JPH09295982A - Production of intermediate for synthesizing cephalosporin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an intermediate for synthesizing cephalosporin useful as e.g. an antibacterial agent, in a site-specific way and in high yield, by reaction of a specific 3-halomethyl-3-cephem-4-carboxylic acid compound with a specifically reactive formamide derivative. SOLUTION: A 7-β-protected amino-3-halomethyl-3-cephem-4-carboxylic acid ester compound (salt) of formula I (R<1> is an amino-protecting group; R<2> is a carboxylic acid-protecting group; X is a halogen) is reacted with a reactive formamide derivative bearing a group of formula II [R<3> and R<4> are each a (substituted) hydrocarbon or may form a ring together with the adjacent nitrogen atom] in the presence of a metal (salt) having reducing power such as a stannous halide or metallic tin, zinc, manganese or iron to obtain the objective intermediate of formula III for synthesizing cephalosporin-based compounds useful as antibacterial agents in a site-specific way and in high yield.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an intermediate for producing a cephalosporin compound having an antibacterial action and a method for producing the same.

[0002]

2. Description of the Related Art Conventionally, in order to produce a cephem compound having a substituted vinyl group at the 3-position, a cephem compound having a methyl group at the 3-position is used as a starting material, and the methyl group at the 3-position is enaminoized and then derivatized. As a means for activating the 3-position formylmethyl group, enoltsylation was performed.

[0003]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention In the conventional method, the enaminoization of the methyl group at the 3-position does not give a single product, and is accompanied by the by-product of Δ ² -form. Therefore, at any step in the series of steps, conversion from Δ ² to Δ ³ form by 1-position sulfoxidation, and then reduction step to sulfide are required.
Further, enoltosylation, which has been conventionally used as a means for activating the 3-formylmethyl group, has low stereoselectivity and its E: Z is about 7: 3. Therefore, there are various problems such as the need for chromatography on silica gel in order to obtain the required E-form. Therefore, it has been desired to establish a method for enaminoization of the 3-position which does not form a Δ ² isomer commensurate with the industrial production cost, and a method for high E-selective enol acylation from formylmethyl derivative derived therefrom.

[0004]

Means for Solving the Problems As a result of various studies conducted by the present inventors in view of the above problems, Formula (I)

Embedded image [In the formula, R ¹ represents an amino-protecting group, R ² represents a carboxyl-protecting group, and X represents a halogen atom. ] The compound or its salt represented by these, and formula (a)

[Chemical formula 26] [In the formula, R ³ and R ⁴ each represent an optionally substituted hydrocarbon group, or may form a ring with an adjacent nitrogen atom. By reacting a reactive formamide derivative having a group represented by

Embedded image [The symbols in the formula are as defined above. ] The compound or its salt represented by these is obtained, and Formula (III)

Embedded image [The symbols in the formula are as defined above. ] By unexpectedly E-selectively and in high yield by reacting a compound represented by the following formula or a salt thereof with an aromatic carboxylic acyl halide.

[Chemical 29] [In the formula, R ⁷ represents an aromatic carboxylic acid acyl group, and other symbols have the same meanings as described above. The present invention has been completed by discovering that a compound represented by the following formula or a salt thereof can be obtained.

That is, the present invention is characterized in that (1) a compound represented by the formula (I) or a salt thereof is reacted with a reactive formamide derivative having a group represented by the formula (a). Method for producing compound represented by (II) or salt thereof, (2) Formula (IV) characterized by reacting compound represented by formula (III) or salt thereof with aromatic carboxylic acid acyl halide A method for producing the compound represented by formula (4) or a salt thereof, (3) the compound represented by formula (IV) or formula (b) optionally substituted with a salt thereof

Embedded image [In the formula, ring B represents a 6-membered aromatic heterocycle having 1 or 2 nitrogen atoms as a hetero atom, and M represents a hydrogen atom or an alkali metal. ] The compound (V) characterized by reacting with the compound or its salt represented by these.

[Chemical 31] [Wherein A is an optionally substituted formula

Embedded image (The symbols in the formulas have the same meanings as described above.), And the other symbols have the same meanings as described above. [4] A method for producing a compound represented by the following formula or a salt thereof, (4) reacting a compound represented by formula (I) or a salt thereof with a reactive formamide derivative having a group represented by formula (a), A compound represented by formula (II) or a salt thereof obtained is subjected to a hydrolysis reaction, and the resulting compound represented by formula (III) or a salt thereof is reacted with an aromatic carboxylic acyl halide to obtain a formula A compound represented by the formula (V) or a salt thereof, which comprises reacting the compound represented by the formula (IV) or a salt thereof with an optionally substituted compound represented by the formula (b) Method for producing salt, formula (5)

[Chemical 33] [In the formula, Het represents an optionally substituted heterocyclic group, and other symbols have the same meanings as described above. ] The compound or its salt represented by these, and the compound etc. of said (5) whose (6) Het is a 2- or 4-pyridyl group which may be substituted.

The details of each definition in the above formula are as follows. In the above formula, R ¹ represents a protecting group for an amino group. In the field of β-lactams and peptides, amino-protecting groups have been thoroughly studied and their protection methods have already been established, and in the present invention, those known as amino-protecting groups are appropriately adopted. sell. Examples of the amino-protecting group include optionally substituted C _1-6
Alkanoyl group, optionally substituted C _3-5 alkenoyl group, optionally substituted C _6-10 aryl-carbonyl group, heterocyclic carbonyl group, optionally substituted C
_1-10 alkylsulfonyl group, camphorsulfonyl group,
Optionally substituted C _6-10 arylsulfonyl group, substituted oxycarbonyl group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, optionally substituted C _6-10 aryl- Methyl group, optionally substituted di C _6-10 aryl-methyl group, _optionally substituted tri C _6-10 aryl-methyl group, _optionally substituted C _6-10 aryl-methylene group, _Optionally substituted C _6-10 arylthio group, substituted silyl group, 2-
C _1-10 alkoxy-carbonyl-1-methyl-1-ethenyl group, formula M′OCO— [in the formula, M ′ represents an alkali metal. ] The group etc. which are represented by these are used.

Examples of the "optionally substituted C _1-6 alkanoyl group" include halogen, oxo, C _1-6 alkoxy, C _1-6 alkanoyl, C _6-10 aryl, halogeno C _6-10 aryl, C _6-10 aryloxy, halogeno C _6-10 aryloxy, optionally substituted with 1-3 substituents selected from such C _6-10 arylthio C _1-6
An alkanoyl group is used, and specific examples include formyl, acetyl, propionyl, butyryl, valeryl,
Pivaloyl, succinyl, glutaryl, monochloroacetyl, dichloroacetyl, trichloroacetyl, monobromoacetyl, monofluoroacetyl, difluoroacetyl, trifluoroacetyl, monoiodoacetyl, acetoacetyl, 3-oxobutyryl, 4-chloro-3-
Oxobutyryl, phenylacetyl, p-chlorophenylacetyl, phenoxyacetyl, p-chlorophenoxyacetyl and the like are used. Examples of the “optionally substituted C _3-5 alkenoyl group” include halogen,
A C _3-5 alkenoyl group which may be substituted with 1 to 3 substituents selected from C _6-10 aryl and the like is used,
Specifically, for example, acryloyl, crotonoyl, maleoyl, cinnamoyl, p-chlorocinnamoyl, β
-Phenylcinnamoyl and the like are used. Examples of the “optionally substituted C _6-10 aryl-carbonyl group” include 1 to 3 substituents selected from halogen, nitro, hydroxy, C _1-6 alkyl, C _1-6 alkoxy and the like. An optionally substituted C _6-10 aryl-carbonyl group is used, specifically, for example, benzoyl, naphthoyl, phthaloyl, p-toluoyl, p-tert-butylbenzoyl, p-hydroxybenzoyl, p-methoxybenzoyl. , P-tert-butoxybenzoyl, p-
Chlorobenzoyl, p-nitrobenzoyl and the like are used.

The "heterocyclic group" in the "heterocyclic carbonyl group" refers to a group formed by removing one hydrogen atom bonded to a carbon atom of the heterocyclic ring, and such a heterocyclic ring is, for example, a nitrogen atom ( 5 to 8 membered ring containing 1 to several, preferably 1 to 4 heteroatoms such as (optionally oxidized), oxygen atom and sulfur atom, or a condensed ring thereof. Specific examples of such a heterocyclic group include 2- or 3-pyrrolyl; 3-, 4- or 5-pyrazolyl; 2-, 4-
Or 5-imidazolyl; 1,2,3- or 1,2,4-
Triazolyl; 1H- or 2H-tetrazolyl; 2-
Or 3-furyl; 2- or 3-thienyl; 2-, 4
-Or 5-oxazolyl; 3-, 4- or 5-isoxazolyl; 1,2,3-oxadiazol-4-yl or 1,2,3-oxadiazol-5-yl; 1,2,4
-Oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl; 1,2,5- or 1,3,4-oxadiazolyl; 2-, 4- or 5-thiazolyl; 3
-, 4- or 5-isothiazolyl; 1,2,3-thiadiazol-4-yl or 1,2,3-thiadiazole-
5-yl; 1,2,4-thiadiazol-3-yl or 1,2,4-thiadiazol-5-yl; 1,2,5- or 1,3,4-thiadiazolyl; 2- or 3-pyrrolidinyl; 2-, 3- or 4-pyridyl; 2-, 3- or 4-pyridyl-N-oxide; 3- or 4-pyridazinyl; 3- or 4-pyridazinyl-N-oxide;
2-, 4- or 5-pyrimidinyl; 2-, 4- or 5-pyrimidinyl-N-oxide; pyrazinyl;
3- or 4-piperidinyl; piperazinyl; 3H-indol-2-yl or 3H-indol-3-yl; 2-, 3- or 4-pyranyl; 2-, 3- or 4-thiopyranyl; benzopyranyl; quinolyl; pyrido [2,3-d] pyrimidyl; 1,5-, 1,6-, 1,7
-, 1,8-, 2,6- or 2,7-naphthyridyl; thieno [2,3-d] pyridyl; pyrimidopyridyl; pyrazinoquinolyl; benzopyranyl and the like are used. The "optionally substituted C _1-10 alkylsulfonyl group" is, for example, substituted with 1 to 3 substituents selected from halogen, C _6-10 aryl, C _6-10 aryloxy and the like. C _1-10 alkylsulfonyl group is also used, and specifically, for example, methanesulfonyl, ethanesulfonyl and the like are used.

Examples of the " _optionally substituted C _6-10 arylsulfonyl group" include halogen, nitro, C
1-3 selected from _1-6 alkyl, C _1-6 alkoxy, etc.
C _6-10 arylsulfonyl group _optionally substituted with one substituent is used, specifically, for example, benzenesulfonyl, naphthalenesulfonyl, p-toluenesulfonyl, p-tert-butylbenzenesulfonyl, p-methoxy. Benzenesulfonyl, p-chlorobenzenesulfonyl, p-nitrobenzenesulfonyl and the like are used.
Examples of the “substituted oxycarbonyl group” include C _1-10
Alkoxy-carbonyl group, C _3-10 cycloalkyloxycarbonyl group, C _5-10 bridged cyclic hydrocarbon oxycarbonyl group, C _2-10 alkenoyloxy-carbonyl group, C
_{In addition to a 6-10} aryloxy-carbonyl group or a C _7-19 aralkyloxy-carbonyl group, these are further C
_1-6 alkoxy group, C _1-6 alkanoyl group, substituted silyl group (substituted silyl group described later, eg, trimethylsilyl, tert
-Butyldimethylsilyl, etc.), a C _1-6 alkylsulfonyl group, a halogen, cyano, a C _1-6 alkyl group, nitro and the like having 1 to 3 substituents. Specifically, for example, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-methanesulfonylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-cyanoethoxycarbonyl, allyloxycarbonyl, p- Methylphenoxycarbonyl, p-methoxyphenoxycarbonyl, p-chlorophenoxycarbonyl, m-nitrophenoxycarbonyl, p-methylbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
p-Nitrobenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, 3,4-dimethoxy-6-nitrobenzyloxycarbonyl and the like are used.

"Carbamoyl group which may be substituted"
Examples of 1 or 2 selected from a C _1-6 alkyl group, a C _6-10 aryl group, a C _1-6 alkanoyl group, a C _6-10 aryl-carbonyl group, a C _1-6 alkoxy-phenyl group and the like. A carbamoyl group which may be substituted with one substituent is used. Specifically, for example, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-
Phenylcarbamoyl, N-acetylcarbamoyl, N
-Benzoylcarbamoyl, N- (p-methoxyphenyl) carbamoyl and the like are used. Examples of the “optionally substituted thiocarbamoyl group” include C _1-6
A thiocarbamoyl group which may be substituted with 1 or 2 substituents selected from an alkyl group, a C _6-10 aryl group and the like is used, and examples thereof include thiocarbamoyl, N-methylthiocarbamoyl and N-phenylthiocarbamoyl. Are used.

