JPH02289571A - 3-alkenyl-1-azabicyclo(3.2.0)hepto-2-ene-2-carboxylic acid derivative and its production and antifungal medicine containing same - Google Patents

Abstract

NEW MATERIAL:The title derivative of formula I [R<1> is (protected) carboxyl; R<2> is (protected) hydroxy lower alkyl; R<3> and R<4> are each H or lower alkyl; R<5> is (substituted) unsaturated heterocycle] or its salt acceptable as a medicine. EXAMPLE:2-(N-allyloxycarbonyl-N-methylaminomethyl)-4-ethoxycarbonyl thiazole. USE:Anti-fungus agents, being highly effective on a great variety of pathogenic microorganisms. PREPARATION:For example, a compound of formula II (R<6> is lower alkoxy or aryl) or its salt is put to ring closure reaction to obtain the objective com pound of the formula I.

Description

[Detailed Description of the Invention] [Industrial Application Field] This invention relates to a novel 3-alkenyl-1-azabisic group [
3.2.0] Hept-2-ene-2-carboxylic acid conductor or a pharmaceutically acceptable salt thereof, more specifically, the above compound having antibacterial activity or a pharmaceutically acceptable salt thereof; relates to a method for producing the above-mentioned compound and to an antibacterial agent containing the above-mentioned compound or a pharmaceutically acceptable salt thereof.

[Object of the Invention] Therefore, the object of the present invention is to develop a novel 3-alkenyl-1-azabisic[3.2.0]hebuto2 compound that exhibits high antibacterial activity against a large number of pathogenic microorganisms and is useful as an antibacterial agent.
An object of the present invention is to provide a -en-2-carboxylic acid salt conductor or a pharmaceutically acceptable salt thereof. Another object of this invention is to provide a novel method for producing the above-mentioned compound or a salt thereof. Still another object of the present invention is to provide an antibacterial agent containing the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient, which exhibits an effective effect on the treatment of infectious diseases caused by pathogenic organisms in humans or animals. The goal is to provide medicine.

[Description of the structure of the invention] 3-alkenyl-1-azabicyl, which is the target substance of the present invention [3.2. O]Hebuto-2-2-2-carboxylic acid conductor is a new compound and can be represented by the formula shown below.

Formula R3 (wherein R1: carboxy group or protected carboxy group R2 = hydroxy (lower) alkyl group or protected hydroxy (lower) alkyl group R3.R4, respectively the same or different, hydrogen or lower alkyl group R': Unsaturated heterocyclic group optionally substituted with one or more suitable substituents] In the above target compound and the intermediate compounds shown below obtained in the manufacturing process thereof, one or more sets of stereoisomers, e.g. Optical and/or geometric isomers may exist based on the presence of asymmetric carbon atoms and/or single or double bonds, and it is to be understood that these isomers are also included within the scope of this invention. It is.

Preferred salts of the target compound (1) are commonly used non-toxic and pharmaceutically acceptable salts, such as alkali metal salts (e.g. sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g. calcium salts). , magnesium salts, etc.), inorganic base salts such as ammonium salts, organic amine salts such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, etc.
salts with bases such as m-based salts such as dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.;
Inorganic acid addition salts (e.g. hydrochloride, hydrobromide, sulfate,
phosphate, etc.), organic acid addition salts (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, etc.):
Salts with basic or acidic amino acids (eg, arginine, aspartic acid, glutamic acid, etc.); intermolecular or intramolecular quaternary salts, etc. are included. The above-described intermolecular quaternary salt is formed, for example, when the unsaturated heterocyclic group represented by R4 in compound (I) contains a tertiary nitrogen atom (for example, pyridyl), and preferred intermolecular quaternary salts include , 1-(lower)alkylpyridinio(lower)alkyl sulfates (e.g. l-methylpyridiniomethylsulfate, 1-ethylpyridinioethylsulfate, etc.), 1-(lower)alkylpyridiniohalides (e.g. 1 - methylviridinioiodide, etc.),
l-carbamoyl (lower) alkylpyridinio (lower)
Alkyl sulfates (e.g. 1-carbamoylmethylpyridiniomethylsulfate, 1-carpamoylethylviridinioethyl sulfate, etc.), 1-carbamoyl (lower) alkylpyridiniohalides (e.g. 1-carbamoylmethylpyridiniomethylsulfate, etc.) !Dide, !ichiriki rubamoylethylpyridinioiodide, etc.). The intramolecular quaternary salt is, for example, R4 in compound (1).
When the unsaturated heterocyclic group represented by contains a tertiary nitrogen atom (for example, pyridyl, etc.) and R1 is a carboxyl group, the preferred intramolecular quaternary salt is 1
-(lower)alkylpyridiniocarboxylate (e.g. 1-methylpyridiniocarboxylate, 1-ethylpyridiniocarboxylate, 1-propylbyridiniocarboxylate, 1-isobrobylbyridiniocarboxylate, 1-butylpyridiniocarboxylate, etc.), 1-[carbamoyl(lower)alkyl]pyridiniocarboxylate [e.g. 1-(carbamoylmethyl]viridiniocarboxylate, 1-(carbamoylethyl)viridiniocarboxylate, 1 -(carbamoylisobrobyl)pyridiniocarboxylate, 1-(carbamoylisobrobyl)pyridiniocarboxylate,
! -(carbamoylbutyl)pyridiniocarboxylate, etc.]. According to this invention, the target compound (
1) and a pharmaceutically acceptable salt thereof are produced according to the process shown in the reaction formula below. (l!) or its salt or its salt N (1-c) or its salt (1-d) or its salt (1-a) or its salt (1-b) or its salt or its salt (I-f ) or its salt (1-g) or its salt (I-h) or its salt Process 6: (IV) (Summer) Process 7: (1-B(1-j) or its salt or its salt The above reaction formula In, R', R', R 3.R' OJ: HiR
'G;! Each previous to the same L/I JRl. is a protected carboxy group R2, is a protected hydroxy (lower) alkyl group R2
, is a hydroxy (lower) alkyl group Rl1 is an unsaturated heterocyclic group containing a protected imino residue, and RSb, which may be further substituted with one or more suitable substituents, contains an imino residue. an unsaturated heterocyclic group,
RSc, which may be further substituted with one or more suitable substituents, is an unsaturated heterocyclic group containing a tertiary nitrogen atom, and which may be further substituted with one or more suitable substituents. Rlld, which is an unsaturated heterocyclic group containing a quaternary nitrogen atom and may be further substituted with one or more suitable substituents, is an unsaturated group substituted with a protected lower alkylamino (lower) alkyl group. The heterocyclic group all1 is substituted with a lower alkylamino (lower) alkyl group, the unsaturated heterocyclic group R6 is an aryl group, or the lower alkoxy group R7 is a lower alkyl group X represents an acid residue, respectively. The starting materials (1) and (1v) in Processes 1 and 6 are new and can be produced, for example, by the method shown below. (IX) (V) (■) or its salt (■) (■) (IX) or its salt or its salt or its salt il Salt or its salt or its salt (Xlll) 方韮一一 (XI) (Xl1) or its salt or its salt (XV) (■!) ([Xa) or its salt (1v) or its salt (XV) (■) or a salt thereof In the above reaction formula, R l . R2, R3,
R4. 1tS, R8 and X each have the same meaning as before; R7 is a protected carboxy group L each represents a leaving group.

In the foregoing and subsequent descriptions of this specification, preferred illustrations and explanations of various definitions included within the scope of this invention are detailed below. "Lower" terms have a carbon number of 1 unless otherwise specified.
~6.

A preferable "protected carboxy group" is one containing an esterified carboxy group, and examples of the "esterified carboxy group" include those shown below. Preferred examples of ester residues in the esterified carboxy group include lower alkyl esters (e.g. methyl ester, ethyl ester, proyl ester, isobroyl ester, butyl ester, isobutyl ester, tertiary butyl ester, bentyl ester). , hexyl esters, etc.) as well as lower alkyl esters which may have at least one suitable substituent, such as lower alkyl oxy(lower) alkyl esters [e.g. acetoxymethyl ester, probionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, bivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-(or 2-)acetoxyethyl ester, 1-(or 2-)
or 3-) acetoxypropyl ester, l-(or 2- or 3- or 4-) acetoxybutyl ester, 1-(or 2-) brobionyloxyethyl ester, 1-(or 2- or 3-) Probionyloxibutyryl ester, 1-(or 2-) isobutyryloxyethyl ester, 1-(or 2-) bivaloyloxyethyl ester, 1-(or 2-) hexanoyloxyethyl ester, isobutyryloxyethyl ester, lyloxymethyl ester, 2-ethylbutylyloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1-(or 2-)pentanoyloxyethyl ester, etc.), lower alkanesulfonyl (lower) alkyl ester ( (e.g., 2-mesylethyl ester, etc.), mono (or di, or tri) yakuchi (lower) alkyl esters (e.g., 2-monoiodide ethyl ester, 2.2.2-trichloroethyl ester, etc.), lower alkoxycarbonyloxy (Lower) alkyl esters [e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, M3-butoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester, 1- (or 2-) ethoxycarbonyloxyethyl ester, 1-(or 2-) isobroboxycarbonyloxyethyl ester, etc.), phthalidylidene (lower) alkyl ester, or (5-lower alkyl di-2-oxo 1,3-dioxol- 4-il)
Methyl ester [e.g. (5-methyl-2-oxo 1
．． 3-dioxol-4-yl)methyl ester, (5-
ethyl-2-oxo-1,3-dioxol-4-yl)
Methyl ester, (5-propyl-2-oxo 1.3
-dioxol-4-yl)ethyl ester, etc.]; Lower alkenyl esters (e.g., vinyl esters, allyl esters, etc.); Lower alkynyl esters (e.g., ethynyl ester, provinyl ester, etc.); (lower) alkyl esters (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3.4
-dimethoxybenzyl ester, 4-hydroxy-3.
5-1 ditertiary butyl benzyl ester, etc.); allyl ester which may have at least one suitable substituent (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tertiary butyl phenyl ester,
xylyl ester, mesityl ester, cumenyl ester, etc.): phthalidyl' ester, etc.

