JPS58185590A - 1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid derivative and preparation thereof - Google Patents

Abstract

NEW MATERIAL:A compound (salt) of formula I [R<1> is (protected) OH or lower alkoxyl; R<2> is (protected) carboxy; R<3> is substituted aryl, (substituted) pyridyl or heterocyclic group containing 3-5 heteroatoms which may have a substituent group]. EXAMPLE:4-Nitrobenzyl-(5R,6R)-3-(4-pyridylthio)-6-[1-methyl-1-(4-nitro benzyloxycarbonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-carboxy late. USE:An antimicrobial agent and inhibitor against beta-lactamases. PROCESS:A compound (salt) of formula II (R<5> is acyl) is reacted with a compound (salt) of the formula R<3>-SH or a compound (salt) of formula III is reacted with an acylating agent and then the compound (salt) of the formula R<3>-SH.

Description

[Detailed description of the invention]

This invention relates to novel 1-azabicycloC3,2,0)hept-2-ene-2-carboxylic acid conductors and their pharmaceutically acceptable salts. More specifically, this invention discloses novel 1-azabicycloC3, which has antibacterial activity and β-lactamase inhibitory activity.
2,0]] Hept-2-ene-2-carboxylic acid derivatives and pharmaceutically acceptable salts thereof, methods for producing them, and infectious disease prevention and treatment agents containing them. That is, one object of the present invention is to develop a novel 1-azabicycloC3,2,0)heptoid that exhibits high antibacterial activity against species 4 pathogenic bacteria and high β-lactamase inhibitory activity and is useful as a preventive and therapeutic agent for infectious diseases. -2-ene-2-carboxylic acid derivatives and pharmaceutically acceptable salts thereof. Another object of this invention is to provide a novel 1-azabicyclo(
3,2,0) The present invention provides a complete method for producing hept-2-ene-2-carboxylic acid derivatives and salts thereof. Yet another object of the present invention is characterized in that it contains the 1-azabicyclo(3,2,0)hept-2-ene-2-carboxylic acid derivative and its pharmaceutically acceptable salts as active ingredients. The purpose of the present invention is to provide a preventive and therapeutic agent for infectious diseases. 1-Azabicyclo 6゜2.0 which is the object of this invention
) Hept-2-ene-2-carboxylic acid derivatives are new compounds and can be represented by the following general formula. I (wherein R is a hydroxy group, a protected hydroxy group or a lower alkoxy group, R is a carboxy group or a protected carboxy group, R is an aryl group having an appropriate substituent, A pyridyl group or a suitable substituent may be present in the target compound and in the starting material compound (
In 1), one or more stereoisomer pairs exist, such as optical isomers based on the 3-position and the holed asymmetric carbon atom of the 1-azabicyclo(3,2,0)hept-2-ene ring. However, such isomers are also included within the scope of this invention. The pharmaceutically acceptable salts of the target compound (11) include conventional non-toxic salts, such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and ammonium salts. Salts with inorganic bases, such as triethylamine salts, pyridine salts,
Salts with bases, such as salts with organic bases such as organic amine salts such as picoline salts, ethanolamine salts, triethanolamine salts, synchlohexylamine salts, NlN-dibenzylethylenediamine salts, etc., e.g. hydrochloride, hydrogen bromide. Inorganic acid addition salts such as acid salts, sulfates, and phosphates. For example, formate, acetate, trifluoroacetate, microorganisms:
yn salt, tartrate. 1. Salts with acids such as organic acid addition salts such as methane sulfonate, benzenesulfonate, toluenesulfonate, etc.; salts with basic or acidic amino acids such as arginine salt, aspartate, glutamate; Examples include intermolecular or intramolecular quaternary salts. The intermolecular quaternary salt can be formed when the heterocyclic group in the compound (11) contains a nitrogen atom, such as a pyridyl group, and such intermolecular quaternary salts include, for example, 1-methylpyridinium methylsulfate, 1-ethylpyridinium ethylsulfate, etc.
-Lower alkylpyridinium lower alkylpyridinium (lower alkyl)L/SlV phates, 1-lower alkylpyridinium halogenides such as 1-methylpyridinium iodite, and the like. The intramolecular quaternary salt can be formed when the heterocyclic group in R of compound (1) contains a nitrogen atom, such as a pyridyl group, and R2 is a carboxy group, and such a molecule Examples of quaternary salts include 1-methylpyridinium carboxylate, 1-ethylhyridinium carboxylate, 1-propylpyridinium carboxylate, 1-isopropylpyridinium carpoquinate, and 1-butylpyridinium carboxylate. Examples include lower alkylpyridinium carboxylates. The target compound (1) and its pharmaceutically acceptable salts in this invention can be produced by the method shown in the reaction formula below. (1) Production method 1 (11l1l (11 or a salt thereof (in the formula, B1 and B2 each have the same meaning as before) (C
1 method C +1-g) (1-old or its salt or its salt

[II
-k] and its salt (in the formula, R7 means a carboxyl group or a protected carboxy group, R means a lower alkyl group, and Rb has the same meaning as before) In the raw material compound (1), a compound represented by the following formula These compounds are particularly useful intermediates for the preparation of various 1-azabinclo(3,2,0)hept-2-ene-2-carboxylic acid derivatives, including the object compounds of the present invention. (wherein 9 and RH each have the same meanings as before) Suitable examples and illustrations of the various definitions used in this specification and falling within the scope of this invention are all set forth in detail below. The term "lower" means 1 to 1 carbon atom, unless otherwise specified.
It means a fundamental tone with 6 pieces. Examples of "protected hydroxy groups" include hydroquine groups substituted with conventional hydroxy protecting groups commonly used in beta-lactam compounds such as chenamycin derivatives or analogs thereof; Examples of such groups include acyl groups described below, such as benzyl, benzhydryl, trityl, etc., or di- or triphenyl (
(lower) alkyl groups such as trimethylsilyl, triethylsilyl, isopropyl-dimethylsilyl, tert-butyl-dimethylsilyl,
Tri(lower)alkylsilyl groups such as diisopropyl-methylsilyl, triarylsilyl groups such as triphenylsilyl, trisubstituted silyl groups such as trial(low e)alkylsilyl groups such as tribenzylsilyl, etc. can be mentioned. Examples of "acyl groups" include aliphatic acyl groups, aromatic acyl groups, heterocyclic acyl groups, and aromatic heterocyclic groups derived from carboxylic acids, reconstituted acids, nurphonic acids, phosphinic acids, and phosphoric acids. Examples include aliphatic acyl groups substituted with . Examples of aliphatic acyl groups include formyl, acetyl,
Lower alkanoyl groups such as propionyl, butyryl, isobutyryl, valeryl, isovaleryl, piparoyl, hexanoyl, lower alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanenulfonyl, such as methoxycarbonyl, ethoxycarbonyl, propoquine carbonyl, butoxycarbonyl, Lower alkoxycarbonyl groups such as tertiary butoxycarbonyl; lower alkenoyl groups such as acryloyl, methacryloyl, crotonoyl; (03-
C7)-Cycloalkanecarbonyl groups, such as 2-trimethylsilyl! Birds such as Reethoxycarboni M (low grade)
AlkylsilyA/(lower)alkoxycarbonyl group, such as diethylphosphono, diethylphosphono, etc.
Examples include saturated or unsaturated, cyclic or acyclic acyls such as lower) alkylphosphono groups and the like. Aromatic acyl groups include, for example, aroyl groups such as benzoyl, toluoyl, xyloyl, etc., arene-nulfonyl groups such as benzenesulfonyl and tosyl, arylhonufinoyl groups such as diethylphosphonoyl, and e.g. Examples include diarylhonuphono groups such as honuphono, ditolylphosphono, and dinaphthylphosphono. Examples of the heterocyclic acyl group include furoyl, thenoyl,
Examples include heterocyclic carbonyl groups such as nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, and tetrazolylcarbonyl. Examples of the aliphatic acyl group substituted with an aromatic group include t
is an alkanoyl group such as a phenyl(lower)alkanoyl group such as phenylacetyl, phenylpropionyl, phenylhexanoyl, an alkanoyl group such as a phenyl(lower)alkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, etc. (lower) alkoxycarbonyl groups, such as phenoxy (lower) alkanoyl groups such as phenoxyacetyl and phenoxypropionyl. Aliphatic acyl groups substituted with heterocyclic groups include thenyl acetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolyl acetyl, thiadiazolyl acetyl, thenylpropionyl, thiadiazolylpropionyl, etc. can be mentioned. These acyl groups may further include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc., halogens such as chlorine, bromine, iodine, fluorine, etc., such as methoxy, ethoxy, propoxy,
Lower alkoxy such as isopropoquine, butoxy, pentyloxy, hexyloxy, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio,
Lower alkylthio groups such as pentylthio and hexylthio,
It may be substituted with one or more suitable substituents such as a nitro group, and examples of acyl groups having such a substituent include chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, etc. Mono(or di- or tri)halo(low Wk)alkanoyl groups such as chloromethoxy carbonyl, dichloromethoxycarbonyl, 2,2,2-4-lichloroethoxycarbonyl, etc. Hatori) halo(lower) alkoxycarbonyl group, e.g. nitrobenzyloxycarbonyl, chlorobenzyloxycarbonyl,
Examples include nitro (or halo or lower alkoxy) phenyl (lower) alkoxycarbonyl such as methoxybenzyloxycarbonyl. More preferred examples of protected hydroxy groups defined in this way include chemical groups which may contain a nitro group, di- or trifluorene/L' (low M) alkoxy groups. The most preferred is 4-nitrobenzyloxycarbonyloxy group. Examples of the "lower alkoxy group" include linear or branched lower alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, and hexyloxy. Examples of "protected carboxy groups" include en-tep-treated carboxy groups commonly used at the 3- and 4-positions of penicillin and cephalonuporin compounds. “Ester moiety” of “enuterized carboxy group”
Examples include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester, etc.o low e alkyl esters, such as vinyl esters, Lower alkenyl esters such as allyl esters, e.g. - lower alkoxy(lower)alkyl esters such as ethoxymethyl ester, e.g. lower alkylthio(lower)alkyl esters such as methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, e.g. 2-amino-2- Amino- and carboxy-substituted lower allyl esters such as carboxyethyl ester, 6-amino-3-carboxyethyl ester, 5 e.g. 2-tert-butoxycarbonylamino-
2-benzhydryloxycarbonylethyl ester,
Lower alkoxycarbonylamino and mono-(or lower IJ) alkoxycarbonyl-substituted lower allyl esters such as 3-tertiary poxycarponylamino-3-penzhydryloxycarponyl globyl ester protected amino and protected carboxy-substituted lower alkylethyl, such as
Examples j Mono(mono- or tri-)halo(lower) alkyl esters such as 2-iodoethyl ester, 2,2,2-trichloroethylethyl, etc., e.g. eba-acetoxymethyl ester, propionyloxymethyl ester,
Butyryloxymethyl ester, isobutyryloxymethyl ester, valeryloxymethyl ester, piparoyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, 1-acetoxypropyl ester, etc. Lower alkanoyloxy (lower) alkyl esters, such as mesyl methyl ester, lower alkanesulfonyl (low m) alkyl esters such as 2-mesylethyl ester, e.g. evahensyl ester, 4-methoxypenzyl ester, 4-nitrobenzyl ester , phenethyl ester, benzhydryl ester, trityl ester, bis(methoxyphenyl)methyl ester, 3
．． 4-dimethoxybenzyl ester, 4-hydroxy-
Mono(
or di- or tri)phenyl (al(lower) alkyl esters optionally bearing one or more suitable substituents such as lower n>alkyl esters, e.g.
It may contain one or more of a number of undue substituents such as phenyl ester, tolyl ester, tertiary butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, salicyl ester, etc. Alkyl ester 1 Examples include heterocyclic esters such as phthalidyl ester, trisubstituted silyl esters such as trimethylsilyl ester, triethylsilyl ester, tertiary butyl-dimethylsilyl ester, isopropyldimethylsilyl ester, and phenyldimethylsilyl ester. . The carboxy group thus defined and protected. As a more preferred example, the mono- or di-moshi which may have a nitro group is a triphenyl (lower) alkoxycarbonyl group, and the most preferred example is a 4-
It is a nitrobenzyloxycarbonyl group. Examples of "aryl groups having appropriate substituents" include phenyl, tolyl, xylyl, cumenyl, etc., and these groups have one or more amino groups, nitro groups, such as fluorine, chlorine, It has a halogen such as bromine or iodine, the aforementioned lower alkoxy group, carboxy group, aforementioned protected carboxy group, hydroxy group, etc. as a substituent. A more preferable example of the thus defined "aryl group having a suitable substituent" is an aminoaryl group such as aminophenyl such as 2-aminophenyl. Examples of the "suitable substituent? Pyridyl method which may have one" include 2-pyridyl, 3-pyridyl, 4-pyridyl, etc., and these groups have one or more amino groups as a substituent. , nitro groups such as fluorine, chlorine, bromine,
It may contain a halogen such as iodine, the above-mentioned lower alkoxy group, carboxy group, the above-mentioned protected carboxy group, hydroxy group, etc. More preferable examples of the thus defined "pyridyl group which may have an appropriate substituent group" include pyridyl groups which may have an amino group, and the most preferable examples include pyridyl groups which may have an amino group. -Aminopyridines such as pyridyl, 3-pyridyl, 4-pyridyl or 3-aminopyridin-4-yl may be mentioned.
The "heterocyclic group containing 3 to 5 heteroatoms" in "heterocyclic group containing 5 heteroatoms" is an oxygen atom. Examples include saturated or unsaturated, monocyclic or polycyclic sub-heterocyclic groups containing a total of 6 to 5 heteroatoms such as sulfur atoms, nitrogen atoms, etc. Among these, particularly preferred heterocyclic groups include: For example, 4H-1,2,4-triazolyl, I
H-1,2,3-) riazolyl, 2)1-1.2.3-
) an unsaturated 3- to 8-membered (more preferably 5- to 6-membered) monocyclic heterocycle containing 3 to 4 nitrogen atoms, such as a triazolyl group such as riazolyl, for example a tetrazolyl group such as 1H-tetrazolyl and 2H-tetrazolyl; a formula group, e.g. 1,2.4
- unsaturated 3-8 membered containing 1-2 oxygen atoms and 2-3 nitrogen atoms, such as oxadiazolyl groups such as oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc. preferably 5-6 members)
Monocyclic heterocyclic group 1 such as 1,2,3-thiadiazolyl,
Unsaturated 3 containing 1 to 2 sulfur atoms and 2 to 3 nitrogen atoms, such as thiadiazolyl groups such as 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc. ~8 members (or better yet, 5~)
6-membered) monocyclic heterocyclic group, such as tetrasilo (1,5-b
) An unsaturated condensed polycyclic heterocyclic group containing 3 to 5 nitrogen atoms, such as a tetracyclopyridazinyl group such as pyridazinyl. Further, the above complex compound may be a lower alkyl group such as methyl, ethyl, lower alkoxy group such as methoxy, ethoxy, propoxy, lower a/l/kylthio group such as methylthio, ethylthio, etc., such as methylamino, etc. lower alkylamino groups, hydroxy groups such as chloro,
Halogens such as bromo, amino, the above-mentioned protected amino groups, cyano groups, nitro groups, carboxy groups, the above-mentioned protected carboxy groups, sulfo groups, such as formimidoylaminomethyl, formimidoylaminoethyl/I/, aceto Lower alkanimidoylamino (lower) alkyl groups such as imidoylaminomethyl, nitrophenyl (lower) alkoxycarbonyl (lower) alkanimidoylamino (lower) alkyl groups such as 4-nitrobenzyloxycarbonylacetimidoylaminomethyl, etc. a protected lower alkanimidoylamino(lower)alkyl group, such as a heterocyclic group such as pyridyl such as 4-pyridyl.
If so, it may be substituted with two or more substituents. A more preferable example of the "heterocyclic group containing 3 to 5 hetero atoms, which may have an appropriate substituent" that can be defined in this way is, for example, 5-methyl 1.3.4-oxadi 5-lower alkyl such as azol-2-yl 1,3.4
an oxadiazole group optionally substituted with lower alkyl such as -oxadiazol-2-yl, e.g. 1-
1-lower alkyl such as meth/l/-IH-tetrazol-5-yl; a tetrazolyl group optionally substituted with lower alkyl such as 1H-tetrazol-5-yl, e.g. 5-methyl-1,3,4 -Thiadiazo-tv-2-
5-lower alkyl-1,3,4-thiadiazol-2-yl such as yl, 5-lower alkanimidoylamino (lower ) alkyl-1,3
,4-thiadiazol-2-yl,5-

