JPH08245628A - Carbapenem compound, its production and agent - Google Patents

Abstract

PURPOSE: To obtain the subject compound, having antimicrobial activities with wide spectra and useful as an excellent antimicrobial agent by carrying out the addition elimination reaction of specific compounds. CONSTITUTION: This compound of formula I [R<1> is a (substituted)lower alkyl; X is O or S; R is a lower alkylene; A is a direct bond, O, S or NR' (R' is H or a lower alkyl); Q is an unquaternized heterocyclic ring which may be substituted], e.g. allyl (5S,6S,7S,11S)-5-[(R)-1-hydroxyethyl]-4-oxo-11-[3-(1H-1,2,4- triazol-1-yl)-propyl]-8-oxa-3-azatricyclo[5.4.0.0<3> ,<6> ]undec-1-ene-2-carboxylate. The compound of formula I is obtained by reacting a compound of formula II (W and B are each a mutually reactive and eliminative group), etc., with a compound of formula III, etc., accompanied by the elimination of W-B and, as necessary, removing protecting groups. Furthermore, the reaction is preferably carried out in an inert solvent, e.g. dioxane under conditions of -78 to +50 deg.C for 15-24hr, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel carbapenem compound or an ester or salt thereof which has an excellent antibacterial action and can be orally administered not only as an injection.

[0002]

2. Description of the Related Art There have been many reports on carbapenem antibiotics represented by thienamycin (for example, Robert B Morin, Marvin Gorman “Chemistry and Biology of β-Lactam Antibiotics. Lact
am Antibiotics) "Volume 2, Page 227 (Academic Press In
c.) (1982)). Recently, a polycyclic carbapenem having a skeleton different from that of a conventional carbapenem has been reported (JP-A-4-
178389, JP-A-5-86062). Japanese Patent Laid-Open No. 4-178389 discloses a formula

Embedded image [In the formula, R ¹ represents a hydrogen atom or an optionally substituted hydrocarbon group, COOR ² represents an optionally esterified carboxyl group, and ring B represents an optionally substituted cyclic group. ] The tricyclic carbapenem compound represented by these or its salt is disclosed. In addition, JP-A-5-86062
No., the formula

[Chemical 6] [Wherein R ¹ is a hydrogen atom or an optionally substituted lower alkyl, lower alkenyl, lower alkynyl or cycloalkyl group, COOR ² is an optionally esterified carboxyl group, and ring B is saturated or An unsaturated 6-membered heterocyclic ring, R ^b is 1) an alkyloxycarbonyl group or 2) a group represented by the formula: —W ^b —U ^b {W ^b
Is a bond, a sulfur atom (which may be mono- or dioxidized), an oxygen atom or an optionally substituted N
H represents a straight chain or branched lower alkylene or lower alkenylene which may intervene, and U ^b is a) an optionally substituted aromatic hydrocarbon or heterocycle,
b) cyano, amino, carbamoyl, carboxy, sulfamoyl, halogen, amidino, hydroxy or methyl group, c) optionally substituted alkylamino, alkylammonium, acylamino, alkyloxy, alkylthio, alkylsulfonyl, alkylsulfonylamino, Acyloxy or alkylcarbamoyl group or d) formula:

[Chemical 7] Is an optionally substituted quaternized nitrogen-containing heterocycle,
R ^d represents an optionally substituted alkyl group)} and represents the same or different 1 to 3 substituents. ] The tricyclic carbapenem compound represented by these or its salt is disclosed.

[0003]

Carbapenem compounds generally show excellent antibacterial activity against Gram-positive and Gram-negative bacteria, but their antibacterial activity is not sufficient, their physicochemical properties and their stability in the body are high. In particular, there is a problem in stability against renal dehydropeptidase-1 (DHP-1) and the like. Therefore, it has been strongly desired to develop a carbapenem compound which has an excellent antibacterial activity, exhibits stable in vivo and excellent pharmacokinetics, and can be orally used in some cases.

[0004]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that in a tricyclic carbapenem in which a saturated 6-membered heterocycle is condensed at the 1,2-position of a carbapenem skeleton, the saturated 6-membered heterocycle is used. It has only an oxygen atom or a sulfur atom at the 8-position as a heteroatom forming a ring skeleton, and has -RAQ (R
Is a lower alkylene group, A is a bond, an oxygen atom, a sulfur atom (which may be mono- or dioxidized) or -NR'- (R 'is a hydrogen atom or a lower alkyl group), and Q is a substituent. The carbapenem compound is characterized for the first time by its chemical structure that an optionally quaternized non-quaternized nitrogen-containing heterocyclic group is attached to the 11-position. Unexpectedly based on the chemical structure, it exhibits excellent antibacterial activity against a wide range of pathogens including Gram-positive to Gram-negative bacteria including Haemophilus influenzae, as well as chemical stability and in vivo stability, especially DH.
It was found that the composition exhibits stability against PI and further excellent oral absorption, and the present invention was completed based on these. That is, the present invention provides (1) formula (I):

Embedded image [Wherein R ¹ is an optionally substituted lower alkyl group, X is an oxygen atom or a sulfur atom, R is a lower alkylene group, and A is a bond, an oxygen atom, a sulfur atom (mono- or di-oxidized). May be present) or -NR '-(R'
Represents a hydrogen atom or a lower alkyl group), and Q represents an optionally substituted non-quaternized nitrogen-containing heterocyclic group. ] The carbapenem compound represented by these, its ester, or its salt (it may abbreviate as compound (I) hereafter),

(2) -R-A-Q

[Chemical 9] (3) R ¹ is the compound according to the above (1)

[Chemical 10] The compound according to (1) above, which is:

[Chemical 11] And a compound or an ester or salt thereof represented by the formula: and a compound or an ester or a salt thereof represented by the formula: Q-A-B [wherein, W and B are groups capable of leaving by reacting with each other,
Other symbols have the same meanings as above] and a reaction with elimination of WB, and a protecting group is removed as necessary, The method for producing a compound according to (1) above, (5) A medicament containing the compound according to (1) above, and (6) a medicament according to (5) above which is an antibacterial agent.

In the above formula, the alkyl group of the optionally substituted lower alkyl group represented by R ¹ is a linear or branched C _1-4 alkyl group (eg, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl etc.) are used, and examples of the substituent thereof include cyano group, amino group, mono- or di-C _1-4 alkyl (eg methyl, ethyl, isopropyl etc.) amino group, hydroxyl group,
C _1-4 alkyl-oxy group, carbamoyloxy group, C
_1-4 alkyl-thio group, C _1-4 alkyl-sulfonyl group,
Halogen (eg, fluoro, chloro, bromo, etc.), sulfamoyl group, C _1-4 alkoxy-carbonyl group (eg,
Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), sulfooxy group and the like can be used. The number of such substituents is preferably 1 to 3, and in the case of a plurality of substituents, they may be the same or different. When the alkyl group is substituted with an amino group or a hydroxyl group, these may be protected with an easily removable protecting group. Trimethylsilyl as such a protecting group,
Preferred are silyl groups such as triethylsilyl and t-butyldimethylsilyl, and alkoxycarbonyl groups such as allyloxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl and p-nitrobenzyloxycarbonyl. More preferably R ¹ is a formula

[Chemical 12] [In the formula, R ³ represents a hydrogen atom, halogen, or an optionally substituted hydroxyl group or amino group]. As the substituent of the hydroxyl group or amino group represented by R ³ , the above-mentioned removable protecting groups for those groups are used. R ³ is more preferably a hydroxyl group. Particularly preferred as R ¹ is a (1R) -hydroxyethyl group.

X represents an oxygen atom or a sulfur atom, and an oxygen atom is particularly preferable. As the lower alkylene used as R, linear or branched C _1-4 alkylene (eg, methylene, ethylene, propylene, etc.) and the like are preferable. A represents a bond, an oxygen atom, a sulfur atom (which may be mono- or dioxidized) or -NR'- (R 'represents a hydrogen atom or a lower alkyl group). As the lower alkyl group represented by R ′, a linear or branched C _1-4 alkyl group (eg, methyl, ethyl, etc.) and the like are preferable. This lower alkyl group is a halogen (eg, fluoro,
Chloro, bromo, etc.), hydroxy group, C _1-6 alkyloxy group (eg, methoxy, ethoxy, etc.), amino group,
It may be substituted with 1 to 3 mono- or di-C _1-4 alkylamino groups (eg, dimethylamino, etc.) and the like. Q represents an optionally substituted non-quaternized nitrogen-containing heterocyclic group. Examples of such a nitrogen-containing heterocyclic group include, in addition to one non-quaternized nitrogen atom,
1 hydrogen atom from a 4- to 6-membered non-quaternized nitrogen-containing heterocycle, which may contain 1 to 3 heteroatoms selected from non-quaternized nitrogen, sulfur and oxygen atoms. A group which can be removed by itself is used, and the nitrogen-containing heterocycle may be further condensed with a benzene ring or a 5- or 6-membered heterocycle containing 1 to 4 nitrogen atoms. As such a non-quaternized nitrogen-containing heterocycle, an unsaturated nitrogen-containing heterocycle is preferable, and for example, monocyclic azeto, pyrrole, imidazole, pyrazole, 1,2,3-
Triazole, 1,2,4-triazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadi Azole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4- Triazine or 1,3,
5-triazine or its structurally possible hydrogenated form, or polycyclic indole, isoindole, benzimidazole, benzoxazole, benzisoxazole,
Examples thereof include benzthiazole, benzisothiazole, pyrrolopyrimidine, purine and the like, or structurally possible hydrogenated forms thereof.

Examples of the substituent of the non-quaternized nitrogen-containing heterocyclic group represented by Q include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.), C _3-6 Alkenyl groups (eg, allyl, 2- or 3-butenyl, etc.), C _6-10 aryl groups (eg, phenyl, naphthyl, etc.), C _3-6 cycloalkyl groups (eg,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., hydroxy group, C _1-4 alkoxy group (eg, methoxy, ethoxy, etc.), C _1-4 alkoxy C
_1-4 alkoxy (eg, methoxymethoxy, etc.), tri-C _1-6 alkylsilyloxy group such as trimethylsilyloxy or t-butyldimethylsilyloxy, allyloxycarbonyloxy group, C _1-4 alkylthio group (eg, methylthio) , Ethylthio, etc.), amino group, mono- or di-C _1-4 alkylamino group (eg, methylamino or dimethylamino etc.), allyloxycarbonylamino group, hydroxy-C _1-4 alkyl group (eg, hydroxymethyl) , 2-hydroxyethyl or 3-
Hydroxypropyl etc.), amino-C _1-4 alkyl group (eg aminomethyl or 2-aminoethyl etc.),
Mono- or di-C _1-4 alkylamino-C _1-4 alkyl group (eg, 2-dimethylaminoethyl etc.), carboxy-
C _1-4 alkyl group (eg, carboxymethyl or 2-
Carboxyethyl, etc.), halogen (eg, fluoro or chloro, etc.), oxo group, thioxo group, or 4- to 6-membered heterocyclic group containing 1 to 4 heteroatoms such as nitrogen atom, oxygen atom, sulfur atom, etc. Used.
The "nitrogen-containing heterocyclic group" may be substituted with 1 to 5 of these substituents at substitutable positions, and when there are plural substituents, the substituents may be the same or different. Examples of the heterocycle used as the above-mentioned “4 to 6-membered heterocyclic group containing 1 to 4 heteroatoms” include:
Azeto, furan, pyrrole, thiophene, thiazole,
Examples thereof include isothiazole, oxazole, isoxazole, pyrazole, imidazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, triazine, morpholine, quinuclidine, and structurally possible hydrogenated forms thereof.

The group represented by the formula -RAQ is, for example, a group represented by the formula:

[Chemical 13] Is an optionally substituted non-quaternized nitrogen-containing heterocyclic group having a bond at a carbon atom, and other symbols have the same meanings as described above. ] And the like are specifically used.

Embedded image As the group represented by, among the "optionally substituted, non-quaternized nitrogen-containing heterocyclic group" represented by Q, a group having a bond at the nitrogen atom is used, and examples thereof include 1- Imidazolyl, 1-pyrazolyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazole-
1-yl, 1,2,4-triazol-4-yl, 1-tetrazolyl, 2-tetrazolyl and the like are preferable.

[Chemical 15] The group represented by is a group having a bond at a carbon atom in the “optionally substituted, non-quaternized nitrogen-containing heterocyclic group” represented by Q. For example, azetidine- 3-yl, imidazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, tetrazole
-5-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 2-imidazolin-2-yl, 2 -Oxazolin-2-yl, 2-thiazolin-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2
-Pyrimidyl, 2-pyrazinyl, 3-pyridazinyl, 4-pyridazinyl and the like are preferable.

Preferred substituents represented by AQ include, for example, 1H-imidazol-1-yl, 2-methyl-1H-imidazol-1-yl, 1H-1,2,4.
-Triazol-1-yl, 4H-1,2,4-triazol-4-yl, 3-methyl-1H-1,2,4-triazol-1-yl, 5-methyl-1H-1,2,4
-Triazol-1-yl, 3-methyl-4H-1,
2,4-triazol-4-yl, 1-methyl-1H-
Tetrazol-5-ylthio, 1,2,3-thiadiazol-5-ylthio, 1,2,4-thiadiazole-5
-Ylthio, 1,3,4-thiadiazol-2-ylthio, 2-pyridyloxy, 3-pyridyloxy, 4-pyridyloxy, 2-pyridylthio, 3-pyridylthio,
4-pyridylthio, 3-pyridazinylthio, 4-pyridazinylthio, 2-thiazolin-2-ylthio, 1-methyl-2-imidazolin-2-ylthio, 2-oxazolin-2-ylthio, 2-thiazolin-2-ylamino and the like can be mentioned. be able to. Of these, among others, 1H-1,2,4-triazol-1-yl, 1,2,
3-thiadiazol-5-ylthio and the like are preferable. −
R-A-Q has a formula with a coordination to the carbapenem skeleton.

Embedded image What is represented by is preferable.

As the salt of the compound represented by the formula (I) or its ester, a pharmacologically acceptable salt is preferably used. As the pharmacologically acceptable salt, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like are used. Inorganic bases that can form these salts include alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.), and organic bases such as trimethylamine, triethylamine, pyridine, picoline, N, N′-dibenzylethylenediamine, ethanolamine, diethanolamine, tris (hydroxymethylamino) methane, dicyclohexylamine and the like are used as the inorganic acid, for example, hydrochloric acid,
Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. are organic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid. ， P
-Toluenesulfonic acid and the like are used as the basic or acidic amino acid, for example, arginine, lysine, ornithine, aspartic acid, glutamic acid and the like. Among these salts, the salt with a base (that is, a salt with an inorganic base, a salt with an organic base, a salt with a basic amino acid) is a carboxyl group of the substituent of compound (I) or a group represented by Q. A salt that can be formed when an acidic group such as a carboxyl group is present, and a salt with an acid (that is, a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid) is a substitution of compound (I). The group means a salt which can be formed with an amino group or a basic group such as an amino group in R ¹ and Q.

