 7.75
(1H, s, triazine-H), 7.80 (4H, s,

[Formula]) (2) 2-thiouracil 0.384 instead of triazine
When carried out in the same manner as (1) using g, 7β-(D-
1.10 g (yield: 89.6%) of 5-carboxy-5-phthalimidovaleramide)-3-(4-hydroxypyrimidin-2-yl)thiomethyl-3-cephem-4-carboxylic acid was obtained. IR (KBr) cm ⁻¹ ; 1770, 1710, 1530 NMR (D ₂ O + NaOD) δ; 1.3−2.6 (6H, m, −
(CH ₂ ) ₃ −), 3.02, 3.50 (2H, ABq, J=18
Hz, 2−CH ₂ ), 3.97, 4.33 (2H, ABq, J=
13Hz, 3-CH ₂ ), 5.01 (1H, d, J = 5Hz,
C ₆ −H), 5.54 (1H, d, J=5Hz, C ₇ −
H), 6.23, 7.84 (2H, dd, J=7Hz,

[Formula]), 7.82 (4H, s,

[Formula]) Example 52 0.195g of 2-mercaptobenzimidazole and
Mix 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid and add 2 ml of formamide.
and 2 ml of acetonitrile were added. A solution of 0.558 g of methyl O-phenylene phosphate in 1.5 ml of methylene chloride was added to the obtained solution under stirring at -10°C to -5°C.
The mixture was added to the mixture while cooling and stirred at 0-5°C for 1 hour. The reaction mixture was treated in the same manner as in Example 51-(1) to yield 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-(benzimidazol-2-yl)thiomethyl-3-cepheme-4. −
0.560 g (yield 88.1%) of carboxylic acid was obtained. IR (KBr) cm ^-1 ; 1785, 1770, 1710, 1640, 1390 NMR (D ₂ O-NaHCO ₃ ) δ; 1.3-2.6 (6H, m,
−(CH ₂ ) ₃ −), 2.96, 3.23 (2H, ABq, J−18
Hz, 2- _CH2 ), 3.84, 4.40 (2H, ABq, J=13
Hz, 3- _CH2 ), 4.57 (1H, m, CH-), 4.92
(1H, d, J=5Hz, C ₆ −H), 5.52 (1H, d,
J=5Hz, _C7 -H), 6.9-7.8(8H, m,

【formula】

[Formula]) Example 53 (1) 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3
-Cefem-4-carboxylic acid ditriethylamine salt 1.637g and 2-mercaptobenzoic acid 0.53g
were mixed, and 14 ml of methylene chloride and 7 ml of THF were added. Methyl 0-phenylene phosphate was added to the resulting solution while stirring and cooling to -20--15°C.
A solution of 0.863 g of methylene chloride in 2.3 ml was added and then stirred at 0-5°C for 0.5 hour. When the reaction mixture is treated in the same manner as in Example 46-(1), 7β-(D
-5-carboxy-5-phthalimidovaleramide)-3-(2-carboxyphenyl)thiomethyl-3-cephem-4-carboxylic acid 1.36 g
(yield 91.7%) was obtained. IR (KBr) cm ^-1 ; 1770, 1710, 1535, 1465,
1390 NMR (DMSO-d ₆ ) δ; 1.2-2.4 (6H, m, -
(CH ₂ ) ₃ −), 3.55 (2H, br, 2−CH ₂ ), 4.06
(2H, br, 3-CH ₂ ), 4.75 (1H, t, J=7
Hz, CH-), 5.06 (1H, d, J=5Hz, C ₆
−H), 5.61 (1H, q, J=5&8Hz, C ₇ −
H), 7.0−7.7 (4H, m,

[Formula]), 7.89 (4H, m,

[Formula]), 8.79 (1H, d, J = 8 Hz, CONH) (2) Using 0.443 g of 2-mercaptopyridine N-oxide in place of 2-mercaptobenzoic acid.
The reaction was carried out in the same manner as in (1). The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 50 ml of water-acetonitrile (1:1). The acetonitrile was distilled off under reduced pressure and the resulting precipitate was collected, washed with 10 ml of cold water and dried in vacuum to give 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-(N-oxidepyridin-2-yl). Thiomethyl-3-cephem-4
-1.31 g (yield 92.3%) of carboxylic acid was obtained. IR (KBr) cm ^-1 ; 1775, 1715, 1530, 1470,
1390 NMR (D ₂ O + NaOD) δ; 1.3−2.6 (6H, m, −
(CH ₂ ) ₃ −), 2.99, 3.53 (2H, ABq, J=18
Hz, 2-CH ₂ ), 3.90, 4.25 (2H, ABq, J=
14Hz, 3-CH ₂ ), 4.95 (1H, d, J = 5Hz,
C ₆ −H), 5.53 (1H, d, J=5Hz, C ₇ −
H), 7.1−8.5 (8H, m,