“Optionally substituted C _6-10 aryl-
Examples of the “methyl group” include halogen, nitro, C
1-3 selected from _1-6 alkyl, C _1-6 alkoxy, etc.
C _6-10 aryl-methyl group which may be substituted with one substituent is used, specifically, for example, benzyl, naphthylmethyl, p-methylbenzyl, p-methoxybenzyl, p-chlorobenzyl, p -Nitrobenzyl and the like are used. Examples of the “ _optionally substituted di C _6-10 aryl-methyl group” include halogen, nitro, C
1-3 selected from _1-6 alkyl, C _1-6 alkoxy, etc.
_{DiC 6-10} aryl-, which may be substituted with one substituent
A methyl group is used, and specifically, for example, benzhydryl, di (p-tolyl) methyl and the like are used. Examples of the “ _optionally substituted tri-C _6-10 aryl-methyl group” include halogen, nitro, C _1-6 alkyl,
A tri-C _6-10 aryl-methyl group which may be substituted with 1 to 3 substituents selected from C _1-6 alkoxy and the like is used, and specific examples include trityl and tri (p-
Trilyl) methyl and the like are used. Examples of the “ _optionally substituted C _6-10 aryl-methylene group” include:
A C _6-10 aryl-methylene group which may be substituted with 1 to 3 substituents selected from halogen, nitro, C _1-6 alkyl, C _1-6 alkoxy and the like is used. For example, benzylidene, p-methylbenzylidene, p
-Chlorobenzylidene or the like is used. Examples of the “ _optionally substituted C _6-10 arylthio group” include:
A C _6-10 arylthio group which may be substituted with 1 to 3 substituents selected from halogen, nitro, C _1-6 alkyl, C _1-6 alkoxy and the like is used. Specifically, for example, o-Nitrophenylthio and the like are used.

The "substituted silyl group" is referred to as the protected amino group in combination with the formula R ⁸ R ⁹ R ¹⁰ SiNH-, (R ⁸ R ⁹ R ¹⁰ Si) ₂
N- or

Embedded image [Wherein R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ^11a and R ^12a are each a C _1-6 alkyl group or a C _6-10 aryl group,
Z ^a represents a C _1-3 alkylene group (methylene, ethylene, propylene)]. Preferable examples of “substituted silyl group” include, for example, trimethylsilyl, tert-butyldimethylsilyl, —Si (CH ₃ ).
_{2 CH 2 CH 2 Si (CH} 3) 2 - and the like. "2-C
Specific examples of the " _1-10 alkoxy-carbonyl-1-methyl-1-ethenyl group" include 2-methoxycarbonyl-1-methyl-1-ethenyl, 2-ethoxycarbonyl-1-methyl-1-ethenyl, 2 -Tert-butoxycarbonyl-1-methyl-1-ethenyl, 2-cyclohexyloxycarbonyl-1-methyl-1-ethenyl,
2-norbornyloxycarbonyl-1-methyl-1-
Ethenyl and the like are used. As the “alkali metal” represented by M ′, for example, sodium, potassium and the like are preferable, and sodium and the like are particularly preferable. R ¹ is C such as tert-butoxycarbonyl
_1-10 alkoxy-carbonyl group, C optionally substituted by C _6-10 aryl group such as formyl and phenylacetyl
_1-6 alkanoyl group and the like are preferable.

The protecting group for the carboxyl group represented by R ² is usually used in the field of synthetic organic chemistry, particularly for protecting β-lactam antibiotics such as cephalosporins. Is used. Examples of such a protecting group include an optionally substituted C _1-6 alkyl group, C _2-6 alkenyl group, C _6-10 aryl group, C _7-20 aralkyl group and the like. Examples of the substituent of the C _1-6 alkyl group, C _2-6 alkenyl group, C _6-10 aryl group or C _7-20 aralkyl group include, for example, hydroxyl group, nitro group, halogen and C _1-6 alkoxy. Group, C _1-10 alkanoyloxy group, C _3-10 cycloalkyl-carbonyloxy group, C _6-10 aryl-carbonyloxy group, C _1-10 alkoxy-carbonyloxy group, C _3-10 cycloalkyloxy-carbonyl Oxy group, C _6-10 aryl-carbonyloxy group, tri (C
_1-6 alkyl) silyl group (eg trimethylsilyl, te
(rt-butyldimethylsilyl), a C _1-6 alkylthio group, and the like. The number of such substituents is preferably 1 to 3, and in the case of a plurality of substituents, they may be the same or different. R ² is preferably benzhydryl, methoxybenzyl or the like.

X represents a halogen atom. Although chlorine, bromine, fluorine, iodine and the like are used as the halogen atom, chlorine and bromine are preferable. Equation (a)

Embedded image [The symbols in the formula are as defined above. ] As a reactive formamide derivative having a group represented by the following, a 3-position substituent of the compound [II] is obtained by reacting with the compound [I].

Embedded image [The symbols in the formula are as defined above. Is not particularly limited as long as it is a compound forming

Embedded image [In the formula, R ⁵ and R ⁶ each represent a lower alkoxy group or a di-lower alkylamino group. ] The compound etc. represented by these are used.

The "optionally substituted hydrocarbon group" represented by R ³ and R ⁴ is an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted alkynyl. Groups, optionally substituted aryl groups, optionally substituted aralkyl groups, and the like. Examples of the “alkyl group” of the “optionally substituted alkyl group” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl. Preferred are C _1-6 alkyl groups such as methyl, ethyl,
Isopropyl and the like are preferable. Examples of the “alkenyl group” of the “optionally substituted alkenyl group” include:
Vinyl, allyl, isopropenyl, methallyl, 1,1-
C such as dimethylallyl, 2-butenyl and 3-butenyl
_{A 2-6} alkenyl group and the like are preferable. Examples of the "alkynyl group" of the "optionally substituted alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 2-
C such as putinyl, 2-pentynyl and 2-hexynyl
_2-6 alkynyl group and the like. Examples of the “aryl group” of the “optionally substituted aryl group” include C _6-10 aryl groups such as phenyl and naphthyl. The “aralkyl group” of the “optionally substituted aralkyl group” is preferably a C _7-19 aralkyl group such as benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl, naphthylmethyl and benzhydryl.

The substituent which the above-mentioned "hydrocarbon group" may have is, for example, a heterocyclic group, a hydroxyl group, a C _1-6 alkoxy group, a C _3-7 cycloalkyloxy group, a C _6-10 aryloxy group. Group, C _7-19 aralkyloxy group, heterocyclic oxy group, mercapto group, C _1-6 alkylthio group, C _3-10 cycloalkylthio group, C _6-10 arylthio group, C _7-19 aralkylthio group, heterocycle Thio group, amino group, mono C _1-6
Alkylamino group, di-C _1-6 alkylamino group, tri-C
_1-6 alkylammonium group, C _3-10 cycloalkylamino group, C _6-10 arylamino group, C _7-19 aralkylamino group, heterocyclic amino group, cyclic amino group, azido group, nitro group, halogen atom, Cyano group, carboxyl group, C
_1-10 alkoxy - carbonyl group, C _6-10 aryloxy - carbonyl group, C _7-19 aralkyloxy - carbonyl group, C _6-10 aryl - carbonyl group, C _1-6 alkanoyl group, C _3-5 alkenoyl group , C _6-10 aryl-carbonyloxy group, C _2-6 alkanoyloxy group, C _3-5 alkenoyloxy group, C _1-6 alkylsulfonyl group, C
_6-10 arylsulfonyl group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, optionally substituted carbamoyloxy group, phthalimido group, C _1-6 alkanoylamino group, C _{6- 10} aryl-carbonylamino group, C _1-10 alkoxy-carboxamide group, C _6-10 aryloxy-carboxamide group, C _7-19 aralkyloxy-carboxamide group, etc., and the same or different 1 to 4 groups are present. May be.

Among the specific examples of the substituent of the above-mentioned "hydrocarbon group", the "optionally substituted carbamoyl group" is, for example, C _1-6 alkyl group, C _6-10 aryl group, C _1-6.
Alkanoyl group, C _6-10 arylcarbonyl group, C _1-6
A carbamoyl group which may be substituted with 1 or 2 substituents selected from an alkoxy-phenyl group, a cyclic aminocarbonyl group and the like are used, and specifically, for example, carbamoyl, N-methylcarbamoyl, N-
Ethylcarbamoyl, N, N-dimethylcarbamoyl,
N, N-diethylcarbamoyl, N-phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl, N- (p-methoxyphenyl) carbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, morpholinocarbonyl, etc. Used. "A thiocarbamoyl group which may be substituted"
Is, for example, a thiocarbamoyl group which may be substituted with 1 or 2 substituents selected from C _1-6 alkyl group, C _6-10 aryl group and the like.
Thiocarbamoyl, N-methylthiocarbamoyl, N-
Phenylthiocarbamoyl or the like is used. An “optionally substituted carbamoyloxy group” includes, for example, C
1 selected from _1-6 alkyl group, C _6-10 aryl group, etc.
Alternatively, a carbamoyloxy group which may be substituted with two substituents is used, and specifically, for example, carbamoyloxy, N-methylcarbamoyloxy, N, N-
Dimethylcarbamoyloxy, N-ethylcarbamoyloxy, N-phenylcarbamoyloxy and the like are used.

The heterocyclic group in the substituent of the "hydrocarbon group", the heterocyclic oxy group, the heterocyclic thio group and the heterocyclic amino group is the same as the heterocyclic group in the above "heterocyclic carbonyl group". Groups are used. "Alkyl group" of "alkyl group which may be substituted", "alkenyl group" of "alkenyl group which may be substituted",
Examples of the substituent which the “cyclic hydrocarbon group” of the “aralkyl group” of the “optionally substituted aralkyl group” and the “optionally substituted cyclic hydrocarbon group” may have are as described above. Optionally substituted hydrocarbon group "
The same as the substituent which the “hydrocarbon group” of may have, etc. are used. As the ring formed by R ³ and R ⁴ together with the adjacent nitrogen atom, a 5- to 7-membered saturated or unsaturated nitrogen-containing heterocycle is used, and specifically, for example,
Examples thereof include morpholine and piperidine. R ³ and R ⁴
Is preferably a C _1-4 alkyl group such as methyl. The lower alkoxy group represented by R ⁵ and R ⁶ is a C _1-6 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy. Etc. Examples of the di-lower alkylamino group represented by R ⁵ and R ⁶ include di-C _1-6 alkylamino groups such as dimethylamino. Both R ⁵ and R ⁶ are preferably a C _1-6 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like. Examples of the reactive formamide derivative having a group represented by the formula (a) include dimethylformamide dialkyl acetal (eg, dimethylformamide dimethyl acetal, dimethylformamide diethyl acetal, dimethylformamide di-n-propyl acetal, dimethylformamide diisopropyl acetal, dimethyl formamide). Dimethylformamide di-C _1-6 alkyl acetal such as formamide di-n-butyl acetal) and the like are preferable.

In the production of the above compound [II], it is preferable to react in the presence of a reducing metal or a salt thereof. Examples of the metal having a reducing power include tin, zinc, manganese, iron and the like, and salts thereof include halides (eg SnCl ₂ , FeCl ₂ , MnCl ₂ etc.) and the like. As the metal having a reducing power or a salt thereof, divalent tin halide such as SnCl ₂ or metal tin is preferable. The aromatic carboxylic acyl group in the aromatic carboxylic acyl halide and the aromatic carboxylic acyl group represented by R ⁷ are an optionally substituted aromatic heterocyclic carbonyl group or an optionally substituted arylcarbonyl group. Etc. The aromatic heterocycle in the aromatic heterocycle carbonyl group is a 5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms such as nitrogen atom, oxygen atom and sulfur atom (eg, pyridyl, thienyl, furyl, Pyrazinyl etc.) and the like are preferable. As the arylcarbonyl group, a C _6-10 aryl-carbonyl group such as benzoyl is preferable. The aromatic heterocyclic carbonyl group and the arylcarbonyl group are the same as the substituents, hydrocarbon groups and substituted hydrocarbon groups exemplified in the “optionally substituted hydrocarbon group” for R ³ and R ⁴ above. It may be substituted, and the number thereof is preferably 1 to 4. Substituents for such aromatic heterocyclic carbonyl and arylcarbonyl groups include electron withdrawing groups, especially halogeno C _1-6.
Alkyl group (eg, trifluoromethyl, etc.), nitro group,
Halogen atom (eg, fluorine, chlorine, etc.), cyano group, C
_1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl etc.), C _6-10 arylsulfonyl group (eg, phenylsulfonyl etc.), C _1-10 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl etc.) , A C _6-10 aryloxy-carbonyl group (eg,
Phenoxycarbonyl etc.) and the like are preferable. As the halide in the aromatic carboxylic acid acyl halide, chloride, bromide and the like are preferable. Examples of the aromatic carboxylic acid acyl halide include pyridinecarbonyl chloride such as isonicotinoyl chloride and picolinoyl chloride, p-trifluoromethylbenzoyl chloride,
It may be substituted with a halogeno C _1-6 alkyl group such as p-nitrobenzoyl chloride or p-chlorobenzoyl chloride (eg, trifluoromethyl etc.), a nitro group, a halogen atom (eg, fluorine, chlorine etc.) and the like. Benzoyl chloride and the like are preferred.

