PRODUCTION of 7-AMINOCEPHALOSPORANIC ACID DERIVATIVE

Technical Field

The present invention relates to a method of producing a 7-aminocephalosporanic acid derivative useful as a starting material for cephalosporin antibiotics [JP-A- 149682/1987, JP-A-238589/1989, JP-A-14586/1991, JP-A- 338332/1992 and so on (the term "JP-A-" as used herein means an "Japanese Patent Unexamined Publication")].

Background art

Conventionally, 7-aminocephalosporanic acid (hereinafter referred to as 7-ACA) has been silylated by bis-trimethylsilylurea or bis-trimethylsilylacetamide as a silylating reagent. Not only these silylating reagents are expensive and necessitate high-temperature reaction conditions, but also, a decomposition reaction concurs, resulting in low yields. Another known method uses chlorotrimethylsilane (hereinafter refferred to as TMSC) as a silylating reagent but this method also necessitates drastic reaction conditions and, in addition, an organic base, such as triethylamine, must be used, resulting in low yields.

On the other hand, hexamethyldisilazane (hereinafter referred to as HMDS) is also commonly used as a silylating reagent but the use of a catalyst is essential because its reactivity is poor. Examples of such catalysts include TMSC, iodotrimethylsilane (hereinafter referred to as TMSI) (WO87/01116, JP-A-184161/1994) and saccharin (JP-A- 45192/1982); however, even when these catalysts are used, the yields of the desired silyl derivative is not as high as expected. It is also known practice to use an organic oxo acid, trifluoroacetic acid, or the like, as a catalyst (WO86/03204, JP-A-165765/1995 and JP-A-81479/1996) but none

has ever attempted to use a sulfur-containing acid or an ammonium salt thereof or a Lewis acid.

There is a need for the development of a method enabling the production of a 7-aminocephalosporanic acid derivative useful as a starting material for cephalosporin antibiotics in higher yields with simple procedures.

Disclosure of Invention Through extensive investigation of various catalysts, the present inventors found a production method enabling efficient obtainment of the desired product using a certain acid as a catalyst.

Accordingly, the present invention relates to a method of producing a compound represented by the formula:

wherein X' represents an amino group that may be protected or trimethylsilylated; Y' represents a carboxyl group that may be protected or trimethylsilylated; Z represents hydrogen, an alkoxy group, an alkyl group that may be substituted for or an alkenyl group that may be substituted for; at least one of X' and Y' is trimethylsilylated, which comprises reacting a compound represented by the formula:

Y

wherein X represents an amino group that may be protected; Y represents a carboxyl group that may be protected; Z

represents hydrogen, an alkoxy group, an alkyl group that may be substituted for or an alkenyl group that may be substituted for; at least one of X and Y is not protected, with hexamethyldisilazane in an inert solvent in the presence of a sulfur-containing acid or an ammonium salt thereof or a Lewis acid.

Best Mode for Carrying Out the Invention

The protecting group for the "amino group that may be protected" represented by X or X' is exemplified by known amino group-protecting groups in the field of /?-lactam and peptides. Examples of such protecting groups include Cι_ ₆ alkanoyl groups that may be substituted for, C ₃ - ₅ alkenoyl groups that may be substituted for, Cβ-io aryl-carbonyl groups that may be substituted for, heterocyclic carbonyl groups, Cι- ₁₀ alkylsulfonyl groups that may be substituted for, camphorsulfonyl groups, Cβ-io arylsulfonyl groups that may be substituted for, substitutional oxycarbonyl groups, carbamoyl groups that may be substituted for, thiocarbamoyl groups that may be substituted for, Cβ-io aryl-methyl groups that may be substituted for, di-Cβ-io aryl-methyl groups that may be substituted for, tri-Cβ-io aryl-methyl groups that may be substituted for, C ₆ - ₁₀ aryl-methylene groups that may be substituted for, Cβ-io arylthio groups that may be substituted for, 2-Cι-ιo alkoxy-carbonyl-1- methyl-1-vinyl groups, and groups represented by the formula M'OCO- (M' represents an alkali metal).

Examples of "Ci-6 alkanoyl groups that may be substituted for" include Ci- ₆ alkanoyl groups that may be substituted for by 1 to 3 substituents selected from the group comprising halogens, oxo, Ci- ₆ alkoxys, Ci- ₆ alkanoyls, Cβ-io aryls, halogeno-Cδ-io aryls, C6-10 aryloxys, halogeno-Cβ-io aryloxys and Cβ-io arylthios, specifically, for example, 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 and p-chlorophenoxyacetyl.

Examples of "C ₃ - ₅ alkenoyl groups that may be substituted for" include C ₃ - ₅ alkenoyl groups that may be substituted for by 1 to 3 substituents selected from the group comprising halogens and Cβ- ₁₀ aryls, specifically acryloyl, crotonoyl, maleoyl, cinnamoyl, p-chlorocinnamoyl and /3-phenylcinnamoyl.

Examples of "C6- ₁ 0 aryl-carbonyl groups that may be substituted for" include Cβ-io aryl-carbonyl groups that may be substituted for by 1 to 3 substituents selected from the group comprising halogens, nitro, hydroxy, Ci- ₆ alkyls and Ci- ₆ alkoxys, specifically benzoyl, naphthoyl, phthaloyl, p-toluoyl, p-tert-butylbenzoyl, p- hydroxybenzoyl, p-methoxybenzoyl, p-tert-butoxybenzoyl, p- chlorobenzoyl and p-nitrobenzoyl.