【formula】

[Formula]) Example 54 1-carboxymethyl-5-mercapto-1H
-Tetrazole 0.288g and triethylamine 0.363g
Add 6 ml of methylene chloride to g. 7β in this solution
-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-CFM-4-carboxylic acid ditriethylamine salt
Add 0.847g. Add −20% to this solution while stirring.
A solution of 0.450 g of methyl 0-phenylene phosphate in 1.2 ml of methylene chloride is added at ~-15°C.
This solution was stirred at -5 to 0°C for 1 hour, and the resulting reaction solution was treated in the same manner as in Example 46-(1).
7β-(D-5-carboxy-5-phthalimidovaleramide)-3-(1-carboxymethyl-1H
-tetrazol-5-yl)thiomethyl-3-CFM-4-carboxylic acid 0.711g (yield 91.8%)
was gotten. IR (KBr) cm ^-1 ; 1770, 1710, 1530 NMR (DMSO-d ₆ ) δ; 1.3-2.4 (6H, m, -
(CH ₂ ) ₃ −), 3.62 (2H, br, 2−CH ₂ ), 4.17 &
4.47 (2H, ABq, J=14Hz, 3-CH ₂ ), 4.71
(1H, t, J=6Hz, CH-), 4.99 (1H,
d, J=5Hz, _C6 -H), 5.28(2H, s,
NCH ₂ CO), 5.62 (1H, q, J=5&8Hz, C7
-H), 7.89 (4H, s,

[Formula]), 8.77 (1H, d, J=8Hz, CONH) Example 55 (1) 7β-(D-5-carboxy-5-phthalide valeramide)-3-hydroxymethyl-3-
Add 0.975 g of ditriethylamine salt of cefem-4-carboxylic acid and 0.172 g of ethanethiol to 10 ml of methylene chloride while stirring at -20 to -15°C.
Methyl 0-phenylene phosphite 0.514
A solution of 1.39 ml of methylene chloride is added dropwise thereto, and the mixture is stirred at 0-5° C. for 1 hour. 20% water to reaction solution
ml and 20 ml of THF, then adjust the pH to 2 with 35% hydrochloric acid. Add 30 ml of methylene chloride to this mixture and separate the liquid. The aqueous layer is extracted with 15 ml of methylene chloride-THF mixture (2:1, v/v).
Combine the organic layers, wash twice with 10 ml of water, then add 10 ml of water.
Add ml. Adjust the pH of the mixture to 7 with 1N NaOH, separate the layers, and extract the organic layer with 5 ml of water.
Combine the aqueous layers and concentrate under reduced pressure. The concentrated solution was subjected to Amberlite XAD-2 column chromatography (100-200 Metssie XAD-2: 70 ml,
Column height: 40 cm) and eluted with water and a water-acetone mixture (20:1, v/v). Each section was analyzed by TLC (developing solvent; acetonitrile: water: 99
% formic acid = 40:2:0.1), and the target substance (Rf:
The sections containing approximately 0.16) are combined, concentrated under reduced pressure, and then lyophilized to yield 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-ethylthiomethyl-3-CEFM-4-carboxylic acid. 0.515 g (yield 63.0%) of disodium salt was obtained. IR (KBr) cm ^-1 : 1760, 1710, 1610, 1390 NMR (D ₂ O) δ; 1.18 (3H, t, CH ₃ ), 1.4 ~
2.7 (8H, m, -( _CH2 ) _3- , _-CH2 - _CH3 ),
2.93 & 3.55 (2H, ABq, J=18Hz, 2-
CH ₂ ), 3.23 & 3.81 (2H, ABq, J=14Hz, 3
−CH ₂ ), 4.98 (1H, d, J=5Hz, C ₆ −
H), 5.48 (1H, d, J=5Hz, _C7 -H),
7.88 (4H, s,