[4-Nitrobenzyloxycarbonylacetimidoylaminomethy/
L')-1,3,4-thiadiazol-2-yl, etc.
-Nitropheni/L/(lower)alkoxycarbonyl(
lower) alkanimidoylamino (lower) alkyl-1
,3.4-thiazol-2-yl, e.g. 5-(4
-pyridyl)-1,3,4-thiadiazol-2-yl, etc.
Thiadiazolyl group optionally substituted with lower alkyl or lower alkanimidoinoleamino(lower)alkyl or protected lower alkanimidoylamino(lower)argyl or heterocyclic group such as 5-lower alkyl-4H-1,2,4- such as -methyl-4H-1,2,4-) riazol-6-yl
) a triasilyμ group optionally substituted with lower alkyl such as lyazol-3-yl, e.g. tetracyloC1
, 5-b] and a tetracylopyridazinyl group such as pyridazin-6-yl. Examples of the "lower alkyl/I/group" include straight M or branched alkyl Jv groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, and hexyl, and more preferably C engineering ~ heart. It is an alkyl group, most preferably a methyl group. Examples of the "acylv group" in R5 include the same groups as listed for the hydroxy protecting group of the "protected hydroxy group", preferably diarylphosphono groups which may have nor\logen, arene, etc. Examples include sulfonyl groups and lower alkanesulfonyl groups, and more preferred are diarylphosphono groups and halo(lower) alkanesulfonyl groups such as trifluoromethanesulfonyl. Examples of "acid residues" include halogens such as chlorine, odorant, and iodine, monomers such as methylsulfo and ethylsulfo,
(lower) alkyl sulfo group with 7-substituted sulfo group,
The method for producing the target compound of the present invention containing a sulfonyl group will be described in detail below. (1) Production method 1 Compound (I) or its salt is prepared by subjecting compound 1) or its salt to a complete reaction with an acylating agent (first step), and then adding compound (I) or its salt to the resulting compound (1)'ftakeso salt. (2nd step) can be produced by reacting a salt thereof with (2nd step). (1) 1st step This step can be carried out by a conventional acylation method. Suitable salts of compounds 1) and Il) include ,Compound(
The same salts as those exemplified in 'l) can be mentioned. Suitable acylating agents are those capable of introducing the above-mentioned acyl group into compound 1), and preferred examples of such acylating agents include organic sulfonic acids, organic phosphinic acids, organic phosphoric acids, , acid halides, acid anhydrides, etc., such as benzenesulfonyl chloride, p-
Arenesulfonyl halides such as toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, and p-promobenzenenulfonyl chloride; Arene sulfonic acid, for example, lower alkannulfonyl halide which may be substituted with halogen, such as methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, etc., such as methanesulfonyl anhydride, ethanesulfonic anhydride, anhydrous (lower) alkane-nurphonic acid which may contain a halogen such as trifluoromethane-nurphonic anhydride, e.g. diethylphosphonochloride;
Examples include diarylphosphonohalides such as ditolylphosphonochloride, di(lower)alkylphosphonohalides such as diethylphosphonochloride, diarylphosphinoylhalides such as diphenylphosphinoylhalide, and the like. The reaction is typically carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, hexamethylphosphoramide, ethylene chloride, tetrahydrofuran, ethyl acetate, dimethylsulfoxide, N,N-dimethylformamide, pyridine, or The reaction is carried out in other organic solvents, or mixtures thereof, which do not adversely affect the reaction. If a free acid or a salt thereof is used as the acylating agent in this reaction, the reaction is preferably carried out in -diisopropylcarbodiimide, N , N-dicyclohexylcarbodiimide, N-cyclohexyl-N-morpholinoethylcarbodiimide, N-cyclohexyl-N-(4-diethylaminocyclohexyl)carbodiimide, N-ethyl-N-(3-dimethylaminopropyl)carbodiimide, and other carbodiimide compounds. , N,N-carbonyldi(imidazole), N,N-carbonylbis(2-methylimidazole), e.g. pentamethyleneketene-N
-Ketenimine compounds such as cyclohexylimine, diphenylketene-N-cyclohexylimine, ethoxyacetylene, 1-alkoxy-1-chloroethylene, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, sulfur trichloride, thionyl chloride, chloride Oxalyl, combination of triphenylphosphine and carbon tetrachloride or diazendicarpoxylate, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5-(m
-sulfophenyl) isoxazolium hydroxide inner salt, 1-(p-chlorobenzenesulfonyloxy)
-6-Chloro-1H-benzotriazole, N,N-dimethylformamide and thionyl chloride, honugen, phosphorus oxychloride, etc. prepared by reaction in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent, etc. . The reaction may also be carried out in the presence of an inorganic or organic base; examples of such bases include, for example, alkali metal bicarbonate salts such as sodium bicarbonate, potassium bicarbonate, etc.; Alkali metal carbonate salts 1 Alkaline earth metal carbonate salts such as magnesium carbonate, calcium carbonate, etc., such as trimethylamine, triethylamine, N,N-diisopropyl-N
- tri(lower)alkylamines such as ethylamine, pyridine compounds such as pyridine, picoline, lutidine, N,N-di(lower)alkylaminopyridines such as N,N-dimethylaminopyridine, quinoline, e.g. N-lower alkylmorpholine such as methylmorpholine, N,N such as N,N-dimethylbenzylamine
-Di(lower)alkylbenzylamine, etc. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. Regarding compound (1), 6 represented by the following formula (IA)
, 7-thioxo-1-azabicyclo(3,2,0)heptane ring has tautomerism with the 6-hydroxy7-ogiso-1-azabicyclo(3,2,0)hept-2-ene ring of the following formula (IB) Therefore, these compounds are substantially the same. t MA ) t l[B )
Compound (11 or its salt) can be formed into a monolayer by a conventional method, but it can also be used as a raw material compound in the second step without isolation. (11) Second step In this step, an acyloxy group is added to the formula knee 5-R3 (in the formula,
Rtrl (same meaning as before) can be converted into a group represented by the above formula. Suitable salts of compound 1Iv) include salts with bases exemplified in compound (11), and further compounds α)
When R is a pyridyl group which may have an appropriate substituent, the salt reaction with the acid exemplified in compound (1) is usually
It is carried out in customary solvents such as those mentioned in the description of the first step. This reaction can also be carried out in the dark or in the presence of an organic base as listed in the description of the first step. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. (2) Production method 2 Compound CI-b) or a salt thereof is a compound (1=a)
or a salt thereof, a hydroxy protecting group at - and R
It can be produced by subjecting it to an elimination reaction of the carboxy protecting group in the process. A suitable salt of compound (1-a) is the target compound (1-a).
The same salts mentioned in 1 can be mentioned. A suitable salt of compound (1-b) includes the target compound (1-b).
) The same salts mentioned above can be mentioned. This reaction is carried out by conventional methods such as hydrolysis, reduction, etc. (1) Hydrolysis Hydrolysis is preferably carried out in the presence of a base or acid. Suitable bases include, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide, alkali metal hydroxides such as sodium carbonate, potassium carbonate, etc. Carbonates, such as magnesium carbonate, carbonic power!
Examples include alkaline earth metal carbonates such as lesium, for example alkali metal elutriates such as sodium hydrogen carbonate and potassium hydrogen carbonate. Suitable acids include, for example, formic acid, acetic acid, propionic acid,
Examples include organic acids such as trifluoroacetic acid, benzene-nulphonic acid and p-)luenesulfonic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Acid hydrolysis using trifluoroacetic acid is usually carried out in the presence of a cation scavenger such as phenol, anisole, etc. In this reaction, when the hydroxy protecting group is a tri(lower)alkylsilyl (low iu alkoxycarbonyl group), hydrolysis is carried out in the presence of a tri(lower)alkylammonium halide such as triptylammonium fluoride. The reaction is usually carried out in water, methylene chloride, alcohols such as methanol, ethanol, solvents such as tetrahydrofuran, dioxane, acetone or other organic solvents that do not adversely affect the reaction, or mixtures thereof. Furthermore, if the base or acid is liquid, they can also be used as a solvent.The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.(11) Reduction and elimination As a reduction method that can be applied to the reaction, for example, a metal such as zinc or zinc amalgam, or a chromium compound such as chromium chloride or chromium acetate, and acetic acid,
Reduction using combinations with organic or inorganic acids such as propionic acid, hydrochloric acid, sulfuric acid, and palladium, such as palladium sponge, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium sulfate, palladium barium carbonate, etc. Catalysts, such as nickel catalysts such as reduced nickel, nickel oxide, Raney nickel,
Examples include catalytic reduction carried out in the presence of customary metal catalysts such as platinum catalysts such as platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, platinum wires, etc. When catalytic reduction is applied, the reaction is carried out under conditions near neutrality. The reaction is usually carried out in water, alcohols such as methanol, ethanol, propatool, etc., customary solvents such as dioxane, tetrahydrofuran, acetic acid, and other organic solvents that do not adversely affect the reaction, or mixtures thereof. . The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. The elimination reaction is appropriately selected depending on the type of hydroxy-protecting group and carboxy-protecting group to be eliminated. In this production method, lower alkanimidoylamino (
If the compound contains lower) alkyl, this substituent is converted into free lower alkanimidoylamino(lower) alkyl during the reaction, and such cases are also included in this reaction. Furthermore, in this production method, when the hydroxy protecting group of Ra is first eliminated and then the carboxy protecting group of RaO is eliminated to obtain the target compound t, 1-b), or when the carboxy protecting group of R is first eliminated. , then when the hydroxy protecting group of R^ is removed to obtain the target compound (1-b)g,
Or, any case in which the hydroxy protecting group of Ra and the carboxy protecting group of R are simultaneously eliminated to obtain the target compound (1-bi) is included in the scope. (3) Production method 6 Compound [1-d) or its salt is compound (I-c)
Alternatively, it can be produced by reacting a salt thereof with compound ('l). Suitable salts of compound (1-c) and compound (1-d) include the same salts as exemplified for compound (1). This reaction can be carried out in the presence of a base as exemplified in Production Method 1. This reaction can usually be carried out in a conventional solvent such as water, dioxane, tetrahydrofuran, or a solvent that does not adversely affect the reaction, or a mixture thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. When the raw material compound or the target compound has an optical isomer during the reactions of the above production methods 1 to 2 or during the post-treatment of those reactions, one optical isomer may change into another optical isomer. However, such cases are also included within the scope of the present invention. When the target compound (1) has a free carboxy group at the R position, it can be converted into its pharmaceutically acceptable salts by a conventional method. New raw material compound used in production method 1 (Production 1f of 11)
cA-C will be explained in detail below. (A) Method A-i Compound (lb) can be produced by total reaction of compound +1-a) with a lower alkylating agent. Suitable lower alkylating agents used in this reaction include, for example, cy(lower)alkyl sulfates such as dimethyl sulfate, diethyl sulfate, lower alkyl sulfonic esters such as methyl nurphonate, eg methyl iodide, iodide, etc. Commonly used lower alkylating agents applicable to lower alkylation of hydroxy groups include lower alkyl halides such as ethyl and propyl bromide. This reaction can be carried out in the presence of an inorganic or organic base as described in Production Method 1, and may also be carried out in the presence of a lower alkyl lithium such as butyl lithium, e.g. sodium hydride,
It can also be carried out in the presence of an alkali metal hydride such as potassium hydride, for example an alkaline earth metal hydride such as calcium hydride. This reaction is typically performed using tetrahydrofuran, dioxane, N
, N-dimethylformamide, dimethyl sulfoxide,
The reaction is carried out in a conventional solvent such as hexamethylphosphoramide, a solvent that does not adversely affect the tobacco reaction, or a mixture of these solvents.The reaction temperature is not particularly limited, and is usually under cooling or heating. Method A-2 Compound CI-c) can be prepared by subjecting the compound to <1-bH-hydrolysis. It is preferable to carry out the reaction in the presence of the compound (I-c), and therefore, the explanation can be referred to for the reaction conditions such as solvent and reaction temperature. (E) Method B-1 Compound tl-d+4 Compound (11-(as a suitable salt of 11), compound 01
The same salt mentioned above can be mentioned. This reaction involves potassium permanganate, e.g. chromic acid,
This is carried out by conventional methods using oxidizing agents applicable to converting hydroxymethyl groups into carboxy groups, such as sodium chromate, dichromic acid, dichromate compounds such as sodium dichromate, pyridinium dichromate, etc. be able to. The reactions are usually carried out in conventional solvents such as water, acetone, dioxane, dimethylformamide, pyridine, or other organic solvents that do not adversely affect the reaction, or mixtures thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. Method B-2 Compound tl-e) or a salt thereof can be produced by subjecting compound (1-d) or a salt thereof to an on-stage reaction with malonic acid, a derivative thereof, or a derivative thereof. Suitable salts of compound (1-e) include the same salts mentioned for compound CI). Suitable salts of malonic acid or its derivatives include the same salts as mentioned for compound (J) with bases. Suitable derivatives of malonic acid include monoesters or diesters such as those exemplified for protected carboxy groups. The reaction is usually carried out using dioxane, tetrahydrofuran, N, N
- It can be carried out in the presence of a condensing agent as mentioned under Preparation 1, in a customary solvent such as dimethylformamide, or in any other organic solvent that does not adversely affect the reaction, or in a mixture thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out in a range of from cooling to heating. Method B-3 Compound (1-r) or a salt thereof is compound (I-e)
Alternatively, it can be produced by reacting a salt thereof with an acid azide. A suitable salt of compound [11-r] is compound (1)
I can list all the same salts mentioned above. Suitable acid azides may have substituents such as benzene sulfonyl azide, p-)luenesulfonyl azide, dodecylbenzenesulfonyl azide, p-carboxybenzenesulfonyl azide, and naphthalene-2-sulfonyl azide. Examples include arenesulfonyl azide and lower alkanesulfonyl azide such as methane sulfonyl azide and ethanesulfonyl azide. The reaction is usually carried out in conventional solvents such as tetrahydrofuran, dioxane, methylene chloride, acetonitrile, N,N-dimethylformamide, or other organic solvents that do not adversely affect the reaction, or mixtures thereof, preferably This is carried out in the presence of a base as mentioned in Production Method 1. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. Method B-4 Compound (1) or its salt can be produced by subjecting compound t1-f) or its salt to a ring-closing reaction. Examples of reagents used in this ring-closing reaction include metals such as copper, lead acetate, palladium acetate, rhodium acetate,
Examples include metal acetates such as copper acetate, metal sulfates such as copper sulfate, and the like. The reaction is usually carried out using conventional solvents such as benzene, toluene, tetrahydrofuran, dioxane, acetonitrile, or any other solvent that does not adversely affect the reaction.
or in a mixture thereof. The reaction temperature is not particularly limited, and is usually carried out at room temperature to reflux. (C) Method C-i Compound (1-h)'E or a salt thereof is prepared from compound (1-g
) or a salt thereof with a lower alkylating agent. Suitable salts of compounds (Il-g) and (It-h) include the same salts as mentioned for compound (I). This reaction can be carried out in substantially the same manner as method A-1, and therefore, the aforementioned methods p and -1 can be used for reaction reagents and reaction conditions such as solvent and reaction temperature. Method c-2 Compound (I-x) is obtained by (1) subjecting compound (1-h) or its salt to a total ozone reaction, (11) decomposing the generated ozonide by a conventional method, and (011) generating the generated compound. Formi μ protecting group? This reaction can be shown by the following reaction formula: +1-h
) Ozonide This reaction can be carried out by any conventional method applicable to the conversion of an allyl group to a dialkoxyethyl group. The ozonide produced from the raw material compound and ozone is usually decomposed by reduction or heating. The reduction in this reaction can be carried out in substantially the same manner as the reduction described in Production Method 2, therefore, the explanation can be referred to for the reaction conditions such as solvent and reaction temperature in 1, and additional suitable reducing agents can be used. Examples include trialkyl phosphites such as trimethyl sulfite, triphenylphosphine, dimethyl sulfite, sodium bisulfite, sodium sulfite, sodium iodide, and stannous chloride. Suitable examples of formyl protecting groups include, for example, tri(lower) alkyl orthoformates such as trimethyl orthoformate, etc., which are added to the formyl compound in the presence of an acid such as those mentioned for hydrolysis in method 2 of aa. Examples include di(lower) alkyl acetals produced by Solvolysis is usually carried out in the presence of a lower alcohol such as methanol or ethanol, or in the presence of an inorganic base or an alkali metal alkoxide such as sodium methoxide as exemplified in the hydrolysis of Preparation Method 2. . This reaction is usually carried out in conventional solvents such as methanol, ethanol, propatool, or other organic solvents that do not adversely affect the reaction, or mixtures thereof. Although the reaction temperature is not particularly limited, it is preferably carried out under cooling or heating. Method c-3 Compound (1-j) can be produced by subjecting compound (II-1) to total hydrolysis. The hydrolysis in this reaction is preferably carried out in the presence of an acid as exemplified in the hydrolysis of Production Method 2, and therefore the above explanations can be used for reaction conditions such as acid, solvent, reaction temperature, etc. Method c-4 Compound (1-k) or a salt thereof can be produced by oxidizing compound (II-jl). Suitable salts of compound (1-k) include salts with bases exemplified in the compound. Suitable oxidizing agents to be used in this reaction include method B-1.
Examples include conventional oxidizing agents that can be applied to convert formyl groups into carboxy groups, such as those listed in . This reaction is usually carried out in conventional solvents such as methylene chloride, acetone, dioxane, diethyl ether, benzene, toluene, or other organic solvents that do not adversely affect the reaction, or mixtures thereof. The reaction temperature is not particularly limited, and the reaction is preferably carried out under cooling or heating. The object compound (1) of this invention and its pharmaceutically acceptable salts are novel, exhibit high absorption, and exhibit high antibacterial activity by inhibiting the growth of a wide range of pathogenic bacteria, including Durham-positive and Durham-negative bacteria. , is useful as a preventive and therapeutic agent for infectious diseases. In this invention, the target compound having high antibacterial activity is a compound represented by the following formula and a pharmaceutically acceptable salt thereof. 10 (in the formula, R1 means all hydroxy groups or lower alkoxy groups, and R3 has the same meaning as before). In particular, the compound having the highest antibacterial activity is the compound represented by the following formula and its alkali metal salt. 1 0 (in the formula, R1 and R3u each have the same meaning as before). Furthermore, the objective compound (11) of the present invention and its pharmaceutically acceptable salts are also useful as β-futamase inhibitors.Hereinafter, in order to demonstrate the usefulness of the objective compound (I), the objective compound (11) of the present invention ( 1) Antibacterial activity and β-
The test results regarding the lactamase inhibitory effect are shown. (1) In vitro antibacterial activity test compound (1> (5R,6R)-3-(4-pyridylthio)
Sodium -6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabinclo(3,2,0)hept-2-ene-2-carboxylate (hereinafter referred to as compound A) (5R ,6R)-6-(5-methyl-1,3,4
-thiadiazol-2-ylthio)-6-(1-hydroxy-1-methyμethyl)-7-oxo-1-azabicyclo(3,2,0)hept-2-ene-2-carboxylic acid potassium (hereinafter (referred to as Compound B) Test Method The in vitro antibacterial activity was measured using the following multiple dilution agar plates. Each test strain was cultured overnight in trypticase soypros, and then cultured in a platinum loop (10 viable bacteria/ml) on Heart Infuji Town agar (H) containing test compounds at various concentrations.
After inoculating the cells (nee sinner) and incubating at 37°C for 20 hours,
The minimum inhibitory concentration (MIC) was expressed in μ9/gl. Test results (2) β-lactamase activity inhibition effect (β-lactamase inactivation test compound) (5R,6S)-3-(4-pyridylthio)-
6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo(3,2,[l)hept-2-
Sodium ene-2-carboxylate (hereinafter referred to as compound C) Trunk + (5R,6R)-3-(1-methyl-1H-tetrazol 1v-5-ylthio)-6-(1-hydroxy-1-methylethyl )-7-oxo-1-azabicycloC3,2,0)hep)-2-ene-2-potassium carboxylate (hereinafter referred to as compound) Top gloss! Nijijiku (a) Escherichia coli 18 derived R-TEM
Venicillinase (b) From Enterobacter cloacani 91 Ia Cephalonuporinase test method Test compound solution containing β-lactamase (100μ97
xl) was incubated at 37°C for 5 minutes, and residual β-lactamase activity was measured by ultraviolet absorption method using a discolored cephalonuporin gold substrate. The inactivation rate of β-lactamase activity in the absence of the test compound is shown as a percentage. Test results ■ Synergistic test compound for mouse infection prevention effect (a) Compound C1 as a compound of the present invention A mixture of ceftizoxime as a known antibacterial agent in a N ratio of 1:1] Compound C1 as a compound of the present invention a known antibacterial agent 5% mucin suspension of male Maunus test method Escherichia coli (36 <1.1'X10 colony forming units) in a 1:1 weight ratio test animal weighing 21.5 cm and 1.5 g using cefazolin as the agent. +0.5+++/
) 'f: Administered intraperitoneally. One hour after administration, various concentrations of the test compound were subcutaneously administered, and the ED5o value was calculated from the number of mice that survived for 4 days. : Test results When administering the object compound of this invention (11 and its pharmaceutically acceptable salts) for therapeutic purposes, it contains the above-mentioned compound as an active ingredient and a pharmaceutically acceptable carrier such as oral or parenteral. or in the form of conventional preparations with organic or inorganic, solid or liquid excipients suitable for external use.Such preparations include solids such as tablets, granules, powders, capsules; Contains liquids such as solutions, suspensions, syrups, emulsions, and lemonades.
It will be done. Furthermore, if necessary, adjuvants, stabilizers,
Wetting agent, other lactose, magnesium stearate, clay, sucrose, cornstarch, talc, stearic acid,
gelatin, agar, pectin, peanut oil, olive oil,
All commonly used additives such as cocoa butter, ethylene glycol, citric acid, tartaric acid, oxalic acid, Fuma A/acid, etc. can be included. The dosage of the compound depends on the patient's age, condition, type of disease,
Depending on the type of compound administered, generally doses of 91 Da to about 40 [JO] or more can be administered to the patient per day. The average dose of the compound of the present invention is about 50 Da, 100 to 100 Da. 250 calls, 500
q, 100 to 2000 Da can be used to treat diseases caused by pathogenic microorganisms. Furthermore, the target compounds of the present invention and their medically acceptable salts are also useful as β-lactamase activity inhibitors, and can be used as a combination with antibacterial agents such as penicillin compounds and cephalosporin compounds. . A more preferred combination is a combination of the compound of the present invention and an antibacterial agent such as ampicillin, amoxicillin, cefazolin, or ceftizoxime. In a mixture of the target compound (1) and its pharmaceutically acceptable salts with other antibacterial agents, the mixing ratio is appropriately selected depending on the type of pathogenic bacteria and the patient's symptoms, but usually the weight ratio is 1:50 to 50. :1. Preferably 1:4 to 4
:1, most preferably 1:1. Such combinations can be administered to humans or animals in a conventional manner. That is, as a preparation for administration to humans, intravenous or subcutaneous injections are usually preferred, but oral preparations such as powders and capsules, suppositories, and ointments can also be used. When this mixture is used as an injection, it is mixed with a solid or liquid carrier or diluent that is usually used in injectable antibacterial agents, and the most preferred carrier or diluent is water. . It can also be used in combination with an anesthetic such as lidocaine. Furthermore, when this mixture is used as a suppository or ointment, it is mixed with a commonly used base. The dosage of this combination drug is appropriately selected depending on various factors such as the type of compound to be mixed, the mixing ratio, the weight and age of the patient, the severity of infection, and the method of administration, and is administered at intervals of 1 to 12 hours. . This invention will be explained below with reference to Examples. Methylene chloride [110 g
+/) solution, 2,6-lutidine (4,11s+/) and benzyl chloroformate t 5.03g? ) 'to
'C and stir for 30 minutes at 0°C. The reaction mixture was diluted with ethyl acetate (800 g/) and diluted with dilute hydrochloric acid, brine,
Hydrogen ash) IJum saturated aqueous solution and saline solution
Wash Naniji. The organic layer is dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. Residue whole silicage/l/ (20
0 g) and eluted with a mixed solvent of methylene chloride and ethyl acetate (20:1 to 4:1).