Esters of the compounds of formula (I) may be formed at the carboxyl group at the 3-position of the carbapenem compound or / and when a carboxyl group is present in the group represented by Q. The (R ² in the example COOR ²⁾ ester residue such esterified carboxyl group, in the field of β- lactam such as cephalosporins, for example cephalosporin 4-position in vivo elimination easy Examples thereof include an ester residue that is commonly used as a group that forms an ester (so-called prodrug ester) and a group that is commonly used as an ester residue of a carboxylic acid in the pharmaceutical field. Specifically, for example,
C _1-7 alkyl group which may be substituted, C _2-6
An alkenyl group, a C _6-10 aryl group, a C _7-12 aralkyl group or the like is used. Examples of such an optionally substituted C _1-7 alkyl group include methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like, and examples of the C _2-6 alkenyl group include vinyl, allyl, crotyl and the like. , C _6-10 aryl groups include phenyl and naphthyl, and C _7-20 aralkyl groups include benzyl, phenethyl, benzhydryl, trityl and the like. Further, as R ² , the formula:

[Chemical 17] [Wherein, R ⁴ represents a hydrogen atom or an optionally substituted C _1-6 alkyl group or a cyclo C _3-6 alkyl group, and R ⁵ represents an optionally substituted C _1-10 alkyl group, Cyclo C _3-10 alkyl group, C _1-10 alkyloxy group, cyclo C _3-10 alkyloxy group, cyclo C _3-10 alkyl C _1-6 alkyl group, cyclo C _3-10 alkyl C _1-6 alkyloxy Group, C _2-6 alkenyl group, C _6-10 aryl group, or C _7-12 aralkyl group] can be advantageously used. In the above formula, examples of the C _1-6 alkyl group represented by R ⁴ include methyl, ethyl, propyl, isopropyl, butyl, and 2,2-dimethylpropyl, and examples of the cycloC _3-6 alkyl group include cyclo. Propyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. are used. Examples of the alkyl group of the C _1-10 alkyl group and the C _{1-1 0} alkyloxy group represented by R ⁵ include methyl, ethyl, propyl,
Isopropyl, butyl, pentyl, 2,2-dimethylpropyl, hexyl, peptyl, decyl, etc. are cyclo C
_3-10 alkyl group, cyclo C _3-10 alkyloxy group, cyclo C _3-10 alkyl C _1-6 alkyl group, and cyclo C
Examples of the cycloalkyl group of the _3-10 alkyl C _1-6 alkyloxy group include cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like include cyclo C _3-10 alkyl C _1-6 alkyl group and cyclo C _3-10 alkyl C
As the C _1-6 alkyl group _1-6 alkyloxy group, for example methyl, ethyl, propyl, heptyl, pentyl, hexyl and the like. Examples of the C _2-6 alkenyl group include vinyl, allyl and crotyl, examples of the C _6-10 aryl group include phenyl and naphthyl, and examples of the C _7-12 aralkyl group include benzyl and phenethyl.

Particularly preferred ester residues represented by R ² are groups often used in the process of manufacturing pharmaceuticals (eg, methoxyethoxymethyl group, methoxymethyl group, methylthiomethyl group, tertiary butyl group, 2,2). , 2-
Trichloroethyl group, benzyl group, p-nitrobenzyl group, o-nitrobenzyl group, phenethyl group, bis (methoxyphenyl) methyl group, p-methoxybenzyl group,
3,4-dimethoxybenzyl group, benzhydryl group, trityl group, trimethylsilyl group, 2-trimethylsilylethyl group, allyl group, or the like), or a group which gives a biologically unstable ester derivative suitable for oral administration. For example, acetoxymethyl group, 1-acetoxyethyl group, 1-acetoxypropyl group, pivaloyloxymethyl group, isopropyloxycarbonyloxymethyl group, 1- (isopropyloxycarbonyloxy) ethyl group, cyclohexyloxycarbonyloxymethyl group, 1- (cyclohexyloxycarbonyloxy) ethyl group, ethoxycarbonyloxymethyl group, 1- (ethoxycarbonyloxy) ethyl group, phthalidyl group,
(2-oxo-5-methyl-1,3-dioxole-4-
Il) methyl group).

Production Method 1 The compound (I) of the present invention has, for example, the formula (II):

Embedded image And a compound or an ester or salt thereof represented by the formula: and a compound or an ester or a salt thereof represented by the formula (III): Q-A-B (III) A group that can be separated,
Other symbols have the same meanings as defined above.] And the reaction is accompanied by elimination of WB, and the protective group is removed as necessary to produce the compound. A known addition / elimination reaction can be used for such a reaction [eg, Annual Reports in Organic Synthesis (Annu
al Reports in Organic Sythesis) 1975-1993, Academi
c Press, Inc, San Diego], FACarey and RJSundb
erg Advanced Organic Chemistry Second Edition, Ple
num Press, New York and London (1983), and Comprehensive Organic Synthesis (Comprehensiv
eOrganic Synthesis), Volume 6, Pergamon Press, Oxfo
rd (1991), etc.]. In the above formula, as W, a leaving group used in the field of synthetic organic chemistry can be widely adopted. Among them, hydroxyl group, halogen such as chloro, bromo, iodo, substitution of methanesulfonyloxy, trifluoromethanesulfonyloxy, etc. Optionally substituted (C _1-5 ) alkanesulfonyloxy group or optionally substituted (C-).
_6-10 ) Aromatic hydrocarbon sulfonyloxy groups are preferred.
The reaction for converting the compound (II) in which W is a hydroxyl group into the compound (II) in which W is a leaving group has been well studied in the field of synthetic organic chemistry, and an appropriate reaction may be performed as necessary. Can be adopted.

B of Q-A-B used in the addition-elimination reaction
Examples of the hydrogen atom include a hydrogen atom, an anion or a protecting group, and an appropriate one is selected depending on the type of W and reaction conditions. The reaction can be carried out in the presence of additives, if necessary. Such additives include, for example, triethylamine, diisopropylethylamine, pyridine, and 2,6-lutidine for the purpose of neutralizing an acidic substance produced as the reaction proceeds when B is hydrogen. It is preferable to add aliphatic or aromatic amines, basic salts such as sodium carbonate, sodium hydrogen carbonate and potassium carbonate. As the protecting group represented by B,
Amino group, hydroxyl group or carboxyl group protecting group exemplified below is used. When B is a protecting group, it is deprotected in the reaction system, so a deprotecting reagent must be added. The deprotecting agent to be added depends on the protecting group used, but for example, TW Green and
PGM Wuts, Protective Groups
In Organic Synthesis (Protective Groups
in Organic Synthesis), Second Edition, John Wely & Sons I
A deprotecting agent usually used in the relevant field described in nc. New York (1991) and the like is adopted. This addition-elimination reaction is usually carried out by stirring in an inert solvent. The inert solvent used in the reaction is not particularly limited as long as it does not interfere with the reaction, but for example, aliphatic hydrocarbons such as pentane and hexane, aromatic hydrocarbons such as benzene, toluene and xylene, such as dioxane and diene. Ethers such as ethoxyethane and tetrahydrofuran,
For example, halogenated hydrocarbons such as dichloromethane and chloroform are preferable. The reaction temperature is the starting compound (I
The temperature is usually -100 ° C to 100 ° C, preferably -78 ° C to 50 ° C, although it varies depending on I), (III), the type of additive, the type of solvent and the like. The reaction time is usually 1 minute to 48 hours, preferably about 15 minutes to 24 hours. In the structural formula of compound (II), when a moiety other than W contains a reactive group such as an amino group, a hydroxyl group or a carboxyl group, these groups are protected by a protecting group described below according to a conventional method. May be. After the reaction, these protecting groups can be removed by a conventional method.

As a concrete method, when W is a hydroxyl group, the so-called Mitsunobu reaction or its similar reaction can be advantageously employed. Further, even if W is a hydroxyl group, it can be subjected to an addition-elimination reaction after converting it into a removable group by a known method. W of compound (II) used in the above Mitsunobu reaction or its similar reaction is a hydroxyl group, which is produced by a known method (eg, JP-A-5-86062). B of Q-A-B used in that case is a hydrogen atom, and although various groups described above can be used as Q, it is preferable that Q-A-B is acidic. As the oxygen atom scavenger used in this reaction, a trivalent phosphorus compound is preferable. Examples of the trivalent phosphorus substituent on the phosphorus compound of phenyl, (C _6-10) aryl groups such as tolyl, propyl, (C _1-10) such as butyl group, cyclopentyl, cyclohexyl and the like (C _{3- 10} ) cycloalkyl groups, (C _1-10 ) alkyloxy groups such as methoxy and ethoxy, (C _3-10 ) cycloalkyloxy groups such as cyclopentyloxy and cyclohexyloxy, and di (C _1-) such as dimethylamino and diethylamino. ₁₀ ) Alkylamino group etc. are adopted,
The three substituents may be the same or different from each other.
Preferably, tri (C _6-10 ) arylphosphine such as triphenylphosphine and tritolylphosphine, tri (C _1-10 ) alkylphosphine such as tripropylphosphine and tributylphosphine, tri (C _1-10 ) phosphine, tricyclopentylphosphine, tricyclohexylphosphine and the like C _3-10 ) Cycloalkylphosphine, more preferably triphenylphosphine and tributylphosphine. Examples of hydrogen atom scavengers used in this reaction include di (C _1-10 ) alkyl azodicarboxylates such as diethyl azodicarboxylate and diisopropyl azodicarboxylate,
Substituted azodicarboxamides such as N, N, N'N'-tetramethylazodicarboxamide and N, N, N'N'-tetraisopropylazodicarboxamide, active alkyl halides such as carbon tetrachloride and carbon tetrabromide And so on. More preferably, diethyl azodicarboxylate, diisopropyl azodicarboxylate, N, N,
N'N'-tetramethylazodicarboxamide, N,
N, N'N'-tetraisopropylazodicarboxamide. This reaction is usually performed by stirring in an inert solvent. The inert solvent used in the reaction is not particularly limited as long as it does not interfere with the reaction, but is, for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, diethoxyethane and tetrahydrofuran, such as dichloromethane. , Halogenated hydrocarbons such as chloroform, alkylnitriles such as acetonitrile and propionitrile, and nitroalkanes such as nitromethane and nitroethane are preferable. The reaction temperature depends on the starting compounds (II), (II
I), a scavenger for oxygen atoms, a scavenger for hydrogen atoms, a solvent, etc., but it is usually -40 ° C to 100 ° C.
C, preferably -20 to 50 ° C. The reaction time is usually 1 minute to 48 hours, preferably 15 minutes to 2
It takes about 4 hours. Compound (II) can be produced by a known method (eg, JP-A-5-86062, Compendium of Compound).
Organic Synthetic Methods (Compendium
of Organic Synthetic Methods), Volumes 1-7, J
ohn Wely & Sons Inc. New York (1971-1992), and Comprehensive Organic Synthesis (Comp
rehensive Organic Synthesis), Volumes 1-9, Pergamon P
ress, Oxford (1991), RCLarock, Comprehensive Organic Transformation (Comprehe
nsive Organic Transformation), VCH, New York (1989
Year))). In addition, as the compound (III), a commercially available product may be used,
Alternatively, it may be produced by a known method (eg, Comprehensive heterocyclic chemistry (Comprehensive
Heterocyclic Chemistry), Volumes 1-8, Pergamon Press,
Oxford (1984), Comprehensive Organic
Synthesis (Comprehensive Organic Synthesis), 1st
-9 volumes, Pergamon Press, Oxford (1991), etc.).

Production Method 2 Compound (I) wherein A is an oxygen atom, a sulfur atom (which may be mono- or dioxidized) or -NR'- (R 'has the same meaning as described above) can be prepared by, for example, a compound represented by the formula: (IV):

[Chemical 19] [Wherein W'is a hydroxyl group, a mercapto group or-
NR'-H (R 'has the same meaning as above), and other symbols have the same meaning as above. ] The compound or its ester represented by these or its salt reacts with W ', and A'-Q
[A 'is an oxygen atom, a sulfur atom (which may be mono- or dioxidized) or -NR'- (R' has the same meaning as described above)] or its ester or its salt (compound ( V)) and reacting with V)) to remove a protecting group, if necessary. For such a reaction, for example, a known substitution reaction or heterocyclic ring formation reaction can be used [eg, Annual Report in Organic Synthesis (Annual R
eports in Organic Sythesis) 1975-1993, Academic Pr
ess, Inc, San Diego], FACarey and RJ Sundberg
Advanced Organic Chemistry 2nd Edition (Adva
nced Organic Chemistry Second Edition) Plenum Pres
s New York and London (1983), Comprehensive
Heterocyclic Chemistry (Comprehensive He
terocyclic Chemistry), Volumes 1-8, Pergamon Press, Ox
ford (1984) and Comprehensive Organic Synthesis (Comprehensive Organic Synthesis),
Volume 6, Pergamon Press, Oxford (1991), etc.]. In the structural formula of compound (IV), when a reactive group such as an amino group, a hydroxyl group or a carboxyl group is contained in a portion other than W ′, these groups are protected by a protecting group described below according to a conventional method. May be. After the reaction, these protecting groups can be removed by a conventional method.

W'in compound (IV) and compound (V) are
Examples of the reaction for forming the group represented by A′-Q include a substitution reaction. Examples of the compound (V) used in such a reaction include a leaving group (eg, halogen such as fluoro, chloro and bromo, p-
Toluenesulfonyloxy, methanesulfonyloxy,
Heterocycles having a substituted sulfonyloxy group such as trifluoromethanesulfonyloxy) on the ring and containing 1 to 4 nitrogen atoms can be mentioned. Examples of such a heterocycle include 2-chloropyridine, 4-chloropyridine, 2-chloropyrimidine, 3-chloropyridazine, and 2-chloropyrazine. The reaction can be carried out in the presence of additives as necessary. Examples of such additives include triethylamine, diisopropylethylamine, pyridine,
Examples thereof include aliphatic or aromatic amines such as 2,6-lutidine, basic salts such as sodium carbonate, sodium hydrogen carbonate and potassium carbonate. This reaction is usually performed by stirring in an inert solvent. The inert solvent used in the reaction is not particularly limited as long as it does not interfere with the reaction, but is, for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, diethoxyethane and tetrahydrofuran, such as dichloromethane. , Halogenated hydrocarbons such as chloroform, acetonitrile,
Alkyl nitriles such as propionitrile and nitroalkanes such as nitromethane and nitroethane are preferred. The reaction temperature will differ depending on the starting compounds (IV), (V), the type of solvent, etc., but is usually -40 ° C to 100 ° C,
It is preferably 0 ° C to 50 ° C. Reaction time is usually 1
Minutes to 48 hours, preferably about 15 minutes to 24 hours.

The reaction of W'in compound (IV) and compound (V) to form a group represented by A'-Q includes, for example, an addition reaction. The compound (V) used in such a reaction has, for example, two electrophilic functional groups capable of reacting with a nucleophile in the molecule and reacts with the nucleophile to contain 1 to 4 nitrogen atoms. A compound capable of forming a heterocyclic ring can be mentioned. As such an electrophilic functional group, for example, a cyano group,
Examples thereof include imino group, ester group, keto group or its equivalent, aldehyde group or its equivalent, halogen (eg, chloro, bromo), isocyanato group, isothiocyanato group and the like. Specific examples of the compound (V) include α-thiocyanoacetophenone, α-thiocyanoacetone, 2-chloroethyl isothiocyanate, and 3-chloropropyl isothiocyanate. The reaction can be carried out in the presence of additives as necessary. Such additives include, for example, triethylamine, diisopropylethylamine,
Examples thereof include aliphatic or aromatic amines such as pyridine and 2,6-lutidine, and basic salts such as sodium carbonate, sodium hydrogen carbonate and potassium carbonate. This reaction is usually performed by stirring in an inert solvent. The inert solvent used in the reaction is not particularly limited as long as it does not interfere with the reaction, but is, for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, diethoxyethane and tetrahydrofuran, such as dichloromethane. , Halogenated hydrocarbons such as chloroform are preferred. The reaction temperature will differ depending on the starting compounds (IV), (V), the type of solvent, etc., but is usually -50 ° C to 100 ° C,
It is preferably -20 ° C to 50 ° C. The reaction time is usually 1 minute to 48 hours, preferably about 15 minutes to 24 hours. The compound (IV) used in the above reaction can be produced by a known method (eg, JP-A-5-86062, Comprehensive Organic Synthesis (Comprehensiv)).
e Organic Synthesis), Volumes 1-9, Pergamon Press, Oxf
ord (1991), RC Larock, Comprehensive Organic Transformation (Comprehensiv
eOrganic Transformation), VCH, New York (1989), etc.). Compound (V) may be a commercially available product or may be produced by a known method (eg, Comprehensive Heterocyclic Chemistry).
Cyclic Chemistry), Volumes 1-8, Pergamon Press, Oxford
(1984), Comprehensive Organic Synthesis, Volumes 1-9,
Pergamon Press, Oxford (1991), etc.).