Formula (b)

Embedded image [The symbols in the formula are as defined above. In the compound represented by the above formula, the following compounds are specifically used as the compounds [B ¹ ] and [B ² ].

Embedded image In the above formula, an optionally substituted formula represented by A

Embedded image [The symbols in the formula are as defined above. In the group represented by the above formula, the following are specifically used as the group [A ¹ ].

Embedded image

The following are specifically used as the group [A ² ].

Embedded image

Compounds [B ¹ ] and [B ² ] and the imidazole ring and / or ring B of the groups [A ¹ ] and [A ² ].
And the compound [B ³ ] and the group [A ³ ] may preferably have 1 or 2 substituents. Examples of such a substituent include a hydroxyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-10 cycloalkyl group, and a C _5-6. Cycloalkenyl group, C _3-10 cycloalkyl C _1-6 alkyl group,
C _6-10 aryl group, C _7-12 aralkyl group, heterocyclic group, C
_1-6 alkoxy group, C _1-6 alkoxy-C _1-6 alkyl group, amino C _1-6 alkoxy group, C _3-10 cycloalkyloxy group, C _6-10 aryloxy group, C _7-19 aralkyloxy group group, a mercapto group, a mercapto C _1-6 alkyl group, a sulfo group, sulfo C _1-6 alkyl group, C _1-6 alkylthio group, C _1-6 alkylthio C _1-6 alkyl group, C _{3-1 0} cycloalkylthio Group, C _6-10 arylthio group, C _7-19 aralkylthio group, amino C _1-6 alkylthio group, amino group, amino C _1-6 alkyl group, mono C _1-6 alkylamino group, di C _1-6 Alkylamino group, mono C _1-6 alkylamino C _1-6 alkyl group, di C _1-6 alkylamino C _1-6 alkyl group, C _3-10 cycloalkylamino group, C _6-10 arylamino group, C _7-19 aralkylamino group, cyclic amino group, cyclic amino C _1-6 alkyl group, a cyclic amino C _1-6 alkylamino group, a ureido group, C _1-6 alkyl ureido group, an azide group, a nitro group, a halogen atom, halogeno C
_1-6 alkyl group, cyano group, cyano C _1-6 alkyl group, carboxyl group, carboxy C _1-6 alkyl group, C _1-10 alkoxy-carbonyl group, C _1-10 alkoxy-carbonyl C _1-6 alkyl group , C _6-10 aryloxy-carbonyl group, C _7-19 aralkyloxy-carbonyl group, C _6-10
Aryl-acyl group, C _1-6 alkanoyl group, C _2-6 alkanoyl C _1-6 alkyl group, C _3-5 alkenoyl group, C
_6-10 aryl-acyloxy group, C _2-6 alkanoyloxy group, C _2-6 alkanoyloxy C _1-6 alkyl group, C
_3-5 Alkenoyloxy group, carbamoyl C _1-6 alkyl group, carbamoyl group, thiocarbamoyl group, carbamoyloxy group, carbamoyloxy C _1-6 alkyl group, C
_1-6 alkanoylamino group, _C6-10 aryl-acylamino group, sulfonamide group, carboxamino group, C
_{A 1-10} alkoxy-carboxamide group, a _C6-10 aryloxy-carboxamide group, a _C7-19 aralkyloxy-carboxamide group and the like are used.

In the above formula, as the alkali metal represented by M, sodium, potassium and the like are used. Examples of the compound represented by the formula (b) include 6-mercaptoimidazo [1,
2-b] pyridazine alkali metal salt and the like, and as A, imidazo [1,2-b] pyridazin-6-yl and the like are preferable. In the above formula, the heterocyclic group in the “optionally substituted heterocyclic group” represented by Het is the same as the “heterocyclic group” in the “heterocyclic carbonyl group”, and its substituent The substituents and hydrocarbon groups in the “optionally substituted hydrocarbon group” represented by R ³ and R ⁴ above are used, and the number thereof is preferably 1 to 4. Het may be substituted 2 or 3
A -pyridyl group is preferred.

The salts of compounds (I) to (V) include inorganic base salts, ammonium salts, organic base salts, inorganic acid addition salts,
Examples thereof include organic acid addition salts. Inorganic base salts include alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, etc.), and organic base salts include, for example, trimethylamine salt, triethylamine salt, tert-butyldimethylamine salt. , Dibenzylmethylamine salt, benzyldimethylamine salt, N, N-dimethylaniline salt, pyridine salt,
The quinoline salt, etc., and the inorganic acid addition salts include, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
Examples of organic acid addition salts include formate, acetate, trifluoroacetate, methanesulfonate, p-toluenesulfonate and the like. Examples of the salt of the compound (b) include alkali metal salts such as lithium salt, sodium salt and potassium salt, addition salts with trialkylamine such as triethylamine and diisopropylamine, and the like.

Next, the reaction conditions and the like of each reaction in the production method of the present invention will be described in detail.

Embedded image [The symbols in the formula are as defined above. ]

[First Step] In the reaction, about 1 to 10 equivalents of the reactive formamide derivative having a group represented by the formula (a) is used with respect to 1 mol of the compound represented by the formula (I) or a salt thereof. , Preferably about 2 to 4 equivalents, and the reaction temperature is about 0 to 80.
It is carried out by reacting at 15 ° C, preferably about 10 to 40 ° C for about 15 minutes to 2 hours, preferably about 30 minutes to 1 hour.
The reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include dioxane, tetrahydrofuran, diethyl ether,
Ethers such as tert-butyl methyl ether, diisopropyl ether, ethylene glycol-dimethyl ether, esters such as ethyl formate, ethyl acetate, n-butyl acetate, such as dichloromethane, chloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane. Halogenated hydrocarbons such as n-hexane, benzene, toluene and the like hydrocarbons such as formamide, N, N-dimethylformamide, N, N-
Amides such as dimethylacetamide, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, and dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, etc., alone or as a mixed solvent. Used as. In order to accelerate the reaction, it is preferable to react in the presence of sodium iodide, a reducing metal or a salt thereof. The amount of sodium iodide used is usually about 1 to 4 equivalents, preferably about 1 to 2 equivalents to 1 equivalent of the compound represented by the formula (I) or a salt thereof.
Is equivalent. The amount of the reducing metal or a salt thereof used is usually about 1 to 4 equivalents, preferably about 1.5 to 2 equivalents, relative to 1 equivalent of the compound represented by the formula (I) or a salt thereof. The compound represented by the formula (I) or a salt thereof can be prepared by a known method (for example, The Journal of Antibiotics Volume 38, 1738).
~ 1751 page, 1985 etc.) or a method analogous thereto.

[Second Step] A normal hydrolysis reaction,
For example, about 1 to 5 times mol, preferably about 2 times mol of phosphoric acid is added to 1 mol of the compound represented by the formula (II) or a salt thereof, and the reaction temperature is about 0 to 50 ° C., preferably about 30 to Three
The reaction is carried out at 5 ° C. for about 30 minutes to 6 hours, preferably about 1 to 2 hours. The reaction is generally carried out in the solvent as exemplified in the first step above.

[Step 3] In the reaction, about 0.9 to 3 equivalents, preferably about 1 equivalent of aromatic carboxylic acid acyl halide is used with respect to 1 mol of the compound represented by the formula (III) or a salt thereof.
The reaction temperature is about -10 to 50 ° C, preferably about 0.
The reaction is carried out at -10 ° C for about 5 minutes to 2 hours, preferably about 10 to 30 minutes. In addition, this reaction can be promoted by adding a base. Examples of such a base include cyclic amines such as imidazole, N-methylimidazole and N-methylmorpholine, and chain amines such as trialkylamines such as triethylamine and diisopropylethylamine. The amount of the base used is the compound represented by the formula (III) or a salt thereof 1.
About 1 to 5 equivalents, preferably about 1.2 to 3 per mol
Is equivalent. The reaction is generally carried out in the solvent as exemplified in the first step above.

[Fourth Step] In the reaction, about 1 to 2 equivalents, preferably 1 to 2 equivalents of the compound represented by the formula (b) or a salt thereof is used with respect to 1 mol of the compound represented by the formula (IV) or a salt thereof. About 1.1 to 1.5 equivalents are added, and the reaction is carried out at a reaction temperature of about −10 to 50 ° C., preferably about 0 to 10 ° C. for about 15 minutes to 3 hours, preferably about 30 minutes to 1 hour. The reaction is generally carried out in the solvent as exemplified in the first step above. After completion of the reaction in each step, the obtained compound is subjected to the next reaction without isolation, or if necessary, known means,
For example, it can be isolated and purified by concentration, vacuum concentration, distillation, fractional distillation, solvent extraction, liquid conversion, phase transfer, chromatography, crystallization, recrystallization and the like.

Formula (V) obtained by the production method of the present invention
The compound represented by or a salt thereof can be converted into a compound represented by the formula (VIII) or a salt thereof by the method described below. The compound represented by the formula (VIII) or an ester or salt thereof has a broad antibacterial spectrum and an excellent antibacterial activity against Gram-negative bacteria including Pseudomonas and Gram-positive bacteria including Staphylococcus and MRSA. Therefore, it is useful as an antibacterial agent against infectious diseases based on these bacteria.

Embedded image (In the formula,

Embedded image R ¹³ is an optionally substituted hydrocarbon group, R ¹⁴ is an optionally protected amino group, R ¹⁵ is an optionally substituted hydrocarbon group, and other symbols are as defined above. Show. As the optionally substituted hydrocarbon group represented by R ¹³ and R ¹⁵ , the same groups as the optionally substituted hydrocarbon group represented by R ³ and R ⁴ are used. As the optionally protected amino-protecting group for R ¹⁴ , the same groups as those for R ¹ are used.

Specific examples of each substituent unless otherwise specified in the present specification are as follows. Halogen atom: fluorine, chlorine, bromine, iodine, etc .; C _1-6 alkyl group: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,
2,2-dimethylpropyl, hexyl, etc .; C _2-6 alkenyl groups: vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3
-Butenyl, methallyl, 1,1-dimethylallyl, etc .; C _2-6 alkynyl group: ethynyl, 1-propynyl, 2-
Propinyl, 2-butynyl, 2-pentynyl, 2-hexynyl, etc .; C _3-10 cycloalkyl group: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, etc .; C _5-6 cycloalkenyl group: cyclo Pentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, etc .; C _6-10 aryl group: phenyl, naphthyl, etc .; C _7-20 aralkyl group: benzyl, 1-phenylethyl,
2-phenylethyl, phenylpropyl, naphthylmethyl, benzhydryl, etc .;

Halogeno C _1-6 alkyl group: fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoro Ethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-iodoethyl, etc .; Cyano C _1-6 alkyl group: cyanomethyl, 2-cyanoethyl, etc .; Carboxy C _{1- 6} alkyl groups: carboxymethyl, 1-
Carboxyethyl, 2-carboxyethyl, etc .; Sulfo C _1-6 alkyl group: sulfomethyl, 2-sulfoethyl, etc .; Hydroxy C _1-6 alkyl group: hydroxymethyl, 1-
Hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, etc .; Mercapto C _1-6 alkyl group: mercaptomethyl, 1-
Mercaptoethyl, 2-mercaptoethyl, etc .; Amino C _1-6 alkyl group: aminomethyl, 2-aminoethyl, 3-aminopropyl, etc .; Mono C _1-6 alkylamino C _1-6 alkyl group: methylaminomethyl, ethyl Aminomethyl, 2- (N-methylamino) ethyl, 3- (N-methylamino) propyl, etc .; Di C _1-6 alkylamino C _1-6 alkyl group: N, N-dimethylaminomethyl, N, N- Diethylaminomethyl, 2
-(N, N-dimethylamino) ethyl, 2- (N, N-diethylamino) ethyl, 3- (N, N-dimethylamino) propyl, etc .; Cyclic amino C _1-6 alkyl group: pyrrolidinomethyl, piperidinomethyl, Piperazinomethyl, morpholinomethyl,
2- (morpholino) ethyl etc .; C _1-6 alkoxy C _1-6 alkyl group: methoxymethyl, ethoxymethyl, 2-methoxyethyl etc .; C _1-6 alkylthio C _1-6 alkyl group: methylthiomethyl, 2-methylthio C _3-10 cycloalkyl C _1-6 alkyl group: cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclodecylmethyl, etc .; C _2-6 alkanoyl C _{1 -6} alkyl group: acetylmethyl,
1-acetylethyl, 2-acetylethyl, etc .; C _2-6 alkanoyloxy C _1-6 alkyl group: acetoxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, etc .; C _1-10 alkoxy-carbonyl C _1-6 alkyl Group: methoxycarbonylmethyl, ethoxycarbonylmethyl, te
rt-butoxycarbonylmethyl and the like; carbamoyl C _1-6 alkyl group: carbamoylmethyl,
2-carbamoylethyl and the like; carbamoyloxy C _1-6 alkyl group: carbamoyloxymethyl, 1-carbamoyloxyethyl and the like;