[R,4R1-3-benzyloxycarbonylamino-4-allyl-2-oxoazetidin-1-ylku-6-methylbut-2-enoic acid methyl t10.7f+
is obtained as an oil. IRI CH2Cl2): Ro380.1750.172
0cNNMR (CD30D) δ: 1.95 (s, 3H)
, 2.17ts. 3H), 2.44ft, 2H, J=7H2), 3.7
3ts, 3H+, 4.36 (dt, 1H, J = 2.5° 7Hz 1.4.44 + d, IH,, 7 = 2.5Hz). 4.9 5.2 (m, 2H), 5.101s, 2H]. 5.5-6.0<m, 1H), 7.34[S, 5H1
Production Example 2 Ozone was added to [13R,4B)-3-benzyloxycarbonylamino-4-allyl-2-oxoazetidine-1
-irku 6-methybdo-2-enoic acid methi/L/(5
g) in methanol (100 ml solution at -60°C until a blue color appears and the remaining gas is removed.
) at -60°C and the reaction temperature was increased to 0°C over 15 minutes.
to rise to. After stirring for 1 hour at 0°C, the mixture was allowed to stand at room temperature for 20 hours. Add dimethyl sulfide (
21/), trimethyl orthoformate (5*t) and p-
) Add A/enesulfonic acid monohydrate (1501v) Th and heat at 50°C for 6 hours. Pyridine (
1. Add 0,076 tl) it at room temperature. The mixture was evaporated to dryness. The residue is dissolved in total ethyl acetate, and this solution is washed successively with water, dilute hydrochloric acid, brine, aqueous sodium bicarbonate, and brine. The organic layer is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue was dissolved in methanol (100ml
), heated at 50°C for 3 hours, and left at room temperature for 2 days. The solvent was distilled off under reduced pressure, and the residue was purified by total silica gel (10
01) and eluted with a mixed solvent of methylene chloride and acetone (tIDO: 1 to 2:1), (3R,4R)-3-benzyloxycarbonylamino-4-(2,2-dimethoxy Ethyl]azetidine-
2-one (2,83 g) is obtained as an oil. IR (am2c12): 1770, 172DC! r”
NMR Gesetone-d6) δ: 1.8-2.2 (m, 2H
), 3.30 (s, 6H), 3.66+dt, 1m,,
r=3°7Hz), 4.42+da, IH,, r=3.
9Hz+. 4.51tt, 1H, J=5.5Hz), 5.12[s
. 2H), 7.0 (brs, 1H], 7.2 (m, 1]
(). 7.40(8,5H) Production Example 6 (3R,4R)-3-benzyloxycarbonylamino-4-+2.2-dimethoxyethyl/L/)azetidine-
To a solution of 2-one (2,15 Da) in acetic acid (35,2*t), dimethylnurphyte (2 g/) and water (8,8*
t)i Add at room temperature and heat at 50°C for 4.5 hours. The reaction mixture was subjected to total vacuum distillation, and the residue was dissolved in xylene (40 g/
) dissolves in The mixture was distilled under reduced pressure and the residue was chromatographed on 1 vol Dl of silica gel, eluting with a mixed bath of methylene chloride and acetone (5:1 to 2:1) to give a crystalline solid. obtain. When the crude crystals were washed with ether and dried over dinipentoxide, (3R,4R)-3-
Benzyloxycarbonylamino-4-(2-oxoethyl)azetidin-2-one (863q)k is obtained. uuca2c12):1780.1720αNMR[aceto>-d]δ:2.7-3.1<m, 2H)
, 3.8-4.0 (m, iH), 4.43 (dd, IH
, J=2.8Hz), 5.07(s, 2H),
6.9-7.2 (Broad, Hr), 7.3 [] (s,
5H>. 9.69 (S, IH) Production Example 4 Io(3R,4R)-3-benzyloxycarbonylamino-4-(2-oxoethyl)azetidin-2-one (8
Add 123 Iq of sodium borohydride (123 Iq.
Stir for a minute. Add acetic acid (0,37 g/> to the mixture at 0 °C
After stirring at the same temperature for 15 minutes, the dissolved DX was completely distilled off under reduced pressure. The residue was chromatographed on silica gel (17y) and chromatographed in a mixed bath of methylene chloride and methanol [(2
Bathing from 0:1 to 10:11 gives a crystalline solid. The crude crystals were washed with ether and dried over phosphorous pentoxide, resulting in (3B,4R)-3-benzyloxycarbonylamino-4-[2-hydroxyethyl)azetidine-2-
On+7.481fl: iru. m11. 120-121°C IR (CHC1l: 1770.172DC?+11 2 NMR (acetone-(16)δ: 1.7-2.11 t
m, 2 old, 2.82 (8, IH), 3.5 3.
8 (m, 3H), 4.39 (aa, In, J = 3,8H
2), 5.05 [8°2 H), 6.9-7.3
(Broad, 2H), 7.30 (El, 5H) Production Example 5 (3E, 4B)-3-Benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one (765■) in methylene chloride (30ml) 2 to suspension
, 2-dimethoxypropane (0,513 ml) and trifluoroborate (niteller) (0,026 g/) Th0
C. and stirred for 10 minutes at 0.degree. C. and then for 5 hours at room temperature. The reaction mixture is poured into methylene chloride (301+/) and a mixture of sodium bicarbonate and sodium chloride (1:1). The organic layer was separated and the aqueous layer was dissolved in methylene chloride (
20 resistance). The organic layers 2 are combined, washed with brine, dried over magnesium sulfate, and then the solvent is completely distilled off under reduced pressure. The residue was subjected to chromatography on silica gel (16y) using a mixed solvent of methylene chloride and acetone (10:1 to
(6R37R)-7-pendyloquinecarponylamino-2,2-dimethyl-1-aza-6-oxabicycloC4,2,0)octan-8-one (753q). Obtained as an oil. 1 Engineering R (CH2C12): 1760, 1725cIRNM
Etacetone. ) δ: L36 (s, 3H), 1.6
1 (s. 3H), 1.4 2.1tm, 2H), 3.5-3.9
tm, 3HL4.33+ad, 1a, J=2°8Hz+
, 5.38 [S, 2H1,7,3 (Broad. IH), 7.35+ 8.5H) Production Example 6 [5R, 7R)"7-penzyloxycarponi! raremino-2,2-dimethyl- A mixture of 3-oxabicyclo(4,2,O)octan-8-one (748~) and 10% palladium on carbon (18Qlli') in ethyl acetate (15 m) was heated in hydrogen gas at room temperature for 1. Stir for 5 hours. The mixture is filtered and the solvent of the filtrate is distilled off under reduced pressure to give (6R,7R)-7-amino-2,2-dimethyl-1-aza-6-oxabicyclo(4,2 , 0) Octan-8-one (382■) is obtained as a crystalline solid. TR (CH2C12): 1740 cM NMR (CDCl3) δ: 1.42 (8,3H),
1.72 (s. 3H), 1.5 2.1 [m, 2H), 1J36 (s. 2H), 3.34taad, IH, J=2.5゜IQ
Hz), 3.6-3.9 ('m, 3H) Production Example 7 (6B, 7R-7-amino-2,2-dimethyl-1
-Aza-6-oxabicycloC,4,2,0)octan-8-one t300q+ solution with pyridine (0,25#
Il] and freshly prepared acetic acid-formic anhydride tO,3
8jj/) Add at ffiOoC. After stirring at the same temperature for 45 minutes, the reaction mixture is subjected to vacuum distillation. The entire residue was dissolved in xylene and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (6 g) using a mixed solvent of methylene chloride and methanol (25:1).
~10:1), r6R,7R)-2,2
-dimethyl-7-formamido-1-aza-3-oxabicyclo(4,2,0)octan-8-one (378W
g) is obtained as an oil. 1 1R[aH2c12>: 1755, 168 NM
R[CDC13)δ: 1.43(s, 3H1,1,72
(s. 3Hl, 1.8-2.1 (m, 2Hl,
3.56 (ddd. IE (, J=2.5.10H2), 3.7-3.9tm
. 2H), 4.37tad, 1a,, r=:2,8az)
. 7.33+Broad d, IH, J=43Hz). 8.11 (s, IH) Production Example 8 [6R,7R)-2,2-dimethyl-7-formamido-1-aza-3-oxabicyclo(4,2,0)octan-8-one (345ql 2,6-lutidine (
2.05ml) and 9% oxychloride (0.52ml)
Add everything at 0°C. After stirring at 0° C. for 6 hours, pour into a mixture of ethyl acetate (80°C) and ice water. Separate the entire organic layer, 1
The mixture is washed successively with 0% phosphoric acid, water, a food bottle, an aqueous solution of a mixture of sodium hydrogen suboxide, sodium chloride and sodium chloride (1:1), and brine, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The crystalline residue was washed with a mixed solvent of petroleum ether and ether (1:1) and dried over silica pentoxide, resulting in (
6R97R)-2,2-dimethyl-7-isocyano-1
-aza-3-oxabicycloC4,2,0:)octan-8-one (205■) is obtained. =1 Engineering R (CH2C12) = 2140.1770 units NMR (
CDC13) δ: 1.45 (s, 3H), 1.72 [8
゜3H), 1.4-2.1 (m, 2H),
3.7-3.9℃m, 3H), 4.30(d, IH,
, r=2Hz) Production Example 9 [6R,7R)-2,2-dimethyl-7-cyano-
l-aza-ro-oxabicyclo(4,2,0)octan-8-one + 50[]~) of tetrahydrofuran (1
5m? ) gM of n-butyllithium hexane solution +1
．． Add 2.33+/1 of the 55M solution at -70°C.
Stir for 15 minutes at 0°C. Acetone+ 0.265+
*1) in tetrahydrofuran (2.4 eq. L) was added at -70°C, and the mixture was stirred at -70°C for 25 minutes. Acetic acid (0,477 ml) is added to the mixture at -70°C. After stirring for 20 minutes at -70°C, the entire solvent of the mixture is distilled off under reduced pressure. The residue was dissolved in ethyl acetate (80%) and washed with an aqueous solution of hydrogen carbonate. Separate the aqueous layer and extract with ethyl acetate (20*J). The organic layers are combined, washed with brine, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. Washing with crystalline residual total isopropyl ether and filtration gives t6R,7R)-2,'
1-Dimethyl-7-(1-hydroxy-1-methylethyl)-7-isocyano-1-aza-6-oxabicycloC4,2,0)octan-8-one (4,60q) is obtained. The mother liquor was subjected to chromatography on silica gel [5 g], and a mixed solvent of hexane and ethyl acetate (20:1~
1:1), further (6R17R)-2,2
-dimethyl-7-(1-hydroxy-1-methylethyl)-7-isocyano-1-aza-3-oxabicyclo(
4,2,0)octan-8-one(65ri)C(6R,
7B)-isomer] and its +6R,7S) isomer t
1 [13”f lkm. +6R,7R1-isomer: IR (CH2C12): 2125.176 NMR (C
DC13) δ: t38(s, 3H], 1.43t
s. 3H), 1.50 (8,3H), 1.74 (s, filter Hl
. 1.5-2.2 (m, 2H32, IQts, 1a+. 3.7-4.0 (m, 3H) (6R,7S)-isomer: IR [CHC1): 2125.176 CD013) δ: 1.40 (S, 3H), 1.
48 (S. 3H1,1,63[S,3H1,1,74[8,3H1
゜1.5-1.9℃m, 1a), 2.21ts, IH+
. 2.6-3.0(m, 1H1,3,7-4,0(m, 3
H1 Production Example 10 (6R,7R)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-7-, (fucyano-1-aza-3-ogisabicycloC4,2,0)octane- 8-
Tributyltin hydride (3
,07txl) and azobisbutyronitrile t
170#) t-Add at room temperature and reflux for 30 minutes. The reaction mixture was chromatographed on silica gel (65 g) using a mixed solvent of methylene chloride and acetone, tlO: 1 to 2.
: Elutes at 1). The obtained crude product was mixed with silica gel (
75p+ chromatography, eluting with a mixed solvent of hexantoethyl acetate, and purifying (6R17S
)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-1-aza-3-oxabicyclo(4,2
,0) Octane-8-one (0,545g) (<,5R
,7s]-isomer] and its (6R97R)-isomer t1.406 g). (6,R,7S)-isomer: R(CH2C12): 176 1 NMR (CDC13) δ: 1.29 (8,3H), 1.
36+8. Old 1.42 (s, 3a), 1.74 (s,
3H), 1.5-2. Qtm, 2H), 1.96(s,
, 1a), 2.81 (d, IH,, r=2az), 3.
52tddd, iH. -r=2.5.5.11Hz), 3.83tad, 2H
. J=3, 8.5Hz) (6R, 7R)-isomer: Engineering R (CHC engineering +: 173511 2 NMR (CDC13) δ: 1.28 (S, 3H), 1.
40 (S, 3H). 1.47 (S, 3H), 1.74 (8, RoH], 1
．． 5-2.0(m, IH+, L98(s, 1gz, 2.
5-2.9 [m, IH), 3.15 (d, IH, J=5
Hz), 3.6-3.9 [m, 3H) Production Example 11 (6R,7Rl-2,2-dimethyl-7-+1-hydroxy-1-methylethyl)-1-a4-3-oxabicyclo (4,2,0)octane-8-one (6001q)
n-butyllithium (1,55M hexane solution 2.3611Z) was added to a solution of tetrahydrofuran (24 liters).
Add at 70°C and stir for 15 minutes at the same temperature. Add 10 g of 4-nitrobenzyl (788 cape 1) solution in tetrahydrofuran (7d) to the above mixture at -70°C.
Add with . After stirring at the same temperature for 15 minutes, the temperature of the reaction mixture was raised to O'C over 50 minutes, and after stirring at 0°C for 30 minutes, the solvent was distilled off under reduced pressure. Residue? The solution is washed with aqueous sodium bicarbonate solution. Separate the aqueous layer and extract with ethyl acetate (20 J). The organic layers are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. Silica gel residue