The "heterocyclic group" in "heterocyclic carbonyl groups" is a group resulting from removal of one hydrogen atom bound to a carbon atom of a heterocyclic ring, exemplified by a 5- to 8-membered ring containing one to several, preferably 1 to 4 hetero atoms such as nitrogen atoms (which may by oxidated), oxygen atoms and sulfur atoms, or a condensed ring thereof. Such heterocyclic groups include 2- or 3-pyrrolyl; 1-, 2-, 3-, 4- or 5- pyrazolyl; 2-, 4- or 5-imidazolyl; 1,2,3- or 1,2,4- triazolyl; IH- or 2H-tetrazolyl; 2- or 3-furyl; 2- or 3- thienyl; 2-, 4- or 5-oxazolyl; 3-, 4- or 5-isoxazolyl; l,2,3-oxadiazol-4-yl or l,2,3-oxadiazol-5-yl; 1,2,4- oxadiazol-3-yl or l,2,4-oxadiazol-5-yl; 1,2,5- or 1,3,4- oxadiazolyl; 2-, 4- or 5-thiazolyl; 3-, 4- or 5- isothiazolyl; l,2,3-thiadiazol-4-yl or l,2,3-thiadiazol-5- yl; l,2,4-thiadiazol-3-yl or l,2,4-thiadiazol-5-yl; 1,2,5-

or 1,3,4-thiadiazolyl; 2- or 3-pyrolidinyl; 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; 2-, 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-naphthylidyl; thieno[2,3-d]pyridyl; pyrimidopyridyl; pyrazinoquinolyl; and benzopyranyl.

Examples of "Cι-ιo alkylsulfonyl groups that may be substituted for" include Cι-ιo alkylsulfonyl groups that may be substituted for by 1 to 3 substituents selected from the group comprising halogens, Cβ-io aryls and Cε-io aryloxys, specifically methanesulfonyl and ethanesulfonyl. Examples of "Cβ-io arylsulfonyl groups that may be substituted for" include Cβ-io arylsulfonyl groups that may be substituted for by 1 to 3 substituents at any possible positions selected from the group comprising halogens, nitro, Ci-6 alkyls and Cχ-6 alkoxys, specifically benzenesulfonyl, naphthalenesulfonyl, p-toluenesulfonyl, p- tert-butylbenzenesulfonyl, p-methoxybenzenesulfonyl, p- chlorobenzenesulfonyl and p-nitrobenzenesulfonyl.

Examples of "substitutional oxycarbonyl groups" include Cι-ιo alkoxy-carbonyl groups, C ₃ - ₁₀ cycloalkyloxycarbonyl groups, C ₅ -. ₁₀ crosslinked ring hydrocarbon oxycarbonyl groups, C ₂ - ₁₀ alkenoyloxy-carbonyl groups, Cβ-io aryloxy-carbonyl groups and C ₇ .- ₁₉ aralkyloxy- carbonyl groups, as well as those having 1 to 3 substituents at any possible positions selected from the group comprising Cχ- ₆ alkoxy groups, Cj 6 alkanoyl groups, substitutional silyl groups (e.g., trimethylsilyl, tert- butyldimethylsilyl) , Cι_6 alkylsulfonyl groups, halogens, cyano, Ci- ₆ alkyl groups and nitro. Specifically, such "substitutional oxycarbonyl" groups include 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 and 3,4- dimethoxy-6-nitrobenzyloxycarbonyl.

Examples of "carbamoyl groups that may be substituted for" include carbamoyl groups that may be substituted for by 1 or 2 substituents selected from the group comprising Cι_ ₆ alkyl groups, Cε-io aryl groups, Cι_ ₆ alkanoyl groups, β-io aryl-carbonyl group and Ci-6 alkoxy-phenyl groups, specifically N-methylcarbamoyl, N-ethylcarbamoyl, N,N- dimethylcarbamoyl, N,N-diethylcarbamoyl, N-phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl and N-(p- methoxyphenyl)carbamoyl. Examples of "thiocarbamoyl groups that may be substituted for" include thiocarbamoyl groups that may be substituted for by 1 or 2 substituents selected from the group comprising Ci-6 alkyl groups and Cβ-io aryl groups, e.g., thiocarbamoyl, N-methylthiocarbamoyl and N- phenylthiocarbamoyl.

Examples of "C ₆ - ₁₀ aryl-methyl groups that may be substituted for" include Cβ-io aryl-methyl groups that may be substituted for by 1 to 3 substituents selected from the group comprising halogens, nitro, Ci- ₆ alkyls and Ci-β alkoxys, specifically benzyl, naphthyl ethyl, p- methylbenzyl, p-methoxybenzyl, p-chlorobenzyl and p- nitrobenzyl.

Examples of "di-Cβ-io aryl-methyl groups that may be substituted for" include di-C ₆ -ιo aryl-methyl groups that may be substituted for by 1 to 3 substituents selected from

the group comprising halogens, nitro, Ci-e alkyls and Ci-e alkoxys, specifically benzhydryl and di(p-tolyl)methyl.

Examples of "tri-C ₆ -ιo aryl-methyl groups that may be substituted for" include tri-C6-ιo aryl-methyl groups that may be substituted for by 1 to 3 substituents selected from the group comprising halogens, nitro, Cι_ ₆ alkyls and Ci-e alkoxys, specifically trityl and tri(p-tolyl)methyl.

Examples of "Cβ-io aryl-methylene groups that may be substituted for" include Cβ-io aryl-methylene groups that may be substituted for by 1 to 3 substituents selected from the group comprising halogens, nitro, Cι_ ₆ alkyls and Ci-β alkoxys, specifically benzylidene, p-methylbenzylidene and p-chlorobenzylidene.