C _1-6 alkoxy group: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, 2,2-dimethylpropyloxy, hexyloxy, etc .; C _3-10 cycloalkyloxy group : Cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, cyclodecyloxy and the like; C _6-10 aryloxy group: phenoxy, naphthyloxy and the like; C _7-19 aralkyloxy group: Benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, benzhydryloxy, etc .; Amino C _1-6 alkoxy group: aminomethoxy, 2-aminoethoxy, 3-aminopropoxy, etc .;

C _1-6 alkylthio group: methylthio, ethylthio, propylthio, butylthio, isobutylthio,
t-butylthio, pentylthio, 2,2-dimethylpropylthio, hexylthio, etc .; C _3-10 cycloalkylthio group: cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio, cyclooctylthio, cyclodecylthio. C _6-10 arylthio group: phenylthio, naphthylthio, etc .; C _7-19 aralkylthio group: benzylthio, phenylethylthio, benzhydrylthio, tritylthio, etc .; Amino C _1-6 alkylthio group: aminomethylthio, 2-
Aminoethylthio, 3-aminopropylthio, etc .; C _1-6 alkylsulfonyl group: methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, t
-Butylsulfonyl, pentylsulfonyl, 2,2-dimethylpropylsulfonyl, hexylsulfonyl and the like;

Mono C _1-6 alkylamino group: methylamino, ethylamino, n-propylamino, n-butylamino, etc .; Di C _1-6 alkylamino group: dimethylamino, diethylamino, methylethylamino, di- ( n-propyl) amino, di- (n-butyl) amino and the like; tri C _1-6 alkylammonium group: trimethylammonium and the like; C _3-10 cycloalkylamino group: cyclopropylamino, cyclopentylamino, cyclohexylamino and the like; C _6-10 arylamino group: anilino, N-methylanilino, etc .; C _7-19 aralkylamino group: benzylamino, 1-phenylethylamino, 2-phenylethylamino, benzhydrylamino, etc .; cyclic amino group: pyrrolidino, piperidino , Piperazino,
Morpholino, 1-pyrrolyl, etc .; Cyclic amino C _1-6 alkylamino group: pyrrolidinoethylamino, piperidinoethylamino, piperazinoethylamino, morpholinoethylamino, etc .; C _1-6 alkanoylamino group: acetamide, propion Amide, butyroamide, valeroamide, pivaloamide, etc .; C _6-10 aryl-carbonylamino group: benzamide,
Naphthoylamide, phthalimide, etc .; C _6-10 aryl-C _1-6 alkanoylamino group: phenylacetylamino, etc .;

C _1-6 alkanoyl group: formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl,
Succinyl, glutaryl, etc .; C _2-6 alkanoyloxy groups: acetoxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy, etc .; C _3-5 alkenoyl groups: acryloyl, crotonoyl,
Maleoyl, etc .; C _3-5 alkenoyloxy group: acryloyloxy, crotonoyloxy, maleoyloxy, etc .; C _6-10 aryl-carbonyl group: benzoyl, naphthoyl, phthaloyl, phenylacetyl, etc .; C _6-10 aryl-carbonyl Oxy group: benzoyloxy, naphthoyloxy, phenylacetoxy, etc .; C _3-10 cycloalkyl-carbonyl group: cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, cyclodecylcarbonyl, etc. C _5-6 cycloalkenyl-carbonyl group: cyclopentenylcarbonyl, cyclopentadienylcarbonyl, cyclohexenylcarbonyl, cyclohexadienylcarbonyl, etc. C _7-19 aralkyl-carbonyl group: phenylacetyl,
Phenylpropionyl, α, α-diphenylacetyl,
α, α, α-triphenylacetyl, etc .; C _6-10 aryl-C _1-6 alkanoyl group: phenylacetyl, etc .; C _6-10 aryl-C _1-6 alkanoyloxy group: phenylacetyloxy, etc .; C _{1- 6} alkylsulfonyl group: methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, t
-Butylsulfonyl, etc .; _C6-10 arylsulfonyl group: phenylsulfonyl, etc .;

C _1-10 alkoxy-carbonyl group: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, 2,2-dimethylpropyloxycarbonyl, Hexyloxycarbonyl, heptyloxycarbonyl, decyloxycarbonyl, etc .; C _1-10 alkoxy-carbonyloxy groups: methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy,
Butoxycarbonyloxy, isobutoxycarbonyloxy, t-butoxycarbonyloxy, pentyloxycarbonyloxy, 2,2-dimethylpropyloxycarbonyloxy, hexyloxycarbonyloxy, heptyloxycarbonyloxy, decyloxycarbonyloxy, etc .; C _3-10 Cycloalkyloxy-carbonyl group: cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycarbonyl,
Cyclooctyloxycarbonyl, cyclodecyloxycarbonyl and the like; C _3-10 cycloalkyloxy-carbonyloxy group: cyclopropyloxycarbonyloxy, cyclobutyloxycarbonyloxy, cyclopentyloxycarbonyloxy, cyclohexyloxycarbonyloxy, cycloheptyloxycarbonyloxy , Cyclooctyloxycarbonyloxy, cyclodecyloxycarbonyloxy and the like; C _3-10 cycloalkyloxy-carbonyloxy group: cyclopropyloxycarbonyloxy, cyclobutyloxycarbonyloxy, cyclopentyloxycarbonyloxy, cyclohexyloxycarbonyloxy, cycloheptyl Oxycarbonyloxy, cyclooctyloxycarbonyloxy, cyclodecyl Such alkoxycarbonyloxy; C _5-10 bridged cyclic hydrocarbon-oxy - group: norbornyloxy oxycarbonyl, such as adamantyloxycarbonyl; C _2-10 alkenyloxy - group: such as allyloxycarbonyl; C _6-10 aryl Oxy-carbonyl group: phenoxycarbonyl, naphthyloxycarbonyl, etc. C _7-19 aralkyloxy-carbonyl group: benzyloxycarbonyl, benzhydryloxycarbonyl, etc .; Amino C _1-6 alkyl-carbonyl group: 2-aminoethylcarbonyl, 3 -Aminopropylcarbonyl and the like; Mono C _1-6 alkylamino C _1-6 alkyl-carbonyl group: methylaminomethylcarbonyl, 2-ethylaminoethylcarbonyl and the like; Di C _1-6 alkylamino C _1-6 alkyl-carbonyl group :
Dimethylaminomethylcarbonyl, diethylaminomethylcarbonyl, etc .; Cyclic aminoalkylcarbonyl groups: imidazolinomethyl, pyrazolinoethyl, etc .;

C _1-10 alkoxy-carboxamide group: methoxycarboxamide (CH ₃ OCONH-), ethoxycarboxamide, tert-butoxycarboxamide, etc .; C _6-10 aryloxy-carboxamide group: phenoxycarboxamide (C ₆ H ₅ OCONH-) C _7-10 aralkyloxy-carboxamide group: benzyloxycarboxamide (C ₆ H ₅ CH ₂ OCONH-),
Benzhydryloxycarboxamide and the like; C _1-6 alkylureido group: methylureido, ethylureido, n-propylureido and the like; sulfonamide group: methanesulfonyl, ethanesulfonyl and the like;

[0039]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Examples. However, these are merely examples and do not limit the present invention in any way. Example 1 Preparation of 7-β-t-butoxycarbonylamino-3-[(E) -2-dimethylamino] vinyl-3-cephem-4-carboxylic acid benzhydryl ester 7-β-t-butoxycarbonylamino- 3-chloromethyl-3-
Cephem-4-carboxylic acid benzhydryl ester 515mg
Was dissolved in 10 ml of acetonitrile, 180 mg of sodium iodide was added with stirring at room temperature, and the mixture was stirred for 30 minutes. After distilling off acetonitrile under reduced pressure, the residue was redissolved in ethyl acetate and washed with water. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in 3 ml of 1,3-dimethyl-2-imidazolidinone (DMI) and stirred at room temperature under anhydrous tin fluoride (I
I) 313 mg, and then dimethylformamide dimethylacetal (DMF / DMA) 0.27 ml were sequentially added. After stirring at room temperature for 30 minutes, it was dissolved in ethyl acetate and washed with water. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (40 g, ethyl acetate-n hexane, 1: 1) to obtain 240 mg (Y = 45%) of the title compound (yellow powder). ¹ H-NMR (CDCl ₃ , δ): 1.49 (9H, s), 2.89 (6H, s), 3.18 (2H, m),
5.07 (1H, d, J = 4Hz), 5.29 (1H, dd, J = 4Hz, J = 8Hz), 5.66 (1H,
d, J = 8Hz), 6.50 (1H, d, J = 13.5Hz), 6.75 (1H, d, J = 13.5Hz),
6.87 (1H, s,), 7.2-7.6 (10H, m) .IR (KBr, cm ^-1 ): 3325,2975,2925,1760,1710,1690,1610,15
35,1380,1240,1160,1110,1015,740,700,600.

Example 2 7-β-formamide-3-[(E) -2-dimethylamino] vinyl-3
-Production of cephem-4-carboxylic acid benzhydryl ester 7-β-formamide-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester 451 mg was dissolved in dimethylformamide (DMF) 3 ml and stirred at room temperature. Meanwhile, 200 mg of sodium iodide, 380 mg of tin (II) chloride anhydride, and 0.27 ml of dimethylformamide dimethyl acetal were sequentially added. After stirring at room temperature for 1.5 hours, it was dissolved in ethyl acetate and washed with water. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (40 g, ethyl acetate) to obtain 40 mg of the title compound. ¹ H-NMR (CDCl ₃ , δ): 1.49 (9H, s), 2.60 and 3.33 (2H, ABq, J =
14Hz), 2.80 (6H, s), 5.07 (1H, d, J = 4Hz), 5.59 (1H, dd, J = 4H
z, J = 8.6Hz), 6.23 (2H, s), 6.75 (1H, s), 7.2-7.6 (10H, m), 7.
89 (1H, d, J = 8.6Hz), 8.46 (1H, s) .IR (KBr, cm ^-1 ): 1760,1680,1610,1530,1380,1235,1180,11
10,1000,740,700,600.

Example 3 7-β-Phenylacetamide-3-[(E) -2-dimethylamino]
Production of vinyl-3-cephem-4-carboxylic acid benzhydryl ester 7-β-phenylacetamido-3-bromomethyl-3-cephem-4-carboxylic acid benzhydryl ester 5.78 g of DMF30
Dissolve in 1.5 ml, add 1.8 g of sodium iodide, and in a warm bath at 38 ° C 50
Stir for minutes. Then, at room temperature, 3.8 g of anhydrous tin (II) chloride and 2.7 ml of dimethylformamide dimethylacetal were added, and the mixture was stirred at room temperature for 30 minutes, then, dissolved in 100 ml of ethyl acetate and washed with water.
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (150 g, ethyl acetate) to obtain 2.4 g of the title compound. ¹ H-NMR (CDCl ₃ , δ): 2.44 and 3.20 (2H, ABq, J = 14Hz), 2.79
(6H, s), 3.71 (2H, s), 5.01 (1H, d, J = 3.8Hz), 5.41 (1H, dd, J =
3.8Hz, J = 8.6Hz), 6.12 (1H, d, J = 13.6Hz), 6.22 (1H, d, J = 13.
6Hz), 6.74 (1H, s) 7.2-7.6 (15H, m) .IR (KBr, cm ^-1 ): 1750,1680,1610,1535,1495,1380,1235,11
90,1180,1010,695.