401) and a mixed solvent of hexane and ethyl acetate (10:1 to 1:1).
Elution with 1 gives a crystalline residue. When this residue is washed with isopropyl ether and filtered, (6R,7R)
-2,2-dimethyl-7-[1-methyl-1-(4-nitrobenzylox7carbonyloxy]ethyl)-1-
Aza-3-oxabicycloC4,2,0:)octane-
Get 8-on (520 Da). ntcHa1): 1740.152[], 135g1
2 NMR (CDCl3'Iδ: 1.41 (s, 3H)
, 1.62 (S. 3H), 1.77TS, 6H), 1.5-1.9 (m. IH), 2.2-2.5tm, 1H+, 3.42 [a. IH, -r=5.5Hz), 3.6 4. Q(m, 3H
1゜5.20 (S, 2H), 7゜88 (A2B2
．． 4H. J=9Hz) Production Example 12 (6R,7R]-]2.2-dimethyl-7-C1-methyl-1-c4-nitrobenzylox7carbonyloxy]ethyl]-1-aza-6-oxabicyclo(4, 2,
0) Octan-8-one (200 l) in acetic acid (5,2x
l) and water [Q, 8g? ) mixed bath g! 1 to 65°C
Heat for an hour. After the reaction solution is cooled to room temperature, it is subjected to vacuum distillation. When the crystalline residue is washed with ether, +3B
, 4R)-4-t 2-hydroxyethyl)-3-[
1-Methyl-1-(4-nitrobendi!reoxica!levonyloxinethyl)azetidin-2-one (151
#) get. 1E(cH2a12): 3575.3375, 175
0, 1520, 1350α NMR (DMSO-d
) δ: 1.57ts, 3H), 1.64ts. 3H), 1.88((1-2H, J=7H2), 3.1
-3.6tm, 3H), 3.6-3.9tm, IH). 4.47 (t, IE, J=5Hzl, 5.23(s. 2H), input 9QtA2B2.4a,, r=9az). 8.08ts, iH) Production Example 13 n-Butyllithium (1,55M hexane solution 2.82
s/)yN-isopropylcyclohexylamine (0,
72 m) of tetrahydrofuran (6 liters) solution
Add at °C and stir for 20 minutes at the same temperature. This mixture was mixed with methyl 3-methyl-2-((4R)-2-oxo-4-allylazetidin-1-yl)budo-2-enoate (24
-7[1
'O, stirred at the same temperature for 1 hour, then -30°C.
Stir for 30 minutes. Acetone (1,12 liters)
K was added to the reaction mixture at -70''C and kept at the same temperature for 1 hour.
Stir for 30 minutes at -30 to -15°C. 6N hydrochloric acid was added to the reaction mixture at 70°C, and ethyl acetate/'+2001
Dilute with 11). Solution total water, saline solution, hydrogen carbonate) U
Wash with rum aqueous solution and brine, dry over magnesium sulfate, and evaporate to dryness under reduced pressure. Triethylamine [0
, 15 liters) Add the remaining solution to a solution of methylene chloride (3 liters) at 0°C, and stir overnight at room temperature. The reaction mixture was diluted with ethyl acetate (20?) and the total solution was 0.1N hydrochloric acid + 1
After washing with an aqueous IJX solution and a saline solution and drying over magnesium sulfate, the dissolved IJX is distilled off under reduced pressure. Residual whole silica gel (10g
) and eluted with a mixed bath of benzene and acetone [(10:1 to 2:1), 3-methyl-2-((38°4R)-3-(1-hydroxy-1
-methyμethyl/L/1-methyl 2-oxo-4-allylazetidin-1-ylcob)-2-enoate (1[]()
y);xRtca2a12)=1740.1715ff
NMR (CD (J3) δ: 1.31 (8,3H), 1.
38 (S, 3H1゜1.96ts, 3B), 2.18t
s, 3a), 2.2-2.5 (m, 3H), 2.90t
d, IH, J=3Hz), -3,76%s, 3H), 3
．． 81tdt. iH, J=3.7Hz 1,4.9-5.2(m, 2H
). 5.5-6.0 < m, IH) and 3-methyl-2-((3R,4R)-ro-(1-hydroxy-1
-methylethyl)-2-oxo-4-allylazetidin-1-ylcob)-2-enoate (50q)i NMR (CDC13) δ: 1.39 (s, 3H), 1.
52 [s. 3g), 1.99ts, 3a), 2.19(8,3H1
゜2.21 (broad s, 1H), 2.74 (t, 2
H. J=7E! Z), 3.39 (a, IH, J=6H2). 3.74 (s, 3H1, 4, 12tat, or, r-6
,7H2), 4.9 5.2tm, 2H1,5,5-5
,9(m,IF[]
dilute l) solution to 2-((3S, 4B)-3-(1-
Methyl (hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-methylbuto-2-enoate t150mIP> of tetrahydrofuran +3
m/) solution over 3 minutes at -70°C, and stirred at the same temperature for 5 minutes. To this mixture was added tetrahydrofuran (1,6
1) Add the solution over 5 minutes at -70°C and stir at the same temperature for 15 minutes. The reaction temperature was raised to O'C over 30 minutes and stirred at the same temperature for 2 hours. Acetic acid +0.037g/) (i70
After addition at °C, the solvent is distilled off under reduced pressure. Dissolve the residue in ethyl acetate (50@l) and add this solution to water (t10g/)
, 10% cynic acid (IQsg/), sinate buffer (pH
7,Q)C Wash twice with 10@l, aqueous sodium hydrogen ashate solution and saline. After drying the organic layer over magnesium sulfate, the solvent was completely distilled off under reduced pressure. The residue was chromatographed on silica gel (10 Da) and eluted with a mixed bath of hexantoethyl acetate [+5:1 to 1:1] to give 6-methyl-2-((33,4R)-3-(1
-Methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-2-oxo-4-allylazetidin-1-yl]methylbudo-2-enoate (135#) k Obtained as an oil. IR(CHal):1740.1710.1520.
1345z 1 2 NMR (CDC!13) δ: 1.66 (8,3H), 1
．． 69 (S. 3H), 1.97 (8, 3H1, 2, 19 [S, 3H1
゜2.2-2.5 (m, 2H), 3.4Q (d, IH. J=2.5Hz), 3.71 (s, 3FK
), 4.03(at, 1a, J=2.5.6.5a
z), 4.5'-5,2(me2H), 5.19ts
, 2a+, 5.5-5.9 (m, IB), 7.90tA
2B2.4a. J=9H2) Production Example 15 Pyridinium dichromate i,74y)'r, (filter R14
R)-4-+2-hydroxyethyl)-3-[1-methyl-1-+4-nitrobenzyloxycarbonyloxy)ethyl w:)-2-oxoazetidine (1,0Of l
of N,N-dimethylformamide (0 to 20 gtl tissue)
C. and the reaction temperature is raised to 1.degree. C. under constant stirring. After stirring at room temperature for 16 hours, the reaction mixture was diluted with ethyl acetate (15
0g/), 10% sodium bisulfite aqueous solution +40g
/l and 3N hydrochloric acid (15 g/l). Separate the organic layer and remove the remaining aqueous layer with ethyl acetate (100+ m?).
) and extract twice. Combine the organic layers, add water and salt)
After sequentially washing with an aqueous solution of IJum and drying over magnesium sulfate, the solvent was completely distilled off under reduced pressure. The residue was dissolved in chloroform (30M/) iWL, 5% aqueous sodium bicarbonate solution (20g/), 25% aqueous sodium bicarbonate solution (20g?) and water (15ml, twice).
Extract with The extracted aqueous solutions are combined, acidified with 6N hydrochloric acid, filtered with chloroform (20 g?), and extracted again. All the extracts were combined, washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated to dryness.
)-3-(1-)f#-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-4-oxoazetidin-2-yl]acetic acid t51Q1q) is obtained. Engineering u'tcH2a12): 1735.1520.135
0CM Production Example 16 Ozone t% 6-Methitv-2-((3s, 4R)-
Ethyl acetate (3+++/) of methyl 3-(1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-2-oxo-4-allylazetidin-1-yl]budo 2-enoate [50 Da] Bubble the solution at -70°C until a blue color develops. After stirring at the same temperature for 15 minutes, ozone in the mixture is removed by blowing in nitrogen gas. The reaction mixture was diluted with ethyl acetate (2011) and dissolved in g!
Sodium bisulfite and sodium sulfite +2:
1) Wash with the aqueous solution and saline. The organic layer is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue was dissolved in total methylene chloride (t3m), and m-chloroperbenzoic acid (48 ml) was added at 0°C. The mixture is stirred at ambient temperature for 24 hours. Furthermore, m-chloroperbenzoic acid (48
ql" is added and stirred at room temperature for 24 hours. The solvent of the mixture is completely distilled off under reduced pressure. The residue is dissolved in methanol-A/(3g?) and heated at 50"C for 24 hours. The mixture was subjected to vacuum distillation, and the residue was subjected to chromatography on total silica gel (4f), using a mixed solvent of methylene chloride and methanol t2.
0:1 to 5:1), ((2R,33)-3
-(1-Methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-4-oxoazetidine-2-
Vinegar* (obtained as 43#i oil. ■RCcH2C12): 174D, 1520.135D
1HMR+CDC131δ: 1.60 (Broad 3
, 6H1゜2.3-2.8<m, 2H), 3.36 (Broad S. IH+, 3.77-4Q (, 1H), 5.i6 (s. 2H), 7.1-7. 3 + broad, 1H1,7
,84<A2B2,4H,,T=8H2),9.1-
9.6 (Broad, 1H) Production Example 17 N,N-carbonyldiimidazole (540■) was converted into (
(2R,3Ft)-3-(1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-4-
Add oxoazetidin-2-yl]acetic acid (1.06 g) to a solution of tetrahydrofuran (50 g) at room temperature. After stirring at the same temperature for 7 hours, malonic acid mono-4-nitrobenzyl ester magnesium salt t1.45y]k was added,
Stir overnight at room temperature. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate (1 [IQmt), and then filtered. F
0.1N hydrochloric acid, water, chloride) IJum saturated aqueous solution, sodium bicarbonate aqueous solution, water, chloride) IJum saturated water bath solution, 5% citric acid aqueous solution, water and chloride)
Wash sequentially with IJum saturated water solution. After drying over magnesium sulphate, the solution is evaporated to dryness. The residue was subjected to chromatography on silica gel (3Qp). Mixed solvent of methylene chloride and ethyl acetate (50:1-2:
When eluted with 1), a foamy substance is obtained. this? A mixture of chloroform and diisopropyl ether (crystallized from 4 medium, washed with diisopropyl ether, and dried in vacuum gives 4-(t 2R, 3n > -6-(1-methyl-1
-(4-nitrobenzyloxycarbonyloxy)ethyl)-4-oxoazetidin-2-yl-3-oxobutanoic acid 4-nitrobenol [1,31f Hrm. Melting point 123-125°C (decomposition). ■R+ca2c12+: 3400.1760.1750
．． 1720°1525, 1350cM NMR (7 sets 7-d6) δ: 1.64 (s, 3H)
, 1.74 (s. 3H), 3.35 (cl, 2H, J=6.5H2). 3.65 (d, IH, J=6Hz), 3.74 (S
. 2H), 4.20+m, IH), 5.28(S, 2E(
l. 5.31 [8,2H], 7.18t S, IH]
, 7.93FA2B2,8H, J=8Hz 1 Production Example 18 Ct2R,3s)-3-(1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-4-oxoazetidin-2-yl]acetic acid ( 56,411 g) in tetrahydrofuran (1.13 m?),
Add carbonyldiimidazole [27,5q) at room temperature. After stirring at room temperature for 6 hours, malonic acid mono-4-nitrobenzyl ester magnesium salt (84,8#l- was added,
Stir overnight at room temperature. All of the solvent was distilled off, and the residue was dissolved in ethyl acetate (30 kg) and filtered using diatomaceous earth. The furnace solution is washed with 1N hydrochloric acid, water, phosphate buffered axillary (pH 6,8) and sodium chloride saturated water bath solution. After drying over magnesium sulfate, the solution is filtered and the solvent is distilled off under reduced pressure. What remains. Oily substance (7
8,8q) was subjected to chromatography on silica gel [1,6y), and a mixed solvent of methylene chloride and ethyl acetate (1,6y) was subjected to chromatography on silica gel [1,6y).
4-(+2R, 33
1-Ro-(1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-4-oxoazetidin-2-yl 1)-3-oxobutanoate 4-nitrobenzyl [64,2~) is amorphous Obtained as a solid. Engineering R (CH2Cl21:3380,1760.1740
．． 1720°1520, 134Dc7n NMR (CDCl31δ: 1.62[8,3H), 1.
66 [8. 3H1,2,86-3,12(m,2H),3.41(
d, 1H, J=2Hzl, 3.65+8.2H). 3.94-4.18 (m, IH), 5.25+s, 2a
+. 5.34 (s, 2H), 6.60 (broad s, 1HI. 7.63 (a, 4H, J=9Hz), B, filter 0
(d. 4H, J=9Hz) Production Example 19 P-) Luenesulfonyl acid + 435~) was dissolved in acetonitrile (3.9 ml + 4-C[2R. 3R)-3-(1-methyl-1- Add to a solution of 4-nitrobenzyl (4-nitrobenzyloxycarbonyloxy)ethyl)-4-oxoazetidin-2-yl]-6-oxbutanoate [1,00 g) in acetonitrile (20πt) at 0°C. After stirring at the same temperature for 5 minutes, triethylamine [0,923yl)f was added dropwise to the mixture. 0°
After stirring for a further 20 minutes at C, evaporate to dryness. The residue was subjected to silicage/L/(2Qp) chromatography, n
-Mixed solvent of hexane and ee:r-thyl (10:1~1
:4), 2-diazo-4-((2R,3R
1-3-(1-Methyl-1-[4-nitrobenzyloxycarbonyloxy)ethyl)-4-oxoazetidin-2-ylcy 4-nitrobenzyl 6-ogisoptanoate + 1.08 g) is obtained. IR[CH2Cl2): 3400.215[], 176
5.1750°1720.1655.1525.135
0cx 1HMR+ CDCl3] δ: 168 (s, filter ET), 1.79 [S. 3H1, 3, 4-3, 7cm, 2H), 3.46 (a. 2H, J=4.5H2), 4.0-4.3tm, 1H+
. 5.20[S, 2H), 5.35[S, 2Hl
, 6.22+8.1H], 7.80(A2B2.4H
, J=12HZ l , 7.85 (A 2 B 2
．． 4 F(, J-6F(z + production side 20 4-C(2R,3S l-3-(1-methyl-1-(4
-Nitrobenzyloxycarbonyloxy)ethyl)-
To a solution of 4-nitropenyl 4-oxoazetidin-2-yl]-ro-oxobutanoate [58,3q) in acetonitrile (1,17 ml) was added p-toluene-nulfonyl azide (25,3~) in acetonitrile + 0. 228
ml) Add at m solution k OoC. After stirring for 5 minutes at the same temperature, a solution of triethylamine (567 μg) in acetonitrile + 0.483 liters was added dropwise. The reaction temperature was raised by pressing down for 15 minutes in a room temperature oven, and then raised at the same temperature for 20 minutes.
Leave for a minute. 1tTf was distilled off and the residue [85,9q
) All silica gel (1 g) was subjected to flash chromatography using a mixed solvent of notylene chloride and ethyl acetate + 5[
]:1 to 3:1), 2-diazo-4-[[
2R. 3s+-3-(1-Methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-4-oxoazetidin-2-yl]-3-ogisoptanoate 4-nitrobenzyl (58,4~) amorphous solid get as. ■ntcn2c12):3380.2140.1760
．． 1740°1715.1645.1520.134!
IMNMR (CDC131δ: 1.63 (s, 3H),
1.67 (S. 3 H), 2.88-3. Filter 4 (m, 2Hl, 3.46
(d, 1H,, d = 2H21,3,9[]-4,2[]
(rn. IH), 5. :26+8,2H), 5.45(S,2
H1゜648 (Broad s, IHI, 7.65td,
4H. J=9Hzl, 8. RoQ (d, 2H, J = 9Hzl. 8.64 (d, 2H, J = 9Hz 1 Production Example 21 2-Diazo-4-C, < 2R, 3R)-Ro-(1-methyl-1-( 4-nitrobenzyloxycarbonyloxy)ethyl)-4-oxoazetidin-2-itetv)
-4-nitrobenzyl-3-ogisoptanate (1,[1
0g1 and rhodium acetate (lD5■) in benzene (,50
m/) Reflux the mixture for 25 minutes. Cool to room temperature and pass the mixture through cellulone powder. When the added liquid is evaporated to dryness, τ2R, 5R. 6R)-3,7-thioxo6-[1-methyl-1-(
4-Nitrobenzyloxycarbonyloxy)ethylcou 1-azabicycloC3,2, [ ] )] butane-2
-4-nitrobenzyl carboxylate t094 g) Obtained as a completely amorphous solid. I IR(CH2C12):1770.1750.1525
．． 1350CM NMR (CDCl3) δ: 1.64 (s
, 3H), 1.84(s. 3H1,2,74(dd, IH, J=19I(z. 8Hz), 3.34[dd, 1)(,J=19Hz. 3Hz), 3.77[ d, 1H, J=6Hz). 4.34taz, La, J=6Hz, 8Hz+. 4.76 (S, 1H1, 5, 18 (S, 2H), 5.ro2 [A B , 2H, J=16H2), 7.88+
A2B2゜ 2 4H, J=9Hz), 7.91 t A2B2.4I
(.J=9H2) Production Example 22 0OPNB 2-Diazo-4-([2R,3S]-6-(1-methyl-1-(4-nitrobenzyloxycarbonyloxy)
ethyl)-4-oxoazetidin-2-yl]-5-ogisoptanic acid 4- = ) Ohenge/l'(58,0
~) and rhodium acetate (Il+ [0,1ysy) in benzene [3,4 ml] is refluxed for a total of 30 minutes. After cooling to room temperature, the mixture was filtered through diatomaceous earth and the solvent was distilled off to give (2R,5R,63)-3,7-thioxo-6-[1-methyl-1-(4-nitrobenzyloxy). carbonyloxy)ethylcou 1-azabicycloC
3,2,0) Hebutane-2-carboxylic acid 4-nitrobenzyl (47,8)k Obtained as an amorphous solid. Engineering RtcH2c12+: 1760.1735.1730
．． 1515°134f'X NMR [CDC13) δ: 1.70 (8,3H), 2.
49 (AB part of ABX system centered on 2,49, 2H
, 'JAB=18H2, JAX=JBX-=7Hz),
3.78 (d, IH0J=2Hz3.4.211dt,
IH+J=2.7Hz), 4.79(S, IH
), 5.21(8,2H1,5,30(ABq,IH
, J=12H2L7.53 (d, 2H,, r=9Hz
), 6.22+ti. 2H, J=9H2) Production Example 23 2-C(33,4R) -3-+ 1-hydroxy-1
-Methylethyl)-2-oxo-4-allylazetidin-1-ylcu-6-methylbut-2-enoic acid/l/
(2,41fl tetrahydrofuran + 72.5t
n-butyllithium (1,74M hexane solution 5.41!Z) solution was added dropwise to the solution at -78°C. Stir at the same temperature for 10 minutes, and add hexamethylhonulic triamide (1,64 yttl). The solution was stirred at 78°C for 15 minutes, dimethyl sulfate (1,62 Mt) and tetrahydrofuran (14,6 ml)
) Add bath liquid. The reaction temperature was raised to room temperature over 1.5 hours and stirred overnight at room temperature. Vinegar and acid (0,539H) were added to this mixture, and the solvent was distilled off. Ethyl acetate + 240m for the residue? ') and washed with a mixture of 10% sodium bicarbonate (10 tnl) and a saturated aqueous solution of sodium chloride. After drying with magnesium sulfate, it is filtered and the solvent is distilled off under reduced pressure.The residue is subjected to chromatography on silica gel [IQQp] and mixed with a mixed solvent of ethyl acetate and methylene chloride (1:
100-1:1), 2-C[33,4B]
-ro-(1-methoxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl)-3-methylp)-2-I7m methyl, 661 is obtained as an oil. IR (CH2Cl2): 1745, 1720, 1
385, 136 father NMR (CDC13) δ: 1.3
0 ('S, 3H1,1,34 [S. 3H], 1.96t s, 3H), 2j8+ 8,3H
1°2.41+t, 2p,, near H2l, 2.
97 (d. 1H,, T=3H2l, 3,25(S, 3H1,3,7
7[s, 3H1,4,Q (dt, IH, J=3.7Hz
). 4.95-5.4 (m, 2H), 5.5-6.1+rn
, IH) Production Example 24 0OCH3 1.45 g of methyl enoate) in a methanol (87 cm) bath solution at -78°
It lasts 50 minutes at C. Add nitrogen gas to the resulting blue solution.
Blow for 0 minutes, dimethyl sulfide + 14.5 ml.
Add li. The mixture was allowed to rise in temperature by 20°C over 20 minutes, then left at the same temperature for 2 hours and at 0°C for a further 4 hours.
Then leave it at room temperature overnight. Trimethyl orthoformate (7,25 rl) and p-)luenesulfonic acid monohydrate (93,3~) are added to this, and the mixture is stirred at 50°C for 1 hour. After cooling to 0°C, pyridine (40.4 μg) is added. After concentration, the residue was dissolved in ethyl acetate (100+11
Wash with a mixture of 1N hydrochloric acid (0.5 ml) and a saturated water bath solution. Aqueous washing liquid total ethyl acetate zv+50m? ) and the extracted acids are combined and washed sequentially with a mixture of 10% sodium hydrogen ash aqueous solution and a mixture of saturated aqueous acid (U) and a saturated aqueous solution of 1-IJium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated to dryness under reduced pressure. Rest; forest? Dissolve in methanol + 43.5 ml) and add sodium methoxide (4.9 M. 0.15111/1 at 0°C. After stirring at the same temperature for 30 minutes, add acetic acid (42.2 ml) and remove the solvent under reduced pressure. The residue was chromatographed on silica gel (3 (3 g) and eluted with a mixed solvent of methylene chloride and ethyl acetate +20:1 to 1:2), yielding +38,4
R)-4-[2,2-dimethoxyethy)v)-ro-(1
-methoxy-1-methylethyl)azetidin-2-one1. D3f>v Obtained as an oil. xntcu C1):34[][1,1755,136
5,1130,107 [3cw 12 Production Example 25 + 38, 4R)-4-(2,2-dimethoxyethyl)-3-+1-methoxy-1-methylethyl)azetidin-2-one (80 of 1,031 % aqueous acetic acid (50ml
) Melt i'! After stirring for 4 hours at 50° C., the solution is evaporated to dryness under reduced pressure. Residue? When dissolved in 18tnl of toluene and all of the toluene distilled off under reduced pressure, t 3s , 4R)
-3-[1-methoxy-1-methylethyl)-4-(2
-oxoethyl)azetidin-2-one +760q)!
r Obtained as an oil. ntca2a12):3410.2930.1755
．． 1725°138[], 1365.1070z Production Example 26 [38,4R1-3-+ 1-methoxy-1-methylethyl)-4-+2-oxoethyl)azetidin-2-one+760! ] to an acetone (60*t1 solution) was added dropwise 2N Diones (4.10ml) at 0°C. After stirring at the same temperature for 30 minutes, isopropyl alcohol [8ml
l+ is added and then evaporated to dryness under reduced pressure. Dissolve the residue in a saturated aqueous solution of IJ+40*J+ and extract 5 times with chloroform+80*L]. After drying the extract over magnesium sulfate, it is filtered and the solvent is distilled off under reduced pressure. The residue was subjected to chromatography on silica gel (Oli'), and a mixed solvent of methylene chloride and methanol (
10:1 to 1:2), then eluted with a mixed solvent of acetic acid and ethyl acetate (1:501) to give 2-[It2R.38)-6-(1-methoxy-1-methylethyl)-4
-oxoazetidin-2-yl]acetic acid (545,1~)
obtained as an amorphous solid. . ER (0H2C121:34GO, 2940, 1760
,1735°1385.1370.1070m 107OD201δ:1.27(S,6H>,2.
50-3.50+m, 2H), 2.76+[,,IH,
J=3H2l. 3.21 + 8, RoH), 3.92 [d-t
, 1H, J=3.7Hz) Production Example 27 2-C(2R,3S)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]acetic acid +65.6■) Tetrahydrofuran [3.25ml
) solution of carbonyldiimidazole (58,1q)'r
Add at room temperature. After stirring at room temperature for 6 hours, mono-p-nitropendyl ethermagnesium malonate q (17
Add 9.7q) and stir overnight at room temperature. solvent? The residue was dissolved in ethyl acetate [10'ml] and filtered. The furnace solution is washed successively with 1N hydrochloric acid, water, 10% aqueous sodium bicarbonate solution, water, 5% aqueous citric acid solution, water, and mW of saturated sodium chloride water. After drying with magnesium sulfate, it is filtered and the solvent is distilled off under reduced pressure. Remaining ffi[1D 1.21ngIfshi') Force'y'tV
('l f l a gold-producing solvent of methylene chloride and acetone (80:1 to 4:1)
When eluted with
-yl)-3-oxobutanoate 4-nitropenyl (7
1,0! ng) as an amorphous solid. Engineering R (CH2C12): 1755.1715.1600
．． 1520.134 NMR (CDC131δ: 1.2
6 [S, 3H), 1.29 (S. 3H1, 2, 5-3, 4 (m, 2H+, 2.87 (d. 1H, J = 3Hz), 3.2 (S, 3H 1, 3, 59+
s, 2n), 3.91 t d t, 1H,
J = 3.7Hz). 5.29 (S, 2H), 6,16 (Broad S, 1H
). 7.56 (d-, 2H, J=9Hz), 3.26+6
. 2H, J=9Hz] Production Example 28 4-((2R,33)-3-[1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl)-3-
Acetonitrile of oxobutanoic acid 4-nitrobendi (1161.1') (1,22m+/RJr&ni,p-) acetonitrile of luenesulfonyl azide (38,3~) c
Q, 345 ml) tlJ liquid was added at the total []''C. After stirring at the same temperature for 10 minutes, triethylamine (81,3
μe ) in acetonitrile (0,732ml) solution total 0
Add dropwise at °C. After stirring at the same temperature for 60 minutes, the solvent was distilled off and the residue was subjected to flash chromatography on silica gel (0.9 g), eluting with methylene chloride and ethyl acetate (40:1 to 3:1). Then, 2-diazo-
4-C(2R,3S)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-ylku6-
4-nitrobenzyl ogisoptanoate (56,5~)'i
= Obtained as a shaped solid. IR (CH2C12): 34D0.2150.1760
．． 1720°1650.1610.1530.1ro50
z 1HMR (CDCl5) δ: 1.26 (s, 3
H], 1.30 (8. H), 2.6-3.5tm, 2H+, 2.95+(+
. IH, J=3Hz), 3.2(8,3H1,3,97(
dt, 1H, J=3.7Hz), 5.37[s. 2H), 6.15 (Broad s, 1H1,7,55[
d, 2H, J=3H2), 825 (d, 2H. J-8H2) Production Example 29