More preferred protected carboxy groups defined in this way include C, -C4 alkenyloxycarbonyl and phenyl (or nitrophenyl) (C+ -
C4) alkoxycarbonyl, the most preferred being allyloxycarbonyl.

Suitable [hydroxy (lower) alkyl] is a straight or branched lower alkyl substituted with a hydroxy group, such as hydroxymethyl, hydroxyethyl, hydroxybubutyr, 1-(hydroxymethyl)ethyl, 1
-Hydroxy-1-methylethyl, hydroxybutyl,
Hydroxybentyl, hydroxyhexyl, etc. are shown,
Among these, the more preferable one is hydroxy (C+C4
) alkyl, most preferably l-hydroxyethyl. Suitable "protected hydroxy (lower) alkyl" includes: - The hydroxy group in the above-mentioned hydroxy (lower) alkyl is a commonly used hydroxy protecting group, for example, a protecting group as described in the explanation of the imino protective group below. , preferably lower alkenyl, oxycarbonyl and phenyl (or nitrophenyl) (lower) alkoxycarbonyl;
Furthermore, C6-CI. al(lower)alkyl, such as mono- or di- or triphenyl(lower)alkyl (e.g. benzyl, penzhydryl, trityl, etc.); trisubstituted silyl, e.g. tri(lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tertiary butyldimethylsilyl, diisobutylmethylsilyl, etc.), tri(Ca-C+.)arylsilyl (e.g. triphenylsilyl, etc.), tris[ (
Ca-C,. )al(lower)alkyl]silyl, such as those protected with tris[phenyl(lower)alkyl]silyl (eg, tribenzylsilyl, etc.).

More preferred among the [protected hydroxy (lower) alkyl] described above are {phenyl (or nitrophenyl) (CtC4) alkoxy) carbonyloxy (C.-C4) alkyl, C2-C4 alkenyloxycarbonyl They include oxy(c+-C4)alkyl and (tri(Cl-C4)alkylsilyl)oxy(c+-C4)alkyl, and the most preferred is 1-tert-butyldimethylsilyloxyethyl.

Suitable "lower alkyl" is a linear or branched one, such as methyl, ethyl, proyl, isobrobyl, butyl, tertiary butyl, pentyl, hexyl, etc., and among these, preferred are C, -C4 is alkyl,
The most preferred is methyl. "Unsaturated heterocyclic group" in the term "unsaturated heterocyclic group optionally substituted with one or more suitable substituents" means at least one heteroatom, such as an oxygen atom, a sulfur atom, or a nitrogen atom. means an unsaturated monocyclic or polycyclic heterocyclic group containing atoms.

Examples of preferred unsaturated heterocyclic groups include the following.

3- to 8-membered, more preferably 5- to 6-membered unsaturated heteromonocyclic groups having 1 to 4 nitrogen atoms, such as imidazolyl,
pyrazolyl, pyridyl, birimidyl, birazinyl, pyridazinyl, triazolyl (e.g. 4H-1.2.4-triazolyl, IH-1.2.3-triazolyl, 2H
-1.2.3 - triazolyl, etc.), tetrazolyl (
For example, IH-tetrazolyl, 2H-tetrazolyl, etc.)-dihydrotriazinyl (for example, 4,5-dihydro-1.
2.4-triazinyl, 2.5-dihydro-1.2.4
unsaturated fused heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolizinyl, penzimidazolyl, quinolyl, isoquinolyl, indazolyl, penzotriazolyl, tetrazopyridyl, tetrazopyridazinyl (e.g. 3-8 containing 1-2 oxygen atoms and 1-3 nitrogen atoms
membered, preferably 5- to 6-membered, unsaturated heteromonocyclic groups, such as oxazolyl, isoxazolyl, oxadiazolyl (
For example, 1.2.4-oxadiazolyl, 1,3.4-oxadiazolyl, 1,2.5-oxadiazolyl, etc.)
etc.; unsaturated fused heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as penzoxazolyl, penzoxadiazolyl, etc.; 1 to 2 sulfur atoms and 1 3-8 containing ~3 nitrogen atoms
membered, preferably 5- to 6-membered, unsaturated heteromonocyclic groups, such as 1.3-thiazolyl, 1.2-thiazolyl, 2-thiazolinyl, thiadiazolyl (e.g. 1,2.4-thiadiazolyl, 1,3.4 unsaturated fused heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as penzothiazolyl, pen Zothiadiazolyl etc. The above-mentioned heterocyclic group may have one or more suitable substituents, preferably one or two, and examples of such substituents include the following: .

Lower alkyl groups as described above, more preferably CI-C
4 Alkyl (such as methyl) 2 Lower alkylamino (lower) alkyl containing lower alkyl similar to the green lower alkyl group described above, preferably C. -C4 alkylamino (CI-C4) alkyl (e.g. methylaminomethyl etc.): The amino group of the lower alkylamino (lower) alkyl as mentioned above is a commonly used amino protecting group as described in the explanation of the imino protecting group below. protected lower alkylamino (lower) alkyl, more preferably N-(CI C4)alkyl, including an amino group protected by N- (
C2-C4) alkenyloxycarbonylamino (
C+ -C. t) alkyl (e.g. N-allyloxycarbonyl-N-methylaminomethyl, etc.); etc.

When the above heterocyclic group has an imino residue in the ring, the imino residue may be substituted with a suitable substituent such as an imino protecting group as described below. More preferred are C2-C4 alkenyloxycarbonyl (eg, allyloxycarbonyl).

A suitable "unsaturated heterocyclic group having a tertiary nitrogen atom and optionally substituted with a suitable substituent" means
"Unsaturated heterocyclic group optionally substituted with a suitable substituent" means a heterocyclic group containing at least one tertiary nitrogen atom.

As mentioned above, "a quaternary nitrogen-containing unsaturated heterocyclic group which may be substituted with a suitable substituent" means "a quaternary nitrogen-containing unsaturated heterocyclic group which may be substituted with a suitable substituent". The term "unsaturated heterocyclic group" means one in which the heterocycle contains at least one quaternary nitrogen atom.

A suitable "unsaturated heterocyclic group having an imino residue, which may be substituted with a common substituent" means, as mentioned above, "an unsaturated heterocyclic group having an imino residue, which may be substituted with a common substituent" The term "unsaturated heterocyclic group" means one in which the heterocycle includes at least one imino residue.

A suitable "unsaturated heterocyclic group having a protected imino residue, which may be substituted with a suitable substituent" means, as mentioned above, "an unsaturated heterocyclic group having a protected imino residue, which may be substituted with a suitable substituent". means that the heterocycle in the optional unsaturated heterocyclic group J contains at least one protected imino residue. As mentioned above, "unsaturated heterocyclic group" refers to lower alkylamino (lower) alkyl in which the heterocycle in "unsaturated heterocyclic group optionally substituted with a suitable substituent" is protected. It means something that has a group as a substituent. A suitable "unsaturated heterocyclic group substituted with a lower alkylamino (lower) alkyl group" is, as mentioned above, "an unsaturated heterocyclic group which may be substituted with a suitable substituent. '' in which the heterocycle has a lower alkylamino (lower) alkyl group as a substituent.

Further, in the above-mentioned heterocyclic group, for example, when imidazolyl is taken up, there are a wide variety of mutants as shown in the balanced formula below.

All of the above-mentioned tautomers are included within the scope of this invention. However, in this specification, for convenience, target substances and intermediate compounds containing such tautomer groups will be expressed by the following formula H in the case of imidazolyl. Suitable "lower alkoxy groups" include linear or branched ones, such as methoxy, ethoxy, broboxy, isoproboxy, butoxy, isobutoxy, benzyloxy,
It includes isobentyloxy, hexyloxy, etc., and among these, C, -C4 alkoxy group is more preferred.

Common "acid residues" include, for example, inorganic acid residues such as azides and halogens (i.e. chlorine, bromine, fluorine, iodine), acids such as acyloxy (eg benzenesulfonyloxy, tosyloxy, methanesulfonyloxy, acetoxy, etc.) The residue is more preferably halogen, and most preferably iodine.

Suitable "aryl groups" include CIS-CI such as phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, etc.
Oaryl groups are included, and among these, phenyl group is more preferred.

Suitable "leaving groups" include the acid residues described above,
Among these, lower alkanoyloxy is more preferred, and acetoxy is most preferred.

Suitable "imino-protecting groups" include acyl groups such as aliphatic acyl, aromatic acyl, heterocyclic acyl, and aliphatic acyl substituted with an aromatic group or a heterocyclic group,
They are derived from the corresponding carboxylic, carbonic, sulfonic or carbamic acids. Aliphatic acyl includes, for example, alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, probionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), e.g. lower alkylsulfonyl (e.g. mesyl, ethylsulfonyl, probylsulfonyl, etc.). Isobrobylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl,
alkylsulfonyl, such as hexylsulfonyl,
Carbamoyl, N-alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl etc.), alkoxycarbonyl such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, proboxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl etc.) Alkenyloxycarbonyl such as alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g. acryloyloxy, methacryloyloxy, crotonyl, etc.), e.g. cyclo(lower)alkanylcarbonyl (For example, cycloalkane carbonyl such as cyclopropane carbonyl, cyclopentane carbonyl, cyclohexane carbonyl, etc.). Aromatic acyls include aroyl (e.g. benzoyl,
(toluoyl, xyloyl, etc.), N-arylcarbamoyl (eg, N-phenylcarbamoyl, N-}lylcarbamoyl, N-naphthylcarbamoyl, etc.), arenesulfonyl (eg, benzenesulfonyl, tosyl, etc.), and the like.