Examples of "Cβ-io arylthio groups that may be substituted for" include Cβ-io arylthio groups that may be substituted for by 1 to 3 substituents selected from the group comprising halogens, nitro, Cι_ ₆ alkyls and Ci- ₆ alkoxys, specifically o-nitrophenylthio. Examples of "2-Cι_ιo alkoxy-carbonyl-1-methyl-l-vinyl groups" include 2-methoxycarbonyl-l-methyl-l-vinyl, 2- ethoxycarbonyl-1-methyl-l-vinyl, 2-tert-butoxycarbonyl-l- methyl-1-vinyl, 2-cyclohexyloxycarbonyl-l-methyl-l-vinyl and 2-norbornyloxycarbonyl-l-methyl-l-vinyl. The "alkali metal" represented by M' in the "group represented by the formula M'OCO-" is preferably sodium, potassium, or the like, for example, with greater preference given to sodium etc.

X is preferably an amino group that may be protected by a Ci- ₆ alkanoyl group (e.g., phenylacetyl) that may be substituted for by (1) a formyl, (2) a Cι_ιo alkoxy¬ carbonyl group (e.g., tert-butoxycarbonyl) or (3) a Cβ-io aryl group, more preferably a non-substitutional amino group.

As a protecting group for the "carboxyl group that may be protected" represented by Y or Y', a carboxyl group- protecting group in common use in the field of organic synthetic chemistry, especially in the field of /9-lactam antibiotics such as cephalosporin, is used. Examples of such protecting groups include Ci- ₆ alkyl groups that may be substituted for, C2- ₆ alkenyl groups that may be substituted for, C6-10 aryl groups that may be substituted for and C7-. ₂ 0 aralkyl groups that may be substituted for. Examples of "Ci-6 alkyl groups that may be substituted for" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

Examples of "C2-6 alkenyl groups that may be substituted for" include vinyl, allyl, isopropenyl, methallyl, 1,1-dimethylallyl, 2-butenyl and 3-butenyl.

Examples of "Cβ-io aryl groups that may be substituted for" include phenyl and naphthyl.

Examples of "07-20 aralkyl groups that may be substituted for" include benzyl, 1-phenylethyl, 2- phenylethyl, phenylpropyl, naphthylmethyl and benzhydryl.

Examples of substituents for the above-mentioned Ci- ₆ alkyl groups, C ₂ -6 alkenyl groups, C ₆ - ₁ 0 aryl groups and C7_ ₂₀ aralkyl groups include hydroxy group, nitro group, halogens, Ci- ₆ alkoxy groups, Ci- ₁₀ alkanoyloxy groups, C3_ ₁₀ cycloalkyl-carbonyloxy groups, Cβ-io aryl-carbonyloxy groups, Ci- ₁₀ alkoxy-carbonyloxy groups, C3..10 cycloalkyloxy-carbonyloxy groups, Cβ-io aryl-carbonyloxy groups, tri(Cχ- ₆ alkyl)silyl groups (e.g., trimethylsilyl, tert-butyldimethylsilyl) and Ci-β alkylthio groups. The number of such substituents is preferably 1 to 3; the substituents may be identical or not.

Y is preferably a carboxyl group that may be protected by benzhydryl or ethoxybenzyl, more preferably a non- substitutional carboxyl group.

In the present invention, at least one of X and Y in the starting material (II) must be in an unprotected state, i.e., both X and Y must not be concurrently protected.

In the present invention, when X is a protected amino group, X* represents a protected amino group; when X is an amino group, X* represents a trimethylsilylated amino group.

Also, when Y is a protected carboxyl group, Y' represents a protected carboxyl group; when Y is a carboxyl group, Y' represents a trimethylsilylated carboxyl group.

The alkoxy group represented by Z is exemplified by Ci- ₆ alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy and hexyloxy.

The "alkyl group that may be substituted for" represented by Z is exemplified by Ci-β alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl and hexyl. The "alkenyl group that may be substituted for" represented by Z is exemplified by C ₂ - ₆ alkenyl group such as vinyl, allyl, 1-propenyl, isopropenyl, 2-methylallyl, 2- butenyl and 3-butenyl.

Examples of substituents for the "alkyl group that may be substituted for" or the "alkenyl group that may be substituted for" include Ci- ₁₀ alkanoyloxy groups, heterocyclic groups, hydroxy group, Ci- ₆ alkoxy groups, C^-η cycloalkyloxy groups, Cε-io aryloxy groups, C ₇ - ₁₉ aralkyloxy groups, heterocyclic oxy groups, mercapto group, Ci- ₆ alkylthio groups, 03-10 cycloalkylthio groups, Cβ-io arylthio groups, C ₇ - ₁₉ aralkylthio groups, heterocyclic thio groups, amino group, mono-Ci-β alkylamino groups, di- C1-6 alkylamino groups, tri-Cι-6 alkylammonium groups, C ₃ - ₁₀ cycloalkylamino groups, Cβ-io arylamino groups, C ₇ - ₁₉ aralkylamino groups, heterocyclic amino groups, cyclic amino groups, azide group, nitro group, halogen atoms.

cyano group, carboxyl group, Cι_ιo alkoxy-carbonyl groups, Cε-io aryloxy-carbonyl groups, C ₇ - ₁ 9 aralkyloxy-carbonyl groups, Cβ-io aryl-carbonyl groups, Ci-6 alkanoyl groups, C ₃ -5 alkenoyl groups, Cβ-io aryl-carbonyloxy groups, C ₂ - ₆ alkanoyloxy groups, 0 ₃ -5 alkenoyloxy groups, Cι_ ₆ alkylsulfonyl groups, C6-10 arylsulfonyl groups, carbamoyl groups that may be substituted for, thiocarbamoyl groups that may be substituted for, carbamoyloxy groups that may be substituted for, phthali ide groups, Ci- ₆ alkanoylamino groups, Cβ-io aryl-carbonylamino groups, Cι_ιo alkoxy- carboxamide groups, Cβ-io aryloxy-carboxamide groups and C ₇ - ₁₉ aralkyloxy-carboxamide groups; 1 to 4 identical or different substituents at any possible positions may be present.