[C0OPNB 2-siacy4-C(2R,3s)-3-[1-methoxy-1-methylethyl)-4-oxoazetidine-2
-yl]-4-nitrobenzyl-6-oxobutanoate +
56.5111f) Tove rhodium (■) (approximately 1~
) and dry benzene + 5.6 t) at reflux for a total of 60 minutes. After cooling to room temperature, the mixture was completely filtered and the solvent was distilled off under reduced pressure to obtain (2R05R, 68)-3,7-
Thioxo 6-(1-methoxy-1-methylethyl)-
1-Azabicyclo(3,2,0,1 heptane-2-carboxylic acid 84-nitrobenzyl + 50.0qi amorphous color obtained. xR(cH2c12): 177[], 1750.160
5.1525°135 [ICIn NMR [CDC13) δ: 1.63 (s, 3H), j,
Ro71s. 3a), 2.1ad, IH, J=8.18Hz+. 2.93taa, IH, J=8.18nz'+. 3.2(d, 1H, J=3Hz+, 3.25(s. 3u+, 4.1+at, 1a, J=3 and 8Hz l
. 4.72 [S, 1H1, 5-34 (S, 2H]. 7.45td, 2a, J=9Hz), 8.14+d. 'lH, J=9Hz) Production Example 30 Hydrogenation) N of IJum (38,1q, 50% oily)
, N-dimethylformamide + 1.14txt) suspension, t 6R07s + -2,2-dimethyl-7-
(1-hydroxy-1-methylethyl)-1-aza-6
-OxabicycloC4,2,0]]Octane-8-one 84.6~''N,N-dimethylformamide +25.
4.t) Add the bath solution dropwise at 0°C. After stirring at the same temperature for 0 minutes, a solution of dimethyl sulfuric acid (+75.1 μg) in N,N-dimethylformamide (0.676 ml) was added, stirred at 0°C for 6 hours, and further stirred at room temperature for 165 hours. 1.[146ml] of acetic acid is added to the mixture, and the solvent is distilled off under reduced pressure.The residue is diluted with ethyl acetate (20ml/l).
The solution is diluted with aqueous IJum solution, then chlorinated with IJum aqueous solution, 10% sodium hydrogen carbonate aqueous solution, and washed sequentially with a saturated aqueous solution of IJum. The aqueous washings are extracted with ethyl acetate and the extract is washed with aqueous sodium chloride solution. The combined extracts are dried over magnesium sulfate, filtered, and the solvent is distilled off under reduced pressure. 1 left (
92,9111 was chromatographed on silica gel (2.5 g) and eluted with a mixed solvent of ethyl acetate and methylene chloride (+1:100 to 1:6) to give 16R, 7S.
)-2,2-dimethyl-7-(1-methoxy-1-methylethyl)-1-aza-6-oxabicycloC4,2,
[I) Octan-8-one + 69.1M 11 Obtained as a pale yellow solid. xRtcH2c121:1745.1370.135[
J, 107 []. 060tM NMR (CDC13) δ: 1.26 (S, 6H), 1.
4 [J (8°3H], 1.6 2.0 (m, 2H1,1
, 77 (s. 3a), 2.89td, 1H0J=3Hz33.2Q(
s, 3H1,3,58 (ddd, iH. J=3.6,9az>, 3.86+aa, 2H. J=3.7Hzl Production Example 61 +6R,7S)-2,2-dimethyl-7-+1- methoxy-1-methylethyl)-1-aza-3-oxabicyclo(4,2,O,loctan-8-one (142,3q
) of acetic acid (2.28 yt) and ice tO (57 liters) was heated at 65°C for 1.5 hours. The reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. Xylene is added to the residue, and the bath medium is completely distilled off under reduced pressure. The remaining residue is dissolved in a mixed solvent of methanol and xylene, and the solution is evaporated to dryness under reduced pressure. Repeat this operation once, remaining ik silica gel + 1.5g
) and eluted with a mixed solvent of methylene chloride and acetone (10:1 to 1:1), (3
8゜4R)-4-(2-hydroxyethyl)-6-(1
-methoxy-1-methylethyl)azetidin-2-one+ 111.61191 is obtained. IR (CH2Cl21: 3400.29 0.176
0.1370°1061060 (7)N CDCl3)δ:1.26ts, 3f(+
, 1.32(s. 3H), 1.7-2.0+m, 2H1,3,06(d. 1H,, T=3Hzl, 3.24(s, 3H1,3,6
-3,9 (m, 3H), 6.5 (broad s,
1H1+ 3s,,LR)-4-X2-hydroxyethyl)-3-+1-methoxy-1-methylethyl)azetidin-2-one+50.71By+ of acetone I 5
．． 42wt1) solution was added with 2N Dione reagent 10.
Add 542 nl) of acetone to the molten turtle over 30 minutes at room temperature and stir for 1 hour. After adding excess isopropyl alcohol to the mixture, the solvent is distilled off. The whole residue is dissolved in chloroform and washed with saturated aqueous sodium chloride solution. Extract the washing solution with chloroform. The extracts were combined, dried over magnesium sulfate, and filtered.
Evaporate to dryness. The crystalline residue was washed with isopropyl alcohol to give 2-C(2R. 3B)-(1-methoxy-1-methylethyl/L/)
-4-oxoazetidin-2-yl]acetic acid 125.1q
). Concentration of the mother liquor and washing of the crystalline residue with hexane further yields the above product (19.4 Wtg). The total yield is 44.5 ■. xntca2ax, ):3400.294 [J, 176
[1,1735゜1385.1370.1070ffi
"Production Example 33 t6R,7R)-2,2-dimethyl-7-(1-hydroxy-1-methylethytv)-', -other6-
OxabicycloC4,2,0)octane-8-one+4
3.0■) of tetrahydrofuran (1,29*l lk
m, n-butyllithium + 1.74M hexane solution 0
．． 128 shoulder e) 't - Drop at -78°C. 1 at the same temperature
After stirring for 0 minutes, hexamethylphonopholic triamide (
Add 686μffl. This melting surface is heated to 1 at 78°C.
Stir for D minutes, add 1v EV acid [382 μe] to tetrahydrofuran (D, filter 44 tnt 1 m>'&
Add. The mixture was allowed to rise to room temperature 1 over a total of 1 hour and stirred overnight at room temperature. After adding 12.7 μg of acetic acid, the solvent was distilled off, the residue was dissolved in ethyl acetate (10 ml), and 10% sodium hydrogen carbonate aqueous solution M [0.3 nl
) and chloride) IJum saturated water surface 1! r Extract with ethyl (1011 tl) and wash the combined extract a+ with a saturated sodium chloride water bath solution. After drying with magnesium sulfate, filtrate with ethyl acetate bath and remove solvent. Distill under reduced pressure. The residue was chromatographed on silica gel (2.2 g) and washed out with a mixed solvent of ethyl acetate and methylene chloride (1:13Q to 1:1) to give ( 6 R',
7 R )-2,2-dimethyl-7-(1-methoxy-1-methylethyl)-1-aza-3-oxabicyclo(4.2.0)octan-8-one +24.0Hyl
Obtained as a white solid. IRtcH2c12):2930.1740.1370
．． 1075z 1NMR (CDCl5) δ: 1.21
ts, 31(), 1.37ts. 3H), 1.39 (8.3H].1.5-1.8tm. IH), 1.74 (8.3H), 2.3-3.0 (m. IH), 3.16 (d .IH.J=5H2), 3.25
(s, 3H), 3.5-4.0 [m. 1H), 3.37
<dd. 2H, J=3.1 (3Hz) Production Example 34 + 6R, 7R l-2.2-dinotyl-7-(
1-Methoxy-1-methylethyl)-1-aza-6-oxabicyclo(4.2.0)octan-8-one(
345■), acetic acid 1 5.5 2tttl) and water +
Heat the mixture of 1.38 ml at 65°C for 0 minutes. The reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. Add xylene to the residue and evaporate to dryness. The crystalline solution is dissolved in a mixture of methanol and xylene and the solvent is distilled off under reduced pressure. After repeating this operation once and washing the crystalline residue with hexane, [3R,4R1-4-(2-hydroxyethyl)-3-+1-methoxy-1-methylethyl/L/
) azetidin-2-one (275 ■I obtained. IR (an2a12+: 3600, 2900, 1
750mNMR(CDCl5)δ:1.31(s
, 3H l , 1.43 [ s . 3H), 2.0-2.2tm. 2H), 1.6[]()
ν1 de S, IH), 3.26 (S, 3H), 3
．． 5 (d. 1 H, J=6Hz 1, ”), 6-4. [] [
m, RoH). 6.66 [Broad s, iH) Production Example 35 +3R,4R)-4-(2-hydroxyethyl)-3-
+1-methoxy-1-methylethyl)azetidine-2-
On (2501 in acetone (26,7yt) solution,
2NS) Yones reagent (2,67 shoulder t) acetone +
24.0" rtttl) solution over 40 minutes at room temperature, and stirred for an additional 40 minutes. After adding excess isopropyl alcohol, all the solvent was distilled off. Dissolve all remaining residue in chloroform and dilute with sodium chloride saturated water bath solution. The aqueous layer is extracted four times with chloroform, the chloroform solutions are combined and dried over magnesium sulfate, and after filtration the solvent is distilled off. The crystalline residue is washed with hexane and the 2-([2E! roR)-ro-(1-mer-xy-1-methylethyl)v)
-4-oxoazetidin-2-yl]acetic acid

[211〃Wisdom] Gain all. XRI Nujol): 3280. Ro200.1760.
171 [Jbi NMR [D20) δ: 1.25t8.3
H1,1,36[S,3H1゜2.98(d,2H,J
=7Hz), 3.22 (s. 3H), 3.54 (d, 1H,, T = 5H2), 4.1
9 (dt, 1H, J, = 5.'7Hz) Production example 36 N,N'-carbonyldiimidazole [487,4''I
iJ Hr2-((2R, R1-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl) vinegar
) to the solution at room temperature. After stirring for 5 hours at the same humidity, malonic acid 7-p-nitrobenzyl magnesium salt t1.
Add 505 f' and stir overnight at room temperature. The solvent is distilled off under reduced pressure, and the residue is dissolved in the remaining total ethyl acetate and filtered. : The F3 solution is washed sequentially with 0.1N hydrochloric acid, water, 10% aqueous sodium bicarbonate solution, water, 5% aqueous citric acid solution, water and mR saturated water. After drying with magnesium sulfate, the solution is completely filtered and evaporated to dryness. The residue was chromatographed on silica gel (25 ml) and eluted with ethyl acetate in methylene chloride (0-50%) to give 4-((2R,3R)-3-(1-methoxy-1).
-methylethyl)-4-oxoazetidin-2-yl]
-4-nitrobenzyl 3-ogisoptanate (775q)
get. Engineering R (CH2C121:3400.3020.1760
．． 1720°1610.1520.1350 NMR (CDCl5) δ: 1.24 (s, 3H)
, 1.44(s, 3H3,23(8,3H),3
．． 2-3.4tm, 3H). 3.62 (S, 2H), 4.0-4.2tm, IH). 5.32 (8, 2H), 6.20 (Broad S. 1H), 7.60td, 2H, -r=8E (z>, 8.
30 (d, 2H,, T = 3Hz) Production Example 37 A solution of p-) luenesulfonyl azide (470) in acetonitrile/L'[4,23 shoulder t) was converted into 4-([2R. 3R]-3- tl-methoxy-1-methylethyl)-4
-oxoazetidine-2-iμ]-3-oxobutanoate 4-nitrobenzyl + 752q+ acetonitrile [1
5,04yt) solution at 0°C. After stirring at the same temperature for 10 minutes, add triethylamine + 0.9
97tnl] of acetonitrile [8,973+/
) Drop the bath solution. Stirred for an additional 50 minutes at 0°C)
, and then evaporated to dryness. The residue was chromatographed on silica gel (11f) and eluted with ethyl acetate in methylene chloride ~50%, yielding 2-diazo-4-C.
[2R,3R)-4-nitrobenzyl-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl)-3-oxobutanoate

[733~] is obtained. xR(cH2a12):3400.2930.215D
, 176[]. 1720.1650.1610.1530.1350c
x 1NMB[CDCl5)δ: 1.27(s, 3H
l, 1.44 (s. ro Hl, 3.26+s, 3a), 3.35ta, 1n,
J=7Hz+, 3.58<m, 2H1,4,16gm. IHI, 5.4218, 2H), 6.23 (Broad s
, 1H1,7,62+d, 2H,J=9Hz+. 8.33td, 2a, J=9Hz+ Production example 38 2-diazo-4-((2R,3R+-3-+ 1-methoxy-1-methylethyl)-4-oxoazetidine-2
-yl]-4-nitropenzyl-3-oxobutanoate (7
071+17) and rhodium acetate (ill about 5
Reflux the mixture of benzene (20 mg?l) for a total of 60 minutes.
]-6,7-thioxo6-

[1-Methoxy-1-methylethyl]-1-azabicyclo(3,2,D J hebutane-2-carvone n4-nitrobenzyl [680Q)
k gain; b. Engineering Rtcn2c12): 177D, 175D, 161D
, 152D. 1350α NMR+ CDC13) δ:1.25+8,3H1,1
,46(S. 3H1,2,60(dd,iH,J==7.19Hz
＋. 3.18(s, 3H+, 3.64<a, 1a, J=5H
z+, 3.96tdd, 1a, J=7.19nz+. 4.18tdt, 1H, J=5.7Hz+, 4.68+
s, IHL, 5.3Q+ABq, 2H, J=16H2l
. 7.601d, 2H, J=8Hz), 8.26+d. 2H, J-8Hz) Production Example 39 [5R,7R]-]2.2-dimethy/L/-7-11)
f-1-(4-nitrobenzyloxycarbonyloxy)ethylcou-1-aza-6-ogisabicyclo(4,2
, (3) 11.99 g of octan-8-one) in acetone [119.9xl) was mixed with 2N Jones reagent +
38.13tel) of acetone (119,9xl +
It was added dropwise to the solution over 1 hour at room temperature and stirred for 30 minutes. After adding excess isopropyl alcohol to the reaction solution, the solvent was distilled off. Dilute the residue with ethyl acetate

[Dissolve in 1xl and wash with water. Wash and extract with ethyl acetate + 2 DOgt). The organic layers were combined, washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off.
−[(2F!, 3n+=3-(1-methyl-1-(4-
Nitrobenzyloxycarbonyloxy)ethyl)-4
-oxo-azetidin-2-yl]acetic acid (11,8y)
get. IRtcHCl): 1735.1520.1350
z 1 2 Production example 40 5-aminomethyl-1,3,4-thiadiazole-4-
N,N-diisopropyl-
N-dimethylformamide ([1,426xl) bath solution of N-ethylamine IO, D474tnt+ and benzyl N-(4-nitrobenzylox7carbonyl)acetimidate (89,4s+1l (i7) were added and stirred at room temperature for 6 hours. The reaction mixture was then left at 5°C for 2 days. The reaction mixture was evaporated to dryness, and the residue was dissolved in ethyl acetate and washed with water. After drying with YNe magnesium, the entire bath was distilled off, washed with methylene chloride, and then taken out in a furnace. Then, a yellow powder of 5-(N-(N
-(4-nitrobenzyloxycarbonyl)acetimidoyl)aminomethyl)-1,3,4-thiadiazole-2-thiol [67-] is obtained. xRtnujo-zshi):337[1,168D, 1ro4
Dff 1NM hill [DMSO-46] δ knee 2.13
(8, 3H), 3.03.8