Example 4 7-β-formamide-3-[(E) -2-dimethylamino] vinyl-3
-Preparation of cephem-4-carboxylic acid p-methoxybenzyl ester 7-β-formamide-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 397 mg was dissolved in DMF 3 ml, sodium iodide 200 mg Then, anhydrous tin chloride (I
I) 380 mg, dimethylformamide dimethylacetal
0.3 ml was sequentially added, and the mixture was stirred at room temperature for 1 hour, then dissolved in 20 ml of ethyl acetate and washed with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (40 g, ethyl acetate) to give the title compound (50 m)
got g. ¹ H-NMR (CDCl ₃ , δ): 2.89 (6H, s), 3.02 and 3.17 (2H, ABq, J =
14Hz), 3.83 (3H, s), 5.06 (1H, d, J = 4.5Hz), 5.04 and 5.21 (2
H, ABq, J = 11.6Hz), 5.51 (1H, dd, J = 4.5Hz, J = 8Hz), 6.36 (1H,
d, J = 13.6Hz), 6.68 (1H, d, J = 13.6Hz), 6.89 and 7.35 (4H, d
d), 8.36 (1H, s).

Example 5 7-β-Phenylacetamide-3-[(E) -2-dimethylamino]
Production of vinyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester While stirring 30 ml of dimethylformamide at room temperature, 3 g of sodium iodide and 3.8 g of anhydrous tin (II) chloride were added and dissolved. After cooling to an internal temperature of 15 ° C, 4.87 g of 7-β-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester was added and dissolved, and then dimethylformamide di-n-propyl was added. 8 ml of acetal was added. After stirring at room temperature for 45 minutes, a solution of ethylenediaminetetraacetic acid tetrasodium salt (hereinafter abbreviated as EDTA-4Na) 11 g / water 20 ml, 200 ml of tetrahydrofuran and 100 ml of saturated saline were added and stirred. The tetrahydrofuran layer was separated and the aqueous layer was washed with 100 ml of tetrahydrofuran. The tetrahydrofuran layers were combined and washed with 100 ml of saturated saline three times. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The crystalline residue was triturated with isopropyl ether and filtered. 5 g of the title compound was obtained. mp 166-168 ° C ¹ H-NMR (CDCl ₃ , δ): 2.89 (6H, s), 2.95-3.00 (2H), 2.79 (6H,
s), 3.67 (2H, s), 3.79 (3H, s), 5.02 (1H, d, J = 4Hz), 5.02 and
5.20 (2H, ABq, J = 14Hz), 5.40 (1H, dd, J = 4Hz, J = 8.2Hz), 6.37
(1H, d, J = 13.6Hz), 6.65 (1H, d, J = 13.6Hz), 6.65-6.75 (1H,
m), 6.87 (2H, d, J = 8.8Hz), 7.25-7.40 (7H, m) IR (KBr, cm ^-1 ): 1760,1680,1660,1615,1535,1515,1380,13
00,1240,1190,1170,1110,1030,820.

Example 6 7-β-t-Butoxycarbonylamino-3-formylmethyl-3
-Preparation of cephem-4-carboxylic acid benzhydryl ester 7-β-t-butoxycarbonylamino-3-chloromethyl-3-
5.15 g of cephem-4-carboxylic acid benzhydryl ester
Was dissolved in 30 ml of dimethylformamide, and under stirring at room temperature, 2 g of sodium iodide, 3.8 g of anhydrous tin (II) chloride and then 2.7 ml of dimethylformamide dimethylacetal were sequentially added. After stirring at room temperature for 45 minutes, a solution of ethylenediaminetetraacetic acid tetrasodium salt (hereinafter abbreviated as EDTA-4Na) 11 g / water 20 ml and then acetone 100 ml were added. It was filtered and the filtrate was evaporated under reduced pressure. It was redissolved in 100 ml of ethyl acetate and washed with 100 ml of saturated saline. 10 ml of M-phosphoric acid aqueous solution in the ethyl acetate extract,
50 ml of water was added and the mixture was stirred at room temperature for 3 hours. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography (ethyl acetate-n-hexane, 1: 2) and developed with the same solvent. 2.1 g (Y = 41%) of the title compound was obtained. ¹ H-NMR (CDCl ₃ , δ): 1.50 (9H, s), 3.25 and 3.57 (2H, ABq, J =
18.8Hz), 3.51 and 3.68 (2H, ABq, J = 16.2Hz), 5.00 (1H, d, J =
4.8Hz), 5.30 (1H, d, J = 9Hz), 5.66 (1H, dd, J = 4.8Hz, J = 9Hz),
6.88 (1H, s), 7.2-7.5 (10H, m), 9.56 (1H, s) .IR (KBr, cm ^-1 ): 3325,2980,1780,1700,1630,1510,1455,13
70,1320,1240,1160,1100,740, 700,600.

Example 7 7-β-t-Butoxycarbonylamino-3-formylmethyl-3
-Preparation of cephem-4-carboxylic acid benzhydryl ester 7-β-t-butoxycarbonylamino-3-chloromethyl-3-
5.15 g of cephem-4-carboxylic acid benzhydryl ester
2.5 g of the title compound was obtained in the same manner as in Example 6 using 6 ml of dimethylformamide and diethyl acetal.

Example 8 Preparation of 7-β-formamide-3-formylmethyl-3-cephem-4-carboxylic acid benzhydryl ester 7-β-formamide-3-chloromethyl-3-cephem-4-carboxylic acid benz Dissolve 4.5 g of hydryl ester in 30 ml of dimethylformamide, and add sodium iodide 2 under stirring at room temperature.
3.8 g of anhydrous tin (II) chloride and 2.7 ml of dimethylformamide dimethyl acetal were sequentially added. Room temperature 1.5
After stirring for an hour, DMF was distilled off under reduced pressure (pump). The residue was redissolved in 100 ml of ethyl acetate, washed with saturated brine, 10 ml of N-hydrochloric acid and 90 ml of water were added to the ethyl acetate solution, and the mixture was stirred at room temperature for 30 minutes. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate-n-hexane, 1: 1),
It was developed with ethyl acetate. 1.6 g (Y = 36%) of the title compound was obtained. ¹ H-NMR (CDCl ₃ , δ): 3.26 and 3.53 (2H, ABq, J = 18.8Hz), 3.4
7 and 3.71 (2H, ABq, J = 17Hz), 5.02 (1H, d, J = 5Hz), 5.94 (1H,
dd, J = 5Hz, J = 9Hz), 6.88 (1H, s), 7.2-7.5 (10H, m), 8.23 (1H,
s), 9.55 (1H, s) .IR (KBr, cm ^-1 ): 1780,1720,1680,1520,1495,1370,1240,11
70,740,700,600.

Example 9 7-β-phenylacetamide-3-formylmethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 7-β-phenylacetamide-3-[(E) -2-dimethylamino]
5 g of vinyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester was dissolved in 100 ml of ethyl acetate, and 20 ml of M-phosphoric acid aqueous solution was added. The mixture was placed in a 35 ° C warm bath and stirred for 1 hour. After cooling the reaction solution, it was washed with 100 ml of saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate) and developed with the same solvent. 3.3 g of the title compound was obtained. ¹ H-NMR (CDCl ₃ , δ): 3.19 and 3.52 (2H, ABq, J = 18Hz), 3.40
(1H, d, J = 17Hz), 3.64 (2H, d, J = 2.5Hz), 3.80 (3H, s), 4.93 (1
H, d, J = 5Hz), 5.16 (2H, s), 5.82 (1H, dd, J = 5Hz, J = 9Hz), 6.09
(1H, d, J = 9Hz), 6.88 (2H, d, J = 8.7Hz), 7.2-7.4 (9H, m), 9.63
(1H, s) .IR (KBr, cm ^-1 ): 3025,2950,2840,1770,1715,1655,1610,15
15,1385,1360,1240,1170,1100,1030,820,695.

Example 10 Preparation of 7-β-t-butoxycarbonylamino-3-[(E) -2-isonicotinoyloxy] vinyl-3-cephem-4-carboxylic acid benzhydryl ester 7-β-t -Butoxycarbonylamino-3-formylmethyl-3
-Cephem-4-carboxylic acid benzhydryl ester 509 mg
Was dissolved in 3 ml of dimethylformamide, and 170 mg of isonicotinic acid chloride and 140 mg of imidazole were added with stirring under ice cooling, and the mixture was stirred for 15 minutes. It was redissolved in ethyl acetate and washed with saturated brine. The extract was dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give the title compound (500 mg). ¹ H-NMR (CDCl ₃ ,, δ): 1.48 (9H, s), 3.65 (2H, s), 5.05 (1H, d, J
= 4.6Hz), 5.38 (1H, d, J = 9.6Hz), 5.70 (1H, dd, J = 4.6Hz, J = 9.
6Hz), 6.98 (1H, s), 7.2-8.9 (16H, m) .IR (KBr, cm ^-1 ): 2970,1780,1710,1500,1360,1320,1280,12
40,1155,1120,750,695.

Example 11 Preparation of 7-β-t-butoxycarbonylamino-3-[(E) -2-benzoyloxy] vinyl-3-cephem-4-carboxylic acid benzhydryl ester 30 ml of dimethylformamide are stirred at room temperature. On the other hand, 3 g of sodium iodide and 3.8 g of anhydrous tin (II) chloride were added and dissolved. After cooling to an internal temperature of 15 ° C, 5.15 g of 7-β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester was added and dissolved, and then dimethylformamide di-n- 8 ml of propyl acetal was added. After stirring for 30 minutes at room temperature, a solution of 11 g of ethylenediaminetetraacetic acid tetrasodium salt (hereinafter abbreviated as EDTA-4Na) in 20 ml of water and then 100 ml of tetrahydrofuran were added and stirred. The tetrahydrofuran layer was separated and the aqueous layer was replaced with tetrahydrofuran 1
Washed with 00 ml. The tetrahydrofuran layers were combined and washed with 100 ml of saturated saline. Tetrahydrofuran was distilled off under reduced pressure. 20 ml of ethyl acetate and M-phosphoric acid solution in the residue
Was added and the mixture was stirred in a 35 ° C. water bath for 1 hour. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Foamy residue in dimethylformamide
Dissolve in 30 ml and benzoyl chloride 1.
2 ml and 1.4 g of imidazole were added and stirred for 30 minutes. 200 ml of ethyl acetate was added to the reaction solution, and the mixture was washed with saturated saline (100 ml × 3 times). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue
(Ethyl acetate-n hexane, 1: 2) and developed with the same solvent. 3.8 g of the title compound was obtained. Recrystallization from ethyl ether gave 2.4 g of the title compound crystals. mp 174-176 ℃ (decomp.) ¹ H-NMR (CDCl ₃ , δ): 1.48 (9H, s), 3.65 (2H, s), 5.05 (1H, d, J
= 5Hz), 5.31 (1H, d, J = 9.6Hz), 5.65 (1H, dd, J = 5Hz, J = 9.6H
z), 6.99 (1H, s), 7.2- 8.1 (17H, m) .IR (KBr, cm ^-1 ): 3350,3080,2980,1790,1725,1705,1520,14
50,1380,1365,1320,1260,1240,1205,1160,1120,705.

Example 12 Preparation of 7-β-t-butoxycarbonylamino-3-[(E) -2- (4-nitrobenzoyl) oxy] vinyl-3-cephem-4-carboxylic acid benzhydryl ester Dimethylformamide While stirring 60 ml at room temperature, 6 g of sodium iodide and 7.6 g of anhydrous tin (II) chloride were added and dissolved. After cooling to an internal temperature of 15 ° C, 10.3 g of 7-β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester was added and dissolved, and then dimethylformamide di-n- 16 ml of propyl acetal was added. After stirring at room temperature for 50 minutes, a solution of ethylenediaminetetraacetic acid tetrasodium salt (hereinafter abbreviated as EDTA-4Na) 22 g / water 40 ml and then methyl ethyl ketone 300 ml were added and stirred. Separate the methyl ethyl ketone layer and add the water layer to methyl ethyl ketone 1
Washed with 00 ml. The methyl ethyl ketone layers were combined and washed with 100 ml of saturated saline. The solvent was evaporated under reduced pressure, ethyl acetate and 40 ml of M-phosphoric acid aqueous solution were added to the residue, and the mixture was stirred in a 35 ° C water bath for 1 hour. After washing the ethyl acetate layer with saturated saline,
The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Dissolve the foamy residue in 50 ml of dimethylformamide,
3.7g of para-nitrobenzoyl chloride under ice-cooled stirring
2.8 g of imidazole was added and stirred for 10 minutes. 200 ml of ethyl acetate was added to the reaction solution, and the mixture was washed with saturated saline (100 ml × 3 times). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate-n hexane, 1: 1) and developed with the same solvent.
The crystals are triturated with ethyl ether and collected by filtration to give the title compound as crystals.
5 g were obtained. mp 145-147 ° C (decomp.) ¹ H-NMR (CDCl ₃ , δ): 1.48 (9H, s), 3.65 (2H, s), 5.06 (1H, d, J
= 4.9Hz), 5.30 (1H, d, J = 10Hz), 5.69 (1H, dd, J = 4.9Hz, J = 10H
z), 6.98 (1H, s), 7.2-8.4 (17H, m) .IR (KBr, cm ^-1 ): 3325,3090,2975,1785,1735,1710,1690,15
25,1380,1370,1340,1260,1220,1160,1125.