Here, the heterocyclic groups of the heterocyclic groups, heterocyclic oxy groups, heterocyclic thio groups and heterocyclic amino groups are exemplified by the same groups as those mentioned to exemplify the heterocyclic group in the above-described "heterocyclic carbonyl group." Examples of "carbamoyl groups that may be substituted for" include carbamoyl groups that may be substituted for by 1 or 2 substituents selected from the group comprising Cι_6 alkyl groups, Cβ-io aryl groups, Cχ-6 alkanoyl groups, Cε-io arylcarbonyl groups and Cι_6 alkoxy-phenyl groups, and cyclic aminocarbonyl groups, specifically carbamoyl, N- methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl, N-(p-methoxyphenyl)carbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl and morpholinocarbonyl.

Examples of "thiocarbamoyl groups that may be substituted for" include thiocarbamoyl groups that may be substituted for by 1 or 2 substituents selected from the group comprising Ci- ₆ alkyl groups and Cβ-io aryl groups.

specifically thiocarbamoyl, N-methylthiocarbamoyl and N- phenylthiocarbamoyl.

Examples of "carbamoyloxy groups that may be substituted for" include carbamoyloxy groups that may be substituted for by 1 or 2 substituents selected from the group comprising Ci- ₆ alkyl groups and s-io aryl groups, specifically carbamoyloxy, N-methylcarbamoyloxy, N,N- dimethylcarbamoyloxy, N-ethylcarbamoyloxy and N- phenylcarbamoyloxy.

Z is preferably (i) an alkyl group substituted for by an alkanoyloxy group, a heterocyclic group, a heterocyclic thio group, or the like, or (ii) an alkenyl group substituted for by an triCι- ₆ -alkylammonium group, an alkanoyloxy group, a heterocyclic group, a heterocyclic thio group.

Here, the alkanoyloxy group is preferably a Cι_ ₆ alkanoyloxy group, for example, specifically formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, pivaloyloxy, or the like.

The heterocyclic group is preferably, for example, imidazo[1,2-b]pyridazinium-1-yl, 5-amino-l-hydroxyethyl- pyrazolinium-2-yl, or the like.

The heterocyclic thio group is preferably, for example, (N-methylpyridinium-4-yl)thio, (1- methylimidazo[l,2-b]pyridazinium-6-yl)thio, or the like.

The triCι- ₆ -alkylammonium group is preferably, for example, N,N,N-carbamoylmethylethylmethylammoniumyl, or the like. Z is more preferably a Cι_β alkyl group substituted for by a Cι_e alkanoyloxy, with greater preference given to acetyloxymethyl.

Preferable examples of compound (II) are compounds wherein X is an amino group, Y is a carboxyl group and Z is an alkyl group substituted for by an alkanoyloxy group.

More preferable examples of compound (II) are compounds wherein X is an amino group, Y is a carboxyl group and Z is a Ci-6 alkyl group substituted for by a Ci- ₆ alkanoyloxy group. Still more preferable examples of compound (II) are compounds wherein X is an amino group, Y is a carboxyl group and Z is an acetoxymethyl group.

Examples of inert solvents include halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane; aromatic hydrocarbons such as toluene and xylene; and saturated hydrocarbons such as cyclohexane. Preferable inert solvents are halogenated hydrocarbons, with greater preference given to 1,2-dichloroethane, dichloromethane, or the like. Because compound (I) as obtained by the production method of the present invention is easily decomposed in the presence of a trace amount of water, the reaction is normally carried out in the absence of water.

Regarding "a sulfur-containing acid or an ammonium salt thereof or a Lewis acid," the sulfur-containing acid is exemplified by a compound represented by the formula:

TS(0) _n H (T represents a hydrogen atom, a hydroxyl group, a halogen atom or a hydrocarbon group that may be substituted for; n represents 1, 2 or 3).

The halogen atom represented by T is exemplified by fluorine and chlorine.

The "hydrocarbon group that may be substituted for" represented by T is exemplified by Cι_6 alkyl groups, C ₂ - ₆ alkenyl groups, Cβ-io aryl groups and C7-20 aralkyl groups.

These groups are the same as those mentioned above.

Examples of substituents for the "hydrocarbon group that may be substituted for" include hydroxyl group, halogens (e.g., fluorine, chlorine, bromine), amino group and carboxyl group. The number of these substituents is

preferably 1 or 2, and they may be identical or not. When the hydrocarbon group is a Ce-io aryl group or a C7-20 aralkyl group, it may have a C ₁ - ₄ alkyl group (e.g., methyl, ethyl) as a substituent. Sulfur-containing acids include sulfuric acid, sulfuric anhydride, sulfonic acids, sulfinic acids and sulfenic acids, preferably an acid which has a sulfonic group, specifically sulfuric acid, methanesulfonic acid, p- toluenesulfonic acid, benzenesulfonic acid and chlorosulfonic acid.