Heterocyclic acyl includes heterocyclic carbonyl (eg, furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, etc.).

Examples of aliphatic acyl groups substituted with aromatic groups include phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.)
aralkanoyl, such as phenyl(lower)alkoxycarbonyl (e.g. penzyloxycarbonyl, phenethyloxycarbonyl, etc.), e.g. phenoxy(lower)alkanoyl such as phenoxy(lower)alkanoyl (e.g. phenoxyacetyl, phenoxybrobionyl, etc.) ) and the like.

Examples of the aliphatic acyl group substituted with a heterocyclic group include heterocyclic (lower) alkanoyl (e.g., thienyl acetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolyl acetyl, thiadiazolyl acetyl, This includes heterocyclic alkanoyls such as chenylpropionyl, thiadiazolylbutionyl, etc.). These acyl groups may further include, for example, lower alkyl groups (e.g. methyl, ethyl, probyl, isobrobyl, butyl, bentyl, hexyl, etc.), halogens (i.e. chlorine,
bromine, iodine, fluorine), lower alkoxy groups (e.g. methoxy, ethoxy, propoxy, isoproboxy, butoxy, benzyloxy, hexyloxy, etc.), lower sulfylthio groups (e.g. methylthio, ethylthio, propylthio, isobrobylthio, butylthio, bentylthio, hexylthio, etc.) ), nitro group, lower alkylamino group (e.g. methylamino, ethylamino, propylamino, isopropylamino, etc.), protected lower alkylamino group (e.g. N-aryloxycarbonyl-N-methylamino, etc.), etc. Preferred acyl groups which may be substituted with one or more suitable substituents include mono (or di, or tri)
haloalkanoyl (e.g. chloroacetyl, promoacetyl, dichloroacetyl, trifluoroacetyl, etc.),
Mono (or di, or tri) haloalkoxycarbonyl (e.g. chloromethoxycarbonyl, dichloromethoxycarbonyl, 2,2.2-}-licroethoxycarbonyl, etc.), nitro (or yakuchi, or lower alkoxy) aralkoxycarbonyl (e.g. nitropenzyloxycarbonyl, chloropenzyloxycarbonyl, methoxybenzyloxycarbonyl, chloropenzyloxycarbonyl, methoxybenzyloxycarbonyl, etc.), mono (or di, or tri) methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, trichloromethylsulfonyl, etc.). More preferred examples of the imino-protecting group defined above include (C2C4)alkenyloxycarbonyl,
Phenyl (or nitrophenyl) (CI-C4
) alkoxycarbonyl, C, -C. Alkylamino (C+-.C4)alkanoyl and N- (C2
C4) Alkenyloxycarbonyl-N- (C+
-Ca)alkylamino(c+-C4)alkanoyl, etc., and most preferred are aryloxycarbonyl, (methylamino)acetyl and N
-allyloxycarbonyl-N-methylaminoacetyl. Next, the process for producing the object substance (1) of the present invention will be described in detail.

(1) Process 1: Compound (1) or a salt thereof can be obtained by subjecting compound (I+) or a salt thereof to a ring-closing reaction. Examples of the salt of the compound (1 summer) include those listed as the salt of the compound (!). This reaction is carried out using a conventional solvent that does not adversely affect the progress of the reaction, such as dioxane, hexamethylphosphoramide, benzene, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, pyridine, etc., or a mixed solvent thereof.
It is preferable to carry out I1) by heating. This reaction can also be carried out in the presence of hydroquinone. The reaction temperature of this reaction is not particularly limited, and it is usually carried out with or under heating.

(2) Process 2: Compound (1-b) or a salt thereof is prepared by subjecting compound (1-a) or a salt thereof to RI. It can be obtained by subjecting it to the elimination reaction of the carboxy protecting group.

Examples of the salts of compound (I-a) and compound (1-b) include those listed as the salt of compound (1).

This reaction is carried out according to conventional methods such as hydrolysis and reduction.

(a) Hydrolysis: Hydrolysis is preferably carried out in the presence of a base or acid. Common bases include alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydrides (e.g. sodium hydroxide, etc.). , potassium hydride, etc.), alkaline earth metal hydrides (e.g. calcium hydride, etc.), alkali metal alkoxides (
For example, sodium methoxide, sodium ethoxide,
Potassium tert-butoxide, etc.), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal hydrogen carbonates (e.g. sodium bicarbonate, potassium bicarbonate, etc.) ) etc. are included.

Suitable acids include organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-
}) and inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.). Among these, hydrolysis under acidic conditions using trifluoroacetic acid is generally performed using cation scavengers (e.g. phenol, anisole, etc.).
is promoted by the addition of

This reaction is preferably carried out in a conventional solvent that does not adversely affect the progress of the reaction, such as water, methylene chloride, alcohol (eg, methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, or a mixed solvent thereof. Among bases and acids, liquid ones can be used also as a solvent.

The reaction temperature is not particularly limited, and the reaction is generally carried out under cooling or heating.

(El) Reduction The reduction method applied to this elimination reaction includes, for example, metals (e.g. zinc, zinc amalgam, etc.) and Cr compounds (
Reduction methods using a combination of organic or inorganic acids (e.g. acetic acid, probionic acid, hydrochloric acid, sulfuric acid, etc.); e.g. palladium catalysts (e.g. palladium sponge, palladium black, palladium oxide, palladium chloride, etc.); carbon, colloidal palladium, palladium-barium sulfate, palladium-barium carbonate, baladium carbon hydroxide, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), platinum catalysts (
For example, platinum plate, sponge platinum, platinum black, colloidal platinum,
Examples include catalytic reduction carried out in the presence of a conventional metal catalyst such as platinum oxide, platinum wire, etc.

When a catalytic reduction method is employed, the reaction is preferably carried out under conditions near neutrality.

This reaction can be carried out using conventional solvents that do not have an adverse effect on the progress of the reaction,
For example, the reaction is preferably carried out in water, alcohol (eg, methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, a buffer solution (eg, phosphate buffer, acetate buffer, etc.), or a mixed solvent thereof.

The reaction temperature is not particularly limited, and the reaction is generally carried out under cooling or heating.

When the carboxy protecting group is an allyl group, it can also be protected from hydrolysis using a baladicum compound.

Suitable palladium compounds used in this reaction include palladium on carbon, palladium hydroxide on carbon, palladium chloride, such as tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), di[ 1. Palladium ligand complexes such as 2-bis(diphenylphosphino)ethane]palladium(O), tetrakis(triphenylphosphite)palladium(0), tetrakis(triethylphosphite)palladium(0), etc. Can be mentioned.

The reaction can be carried out using, for example, amines (e.g. morpholine, N-methylaniline, etc.), active methylene compounds (e.g. dimedone,
benzoyl acetate, 2-methyl-3-oxovaleric acid, etc.), cyanohydrin compounds (e.g. α-tetrahydrocyanide biranyloxybenzyl cyanide, etc.), (lower) alkanoic acids or their salts (e.g. phosphoric acid, acetic acid, ammonium phosphoric acid) It is preferable to carry out the reaction in the presence of a scavenger for allyl groups generated during the reaction, such as sodium acetate, sodium acetate, etc.).

This reaction is effective for lower alkyl amines (e.g. butylamine,
This can be carried out in the presence of a base such as triethylamine, etc.), pyridine, etc.

When a palladium ligand complex is used in this reaction, it is preferable to carry out the reaction in the presence of a corresponding ligand such as triphenylphosphine, triphenyl phosphite, triethyl phosphite, and the like. This reaction is usually carried out in any conventional solvent that does not adversely affect the progress of the reaction, such as water, methanol, ethanol, propanol, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, ethyl acetate, etc. , or a mixed solvent thereof.

The elimination reaction can be selected depending on the type of carboxy protecting group to be eliminated. This process also includes cases where the hydroxy protecting group at R2 and/or the imino and/or hydroxy protecting group at R5 are simultaneously eliminated during the reaction. (3) Process 3: Compound (1-d) or a salt thereof can be obtained by subjecting compound (I-c) or a salt thereof to an elimination reaction of the hydroxy protecting group at R2. As suitable salts of compounds (1-c) and (1-d), those listed as the salt of compound (1) are directly exemplified. This reaction is carried out by conventional methods such as hydrolysis and reduction. The hydrolysis and reduction methods and reaction conditions (e.g. reaction temperature, solvent, etc.) are the same as those described in Process 2 (
The conditions are substantially the same as those described for the elimination reaction of the carboxy protecting group in I-a). Therefore, reference should be made to those descriptions.

When the human oxygen protecting group is a tri(lower) alkylsilyl group, the removal of the protecting group can also be carried out in the presence of a tetra(lower) alkylammonium fluoride (eg, tetrabutylammonium fluoride, etc.).

This process includes cases where the carboxy protecting group at R' and/or the imino and/or hydroxy protecting group at RS are simultaneously removed with tA during the reaction.

(4) Process 4: Compound (1-f) or a salt thereof can be obtained by subjecting compound (1-e) or a salt thereof to an elimination reaction of the imino protecting group in all.