[Formula]) (2) 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3
-Cefem-4-carboxylic acid dipotassium salt
Add 2 ml of formamide and 2 ml of acetonitrile to 0.580 g and 0.165 g of thiophenol. A solution of 0.558 g of methyl 0-phenylene phosphate in 1.5 ml of methylene chloride was added to the resulting solution with stirring at -30 to -20°C, and then heated to 45°C at 0 to 5°C.
Stir for a minute. Concentrate the reaction solution under reduced pressure, and add 40 ml of cold water to the concentrated solution. Take the resulting powder, wash with 10 ml of cold water, and then dissolve in 20 ml of 50% aqueous acetonitrile. pH of solution
After adjusting to 7 with 1N NaOH, acetonitrile was distilled off under reduced pressure. The concentrated solution was subjected to XAD-2 column chromatography using 1N NaOH in the same manner as in (1) (target product Rf: approximately 0.36), and 7β-(D
-5-carboxy-5-phthalimidovaleramide)-3-phenylthio-3-cephem-4
-carboxylic acid disodium salt 0.397g (yield
62.1%). IR (KBr) cm ^-1 : 1765, 1710, 1605, 1390 NMR (DMSO−d ₆ + D ₂ O) δ; 1.2 to 2.5 (6H,
m, −(CH ₂ ) ₃ −), 3.11 & 3.49 (2H, ABq, J
=18Hz, 2-CH ₂ ), 4.36 (1H, m, >CH
−), 4.81 (1H, d, J=5Hz, C ₆ −H),
5.42 (1H, d, J=5Hz, C7 _- H), 7.34
(5H, br,

[Formula], 7.84 (4H, s,

[Formula]) Example 56 Ditriethylamine salt of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid
Dissolve 3.53 g and 0.76 g of triethylamine in 25 ml of methylene chloride. Add this solution to -45~ while stirring.
Methyl 0-phenylene phosphate at -40℃
A solution of 2.79 g of methylene chloride in 7.5 ml is added dropwise and stirred at the same temperature for 30 minutes. Add 50% ether to this reaction solution.
ml and stir for 20 minutes at 20-25°C. The resulting powder is taken, washed with ether, and dried under vacuum. The resulting powder was mixed with 10 ml of water and 20 ml of acetonitrile.
ml of the mixed solution, adjust the pH to 7.0 with 1N NaOH, and then distill off the acetonitrile under reduced pressure. The concentrated solution was subjected to Amberlite XAD-2 column chromatography (100 to 200 meshes of XAD-2: 150
ml, column height: 45 cm) and eluted with water. The eluate was subjected to TLC (developing solvent; acetonitrile:
Water: 99% formic acid = 80:15:2), and the sections containing the target substance (Rf: approximately 0.12) were collected. The resulting solution was concentrated, adjusted to pH 6.0 with 1N NaOH, and then lyophilized to give 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-cephem-3-
2.76 g (yield 90.7%) of triethylammoniomethyl-4-carboxylic acid disodium salt was obtained. IR (KBr) cm ^-1 ; 3450, 1775, 1710, 1612, 1465 NMR (D ₂ O) δ; 1.34 (9H, t, J = 7Hz, (-
CH ₃ ) × 3), 1.30 to 2.60 (6H, m, -(CH ₂ ) ₃
-), 2.9 to 4.3 (10H, m, 2- _CH2 , 3- _CH2 ,
N ( CH ₂ CH ₃ ) ₃ ), 5.13 (1H, d, J = 5Hz, C ₆
-H), 5.61 (1H, d, J=5Hz, C ₇ -H),
7.88 (4H, S,

[Formula]) Example 57 Ditriethylamine salt of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid
3.53g and 1-(2-dimethylaminoethyl)-1H
- Dissolve 1.33 g of tetrazole in 25 ml of methylene chloride. A solution of 2.79 g of methyl 0-phenylene phosphate in 7.5 ml of methylene chloride is added dropwise to this solution while stirring at -45 to -40°C, and the mixture is stirred at the same temperature for 30 minutes. The reaction solution is then stirred at 20-25°C for 20 minutes. The resulting powder is taken, washed with methylene chloride, and dried under vacuum. When the obtained powder is treated in the same manner as in Example 56 (target Rf: approximately 0.17), 7β-
(D-5-carboxy-5-phthalimidovaleramide)-3-cephem-3-[dimethyl[2-
2.67 g (yield 82.3%) of (1,2,3,4-tetrazol-1-yl]ethylammonio]methyl-4-carboxylic acid disodium salt was obtained. IR (KBr) cm ^-1 ; 3450 , 1770, 1710, 1613, 1390 NMR (D ₂ O) δ; 1.30-2.60 (6H, m, -(CH ₂ ) ₃
-), 3.00~4.30 (10H, m,