Production Method 3 The compound (I) of the present invention has, for example, the formula (VI):

Embedded image [In the formula, Y and Z are groups that react with each other to form a double bond, and other symbols have the same meanings as described above. ] It can manufacture by subjecting the compound represented by this, its ester, or its salt to a ring-closing reaction. Y and Z are groups which react with each other to form a double bond, in other words, groups which Y and Z react with each other and are eliminated to form a double bond. As specific Y and Z, for example, = O,
In addition to = S, = Se, etc., those described in JP-A-4-178389 are used. The ring closure reaction is a reaction known per se [eg, an annual report
Organic Synthesis (Annual Reports in Organi
c Sythesis) 1975-1993, Academic Press, Inc, San Di
ego], Advanced Organic Chemistry Second Edition P
lenum Press New York and London (1983), etc.]. Specifically, a Wittig type reaction (Wittig, Horner, Emmons reaction), a Peterson type reaction, an aldol type reaction with dehydration, a McMurry type reaction using a low-valence metal, and the like can be used. More desirably, for example, as Y and Z,
O, S, Se, P (R ⁶ ) ₃ ,

[Chemical 21] [In the formula, R ⁶ and R ⁷ represent a lower alkoxy group, a lower alkyl group or an aryl group. ], Etc. are used. More specific methods include, for example, the following production methods.

Production Method 3-1 Compound (I) has the formula (VI-1):

[Chemical formula 22] [In the formula, each symbol has the same meaning as described above. Compound or its ester or a salt thereof], _{^{formula: P (R 6) 3 (}} VII) or ^{_{P (R 6) 2 R 7}} (VI
I ') [In the formula, each symbol has the same meaning as described above. ] It is obtained by reacting with a compound represented by the above, and removing a protecting group if necessary. When a reactive group such as an amino group, a hydroxyl group or a carboxyl group is contained in the structural formula of compound (VI-1), these groups may be protected by a protecting group described below according to a conventional method. .. After the reaction, these protecting groups can be removed by a conventional method. Examples of the lower alkoxy group represented by R ⁶ or R ⁷ include C _1-6 alkoxy groups such as methoxy, ethoxy, propoxy and butoxy, and examples of the lower alkyl group include C, such as methyl, ethyl, propyl, butyl and pentyl.
_1-6 alkyl group and the like, and as the aryl group, C _6-10 aryl group etc. such as phenyl are used. These reactions are usually carried out by heating without solvent or in an inert solvent. The inert solvent used in the reaction is not particularly limited as long as it does not interfere with the reaction. Halogenated hydrocarbons such as Compound (VI
I) or (VII ') is used in an amount of 2 molar equivalents or more, preferably 2 to 10 molar equivalents, of the compound (VI-1). The reaction temperatures are as follows: raw material compounds (VI-1), (VII), (VI
Although it depends on I '), the type of solvent, etc., it is usually about 20 to 160 ° C, preferably about 80 to 140 ° C. The reaction time is usually 30 minutes to 100 hours, preferably about 1 to 72 hours.

Production Method 3-2 The compound (I) has the formula (VI-2):

[Chemical formula 23] [In the formula, each symbol has the same meaning as described above. ] The compound represented by the following formula or its ester or its salt is subjected to a ring-closing reaction, and further, if necessary, the protecting group is removed. Similar to Production Method 3-1, when a reactive group such as an amino group, a hydroxyl group or a carboxyl group is contained in the structural formula of the compound (VI-2), these groups are described below according to a conventional method. It may be protected by a protecting group or may be removed after the reaction by a conventional method. The ring closure reaction is carried out in an inert solvent. As the preferred inert solvent, aromatic hydrocarbons, ethers and halogenated hydrocarbons as used in the above-mentioned production method 3-1 are used. The reaction is carried out by heating in the temperature range of about 0 to 160 ° C, preferably about 30 to 140 ° C. The reaction time varies depending on the kind of compound (VI-2) and the reaction temperature, but is usually about 30 minutes to 100 hours, preferably about 1 hour to 72 hours. In the starting compound, R ^1, (R ² in COOR ²⁾ ester residue when the carboxyl group is esterified or Q
When an amino group is present in the substituent represented by, the amino group is preferably protected by a protecting group, and examples of the protecting group for the amino group include those used in the field of β-lactams and peptides. Among them, for example, formyl, chloroacetyl, phenylacetyl, phenoxyacetyl, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, etc.
2,2,2-trichloroethoxycarbonyl, trityl, allyloxycarbonyl and the like are preferable. Also, R
^{When a} hydroxyl group is present in the substituent represented by ¹ , R ² or Q, this hydroxyl group is preferably protected, and examples of the protecting group for this hydroxyl group include those used in the field of β-lactams and peptides. Among these, chloroacetyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, methylthiomethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2 -Tetrahydropyranyl, 4-methoxy-4-tetrahydropyranyl p-nitrobenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, allyloxycarbonyl and the like are used, and R
^{When a} carboxyl group is present in the substituent represented by ¹ , R ² or Q, the carboxyl group is preferably protected, and examples of the protecting group for the carboxyl group include those used in the field of β-lactam and peptides. Among these, for example, benzyl, benzhydryl, trityl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl, phenethyl, 2-trimethylsilylethyl, bis (p-methoxyphenyl) methyl can be suitably used. , Tertiary butyl, allyl, etc. are used.

In the above formula (VI),

[Chemical formula 24] (Each symbol has the same meaning as described above.) Also in the case where a compound in which = Y represents = S or = Se, the above production methods 3-1 and 3-
Compound (I) can be produced in the same manner as in 2.
The starting compound (VI) used in the production method 3 can be produced by a method known per se (eg, JP-A-5-8606).
2, or Comprehensive Organic Synthesis, Volumes 1-9, Pergamon Press, Oxford (1991), etc.). The group represented by Q may be a different Q by performing appropriate functional group conversion at the stage leading to the production of compound (I) or (VI) or at the stage of compound (I) or (VI). It may be converted into a group represented. Known reactions can be used for such conversion reaction (eg, RC La
rock, Comprehensive Organic Transformatio
n), VCH, New York (1989), etc.). As the salt and ester of the raw material compound, the same salts and esters as those of the compound represented by the formula (I) are used. The ester of the target compound and the starting compound can be obtained by preparing the compound represented by the formula (II), (IV) or (VI), or by the formula (I), (II), (IV) or (VI). At the stage of the compound represented by), it may be converted into different R ² if necessary. For this conversion, a reaction usually employed for the same purpose in the field of β-lactam type antibacterial agents can be used.

The target compound (I) thus obtained
Can be isolated and purified by known means, for example, solvent extraction, liquid conversion, phase transfer, salting out, crystallization, recrystallization, chromatography and the like. When the reaction product contains a protecting group, the compound (I) can be obtained by removing the protecting group by a conventional method, if necessary. Conventionally, in the field of β-lactam and peptide synthesis, amino, hydroxyl or carboxyl protecting groups have been thoroughly studied, and methods for protection and deprotection have been established. It can be used in a method for producing an intermediate. For example, as a method for removing the protecting group, an acid method, a base method, a zero-valent palladium method, an aluminum chloride method, a hydrazine method, a reduction method, N 2
-A known method such as a method using sodium methyldithiocarbamate can be appropriately selected and used. Compound (I) exhibits excellent antibacterial activity against Gram-positive and Gram-negative bacteria including clinical isolates, has extremely low toxicity, is well absorbed orally, and is physicochemically and biochemically stable (particularly Since it is a stable and valuable antibiotic against DHP-I, it is used as a medicine for humans and livestock, and can be safely used as an antibacterial agent for treating and preventing infectious diseases caused by various bacteria.

Further, the compound (I) of the present invention can be added to animal feed as a bactericide for preserving the feed. It can also be used as a germicide to remove harmful bacteria on medical and dental equipment. The compound (I) of the present invention is used alone or in combination with other active ingredients (other antibacterial agents, anti-inflammatory agents, antipyretics, analgesics, etc.), if necessary, in addition to a pharmaceutically acceptable carrier, for example, a stabilizing agent. Auxiliaries such as agents and dispersants can be appropriately added and used in the form of injections, capsules, tablets, solutions (such as suspensions and emulsions) and the like according to a conventional method. They can be administered parenterally (eg injected intravenously or intramuscularly) or orally. Formulations for injection may be presented in the form of an ampoule or container containing a preservative. The formulation may be a suspension, solution or emulsion in an oily or aqueous solvent, known suspension agents,
An auxiliary agent such as a stabilizer and / or a dispersant may be appropriately contained. Further, the compound (I) can be used as a powder or powder immediately after use by dissolving it in a suitable solvent, for example, sterilized water containing no pyrogen.

Compound (I) is a binder (eg syrup,
Gum arabic, gelatin, sorbitol, tragacanth gum, polyvinylpyrrolidone, methylcellulose, etc.),
Fillers (eg lactose, sugars, corn starch, calcium phosphate, sorbitol, glycine, etc.),
Tablets for oral administration after appropriately mixed with a hardening agent (eg magnesium stearate, talc, polyethylene glycol, silica, etc.), a disintegrating agent (eg starch by starch etc.) or a wetting agent (eg sodium lauryl sulphate etc.) , Capsules, powders and powders. Tablets, powders and the like can be film-coated by a method known per se. Oral preparations may be used as liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups and elixirs. In addition, components such as known antioxidants, preservatives, binders, wetting agents, lubricants, thickeners, flavoring agents and the like may be mixed with these preparations. Further, other active ingredients (for example, other β-lactam antibiotics) can be mixed with the preparation to give a preparation having a broader spectrum of antibacterial activity.

The compounding ratio of the compound (I) to the whole pharmaceutical composition containing the compound (I) varies depending on its form, but may be a ratio which is generally used as an antibacterial agent, for example, capsules, tablets, granules and the like. It is about 30 to 95% by weight in the solid preparation. Compound (I) is used as a therapeutic agent for bacterial infection, for example, in humans and other mammals (eg, mouse, rat, rabbit, dog, cat, cow, pig, etc.), for example, respiratory infection, urinary tract infection, suppuration. It can be used for the treatment and prevention of sexually transmitted diseases, biliary tract infections, intestinal infections, obstetrics and gynecology infections, otolaryngology infections, surgical infections and the like. The daily dose of compound (I) will vary depending on the patient's condition, body weight, method of administration, etc., but in parenteral administration, the active ingredient (ie, compound (I)) is about 0.5 to 80 mg per 1 kg of adult body weight. , Preferably about 2 to 40 m
g, which is suitably administered by intravenous or intramuscular injection in 1 to 4 divided doses daily. The oral dose is about 1 to 500 mg, preferably about 10 as an active ingredient per 1 kg of adult body weight divided into 1 to 3 times per day.
To 100 mg is suitable.

[0028]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below with reference to Examples and Examples. However, these are merely examples and do not limit the present invention in any way. The following reference example,
Elution in the column chromatography of the examples was TL.
It was carried out under observation by C (thin layer chromatography). In TLC observation, 60F254 manufactured by Merck was used as a TLC plate, the solvent used as an elution solvent in column chromatography was used as a developing solvent, and a UV detector was used as a detection method. The silica gel for the column is Kieselgel 60 (70-
230 or 230-400 mesh) was used. CH
P-20P resin is manufactured by Mitsubishi Kasei. If necessary, the solvent was purified and dried before use. The IR spectrum is IR-810 manufactured by JASCO Corporation or FT-200 manufactured by Horiba.
It measured using. The NMR spectra were measured using Varian (Vari) with tetramethylsilane or sodium 3- (trimethylsilyl) propionate as internal or external reference.
It was measured with a GEMINI 200 (200 MHz) spectrometer manufactured by an), and all δ values are shown in ppm. In the mixed solvent, the value shown in parentheses is the volume mixing ratio of each solvent. The percentage in the mixed solvent indicates the volume percentage. The symbols in the reference examples and examples have the following meanings. s: singlet d: doublet t: triplet q: quartet quint: quintet-like dd: double doublet ddd: double doublet ddt: double double triplet m: multiplet dt: double triplet dq: double quartet tt: triple triplet qd: quadruple doublet br: wide J: coupling constant Also, in the structural formulas of Examples, Aloc represents an allyloxycarbonyl group, allyl represents an allyl group, and TBS represents tert.
Each represents a -butyldimethylsilyl group.

Reference Example 1 1-Bromo-3- (tert-butyldimethylsilyloxy) propane 3-bromopropanol (25 g) and tert-butyldimethylchlorosilane (27.1 g) were dissolved in dry dichloromethane (180 ml), Dimethylformamide (36 ml) and triethylamine (50 ml) were added under ice-cooling, and the mixture was allowed to stand at room temperature (25 ° C, the same below) for 1 hour.
It was stirred for 8 hours. Dichloromethane was distilled off under reduced pressure, ether (200 ml) was added to the obtained residue, and water (100 ml × 3),
The extract was washed successively with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was distilled under reduced pressure to give the title compound (36.1 g) as a colorless oil. bp 103-105 ℃ (20 mmHg) IR (neat):.. 2950, 2930, 2850 cm -1 1 H-NMR (CDCl 3) δ: 0.07 (6 H, s), 0.90 (9 H, s),
2.03 (2 H, tt, J = 5.8,6.4 Hz), 3.52 (2 H, t, J =
6.4 Hz), 3.74 (2 H, t, J = 5.8 Hz). Reference Example 2 1- (tert-Butyldimethylsilyloxy) -3-iodopropane Sodium iodide (42.9 g) in acetone (200 ml) solution 1-
Bromo-3- (tert-butyldimethylsilyloxy) propane
(36.1 g) was added and the mixture was heated under reflux for 3 hours. Ether (150 ml) was added to the residue obtained by evaporating the solvent under reduced pressure, and water (150 m
l), 10% sodium bisulfite (150 ml), 5% sodium bicarbonate water (15
It was washed successively with 0 ml) and saturated saline (150 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was distilled under reduced pressure to give the title compound (41.1 g) as a colorless oil. bp 114-118 ℃ (19 mmHg) IR (neat):.. 2950, 2930, 2850 cm -1 1 H-NMR (CDCl 3) δ: 0.07 (6 H, s), 0.90 (9 H, s),
1.99 (2 H, tt, J = 5.6,6.6 Hz), 3.28 (2 H, t, J =
6.6 Hz), 3.67 (2 H, t, J = 5.6 Hz).