Example 13 7-β-t-butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
Production of Carboxylic Acid Benzhydryl Ester 30 ml of dimethylformamide was dissolved with stirring at room temperature while adding 2 g of sodium iodide and 3.8 g of anhydrous tin (II) chloride. After cooling to an internal temperature of 5-10 ° C, 5.15 g of 7-β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester was added and dissolved, and then dimethylformamide dimethylacetal was added. 6 ml was added. After stirring at room temperature for 2 hours, a solution of ethylenediaminetetraacetic acid tetrasodium salt (hereinafter abbreviated as EDTA-4Na) 11 g / water 20 ml and then ethyl acetate 200 ml were added and stirred. The ethyl acetate layer was decanted and the precipitate was washed with ethyl acetate. The ethyl acetate layers were combined and washed with 100 ml of saturated saline. The ethyl acetate extract was concentrated under reduced pressure to about 100 ml, 20 ml of M-phosphoric acid aqueous solution and 80 ml of water were added, and the mixture was stirred at room temperature for 4 hours. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Dissolve the foamy residue in 30 ml of dimethylformamide, add 1.7 g of isonicotinic acid chloride hydrochloride and 1.4 g of imidazole under ice-cooling stirring.
After stirring for 15 minutes, 1.4 g of 6-mercaptoimidazo [1,2-b] pyridazine sodium salt was added, and the mixture was further stirred at room temperature for 1 hour. 200 ml of ethyl acetate was added to the reaction solution, and saturated saline solution (100
(ml x 3 times). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate) and developed with the same solvent.
3.5 g (Y = 54%) of the title compound were obtained. Recrystallized from ethyl acetate-isopropyl ether (1: 2) to give 2.6 g (Y
= 40%). mp 116-120 ° C. Elemental _{analysis; C 33 H 31 N 5 O} 5 S · 0.5H 2 O Calculated: C, 60.91; H, 4.96 ; N, 10.76 Found: C, 61.03; H, 4.98 ; N, 10.46 ¹ H-NMR (CDCl ₃ , δ): 1.48 (9H, s), 3.68 and 3.81 (2H, ABq, J =
18Hz), 5.04 (1H, d, J = 4.8Hz), 5.87 (1H, d, J = 9.6Hz), 5.67 (1
H, dd, J = 4.8Hz, J = 9.6Hz), 6.85 (1H, d, J = 9.4Hz), 6.99 (1H,
s), 7.2- 7.6 (10H, m), 7.72 (1H, s), 7.82 (1H, d, J = 9.4Hz),
7.93 (1H, s) .IR (KBr, cm ^-1 ): 2970,1780,1715,1525,1450,1360,1310,12
80,1240,1200,1155,1100,695.

Example 14 7-β-t-Butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
Preparation of carboxylic acid benzhydryl ester 7-β-t-butoxycarbonylamino-3-chloromethyl-3-
5.15 g of cephem-4-carboxylic acid benzhydryl ester
Example 13 Using 6 ml of dimethylformamide dimethyl acetal and 1.78 g of 2-picolinoyl chloride hydrochloride, Example 13
2.2 g of the title compound was obtained in the same manner as.

Example 15 7-β-t-butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
Production of Carboxylic Acid Benzhydryl Ester 30 ml of dimethylformamide was added to and dissolved with stirring at room temperature, 3 g of sodium iodide and 3.8 g of anhydrous tin (II) chloride. After cooling to an internal temperature of 18-20 ° C, 5.15 g of 7-β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester was added and dissolved, and then dimethylformamide diethyl acetal was added. 7 ml was added. After stirring at room temperature for 1 hour, a solution of ethylenediaminetetraacetic acid tetrasodium salt (hereinafter abbreviated as EDTA-4Na) 11 g / water 20 ml was added and stirred with 200 ml of ethyl acetate. The ethyl acetate layer was decanted and the precipitate was washed with ethyl acetate. The ethyl acetate layers were combined and washed with 100 ml of saturated saline. 20 ml of M-phosphoric acid aqueous solution was added to the ethyl acetate layer, and the mixture was stirred in a 35 ° C water bath for 2 hours. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Dissolve the foamy residue in 30 ml of dimethylformamide and, under ice-cooling stirring, 0.8 ml of benzoyl chloride, 1 g of imidazole.
After stirring for 40 minutes, 6-mercaptoimidazo [1,2-b]
Pyridazine sodium salt (1.74 g) was added, and the mixture was further stirred with ice cooling for 1 hour. 200 ml of ethyl acetate was added to the reaction solution, and the mixture was washed with saturated saline (100 ml × 4 times). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in a small amount of ethyl acetate, isopropyl ether was added until it became cloudy, inoculated and allowed to stand in a cool place. The crystals were collected by filtration to give the title compound
1.7 g was obtained.

Example 16 7-β-t-butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
Production of carboxylic acid benzhydryl ester 15 ml of dimethylformamide was stirred at room temperature, and 1.5 g of sodium iodide and 1.9 g of anhydrous tin (II) chloride were added and dissolved. After cooling to an internal temperature of 5-10 ° C, 2.6 g of 7-β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester was added and dissolved, and then dimethylformamide di- t-butyl acetal 4.5 ml
Was added. After stirring at room temperature for 30 minutes, a solution of 5 g of EDTA-4Na / 10 ml of water and then 100 ml of ethyl acetate were added and stirred. The ethyl acetate layer was decanted and the precipitate was washed with ethyl acetate. The ethyl acetate layers were combined and washed with 50 ml of saturated saline. The ethyl acetate extract was concentrated under reduced pressure to about 70 ml, 10 ml of M-phosphoric acid aqueous solution was added, and the mixture was stirred at room temperature for 4 hours. The ethyl acetate layer was washed with 50 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The foamy residue was dissolved in 30 ml of dimethylformamide, and 0.9 g of isonicotinic acid chloride hydrochloride and 0.7 g of imidazole were added under ice-cooling stirring.
After stirring for 5 minutes, 0.85 g of 6-mercaptoimidazo [1,2-b] pyridazine sodium salt was added, and the mixture was further stirred at room temperature for 1 hour. 200 ml of ethyl acetate was added to the reaction solution, and saturated saline solution (100
(ml x 3 times). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate) and developed with the same solvent.
1.4 g (Y = 44%) of the title compound was obtained.

Example 17 7-β-t-butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
Production of carboxylic acid benzhydryl ester 15 ml of dimethylformamide was stirred at room temperature, and 1.5 g of sodium iodide and 1.9 g of anhydrous tin (II) chloride were added and dissolved. After cooling to an internal temperature of 5-10 ° C, 2.6 g of 7-β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester was added and dissolved, and then dimethylformamide diisopropylacetal was added. 4.2m
l was added. After stirring for 60 minutes at room temperature, 5.5 g of EDTA-4Na / water 10
Then, 100 ml of ethyl acetate was added and the mixture was stirred. The ethyl acetate layer was decanted and the precipitate was washed with ethyl acetate. The ethyl acetate layers were combined and washed with 50 ml of saturated saline. The ethyl acetate extract was concentrated under reduced pressure to about 70 ml, and then M-
10 ml of a phosphoric acid aqueous solution was added, and the mixture was stirred in a 35 ° C warm bath for 1 hour and 40 minutes. The ethyl acetate layer was washed with 50 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The foamy residue was dissolved in 15 ml of dimethylformamide, and 0.9 g of isonicotinic acid chloride hydrochloride and 0.7 g of imidazole were added with stirring under ice cooling, and the mixture was stirred for 10 minutes, then 6-mercaptoimidazo [1,2-b] pyridazine sodium salt. 0.85 g of salt was added, and the mixture was stirred with ice cooling for 1 hour. 150 ml of ethyl acetate was added to the reaction solution, and the mixture was washed with saturated saline (50 ml × 2 times). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 2.74 g of the crude title compound.
The residue was dissolved in a small amount of ethyl acetate, isopropyl ether was added until it became cloudy, inoculated and allowed to stand in a cool place.
The crystals were collected by filtration to obtain 2.2 g (Y = 68%) of the title compound.

Example 18 7-β-t-Butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
Production of Carboxylic Acid Benzhydryl Ester 30 ml of dimethylformamide was added to and dissolved with stirring at room temperature, 3 g of sodium iodide and 3.8 g of anhydrous tin (II) chloride. After cooling to an internal temperature of 15 ° C, 5.15 g of 7-β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester was added and dissolved, and then dimethylformamide di-n- 8 ml of propyl acetal was added. After stirring at room temperature for 1 hour, a solution of ethylenediaminetetraacetic acid tetrasodium salt (hereinafter abbreviated as EDTA-4Na) 11 g / water 20 ml was added and stirred with 200 ml of ethyl acetate. The ethyl acetate layer was decanted and the precipitate was washed with ethyl acetate. The ethyl acetate layers were combined and washed with 100 ml of saturated saline. Add 20 ml of M-phosphoric acid aqueous solution to the ethyl acetate layer, and in a 35 ° C water bath 1
Stirred for hours. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
Dissolve the foamy residue in 30 ml of dimethylformamide,
With stirring under ice cooling, 2.5 g of isonicotinic acid chloride hydrochloride,
After adding 1.9 g of imidazole and stirring for 30 minutes, 2.4 g of 6-mercaptoimidazo [1,2-b] pyridazine sodium salt was added and further stirred for 1 hour with ice cooling. 200 ml of ethyl acetate in the reaction solution
Was added, and the mixture was washed with saturated saline (100 ml x 3 times). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in a small amount of ethyl acetate, isopropyl ether was added until it became cloudy, inoculated and allowed to stand in a cool place. The crystals were collected by filtration to obtain 4.7 g (Y = 73%) of the title compound.

Example 19 7-β-t-Butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
Preparation of carboxylic acid benzhydryl ester 7-β-t-butoxycarbonylamino-3-chloromethyl-3-
5.15 g of cephem-4-carboxylic acid benzhydryl ester
Using 9.6 ml of dimethylformamide di-n-butyl acetal, 4.4 g of the title compound crystal (Y = 6) was prepared in the same manner as in Example 18.
9%).

Example 20 7-β-Phenylacetamide-3-[(E) -2- (imidazo [1,2-
b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester preparation 7-β-phenylacetamido-3-formylmethyl-3-cephem-4-carboxylic acid p-methoxy Benzyl ester 0.87g
Was dissolved in 6 ml of dimethylformamide, and 0.36 g of isonicotinic acid chloride and 0.2% of imidazole were stirred while cooling with ice.
8 g were added. After 15 minutes, 0.34 g of 6-mercaptoimidazo [1,2-b] pyridazine sodium salt was added, and the mixture was further stirred with ice cooling for 1 hour. 30 ml of ethyl acetate and 30 ml of tetrahydrofuran were added to the reaction solution, and the mixture was washed with saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to give the title compound 0.3
got g. mp 182-185 ° C (decomp.) ¹ H-NMR (CDCl ₃ , δ): 3.62 and 3.73 (2H, ABq, J = 13Hz), 3.66
(2H, s), 3.80 (3H, s), 4.84 (1H, d, J = 4.8Hz), 5.21 (2H, s), 5.
83 (1H, dd, J = 4.8Hz, J = 9Hz), 6.37 (1H, d, J = 9Hz), 6.8-7.9 (1
5H, m) .IR (KBr, cm ^-1 ): 1770,1700,1640,1525,1515,1360,1315,12
10,1170,1100,800.

Example 21 7-β-t-Butoxycarbonylamino-3-[(E) -2- (4-trifuryloromethylbenzoyl) oxy] vinyl-3-cephem-
Production of 4-Carboxylic Acid Benzhydryl Ester 30 ml of dimethylformamide was added to and dissolved with stirring at room temperature, 3 g of sodium iodide and 3.8 g of anhydrous tin (II) chloride. After cooling to an internal temperature of 15 ° C, 5.15 g of 7-β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester was added and dissolved, and then dimethylformamide di-n- 8 ml of propyl acetal was added. After stirring at room temperature for 60 minutes, a solution of EDTA-4Na 11 g / water 20 ml and then tetrahydrofuran 200 ml were added and stirred. The tetrahydrofuran layer was separated and the aqueous layer was washed with 100 ml of tetrahydrofuran. Combine the tetrahydrofuran layers,
It was washed with 50 ml of saturated saline. The solvent is distilled off under reduced pressure,
Ethyl acetate (100 ml) and M-phosphoric acid aqueous solution (20 ml) were added to the residue, and the mixture was stirred in a water bath at 35 ° C for 1.5 hr. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 30 ml of the residue is dimethylformamide
The mixture was dissolved in, and imidazole 1 g and p-trifluoromethylbenzoyl chloride 1.4 ml were sequentially added under ice-cooling stirring, and the mixture was stirred for 10 minutes. 200 ml of ethyl acetate was added to the reaction solution, and the mixture was washed with saturated saline (100 ml × 3 times). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue crystals were triturated with ethyl ether and collected by filtration to obtain 3.8 g of the title compound crystals. mp 174-176 ℃ ¹ H-NMR (CDCl ₃ , δ): 1.48 (9H, s), 3.65 (2H, s), 5.04 (1H, d, J
= 4.8Hz), 5.30 (1H, d, J = 9Hz), 5.67 (1H, dd, J = 4.8Hz, J = 9H
z), 6.97 (1H, s), 7.2- 8.2 (16H, m) .IR (KBr, cm ^-1 ): 3325,2980,1790,1730,1690,1515,1380,13
70,1320,1270,1160,1120,1060,855,765,695.