Regarding "a sulfur-containing acid or an ammonium salt thereof or a Lewis acid," the Lewis acid may be any one, so long as it serves as an electron pair receptor, exemplified by BF ₃ * (C ₂ H ₅ ) ₂ θ, AICI ₃ , ZnCl ₂ , FeCl ₃ and TiCl ₄ . The "sulfur-containing acid or ammonium salt thereof or Lewis acid" is preferably sulfuric acid, ammonium sulfate, methanesulfonic acid or BF ₃ *(C ₂ Hs)0, with greater preference given to sulfuric acid. The amount of "sulfur-containing acid or ammonium salt thereof or Lewis acid" used is normally 0.005 to 0.5 equivalents, preferably 0.02 to 0.1 equivalent relative to compound (II).

The amount of hexamethylsilazane used is normally 1 to 5 equivalents, preferably 2.0 to 3.5 equivalent relative to compound (II) .

Although the reaction may be carried out at a reaction temperature between room temperature and the boiling point of the solvent, it is preferably carried out at 60 to 100°C.

Reaction time is normally about 0.1 to 20 hours, preferably about 0.5 to 10 hours.

Compound (I) as obtained by the present invention serves as a useful intermediate for the production of a

large number of cephalosporin antibiotics; the desired cephalosporin antibiotic can be produced from compound (I) by, for example, the method described below.

Deprotection

Acylation at 7-position

[In the above formulas, A represents an alkyl group; B represents a substituent; R represents a nucleophilic substituent; R' represents an acyl groups; the other symbols have the same definitions as those shown above.]

Here, the alkyl group represented by A has the same definition as that for the alkyl group defined for the "alkyl group that may be substituted for" represented by Z.

The substituent represented by B has the same definition as that for the substituent defined for the "alkyl group that may be substituted for" represented by Z, except that it does not represent a halogen atom. B is preferably a Cι_ιo alkanoyloxy group, more preferably a Ci-6 alkanoyloxy.

The nucleophilic substituent represented by R is a nucleophilic substituent in common use in the field of

cephalosporin antibiotics. Examples of such nucleophilic substituents include the imiazolium-1-yl group described in JP-A-149682/1987, which forms a condensed ring at the 2,3- or 3,4-position. A particularly preferable nucleophilic substituent is the imidazopyridazinium-1-yl group.

The acyl group represented by R' is an acyl group in common use in the field of cephalosporin antibiotics. Examples of such acyl groups include the group represented by the formula:

N ¹¹ —OR 1 ³

wherein Ri represents an amino group that may be protected; R ₃ represents a hydrogen atom or a hydrocarbon residue that may be substituted for, which is described in JP-A- 149682/1987.

Here, the "amino group that may be protected" represented by Ri is exemplified by the same amino groups as those mentioned to exemplify X above.

The "hydrocarbon residue that may be substituted for" represented by R ₃ is exemplified by the same groups as the "Ci-6 alkyl groups that may be substituted for," "C ₂ - ₆ alkenyl groups that may be substituted for," "Cβ-io aryl groups that may be substituted for" and "C7_ ₂ o aralkyl groups that may be substituted for" mentioned to exemplify the protecting group for Y and Y'.

In the method above, compound (I') is first iodated to yield compound (III).

Iodation can be achieved by a commonly known method; for example, it is achieved using an iodating reagent such as an iodotrialkylsilane (e.g., iodotrimethylsilane) . The

amount of iodating reagent used is, for example, 1.7 to 2.0 equivalents relative to compound (I ¹ ). Reaction temperature is, for example, 5°C to room temperature (about 15°C), reaction time being, for example, about 1 to 3 hours.

Next, compound (III) is subjected to 3-position nucleophilic substitution reaction to yield compound (V) . 3-position nucleophilic substitution reaction is achieved by a commonly known method using a nucleophilic reagent. When the nucleophilic reagent used is imidazopyridazine, for example, the amount of imidazopyridazine used is, for example, about 3 to 4 equivalents relative to compound (I ¹ ). Reaction temperature is, for example, 30 to 40°C, reaction time being, for example, about 2 to 5 hours.

Compound (V) is then subjected to deprotection reaction to yield compound (VI). Deprotection reaction can be achieved by a commonly known method. When the protecting group used is a benzhydryl group, a p-methoxybenzyl group, a tert-butyl group, a tert-butoxycarbonyl group or a formyl group, for example, the protecting group is removed by treatment with formic acid, hydrochloric acid, trifluoroacetic acid, acetic acid, phenol or cresol. The trimethylsilyl group is removed by treatment with water or an alcohol (e.g., methanol, 2-propanol).

Compound (VI) thus obtained is subjected to 7-position acylation reaction to yield compound (VII).

7-position acylation can be achieved using a method in common use in the field of cephalosporin antibiotics, such methods including the method described in JP-A-149682/1987 and methods based thereon.

When desired, compounds (III), (V), (VI) and (VII) above may be isolated and purified by known means of separation and purification, e.g., concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, re-dissolution and chromatography.

The present invention is hereinafter described in more detail by means of the following working examples, comparative examples and reference example, which are not to be construed as limitative.

In the working examples and reference example below, the production of compound (I) and the production of the 3- iodomethyl derivative obtained by reaction of compound (I) and TMSI were confirmed by NMR analysis. Since compound (I) and the 3-iodomethyl derivative are both instable compounds, the yields of compound (I) was assessed by HPLC analysis of the compound obtained by reacting the 3- iodomethyl derivative with imidazopyridine, and subsequently subjecting the reaction product to deprotection reaction, i.e., 7-amino-3- (imidazopyridazinium)methylceph-3-em-4-carboxylate.