[Formula] 2-CH ₂ -NCH ₂ ), 4.90-5.40 (3H, m, -
NCH ₂ , C ₆ −H), 5.53 (1H, d, J=5Hz,
C ₇ −H), 7.82 (4H, s,

[Formula]), 9.37 (1H,s,

[Formula]) Example 58 Dipotassium salt monohydrate of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid
Dissolve 1.20 g and 312 mg of 4-cyanopyridine in 4 ml of formamide and 8 ml of acetonitrile. A solution of 1.12 g of methyl 0-phenylene phosphate in 3 ml of methylene chloride is added dropwise to this solution at 0 to 5° C. while stirring, and the mixture is stirred at the same temperature for 30 minutes. In this solution
After adding 3.5 ml of 1N NaOH, methylene chloride and acetonitrile are distilled off under reduced pressure. The concentrated solution was subjected to silica gel column chromatography (50 g of silica gel was mixed with acetonitrile-water-99% formic acid (80:15:
Fill the column with the mixture of 2). Column height:
38cm) and acetonitrile-water (2.5:1)
It was eluted with a mixture of The eluate was examined by TLC (developing solution; acetonitrile: water: 99% formic acid = 80:15:2), and a section containing the target product (Rf: approximately 0.22) was collected.
The resulting solution was concentrated, adjusted to pH 6.0 with 1N NaOH, and lyophilized to give 7β-(D-5-carboxy-
1.08 g (yield: 88.3%) of disodium salt of 5-phthalimidovaleramide)-3-cephem-3-(4-cyanopyridinio)methyl-4-carboxylic acid was obtained. IR (KBr) cm ^-1 ; 3420, 1770, 1710, 1613, 1395 NMR (D ₂ O) δ; 1.40-2.70 (6H, m, -(CH ₂ ) ₃
−), 3.04 & 3.68 (2H, ABq, J=18Hz, 2−
_CH2 ), 5.13 (1H, d, J=5Hz, _C6 -H),
5.44 & 5.70 (2H, ABq, J=15Hz, 3-CH ₂ ),
5.63 (1H, d, J=5Hz, C ₇ −H), 7.82 (4H,
s,

[Formula]), 8.57 & 9.36 (4H, dd,

[Formula]) Example 59 Dipotassium salt monohydrate of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid
Dissolve 1.20 g and 411 mg of methyl nicotinate in 4 ml of formamide and 8 ml of acetonitrile. A solution of 1.49 g of methyl 0-phenylene phosphate in 4 ml of methylene chloride is added dropwise to this solution while stirring at -10 to -5°C, and the mixture is reacted at the same temperature for 30 minutes. This reaction solution was post-treated in the same manner as in Example 58 (Rf of target product: approximately 0.23) and 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-cephem-3-(3-
1.18 g (yield 91.5%) of methoxycarbonylpyridinio)methyl-4-carboxylic acid disodium salt was obtained. IR (KBr) cm ^-1 ; 3445, 1770, 1708, 1613, 1395 NMR (D ₂ O) δ; 1.30-2.60 (6H, m, -(CH ₂ ) ₃
−), 2.95 & 3.62 (2H, ABq, J=18Hz, 2−
CH ₂ ), 4.10 (3H, s, -CH ₃ ), 5.12 (1H, d,
J = 5Hz, C ₆ −H), 5.36 & 5.72 (2H, ABq,
J = 15Hz, 3-CH ₂ ), 5.62 (1H, d, J = 5
Hz, _C7 -H), 7.79 (4H, s,