Example 22 Preparation of 7-β-phenylacetamide-3-[(E) -2- (4-nitrobenzoyl) oxy] vinyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 30 ml of dimethylformamide While stirring at room temperature, 3 g of sodium iodide and 3.8 g of anhydrous tin (II) chloride were added and dissolved. After cooling to an internal temperature of 15 ° C, 4.87 g of 7-β-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester was added and dissolved, and then dimethylformamide di-n-propyl was added. 8 ml of acetal was added. After stirring at room temperature for 60 minutes, a solution of EDTA-4Na 11 g / water 20 ml and then tetrahydrofuran 200 ml were added and stirred. The tetrahydrofuran layer was separated and the aqueous layer was replaced with tetrahydrofuran 5
Washed with 0 ml. The tetrahydrofuran layers were combined and washed with 50 ml of saturated saline. Tetrahydrofuran was distilled off under reduced pressure, and ethyl acetate and M-phosphoric acid aqueous solution 20 ml were added to the residue.
Was added and the mixture was stirred in a 35 ° C. water bath for 1 hour. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 30m of the residue is dimethylformamide
The mixture was dissolved in 1 l, and imidazole 1 g and p-nitrobenzoyl chloride 1.8 g were sequentially added under ice-cooling stirring, and the mixture was ice-cooled stirring for 60 minutes.
100 ml of ethyl acetate was added to the reaction solution, and saturated saline solution (100 ml
× 3 times). The solvent was distilled off under reduced pressure, water and ethyl ether were added to the residue, and the crystalline solid was collected by filtration. After drying, 3.6 g of the title compound was obtained. mp 156-159 ° C ¹ H-NMR (CDCl ₃ , δ): 3.52 (2H, s), 3.66 (2H, s), 3.81 (3H, s),
4.99 (1H, d, J = 4.9Hz), 5.23 (2H, d, J = 2.1Hz), 5.83 (1H, dd, J
= 4.9Hz, J = 9.4Hz), 6.23 (1H, d, J = 9.4Hz), 6.8-8.3 (11H,
m) .IR (KBr, cm ^-1 ): 3250,1780,1735,1705,1650,1525,1510,13
50,1260,1220,1170,1125,1100,1030,1010,710.

Example 23 7-β-t-butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
Production of Carboxylic Acid Benzhydryl Ester 30 ml of dimethylformamide was added to and dissolved with stirring at room temperature, 3 g of sodium iodide and 3.8 g of anhydrous tin (II) chloride. After cooling to an internal temperature of 15 ° C, 5.15 g of 7-β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester was added and dissolved, and then dimethylformamide di-n- 8 ml of propyl acetal was added. After stirring for 50 minutes at room temperature, EDTA-4Na 11 g / water 20 ml solution, then tetrahydrofuran 200 ml and saturated saline solution 50 m
l was added and stirred. The tetrahydrofuran layer was separated and the aqueous layer was washed with 100 ml of tetrahydrofuran. The tetrahydrofuran layers were combined and washed with 100 ml of saturated saline.
The solvent was distilled off under reduced pressure, and the residue was diluted with 100 ml of ethyl acetate and M-
20 ml of a phosphoric acid aqueous solution was added, and the mixture was stirred in a 35 ° C water bath for 1 hour. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Dissolve the foamy residue in 30 ml of dimethylformamide and add 1 g of imidazole and 1.9 g of p-nitrobezoyl chloride under ice cooling and stirring.
The mixture was stirred under ice cooling. Then 6-mercaptoimidazo [1,
2.5 g of 2-b] pyridazine sodium salt was added, and the mixture was further stirred with ice cooling for 1 hour. 200 ml of ethyl acetate was added to the reaction solution, and the mixture was washed with saturated saline (100 ml × 3 times). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in a small amount of ethyl acetate, isopropyl ether was added until it became cloudy, inoculated and allowed to stand in a cool place. The crystals were collected by filtration and dried by a pump to obtain 4.15 g of the title compound. The mother liquor was purified by subjecting it to column chromatography (silica gel 50 g, ethyl acetate) to obtain 0.55 g of the title compound crystals. 4.7 g (Y = 73%) of the title compound crystal was obtained.

Example 24 7-β-t-butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
Production of Carboxylic Acid Benzhydryl Ester 30 ml of dimethylformamide was added to and dissolved with stirring at room temperature, 3 g of sodium iodide and 3.8 g of anhydrous tin (II) chloride. After cooling to an internal temperature of 15 ° C, 5.15 g of 7-β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester was added, and immediately dimethylformamide di-n-propylacetal 8 ml was added. Was added dropwise. After stirring at room temperature for 60 minutes, a solution of 11 g of EDTA-4Na / 20 ml of water, 200 ml of tetrahydrofuran and 50 ml of saturated saline were added and stirred. The tetrahydrofuran layer was separated and the aqueous layer was washed with 100 ml of tetrahydrofuran. The tetrahydrofuran layers were combined and washed with 100 ml of saturated saline. The solvent was evaporated under reduced pressure, 100 ml of ethyl acetate and 20 ml of M-phosphoric acid aqueous solution were added to the residue, and the mixture was stirred in a 35 ° C water bath for 1.5 hours. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 30 ml of dimethylformamide, and the mixture was stirred under ice-cooling with imidazole.
1g, p-trifluoromethylbezoyl chloride 1.4ml
Were added sequentially. After stirring for 20 minutes under ice-cooling, add 2.5 g of 6-mercaptoimidazo [1,2-b] pyridazine sodium salt and add 1 more.
The mixture was stirred for ice-cooling for an hour. 200 ml of ethyl acetate was added to the reaction solution,
It was washed with saturated saline (100 ml × 3 times). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in 15 ml of ethyl acetate-diisopropyl ether (1: 2), and the crystals precipitated after inoculation were left in a freezer for 3 days and nights. 10 ml of isopropyl ether was added and the crystals were disentangled and collected by filtration, and the crystals were washed with ethyl acetate-diisopropyl ether (1: 4).
The crystals were dried by a pump to obtain 5.02 g (Y = 78%) of the title compound. Column chromatography of the mother liquor (silica gel 50 g,
It was then purified by subjecting it to ethyl acetate) to obtain 0.2 g of the title compound crystal.
(Total yield = 81%).

Example 25 7-β-t-butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
Preparation of carboxylic acid benzhydryl ester 7-β-t-butoxycarbonylamino-3-chloromethyl-3-
5.15 g of cephem-4-carboxylic acid benzhydryl ester
Dimethylformamide di-n-propyl acetal 8ml, 4-
Chlorobenzoyl chloride 1.3 ml, imidazole 1 g,
6-mercaptoimidazo [1,2-b] pyridazine sodium salt
3.7 g of the title compound was obtained in the same manner as in Example 24 except that 2 g was used. Example 26 7-β-t-Butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
Preparation of carboxylic acid benzhydryl ester 7-β-t-butoxycarbonylamino-3-chloromethyl-3-
5.15 g of cephem-4-carboxylic acid benzhydryl ester
Dimethylformamide di-n-propyl acetal 8ml, orthotoluoyl chloride 1.3ml, imidazole 1g, 6
-Mercaptoimidazo [1,2-b] pyridazine sodium salt 2
3.8 g of the title compound was obtained in the same manner as in Example 24 using g. Example 27 7-β-t-Butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
Preparation of carboxylic acid benzhydryl ester 7-β-t-butoxycarbonylamino-3-chloromethyl-3-
5.15 g of cephem-4-carboxylic acid benzhydryl ester
Dimethylformamide di-n-propyl acetal 8ml, paratoluoyl chloride 1.3ml, imidazole 1g, 6-
Mercaptoimidazo [1,2-b] pyridazine sodium salt 2g
In the same manner as in Example 24, 2.6 g of the title compound was obtained.

Example 28 7β-t-Butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
Preparation of carboxylic acid benzhydryl ester 7 β-t-butoxycarbonylamino-3-chloromethyl-4-carboxylic acid benzhydryl ester (2.0 g) in tetrahydrofuran (10 ml) solution at room temperature under dehumidification at 1.3 equivalent sodium iodide (757 mg) was added and the mixture was stirred for 15 minutes. After that, 2.0 equivalents of tin powder (922 mg) and N, N-dimethylformamide diisopropyl acetal (1.62 ml) were added, and the mixture was reacted at room temperature for 2 hours (no heat generation). 50 ml of ethyl acetate was added to the reaction solution, and the mixture was filtered through Celite (30 ml), and the filtrate was diluted with ethylenediaminetetraacetic acid disodium salt (2 g).
It was washed 3 times with an aqueous solution (50 ml). Celite (30
ml), 7 ml of 1N hydrochloric acid was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed twice with 50 ml of saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The resulting pale yellow powder was dissolved in 10 ml of dimethylformamide, 1.2 equivalents of isonicotinic acid chloride hydrochloride (830 mg) and imidazole (317 mg) were added at 0 ° C., and the mixture was stirred for 15 minutes. Then 1.2 equivalents of 6-mercaptoimidazo [1,2-b] pyridazine sodium salt (672 mg)
Was added and the temperature was gradually raised to room temperature over 2 hours with stirring. 50 ml of ethyl acetate was added to the reaction solution, and the mixture was washed twice with 50 ml of saturated saline and twice with 5 ml of saturated saline containing 1N-hydrochloric acid (50 ml). The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (100 ml, ethyl acetate 100%).
β-t-butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
The carboxylic acid benzhydryl ester was isolated (1.55
g, 62% yield).

Example 29 Preparation of 7β-t-butoxycarbonylamino-3-[(E) -2-dimethylamino] vinyl-3-cephem-4-carboxylic acid benzhydryl ester 7β-t-butoxycarbonylamino-3 To a solution of -chloromethyl-4-carboxylic acid benzhydryl ester (784 mg) in tetrahydrofuran (4 ml) was added 1.3 equivalents of sodium iodide (297 mg) at room temperature under dehumidification, and the mixture was stirred for 15 minutes. Then, 10 equivalents of 2.0 equivalents of zinc powder (199 mg) and N, N-dimethylformamide diisopropyl acetal (0.64 ml) activated by washing with 1N hydrochloric acid were respectively prepared.
The mixture was added at 0 ° C. and stirred at room temperature for 45 minutes (exotherm was observed). To the reaction mixture was added 20 ml of ethyl acetate and distilled water (20 ml).
The extract was filtered through Celite (10 ml) three times. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
Silica gel column chromatography (100 ml, ethyl acetate: hexane = 1: 1) gave 7β-t-butoxycarbonylamino-3-[(E) -2-dimethylamino] vinyl-3-cephem
-4-Carboxylic acid benzhydryl ester was isolated (350
mg, yield 50%).

Example 30 Preparation of 7β-t-butoxycarbonylamino-3-[(E) -2-dimethylamino] vinyl-3-cephem-4-carboxylic acid benzhydryl ester 7β-t-butoxycarbonylamino-3 To a tetrahydrofuran (5 ml) solution of -chloromethyl-4-carboxylic acid benzhydryl ester (1.20 g), 1.3 equivalent of sodium iodide (454 mg) was added at room temperature under dehumidification, and the mixture was stirred for 15 minutes. Then, 2.0 equivalents of zinc powder (305 mg) activated by washing with 1N hydrochloric acid and N, N-dimethylformamide dimethyl acetal (0.62 ml) were added at 10-15 ° C, respectively, and stirred at room temperature for 45 minutes (exothermic heat). Was recognized). 40 ml of ethyl acetate was added to the reaction solution, which was washed 3 times with distilled water (40 ml), and the extract was filtered through Celite (30 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Silica gel column chromatography (150 ml, ethyl acetate:
7β-t-Butoxycarbonylamino-3-[(E) -2-dimethylamino] vinyl-3-cephem-4-carboxylic acid benzhydryl ester was isolated with hexane = 1: 1 (610 mg,
Yield 49%).