7-ACA, as a starting material in the following working examples and reference examples, is commercially available (for example, Cheil Jedang Corp., Antibioticos Corp., Biochemie Corp., or the like).

In the working examples and reference example, high performance liquid chromatography (HPLC) analysis was conducted under the following conditions: HPLC conditions:

Detector : An ultraviolet absorption photometer, 254 nm

(wave length) Column : Nucleosil 100-5Cιβ, 4.6 mm i.d. x 150 mm (produced by GL Science) Mobile phase: A mixture of 0.01 M sodium hexanesulfonate solution (pH 2.7) and methanol (95:5)

Flow rate : 1.0 ml/min

Example 1

Production of trimethylsilyl (6R,7R)-7-

(trimethylsilyl)amino-3-acetoxymethylceph-3-em-4- carboxylate

(I")

To a suspension of 28.2 g (100 mmol) of 7-ACA (Cheil Jedang Corp., content 96.7%) in 190 ml of 1,2- dichloroethane, 63 ml (300 mmol, 3.0 equivalents) of hexamethyldisilazane (HMDS) and 0.1 ml (2 mmol, 0.02 equivalents) of sulfuric acid were added, followed by stirring at room temperature for 30 minutes, after which the mixture refluxed for 2 hours, to yield a yellowish transparent solution. An aliquot of this solution was evaporated to dryness under reduced pressure to distill off the solvent and excess HMDS to yield a solid residue. By ^ ^■ HNMR spectral analysis of this residue, the production of the title compound was confirmed. ^ ^■ HNMR (DMSO-dβ): 5 0.06 (S, 9H, -N-Si(CH ₃ ) ₃ ) , 0.30 (s, 9H, -C0 ₂ Si(CH ₃ ) ₃ ), 2.03 (s, 3H, -COCH ₃ ), 3.52, 3.56 (d, 2H, - SCH ₂ -), 4.72-5 _* 04 ( , 4H, -CH ₂ OCO-, C ₆ -H, C ₇ -H) Production of trimethylsilyl (6R,7R)-7- (trimethylsilyl)amino-3-iodomethylceph-3-em-4-carboxylate

The yellowish transparent solution described above, i.e., the trimethylsilyl (6R,7R)-7-(trimethylsilyl)amino-3-

acetoxymethylceph-3-em-4-carboxylate reaction mixture in 1,2-dichloroethane, was cooled to 5 to 10°C; a solution of 180 mmol (1.8 equivalents) of iodotrimethylsilane (TMSI) in 1,2-dichloroethane was added, followed by stirring at about 10°C for 3 hours, to yield a dark orange mixture. An aliquot of this mixture was evaporated to dryness under reduced pressure to distill off the solvent to yield a solid residue. By ¹ HNMR spectral analysis of this residue, the production of the title compound was confirmed. 0 ¹ HNMR (DMSO-dβ): δ 0.04 (s, 9H, -N-Si(CH ₃ ) ₃ ) , 0.31 (s, 9H, -C0 ₂ Si(CH ₃ )3), 3.58, 3.74 (d, 2H, -SCH ₂ -), 4.39 (d, 2H, - CH ₂ I), 4.81 (IH, C ₇ -H), 4.94 (IH, C ₆ "H)

Production of trimethylsilyl (6R,7R)-7- 5 (trimethylsilyl)amino-3-(imidazopyridazinium)methylceph-3- em-4-carboxylate iodide (hereinafter referred to as compound (V ) )

To the dark orange mixture described above, i.e., the 5 trimethylsilyl (6R,7R)-7-(trimethylsilyl)amino-3- iodomethylcef-3-em-4-carboxylate in 1,2-dichloroethane, 37.0 g (300 mmol, 3.0 equivalents) of dry imidazopyridazine (content 96.6%) was added and was stirred at 35 ^β C for 4 hours, after which HPLC analysis demonstrated that the _Q title compound was obtained at a yield of 79.6% (based on 7-ACA, the same applies below) .

Example 2

Production of compound (V) 5

( I I ¹ ) » ^► » ^► »► ( V )

To a suspension of 28.1 g (100 mmol) of 7-ACA (content 97.0%) in 190 ml of 1,2-dichloroethane, 63 ml (300 mmol, 3.0 equivalents) of HMDS and 1.0 ml (8 mmol, 0.08 equivalents) of BF ₃ '(C ₂ Hs) ₂ θ were added, followed by stirring at room temperature for 30 minutes, after which the mixture refluxed for 2 hours to yield a yellowish transparent solution. This solution was cooled to 5 to 10°C; a solution of 180 mmol (1.8 equivalents) of TMSI in 1,2-dichloroethane was added, followed by stirring at about 10°C for 3 hours, to yield a dark orange mixture. To this mixture, 37.0 g (300 mmol, 3.0 equivalents) of dry imidazopyridazine (content 96.6%) was added and stirred at 35°C for 4 hours, after which HPLC analysis demonstrated that compound (V) was obtained at a yield of 73.5%.