As suitable salts of compound (1-e), those listed as salts of compound (1) are directly exemplified. Suitable salts of compound (I-f) are exemplified by those listed as the salt of compound (1). This reaction is, for example, hydrolysis. This is done by conventional methods such as reduction. The hydrolysis and reduction methods and reaction conditions (e.g. reaction temperature, solvent, etc.) are the same as those described in Process 2 (
The conditions are substantially the same as those described for the elimination reaction of the carboxy protecting group in 1-a). Therefore, those explanations should be referred to. This process includes cases in which the carboxy and/or hydroxyl groups in R1 and/or R2 and/or the hydroxyl groups in R' are simultaneously eliminated during the reaction.

(5) Process 5: Compound (1-h) or a salt thereof is obtained by reacting compound (1-g) or a salt thereof with compound (II1). Suitable salts of compounds (1-g) and (T-h) are exemplified by those listed as the salt of compound (1). This reaction is carried out in a solvent that does not adversely affect the progress of the reaction, such as tetrahydrofuran, dioxane, water, acetone, acetonitrile, methanol, ethanol, Mi street solution (for example, phosphate iJt street solution, etc.), or a mixed solvent thereof. It is preferable to do so. The reaction temperature is not particularly limited, and is usually carried out under cooling or heating. (6) Process 6: Compound (1) or a salt thereof can be obtained by subjecting compound (IV) or a reactive conductor at its hydroxy group or a salt thereof to a dehydration reaction. A suitable salt of compound (IV) is compound (1)
The salts listed above are examples. Examples of reactive derivatives at the hydroxy group of the compound (!V) include halides (e.g., chloride, bromide, iodide, etc.), sulfonic acid esters (e.g., methanesulfonic acid ester, benzenesulfonic acid ester, toluenesulfonic acid ester, etc.), and the like. Among these, particularly preferred is esdel sulfonate. This dehydration reaction is carried out, for example, by reacting compound (IV) or a reactive conductor at its hydroxy group or a salt thereof with a base. Suitable bases used in this reaction include, for example, trialkylamines (e.g., trimethylamine, triethylamine, etc.), viridine, vicoline, lutidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3 ．． Organic bases such as Ql non-5-one, 1,4-diazabicyclo[2.2.2]octane, and 1.5-diazabicyclo[5.4.0]undecene-5 are used. This reaction is preferably carried out in a conventional solvent that does not adversely affect the progress of the reaction, such as water, methylene chloride, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixed solvent thereof. ．． A liquid base can also be used as a solvent. The reaction temperature is not particularly limited, and is usually carried out under cooling or heating. (7) Process 7: Compound (1-j) or a salt thereof can be obtained by subjecting compound (1-1) or a salt thereof to an elimination reaction of the amino protecting group in RS. Compounds (1-i) and (I
-j) are exemplified by those listed as the salt of compound (1). This reaction is carried out by conventional methods such as hydrolysis and reduction. The hydrolysis and reduction methods and reaction conditions (e.g. reaction temperature, solvent, etc.)
The conditions are substantially the same as those described for the elimination reaction of the carboxy protecting group in -a). Therefore, reference should be made to those descriptions.

This reaction process also includes the case where, when an imino protecting group is present in the unsaturated heterocyclic group, the protecting group is simultaneously eliminated during the progress of the reaction. Next, the method for producing the new raw material (!Natsu) and (1v) or their salts used in this invention will be described in detail. A Compound (■) or its salt is added to Compound (V) with Compound (■) or its salt.
V! ) or a salt thereof.

Suitable salts of compounds (V!) and (■) include those exemplified as the acid addition salts of compound (1). Compound (V!) or a salt thereof can be produced from a known compound according to the methods shown as production examples in this specification or conventional methods.

This reaction includes, for example, alkali gold hydroxide R (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (magnesium hydroxide, calcium hydroxide, etc.), alkali gold hydride R (e.g. sodium hydroxide, potassium hydride, etc.), alkaline earth metal hydrides (e.g. calcium hydride, etc.), alkali metal alkoxides (e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal carbonates (e.g. sodium carbonate, carbonic acid, etc.) potassium, etc.), alkaline earth metal carbonates (
The reaction is carried out in the presence of a base such as magnesium carbonate, calcium carbonate, etc.) or an alkali metal hydrogen carbonate (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.).

This reaction is preferably carried out in the presence of an enolizing agent. A suitable enolization agent is Toriyakuchi (low grade).
Tri(lower)alkylsilyl alkanesulfonate, preferably tri(c+-C4)alkanesulfonic acid tri(C+-C4)alkylsilyl alkanesulfonate (e.g. trimethylsilyl trifluoromethanesulfonate, etc.), which may contain a halogen, for example Tin compounds such as lower alkyl tin sulfonates, preferably polyoctachinic (C, 1 C4) tin alkyl sulfonates (for example, tin trifluoromethanesulfonate, etc.) are included.

This reaction can be carried out using conventional solvents that do not adversely affect the progress of the reaction.
For example, it is preferable to carry out the reaction in water, methylene chloride, alcohol (eg, methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixed solvent thereof. The liquid base can also serve as a solvent.

The reaction temperature is not particularly limited, and is usually carried out under cooling or heating. ''Lj口LL上 Compound ([X) or its salt can be obtained by reacting compound (■) or its salt with compound (■) or its reactive equivalent. Suitable salts of compound (IX) include those exemplified as salts of compound (I).

A preferable example of compound (■) is glyoxylic acid, the carboxyl group of which may be protected by a conventional carboxy protecting group and derivatized into an esterified carboxyl group as described above. Suitable reactive equivalents of compound (■) include the monohydrate.

It is desirable to carry out this reaction while distilling off the water produced as the reaction progresses by azeotropy. Azeotropic distillation of water can be carried out according to conventional methods (such as azeotropic distillation). This reaction can be carried out using conventional solvents that do not adversely affect the progress of the reaction, such as water, methylene chloride, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, benzene, toluene, xylene, etc., or a mixture thereof. It is preferable to perform this in a solvent. The reaction temperature is not particularly limited, and the reaction is usually carried out with or under heating. The compound (!■) or its salt can be obtained by reacting the compound (X) with the compound (EX) or a reactive salt conductor at its hydroxyl group or a salt thereof. Suitable reactive conductors for the hydroxy group of compound (IX) include, for example, halides (e.g. chloride, bromide, iodide, etc.), sulfonate esters (
Conventional conductors such as methanesulfonate, benzenesulfonate, toluenesulfonate, etc.) are used, and among these, halides are more preferred.

Suitable examples of compound (X) include triphenylphosphine, tri(C+C4)alkylphosphine (eg, triethylphosphine, etc.).

This reaction is performed, for example, on alkali metal bicarbonates (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (e.g. magnesium carbonate, calcium carbonate, etc.), (lower)alkylamines (e.g. trimethylamine, triethylamine, N,N-diisobutyl-N-ethylamine, etc.), pyridine compounds [e.g. biridine, vicolin, lutidine, N,N-di(lower)alkylaminopyridine (e.g. N,N -dimethylaminopyridine, etc.), quinoline, imidazole, N-lower alkylmorpholine (e.g., N-methylmorpholine, etc.)
, N-lower alkylbiveridine (e.g., N-ethylpiveridine, etc.), N,N-di(lower)alkylbenzylamine (e.g., N,N-dimethylbenzylamine, etc.), etc. in the presence of an inorganic or organic base. I'll check it out.

This reaction can be carried out using conventional solvents that do not adversely affect the progress of the reaction.
For example, dioxane, acetonitrile, chloroform, methylene chloride, hexamethylphosphoramide, ethylene chloride, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, N,N-dimethylpolamide, pyridine, etc.
Alternatively, it is generally carried out in a mixed solvent of these.

The reaction temperature is not particularly limited, and is usually carried out under cooling or heating. (D) Method D: Compound (!Xa) or its salt can be obtained by reacting compound (■) or its salt with compound (■a) or its salt. Suitable salts of compound (IXa) include those exemplified as salts of compound (1). A suitable salt of compound (■a) is compound (1-e)
The same salts are mentioned.

Preferred compound (■a). Examples include oxalyl chloride in which one carboxy group in oxalic acid may be protected with a conventional carboxy protecting group as described above. The reaction can be carried out in the presence of a base as described in Method C. This reaction is usually carried out using conventional solvents that do not adversely affect the progress of the reaction, such as dioxane, acetonitrile, chloroform, methylene chloride, hexamethylphosphoramide, ethylene chloride, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, N. The reaction is carried out in N-dimethylformamide, pyridine, etc., or a mixed solvent thereof.