Reference Example 3 4- [3- (tert-Butyldimethylsilyloxy) propyl] tetrahydropyran-3-one Tetrahydropyran-3-one (13.8 g) cyclohexane
Cyclohexylamine (15.8 ml) was added to the (45 ml) solution at 0 ° C., and the mixture was stirred at 0 ° C. for 5 min and at room temperature for 20 min. The solvent was distilled off under reduced pressure, and cyclohexane (30 ml) was added to the obtained residue.
Was added, and water was removed by azeotropic distillation under reduced pressure. This operation was repeated twice more. A tetrahydrofuran solution (45 ml) of the obtained residue was added to a 1.59 M butyllithium hexane solution (9
1.2 ml) in a tetrahydrofuran solution (150 ml) was added dropwise under ice cooling over 70 minutes. After stirring at the same temperature for 30 minutes, 1- (tert-
Butyldimethylsilyloxy) -3-iodopropane (41.5
A tetrahydrofuran solution (100 ml) of g) was added dropwise over 10 minutes, and the mixture was further stirred at the same temperature for 1 hour. 10% Citric acid (400 ml) was added to the reaction solution, and the mixture was vigorously stirred for 10 minutes. The reaction solution was extracted with hexane (1 l), and the extract was washed with water (400 ml × 3) and saturated brine (400 ml) successively, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel 400 g,
The solvent was purified with a developing solvent: ethyl acetate-hexane 1: 9) to obtain the title compound (26.2 g) as a pale yellow oily substance. IR (neat):. 2950, 2930, 2850, 1720 cm -1 1 H-NMR (CDCl 3) δ: 0.05 (6 H, s), 0.89 (9 H, s),
1.3-2.3 (6 H, m), 2.4-2.6 (1 H, m), 3.63 (2 H, t,
J = 6.4 Hz), 3.7-4.1 (2 H, m), 3.99 (2 H, ABq, J =
Reference example 4 4- [3- (tert-butyldimethylsilyloxy) propyl] -5-
Trimethylsilyloxy-3,4-dihydro-2H-pyran Diisopropylamine (7.0 ml) in tetrahydrofuran (100 ml) at -78 ° C, 1.6 M butyllithium hexane solution (28 ml) was added, and then at 0 ° C for 30 minutes. It was stirred. The reaction mixture was cooled to −78 ° C., and a solution of 4- [3- (tert-butyldimethylsilyloxy) propyl] tetrahydropyran-3-one (11.2 g) in tetrahydrofuran (8 ml) was added dropwise over 15 minutes.
After stirring at the same temperature for 30 minutes, chlorotrimethylsilane (10 ml) was added, and the mixture was stirred at -78 ° C for 30 minutes and further cooled under ice for 20 minutes.
Hexane (400 ml) was added to the residue obtained by distilling off the solvent under reduced pressure, washed successively with water (200 ml x 3) and saturated saline (200 ml), dried over anhydrous magnesium sulfate, and then distilled under reduced pressure. Leave
The title compound (14.9 g) was obtained as a pale yellow oil. IR (neat):. 2950, 2930, 2850 cm -1 1 H-NMR (CDCl 3) δ: 0.05 (6 H, s), 0.17 (9 H, s),
0.89 (9 H, s), 1.1-2.2 (7 H, m), 3.62 (2 H, t, J =
6.2 Hz), 3.80 (2 H, ddd, J = 1.6, 3.8, 6.0 Hz), 6.
24 (1 H, d, J = 1.6 Hz).

Reference Example 5 (3S, 4S) -3-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-[(2R, 4S) -4- [3- (tert-butyldimethylsilyl) (Oxy) propyl] -3-oxotetrahydropyran-2-yl]
Azetidin-2-one and (3S, 4S) -3-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-[(2S, 4R) -4- [3-
(tert-Butyldimethylsilyloxy) propyl] -3-oxotetrahydropyran-2-yl] azetidin-2-one (2R, 3R) -4-acetoxy-3-[(R) -1- (allyloxycarbonyloxy ) Ethyl] azetidin-2-one (10.5 g) and 4- [3-
(tert-Butyldimethylsilyloxy) propyl] -5-trimethylsilyloxy-3,4-dihydro-2H-pyran (14.9 g)
Dissolved in dichloromethane (200 ml) and zinc bromide (2.8 g)
Was added and the mixture was stirred at room temperature for 24 hours. A saturated aqueous sodium hydrogen carbonate solution (200 ml) was added, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (200 ml × 2). The extracts were combined, washed with saturated brine (200 ml), and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel 40
0 g, developing solvent: ethyl acetate-hexane, 1: 2) and purified, (3S, 4S) -3-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-[(2R, 4S ) -4- [3- (tert-Butyldimethylsilyloxy) propyl] -3-oxotetrahydropyran-2-
Il] azetidin-2-one, (3S, 4S) -3-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-[(2S, 4R) -4- [3- (tert
-Butyldimethylsilyloxy) propyl] -3-oxotetrahydropyran-2-yl] azetidin-2-one and the starting material (2R, 3R) -4-acetoxy-3-[(R) -1- (allyloxy A mixture of carbonyloxy) ethyl] azetidin-2-one (12.2 g, mixing molar ratio = 1: 1: 2) was obtained as a pale yellow oil. IR (neat): 2950, 2930, 2850, 1780, 1750 cm ^-1 . Reference Example 6 2-[(2S, 3S) -3-[(R) -1- (allyloxycarbonyloxy)
Ethyl] -2-[(2R, 4S) -4- [3- (tert-butyldimethylsilyloxy) propyl] -3-oxotetrahydropyran-2-yl] -4-oxoazetidin-1-yl] glyoxylate allyl The mixture (6.0 g) obtained in Reference Example 3 was mixed with dichloromethane (10 g
It was dissolved in 0 ml), pyridine (4.1 ml) was added at −78 ° C., then a dichloromethane solution (40 ml) of allyl chloroglyoxylate (2.4 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (300 ml) was added to the reaction solution, and the pH7 phosphate buffer solution (250
(ml × 2) and saturated saline (250 ml), and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by flash column chromatography (carrier: silica gel 200 g, ethyl acetate-hexane, 1: 3),
The title compound (1.92 g) was obtained as a pale yellow oil. IR (neat): 2950, 2920, 2850, 1810, 1750, 1700 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 0.05 (6 H, s), 0.89 (9 H, s),
1.44 (3 H, d, J = 6.4 Hz), 1.5-2.4 (6 H, m), 2.7-
2.8 (1 H, m), 3.55 (1 H, dd, J = 3.8, 7.2 Hz), 3.63
(2 H, dt, J = 1.4, 6.2 Hz), 3.8-4.2 (4 H, m), 4.6
-4.8 (4 H, m), 5.16 (1 H, dq, J = 7.2, 6.4 Hz), 5.
3-5.5 (4 H, m), 5.8-6.1 (2 H, m).

Reference Example 7 (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [3- (tert-butyldimethylsilyloxy) propyl]- 4-oxo-8-oxa-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Undec-1-ene-2-carboxylic acid allyl 2-[(2S, 3S) -3-[(R) -1- (allyloxycarbonyloxy)
Ethyl] -2-[(2R, 4S) -4- [3- (tert-butyldimethylsilyloxy) propyl] -3-oxotetrahydropyran-2-yl] -4-oxoazetidin-1-yl] glyoxylate allyl
(1.91 g) was dissolved in toluene (40 ml) and hydroquinone (1
(3 mg) and triethyl phosphite (2.8 ml), and add 18
Stirred for hours. The reaction solution was cooled to room temperature and purified by flash column chromatography (carrier: silica gel 100 g, ethyl acetate-hexane, 1: 4) to obtain the title compound (1.33 g) as a pale yellow oil. IR (neat):. 2920, 2850, 1780, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ: 0.04 (6 H, s), 0.89 (9 H, s),
1.42 (3 H, d, J = 6.4 Hz), 1.5-2.1 (6 H, m), 3.60
(2 H, t, J = 6.0 Hz), 3.6-3.7 (1 H, m), 3.78 (1 H,
dd, J = 3.6, 6.8 Hz), 3.8-3.9 (2 H, m), 4.12 (1 H,
dd, J = 3.6, 8.4 Hz), 4.58 (1 H, d, J = 8.4 Hz),
4.6-4.9 (4 H, m), 5.18 (1 H, dq, J = 6.8, 6.4 Hz),
5.2-5.5 (4 H, m), 5.8-6.1 (2 H, m). Reference Example 8 (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- (3-hydroxypropyl) -4-oxo-8-
Oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene
-2-Allyl carboxylate (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [3- (tert-butyldimethylsilyloxy) propyl]- 4-oxo-8-oxa-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate (1.32
g) 0.25 M tetrabutylammonium fluoride and 0.7
A 5 M solution of acetic acid in tetrahydrofuran (19.2 ml) was added, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate (100 ml) was added, and the mixture was washed successively with pH 7 phosphate buffer (100 ml × 2) and saturated saline (100 ml), and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel 30 g, ethyl acetate-hexane,
Purification by 1: 1) gave the title compound (903 mg) as a pale yellow oil. IR (neat):. 2930, 2850, 1780, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.4-
2.2 (6 H, m), 3.6-3.7 (3 H, m), 3.79 (1 H, dd, J =
3.6, 6.6 Hz), 3.8-3.9 (2 H, m), 4.14 (1 H, dd, J =
3.6, 8.4 Hz), 4.5-4.9 (5 H, m), 5.18 (1H, dq, J =
6.6, 6.4 Hz), 5.2-5.5 (4 H, m), 5.8-6.1 (2 H, m).

Reference Example 9 4- (tert-butyldimethylsilyloxymethyl) tetrahydropyran-3-one Tetrahydropyran-3-one (13.5 g) in benzene (10
Cyclohexylamine (15.4 ml) was added to (0 ml) under ice cooling,
The mixture was stirred at 10 ° C for 15 minutes and at room temperature for 15 minutes. The solvent was evaporated under reduced pressure, benzene (30 ml) was added to the obtained residue, and water was removed by azeotropic distillation under reduced pressure. This operation was repeated twice more. Tetrahydrofuran solution of the obtained residue (50 ml)
Was added dropwise to a tetrahydrofuran solution (140 ml) of a 1.6 M butyllithium hexane solution (90 ml) under ice cooling over 60 minutes. After stirring for 20 minutes at the same temperature, blow formaldehyde until the reaction liquid changes color from red to yellow, and then
tert-Butyldimethylchlorosilane (36 g) and 4- (dimethylamino) pyridine (820 mg) were added, and the mixture was stirred at room temperature for 15 hr. 10% Citric acid (400 ml) was added to the reaction solution, which was vigorously stirred for 30 minutes and then extracted with hexane (1.3 l). The extract was washed successively with water (500 ml × 2) and saturated saline (500 ml), and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel 400 g, ethyl acetate-hexane 1:
It was subjected to 8) and then vacuum distilled to obtain the title compound (13.4 g) as a colorless oil. bp 80 ℃ (0.1 mmHg) IR (neat):.. 2950, 2930, 2850, 1715 cm -1 1 H-NMR (CDCl 3) δ: 0.06 (6 H, s), 0.88 (9 H, s),
1.8-2.1 (1 H, m), 2.2-2.4 (1 H, m), 2.5-2.7 (1 H,
m), 3.8-4.1 (6 H, m). Reference Example 10 4- (tert-butyldimethylsilyloxymethyl) -5-trimethylsilyloxy-3,4-dihydro-2H-pyran 4- (tert-butyldimethylsilyl) Oxymethyl) tetrahydropyran-3-one (13.3 g) in dichloromethane (27
Diisopropylethylamine (38 ml) and then trimethylsilyltrifluoromethanesulfonate (36 g) were added to (0 ml) at -78 ° C, and the mixture was stirred at 0 ° C for 3 hours and 20 minutes. Hexane (1 l) was added to the reaction solution, and the resulting mixed solution was washed with a phosphate buffer solution (pH 7, 200 ml) followed by saturated saline solution (100 ml), and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure is subjected to flash column chromatography.
(Carrier: silica gel 225 g, ether-hexane 1:
20) The title compound (6.74 g) was obtained as a pale yellow oily substance by purification. IR (neat): 2950, 2925, 2850, 1650, 1250 cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 0.05 (6 H, s), 0.17 (9 H, s),
0.90 (9 H, s), 1.91 (2H, q, J = 5.2 Hz), 2.2-2.4
(1 H, m), 3.47 (1 H, dd, J = 10.4, 8.6 Hz), 3.7-3.
94 (3 H, m), 6.30 (1 H, d, J = 1.4 Hz).

Reference Example 11 (3S, 4S) -3-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-[(2R, 4R) -4- (tert-butyldimethylsilyloxymethyl) -3-oxotetrahydropyran-2-yl] azetidin-2-one 4- (tert-butyldimethylsilyloxymethyl) -5-trimethylsilyloxy-3,4-dihydro-2H-pyran (6.73 g) and
(2R, 3R) -4-acetoxy-3-[(R) -1- (allyloxycarbonyloxy) ethyl] azetidin-2-one (5.48 g) and diisopropylethylamine (0.37 ml) were added to the reaction solution. Other than the above, the reaction was carried out in the same manner as in Reference Example 5, and (3S, 4S) -3-[(R) -1
-(Allyloxycarbonyloxy) ethyl] -4-[(2R, 4R)-
A diastereomeric mixture containing 4- (tert-butyldimethylsilyloxymethyl) -3-oxotetrahydropyran-2-yl] azetidin-2-one (6.33 g) was obtained as a pale yellow oil. IR (neat): 2950, 2930, 2850, 1780, 1740 cm ^-1 . Reference Example 12 2-[(2S, 3S) -3-[(R) -1- (allyloxycarbonyloxy)
Ethyl] -2-[(2R, 4R) -4- (tert-butyldimethylsilyloxymethyl) -3-oxotetrahydropyran-2-yl] -4-
(Oxoazetidin-1-yl] allyl glyoxylate (3S, 4S) -3-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-[(2R, 4R) -4 obtained in Reference Example 11 Mixture containing-(tert-butyldimethylsilyloxymethyl) -3-oxotetrahydropyran-2-yl] azetidin-2-one (3.57 g)
Was reacted in the same manner as in Reference Example 6 to give the title compound (2.64 g)
And 2-[(2S, 3S) -3-[(R) -1- (allyloxycarbonyloxy) ethyl] -2-[(2R, 4S) -4- (tert-butyldimethylsilyloxymethyl) ) -3-Oxotetrahydropyran-2
A 1: 1 mixture of (-yl] -4-oxoazetidin-1-yl] allyl glyoxylate (620 mg) was obtained as a pale yellow oil. IR (neat): 2950, 2920, 2850, 1810, 1750, 1700 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 0.05 (6 H, s), 0.88 (9 H, s),
1.44 (3 H, d, J = 6.4 Hz), 1.8-2.3 (2 H, m), 3.56
(1 H, dd, J = 3.8, 7.0 Hz), 3.8-4.1 (6 H, m), 4.6-
4.8 (4 H, m), 5.17 (1 H, dq, J = 7.0, 6.4 Hz), 5.3
-5.5 (4 H, m), 5.8-6.1 (2 H, m).