Example 3

Production of compound (V )

To a suspension of 2.81 g (10.0 mmol) of 7-ACA (content 97.0%) in 19 ml of 1,2-dichloroethane, 6.3 ml (30 mmol, 3.0 equivalents) of HMDS and 27 mg (0.2 mmol, 0.02 equivalents) of AICI ₃ (anhydrous) were added, followed by stirring at room temperature for 30 minutes, after which the mixture refluxed for 2 hours. The resulting solution was cooled to 5 to 10°C; a solution of 18 mmol (1.8 equivalents) of TMSI in 1,2-dichloroethane was added, followed by stirring at about 10°C for 3 hours. To this mixture, 3.70 g (30 mmol, 3.0 equivalents) of dry imidazopyridazine (content 96.6%) was added, followed by stirring at 35°C for 4 hours, after which HPLC analysis demonstrated that compound (V ) was obtained at a yield of 68.0%.

Example 4

Production of compound (V)

To a suspension of 5.63 g (20.0 mmol) of 7-ACA (content 96.7%) in 38 ml of 1,2-dichloroethane, 12.6 ml (60 mmol, 3.0 equivalents) of HMDS and 53 mg (0.4 mmol, 0.02 equivalents) of were added, followed by stirring at room temperature for 30 minutes, after which the mixture refluxed for 2 hours. The resulting solution was cooled to 5 to 10°C; a solution of 36 mmol (1.8 equivalents) of TMSI in 1,2-dichloroethane was added, followed by stirring at about 10°C for 3 hours, to yield a suspension. To this mixture, 7.40 g (60 mmol, 3.0 equivalents) of dry imidazopyridazine (content 96.6%) was added followed by stirring at 35°C for 4 hours, after which HPLC analysis demonstrated that compound (V ) was obtained at a yield of 71.9%.

Example 5

Production of compound (V)

To a suspension of 5.63 g (20.0 mmol) of 7-ACA (content 96.7%) in 38 ml of 1,2-dichloroethane, 12.6 ml (60 mmol, 3.0 equivalents) of HMDS and 0.03 ml (0.46 mmol, 0.023 equivalents) of methanesulfonic acid were added, followed by stirring at room temperature for 30 minutes, after which the mixture refluxed for 2 hours. The resulting solution was cooled to 5 to 10°C; a solution of

36 mmol (1.8 equivalents) of TMSI in 1,2-dichloroethane was added, followed by stirring at about 10°C for 3 hours. To this mixture, 7.40 g (60 mmol, 3.0 equivalents) of dry imidazopyridazine (content 96.6%) was added, followed by was stirring at 35 ^β C for 4 hours, after which HPLC analysis demonstrated that compound (V ) was obtained at a yield of 73.3%.

Example 6 Production of compound (V)

To a suspension of 28.2 g (100 mmol) of 7-ACA (content 96.7%) in 190 ml of dichloromethane, 63 ml (300 mmol, 3.0 equivalents) of HMDS and 0.1 ml (2 mmol, 0.02 equivalents) of sulfuric acid were added, then the mixture refluxed for 4 hours. The resulting solution was cooled to 5 to 10°C; a solution of 180 mmol (1.8 equivalents) of TMSI in dichloromethane was added, followed by stirring at about 10°C for 3 hours. To this mixture, a solution of 41.7 g (net weight 350 mmol, 3.5 equivalents) of imidazopyridazine in 27ml of dichloromethane was added, followed by stirring at 35°C for 4 hours, after which HPLC analysis demonstrated that compound (V) was obtained at a yield of 80.4%.

Example 7 Production of l-[ [ (6R,7R)-7-amino-2-carboxy-8-oxo-5-thio-l- azabicyclo[4.2.0]oct-2-en-3-yl]methyl]imidazo[1,2- bjpyridazinium hydroxide-inner salt monohydroiodide(7- ACP-HI)

To the solution of compound (V) produced according to the above-mentioned method, 490 ml of dichloromethane was added, followed by stirring and was cooled to below 10°C; with keeping the temperature below 10°C, 40.4 ml (2 equivalents) of methanol was added to the solution, followed by stirring for 15 minutes and 44.9 g of 57% hydroiodide (2 equivalents) was added dropwise over a period of ca. 30 minutes at room temperature. This solution was cooled to below 5 ^β C, followed by stirring for 1 hour, after which the precipitated crystals were collected by filtration, washed with 110 ml of cold methanol, 220 ml of cold methamol/water(1/1) and then 110 ml of cold methanol, and dried under reduced pressure to yield 48.7 g of 7-ACPΗI (content: 47.3%, net weight: 23.0 g, yield based on 7-ACA: 69.5%).

Comparative Example 1

Production of compound (V )

To a suspension of 2.85 g (10.0 mmol) of 7-ACA (content 95.7%) in 19 ml of 1,2-dichloroethane, 6.3 ml (30 mmol, 3.0 equivalents) of HMDS was added, followed by stirring at room temperature for 30 minutes, after which the mixture refluxed for 2 hours. The resulting solution was cooled to 5 to 10°C; a solution of 18 mmol (1.8 equivalents) of TMSI in 1,2-dichloroethane was added, followed by stirring at about 10 ^β C for 3 hours. To this mixture, 3.70 g (30 mmol, 3.0 equivalents) of dry 0 imidazopyridazine (content 96.6%) was added, followed by stirring at 35°C for 4 hours, after which HPLC analysis demonstrated that compound (V ) was obtained at a yield of 49.5%.