The reaction temperature is not particularly limited, and is usually carried out under cooling or heating. Compound (II) or a salt thereof can be obtained by reacting compound (IXa) or a salt thereof with compound (X). This reaction is usually carried out using conventional solvents that do not adversely affect the progress of the reaction, such as dioxane, acetonitrile, chloroform, methylene chloride, hexamethylphosphoramide, ethylene chloride, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, N. Carry out in N-dimethylformamide, pyridine, benzene, toluene, xylene, etc., or a mixed solvent thereof. The reaction temperature is not particularly limited, and is usually carried out under cooling or heating. Compound (Xll) or a salt thereof can be obtained by reacting compound (XI) or a salt thereof with compound (X[I) or a salt thereof. Suitable salts of compounds (XI) and (Xll) include those exemplified as the salts of compound (1). Suitable salts of the compound (Kari) include those exemplified as the acid salt of the compound (1). This reaction can be carried out using, for example, an alkali metal di(lower)alkylamide, preferably a lithium di(CI-C4)alkylamide (e.g. lithium diisobutyramide, etc.), an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), a hydroxide. Alkaline earth metals (magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydrides (e.g. sodium hydride, potassium hydride, etc.), alkaline earth metal hydrides (e.g. calcium hydride, etc.), alkali metal alkoxides (e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (e.g. magnesium carbonate,
It is carried out in the presence of a base such as calcium carbonate, etc.) or an alkali metal hydrogen carbonate (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, etc.). This reaction is usually carried out using a conventional solvent that does not adversely affect the progress of the reaction, such as water, methylene chloride, alcohol (e.g. methanol, ethanol, etc.), hexane, tetrahydrofuran, dioxane, acetone, benzene, toluene, xylene, etc., or a mixture thereof. It is carried out in a solvent. The reaction temperature is not particularly limited, and is usually carried out under cooling or heating. Compound (XI) is prepared according to conventional methods as described in the Examples of US Pat. No. 4,348,320. The compound (IV) or its salt is the compound (Xllll)
or its salt by subjecting it to a ring-closing reaction. This reaction can be carried out using conventional solvents that do not adversely affect the progress of the reaction, such as dioxane, hexamethylphosphoramide, benzene, toluene, xylene, dimethyl sulfoxide,
This is preferably carried out by heating the compound (■) in a solvent such as N,N-dimethylformamide, pyridine, or a mixed solvent thereof. However, the reaction temperature is not particularly limited, and the reaction is usually carried out with or under heating. Compound (XV) can be obtained by reacting compound (XIV) with compound (XIV). This reaction is usually carried out using conventional solvents that do not adversely affect the progress of the reaction, such as dioxane, acetonitrile, chloroform, methylene chloride, hexamethylphosphoramide, ethylene chloride, hexane, tetrahydrofuran, ethyl acetate,
It is carried out in dimethyl sulfoxide, N,N-dimethylformamide, pyridine, benzene, toluene, xylene, etc., or a mixed solvent thereof. The reaction temperature is not particularly limited, and is usually carried out under cooling or heating. The compound (■) or a salt thereof can be obtained by reacting the compound (XI/) with the compound (X[I) or a salt thereof. This reaction can be carried out using conventional solvents that do not adversely affect the progress of the reaction, such as dioxane, hexamethylphosphoramide, benzene, toluene, xylene, dimethyl sulfoxide,
Compound (XV) and (X[I) in N,N-dimethylformamide, pyridine, etc., or a mixed solvent thereof.
Preferably, this is done by heating. This reaction can also be carried out in the presence of hydroquinone. The reaction temperature is not particularly limited, and the reaction is usually carried out with or without heating.

The target substances obtained according to Processes 1 to 7 are separated and purified by conventional methods such as extraction, precipitation, fractional crystallization, recrystallization, and chromatography. The object substance (1) of this invention and its pharmaceutically acceptable salts are novel, have high antibacterial activity, and inhibit the growth of a wide range of pathogenic organisms, including Durum-positive and Durum-negative bacteria. Furthermore, it is very stable against dehydrobebutidase and is excreted in high concentrations through urine, making it highly effective in treating various infectious diseases.

A compound in which R4 is a lower alkyl group in the target substance (1) exhibits particularly high antibacterial activity and extremely high stability against dehydrobebutidase. Next, in order to demonstrate the usefulness of the target substance (!),
Select representative compounds from 1) and record their antibacterial activity data as follows. In vitro antibacterial activity was measured by the agar plate multiple dilution method described below. Tributicase Soy Broth (viable count 10'/ml
) was inoculated onto H1 agar (Hl agar) containing the test compound at various concentrations, and after culturing at 37°C for 2 hours, the lowest growth rate was reached. The inhibitory concentration (MIC) was measured (in μg/ml
)． Compound Kufuyotake 1 Obtained in Example 5-1 When using the object compound (1) of the present invention or a pharmaceutically acceptable salt thereof for therapeutic purposes, oral administration,
Used in the form of conventional pharmaceutical preparations containing said compounds as active ingredients in admixture with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for parenteral and topical administration. .

Pharmaceutical formulations may be in solid form such as tablets, granules, powders, capsules, or liquid forms such as solutions, suspensions, syrups, emulsions, lemonades, etc. If necessary, auxiliary agents, stabilizers, wetting agents, and others such as lactose, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, fallen raw oil, olive oil, cacao fat,
Commonly used additives such as ethylene glycol, tartaric acid, citric acid, fumaric acid, etc. may also be included. The dosage of compound (1) depends on the patient's age, condition, type of disease,
It varies depending on the type of compound (1) used, etc. Generally, doses between 1 mg and about 4000 1 g per day or more may be administered to the patient. The object compound (1) of this invention has an average single dose of about laIg, IOB,
50mg, 100mg, 250mg, 500
mg, loohg, 2000sg may be administered to treat pathogenic bacterial infections. The present invention will be explained in more detail below according to production examples and examples.

■To a solution of 2-allyloxycarbonylaminomethyl-4-ethoxycarbonylthiazole (4.62 g) in dimethylformamide (40 ml) was added methyl iodide (5.5 g).
11) and sodium hydride (62.8% di-oil suspension, 720 mg) were added at 0°C. The reaction solution obtained by stirring at the same temperature under a nitrogen gas atmosphere was poured into ethyl acetate. The mixture was washed sequentially with water and brine, and dried over magnesium sulfate. The residue obtained by distilling off the solvent was developed on column chromatography packed with silica gel, and a mixture of n-hexane and ethyl acetate (
2:1, V/V) to give 2-(N-allyloxycarbonyl-N-methylaminomethyl)-4-ethoxycarbonylthiazole (4.47 g). ? R (Neat): 1690-1710 cm
-'NMR (CDCIs. δ): 1.41 (
31l. t. J-7Hz), 3.01 (311,s)
,4.39 (2H.q.J"711z) ,4.5-
4.7 (211,m) ,4.78 (2H.s)
．． 5.1-5.4 (211, m), 5.6-8.2
(III, m), 8.13 (IH, s) Lactose 2-(N-allyloxycarbonyl-N-methylaminomethyl)-4-ethoxycarbonylthiazole (4.4
Sodium borohydride (1.2 g) was added to a solution of (7 g) in tetrahydrofuran (50 ml). While refluxing the above mixture, methanol (12 m
l) was added, then cooled to 0°C and acetic acid (IJml) was added. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl acetate and washed successively with water and brine. The organic solvent layer was dried and the solvent was distilled off to give 2-(N-allyloxycarbonyl-N-methylaminomethyl)-4-hydroxymethylthiazole (3.8 g). IR
(Neat): 3100-3400.1880-
1700 cm-'NMR (CDCIs.δ):
2.93 (: II1, s), 4.5-4.8 (5B, +
a), 5.0-5.4 (2}L.S). 5.6-
6.2 (1}1,1). 7.19 (Ill,s)
N-(N-allyloxycarbonyl-N-methylaminomethyl)-4-hydroxymethylthiazole (3.7
Activated manganese dioxide (31 g) was added to a solution of g) in ethyl acetate (100 ml). After stirring this mixture at room temperature for 2 hours, the precipitate was filtered off, and the solvent was distilled off from the filtrate under reduced pressure. Dissolve the residue in toluene (100ml),
3-triphenylphosphoranylidenebutan-2-one (5.0 g) was added to the resulting solution, and the reaction mixture was heated at 80°C.
The mixture was stirred for 1 hour. Next, the solvent was distilled off, and the resulting residue was developed on column chromatography packed with silica gel to obtain a mixture of n-hexane and ethyl acetate (2:1, v/v).
When eluted with 2-(N-allyloxycarbonyl-N
-methylaminomethyl)-4-(2-methyl-3-oxo-1-butenyl)thiazole (3.87 g) was obtained. fR (Neat): 1700. 1660
ca+Ichitomi NMR (CDCIs. δ):
2.13 (311.s). 3.36 (311,s
), 2.97 (311,s). 4. 52 (2H
, d, J=511x). 4.67 (211,
s,) ,5.0-5.4(2H,m), 5.6-
6.2 (llI.m). 7.32 (ill, S). 7
．． 39 (Ill, S) rat]j
l) 3-triphenylphosphoranylidenebutane in liquid I
2-one (4.5 g) was added. After this mixture was centrifuged for 4 hours, the solvent was distilled off, and the residue was dissolved in a mixture of tetrahydrofuran (2011) and water (20 ml). Allyl chloroformate (1.5 ml) was added dropwise to the resulting solution.
In the meantime, adjust the pH by adding IN sodium hydroxide aqueous solution.
10, and the liquid temperature was maintained at 5°C. The reaction mixture was diluted with ethyl acetate (100ml) and washed successively with water and brine. After drying, the solvent was distilled off and the residue obtained was developed on column chromatography packed with silica gel, and n-
When eluted with a mixture of hexane and ethyl acetate (2:1, v/v),! -allyloxycarbonyl-4-(2-methyl-3-oxo-1-butenyl)imidazole (2.
4g) was obtained. IR (NuJol): 17
50 cm-'NMR (CDCJs, δ): 2
．． 16 (311, s), 2.42 (3}1, s). 4
．． 91 (21!, d, J-711Z). 5.1-5.
6 (211, m), 5.7-6.3 (lft, m),
7.37(ill,s), 7.59(11,s),
8.18 (III, d, J-1112) Pear 1'' [(By performing substantially the same operation as Bifurcated Production Example 4-1,
2-Methyl-4-(2-methyl-3-oxo-1-putenyl)thiazole was obtained in a yield of 78.1%. NIAR (CDC1s. δ): 2
．． 14 (311, S), 2.3'l (3}1, S)
, 2.7N311, s). 7.20 (111,s),
7.47(III,s) Mouse 1' 1L di-1-allyloxycarbonyl-4-(2-methyl-3'
-oxo-1-butenyl)imidazole (3.54g)
Triethylamine (
2.5 ml) and trifluoromethanesulfonic acid trimethylsilyl ester (3.2 ml) were added at -60°C under a nitrogen gas atmosphere. After stirring for 30 minutes under the same conditions, the mixture was washed successively with water and brine, and dried over magnesium sulfate. The residue obtained by evaporating the solvent was dissolved in methylene chloride (50 ml). This mixture contains (3S,4R)-4-acetoxy3-[(l
n)-s-tert-butyldimethylsilyloxyethyl]-2-oxoazetidine (44 g) and zinc bromide (
3. 4 g) was added, and the resulting mixture was refluxed with stirring for 1 hour. The reaction solution was washed with water, a saturated aqueous solution of sodium bicarbonate, and water in that order. After drying the organic solvent layer, it was distilled off, and the residue was developed on column chromatography packed with silica gel to obtain a mixture of n-hexane and ethyl acetate (1
:2, v/v), (35.4R) -4-
[4-(1-allyloxycarbonylimidazol-4-yl)-3-methyl-2-xo-3-butenyl]-3-((IR)-1-tert-butyldimethylsilyloxyethyl)-2- Oxoazetidine (1.46g
)was gotten. IR (CHiCli): 3400,1760
, 1730.1660 cm-'NMR (CDC
Is. δ): 0.08 (6H, s),
0.118 (911,s), 1.28 (311,d
, J-71st! ), 2.15 (311, S), 2.
6-3.3 (311, m), 3.8-4.3 (2t
l, m). 4.811 (2H, d, J-61Ix)
,5.2-5.6 (21 ports, m) ,5.7-6
．． 2 (2H, m) , 7.31 (IH, s) .
7.62 (Ill,s). 8.14 (Ill,s
) Elbow 1'' By performing substantially the same operation as in 1L Nut Production Example 5-1,
(35,4R)-3-[(In)-1-tert-butyldimethylsilyloxyethyl]-4-[3
-methyl-4-(2-methylthiazol-4-yl)
-2-oxo-3-butenyl]-2-oxoazetidine was obtained in a yield of 48.8%. IR (CH2Ch)
: 3660, 1750, 1655 cat-
'NMR (CDCI,,δ) 7 0.08 (61
1,s). O. ll[l(9+1,S). 1.21(
3H, d, J-611z). 2.20 (3H, s),
2.72 (3H, s) , 2.8-3.4 (311,
w) ,3.8-4.3 (2H,s) ,6.10(
III, br s), 7.32 (Ill, S), 7
．． 40 (111.3) Production {N 5 By performing substantially the same operation as in Production Example 5-1,
(35.4R) -4- [4- (2- (N-allyloxycarbonyl-N-methylaminomethyl)thiazol-4-yl)-3-methyl-2-oxo-3-butenyl]-3-[IR) -1-tert-butyldimethylsilyloxyethyl]-2-oxoazetidine is 65.5%
was obtained in a yield of .