Reference Example 13 (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- (tert-butyldimethylsilyloxymethyl) -4-oxo- 8-oxa-3-azatricyclo [5.4.0.0 ³ '
⁶ ] Undec-1-ene-2-carboxylic acid allyl 2-[(2S, 3S) -3-[(R) -1- (allyloxycarbonyloxy)
Ethyl] -2-[(2R, 4R) -4- (tert-butyldimethylsilyloxymethyl) -3-oxotetrahydropyran-2-yl] -4-
Oxoazetidin-1-yl] allyl glyoxylate (513 m
g) was reacted in the same manner as in Reference Example 7 to give the title compound (279 mg)
Was obtained as a colorless oil. IR (neat):. 2950, 2930, 2850, 1790, 1740 cm -1 1 H-NMR (CDCl 3) δ: 0.05 (6 H, s), 0.88 (9 H, s),
1.42 (3 H, d, J = 6.4 Hz), 1.8-2.0 (2 H, m), 3.81
(1 H, dd, J = 3.8, 6.8 Hz), 3.8-3.9 (5 H, m), 4.15
(1 H, dd, J = 3.8, 8.6 Hz), 4.6-4.9 (5 H, m), 5.17
(1 H, dq, J = 6.8, 6.4 Hz), 5.2-5.5 (4 H, m), 5.8
-6.1 (2 H, m). Reference Example 14 (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11-hydroxymethyl-4-oxo-8 -Oxa
-3-Azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid allyl (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- (tert-Butyldimethylsilyloxymethyl) -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ '
⁶ ] Allyl undeca-1-ene-2-carboxylate (335 mg) was reacted in the same manner as in Reference Example 8 to obtain the title compound (223 mg) as a colorless oil. IR (neat): 3520, 2950, 2860, 1780, 1760, 1710 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.7-
2.1 (2 H, m), 3.82 (1H, dd, J = 3.8, 6.8 Hz), 3.9-
4.0 (4 H, m), 4.19 (1 H, dd, J = 3.8, 8.8 Hz), 4.6
-4.9 (5 H, m), 5.18 (1 H, dq, J = 6.8, 6.4 Hz), 5.
2-5.5 (4 H, m), 5.8-6.1 (2 H, m).

Reference Example 15 (1RS, 6SR, 8S) -1-Hydroxy-8-methyl-3,9-dioxabicyclo [4.3.0] nonane Tetrahydropyran-3-one (5.72 g) in benzene
(40 ml) was cooled to 0 ° C, and cyclohexylamine (6.6
ml), then at 10 ° C for 15 minutes, then at room temperature for 1 min.
Stir for 5 minutes. The reaction solution was concentrated under reduced pressure, and the procedure of adding benzene and concentrating was repeated 3 times to remove water. A tetrahydrofuran solution (10 ml) of the obtained residue was added with 1.6
M butyllithium hexane solution 37.5 ml (60.0 mmol)
Was added dropwise to a tetrahydrofuran solution (70 ml) at 0 ° C. over 1 hour. After stirring at 0 ° C for 30 minutes, a solution of (S) -propylene oxide (4.0 g) in tetrahydrofuran (40
(ml) was added dropwise over 40 hours, and the mixture was stirred at the same temperature for 30 minutes. A 10% citric acid solution (60 ml) was added to the reaction solution at 0 ° C, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was extracted with ethyl acetate, further salted out and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (carrier: silica gel, 250 g, developing solvent: ethyl acetate-hexane, 1: 1), and a mixture of diastereomers of the title compound (7.05 g, main diastereomer: sub-diastereomer). Mer = 2: 1) was obtained as a yellow oil. IR (neat): 3400, 2950, 2850, 1100, 1060 cm ^-1 Main diastereomer ¹ H-NMR (CDCl ₃ ) δ: 1.37 (3 H, d, J = 5.8 Hz), 1.4-
1.9 (3 H, m), 2.0-2.6 (3 H, m), 3.25-3.55 (1 H,
m), 3.40 (1 H, d, J = 12.0 Hz), 3.8-4.0 (1 H, m),
3.88 (1 H, d, J = 12.0 Hz), 4.35-4.6 (1 H, m). Sub diastereomer ¹ H-NMR (CDCl ₃ ) δ: 1.36 (3 H, d, J)
= 6.4 Hz), 1.4-1.9 (3 H,
m), 2.0-2.6 (3 H, m), 3.
25-3.55 (1 H, m), 3.50 (1
H, d, J = 12.0 Hz), 3.8-
4.0 (1 H, m), 3.86 (1 H, m
d, J = 12.0 Hz), 4.35-4.6.
(1 H, m). Reference Example 16 4-[(S) -2- (tert-butyldimethylsilyloxy) propyl] tetrahydropyran-3-one (1RS, 6SR, 8S) -1-hydroxy-8-methyl-3,9-dioxa To a solution of bicyclo [4.3.0] nonane (2.51 g) in dimethylformamide (25 ml) was added triethylamine (6.6 ml), tert-butyldimethylchlorosilane (4.79 g), 4- (dimethylamino) pyridine (0.2 g). The mixture was stirred at 50 ° C for 22 hours. After cooling the reaction solution to room temperature, ether was added, and water was added.
(Twice), washed successively with saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to flash column chromatography (carrier: silica gel, 100 g, developing solvent: ether-hexane, 1: 1).
Purified in 5), a mixture of title compounds (3.02 g, low polarity diastereomer: high polarity diastereomer = 1: 1)
Was obtained as a colorless oil. IR (neat): 2950, 2930, 2850, 1720, 1250 cm ^-1 Low polarity diastereomer ¹ H-NMR (CDCl ₃ ) δ: 0.00 (3 H, s), 0.04 (3 H, s), 0 .
88 (9 H, s), 1.15 (3 H, d, J = 6.0 Hz), 1.2-1.4 (1
H, m), 1.6-2.35 (3 H, m), 2.6-2.8 (1 H, m), 3.7-4.
1 (5 H, m). Highly polar diastereomer ¹ H-NMR (CDCl ₃ ) δ: 0.06 (3 H, s), 0.07 (3 H, s), 0.
88 (9 H, s), 1.16 (3 H, d, J = 6.0 Hz), 1.2-1.4 (1
H, m), 1.6-2.35 (3 H, m), 2.6-2.8 (1 H, m), 3.7-4.
1 (5 H, m).

Reference Example 17 4-[(S) -2- (tert-Butyldimethylsilyloxy) propyl] -5- (trimethylsilyloxy) -3,4-dihydro-2H-pyran Diisopropylamine (1.9 ml) in tetrahydrofuran The solution (30 ml) was cooled to −80 ° C., 7.8 ml (12.5 mmol) of 1.6 M butyllithium-hexane solution was added dropwise, and then 0
The mixture was stirred at ℃ for 30 minutes. Cool the reaction to -80 ° C and
-[(S) -2- (tert-butyldimethylsilyloxy) propyl]
A tetrahydrofuran solution (30 ml) of tetrahydropyran-3-one (3.11 g) was added dropwise over 45 minutes. -80 ° C
After stirring for 30 minutes at chlorotrimethylsilane (2.2 m
l) was added, and the mixture was stirred at the same temperature for 1 hour and at 0 ° C. for 30 minutes. Hexane is added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture is washed with pH 7 phosphate buffer, water, and saturated saline in this order, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. This gave a mixture of two diastereomers of the title compound (4.0 g, 1: 1) as a colorless oil. IR (neat):. 2950, 2920, 2850, 1250 cm -1 1 H-NMR (CDCl 3) δ: 0.06 (6 H, s), 0.18 (9 H, s), 0.
88 (9 H, s), 1.14 (1.5H, d, J = 6.0 Hz) & 1.15 (1.
5 H, d, J = 6.2 Hz), 1.2-2.45 (5 H, m), 3.75-4.05
(3 H, m), 6.22 (0.5 H, d, J = 1.4 Hz) & 6.25 (0.5
H, d, J = 1.4 Hz). Reference Example 18 (3S, 4S) -3-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-[(2R, 4R) -4-[( S) -2- (tert-Butyldimethylsilyloxy) propyl] -3-oxotetrahydropyran-2-yl] azetidin-2-one (2R, 3R) -4-acetoxy-3-[(R) -1- (Allyloxycarbonyloxy) ethyl] azetidin-2-one (2.49 g) and 4-
[(S) -2- (tert-Butyldimethylsilyloxy) propyl]-
Zinc bromide (1.54 g) was added to a dichloromethane solution (50 ml) of 5- (trimethylsilyloxy) -3,4-dihydro-2H-pyran (4.0 g), and the mixture was stirred at room temperature for 40 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (carrier: silica gel, 100 g, developing solvent: ether-hexane, 1: 1 to 2: 1),
The title compound (1.02 g) was obtained as a colorless oil. IR (neat): 3300, 2950, 2920, 2850, 1760, 1250 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 0.055 (3 H, s), 0.062 (3 H, s),
0.88 (9 H, s), 1.16 (3H, d, J = 6.2 Hz), 1.40 (3
H, d, J = 6.6 Hz), 1.3-1.5 (1 H, m), 1.6-2.45 (3
H, m), 2.7-2.9 (1 H, m), 3.43 (1 H, ddd, J = 7.0,
2.2, 1.0 Hz), 3.8-4.15 (5 H, m), 4.55-4.65 (2 H,
m), 5.0-5.2 (1 H, m), 5.2-5.45 (2 H, m), 5.8-6.05
(2 H, m).

Reference Example 19 [(2S, 3S) -3-[(R) -1- (allyloxycarbonyloxy) ethyl] -2-[(2R, 4R) -4-[(S) -2- ( tert-Butyldimethylsilyloxy) propyl] -3-oxotetrahydropyran-2-yl] -4-oxoazetidin-1-yl] glyoxylate allyl (3S, 4S) -3-[(R) -1- (allyloxy Carbonyloxy) ethyl] -4-[(2R, 4R) -4-[(S) -2- (tert-butyldimethylsilyloxy) propyl] -3-oxotetrahydropyran-2-yl] azetidin-2-one (0.38 g) was subjected to the same reaction as in Reference Example 6 to obtain the title compound (0.5 g) as a colorless oil. IR (neat): 2950, 2920, 2850, 1805, 1750, 1700, 125
^{. 0 cm -1 1 H-NMR} (CDCl 3) δ: 0.06 (3 H, s), 0.07 (3 H, s), 0.
88 (9 H, s), 1.17 (3 H, d, J = 6.2 Hz), 1.43 (3 H,
d, J = 6.4 Hz), 1.25-1.75 (2 H, m), 1.95-2.40 (2
H, m), 2.80-3.05 (1 H, m), 3.54 (1 H, dd, J = 7.0,
3.6 Hz), 3.8-4.2 (4 H, m), 4.6-4.7 (3 H, m), 4.75
-4.85 (2 H, m), 5.15 (1 H, dq, J = 7.0, 6.4 Hz),
5.25-5.5 (4 H, m), 5.8-6.1 (2 H, m). Reference Example 20 (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11 - [(S) -2- ( tert- butyldimethylsilyloxy) propyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid Allyl [(2S, 3S) -3-[(R) -1- (allyloxycarbonyloxy) ethyl] -2-[(2R, 4R) -4-[(S) -2- (tert-butyldimethylsilyl) (Oxy) propyl] -3-oxotetrahydropyran-2-yl] -4-oxoazetidin-1-yl] allyl glyoxylate (0.5 g) was subjected to the same reaction as in Reference Example 7 to give the title compound (317 mg). Obtained as a colorless oil. IR (neat): 2950, 2920, 2850, 1785, 1740, 1720, 125
^{. 0 cm -1 1 H-NMR} (CDCl 3) δ: 0.03 (6 H, s), 0.88 (9 H, s), 1.
17 (3 H, d, J = 6.0 Hz), 1.42 (3 H, d, J = 6.6 H
z), 1.6-2.1 (4 H, m), 3.6-3.9 (4 H, m), 3.78 (1 H,
dd, J = 6.6, 3.6 Hz), 4.09 (1 H, dd, J = 8.2, 3.6
Hz), 4.58 (1 H, d, J = 8.2 Hz), 4.6-4.9 (4 H, m),
5.18 (1 H, quint, J = 6.6 Hz), 5.2-5.5 (4 H, m),
5.8-6.1 (2 H, m).

Reference Example 21 (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11-[(S) -2-hydroxypropyl] -4-oxo -8-Oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1
Allyl ene-2-carboxylate (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11-[(S) -2- (tert-butyldimethyl) (Silyloxy) propyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-ene-2-carboxylate Allyl (331 mg) in a tetrahydrofuran solution (9 ml), 0 ℃
1M tetrabutylammonium fluoride and 3M acetic acid in tetrahydrofuran (3 ml) were added at room temperature and
Stirred for hours. Ethyl acetate was added to the reaction solution, which was washed successively with pH 7 phosphate buffer and saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was subjected to flash column chromatography (carrier: silica gel, 30 g, developing solvent: ethyl acetate-hexane, 1:
Purification in 1) gave the title compound (113 mg) as a colorless oil which was simultaneously (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [(S) -2- (tert-Butyldimethylsilyloxy) propyl] -4-oxo-8-oxa-3-
Azatricyclo [5.4.0.0 ^{3 '6]} was recovered undec-1-ene-2-carboxylic acid allyl (113 mg). IR (neat): 3500, 2950, 2930, 2850, 1780, 1740, 172
^{. 0, 1250 cm -1 1 H} -NMR (CDCl 3) δ: 1.22 (3 H, d, J = 6.2 Hz), 1.42
(3 H, d, J = 6.2 Hz), 1.5-2.1 (5 H, m), 3.65-3.95
(4 H, m), 3.78 (1 H, dd, J = 6.8, 3.4 Hz), 4.13 (1
H, dd, J = 8.2, 3.4 Hz), 4.6-4.9 (5 H, m), 5.18
(1 H, dq, J = 6.8, 6.2 Hz), 5.2-5.5 (4 H, m), 5.8-
6.1 (2 H, m). Reference Example 22 4- [2- (tert-butyldimethylsilyloxy) ethyl] -2-
(Methoxycarbonyl) thian-3-one Sodium hydride (2.82 g) in tetrahydrofuran (2
Hexamethylphosphoric triamide (17.9 g) in (00 ml)
A solution of 2-methoxycarbonylthian-3-one (17.4 g) in tetrahydrofuran (50 ml) was added dropwise to the suspension to which the reaction solution was kept at 5 ° C or lower. After stirring under ice-cooling for 15 minutes, add butyllithium (0.11 mol) in hexane to the reaction mixture.
(440 ml) was added dropwise, and the mixture was further stirred for 15 minutes. 1- in the reaction solution
(tert-Butyldimethylsilyloxy) -2-iodoethane (3
Tetrahydrofuran solution (100 ml) of 2.9 g) was added dropwise to 1.5.
Stirred for hours. Add 10% citric acid aqueous solution (240
ml) and ether (500 ml) were added for liquid separation, and the organic layer was washed with water three times and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel 250 g,
Purification with a developing solvent: ether-hexane 1:12) gave the title compound (25.3 g) as a colorless oil. IR (neat): 2950, 2930, 2850, 1750, 1730, 1710, 165
^{. 0, 1590 cm -1 1 H} -NMR (CDCl 3) δ: 0.03 (3 H, s), 0.06 (3 H, s),
0.88 (4.5 H, s), 0.89 (4.5 H, s), 1.3-2.3 (4 H,
m), 2.5-3.4 (4 H, m), 3.6-3.8 (2 H, m), 3.80 (1.5
H, s), 3.81 (1.5 H, s), 3.95 (0.5 H, S), 12.4 (0.5
H, s).