【formula】, 8.0~9.8 (4H, m,

[Formula]) Example 60 Ditriethylamine salt of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid
7.06g and 3-dimethylaminopropionitrile
1.47g was dissolved in 50ml of methylene chloride. Add methyl 0- to this solution while stirring and cooling to -45 to -40℃.
Phenylene phosphate 3.72g methylene chloride 10
ml solution was added dropwise and stirred at the same temperature for 30 minutes. This mixture was then warmed and stirred at 20-25°C for 20 minutes. The resulting powdery precipitate was collected and washed with methylene chloride.
This powder was dissolved in a mixture of 12 ml of water and 24 ml of acetonitrile and adjusted to pH 3.4 with 4N hydrochloric acid. This solution was poured into 310 ml of acetonitrile with stirring and cooled to about 5°C. The solvent was decanted and 90 ml of acetonitrile was added to the remaining viscous oil under stirring. The resulting powdery precipitate was washed with acetonitrile and dried under vacuum to obtain 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-(2-cyanoethyl)dimethylammoniomethyl-3-cepheme-
4.78 g (yield 81.9%) of 4-carboxylic acid was obtained. IR (KBr) cm ^-1 ; 3400, 2247, 1777, 1715,
1617, 1392 NMR (D ₂ O + NaOD) δ; 1.30−2.60 (6H, m, −
(CH ₂ ) ₃ −), 2.8−4.4 (14H, m, N+
(CH ₃ ) ₂ , 2-CH ₂ , 3-CH ₂ , -
CH ₂ CH ₂ CN), 5.20 (1H, d, J=5Hz, C ₆ −
H), 5.61 (1H, d, J=5Hz, _C7 -H), 7.86
(4H, s,

[Formula]) Example 61 6.70 g of 7β-(D-5-carboxy-5-phthalimidovaleramide)-3-hydroxymethyl-3-cephem-4-carboxylic acid dipotassium salt 5
The hydrate was dissolved in 20 ml of water. THF30 in this solution
ml and PH with 4N hydrochloric acid while cooling to 0-5℃.
I changed it to 2.0. 35 ml of methylene chloride was added to this mixed solution to separate the layers, and the aqueous layer was extracted with a mixed solution of 6 ml of THF and 10 ml of methylene chloride. The organic layer and extract were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue were added 10 ml of formamide, 40 ml of acetonitrile and 2.93 g of diethylamine. Add this solution to the solution under stirring.
While cooling to 35 to -30°C, a solution of 3.72 g of methyl 0-phenylene phosphate in 10 ml of methylene chloride was added dropwise and the mixture was cooled at -35 to -30°C for 10 minutes, then at -5 to -30°C.
Stirred at 0°C for 30 minutes. ether to the reaction mixture
Add 100ml, remove the solvent by decanting, and dissolve the remaining viscous oil in a mixture of 7ml of water and 14ml of acetonitrile.
The pH was adjusted to 2.5 using 4N hydrochloric acid at 0-5°C. This solution was brought to pH 6.0 using 4N-NaOH at 0-5°C.
Acetonitrile was distilled off under reduced pressure. The concentrated solution was subjected to silica gel chromatography (250 g of silica gel was packed into a column with acetonitrile-water-formic acid (80:15:2). Column layer height: 63 cm) and eluted with acetonitrile-water (3:1). did. eluate
TLC (silica gel plate, developing solution; acetonitrile: water: 99% formic acid = 80:15:2, detection: UV
7β-(D-5-carboxy-5-
4.81 g (yield: 82.8%) of phthalimidovaleramide)-3-diethylaminomethyl-3-cephem-4-carboxylic acid sodium salt was obtained. IR (KBr) cm ^-1 ; 1766, 1705, 1607, 1391 NMR (D ₂ O) δ; 1.2 to 2.7 (12H, m, CH ₃ × 2,
−(CH ₂ ) ₃ −), 2.8 to 3.6 (6H, m, − CH ₂ CH ₃ ×
2, 2-CH ₂ ), 3.75 & 4.08 (2H, ABq, J = 14
Hz, 3- _CH2 ), 5.07 (1H, d, J=5Hz, _C6
-H), 5.58 (1H, d, J=5Hz, C ₇ -H),
7.86 (4H, s,

【formula】)

Claims (1)

[Claims] 1 formula [In the formula, R ¹ is a hydrogen atom or an acyl group, R is a hydrogen atom or an ester residue, and the dotted line indicates a double bond at the 2- or 3-position of the cefem ring] and a nucleophilic compound. (1 set A trivalent or pentavalent cyclic phosphorus compound having a partial structure represented by, or formula (2) A compound having a partial structure represented by the formula and a reaction product of phosphorus oxyhalide, phosphorus trihalide, or phosphorus pentahalide is reacted in an organic solvent. [In the formula, R ¹ , R and the dotted line have the same meanings as above,
A method for producing a cephalosporin compound represented by R ⁴ represents a residue of a nucleophilic compound.