IR (ClhC1a): 3440, 1770
, 1710. 1675 cm-'NMR (CDC
I3, δ): 0.09 (611, s), 0.9
1 (9H, S). 1.64 (3H, d, J=6Hz)
．． 2.23 (3H, s). 3.16 (311,s)
, 2.6-4.4 (311, m), 3.8-4.3 (
211, m). 4.5-4.8 (211,s), 4.7
8 (211,s), 4.9-5.4 (211.1
I1), 5.6-6.2 (211.01). 7.
48(III,s) Renal status ■1 (35.4R) -4- [4- (1-allyloxylponylimidazol-4-yl)-3-methyl-2
-oxo-3-butenyl] -3- [IR)-1 -
311L Butyldimethylsilyloxyethyl]-2-
Toluene (10 mg) of oxoazetidine (210 mg)
ml) solution of allyl glyoxylate monohydrate (78
B) was added. The resulting mixture was refluxed for 4 hours, during which time water in the mixture was removed azeotropically. Then, the solvent was distilled off, and the residue 2-[(3S,4R)-4
-(4- (1-allyloxycarbonylimidazol-4-yl)-3-methyl-2-oxo-3-butenyl} -3- (IR)-tertiary-butyldimethylsilyloxyethyl)-2-oxoazetidine -1-
Allyl] glyoxylate was dissolved in xylene. The solvent was distilled off under reduced pressure, and the residue was dissolved in methylene chloride (10 ml).
It was dissolved in Add 2.6-lutidine (0.07t) to this solution.
After stirring for 5 minutes, the reaction mixture was diluted with ethyl acetate (5011) and water (5011).
0 ml) at 5°C. After adjusting the pH to around 6.5 using an aqueous sodium hydrogen carbonate solution, the organic solvent layer was separated, washed with brine, dried with magnesium sulfate, and then the solvent was distilled off. After dissolving the residue in degassed N,N-dimethylformamide (10a+1), 2,6-lutidine (0.05 m
l) and triphenylphosphine (0.13g) were added. The reaction mixture was left at room temperature for 6 hours, and then poured into a mixture of ethyl acetate (50 ml) and water (50 ml).
The organic solvent layer was separated and washed with water, IN-cold hydrochloric acid, aqueous sodium bicarbonate solution, and prine in this order, and then dried over magnesium sulfate. The residue obtained by distilling off the solvent was developed on column chromatography packed with silica gel (20 g), and a mixture of n-hexane and ethyl acetate (9:1-4:8
, v/v), 2-[(3S,4
R) - 4 -(4-(1-allyloxycarbonylimidazol-4-yl)-3-methyl-2-oxo-3-butenyl) - 3-{IR)-t-tert-butyldimethylsilyloxyethyl} -2-oxoazetidin-1-yl] -2-triphenylphosphoranylidene allyl acetate (147 mg) was obtained.