Reference Example 23 4- [2- (tert-butyldimethylsilyloxy) ethyl] thian-3-one 4- [2- (tert-butyldimethylsilyloxy) ethyl] -2-
To a tetrahydrofuran-water mixed solution (1: 1, 200 ml) of (methoxycarbonyl) thian-3-one (21.3 g) was added 1N aqueous sodium hydroxide solution (192 ml) at 0 ° C, and the temperature was immediately raised to room temperature. .. When the homogeneous reaction solution became heterogeneous, the mixture was stirred for 7 hours while adding tetrahydrofuran or water (added tetrahydrofuran: 650 ml, water: 310 ml). Most of the tetrahydrofuran was distilled off under reduced pressure, and the resulting aqueous layer was extracted with ether (200 ml X 2). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by flash column chromatography (carrier: silica gel 250 g, developing solvent: ethyl acetate-hexane 1:20) to give the title compound (7.2
g) was obtained as a colorless oil. IR (neat):. 2950, 2920, 2850, 1710 cm -1 1 H-NMR (CDCl 3) δ: 0.03 (6 H, s), 0.88 (9 H, s),
1.3-1.5 (1 H, m), 1.95-2.2 (2 H, m), 2.5-2.75 (3
H, m), 2.85-3.05 (1 H, m), 3.04 (1 H, dd, J = 12.4,
1.6 Hz), 3.37 (1 H, d, J = 12.4 Hz), 3.62 (2 H, t
d, J = 6.2, 1.2 Hz). Reference Example 24 4- [2- (tert-Butyldimethylsilyloxy) ethyl] -5-trimethylsilyloxy-3,4-dihydro-2H-thiindiisopropylamine (1.45 g) Tetrahydrofuran solution (30 ml) was cooled to -80 ° C, 1.6 M butyllithium hexane solution (8.0 ml) was added dropwise, and then at 0 ° C 30
Stir for minutes. The reaction mixture was cooled to -80 ° C and treated with 4- [2- (tert
A solution of -butyldimethylsilyloxy) ethyl] thian-3-one (3.15 g) in tetrahydrofuran (15 ml) was added dropwise over 1 hour. After stirring at -80 ° C for 30 minutes, chlorotrimethylsilane (1.72 g) was added and the mixture was stirred at the same temperature for 3 minutes.
The temperature was raised to 0 ° C. for 30 minutes at −40 ° C. for 30 minutes and further to −20 ° C. for 1 hour, followed by stirring at 0 ° C. for 15 minutes. Hexane was added to the residue obtained by distilling off the solvent under reduced pressure, washing with cold water and saturated brine in that order, and drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound (3.65 g)
Was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.05 (6 H, s), 0.20 (9 H, s), 0.
89 (9 H, s), 1.35-1.55 (1 H, m), 1.90-2.15 (3 H,
m), 2.20-2.35 (1 H, m), 2.55-2.85 (2 H, m), 3.67
(2 H, dd, J = 7.4, 5.8 Hz), 5.15 (1 H, s).

Reference Example 25 (3S, 4S) -3-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-[(2R, 4S) -4- [2- (tert-butyldimethylsilyl) (Oxy) ethyl] -3-oxothian-2-yl] azetidin-2-one Vacuum dried at 100 ° C for 1 hour. -[2- (tert-Butyldimethylsilyloxy) ethyl] -5-trimethylsilyloxy-3,4-dihydro-2H-thiyne (3.64 g) and (2R, 3R) -4-acetoxy-3-
[(R) -1- (Allyloxycarbonyloxy) ethyl] azetidin-2-one (2.7 g) in dichloromethane (15 ml)
Was added and the mixture was stirred at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) and water (50 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes, then the insoluble matter was filtered through Celite and extracted with dichloromethane. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (carrier: silica gel, 100 g, developing solvent: ether-hexane, 1: 2 to 2:
1), and then (3S, 4RS) -3-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-[(2RS, 4S) -4- [2- (tert-butyldimethylsilyl) The title compound (1.78 g) was obtained as a colorless oil from (oxy) ethyl] -3-oxothian-2-yl] azetidin-2-one (3.88 g, mixture of diastereomers). IR (neat):. 3300, 1760, 1700 cm -1 1 H-NMR (CDCl 3) δ: 0.03 (6 H, s), 0.88 (9 H, s),
1.37 (3 H, d, J = 6.6 Hz), 1.9-2.3 (2 H, m), 2.45-
2.9 (5 H, m), 3.20 (1 H, ddd, J = 6.4, 2.6, 0.8 H
z), 3.62 (1 H, d, J = 7.0 Hz), 3.62 (2 H, t, J =
6.4 Hz), 4.11 (1 H, dd, J = 7.0, 2.6 Hz), 4.55-4.65
(2 H, m), 5.08 (1 H, quint, J = 6.6 Hz), 5.2-5.4
(2 H, m), 5.8-6.1 (1 H, m), 6.07 (1 H, brs). Reference Example 26 (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxy Carbonyloxy) ethyl] -11- [2- (tert-butyldimethylsilyloxy) ethyl] -4-oxo-8-thia-3-azatricyclo [5.4.0.
0 ³ ' ⁶ ] Undec-1-ene-2-carboxylic acid allyl (3S, 4S) -3-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-[(2R, 4S) -4 -[2- (tert-Butyldimethylsilyloxy) ethyl] -3-oxothian-2-yl] azetidin-2-one (774 mg) was subjected to the same reaction as in Reference Example 6 and then Reference Example 7, and the title was obtained. The compound (222 mg) was obtained as a colorless oil. IR (neat):. 1780, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ: 0.02 (6 H, s),
0.87 (9 H, s), 1.43 (3
H, d, J = 6.2 Hz), 1.65-
2.15 (4 H, m), 2.45-2.65
(1 H, m), 3.00-3.25 (1 H, m
m), 3.50-4.00 (3 H, m),
3.55 (1 H, dd, J = 7.2,
2.6 Hz), 4.24 (1 H, dd, J
= 9.0, 2.6 Hz), 4.32 (1
H, d, J = 9.0 Hz), 4.6-4.
9 (4 H, m), 5.12 (1 H, d
q, J = 7.2, 6.2 Hz), 5.2-
5.5 (4 H, m), 5.8-6.1 (2
H, m).

Reference Example 27 (5S, 6S, 7S, 11S) -5-[(R) -1-
(Allyloxycarbonyloxy) ethyl] -11- (2-hydroxyethyl) -4-oxo-8-thia-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Undec-1-ene-2-carboxylic acid allyl (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2 -(tert-Butyldimethylsilyloxy) ethyl] -4-oxo-8-thia-3-azatricyclo [5.4.0.
0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate (477 mg)
Was subjected to the same reaction as in Reference Example 8 to give the title compound (368 mg)
Was obtained as a colorless oil. IR (neat):. 3520, 1775, 1740, 1715 cm -1 1 H-NMR (CDCl 3) δ: 1.43 (3 H, d, J = 6.6 Hz), 1.7-
2.3 (4 H, m), 2.4-2.7 (2 H, m), 2.95-3.15 (1 H, m),
3.40-3.75 (2 H, m), 3.58 (1 H, dd, J = 6.6, 2.4 H
z), 3.85-4.05 (1 H, m), 4.23 (1 H, d, J = 9.0 Hz),
4.30 (1 H, dd, J = 9.0, 2.4 Hz), 4.6-4.9 (4 H, m),
5.12 (1 H, quint, J = 6.6 Hz), 5.25-5.6 (4 H, m),
5.8-6.1 (2 H, m). Reference Example 28 (3S, 4S) -3-[(R) -1- (tert-butyldimethylsilyloxy)
Ethyl] -4-[(2R, 4R) -4- [2- (tert-butyldimethylsilyloxy) ethyl] -3-oxotetrahydropyran-2-yl]
Azetidin-2-one (2R, 3R) -4-acetoxy-3-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] azetidin-2-one (1.45 g) and 4-
[2- (tert-Butyldimethylsilyloxy) ethyl] -5-trimethylsilyloxy-3,4-dihydro-2H-pyran (2.00 g)
From the above, a mixture of diastereomers (1.77 g) containing the title compound was obtained as a white solid by the same method as in Reference Example 11. IR (KBr): 3170, 3100, 2950, 2930, 2860, 1760, 1720
^{. cm -1 1 H-NMR (} CDCl 3) δ: 0.04 (6 H, s), 0.07 (6 H, s),
0.87 (9 H, s), 0.88 (9H, s), 1.12 (3 H, d, J = 6.6
Hz), 1.45-1.9 (2 H, m), 1.95-2.2 (1 H, m), 2.3-2.5
(1 H, m), 2.7-2.9 (1 H, m), 3.2-3.3 (1 H, m), 3.6
-3.75 (2 H, m), 3.75-3.95 (2 H, m), 4.00-4.15 (2 H,
m), 4.15-4.35 (1 H, m), 5.77 (1 H, brs).

Reference Example 29 (5S, 6S, 7S, 11R) -5-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] -11- [2- (tert-butyldimethylsilyloxy) ethyl ] -4-Oxo-8-oxa-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Allyl undec-1-ene-2-carboxylate Diastereomeric mixture obtained in Reference Example 28 (1.01
When g) was subjected to the same reactions as in Reference Example 12 and subsequently in Reference Example 13, the title compound (443 mg) was obtained as a white solid. IR (neat):. 2950, 2925, 2850, 1770, 1720 cm -1 1 H-NMR (CDCl 3) δ: 0.01 (3 H, s), 0.02 (3 H, s),
0.07 (3 H, s), 0.08 (3 H, s), 0.87 (9 H, s), 0.89
(9 H, s), 1.20 (3 H, d, J = 6.2 Hz), 1.5-2.2 (4 H,
m), 3.5-3.9 (6 H, m), 4.11 (1 H, dd, J = 8.6, 3.6
Hz), 4.2-4.35 (1H, m), 4.60 (1 H, d, J = 8.6 Hz),
4.6-4.85 (2 H, m), 5.2-5.5 (2 H, m), 5.8-6.1 (1 H,
m). Reference Example 30 (5S, 6S, 7S, 11R) -5-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] -11- (2-hydroxyethyl) -4-oxo-8 -
Oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene
2-Allyl-2-carboxylate To a tetrahydrofuran solution (8 ml) of the compound (559 mg) obtained by the method of Reference Example 29, a mixed solution of 1 M tetrabutylammonium fluoride and 3 M acetic acid in tetrahydrofuran at 0 ° C. (2 ml) Was added, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction solution, pH 7 phosphate buffer,
The extract was washed successively with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is subjected to flash column chromatography (carrier: silica gel, 20
g, developing solvent: ethyl acetate-hexane, 1: 2) to give the title compound (378 mg) as a white solid. IR (KBr):. 3500, 1770, 1700 cm -1 1 H-NMR (CDCl 3) δ: 0.08 (3 H, s), 0.09 (3 H, s),
0.89 (9 H, s), 1.19 (3H, d, J = 6.2 Hz), 1.55-1.65
(1 H, m), 1.75-2.25 (3 H, m), 2.85 (1 H, dd, J =
9.0, 4.6 Hz), 3.40-4.00 (5 H, m), 3.61 (1 H, dd, J
= 4.4, 3.6 Hz), 4.17 (1 H, dd, J = 8.8, 3.6 Hz),
4.30 (1 H, qd, J = 6.2, 4.4 Hz), 4.53 (1 H, d, J =
8.8 Hz), 4.65-4.9 (2 H, m), 5.2-5.6 (2 H, m), 5.85
-6.1 (1 H, m). Reference Example 31 1- (2-Methoxyethyl) imidazolidine-2-thione Sodium hydride (oil, 60%, 9.5 g) in dry THF (1
A solution of 2- (2-aminoethylamino) ethanol (24.7 g) in dry THF (100 ml) was added dropwise to the (00 ml) suspension over 20 minutes under ice cooling, and the mixture was stirred at room temperature for 1 hour. Methyl iodide (14.8 ml) was slowly added dropwise to the obtained reaction mixture under ice cooling, and the mixture was stirred at the same temperature for 10 minutes, and concentrated hydrochloric acid was added to adjust the pH to 1
Adjusted to. THF was distilled off under reduced pressure, and the resulting solution was diluted with water.
(100 ml) was added and washed with ether. Sodium hydroxide (15 g) was added and dissolved in the obtained aqueous solution. 80 ml of 160 ml of the obtained aqueous solution was taken, pH was adjusted to 11 by adding concentrated hydrochloric acid, ethanol (100 ml) was added, and the deposited precipitate was filtered off. Carbon disulfide (8.0 ml) was added to the obtained solution, and the mixture was stirred at 60 ° C for 3 hr, concentrated hydrochloric acid (5 ml) was added to the reaction mixture, and the mixture was stirred at 80 ° C for 8 hr. The solution obtained by distilling off ethanol under reduced pressure was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solution obtained by evaporating the solvent under reduced pressure was purified by column chromatography (carrier: silica gel, 200 g, developing solvent: ethyl acetate-hexane, 2: 1). The obtained solid was recrystallized from ethyl acetate-hexane to give the title compound.
(2.23 g) was obtained as colorless needle crystals. IR (KBr):. 3200, 2980, 2880, 1510 cm -1 1 H-NMR (CDCl 3) δ: 3.36 (3H, s), 3.5-3.7 (4H, m),
3.7-3.9 (4H, m), 5.72 (1H, brs).

Example 1 (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-oxo
-11- [3- (1H-1,2,4-triazol-1-yl) propyl] -8-
Oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene
-2-Allyl carboxylate

[Chemical 25] (5S, 6S, 7S, 11S) -5-[(R) -1-obtained by the method of Reference Example 8
(Allyloxycarbonyloxy) ethyl] -11- (3-hydroxypropyl) -4-oxo-8-oxa-3-azatricyclo
[5.4.0.0 ³ ' ⁶ ] Undec-1-ene-2-carboxylate allyl (150
mg) in dichloromethane (5 ml), diisopropylethylamine (78 μl) and trifluoromethanesulfonic anhydride (69 μl) were sequentially added at -78 ° C, and the mixture was stirred at -78 ° C for 30 minutes.
The mixture was stirred under ice cooling for 1 minute. The obtained solution was cooled to −78 ° C., a solution of diisopropylethylamine (78 μl) and 1H-1,2,4-triazole (71 mg) in dry tetrahydrofuran (1 ml) was added, and the mixture was stirred under ice cooling for 1 hour. . Ethyl acetate (40 ml) was added to the reaction mixture, which was washed successively with pH 7 phosphate buffer (40 ml) and saturated saline (40 ml), and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by flash column chromatography (carrier: silica gel, 10 g, developing solvent: ethyl acetate) to give the title compound (59 mg)
Was obtained as a colorless oil. IR (neat):. 2930, 2850, 1780, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.5-
2.2 (6 H, m), 3.7-3.9 (3 H, m), 3.78 (1 H, dd, J =
3.6, 6.6 Hz), 4.14 (1 H, dd, J = 3.6, 8.4 Hz), 4.2
2 (2 H, t, J = 6.0 Hz), 4.50 (1 H, d, J = 8.4 Hz),
4.6-4.9 (4 H, m), 5.17 (1 H, dq, J = 6.6, 6.4 Hz),
5.2-5.5 (4 H, m), 5.8-6.1 (2 H, m), 7.95 (1 H, s),
8.07 (1 H, s). Example 2 (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-oxo
-11- [3- (1H-1,2,4-triazol-1-yl) propyl] -8-
Oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene
-2-Sodium carboxylate

[Chemical formula 26] The compound (55 mg) obtained by the method of Example 1 was dissolved in dichloromethane (1 ml), and 2-ethylhexanoic acid (16.3 mg) and 2
-Sodium ethylhexanoate (18.8 mg) in dichloromethane-tetrahydrofuran solution (1: 1, 0.87 ml) was added, and then tetrakis (triphenylphosphine) palladium (0) (8.7 mg) was added, followed by stirring at room temperature for 2 hours. did. Ether (20 ml) was added to the reaction mixture, and the mixture was extracted with water (10 ml × 3). The extracts were collected, concentrated under reduced pressure to approximately 5 ml, and the resulting solution was subjected to column chromatography (carrier: CHP-20P, 40
ml, developing solvent: washed with water and soaked in 5% ethanol).
The eluate was concentrated under reduced pressure and lyophilized to give the title compound (25 m
g) was obtained as a white powder. IR (KBr):. 3430, 2960, 2930, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.2 Hz), 1.5-2.
1 (6 H, m), 3.4-3.5 (1H, m), 3.54 (1 H, dd, J = 3.
6, 4.4 Hz), 3.89 (2 H, d, J = 8.4 Hz), 4.13 (1 H, d
d, J = 3.6, 8.4 Hz), 4.2-4.3 (3 H, m), 4.37 (1 H,
d, J = 8.4 Hz), 8.07 (1 H, s), 8.44 (1 H, s).