5 Comparative Example 2

Production of compound (V)

To a suspension of 34.0 g (120 mmol) of 7-ACA (content 96.1%) in 230 ml of 1,2-dichloroethane, 75 ml (360 mmol, 3.0 equivalents) of HMDS and 450 mg (2.5 mmol, 0.02 o equivalents) of saccharin were added, followed by stirring at room temperature for 30 minutes, after which the mixture refluxed for 2 hours. The resulting solution was cooled to 5 to 10 ^β C; a solution of 216 mmol (1.8 equivalents) of TMSI in 1,2-dichloroethane was added, followed by stirring at 5 about 10 ^β C for 3 hours. To this mixture, 44.4 g (360 mmol, 3.0 equivalents) of dry imidazopyridazine (content 96.6%) was added, followed by stirring at 35°C for 4 hours, after which HPLC analysis demonstrated that compound (V ) was obtained at a yield of 64.8%. 0

Reference Example 1

Production of l-[ [ (6R,7R)-7-amino-2-carboxy-8-oxo-5-thia-l- azabicyclo[ .2.0]oct-2-en-3-yl]methyl]imidazo[1,2- b]pyridazinium hydroxide, inner salt (7-ACP) 5 dihydrochloride

H ₂ O 3 ± 0 for PCF) 20

± 5°C

₃ N

<PCCP>

1) After 39.5 g (100 mmol) of deacetylcephalosporin C (DCPC) sodium salt was dissolved in 300 ml of water, the solution was cooled to 0 to 5 ^β C (5 ± 5°C) and adjusted to pH 9.3 (pH 9.3 ± 0.5) with a 10% (w/w) aqueous solution of NaOH.

2) Keeping the temperature below 10 ^β C, 17.5 g (110 mmol, 1.10 equivalents) of phenyl chlorocarbonate is added dropwise over a period of ca. 70 minutes (70 ± 30 minutes); the solution was kept between pH 9.0 and 9.6 with a 10% (w/w) aqueous solution of NaOH for about 30 minutes to minimum pH (stirring for 30 ± 20 minutes).

3) After 240 ml of tetrahydrofuran (THF) was added, the mixture was cooled to 3 to 8°C (5 ± 5°C) and adjusted to pH 2.5 (pH 2.5 ± 0.2) with concentrated hydrochloric acid, then extracted with 150 ml of dichloromethane.

4) After 76.2 ml of THF was added, the aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid, then extracted with 126 m of dichloromethane.

5) The organic layers were combined; 19.3 ml of THF was added, after which the mixture was cooled below -20°C to freeze the water content, then filtered.

6) The frozen product was washed with 42.1 ml of THF precooled below -20°C.

7) The filtrate and washings were combined; 21.8 ml (170 mmol, 1.70 equivalents) of triethylamine and 102.9 ml of dichloromethane were added; the solvent is distilled off under reduced pressure to yield (6R,7R)-7-[ ( (R)-5- phenoxycarbonylamino-5-carboxyvaleramide]-3-hydroxymethyl- 8-oxo-5-thia-l-azabicyclo[ .2.0]oct-2-en-2-carboxylic acid (DPCC).

8) DPCC was azeotropically dehydrated by the addition of 35.7 g of imidazopyridine and 200 ml of dichloromethane.

9) The dry product obtained was azeotropically dehydrated by the addition of 200 ml of dichloromethane. This procedure is repeated 3 times.

10) The thus-obtained dry DPCC product was adjusted to 180 g by the addition of dichloromethane and cooled to -25 to -20°C.

11) After 36.0 g (180 mmol, 1.80 equivalents) of 2- ethoxy-l,3,2-benzodioxaphosphor-2-oxide (EPPA) was added dropwise over a period of 10 minutes, the solution obtained was washed with 4 ml of dichloromethane.

12) After reaction at -20°C for 3 hours, the temperature was raised to 0°C, followed by stirring for 30 minutes, to yield l-[ [ (6R,7R)-7-[ (R)-5- phenoxycarbonylamino-5-carboxyvalerylamide]-2-carboxy-8- oxo-5-thia-l-azabicyclo[4.2.0]octo-2-en-3- yl]methyl]imidazo[l,2-b]pyridazinium hydroxide (PCCP).

13) To PCCP, 300 ml of dichloromethane and 17.8 ml of triethylamine were added; after the mixture was stirred and dissolved at 5 to 15 ^β C for 15 minutes, 87.0 ml of dimethylaniline (DMA) and 230 ml of dichloromethane were added; the mixture cooled below -45°C.

14) To the solution obtained, 61.2 ml of propionyl chloride was added dropwise at -30°C over a period of ca. 5 minutes, followed by reaction for 1 hour.

15) To the reaction mixture, a suspension of 75.2 g of phosphorus pentachloride (PCI ₅ ) in 123.8 ml of dichloromethane, previously cooled to -40°C, was added, followed by reaction at -30°C for 90 minutes.

16) After 374 ml of dichloromethane was then added, the mixture was cooled to -30 ^β C.

17) Additionally, 600 ml of isobutanol was added without delay; the temperature was raised to 25 ^β C, followed by reaction for 1 hour.

18) The reaction mixture was filtered under a nitrogen atmosphere; the filtrate was washed with 300 ml of dichloromethane and dried under reduced pressure to yield l-[ [ (6R,7R)-7-amino-2-carboxy-8-oxo-5-thia-l- azabicyclo[4.2.0]octo-2-en-3-yl]methyl]imidazo[1,2- b]pyridazinium hydroxide (7-ACP) dihydrochloride.

Industrial Applicability

According to the present invention, compound (I), which is useful as a starting material for cephalosporin antibiotics, i.e., a 7-aminocephalosporanoic acid derivative, can be produced at high yields with simple procedures.

In addition, as stated above, the entire process for production of compound (V) from starting material (II) can be achieved on a "one-pot" basis, i.e., in a single solvent without isolation of intermediate compounds.