[Broad S, I
Hl, 4.50 [Broad S. 2H>, 5.20+s, 2H+, 7.62+a, 2H. J29H2l, 8.22(d, 2H, J=9Hz l
. 8.73 + Broad s, 1H) Target compound (Production Example 1 of 11 C00PNB000PN'B (2R, 5R, 6R)-3,7-thioxo 6-[1-
Methyl-1-+4-nitrobenzyloxycarbonyloxy)ethyl, 1-1-azabicyclo(3,2,[])
to] 4-nitrobenzyl butane-2-carboxylate 940
) and 4-(N,N-dimethylamino)pyridine+
21.2q) acetonitrile (50m/) bath solution,
, N-diisopropyl-N-ethylamine + 0.36
”>txt) of acetonitrile + 3.30 tnl
) solution at kO'C, then diphenyl chlorophosphate (0,378xt) in acetonitrile [3,40x
t ] solution is added at O'C. After stirring at the same temperature for 1 hour,
Cool to -15 °C and add N,N-diisopropyl-N-ethylamine (1,21 + l acetonitrile (11,0
sg/l solution then 4-mercaptopyridine t21
Add 2#lr. After standing overnight at -15°C, the solvent was distilled off under reduced pressure. The residue is dissolved in ethyl acetate (100 kg), washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is subjected to chromatography on silica gel [23y] containing 10% water. Mixed solvent of benzene and acetone +1 [
]:1 to filtration:1), and the residue obtained by distilling off the solvent was crystallized from a mixed solvent of acetone and diethyl ether to form (5B,6R)-6-(4-pyridylthio)-6= ,,C1-methyl-1-+4-nitrobenzyloxycarbonyloxyethyl)-7-oxo-1-
AzabicycloC3,2,0)hept-2-ene-2-carboxylic acid 4-nitrobenzyl (621~1 k ?i
Le. M point 165-166°C (decomposition). IR(ca2c12+:1785.1750.1710
．． 1610°1520.135 [] m 1 NMPI (CDCl5) δ: 1.53t 8.3H),
1.80 (8. 3H1,1,70+dd, IH, J=18Hz. 10H2), 3.50 (dd, IH, J=18Hz. 10Hz), 3.72 (d, IH, J=6.5H2)
l. 4.31tdt;, 1H, J=6.5Hz, 10uz3
5.20(8,2H), 5.41(AB(1,2H,J
=9H2>, 7.88t A2B214H, J=8H2
l. 7.89 [A2B2.4H, J':5H2), 7.97
(A2B2.4H, J=3Hz) Example 2 COOPNE COO
PNE(2R,5R,6S)-3,7-thioxo6
-[1-Methyl-1-(4-nitrobenzyloxycarbonyloxy)ethylcou-1-azabicyclo(3,2,
0) 4-nitrobenzyl hebutane-2-carboxylate 14
5.1~) and 4-(N,N-dimethylamino)pyridine (3,27111f) in acetonitrile C7,3t
nl) N,N-diisopropyl-N-ethylamine (56,0Hg) in acetonitrile (0,5D
4xtt l/d liquid then diphenyl chlorophosphate [
58,3 μfil acetonitrile (0,525xt)
Add drops at 0°C in the axillary bath. After stirring at the same temperature for 1 hour, N
, N-diisopropyl-N-ethylamine +186
．． 4 μg) of acetonitrile (1,68 Wl) was dissolved in acetonitrile (1,68 Wl), then 4-mercaptopyridine + 31.3 ~)
Add at 15°C and leave overnight at -15°C. The solution is diluted with 15+1+ ethyl acetate and then washed successively with water and a saturated aqueous solution of IJium chloride. After drying over magnesium sulfate, the solution is filtered and the solvent is distilled off under reduced pressure. Residue silica gel + 4F! chromatography using a mixed solvent of benzene and acetone (3
+5R,6Sl-3-
(4-pyridylthio)-6-(1-methyl-1-(4-
Nitrobenzyloxycarbonyloxyethyl]-7-
Oxo-1-azabicycloC3,2,0)hep)-2-
4-nitrobenzyl ene-2-carboxylate [139. I
Get Njgl. IR(CH2C121:1770.1735.1730
．． 1600°1520.1350cIr1 NMR (CDC13) δ: 1.65ts, 6a), 2.
89td. 2H,, T=9Hzl, 3.78(d, 1H, J=3H
z ), 4.30 (at, iH, J==3.9Hz +
. 5.15 (!3.2H1,5,41(AB(1,2H., T=14H21,7,10-7,82(m, 6H). 8.00-8.35tm, 4H), 8. 62tσ, 2H
1J24Hz) Example 6 5% palladium activity/2 (50gJ), dioxane +3
．． 5g/+ and 1/3QM sodium phosphate buffer 1
A mixture of pH 7, 0, 1, 5) was heated with hydrogen gas at
Leave for 1 hour at room temperature in Qpsil. Add this mixture (
5R, 6R]-3-+ 4-pyridylthio)-6-11
-Methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo1-azabicyclo(3
, 2,0) 4-nitrobenzyl hept-2-ene-2-carboxylate 4311 g) in dioxane (6.5 ml
) and 1730M sodium phosphate buffer (I)H7, [
l, 1.5 ml) was added at DoC and the mixture was heated in hydrogen gas +41 psi). Shake for 100 minutes while raising the reaction temperature to room temperature. 1% sodium hydrogen carbonate aqueous solution + 0.57 ml)
After addition at oC, filter through cellulone powder. Wash the okimasu three times with water (10 liters). Combine the filtrates and concentrate to half the volume. Wash the concentrate three times with ethyl acetate t20m/+ and evaporate to dryness under reduced pressure. The residue is Water containing sodium chloride (t1.75f) (6[]
It was dissolved in water (100++ rl) and a mixture of water and acetone (10 :0~7:3.200 shoulder t
) to develop and elute. The ultraviolet absorption spectrum is λ30.
Both components showing absorption maximum at 2 nm were collected and lyophilized to form (5R,6R]-3-<4-pyridylthio 1-6-+
1-hydroxy-1-methylethyl)-7-oxo-1
-AzabicycloC3,2,0:)hept-2-ene-2
-Sodium carboxylate (obtained as 13,7 #i white powder. IR (Nujol): 3300.1750.16003
1HMR (D20) δ: 1.21 (8,3H), 1.
44 [8,3 old. 2.77tda, 1H,, r=17az, 11az+. 3.71tdd, IH, J=17Hz, IHz33.7
ia, IH, J=6Hz +, 4.35 [dt. IH, J = 6H2, 11Hz 1.7.95 (A2B2゜4H, J = 5Hz) Uv (HO): 3Q2nm (E = 9.922X103
) Example 4 5% palladium activated carbon (163■), dioxane < 1
A mixture of 4.8m/ ) and 1/30M sodium phosphate buffer (6,36+/, pH 7,0) was heated with hydrogen gas (
Shake at room temperature for 1 hour under 40 psi. This reaction solution was mixed with (5R,631-3-(4-pyridylthio)-6-(1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-7-oxo-1-azabincroC3,2,0 ) of 4-nitrobenzyl hept-2-ene-2-carboxylate 132.51f) in a mixture of dioxane [3,7L+w/) and 1/30M sodium phosphate buffer (1,59g/. pH 7,0). Add hydrogen gas (shake in 4Qpail for 2.5 hours under water cooling. Add 1% hydrogen carbonate to the reaction solution) + Jum water bath (1,75 m/ ) k [
Add at 3°C and filter through Celite. The furnace block is washed with water, and the washing liquid and the filtrate are combined and reduced by one crop. Sodium chloride (2.4 g) was added to the concentrated solution, washed three times with ethyl acetate (20 ml), and concentrated under reduced pressure to a concentration of 50 m/ml. (5% chloride of the concentrated solution) 20g/L of IJum aqueous solution
) was pre-washed with nonionic adsorption resin "Diaion HP-2 [1j'" and subjected to chromatography.
Water (240+l) and a mixture of water and acetone t10:D
Develop and elute with ~7:3,120+++l). When the ultraviolet absorption spectrum is A3Q3 nm [the fractions showing the absorption maximum are collected, concentrated, and lyophilized, t5R, (58)
-ro-(4-pidillthio)-6-+1-hydroxy-
1-methylethyl)-7-oxo-1-azabicyclo(
3,2,0) Sodium hept-2-ene-2-carboxylate (40, obtained as OMyl white solid. TRtKBr): 3380.1755.1600.15
75.138shi'1uvtH2o1:303nmtε=
1.03X10 ) NMR [D20) δ: 1.32 (
s, 3 old, 1.39 (S, 3H1゜2.9Ha, 2H
, J=9nz), 3.43(d. 1H, J=3Hz 1,4.26(dt, 1H,:f
=3.9H2), 7.51(d,2H,J==5Hz)
. 8.48ta, 2a,, r=5Hz) Example 5 (1)-coopNBCOOPNB N,N-diisopropyl-N-ethylamine (0,30
9yttl! 2R,5R,6Rl-3,7-thioxo6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethylcou 1-asahicycloC
3,2,0)hebutane-2-carboxylic acid 4-nitrobenzyl + 80 [:l ~ + and 4-(N,N-dimethylamino)pyridine + 18 mg + methylene chloride (40 ml)
Add trifluoromethanesulfonic anhydride (0,261ynl) to the solution at -30"C in methylene chloride +
Add 2.35ml 1) @ liquid. After stirring for 30 minutes at -30°C, 1 reaction surface was coated with N,N-diisopropyl-N-ethylamine t0.772ysl.
Add 5-methyl-1,3,4 at 30°C.
-thiadiazole-/v-2-thiol (205■) N,
Add N-dimethylformamide (IQ+/) solution. The mixture was heated to room temperature over 30 minutes, then heated to room temperature for 2 hours at the same humidity.
．． Stir for 5 hours. The solvent is evaporated under reduced pressure, and the residue is dissolved in ethyl acetate (100 ml). This solution is washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. A mixed solvent of benzene and acetone (5%
0:1 to 20:1), ('5R,6R1-
6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-3-(5-methyl-1,3
,4-thiadiazol-tv-2-ylthio)-7-oxo-1-azabicyclo(3,2,O,1-hept-2-ene-2-carboxylic acid 4-nitrobenzyl 1824#) is obtained as an oil. ■R(ca2a121:1785.1750.1705
．． 152[]. 3503 NMR (CDCl31δ: 1.57 (s, 3H),
1.80(s, 3 old 2.81ts, 3a+, 3.[
14tda, IH, J=10.19Hz1.3.70(
dd, IH, J=8°19az+, 3.75ta, IH
, J==6Hz+. 4.3 (m, 1H), 5.20 (ABq, 2H, J=1
4Hz), 5.42(AB(1,;'H,J=14Hz
17.57td, 2a,, r=9Hz), 7.67td
. 2H, J=9EZ), 8.22(a, 4H, J=9Hz
[(5R,6R)-6-(1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-3-(5
4-nitropenyl(methoxyl-1,3.4-thiadiazol-2-ylthio)-7-oxo-1-azabicycloC3,2,0)hept-2-ene-2-carboxylate (
51] l1171 Platinum tooxide α11 water (tJ+(5
0■], dioxane (6*l), ene, nor[
0.5m? +, 0.1M dipotassium hydrogen phosphate (2,2
8tttl) and water + 2.5ml +,
Shake at room temperature for 1.5 hours in hydrogen gas t40psi+. The catalyst is removed from the furnace and the furnace # is concentrated to half its volume. This concentrate was washed 6 times with diethyl ether and reduced to 1
The solvent is removed under pressure. Dissolve the atrocities in water (25 m/), add potassium chloride (1.25 g/1, aqueous). Isopropyl afrecol (5-60%, 10
Develop and elute at 0πt). Ultraviolet absorption Nubeku) / Shiga exhibits a λ293nmK absorption maximum? When combined and frozen and dried, (5R,6R1-6-1-hydroxy-1-methylethyl)-3-(5-methyl-1,3,4-thiadiazol-2-ylthio)-7-oxo-1- Potassium azabicyclo[6,2,0]hept-2-ene-2-carboxylate [16,9 幇) is obtained. IR (Nushor): 1750ffi NMR (D201δ: 1.23 (8,3Hl, 1.4
2CG, 3Hl. 2.78 (dd, IH, J=10.17Hzl. 2.80ts, 3a), 3.70taa, 1H, J=8
．． 17H2>, 3.74td, In, J=6Hz). 4.3 cm, IH] uv+ H2O1:293nmtε797401 implementation e
A16 (1) N,N-diisopropyl-N-ethylamine [0,03
86m? + methylene chloride [0,347 shoulder l) fusion, (2R,5R,6R)-3,7-dioxo-6-41
-Methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl-4-nitrobenzyl-1-azabicyclo(3,2,0)hebutane-2-carboxylate (100-
) and 4-(N,N-dimethylamino)pyridine +2.1
Add to the +5 m/+ solution of methylene chloride at -30°C. Then trifluoromethanesulfonic anhydride t0.03
Add 26++ l+ of methylene chloride (0,293 t) dissolved acid at -30°0. After stirring at the same temperature for 1 hour, N
, N-diisopropyl-N-ethylamine [0,129
yzt ) in methylene chloride (116 shoulder t) solution and 1
-Methyl-1H-tetrazole-5-thiol [42,
9■) in methylene chloride [2.15ml] at -30°
C Raise the temperature. After stirring at room temperature for 2 hours, leave at 4°C for 2 days. After distilling off the solvent, the residue is dissolved in ethyl acetate. The solution is washed six times with water and aqueous sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off under reduced pressure. Silica gel inactivated with 10% water [2g]
) and eluted with a mixture of benzene and acetone 'fJH+5Q:1~ID:1), (5R16R1-6-(1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl) )-3-
(1-methyl-1H-tetrazo-)v-5-ylthio)
-7-oxo-1-azabicycloC3,2,0)hep)
4-Nitrobenzyl-2-ene-2-kappaponate [8
9#i: Obtained as an oil. ■rucH2c:c2+:1790.1750.170
0.1520°35-NMR (DMSO-d6) δ: 1.45ts, 3H1,
1,66 (s. 3H), 2.3-2.8 (m, IH), 3.11-
67(, iH), 4.3[](s, 3H), 4. Q2(
d. 1H, J=6Hz+, 4.2 4.4[m, IHl. 5.24t Glode S, 2H1, 5, 46 [ABQ. 2H,J: '15Hz+, 7.67 (d, 2!H,J=
9Hz+, 7.72+d, 2H, J==9Hz+. 8.22td, 4H, J=5+Hz) (2) 15R, 6R) -6-11-methy/L/-1-[4-nitrobenzyloxy force! levonyloxy)ethyl)-3
-(1-methyl-1H-tetrazol-5-ylthio)
-7-oxo-1-azabicyclo(3,2,0)hept-2-ene-2-mer 4-nitrobenzyl ponate [50
1111 and platinum oxide (v) monohydrate (25q+), dioxane (10 L), ethanol (0.51), 0.1
In addition to a mixture of M dipotassium hydrogen phosphate aqueous solution (2.35 liters) and water +3.5g/+, hydrogen gas (4Qpsi
Shake at room temperature for 1 hour. The catalyst is removed from the furnace and the furnace liquor is concentrated to half its original volume. The solution was washed with diethyl ether 3 times and the solvent was distilled off under reduced pressure. Residue? Water [25m? ) and potassium chloride [1,25
Add yl. This aqueous solution was added to the nonionic adsorption resin “Diaion HP-”.
2 Chromatography using IAG Jt, developing and elution with water (100 r/) and 10% aqueous isopropyl alcohol + 100 r/). The fractions whose ultraviolet absorption spectrum shows an absorption bar size at λ289 nm are combined and lyophilized to yield +5R, 6R1-6.
-(1-hydroquine-1-methylethyl)=3-(1-
Potassium methyl-1H-tetrazol-5-ylthio)-7-oxo-1-azabicycloC3,2,0)hep)-2-en-2-carboxylate+17q] is obtained. IR (Nujol): 1760m NMR (D20) δ: 1.17 (s, 3H1,1,4
0ts, 3H1゜2.48tdd, 1a, J=10,1
6az+. 3.53 (dd, 1H, J=9.1 (5Hz), 3.7
2(d, IH,, T=75Hz), 4j3(s, 3H1
゜UV[H2O)λmax: 289nm (ε=7470
1 Example 7 (1) N,N-diisopropyl-N-ethylamine (0,24
I2R,5R,6R)-3,7-thioxo6-(
1-Methyl-1-[4-nitrobenzyloxycarbonyloxy)ethylcy 1-azabicycloC3,2,[]
) to] 4-nitrobenzyl butane-2-carboxylate 6
40~) and 4-(N,N-dimethylamino]pyridine (
14,4■) in acetonitrile (32Mt) solution at 0°
Add with C. Then, this was added with diphenyl chlorophosphate (0
, 25'7 rt) in acetonitrile + 2.3 rt) solution at 0°C. After stirring at 0 °C for 60 min, N
, N-diisopropyl-N-ethylamine [0,824
sl ) and 2-aminobenzenethiol (155
11.4 g of acetonitrile+/) solution of ) is added at O'C. After stirring at the same temperature for 1 hour, the mixture was evaporated to dryness under reduced pressure, and the residue was dissolved in ethyl acetate/' (50 m/). This dissolved oil was washed twice with water and once with an aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on silica gel (20 fl) and mixed with a mixed solvent of benzene and acetone (50:1 to 10:
1), (5R,6R1-3-(2-aminophenylthio)-6-C1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-7-oxo-1-azabicyclo(3 ,2,0) 4-nitrobenzyl hept-2-ene-2-carboxylate (603alf
)y obtained as an oil. Engineering RtcH2a12): 1775.1750.1705
．． 1520°65-NMR (CDCl5) δ: 1.52t 8.3H),
1.76[S. 3H), 2.52tad, 1a, J=9.16H2). 3.401d, 1H, J=9.18Hz1.3.70(
d, 1H, J=5.5Hz), 4. Q-4,
3 (m. 3H), 5.18 (S, 2H), 5.41 (ABq. 2H, J=15H2), 6.4-6.7tm, 2H+. 7.0-7.3+m, 2H), 7.52(d, 2u, J
=8Hz>,7.7Q+a,2H,,y=3nz)18
．． 25td, 4H,, y=3Hz+ (2) (51R, 6R)-3-(2-aminophenylthio)-
6-(i-Methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicycloC3,2,0)hept-2-en-2-hydroxycarboxylic acid 4-nitrobenzyl + 490q ) and platinum oxide (v) 1
Hydrate (200μ) was added to a mixture of dioxane (60m/), ethanol (5+++/), 0.1M dipotassium hydrogen phosphate (22.7g/l and water (25M/) and hydrogen gas [40psi+] was added. , shake at room temperature for 50 minutes. The entire catalyst is removed and the PR is concentrated to half of its original volume. The thick paste is washed three times with diethyl ether and evaporated to dryness under reduced pressure. The remaining whole water ( 250 ml) and potassium chloride 12.
Add 5g1Th. This aqueous solution is mixed with a nonionic adsorption resin.
Diamond Aeon F! The product was chromatographed using P-20AGJThJU and developed and eluted with water (1 g) and aqueous isopropyl alcohol (5-60%, 1 g). When the fractions showing the K absorption maximum at 05 nm in the ultraviolet absorption spectrum were combined and lyophilized, [5R,6R)-3-+
2-aminophenyl-rethio-6-(1-hydroxy-
1-methylethyl)-7-oxo-1-azabicycloC
3,2,[] ]]] Potassium hept-2-ene-2-carboxylate+13DIig is obtained. IRI Nuji=-7+/): 1750c! RNMR(D2
01δ: 1.17 (8,3H1,1,41+8.3H)
. 2.41tdd, IH,, T=10.17Hz+. 3.52tdd, IH, J==9.17az 1.3.
70(d, 1H, J=5.5Hz +, 4.[]-4,
4+m. I Hl, 6.8-7.1 (m, 2 H>
, 7. 'l-7.7(m, 2HI UV(H2O)λmax:3Q3nmtε=1192
01 Example 8 (1) [2R, 5R, 63] -3,7-thioxo 6-(1
-methoxy-1-methylethyl)-1-azabicyclo(
3,2,[l) 4-nitrobenzyl heptane-2-carboxylate 150.0 Mg] and a7tonitrile of 4-(N,N-dimethylamino)pyridine (1,62~)+
2.5+++t+ solution, N,N-diisopropyl-N
-ethylamine [27,8 μj () of acetonitrile t
0.25 m/l of bath solution was added dropwise, and then diphenyl chloro9ophosphate [28,9 μE] was added dropwise to acetonitrile [0,26 ml l]. Add at 0°C. After stirring at the same temperature for 1 hour, N,N-diisopropyl-
111 g of N-ethylamine + 92.7 μe) of acetonitrile (0,834 tttl) and pyridine-4-thio-w + 15.6 q) were then added at -15°C. Leave at the same temperature overnight. This solution was concentrated under reduced pressure to 1M, and the residue was diluted with ethyl acetate + 10g/), water and chloride).
Wash twice with IJum saturated aqueous solution. After drying over magnesium sulphate, the solution is filtered and evaporated to dryness. Residue [
68,7Mg)' was subjected to chromatography using silica gel <1.51 inactivated with 10% water and eluted with a mixed solvent of benzene and acetone + 100:1 to 6:1), resulting in (5R86B> -6-(1-methoxy-1-
methylethyl)-7-oxo-3-(4-pyridylthio)-1-azabicycloC3,2,0)hept-2-ene-2-carboxylic acid 4-nitrobenzyl+51.7#)2
Obtained as an amorphous solid. ■RtcH2c12+: 1780.1720.1705
．． 1520゜135g1 C9) (5R,6S)-6-(1-methoxy-1-methylethyl)-7-oxo-3-(4-pyridylthio)-1-azabicycloC3,2,0)hept-2 -4-nitrobenzyl nin-2-carboxylate (371,0~) and platinum oxide αl [123,7q) in dioxane + 44.5 ml
+, 0.1M dipotassium hydrogen phosphate aqueous i'f [23
,7 m/l, water [5,98 g/l and ethanol +
In addition to the 3.71r/l mixture, hydrogen gas (50psi)
Shake for 1 hour at room temperature. The reaction mixture is filtered using a super cell. Wash all the mulberry pieces with water, combine the washing liquid and concentrate. The remaining aqueous solution was washed three times with diethyl ether at 0°C and then concentrated. Potassium chloride (51
1- After addition, 180 ml/l of the aqueous I&+ was subjected to chromatography using a nonionic adsorption resin "Diaion HP-2QAGJ'ii", water (420 ml), 5% aqueous isopropyl alcohol [42 []mt] O! Hi 10%
Aqueous inpropyl alcohol-A/(420xl + TE) is developed and eluted sequentially.
Fractions exhibiting maximum absorption at in were collected, concentrated, and lyophilized to yield +5R,631-6-[1-methquin-1-methylethyl)-7-oxo-6-(4-pyridylthio)-1
-azabicycloC3,2,0)hept-2-ene-2-
Potassium carboxylate 1380CIR NMRI D201δ: 1.3 (8,3H), 1.33
[S, 3H1゜2.89ta, 2a, J=10H2+,
3.24 (S. 3B), 3.58td, IH, J=3Hz), 4.2+
(1t, 1H, J=3 and 10H2), 7.47
('d, 2H, J=6Hz), 8.43(m, 2H)U
V(HOIλmax: 3Q3n'rn'(ε=1D
6X1[] ) Example 9 (1) 0CH30CH3 1 (2R, 5R, 6R)-5,7-thioxo 6-(1-
Methoxy-1-methylethyl/L/1-1-azabicyclo(3,2,D,1-heptane-2-carboxylic acid 4-nitrobenzyl (450~) and 4-fN,N-dimethylamino)pyridine t14.6# ) methylene chloride + 22
．． 5xl] solution, add N,N-diisopropyl-N-ethylamine + 0.249xl + methylene chloride (2
, 241*t) Add the solution at -30°C. To this mixture was added tQ of trifluoromethane anhydride, 211 m/) of methylene chloride + 1.899 g/).
Add the solution at -30°C. After stirring at the same temperature for 30 minutes,
4-(N,N-dimethylamino)pyridine (2,9#)
and N,N-diisopropyl-N-ethylamine +0
．． 0498++l) methylene chloride t0.448sl)
f4 solution, then trifluoromethane anhydride (0
,0422 g/> of methylene chloride (0.68 M/) solution was added at 30°C. After stirring at the same temperature for 30 minutes, this solution was heated to -30°C and mixed with N,N-diisopropyl-N-ethylamine (0,833xl) and methylene chloride [7,4
97vtl]il'fG solution and pyricin-4-thiol t159.511 dissolved in N,N-dimethylformamide (5,63tttl)g! Add all sequentially. Stir at the same temperature for 30 minutes and at 0°C for an additional 30 minutes. After the solvent is distilled off and the residue is dissolved in ethyl acetate, the solvent is distilled off. Silica gel t whose residue was inactivated with 10% water
Chromatography using 13.5f)k and elution with a mixed bath of benzene and acetone from 1100:1 to 6:1) gave 15R,6R) -6-(1-methoxy-
1-methylethyl)-7-oxo-3-(4-pyridylthio)-1-azabicycloC3,2,0)hept-2-
ene-2-carboxylic acid 4-nitrobendi/L'(379
(2) is obtained as a pale yellow solid. Engineering R (CH2Cl2) = 1780, 1710cIRNM
R(CDC131δ: 1.14(s, 3H), 1.43
ts. 3H), 2.57tad, IH, J=10,13az)
. 3.22+ 8.3H), 3.58(d, IH, J==
8Hz l. 3J33tad, 1a, J=10.18Hz+. 4.22tddd, iH, J=8.10.2QHzl. 5.42 (AB(1, 2H, J = i 31Tz)
, 7.2-7.5(m, 2H1,7,6-7,8[
m, 2H), 8.1-8.4+ m, 2H), 8
．． 5-8.7 + m, 'lH1(2) T 5R,6R) -6-+ 1-methoxy-1-methylethyl)-7-ogiso3-(4-pyridylthio)-
1-Azabicyclo[3,2,0':)hept-2-ene-2-carboxylic acid 4-nitrobenzyl
1), 0.1M dipotassium hydrogen sulfate aqueous solution (filtration 3.
23*l>, in addition to a mixture of water + 8.39tgtl and ethanol (5.2l), hydrogen gas t50ps]
Shake at room temperature for 1 hour. After removing the catalyst, the filtrate is concentrated. The remaining aqueous solution is washed six times with diethyl ether at O'C and concentrated. Dilute the residue with water (260
+/) and add potassium chloride (13f)k. Water-soluble a + nonionic adsorption resin “Diaion Hp-20A”
Chromatography using GJ6, developed with water (3e) and 5% aqueous isopropyl alcohol (2e),
Elute. When the two parts whose ultraviolet absorption spectrum shows a λ303nmK absorption bar size are combined and freeze-dried, (5R16R)-6-
(1-methoxy-1-methylethyl)-7-oxo-3
-(4-pyridylthio)-1=azabicyclo[3,2,
D] Potassium hept-2-ene-2-carboxylate (3[
15#)' as a white powder. IR (nujol): 1750, 1600.1570 NMR (D20) δ: 1.22 (8,3H), 1.3
8 (8,3H1゜2.77tad, 1H,, r==1(
1,1;7Hz). 3.24(s, 3g>, 3.52tdd, 1H, J=I
Q, 17Hz), 3.86+d, 1H, J=7Hz). 4.33tddd, 1H, J=7.9,1[IHzl. 7.3-77[m, 2H1+8.3-8.7tm, 2H
+Example 10 Iodomethane (0.5ml) (5R,6Et]-6
-(1-Hydroquine-1-methylethyl/v) -7-oxo-6-(4-pyridylthio)-1-azabicyclo(
3,2,[l':]heptot-2-ene-2-carboxylic acid potassium +23q50% aqueous dioxane (:2+
/+ Add to the solution at 0°C and heat up to room temperature. After stirring the mixture at room temperature for 2 hours, iodomethane (0,
25s+tl and 5% aqueous dioxane [2rl? Add 1. After stirring at room temperature for 2 hours, iodomethane (0,
Add 25 shoulder tl. This mixture was left at 5°C overnight,
Stir for an additional 4 hours at room temperature. The reaction surface is concentrated to half its original volume and the concentrated solution is washed six times with ethyl acetate. Completely concentrate the water N and dissolve the residue in water (10gt+).This water-soluble raw nonionic adsorption resin "Diaion UP-20
Chromatography using AGJTh, water +50
m/] and 10% aqueous isopropyl alcohol (50
It develops and elutes at shoulder T+. Ultraviolet absorption spectrum is λ3
When all fractions showing maximum absorption at 04 nm were lyophilized, [5R,6R)-6-(1-hydroxy-1-methylethyl)-3-[1-methyl-4-pyridiniothio)-7- Oxo-1-azabicycloC3,2,0]]hept-2-ene-2-carboxylate +15# is obtained. NMRLD201δ: 1.31 (3,3H), 1.48
+8,3H). 2.97 (dd, 1H, J-11, 18Hzl. 3.80tdd, IH9J-9, 18Hz+, 3.83
(d, IH, J=6H2), 4.24+S, 3H). 4.5 [m, 1H), 7.78 (d, 2H, J=7Hz
18.43cd, 2u, J=7Hz] UV[H2O)λmax:3Q4nm Example 11 N,N-diisopropyl-N-ethylamine +0.13
5 scraps t) of methylene chloride + 1.21 r/l solution of gold, [2
R,5R,6Rl-3,7-thioxo6-[1-methy/v-1-(4-nitropenzyloxinecarbonyloxy)ethyl)-1-azabicyclo[3,2,0)hebutane- 4-nitrobenzyl 2-carboxylate (350~) and 4-(N,N-dimethylamino)pyridine (7,9
q] in methylene chloride (17.5 l) at -30°C.
Add with . Add trifluoromethanesulfonic anhydride (tQ) to this mixture, methylene chloride (t1.02gt)
Add the bath liquid and continue stirring at the same temperature for 60 minutes. Then N
, N-diisopropyl-N-ethylamine < 0.56
31/) methylene chloride + 5.06ml RIJf
and 5-methy/L'-1,3,4-oxadiazole-2-thiol (225 da) and heated to -30 °C for 30 min.
After stirring for a minute, the temperature was raised to room temperature 1 over 1 hour. After stirring at room temperature for 4 hours, the mixture was left at 5°C for 14 hours. After distilling off the residue, the remaining total ethyl acetate (commonly understood as 2Qytl.This solution?Water and chloride) was washed sequentially with a saturated aqueous solution of IJ, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. . Leftovers? , 7F, chromatography using 10% silica gel (7F)'r, mixture of benzene and acetone) Each section t20:1~ID:
When developed and eluted with 1), t5R,6R)-6-
(1-methyl-1-+4-nitrobenzyloxycarbonyloxy)ethylcou 3-+5-methyl-1,3,4
-oxadiazol-2-ylthio)-7-oxo-1
-azabicycloC3,2,0)hept-2-ene-2-
Carboxylic acid 4-nidobenzi Iv < 290”i/lk
Obtained as an oil. Engineering n+cH2c12＞:1790.1750,1520
．． 1350ci 1NMR (CDC13) δ: 1.59
+8,3H1,1,8[](S. 3H), 2.57[s, 3H1,3,22[dd. 1H, J-11, 13Hzl, 3.75tdd, 1H. J28.18H2l, 31.76(d, 1H, J=6E
(Zl. 4.3-4.6[m, IHL, 5.18+ABq, 2E
(. J-=15Hz35.42tApq, 2H, J=i4
Hz+, 7,54td', 2H, J=9Hz+. 767(d-,2H,J=9Hz 1,822ft1゜2H,J=9Hz +,8.23(d,;!H,J==
9Hz +(2) (5R,6Rl-6-(1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl,:)-3-
(5-methy/L'-1,3,4-oxadiazole-2
-ylthio)-7-oxo-1-asahicyclo[3,2
, [] )] 4-nitrobenzyl hept-2-ene-2-carboxylate +50! >, white oxide M (Vl monohydrate (5
A mixture of 10.5 tl + ethanol and 0.1M aqueous dipotassium hydrogen phosphate solution + 2.35 tl was added to a mixture of water (2.5xl) and dioxane [6xl] and heated in hydrogen gas (40 psi). , shake at room temperature for 1 hour. After removing the catalyst from the furnace, the p-liquid is concentrated to half its original volume. This concentrate? Wash six times with diethyl ether and then evaporate to dryness under reduced pressure. Water leftovers (25 liters)
The nonionic adsorption resin “Diaion HP-2” is dissolved in
It was subjected to chromatography using 0 Aoj and water (10
0ml+ and 10% aqueous isopropyl alcohol+1
Develop and elute with 00*ll. When UV absorption Nuvector shows maximum absorption at 'A29'l nm, the fractions are combined and lyophilized to yield +5R, 6Rl-6-