Example 3 (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-oxo
-11- [3- (1H-1,2,4-triazol-1-yl) propyl] -8-
Oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene
-2-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl

[Chemical 27] The compound (18 mg) obtained by the method of Example 2 was dissolved in dimethylformamide (1 ml) at −15 ° C., 1-iodoethyl cyclohexyloxycarboxylate (30 μl) was added, and −15 to −
The mixture was stirred at 10 ° C for 30 minutes. Ether (30 ml) was added to the reaction solution, and the mixture was washed successively with water (30 ml × 3) and saturated saline solution (30 ml),
It was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (10
Purification with g, ethyl acetate → ethyl acetate-methanol 10: 1) gave the title compound (9 mg) as a colorless oil. IR (neat):. 2930, 2850, 1780, 1750 cm -1 1 H-NMR (CDCl 3) δ: 1.2-2.2 (16 H, m), 1.29 (1.5 H,
d, J = 6.4 Hz), 1.31 (1.5 H, d, J = 6.4 Hz), 1.60
(1.5 H, d, J = 5.4 Hz), 1.62 (1.5 H, d, J = 5.4 H
z), 3.63 (0.5 H, dd, J = 3.6, 5.8 Hz), 3.64 (0.5
H, dd, J = 3.6, 5.8 Hz), 3.7-3.9 (3 H, m), 4.14 (1
H, dd, J = 3.6, 8.6 Hz), 4.2-4.3 (3 H, m), 4.53 (1
H, d, J = 8.6 Hz), 4.6-4.7 (1 H, m), 6.91 (1 H,
q, J = 5.4Hz), 7.95 (1 H, s), 8.09 (0.5 H, s), 8.1
2 (0.5 H, s). Example 4 (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [3- [1- (dimethylamino Ethyl) -1H-tetrazol-5-ylthio] propyl] -4-oxo-8-oxa-
3-Azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-ene-2-carboxylic acid allyl

[Chemical 28] The compound (150 mg) obtained by the method of Reference Example 8 was dissolved in tetrahydrofuran (4 ml), and triphenylphosphine (135 mg) and N, N-dimethyl-2- (5-mercapto-1H) were dissolved at -10 ° C. -Tetrazol-1-yl) ethylamine (72 mg) and diethyl azodicarboxylate (65 µl) were sequentially added, and the mixture was stirred at room temperature for 1 hr. Ethyl acetate (30 ml) was added to the reaction mixture, which was washed successively with pH 7 phosphate buffer (30 ml × 3) and saturated saline (30 ml), and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel, 18 g, developing solvent: ethyl acetate).
Purification was carried out to give a mixture of the title compound and triphenylphosphine oxide (68:32) (189 mg) as a colorless oil. IR (neat): 2940, 2850, 2760, 1780, 1740, 1715 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.6-
2.1 (6 H, m), 2.27 (6H, s), 2.76 (2 H, t, J = 6.6
Hz), 3.34 (2 H, t, J = 7.0 Hz), 3.6-3.8 (1H, m),
3.78 (1 H, dd, J = 3.6, 6.6 Hz), 3.8-4.0 (2 H, m),
4.14 (1 H, dd, J = 3.6, 8.4 Hz), 4.29 (2 H, t, J =
6.6 Hz), 4.58 (1 H, d, J = 8.4 Hz), 4.6-4.9 (4 H,
m), 5.17 (1 H, dq, J = 6.6, 6.4 Hz), 5.2-5.5 (4 H,
m), 5.8-6.1 (2 H, m).

Example 5 (5S, 6S, 7S, 11S) -11- [3- [1- (dimethylaminoethyl) -1H-
Tetrazol-5-ylthio] propyl] -5-[(R) -1-hydroxyethyl] -4-oxo-8-oxa-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Undec-1-ene-2-carboxylic acid

[Chemical 29] The mixture (184 mg) obtained in Example 4 was mixed with dichloromethane (4
2-ethylhexanoic acid (68 μl) and tetrakis (triphenylphosphine) palladium (0) (16 m)
g) was sequentially added, and the mixture was stirred at room temperature for 2 hours. Ether (30 ml) was added to the reaction mixture, and the mixture was extracted with water (10 ml × 3). The extracts were collected and concentrated under reduced pressure to about 4 ml, and the resulting solution was subjected to column chromatography (carrier: CHP-20P, 40 ml, developing solvent: water, followed by washing with 10% ethanol and then 20% ethanol). Purified. The eluate was concentrated under reduced pressure and then lyophilized to give the title compound (26 mg) as a white powder. IR (KBr):. 3420, 2950, 2930, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.6-2.
1 (6 H, m), 2.99 (6 H, s), 3.3-3.4 (2 H, m), 3.4-3.
5 (1 H, m), 3.55 (1 H, dd, J = 3.6, 5.0 Hz), 3.78
(2 H, t, J = 5.8 Hz), 3.9-4.0 (2 H, m), 4.15 (1 H,
dd, J = 3.6, 8.4 Hz), 4.29 (1 H, dq, J = 5.0, 6.4
Hz), 4.7-4.8 (3 H, m). Example 6 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [ 3- (benzimidazol-1-yl) propyl] -4-oxo-8-oxa-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate

Embedded image When benzimidazole was used in place of 1H-1,2,4-triazole in Example 1 and the same reaction was performed, the title compound was obtained as a colorless oil. IR (neat):. 3080, 2920, 1780, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ: 1.40 (3 H, d, J = 6.2 Hz), 1.5-
2.1 (6 H, m), 3.7-3.9 (4 H, m), 4.03 (1 H, dd, J =
3.6, 8.4 Hz), 4.1-4.3 (2 H, m), 4.36 (1 H, d, J =
8.4 Hz), 4.6-4.9 (4 H, m), 5.16 (1 H, dq, J = 6.6,
6.2 Hz), 5.2-5.5 (4 H, m), 5.8-6.1 (2 H, m), 7.2-
7.4 (2 H, m), 7.8-7.9 (2 H, m), 7.92 (1 H, s). (2) (5S, 6S, 7S, 11S) -11- [3- (benzimidazole-1-
Il) propyl] -5-[(R) -1-hydroxyethyl] -4-oxo
-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-
Sodium ene-2-carboxylate

[Chemical 31] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3420, 2920, 2850, 1755, 1595 cm -1 1 H-NMR (D 2 O) δ: 1.22 (3 H, d, J = 6.4 Hz), 1.6-2.
2 (6 H, m), 3.4-3.5 (1H, m), 3.44 (1 H, dd, J = 3.
6, 5.0 Hz), 3.7-3.8 (3 H, m), 4.18 (1 H, d, J = 8.2
Hz), 4.24 (1 H, dq, J = 5.0, 6.4 Hz), 4.3-4.4 (2
H, m), 7.3-7.5 (2 H, m), 7.6-7.8 (2 H, m), 8.22 (1
H, brs).

Example 7 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [3- (1-methylimidazole-2-
Ilthio) propyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid allyl

Embedded image In the reaction of Example 4, N, N-dimethyl-2- (5-mercapto
When 2-mercapto-1-methylimidazole was used instead of -1H-tetrazol-1-yl) ethylamine in the same manner, the title compound was obtained as a colorless oil. IR (neat):. 2920, 2850, 1780, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.5-
2.1 (6 H, m), 3.0-3.1 (2 H, m), 3.61 (3 H, s), 3.6-
3.7 (1 H, m), 3.77 (1 H, dd, J = 3.6, 7.0 Hz), 3.8
-3.9 (2 H, m), 4.12 (1 H, dd, J = 3.6, 8.4 Hz), 4.
59 (1 H, d, J = 8.4 Hz), 4.6-4.9 (4 H, m), 5.17 (d
q, J = 7.0, 6.4 Hz), 5.2-5.5 (4 H, m), 5.8-6.1 (2
H, m), 6.92 (1 H, d, J = 1.2 Hz), 7.04 (1 H, d, J
= 1.2 Hz). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -11- [3- (1-methylimidazol-2-ylthio) propyl] -4 -Oxo-8-oxa-3-azatricyclo [5.4.0.0
³ ' ⁶ ] undec-1-ene-2-carboxylic acid sodium salt

[Chemical 33] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3430, 2950, 2920, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.3-2.
2 (6 H, m), 2.8-3.1 (2H, m), 3.3-3.5 (1 H, m), 3.5
2 (1 H, dd, J = 3.6, 5.0 Hz), 3.72 (3 H, s), 3.8-
4.0 (2 H, m), 4.09 (1 H, dd, J = 3.6, 8.4 Hz), 4.2
8 (1 H, dq, J = 5.0, 6.4 Hz), 4.71 (1 H, d, J = 8.4
Hz), 7.09 (1 H, brs), 7.24 (1 H, brs). Example 8 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy)) Ethyl] -11- [2- [1- (dimethylaminoethyl)
-1H- tetrazol-5-ylthio] ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene -2
-Allyl carboxylate

Embedded image Instead of the compound obtained by the method of Reference Example 8 in the reaction of Example 4, Example 19- of JP-A-5-86062 was used.
By using the compound obtained by the method of (2) in the same manner, the title compound was obtained as a colorless oil. IR (neat): 2950, 2850, 2760, 1785, 1740, 1710 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 1.43 (3 H, d, J = 6.4 Hz), 1.5-
2.5 (4 H, m), 2.27 (6H, s), 2.76 (2 H, t, J = 6.6
Hz), 3.1-3.3 (2 H, m), 3.81 (1 H, dd, J = 3.6, 6.6
Hz), 3.8-4.0 (2 H, m), 4.21 (1 H, dd, J = 3.6, 8.
6 Hz), 4.29 (2H, t, J = 6.6 Hz), 4.6-4.9 (4 H, m),
4.72 (1 H, d, J = 8.6 Hz), 5.18 (1H, dq, J = 6.6,
6.4 Hz), 5.2-5.5 (4 H, m), 5.8-6.1 (2 H, m). (2) (5S, 6S, 7S, 11R) -11- [2- [1- (dimethylaminoethyl) -1H-Tetrazol-5-ylthio] ethyl] -5-[(R) -1-hydroxyethyl] -4-oxo-8-oxa-3-azatricyclo
[5.4.0.0 ³ ' ⁶ ] Undec-1-ene-2-carboxylic acid

Embedded image When the compound obtained in (1) was reacted in the same manner as in Example 5, the title compound was obtained as a white solid. IR (KBr):. 3400, 2960, 2920, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.6-2.
5 (4 H, m), 2.99 (6 H, s), 3.2-3.6 (2 H, m), 3.58
(1 H, dd, J = 3.6, 5.0 Hz), 3.6-3.7 (1 H, m), 3.78
(2 H, t, J = 6.0 Hz), 3.9-4.0 (2 H, m), 4.18 (1
H, dd, J = 3.6, 8.0 Hz), 4.30 (1 H, dq, J = 5.0,
6.4 Hz), 4.7-4.9 (3 H, m).

Example 9 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (imidazol-1-yl) ethyl ] -4-Oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ]
Undeca-1-ene-2-carboxylic acid allyl

Embedded image In the reaction of Example 1, instead of the compound obtained by the method of Reference Example 8, Example 19- of JP-A-5-86062 was used.
Using the compound obtained by the method of (2) and performing the reaction using imidazole instead of 1H-1,2,4-triazole, the title compound was obtained as a colorless oil. IR (neat):. 2940, 1780, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.6 Hz), 1.5-
1.7 (1 H, m), 1.9-2.2 (2 H, m), 2.2-2.5 (1 H, m),
3.6-4.2 (7 H, m), 4.56 (1 H, d, J = 8.6 Hz), 4.6-4.
9 (4 H, m), 5.17 (1 H, quint, J = 6.6 Hz), 5.2-5.6
(4 H, m), 5.8-6.1 (2 H, m), 6.91 (1 H, brs), 7.07
(1 H, brs), 7.56 (1 H, brs). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -11- [2
-(Imidazol-1-yl) ethyl] -4-oxo-8-oxa-3-
Azatricyclo [5.4.0.0 ³ ' ⁶ ] sodium undeca-1-ene-2-carboxylate

Embedded image The compound obtained in (1) was reacted in the same manner as in Example 2 to obtain the title compound as a white solid (however, as a mixture with 0.25 equivalent of 2-ethylhexanoic acid). IR (KBr):. 3410, 1765, 1590, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.25 (3 H, d, J = 6.6 Hz), 1.5-1.
7 (1 H, m), 1.8-2.3 (2H, m), 2.3-2.6 (1 H, m), 3.4
-3.6 (2 H, m), 3.8-4.1 (3 H, m), 4.15 (2 H, t, J =
7.0 Hz), 4.2-4.4 (1 H, m), 4.6-4.9 (1 H, m), 7.22
(1 H, brs), 7.32 (1 H, brs), 8.09 (1 H, brs). Example 10 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyl Oxycarbonyloxy) ethyl] -11- [2- (2-methylimidazole-1-
Yl) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate

[Chemical 38] When 2-methylimidazole was used in place of the imidazole of Example 9 and the same reaction was performed, the title compound was obtained as a colorless oil. IR (neat):. 2930, 2850, 1780, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.6-
2.3 (4 H, m), 2.35 (3H, s), 3.7-4.0 (5 H, m), 3.81
(1 H, dd, J = 3.6, 6.8 Hz), 4.17 (1 H, dd, J = 3.
6, 8.4 Hz), 4.57 (1 H, d, J = 8.4 Hz), 4.6-4.9 (4
H, m), 5.18 (1H, dq, J = 6.8, 6.4 Hz), 5.2-5.5 (4
H, m), 5.8-6.1 (2 H, m), 6.81 (1 H, d, J = 1.6 Hz),
6.92 (1 H, d, J = 1.6 Hz). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -11
-[2- (2-Methylimidazol-1-yl) ethyl] -4-oxo-
Sodium 8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate

[Chemical Formula 39] The compound obtained in (1) was reacted in the same manner as in Example 2 to obtain the title compound as a white solid (however, as a mixture with 0.5 equivalent of 2-ethylhexanoic acid). IR (KBr):. 3420, 2960, 2930, 2860, 1760, 1600 cm -1 1 H-NMR (D 2 O) δ: 0.8-0.9 (3 H, m), 1.26 (3 H, d, J
= 6.4 Hz), 1.2-2.6 (8.5 H, m), 2.48 (3 H, s), 3.5
3 (1 H, dd, J = 3.7, 5.4 Hz), 3.5-3.7 (1 H, m), 3.9
-4.1 (5 H, m), 4.29 (1 H, dq, J = 5.4, 6.4 Hz), 7.
19 (1 H, brs), 7.31 (1 H, brs).