IR (CllaC12): 1785, 174
0 cm-'NMR (CDCI3.6): -0.
20-0.10 (6H, m), 0.50-0.90 (9
11, m). 0.90-1.3 (311, a+), 4
．． 8-5.2 (4N, m), 5.3-5.6 (4t
l, m). 5.6-6.2 (2H.m). 7.2
-8.0 (1711.m). 8.17 (III,
s) N-butyl lithium in n-hexane (3.23i+1)
A 1.55M n-butyllithium solution dissolved in
The mixture was added dropwise to a solution of diisobutylamine (0.77 ml) in tetrahydrofuran (a.oomt) at -78°C. This mixture was heated to 0°C, stirred at the same temperature for 30 minutes, and then cooled again to -78°C to obtain an approximately 0.5M lithium diisobrobylamide solution. On the other hand, 2 − [
(3S, 4R) - 3 - ((lRi 1-3rd
butyldimethylsilyloxyethyl)-4-{(IR
)-1-Methyl-2-oxobupyr}-2-oxoazetidin-1-yl] -2-}-riphenylphosphoranylidene Prepare a solution of allyl acetate (0.500 g) in tetrahydrofuran (10.Oal) Then, the previously obtained lithium diisobutyramide solution (1.82 ml) was added to it.
It was added dropwise at 78°C. After stirring at the same temperature for 30 minutes, 3-pyridinecarbaldehyde (0.1111) was added to this mixture.
A solution of tetrahydrofuran (1.0@1) was added. This was left to stand and the temperature was raised to -30°C over 1 hour. Aqueous ammonium chloride solution (30 ml) was added to this mixture, and the mixture was diluted with ethyl acetate (5 hl). The organic solvent layer was separated, washed with an aqueous ammonium chloride solution, water, an aqueous sodium bicarbonate solution, and brine in this order, and then dried over magnesium sulfate. The residue obtained by distilling off the solvent was developed on column chromatography packed with silica gel (20 g),
Mixture of methylene chloride and acetone (9:1-1:1,
v/v), 2-[(3S,4R)
- 3 - ((IR) 1-1-tert-butyldimethylsilyloxyethyl)-4-((IR)-4-hydroxy-1-methyl-2-oxo 4-(3-pyridyl)
butyl}-2-oxoazetidin-1-yl] -2-
}Riphenylphosphoranylidene allyl acetate (418 mg
)was gotten. IR (CI12Cl2): 2420,. 17
40, 1700. 1820 Cll-'NMR (
CDCl3. δ): -0.1 to 0.16 (6H, ++
+), 0.84 (911,s). 0.95-1.5
7 (611.1) . 2.40-3.37 (5H,
m) , 3.92-4.2 (2H, +a) , 4.4
-4.8 (311, m) , 4.8-6.2 (311
, m), 7.0-8.0 (1711, +o). 8.3
-8.7 (2H, m) East MJL Yu2-[3S,4R) -4- (4- (1-allyloxylponylimidazol-4-yl)-3-methyl-2-oxo-3-butenyl) -3-{(lR)-1-tert-butyldimethylsilyloxyethyl}-2-oxoazetidin-1-yl]-12-triphenylphosphoranylidene allyl acetate (1.2 g) was added to xylene (30
11) and heated at 140°C for 7 hours. The residue obtained by distilling off the solvent from the reaction mixture was applied to column chromatography packed with silica gel, and eluted with a mixture of n-hexane and ethyl acetate (2:1, v/v).
(SR, SS) -3- [2- (1-allyloxycarbonylimidazol-4-yl)-1-methylethenyl] -6- [(IR)-1-tert-butyldimethylsilyloxyethyl]-7- Allyl oxo-1-azabisic[3.2.0]hebut-2-ene-2-carboxylate (0.45 g) was obtained. IR (CIIzClz): 1780, 172
0 cm-'NMR (CDCls.δ): 0
．． 09 (60, S). 0.89 (91+,s). 2
．． 28 (311, d, J=611z) , 3.12
(3H, d, J = 1 + heat z》, 2.9-3.2 (3H,
s). 4.0-4.4 (2H, m), 4.6-5.0
(4H, +s) ,5.0-5.6 (4! mouth, m)
,5.7-6.2 (2}1,m). 6.4(
IH, S), 7.39 (IH, S). a. xt
(SR, [iS) -6 - [ (IR)
-1-tert-butyldimethylsilyloxyethyl]-3-[1-methyl-2-(2-methylthiazole-
Furyl 4-yl)ethenyl]-7-oxo-1-azabicyclo[3,2.01hbut-2-en-2-carboxylic acid was obtained in a yield of 67.0%. IR (ClhCh
): 1780, 1720 cm-'NMR
(CDCI co. δ): 0.09 (all,
S), 0.88 (9+1, S), 1.22 (31
1, d, J=611x). 2. 13 (311
, s), 2. 65 (311, s), 2.9
-3.2 (3H, m), 3.9-4.3 (211, m
), 4.5-4.8 (211, +s), 5.0-5.
5 (211, m), 5.6-6.1 (IH, m)
,6.52 (III,s) ,6.99 (IH,
s) Ki near unaryl was obtained in a yield of 81.8%. IR (CIh
Ch): 1780, 1740. 1710c
m-'NMR (CDCIs, δ): 0.09 (
611, s). 0.90 (911.s), 1.25 (
3H, d, J=711z), 2.21 (3H, s).
3.01 (311,s) ,3.0-3.2 (211
,m). 4.5-4.8 (411,ffl) ,5
．． 0-5.5 (4H, m), 5.6-6.2 (2H,
m), 6.68 (Ill, s) By performing substantially the same operation as in Example 2-1, (5R.BS) -3-
[2- ((2- (N-allyloxycarbonyl-N-methylaminomethyl)thiazol-4-yl)-
1-methylethenyl] -a- [IR)-1-tert-butyldimethylsilyloxyethyl]-7-oxo-1
-Azabishiku mouth [3.2. O] hebuto2-en-2-
Carboxylic acid 2-[(3S,4R)-3-
((tn)-1-tert-butyldimethylsilyloxyethyl}-4-((lR)-4-hydroxy-1-methyl-2-oxo4-(3-biridyl)butyl)-2
-oxoazetidin-1-yl]-2-triphenylphosphoranylidene allyl acetate (1.91 g) +7) A degassed toluene (65.oIIll) solution was heated under reflux for 7 hours. After cooling, toluene was distilled off and the residue was dispersed in methylene chloride. Triethylamine (0.42
111) and methanesulfonic acid chloride (0.21 ml)
was added dropwise with stirring at 5°C, and stirring was continued at the same temperature for 30 minutes. 1.8-diazabisic acid [5
．． 4. Ol Undekar 7-ene (1.12m
1) was added, and the reaction mixture was allowed to warm to room temperature. After stirring for 1 hour at room temperature, the mixture was diluted with ethyl acetate and
It was washed with an aqueous ammonium chloride solution, water, and brine in that order, and dried over magnesium sulfate. The residue obtained by distilling off the solvent was applied to column chromatography packed with silica gel (75a+1) and eluted with a mixture of n-hexitine and ethyl acetate (9:1-1:1, v/v). Then, (4S
．． 5R,65) -6-[(IR)-1-tert-butyldimethylsilyloxyethyl]-4-methyl-7-
Oxo-3-[(E)-2-(3-pyridyl)ethenyl]-1-azabisic [3. 2. Allyl hebuto-2-ene-2-carboxylate was obtained (690
．． 8a+g)IR (CIIzCh): 1770
．． 1710 cm-'NMR (CDCl3, δ)
: 0.12(all,S). 0.92 (9+1,
S). 1.30 (611, d, J-711z), 3.2
3 (IH, dd, J-3. 611z). 3.25-3
．． 7 (Il1, praise). 4.05-4.40 (211
, +++), 4.65-4.85 (211, m). 5.
1-5.6 (211, eyes). 5.85-6.25 (IH
, l), 8.75 (IH, d, J-17112). 7.
23 (IH, dd, J-5. 8112). 7.
7-7.9 (lH.m). 7.91 (18, d, J=
1711z). 8.46 (III, dd, J-
3.5Hz), 8.82 (IH, d, J-31Iz
) Example 4-1 (511.65)-3-[2-(1-allyloxycarbonylimidazol-4-yl)-1-methylethenyl] -6-[(IR)-1-tert-butyldimethylsilyl oxyethyl]-7-oxo-1-azabicyclo[3.2. To a solution of allyl hebuto-2-ene-2-carboxylate (450 og) in tetrahydrofuran (10 ml) was added acetic acid (0.50 ml) and an IM solution of tetrabutylammonium fluoride in tetrahydrofuran (5.0 ml).
Added at ℃. After standing at room temperature for 10 hours, the reaction mixture was partitioned into a mixture of ethyl acetate (50ml) and water (50a+1). The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. The residue obtained by distilling off the solvent was developed on column chromatography packed with silica gel, and a mixture of n-hexane and ethyl acetate (8:2-2:8, v/v) was used.
When eluted with (SR, BS) − 3 − [2− (
1-allyloxycarbonylimidazol-4-yl)
-1-methylethenyl]-6-[(IR]-1-hydroxyethyl]-7-oxo1-azabisic [3.2
．． 0] Allyl hebuto-2-2-2-carboxylate was obtained (210 mg). IR (ClhCh):
3675, 17fiO, 1720 Cll-”NM
R (CDCIs.δ): 1.26 (3H, d,
J-611! ). 2.13 (3H, d.J-IHz)
,3.0-3.4 (311,++) ,4.6-5
．． 0 (4Lm), 5. 1-5.6 (411, m)
, 5.7-6.2 (211, m). 6.42(i
ll, s), 7.40 (1B, s), 8.12 (IH
, d, J-111z) By performing substantially the same operation as in Example 4-1,
(SR,65) -6-[(IR)-1-hydroxyethyl]-3-[1-methyl-2-(2-aminothiazol-4-yl)ethenyl]-7-oxo1-azabisic(3 .2.0] hepto2-en-2
-Allyl carboxylate was obtained in a yield of 53.0%. IR NMR (CH2Ch): 3800, 1775,
1720 cta-' (CDCIs. δ):
lJ1 (31st, d, J=711z), 2.14
(311, s), 2.62 (3H.s). 2.9-3
J (3H, m), 3.8-4.4 (2tl, m),
4.5-4.8 (21st, a+), 5.0-5.5
(211, ■). 5.6-6.2 (11l, m). 6.
50 (III, s). 6.97 (III, s) Tue 1j ((By performing substantially the same operation as in Example 4-1,
(SR,65) -3-[2-(2-(N-allyloxycarbonyl-N-methylaminomethyl)thiazol-4-yl)-1-methylethenyl]-6-[(IR
)-1-Hydroxyethyl]-7-oxo-1-azabisic [3. 2. Ol Hebuto 2-en-2-
Allyl carboxylate was obtained in a yield of 27.6%. IR (CI12Cl2): 3600, 1
780. 1705 cm-'NMR (CDCl
3. 6): 1.32 (311.d, J-61
1z). 2.19 (311.s). 3.00 (3H
．． s). 2.9-3.3 (2H, +a), 4.4-
4.8 (6114) ,5.0-5.5 (4H,s
), 5.6-6.2 (211, ffl), 6. SL
(IH,s). 7.12 (111.s) 衷茄j [(
2A (4S, SR, 6S) - 6 - ((IR) -
1-tertiary butyldimethylsilyloxyethyl]-4-
Methyl-7-oxo-3-[(E)-2-(3-pyridyl)ethenyl]-1-azabisic [3.2.0]
Allyl hebuto-2-ene-2-carboxylate (62.7m
A mixture of acetic acid (0:1151) and tetrahydrofuran (lml) and a solution of IM tetrabutylammonium fluoride in tetrahydrofuran (0.67ml) were added dropwise to the tetrahydrofuran (5.0ml) solution of g) at room temperature. After standing at room temperature for 24 hours, the reaction mixture was diluted with ethyl acetate (4 hl), phosphate buffer (pH 6.86.20)
ml) and water (20 ml). 6. Separate the organic solvent layer and adjust the pH of the phosphate solution. llIi) and brine and dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel (4 m
l) Developed in packed column chromatography and eluted with a mixture of methylene chloride and acetone (4:1, v/v) to give (45,SR,65)-6-[(IR)-1-
hydroxyethyl]-4-methyl-7-oxo3-
[(E)-2- (3-viridi-l)ethenyl]-1-
Allyl hebuto-2-ene-2-carboxylic acid [3.2.0] was obtained (40.2+ag) IR (CIhCh): 3620, 1770.
1710 cva-'NMR (CDCIs.δ)
: 1.31 (311, d, J-811z), 1.
38(311,d,J=?lIz), 3.20(ill
, br s), 3.26 (Ill, dd, J
-3,71lz), 3.58(llI, dq, J
-8,811z) ,4.00-4. :19 (211
,m). 4.53-4.97 (2++, m). 5
．． 08-5.57 (211th chapter). 5.68-6.2
5 (III, +a), 6.72 (IH, d.J-161
Z), 7.11-7.39 (Ill, m). 7.
80-7.85 (IH, m), 7.85 (IH, d,
J-161lz), 8.20-8.8O (211, m) Togoketsu (SR, 651 -3- [2- (1-allyloxylponylimidazol-4-yl)-1-methylethenyl] -6- [IR)-1-Hydroxyethyl]-7-oxo-1-azabisic [3.2.0] allyl hept-2-ene-2-carboxylate (200 mg) was mixed with tetrahydrofuran (4+al) and ethanol ( Triphenylphosphine (37
mg), 5,5-dimethyl-1,3-cyclohexanedione (137+ag) and tetrakis(triphenylphosphine)palladium(0) (54 mg) were added sequentially. This was stirred at room temperature for 1 hour, and the resulting precipitate was collected by filtration and washed with tetrahydrofuran. This precipitate was dissolved in water (20IIIL), this liquid was washed with ethyl acetate, concentrated under reduced pressure, and further freeze-dried.
5R, OS) - 6 - [(IR) - 1-hydroxyethyl] -3- [2- (imidazole-
4-yl)-t-methylethynol]-7-oxo-1-azabisic[3.2.0]hept-2-en-2
-Carboxylic acid was obtained (50 mg), IR (KBr): 1740-1750 cm-'
NMR (D, O, δ): 1.30 (3H, d, J
-6}1! ), 2.03 (3+1, S), 8.22 (i
ll,s) ,8.50(III,s) Medical Care Ji21 0H Perform substantially the same operation as Example 5-1 except that sodium 2-ethylhexanecarboxylate was used instead of dimedone. Therefore, (SR, lis) − 6 −[ (
IR) - 1-hydroxyethyl] -3- [1-
Methyl-2-(2-methylthiazol-.4-yl)ethenyl]-7-oxo1-azabisic[3.2.0
] Sodium hebuto-2-ene-2-carboxylate is 89
, was obtained with a yield of 6%. IR (NujOl):
1745-1755 c+a-'NMR (Dad, δ
): 1.24 (311, d.J=611z). 2
．． 03 (311, s). 2.61 (311, s). 6.
40 (IH, s). 7.23 (IH, s) 茷茄'' 1L
By performing substantially the same operation as in Example 5-1,
(SR, 85) -3-[1-methyl-2-(
2-(N-methylaminomethyl)thiazol-4-yl}ethenyl] -6- [IR)-1-hydroxyethyl]-7-oxo-1-azabisic [3.2.0]
Hebuto-2-ene-2-carboxylic acid was obtained in a yield of 37.9%.