[1-hydroxy-1-methylethyl/L/13-(5-methyl-1,
Obtained as potassium 3,4-oxadiazol-2-ylthio)-7-oxo-1-azabicyclo(3,2,O)hept-2-ene-2-carboxylate (14,3q)t'' powder. NMR [D20] δ: 1.24 (8,3H1,1,4
0(S, 3H1゜2.591S, filter Hl, 3.24(d
d, 1a, y==11.18az), 3.74tad,
IH, J = 6° 18H2), 3.75 (d, 1H, J
=61+z+. 4.2-4.4 r m , I HIUV[H2O1
:λmaX 292 nm Example 12 (1) N,N-diisopropyl-N-ethylamine (0,23
1PR/) methylene chloride (2,08 scraps f) solution, +
2R, 5R, 6R]-3,7-thioxo 6-[1-
Methyl-1-(4-nitrobenzyloxycarbonyloxy)ethylcy-1-azabicycloC3,2,(II
) Hebutane-2-carboxylic acid 4-nitrobenzyl (60
0da) and 4-+N,N-dimethylamino)pyridine+13.5~) of methylene chloride [30,0m? ) to the solution at -30°C. To this mixture was added a solution of trifluoromethane anhydride (0,196 Ml) in methylene chloride + 3.72 s + l, and stirring was continued at -30°C for 20 minutes. N. N-diisopropyl-N-ethylamine [0,680w
1) Then tetracylo[1,5-b)pyridazine-6
A solution of the -thiol (0,256 f) in N,N-dimethylformamide (2,30 liters) is added to the mixture at -30°C. The temperature of this mixture was raised to 20°C over 2 hours, and then all the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate+100 ml and chlorinated six times with cold water.) Washed once with an aqueous IJ solution, dried over magnesium sulfate, and then completely distilled off the solvent under reduced pressure. The residue is chromatographed on silica gel (7,5y+) inactivated with 15% water and eluted with a mixture of benzene and acetone fJI 20:1 to 6:1. Fractions containing the target compound were collected, diluted with benzene to precipitate crystals, and after cooling in a refrigerator, this precipitate was collected.
,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-3
-(tetracylo(1,5-b,lpyridazin-6-ylthio)-1-azabicycloC3,2,0)hebdo2-
Engineering: /-2-J 4-nitrobenzyl luponate (0,53
3g) is obtained. Crystallization from the mother liquor, 8 pure ethyl acetate and n-hexane gave the same product (0.0666f/
Obtained as a pale yellow powder. Total yield 0.5995g0
Melting point 127-128.5°C0rRtcH2c12+:
179D, 1755.1610.153D. 1ro5 (NMR [CDCl31δ: 1.65 (s, 3B)
, 1.83 [8°Hl, 3.5 4.0tm, Ron), 4.5[1tm. IH), 5.18 (s, 2H1,5,43tABq. 2H, J = 14H2l, 7.2-7.3 (m, 6H]. 8.00-83(, 4H3 (2) (5R, 6R) -6-[1-Methyl-1-(4-nitrobenzylox7carponyloxy)ethyl]-7-ogiso3-(tetrazoloC1,5-b)pyridazine-6
-ylthio)-1-azabicyclo[3,2,0]]hept-2-ene-2-carboxylic acid 4nitrobendi1v (Q
, 4ro57y), platinum oxide α) monohydrate +0.2179
f), 0.047M dipotassium hydrogen phosphate aqueous solution i (4
1.1ml +, tetrahydrofuran <52.3g/l
Stir the 4.40 ml mixture in hydrogen gas at room temperature under atmospheric pressure for 3.7 hours. After removing the catalyst, concentrate with a pav to half the initial volume. Washed with diethyl ether six times and subjected to vacuum distillation.The residue was washed with a nonionic adsorption resin [Diaion CHP-20PJ
t220 g/]y chromatography using water + 1.50 i, 5% aqueous isopropyl alcohol (40
0gJ) and 10% aqueous isopropyl alcohol +4
Develop and elute with 00*J). The ultraviolet absorption spectrum is 233.0Rm and 282.0Rm.
Fraction 7 showing an absorption maximum at 5 nm is combined and lyophilized to obtain the crude product tQ, 1459f). This product was reused as “Diaion CHP-2QPJ (1
30g7)' was subjected to chromatography using water (
340 g/), 5% aqueous isopropyl alcohol (36
0 shoulder l) and 10% aqueous isopropyl alcohol (2
Take a bath with 00 shoulder l). Fractions containing the target compound were collected and lyophilized to give [5B, 6R1-6-+1-hydroxy-1-methylethyl)-3-(tetracylo(1,5
-b) Pyridazin-6-ylthio)-7-oxo-1-
Azabicyclo[3°2.0)7')-2-ene-2-
Obtained as potassium carboxylate (0,1299 g) + yellow powder. IRf null): 17501 l NMR [D20) δ: 1,34+s, 3H1,1,5
2+s, 3H3゜3.40 (dd, IH, J=12.1
8Hz). 3.94 (ad, iH, J=9.13Hz 1,3.9
6 (d. 940
0)'l 33. [] nm (ε=115001 Example 13 (1) CO0PNB COOPN
+2R, 5R in the same manner as B Example 12-(1). 6R)-3,7-thioxo6-01-methyl-1-(
4-Nitropenzyloxycarbonyloxy)ethyl)
-1-AzabicycloC3,2,0)hebutane-2-carboxylic acid 4-nitrobenzyl (6[)01Vl was reacted with trifluoromethanesulfonic anhydride [0,196ynl), and then 5-methyl-4H-1, 2,4=triazole-3-thiol 191mg 1 piece, strained,
15 R, 6R+-6-(1-)V-1-[4-nitrobenzyloxy]ethyl,)-3
-+5-methyl-4H-1,2,4-triazole-3
-ylthio)-7-oxo-1-azabicycloC3,2
, 0) 4-nitrobenzyl hept-2-ene-2-carboxylate [622■] is obtained. Engineering RtcH2c12): 3420.1790.1750
．． 171D. 1675.15ro[J, 1ro5[]z 1HMR[C
DCl31δ: 1.57[s, 3H), 1.8Qt
s. 3H], 2.52 (s, 3nl, 3.B) tdd. 1H, J=11.18Hz+, 3.64 (dd. 1H1J-9, 18Hz+, 3.75td, IH+J-
=6Hz+, 4.35tm, 1H1,5,24fABq
, 2H, J=15H2l, 5.47+ABq. 2H,J,,=15H2l,7.64(d,2H,J-
8H2), 7.76 (a, 2H, J=8H2l. 8.30 (d, 4H, J=8H2) (2) (5R, 6R)-6-[1-methyl-1-(4-nitropenzyl) Ogishiruponyloxy)ethyl 1)-3-+
5-Methyl-4H-1,2,4-)lyazol-ro-ylthio)-7-oxo-1-azabicyclo[3,2,0
) hepto-2-ethyl:/-2-carboxylic acid 4-nitrobenzyl (SDIItyl and 5% palladium on activated carbon (5%
0~), 0.048M dipotassium hydrogen phosphate aqueous solution (
A mixture of 4,85yxl l, ethanol (0,5ml) and dioxane (6,0nl) was heated to <4Qpsi
) Shake at room temperature for 2 hours. After removing the catalyst, the filtrate is concentrated to half of its original volume. The concentrated I& was washed 3-] with diethyl ether and evaporated to dryness under reduced pressure TK. The residue was treated with a nonionic adsorption resin “Diaion CHP-20pJ”.
chromatography using water (100 mJ
+ and 5% aqueous isopropyl alcohol (100 scraps t
) to develop and elute. Ultraviolet absorption spectrum is 29
Fractions showing maximum absorption at 2 nm were combined and lyophilized to yield (5R,6R)-6-(1-hydroxy-1-methylethyl)-3-(5-methyl-4H-1,2,4- )
lyazol-3-ylthio)-7-oxo-1-azabicyclo(3,2,[] ]]]hept-2-ene-2-
Carbonated potassium (13.2 .mu.) is obtained as a yellow powder. IR(nuji, -ru)=175[)z 1HMR(D20
) δ: 1.22f 8.3Hl, 1.40+ 8,
RoHl. 2.44+ 8.3nl, 2.56(dd, 1H, J
=10.18H2l, 3.58(d4,1H,J=10
．． 18H2l, 3.72td, 1H, J=7Hz+. 4.28 (dt, 1H, J=7.1Qnz) UV (H
O) λmax: 292nm+E=5.69X1031
Project Example 14 (1) In the same manner as Project Example 12-<1), [2R, 5R. 6R]-3,7-thioxo6-[1-methyl-1=(
4-Nitropenenyloxycarbonyloxy)ethyl]
-1-AzabicycloC3,2,0)hebutane-2-carboxylic acid 4-nitrobenzyl (1,50g) was reacted with anhydrous trifluoromethane nulphon [1t0.489ml)k, and then 2-mercaptopyridine (523,6 ~) is reacted with I5B, 6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-3-(2-pyridylthio)-
1-azabicycloC3,2,0,lhept-2-ene-
2-carboxylic acid (obtains 1,571. TR(CH2C12): 1780, 1750, 171 [
], 15211°1350cIII NMRICDCI31δ:'1.58 [S, RoHl
, 1.80+8°3H), 3,2Q (6d, IH, J-
11,19Hz+. 3.65tad, IH, J=9.19Hz +, 3.7
7(d,,IH,J=6H2+,4.38+ddd,,
1H. , T=6.9, 11H2), 5.20[ABq, 2H. J=14Hz), 5.43 [AB(1, 2H,
:r = 14H2], 7.1-7.8[m, 7H1,8
,0-8,4+m,4H1,8,5-8,6+m,In
+(2) COOPNB
L; In the same way as 12-(2) to implement LIIJ8,
(SR,6R1-6-11-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-ro-(2-pyridylthio)-1-azabicyclo[3
, 2,0) 4-nitrobenzyl hept-2-ene-2-carboxylate [501 ng+ was subjected to catalytic reduction in the presence of platinum (v) oxide monohydrate + 5 DWyl in hydrogen gas + 40 psil to give [5R, 6Rl-6-[1-hydroxy-1-methylethyl]-7-oxo-3-(2-pyridylthio)-1-azabicyclo[3,2,0)hept-
Potassium 2-ene-2-carboxylate [21HQ + is obtained. Engineering R (Nujiral l: 1750z INMR [D20
) δ: 1.22 [! 9.3H1,1,44[s,3r+
). 2.70tdd, IH, J=IQ, 17Hzl. 3.66 (dd, 1H, J=9.17Hz1.3.78
(d, 1B, J=5Hz), 4.36tddd,
, iH. J=5.9.10H2l, 7.4-3.1[m, 3H1
゜8.65 [m,,,I H] UVtH2o>λmax: 3[]4nm (E=1.1
7XI Q41 Example 15 (1) N,N-diisopropyl-N-ethylamine [0,57
9 liters of methylene chloride + 5.21 ml of bath solution, [2
F,5R,6Rl-3,7-thioxo6-(1-methyl-1-14-nitropencyloxycarbonyloxy)ethyl)-1-azabicycloC3,2,[]:)
to] 4-nitrobenzyl butane-2-carboxylate i50
f! 1 and 4-[N,N-dimethylamino)pyridine (33,89) in methylene chloride [75,0 ml] at -50°C. To this solution was added methylene chloride (9,
29 resistance) solution? Add and stir at -30°C for 20 minutes. Then N,N-diisopropyl-N=ethylamine (5
, 31 ml and the salt of -1-mercaptopyridine with stannic chloride and 4(1) (1,7 [11 g) in N,N-dimethylformamide + 15.3 ml' l bath liquid was added to the above mixture, and the reaction temperature The temperature was raised to 20°C over 3 hours.
Mercaftopyridine salt of stannic chloride and hydrochloric acid (0,
570y) N,N-dimethylformamide 15.13
1! ! /) Add more solution. The reaction temperature was raised to 20°C over a total of 1 hour, and the solvent was completely distilled off under reduced pressure. The residue was dissolved in methylene chloride (250 tons), washed six times with cold water and once with an aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Silica gel (150g) inactivated with 15% water
) and eluted with a mixed solvent of benzene and acetone (50:1 to 8:1). Bath 1lX
When the residue obtained by distilling off l is crystallized from a mixed solvent of methylene chloride and diethyl ether, (5R, 6Rl
-6-C1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-3-(3-
pyridylthio)-1-azabicyclo[6,2,0]hept-2-ene-2-carboxylic acid 4-nitrobenzyl u]
, 9747yr* obtained. When the f'd solution is subjected to silica gel column chromatography to y=g and crystallized, the same product +0.268[11i')k is obtained as a pale yellow powder. Total yield 1.242i0 Melting point 162-164°C0 Engineering R+
CH2Cl-2): 1785, 1755, 1710.1
605゜1570.1525, 1ro 5Q> 1HMR
(CDCl3]δ:1.5[](S,,5H1,1,8
0 (S. 3B), 2.44[dd, 1H, J=11.18Fr
z) 3.42 (dd, IH, J=11.18H2). 3.69<d,in, J=6Hz), 42[)trh. 1H), 5.251s, 2n+, 5.45 (ABq. 2ET,, T: 14H2), 7.2-7.4+m, 1
H). 7.5-7.9 (m, 5F!), 8.1-8.4
t m , 4H). 8.6-8.8 (m, 2 HI (2) -6-tl-methyl-1-(4-nitrobenzoloxycarbonyloxy)ethyl)-7-oxo-5-[3-
(pyridylthio) to 1-azabinculoC3,2,[])
] Hegto-2-ene-2-carboxylic acid 4-nitrobenzyl! 1.1579yHr, hydrogen gas [4[1psi
), when subjected to blunt reduction, [5B,6R)-6-(1-
Hydroxy-1-methylethyl)-17-oxo-ro-
(ro-pyridylthio)-1-azabicyclo(3,2,0
:) Potassium hept-2-ene-2-carboxylate (04
ro21f1kfBru. Engineering R (Nujol: 1745 seats N M RI D 201δ: 1.18 (s, 3a+,
1.42+s, 3H+. 2.47 (dd, IH, J-1D17az+. 3.55uda, 1p, y=9.17Hz+, 3.7
1 [3, IH, J=6Hz), 4.23 (c16d, i
H. J2 10.9.6Hzl, 7.5-7.7(m, 1n)
. &0 8.2+m, Ia), 8.5-8.9tm, 2H
IUV(H2O)λmax: 01.5Hmtε=10
970 + Example 16 (1) To γ1 = In the same manner as Example 12-(1), (2B, 5B
. 6R1-3,7-thioxo6-[1-methyl-1-(
4-Nitropenzyloxy(luponyloxy)ethyl]
to 1-azabicycloC3,2,0] 10 g of di-nitrobenzyl butane-2-carboxylate was reacted with 9 ml of anhydrous trifluoromethanesulfone eto4s),
Then, when 5-(4-pyridyl)-1,3,4-thiadiazole-2-thiol (919■) was completely reacted,!
5R,6Rl-6-11-methyl-1-+4-nitropencyloxycarponyloxy)ethyl)-7-oxo-3-(5-(4-pyridyl)-1,3,4-thiadiazole-2 -ylthiocy1-azabicyclo(3,2,
D) 4-nitrobenzyl hept-2-ene-2-carboxylate (1,531 pieces obtained. 'o'ttcn2c12+: 178 (J, 1750,1
700,1520°1350rl 1 N MR+ CD C13) δ:1.59+8,3H)
, 1.82tS. 3H), 3.16+ad, 1H, J=12.19Hz
). 3.74 (d, iH, J=6Hz+, 4.Ql (dd. In, J=8.19nz+, 4.36tm, IH). 5.13fABq, 2H,, T=15H21,5,4
2[ABq, 2H, J=14Hz 1,7.54fd
,. 2H,J=9Hzl,765(d,2H,J-=9Hz
+, 7.77+d, 2n, J:=6nz+. 8.23 (d, '4H, J=9az+, 88Q+d. 2H, J=6H) (2) In the same manner as Example 12-(2), (5R,6R)-6
-(1-methyl-1-(4-nitropencyloxycarbonyloxy)ethyl)-7-oxy-3-(5-(4
-pyridyl)-1,3,4-thiadiazol-2-ylthiocou 1-azabicyclo(3,2,[l)hept-
4-nitrobenzyl 2-en-2-carboxylate (50f
fili'l-1 platinum oxide (lV11 hydrate (50#)
When subjected to catalytic reduction in hydrogen gas in the presence of 15R,6
R1-6-+ 1-hydroxy-1-methylethyl)-
7-Ogiso 3-05-[4-pyridyll-1,3,4
-thiadiazol-2-ylthiocou 1-azabicycloC3,2,0]]potassium hept-2-en-2-carphonate+21 mg). IR (Nujol: 175Dl 1 NMR [D201δ: 1.25(s, 3H1, 1,
47 [S, RoH). 2.87 (dd, IH, J=10.17Hz+. 3.73ta, 1a, J=6Hz+, 3.87+dd. 1a, J=IQ, 17nz+, 4.37tm, IH). 7.77 [(1(1,2H, J=1.7Hzl, 8.6
8 (aa, 2g,, r = 1.7Hz) UV [H2C1λmax: 283nm [ε = 1.38X
10) In the same manner as in Example 12-(1), (2R,
5R. 6R)-3,7-thioxo6-[1-methyl-1-(
4-nitrobenzyloxycarbonyloxy)ethyl)
-1-AzabicycloC3,2,[ ] )]heptane-2
-4-nitrobenzyl carboxylate 0.800p) 171
．． % water trifluoromethanesulfonic acid (0,261πl
) and then 3-amino-4-mercaptopyridine+0.2805M'a=react, [5R, 6
R]-6-11-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-7-oxo-3-+
1.904 g of 4-nitrobenzyl-2-ene-2-carboxylic acid (7") to 3-aminopyridin-4-ylthio)-1-azabicycloC3,2,0) are obtained. IR (aH2cx2): 1785, 1750 , 16
1D, 1530. 1350 m-1 NMR + CDCl5) δ: 1.52 (S, filter Hl,
i, 75 (s. 3at, 2.50+aa, IH, J=11.18Hz3
．． 43fdiIH, J=9.18Hz). 3.74 + 6-, I H,, T=6H2),
4.0-4.5[m, 3Hl, 5.19(S, 2
H), 5.43iABq2H, J=14H2l, Otsu 0
8.3 t m , 1 H) <2) In the same manner as in Example 12-(2), [5R,6R1-6
-(1-Methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-7-oxo-3-13-aminopyridin-4-ylthio)-1-azabicyclo(3,
2, [l) 4-nitrobenzyl hept-2-ene-2-carboxylate (0,900 g) was subjected to catalytic reduction in a hydrogen guff in the presence of platinum oxide σ) monohydrate [0,250 g+]. , +5R,6R)-6-(1-hydroxy-1-
Methyl diethyl)-7-oxo-ro-(ro-aminopyridin-4-y), ruthio)-1-azabicycloC3
, 2,0) Potassium hept-2-ene-2-carboxylate 0.245y] is obtained. Ding R (nu:, >, -/lzl: 1745CInNM
R[D20)δ: 1.18+s, 3H], 1.41ts
, 3H+. 2.45 (6d, IH, J=IO, 13I(z+. 3.53+dd, iH, J=8.IE<Hzl, 3.6
8U■(H2C)λmax:ro03. Onm+E=9
700 + Example 18 (1) [CH3 In the same manner as in Example 12-(1), t2R, 5R, 6R
-6,7-shiogiso6-01-methy/l/-1-(4
-Nitrobenzyloxycarbonyloxy)ethylcou 1-azabicycloC3,2,[] )]butane-2-
750 mg of 4-nitrobenzyl carboxylate,%71
) Lifluoromethanesulfonic acid < 0.245mt
1 total reaction and then with 5-(N-(N-+ 4-nitrobenzyloxycarbonyl)acetimidoyl)aminomethyl)-1,3,4-thiadiazole-2-thiol (496■), (5R16R]-6
-C1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-7-ogiso3-C3-CN
-I N-[4-nitrobenzyloxycarbonyl)acetimidoyl)aminomethylcy 1.3.4-thiadiazol-2-ylthiocou 1-azabicycloC3,2
. Intca2ax2+:1780y1750,1690
．． 16 [J5゜1525.1350 provided) 3H1, 2ro 2+s, 3H+, 3. Q6 (dd. 1H, J=9,19Hz), 3.77i, 1H. J = 5Hz +, 3, 8Q (d, d, 1H, J = 10
゜19Hz+, 4ro7+m, IH+, 5. DD+d. 2H, J=6Hz l, 5.27 (AB (1,2H. J""14Hz), 5,3ro [8,2H3, 5,49
[ABq, 2H, J=13H2l, 6.32ft. 1H,, T=6Hzl, 7.5-7.8(m, 6H+. 8.1-8.5+ m, 6H1 (2) In the same manner as Example 12-(2), (5R, 6R1-6
-(1-Methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-7-Ogisoogi7Carponi I
acetimide-length aminomethyl]-1,3,4-thiadiazol-2-ylthiocou-1-azabicycloC3,
2,0] 4-nitrobenzyl hept-2-ene-2-carboxylate (50 #l:, platinum oxide (%' + monohydrate (5
When subjected to catalytic reduction in a hydrogen gaff in the presence of
5R, 6R)-6-(1-hydroxy-1-methylethyl/L/+7-oxo-3-[5-acetimidoylaminomethyl-1,3,4-thiadiazol-2-ylthio)-1-azabincroC3 , 2, [])] Potassium hept-2-ene-2-carboxylate 13~] is obtained. IR (Nujol): 1750, 1590z 1HM
R(D201δ: 1.23(s, 3H), 1.4
3+s, 3Hl. 2.37ts, 3H), 2.8[]tdd, 1H, J=
=10.18Hz), 3.74[dd, 1H, J=9+
18Hz), 3.75 (d, 1H, J = -6Hz+. 4.32 (m, IH), 5.[]5t S, 2H) Example 19 In the same manner as Example 10, (5R, 6R1- (5-(1
-Hydroxy-1-methylethyl/I/) ~3-ζ6-pyridylthio)-7-oxo-1-azabicycloC3,2
,0) Potassium hept-2-ene-2-carboxylate tO
,0400g) to 50% iodomethane (1,0 shoulder t)
When reacted in aqueous dioxane (6 shoulders), [5R,
6R)-6-11-hydroxy-1-methylethyl l-
3-(1-methyl-6-pyridiniothio)-7-oxo-1-azabicycloi,2.0')hept-2-ene-
2-carboxylate N], 0278F). Ding R (Nujicoll: 175 [] (7) NMRjD20
1δ: 1.22 t, s, 1.43 [S, 3
H1゜2.67tdd, Hr, y=IQ, 18Hz3
3.61tda, IH, J=9.18nz 1,3.7
4 (d, IH, J=6Hz), 4,36 (m, IHl. 4.41[s, 3H1,8,01taajH, J=6.
3Hz), 8.58td, 1H, J=3Hz+. 8.70 ((1, IH, J=6H2], 8.94+s,
1H+UV(H201λm”, X:273.Onm(ε
=80001.298.5Hm(ε=78001 Example 20 R Similarly to Example 10, (5R,6R)-6-(1-
Hydrogin-1-methylethyl)-3-(3-amino-
4-pyridylthio]-7-oxo1-azabicyclo[
6,2,0] Potassium hept-2-ene-2-carboxylate (0, ID95y) with iodomethane + 10.95m
l lr, N, N-diisopropyl-N=ethylamine u), 051m? 50% aqueous geogysan in the presence of +<
When reacted in 44ml), 15R,6R)-6-(
1-Hydroquine-1-methylethyl)-ro-(3-amino-1-methyl-4-pyridiniothio)-7-oxo-
1)-2-ene-2 to 1-azabicyclo[3,2,0)
-carboxylate (obtains 0,08691. Engineering R (nujol: 1760 (7) NMR (D20) δ: 1.24+8,3H1,1,45
(S, 3H1゜2.72+ad, IH, J=11.18
Hz＞. 3.66tdd, H(,:r-=8.13Hz+,3.
77td, IH,, T==6Hz34.22+s, 3H
1゜4.44 (rh, Un, 7.69td, 1H, J=
6H2l, 7.92 (d, 1H, J-45H2l. 8.06+S, IT (> UV[H3O1λmax :220.Onm+ε=14
0001.243.0HmFε=110001.287
．． 0Hm (ε near 1001 Example 21 Similarly to Example 10, (5R,68)-6-(1-
hydroxy-1-methylethyl)-7-oxo-6-(
4-pyridylthio)-1-azabicycloC3,2,[l
) Sodium hept-2-ene-2-7 levonate [
35#)K iodomethane IO34m1)k When reacted, (5R, 63)-6-+ 1-hydroxy-1-methylethy)v)-ro-(1-methyl-4-pyridiniothio)-7-oxo-1- Azabicyclo (I 3.2. []
)] Heptose 2-ene-2-carboxinerate 261
1g] was obtained. NMEID20Iδ: 1.32 (s, 3H31,4[]
IS, filter H) 3.12+d, 2H,, T=9Hz33.
63+d. 1 H, J=3.5Hz), 4.25[S, RoH
l. 4.421dt, 1H, J=3.5.9Hz 1.7.
78+a, 2a, J=+7az+, 3.45ta, 2H
. J Near Hzl Example 22 Sterile 15R,63r -3-(4-pyridifrethio)-6-[1-hydroxy-1-methylethyl)-7
-oxo-1-azabicycloC3,2,[l)hept-2-en-2-cal71 (sodium phosphate t1251
111 and Seftizogishimnat 1 noum (or Seph 7
Fill a completely sterilized vial and seal. When necessary, dissolve in purified water for injection A + 2 * ff + and prepare for injection 4 and 11. Patent applicant: Fujisawa Festival Industry Co., Ltd.