Example 31 Preparation of 7β-t-butoxycarbonylamino-3-[(E) -2-dimethylamino] vinyl-3-cephem-4-carboxylic acid benzhydryl ester 7β-t-butoxycarbonylamino-3 To a tetrahydrofuran (3 ml) solution of -chloromethyl-4-carboxylic acid benzhydryl ester (668 mg) was added 1.3 equivalent of sodium iodide (253 mg) at room temperature under dehumidification, and the mixture was stirred for 15 minutes. Then, 10 equivalents of 2.0 equivalents of zinc powder (170 mg) and N, N-dimethylformamide ditertiary butyl acetal (0.62 ml) each activated by washing with 1N hydrochloric acid were added.
Add at 15 ° C. and stir at room temperature for 45 minutes (exotherm observed). Add 20 ml of ethyl acetate to the reaction mixture and add distilled water (20 m
The extract was filtered through Celite (30 ml) three times with l).
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Silica gel column chromatography (70 ml, ethyl acetate: hexane = 1: 1) gave 7β-t-butoxycarbonylamino-3-[(E) -2-dimethylamino] vinyl-3-cephem-4-carboxylic acid benz Isolated hydryl ester
(300 mg, yield 43%).

Example 32 Preparation of 7β-t-butoxycarbonylamino-3-[(E) -2-dimethylamino] vinyl-3-cephem-4-carboxylic acid benzhydryl ester 7β-t-butoxycarbonylamino-3 To a tetrahydrofuran (3 ml) solution of -chloromethyl-4-carboxylic acid benzhydryl ester (600 mg) was added 1.3 equivalents of sodium iodide (227 mg) at room temperature under dehumidification, and the mixture was stirred for 15 minutes. Then, 2.0 equivalents of tin powder (277 mg) and N, N-dimethylformamide diisopropyl acetal (0.49 ml) were added at room temperature, respectively, and the mixture was stirred for 45 minutes (no heat generation). 50 ml of ethyl acetate was added to the reaction solution, and Celite (20
The mixture was filtered and the filtrate was washed three times with an aqueous solution of ethylenediaminetetraacetic acid disodium salt (2 g) (50 ml). The extract was filtered through Celite (20 ml), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Silica gel column chromatography (100 ml, ethyl acetate: hexane =
1: 1) at 7β-t-butoxycarbonylamino-3-[(E)-
2-Dimethylamino] vinyl-3-cephem-4-carboxylic acid benzhydryl ester was isolated (425 mg, yield 68)
%).

Example 33 7β-t-Butoxycarbonylamino-3-[(E) -2-dimethylamino] vinyl-3-cephem-4-carboxylic acid benzhydryl ester 7β-t-Butoxycarbonylamino-3-chloro Methyl-4-carboxylic acid benzhydryl ester and manganese powder and N,
7β-t-Butoxycarbonylamino-3-[(E) -2-dimethylamino] vinyl-3-cephem-4-according to Example 30 above by reaction with N-dimethylformamide dimethylacetal.
Carboxylic acid benzhydryl ester was similarly obtained. Example 34 7-β-t-butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
Carboxylic acid benzhydryl ester dimethylformamide 30 ml, sodium iodide 3 g, anhydrous tin (II) chloride 3.8 g 7-β-t-butoxycarbonylamino
A 3-formylmethyl derivative prepared from 5.15 g of -3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester and 8 ml of dimethylformamide di-n-propylacetal was dissolved in 25 ml of DMF and allowed to stand for 5 minutes. Taking 1/5 part (0.002 mol) of the mixture, 0.6 g of 2-fluoro-1-methylpyridinium.paratoluenesulfonate was added with stirring under ice cooling. After 10 minutes, 0.28 g of imidazole and then 0.35 g of 6-mercaptoimidazo [1,2-] pyridazine sodium salt were added, and the mixture was stirred and then left overnight under ice cooling. 50 ml of ethyl acetate was added to this reaction solution, and the mixture was washed 4 times with saturated saline.
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (70 ml, ethyl acetate) to give the title compound (570 mg, Y = 44%).

Example 35 7-β-t-butoxycarbonylamino-3-[(E) -2- (imidazo
[1,2-b] Pyridazin-6-yl) thio] vinyl-3-cephem-4-
Carboxylic acid benzhydryl ester 2-Fluoro-1-methylpyridinium / paratoluenesulfonate was replaced with 2-chloro-1-methylpyridinium iodide, and carried out in the same manner as in Example 34, to give 470 m of the title compound.
g (Y = 37%) was obtained. Example 36 7-β-t-Butoxycarbonylamino-3- [2- (4-pyridyl)
Thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester 7-β-t-butoxycarbonylamino-3- [2- (4-trifluoromethylbenzoyloxy) vinyl] -3-cephem-4-carboxylic acid benz 682 mg of a hydryl ester was dissolved in 5 ml of dimethylformamide, 150 mg of 4-mercaptopyridine and 150 mg of potassium carbonate were added under ice-cooling stirring, and the mixture was reacted with stirring at the same temperature for 40 minutes. The reaction solution was redissolved in 30 ml of ethyl acetate and washed 3 times with brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. Silica gel column chromatography (70 ml,
Purification by subjecting to ethyl acetate-n-hexane, 1: 1) gave 450 mg (Y = 75%) of the title compound. ¹ H-NMR (CDCl ₃ , δ): 1.47 (s, 9H), 3.59 and 3.71 (ABq, 2
H, J = 18Hz), 5.02 (d, 1H, J = 4.8Hz), 5.32 (d, 1H, J = 9.6Hz), 5.
65 (dd, 1H, J = 4.8Hz, J = 9.6Hz), 6.66 (d, 1H, J = 15.6Hz), 6.99
(s, 1H), 7.17 (dd, 2H, J = 1.6Hz, J = 4.6Hz), 7.3-7.5 (m, 10H),
8.47 (dd, 2H, J = 1.6Hz, J = 4.6Hz).

Example 37 7-β-t-butoxycarbonylamino-3- [2- (4-pyridyl)
Thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester 7-β-t-butoxycarbonylamino-3- [2-benzoyloxyvinyl] -3-cephem-4-carboxylic acid benzhydryl ester 614mg In the same manner as in Example 36, 540 mg (Y = 90%) of the title compound was obtained. Example 38 7-β-t-butoxycarbonylamino-3- [2- (1-methyl-4-
Pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester iodide 7-β-t-butoxycarbonylamino-3- [2-benzoyloxyvinyl] -3-cephem-4-carboxylic acid benzhydryl ester 616 mg Is dissolved in 5 ml of dimethylformamide,
4-Mercaptopyridine 150 mg, potassium carbonate 1 with stirring under ice cooling
50 mg was added and the mixture was stirred at the same temperature for 50 minutes. Then methyl iodide
0.3 mg was added and stirred for several hours until the reaction was completed. The reaction solution was directly subjected to silica gel column chromatography (70 ml, ethyl acetate) and developed with ethyl acetate. Then acetone-water
Water was added to the residue obtained by concentrating the fractionated solution eluted at (7: 3). The precipitated solid was collected by filtration to give the crude title compound. Silica gel column chromatography (70 ml, ethyl acetate-acetic acid
-Water, 5: 1: 1), and the fractionated solution of the target compound was concentrated under reduced pressure. A small amount of water was added to the residue to loosen the solid, and the residue was dried with a freeze dryer to obtain 0.57 g (Y = 77%) of the title compound. ¹ H-NMR (CDCl ₃ , δ): 1.46 (s, 9H,), 3.74 and 4.34 (ABq, 2
H, J = 18Hz), 4.34 (s, 3H), 5.05 (d, 1H, J = 5Hz), 5.52 (d, 1H, J =
10Hz), 5.70 (dd, 1H, J = 5Hz, J = 10Hz), 6.93 (s, 1H), 7.03 (d, 1
H, J = 15.6Hz), 7.3-7.5 (m, 10H), 7.95 and 8.60 (dd, 4H) .IR (KBr, cm ^-1 ): 1780,1710,1630,1490,1365,1240,1210,11
50,1100,695.

[0072]

According to the production method of the present invention, a synthetic intermediate of a cephem compound useful as an antibacterial agent can be obtained regiospecifically and in high yield.

Claims (13)

[Claims] (1) Formula (1) [In the formula, R ¹ represents an amino-protecting group, R ² represents a carboxyl-protecting group, and X represents a halogen atom. ] The compound or its salt represented by these, and a formula [In the formula, R ³ and R ⁴ each represent an optionally substituted hydrocarbon group, or may form a ring with an adjacent nitrogen atom. ] Reactive formamide derivative having a group represented by the formula: [The symbols in the formula are as defined above. ] Or a salt thereof. 2. The process according to claim 1, wherein the reaction is carried out in the presence of a reducing metal or a salt thereof. 3. The method according to claim 2, wherein the metal having a reducing power or a salt thereof is an optionally halogenated metal tin, zinc, manganese or iron. 4. The method according to claim 2, wherein the metal having a reducing power or a salt thereof is divalent tin halide or tin metal. 5. The formula: [The symbols in the formula are as defined in claim 1. ] The reactive formamide derivative having a group represented by the formula [In the formula, R ⁵ and R ⁶ each represent a lower alkoxy group or a lower alkylamino group, and other symbols have the same meanings as in claim 1. ] It is a compound represented by these.
Production method as described. 6. A compound of the formula [The symbols in the formula are as defined in claim 5.] ] The manufacturing method of Claim 5 whose compound represented by this is dimethylformamide dialkyl acetal. 7. The formula: [In the formula, R ¹ represents a protecting group for an amino group, and R ² represents a protecting group for a carboxyl group. ] A compound represented by the following formula or a salt thereof and an aromatic carboxylic acid acyl halide are reacted with each other. [In the formula, R ⁷ represents an aromatic carboxylic acid acyl group, and other symbols have the same meanings as described above. ] Or a salt thereof. 8. The method according to claim 7, wherein the aromatic carboxylic acid acyl halide is pyridine carbonyl chloride or benzoyl chloride optionally substituted with a halogen atom, a halogeno C _1-6 alkyl group or a nitro group. 9. The formula: [In the formula, R ¹ represents a protecting group for an amino group, R ² represents a protecting group for a carboxyl group, and R ⁷ represents an acyl group of an aromatic carboxylic acid. ] A compound represented by the formula or a salt thereof, which may be substituted, [In the formula, ring B represents a 6-membered aromatic heterocycle having 1 or 2 nitrogen atoms as a hetero atom, and M represents a hydrogen atom or an alkali metal. ] The compound represented by the formula or a salt thereof is reacted with [Wherein A is an optionally substituted formula] (The symbols in the formulas have the same meanings as described above.), And the other symbols have the same meanings as described above. ] Or a salt thereof. 10. The formula: [The symbols in the formulas have the same meaning as in claim 9. ] The compound represented by the formula is a 6-mercaptoimidazo [1,2-b] pyridazine alkali metal salt having the formula: [The symbols in the formulas have the same meaning as in claim 9. ] The compound or its salt represented by this formula is [The symbols in the formulas have the same meaning as in claim 9. ] The manufacturing method of Claim 9 which is a compound or its salt represented by these. 11. The formula: [In the formula, R ¹ represents an amino-protecting group, R ² represents a carboxyl-protecting group, and X represents a halogen atom. ] The compound or salt thereof represented by the formula: [In the formula, R ³ and R ⁴ each may form a ring with a hydrogen atom or an optionally substituted hydrocarbon group, or an adjacent nitrogen atom. ] By reacting with a reactive formamide derivative having a group represented by the following formula: [The symbols in the formula are as defined above. ] Or a salt thereof is subjected to a hydrolysis reaction to obtain a compound of the formula: [The symbols in the formula are as defined above. ] Or a salt thereof and an aromatic carboxylic acid acyl halide are reacted to obtain a compound of the formula: [In the formula, R ⁷ represents an aromatic carboxylic acid acyl group, and other symbols have the same meanings as described above. ] The compound represented by the formula or a salt thereof, which may be substituted, [In the formula, ring B represents a 6-membered aromatic heterocycle having 1 or 2 nitrogen atoms as a hetero atom, and M represents a hydrogen atom or an alkali metal. ] The compound represented by the formula or a salt thereof is reacted with [Wherein A is an optionally substituted formula] (The symbols in the formulas have the same meanings as described above.), And the other symbols have the same meanings as described above. ] Or a salt thereof. 12. The formula: [In the formula, R ¹ represents a protecting group for an amino group, R ² represents a protecting group for a carboxyl group, and Het represents an optionally substituted heterocyclic group. Or a salt thereof. 13. The compound according to claim 12, wherein Het is an optionally substituted 2- or 4-pyridyl group.