IR (Nujol): 1750 cm””NMr
(IhO.δ): 1.2B(311,d,J-
71Ix), 2.10 (311,s), 2.81 (31
1, s), 6.48 (III, s), 7.50 (Il
l, s) MS: 364 (M+◆l) Tue 55 1 Ni 1 Last 11 Female Danseed bN By performing substantially the same operation as Example 5-2 (4S, 5R, 6S) - 6 - [ (In) −
1-hydroxyethyl]-4-methyl-7-oxo3-[(E)-2-(3-pyridyl)ethenyl]-1
-Azabishiku mouth [3.2.0] hepto 2-en-2-
Sodium carboxylate was obtained.

TR (Nujol): 3350, 1740.
1800 cm-'NMR (D, 0, δ): 1
．． 14 (311.d.J-8112), 1.32 (3+
1, d, J-7Hz), 3.19-3.64 (2+1
, at). 3.94-449 (211, m), 6.6
3 (Ill, d, J-1611Z). 7.29 (II
I, dd, J-4, 71lz). 7.63 (II1
．． d, J-1611z) , 8.26 (01, d, J-
4}1x). 8.40 (III, br s) (4S,
SR,6S)-6-[(IR)-1-hydroxyethyl]-4-methyl-7-oxo3-[(
E) Allyl 2-(3-biridyl)ethenyl]-1-azabisic[3.2.0]hept-2-en-2-carboxylate (0.171 g) in acetone (10 ml Hill J
Methyl iodide (0.18 ml) was added to the liquid. 22 at room temperature
After stirring for an hour, methyl iodide (0.18
ml) was added thereto, and the mixture was further stirred for 6 hours. When the solvent and excess methyl iodide are distilled off under reduced pressure, (4S, SR, 5S)
-6-[(IR)-1-hydroxyethyl]-4
-Methyl-7-year-old xo3- [(E)-2- (1-
Methyl-3-viridinio)ethenyl]-1-azabisic[3.2.0]hept-2-ene-2-carboxylic acid allyl iodide was obtained (238 mg).

This product was used as a raw material for the next process without being purified. IR (Nujol): 3340, 1750.
1710 cm-'NMn (DMSO-d6, δ
): 1.17 (311, d, J-411z),
1.25 (:lH.d, J-511z), 3.25-
3.45 (IH, m), 3.45-3.75 (il
l, m) , 3.82-4.15 (III, II+)
, 4.15-4.40 (III, m) , 4.35
(311,s) ,4.65-4.85 (211,
m), 5.13-5.60 (211, ml .5.7
6-6.23 (III, m). 7.13 (Ill
, d, J-1611z), 7.88 (II1, d, J
-161Iz), 8.08 (III.dd, J-6.
81121, 8.60 (III, d, J-8112).
8.81 (lIl, d, JJllz) , 9.12
(ill, s) Example 7 (4S, 5R, 6S) - 6 - [ (Ill)
- 1-Hydroxyethyl 1-4-methyl-7-year-old xo-3-[(E)2-(1-methyl-3-pyridinio)ethenyl]-1-azabishikuchi[3.2.0]hebuto2
-N,N- of en-2-carboxylic acid allyl iodide
In a dimethylformamide (10.0 ml) solution, triphenylphosphine (12.2a+g), tetrakis(triphenylphosphine)palladium (o) (5.4
mg) and a solution (0.49M) of sodium 2-ethylhexanecarboxylate in ethyl acetate (1.90ml) were added. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure.

The residue was dispersed in a mixture of brine and ethyl acetate, and the aqueous layer was separated, washed four times with diisopropyl ether, and then concentrated under reduced pressure. The remaining residue is treated with a non-ionic adsorption resin “Diaion HP-20J (trademark, manufactured by Mitsubishi Chemical Industries, Ltd.)”
(80 ml) packed column chromatography, water (250 ml) and then aqueous acetone (10-3
0%, eluted at 350a+1). When both parts containing the target substance are collected and lyophilized, (45.5R, [+5) -
6-[(In)-1-hydroxyethyl]-4-methyl-3-[(E)-2-(1-methyl-3
-pyridinio)ethenyl]-7-oxo-1-azabisic[3.2.01 Hept-2-ene-2-carboxylic acid was obtained (107 mg).

Claims (3)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula R^1: Carboxy group or protected carboxy group R^2: Hydroxy (lower) alkyl group or protected hydroxy (lower) alkyl group R ^3, R^4: the same or different hydrogen or lower alkyl group R^5: an unsaturated heterocyclic group optionally substituted with one or more suitable substituents) 3-alkenyl-1 - Azabicyclo [3.2
．． 0] hept-2-ene-2-carboxylic acid derivative or a pharmaceutically acceptable salt thereof. (2) A method for producing the compound described in claim (1) or a salt thereof by the method described in any one of the following (a) to (g). (a) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^3, R^4 and R^5 each have the same meaning as before, and R^6 is aryl. or a lower alkoxy group) or its salt is subjected to a ring-closing reaction, formulas ▲mathematical formulas, chemical formulas, tables, etc.▼ (in the formula R^1, R^2, R^3, (R^4 and R^5 each have the same meaning as before) Method for manufacturing the compound represented by (b) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^2, R^3, R^4 and R^5 each have the same meaning as before, R^1_a represents a protected carboxy group) or a salt thereof is subjected to an elimination reaction of the carboxy protecting group in R^1_a Therefore, a compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R^2, R^3, R^4 and R^5 each have the same meaning as above) (c)
Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^3, R^4 and R^5 each have the same meaning as before, and R^2_a is a protected hydroxy (
By subjecting a compound represented by (lower) alkyl group) or its salt to the elimination reaction of the hydroxy protecting group at R^2_a, the formula ▲mathematical formula, chemical formula, table, etc.▼ (in the formula R^1, R^3, R^4 and R^5 each have the same meaning as before, and R^2_b represents a hydroxy (lower) alkyl group) A method for producing a compound or a salt thereof, (d)
Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^3 and R^4 each have the same meaning as before, and R^5_a is protected with one or more protecting groups. represents an unsaturated heterocyclic group containing one or more imino residues,
This unsaturated heterogroup may be substituted with one or more suitable substituents) by subjecting the compound represented by the formula ▲ mathematical formula, chemical formula, table etc.▼ (In the formula, R^1, R^2, R^3 and R^4 each have the same meaning as before, and R^5_b represents an unsaturated heterocyclic group containing one or more imino residues. and this unsaturated heterocyclic group is 1
A method for producing a compound or a salt thereof (which may be substituted with an appropriate substituent as mentioned above), formula (e) ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula R^1_a, R^2 , R^3 and R^4 each have the same meaning as before, R^5_c represents an unsaturated heterocyclic group containing a quaternary nitrogen atom, and this unsaturated heterocyclic group has one or more suitable substituents. By reacting a compound represented by (which may be substituted with a group) or a salt thereof with an alkanimidizing agent, the formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in the formula R^1_a, R^2, R ^3 and R^4 each have the same meaning as before, and ^+R^5_c represents an unsaturated heterocyclic group containing a quaternary nitrogen atom, and this unsaturated heterocyclic group has 1
(f) Formula ▲ Formula , chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^3, R^4 and R^5 each have the same meaning as before) or its reactive derivative in the hydroxy group, or By subjecting the salt to a dehydration reaction,
A compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^3, R^4 and R^5 each have the same meaning as before) (g) method of manufacturing;
Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2, R^3 and R^4 each have the same meaning as before, and R^5_d is a protected lower alkylamino (lower ) means an unsaturated heterocyclic group substituted with alkyl) By subjecting the compound represented by or its salt to the elimination reaction of the amino protecting group in R^5_d, the formula ▲ mathematical formula, chemical formula, table, etc. ▼ (In the formula, R^1, R^2, R^3 and R^4 each have the same meaning as before, and R^5_e represents an unsaturated heterocyclic group substituted with lower alkylamino (lower) alkyl. A method for producing a compound shown in (shown) or a salt thereof. (3) An antibacterial drug comprising the compound according to claim (1) or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient added thereto.