Claims (1)

[Claims] 1) General formula: (In the formula, R1d is a hydroxy group, a protected hydroxy group or a lower alkoxy group, R is a carboxy group or a protected carboxy group, and R3 is an aryl group having an appropriate substituent. , a pyridyl group which may have an appropriate substituent, or a heterocyclic group containing 3 to 5 heteroatoms which may have an appropriate substituent, and their Pharmaceutically acceptable salts. 2) The compound according to claim 1, wherein the compound contains the following steric structure. 1 (In the formula, R1, R2 and R311i each have the same meaning as described in claim 1) 31 R is a hydroxy group % R is a carboxy group as described in claim 21 compound. 4) R is an aminoaryl group, a pyridyl group which may have an amino group, an oxadiazolyl group which may have a lower alkyl, a tetrazolyl group which may have a lower alkyl, a lower alkyl, a lower alkanimidoyl Claim 6) is a thiadiazolyl group which may have an amino(lower) alkyl or heterocyclic group, a triazolyl group which may have a lower alkyl, or a tetracylopyridazinyl group. Compounds described. 5) R is aminophenyl group, pyridyl group, aminoaryl group, 5-(lower)alkyl-1,3,4-oxadiazolyl group, 1-(lower)alkyl-1H-tetrazolyl group, 5-(lower)alkyl- 1,3,4-thiadiazolyl group, 5-(lower) alkanimidoylamino (low M)
Alkyl-1,3,4-thiadiazolyl group, 5-pyridyl-1,3.4-thiadiazolyl group, 5-(lower)alkyl-4FI-1,2,4-triazolyl group, or tetracylo[1,5-b] The compound according to claim 4), which is a pyridazinyl group. 61 (5R,6R) -3-+ 4-pyridylthio)-6-(1-hydroxy-1-methylethyl)-7-
Oxo-1-azabicyclo(3,2,[l)hept-
The compound according to claim 5), which is sodium 2-ene-2-carboxylate. 7) (5R,6R)-6-(1-hydroxy-1-methylethyl)-3-(5-methyl-1,3,4-thiadiazol-2-ylthio)-7-oxo-1-azabicyclo(3 , 2,0) potassium hept-2-ene-2-carboxylate. 3] (5R,6Rl-6-(1-hydroxy-1-
methylethyl)-3-tl-methyl-1H-tetrazol-5-ylthio)-7-oxo-1-azabicycloC
3,2,0) The compound according to claim 5), which is potassium hept-2-ene-2-carboxylate. 9> (5R,6R1-6-+ 1-hydroxy-1
-Methylethyl l-3-(1-methyl-4-pyridiniothio)-7-oxo-1-azabicyclo(3,2,0)
The compound according to claim 5), which is hept-2-ene-2-carboxylate. 10) Compound (Claim 1), wherein compound (11) has the following three-dimensional structure. 1 (In the formula, R1, R2, and R3 each have the same meaning as described in claim 1). 11) Claim 10, wherein R1 is a hydroxy group and R2 is a carboxy group. compound. 12) The chemical complex according to claim 11), wherein R3 is a pyridyl group which may have an amino group. 131 (5R,6S)-3-(4-bi-lysylthio)-6-(1-hydroxy-1-methylethyl]-
7-oxo 1-azabicyclo[6,2,0]hept-
The compound according to claim 12), which is sodium 2-ene-2-carboxylate. 14) (A) Represented by the formula (in the formula, R"H represents a hydroxy group, a protected hydroxy group or a lower alkoxy group, R2 represents a carboxy group or a protected carboxy group, and R5 represents an acyl group) The compound or its salt has the formula %formula% (wherein R3 is an aryl group having a suitable substituent, a pyridyl group optionally having a suitable substituent, or a pyridyl group optionally having a suitable substituent). A compound represented by the formula (in which the sweetening agent) or a salt thereof is reacted with a heterocyclic group containing 3 to 5 heteroatoms or a salt thereof;
(R, R and R each have the same meaning as above) or a salt thereof; The salt is reacted with an acylating agent, and then the resulting compound is reacted with a compound represented by the formula R3-3H (%l) (wherein R has the same meaning as before) or a salt thereof, and all of the compounds or salts thereof are reacted. or a compound represented by formula (3) (wherein each formula (3) means a protected carboxy group and R3 has the same meaning as above) or a salt thereof, with a hydroxy-protecting group in Ra and a carboxy-protecting group in B. to obtain the entire compound represented by the formula or a salt thereof, or (wherein R means hydrogen or an amino group, and R1 has the same meaning as above) The salt is reacted with a compound represented by the formula % (wherein R4 is a lower alkyl group and 15) A process for producing the compound (I) and its salts, which is characterized by obtaining a compound or a salt thereof represented by the general formula (wherein R is a hydroxy group, a protected hydroxy group, or a lower alkoxy group, R is a carboxyl group or a protected carboxy group, R3 is an aryl group having a suitable substituent, a pyridyl group which may have a suitable substituent, or a suitable substituent. A prophylactic and therapeutic agent for infectious diseases containing a compound represented by the formula (representing a heterocyclic group containing 3 to 5 heteroatoms) and a pharmaceutically acceptable salt thereof as an active ingredient. 16) Compound (I)? The agent for preventing and treating infectious diseases according to claim 15, which is contained as an antibacterial agent. 17) The agent for preventing and treating infectious diseases according to claim 15, which contains the compound as an Ilt-β-lactamase inhibitor.