Example 11 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (1H-1 , 2,4-Triazol-1-yl) ethyl] -8-oxa-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate

[Chemical 40] When 1H-1,2,4-triazole was used in place of the imidazole of Example 9 and the same reaction was performed, the title compound was obtained as a colorless oil. IR (neat):. 2945, 1785, 1745, 1720, 1265 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.5-
1.8 (1 H, m), 1.9-2.3 (2 H, m), 2.4-2.7 (1 H, m),
3.6-4.0 (4 H, m), 4.0-4.3 (3 H, m), 4.5-4.9 (5 H,
m), 5.17 (1 H, quint, J = 6.4 Hz), 5.2-5.6 (4 H,
m), 5.8-6.1 (2 H, m), 7.95 (1 H, s), 8.04 (1 H, s). (2) (5S, 6S, 7S, 11S) -5-[(R) -1 -Hydroxyethyl] -4-
Oxo-11- [2- (1H-1,2,4-triazol-1-yl) ethyl]
-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-
Sodium ene-2-carboxylate

Embedded image When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3430, 1765, 1635, 1590, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.25 (3 H, d, J = 6.4 Hz), 1.6-1.
8 (1 H, m), 1.9-2.3 (2H, m), 2.4-2.7 (1 H, m), 3.4
-3.7 (2 H, m), 3.8-4.1 (3 H, m), 4.1-4.4 (3 H, m),
4.6-4.9 (1 H, m), 8.06 (1 H, s), 8.29 (1 H, s). (3) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl ]-Four-
Oxo-11- [2- (1H-1,2,4-triazol-1-yl) ethyl]
-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-
En-2-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl

Embedded image When the compound obtained in (2) was reacted in the same manner as in Example 3, the title compound was obtained as a colorless oil. IR (neat): 3390, 2935, 2860, 1780, 1755, 1275, 1255
^{. cm -1 1 H-NMR (} D 2 O) δ: 1.1-2.3 (19 H, m), 2.4-2.7 (1 H,
m), 3.62 (1 H, dd, J = 6.2, 3.6 Hz), 3.6-4.0 (3 H,
m), 4.0-4.4 (4 H, m), 4.5-4.7 (2 H, m), 6.8-7.0 (1
H, m), 7.94 (0.5 H, s), 7.95 (0.5 H, s), 8.06 (0.
5 H, s), 8.10 (0.5 H, s). (4) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (1H-1,2,4-triazol-1-yl) ethyl]
-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-
Ene-2-carboxylic acid 1- (isopropyloxycarbonyloxy) ethyl

[Chemical 43] When 1-iodoethyl isopropyloxycarboxylate was used instead of 1-iodoethyl cyclohexyloxycarboxylate used in (3) and the reaction solvent was changed to dimethylacetamide, the title compound was obtained as a colorless oil. IR (neat):. 3380, 2975, 1780, 1760, 1265 cm -1 1 H-NMR (CDCl 3) δ: 1.2-1.4 (9 H, m), 1.5-1.8 (1 H,
m), 1.62 (3 H, d, J = 5.4 Hz), 1.8-2.3 (2 H, m),
2.3-2.7 (2 H, m), 3.61 (1 H, dd, J = 6.0, 3.6Hz),
3.7-4.0 (3 H, m), 4.0-4.4 (4 H, m), 4.57 (0.5 H,
d, J = 8.2 Hz), 4.61 (0.5 H, d, J = 8.2 Hz), 4.8-
5.0 (1 H, m), 6.89 (0.5 H, q, J = 5.4 Hz), 6.91
(0.5 H, q, J = 5.4 Hz), 7.93 (0.5 H, s), 7.94 (0.5
H, s), 8.05 (0.5 H, s), 8.08 (0.5 H, s). (5) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (1H-1,2,4-triazol-1-yl) ethyl]
-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-
En-2-carboxylic acid 1- (ethoxycarbonyloxy) ethyl

[Chemical 44] When 1-iodoethyl ethoxycarboxylate was used instead of 1-iodoethyl isopropyloxycarboxylate used in (4) and a similar reaction was performed, the title compound was obtained as a colorless oil. IR (neat):. 3415, 1765, 1265 cm -1 1 H-NMR (CDCl 3) δ: 1.2-1.4 (6 H, m), 1.62 (3 H, d,
J = 5.4 Hz), 1.5-1.7 (1 H, m), 1.9-2.3 (2 H, m),
2.4-2.9 (2 H, m), 3.5-3.7 (1 H, m), 3.7-4.0 (3 H,
m), 4.0-4.4 (6 H, m), 4.59 (0.5 H, d, J = 8.4 Hz),
4.63 (0.5 H, d, J = 8.4 Hz), 6.89 (0.5 H, q, J =
5.4 Hz), 6.91 (0.5 H, q, J = 5.4 Hz), 7.93 (0.5 H,
s), 7.94 (0.5 H, s), 8.07 (0.5 H, s), 8.10 (0.5 H,
s). (6) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (1H-1,2,4-triazol-1-yl) ethyl]
-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-
Acetoxymethyl ene-2-carboxylate

Embedded image When bromomethyl acetate was used instead of 1-iodoethyl isopropyloxycarboxylate used in (4) and a similar reaction was performed, the title compound was obtained as a colorless oil. IR (neat):
. 3380, 2970, 1770, 1740 cm -1 1 H-NMR (CDCl 3) δ: 1.29 (3 H, d, J = 6.2 Hz), 1.5-
1.8 (2 H, m), 1.9-2.3 (2 H, m), 2.15 (3 H, s), 2.4-2.7 (1 H, m), 3.62 (1
H, dd, J = 5.6, 3.6 Hz), 3.6-3.8 (1 H, m), 3.8-4.
0 (2 H, m), 4.0-4.4 (4 H, m), 4.63 (1 H, d, J = 8.4
Hz), 5.89 (1 H, ABq, J = 5.6 Hz), 7.94 (1 H, s),
8.07 (1 H, s).

Example 12 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (3-methyl-1H-1) , 2,4-Triazol-1-yl) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid allyl and (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (5-methyl-1H-1,2,4-triazol-1-yl) ethyl]- Mixture of allyl 4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate (A) and (5S, 6S, 7S, 11S) -5-[( R) -1- (Allyloxycarbonyloxy) ethyl] -11- [2- (3-methyl-4H-
1,2,4-triazol-4-yl) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2
Allyl carboxylate (B)

Embedded image 3-Methyl-1H-1,2,4-in place of the imidazole of Example 9
When the same reaction was performed using triazole, the title compounds (A) and (B) were obtained as colorless oils. (A) IR (neat): . 2945, 1785, 1745, 1720 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.2 Hz), 1.5-
1.7 (1 H, m), 1.9-2.3 (2 H, m), 2.39 (3 H, s), 2.4-
2.5 (1 H, m), 3.6-4.2 (7 H, m), 4.5-4.9 (5H, m),
5.17 (1 H, quint, J = 6.2 Hz), 5.2-5.6 (4 H, m),
5.8-6.1 (2 H, m), 7.77 (0.5 H, s), 7.89 (0.5 H,
. s) (B) IR ( neat):. 2945, 1785, 1745, 1260 cm -1 1 H-NMR (CDCl 3) δ: 1.43 (3 H, d, J = 6.4 Hz), 1.5-
1.7 (1 H, m), 1.9-2.4 (3 H, m), 2.43 (3 H, s), 3.7-
4.0 (6 H, m), 4.21 (1 H, dd, J = 8.4, 3.4 Hz), 4.5
-4.9 (5 H, m), 5.18 (1 H, quint, J = 6.4 Hz), 5.2-
5.6 (4 H, m), 5.8-6.1 (2 H, m), 8.12 (1 H, s). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl ] -11
-[2- (3-Methyl-1H-1,2,4-triazol-1-yl) ethyl]
Sodium 4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate and (5S, 6S, 7S, 11
S) -5-[(R) -1-Hydroxyethyl] -11- [2- (5-methyl-1H-
1,2,4-Triazol-1-yl) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-
Mixture of sodium carboxylates

[Chemical 47] The mixture (A) obtained in (1) was reacted in the same manner as in Example 2 to obtain the title compound as a white solid. IR (KBr):. 3415, 2965, 1765, 1595 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.2 Hz), 1.6-1.
8 (1 H, m), 1.9-2.3 (2H, m), 2.35 (1.5 H, s), 2.38
(1.5 H, s), 2.4-2.7 (1 H, m), 3.4-3.7 (2 H, m),
3.8-4.0 (3 H, m), 4.0-4.4 (3 H, m), 4.70 (1 H, d, J
= 8.2 Hz), 7.92 (0.5 H, s), 8.13 (0.5 H, s). (3) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -11
-[2- (3-Methyl-4H-1,2,4-triazol-4-yl) ethyl]
Sodium 4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate

Embedded image When the compound (B) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3425, 2965, 1765, 1595 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.2 Hz), 1.6-1.
8 (1 H, m), 1.9-2.5 (3H, m), 2.42 (3 H, s), 3.5-3.
7 (2 H, m), 3.8-4.2 (5 H, m), 4.29 (1 H, quint, J
= 6.2 Hz), 4.7-4.9 (1 H, m), 8.42 (1 H, brs).

Example 13 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (4H-1 , 2,4-Triazol-4-yl) ethyl] -8-oxa-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate

[Chemical 49] Instead of the imidazole of Example 9, trimethylsilyl-
The same reaction was performed using 1,2,4-triazole to give the title compound as a colorless oil. IR (neat):. 2945, 1785, 1740, 1265 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.2 Hz), 1.5-
1.7 (1 H, m), 1.9-2.2 (2 H, m), 2.2-2.5 (1 H, m),
3.7-4.1 (6 H, m), 4.18 (1 H, dd, J = 8.4, 3.8 Hz),
4.5-4.9 (5 H, m), 5.18 (1 H, quint, J = 6.2 Hz),
5.2-5.6 (4 H, m), 5.8-6.1 (2 H, m), 8.21 (2 H, s). (2) (5S, 6S, 7S, 11S) -5-[(R) -1- Hydroxyethyl] -4-
Oxo-11- [2- (4H-1,2,4-triazol-4-yl) ethyl]
-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-
Sodium ene-2-carboxylate

Embedded image When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3425, 1760, 1595, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.6-1.
8 (1 H, m), 1.9-2.3 (2H, m), 2.3-2.6 (1 H, m), 3.5
-3.7 (2 H, m), 3.8-4.0 (2 H, m), 4.04 (1 H, dd, J =
8.2, 3.6 Hz), 4.13 (2 H, t, J = 7.0 Hz), 4.28 (1
H, quint, J = 6.4 Hz), 4.7-4.9 (1 H, m), 8.48 (2 H,
s). (3) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (4H-1,2,4-triazol-4-yl) ethyl]
-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-
En-2-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl

[Chemical 51] When the compound obtained in (2) was reacted in the same manner as in Example 3 except that the reaction solvent was changed to dimethylacetamide, the title compound was obtained as a colorless oil. IR (neat):. 3255, 2940, 1780, 1755 cm -1 1 H-NMR (CDCl 3) δ: 1.1-2.5 (20 H, m), 3.6-4.4 (8
H, m), 4.5-4.7 (2 H, m), 6.8-7.0 (1 H, m), 8.23 (2
H, s). (4) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (4H-1,2,4-triazol-4-yl) ethyl]
-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-
En-2-carboxylic acid 1-isopropyloxycarbonyloxyethyl

Embedded image When 1-iodoethyl isopropyloxycarboxylate was used and reacted in the same manner instead of 1-iodoethyl cyclohexyloxycarboxylate used in (3), the title compound was obtained as a colorless oil. IR (neat):. 3265, 2980, 1780, 1760 cm -1 1 H-NMR (CDCl 3) δ: 1.2-1.4 (9 H, m), 1.5-1.7 (4 H,
m), 2.0-2.3 (2 H, m), 2.3-2.6 (1 H, m), 3.6-3.7 (1
H, m), 3.7-4.4 (7 H, m), 4.5-4.7 (1 H, m), 4.8-5.0
(1 H, m), 6.8-7.0 (1 H, m), 8.25 (2 H, s). (5) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-oxo-11- [2- (4H-1,2,4-triazol-4-yl) ethyl] -8
-Oxa- ³ -azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid tert-butylcarbonyloxymethyl ester

Embedded image The title compound was obtained as a colorless oil by substituting iodomethyl tert-butylcarboxylate for the same reaction in place of 1-iodoethyl isopropyloxycarboxylate used in (4). IR (neat):. 3340, 2970, 1780, 1745 cm -1 1 H-NMR (CDCl 3) δ: 1.21 (9 H, s), 1.28 (3 H, d, J
= 6.0 Hz), 1.5-1.7 (1H, m), 1.9-2.2 (2 H, m), 2.3-
2.5 (1 H, m), 3.6-4.4 (8 H, m), 4.65 (1 H, d, J =
8.8 Hz), 5.89 (2 H, ABq, J = 6.0 Hz), 8.27 (2 H,
s).

Example 14 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (pyrazole-1) - yl) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl

[Chemical 54] When the same reaction was carried out using pyrazole instead of imidazole of Example 9, the title compound was obtained as a colorless oil. IR (neat):. 2950, 1785, 1745, 1260 cm -1 1 H-NMR (CDCl 3) δ: 1.41 (3 H, d, J = 6.2 Hz), 1.5-
1.8 (1 H, m), 1.9-2.3 (2 H, m), 2.5-2.8 (1 H, m),
3.6-3.9 (4 H, m), 3.9-4.3 (3 H, m), 4.55 (1H, d, J
= 8.2 Hz), 4.5-4.9 (4 H, m), 5.15 (1 H, quint, J
= 6.2 Hz), 5.2-5.6 (4 H, m), 5.8-6.1 (2 H, m), 6.1
9 (1 H, t, J = 1.8 Hz), 7.20 (1 H, t, J = 1.8 Hz),
7.50 (1 H, t, J = 1.8 Hz). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (pyrazol-1-yl) ethyl] -8-oxa-3
-Azatricyclo [5.4.0.0 ³ ' ⁶ ] sodium undeca-1-ene-2-carboxylate

[Chemical 55] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3395, 2970, 1765, 1595, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.25 (3 H, d, J = 6.4 Hz), 1.5-1.
8 (1 H, m), 1.9-2.2 (2H, m), 2.4-2.7 (1 H, m), 3.4
4 (1 H, dd, J = 5.4, 3.4 Hz), 3.4-3.7 (1 H, m), 3.8
-4.0 (3 H, m), 4.1-4.3 (3 H, m), 4.6-4.9 (1 H, m),
6.27 (1 H, t, J = 2.2 Hz), 7.48 (1 H, d, J = 2.2 H
z), 7.56 (1 H, d, J = 2.2 Hz). (3) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (pyrazol-1-yl) ethyl] -8-oxa-3
- azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl

[Chemical 56] When the compound obtained in (2) was reacted in the same manner as in Example 3, the title compound was obtained as a colorless oil. IR (neat): 3400, 2935, 1785, 1755 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.1-2.2 (19 H, m), 2.5-2.9 (1
H, m), 3.5-3.6 (1 H, m), 3.6-4.3 (7 H, m), 4.5-4.8
(2 H, m), 6.1-6.2 (1 H, m), 6.8-7.1 (1 H, m), 7.2
-7.4 (1 H, m), 7.48 (1 H, s).

Example 15 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (1H-1 , 2,3-Triazol-1-yl) ethyl] -8-oxa-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Undec-1-ene-2-carboxylic acid allyl (A)
And (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (2H-1,2,3-triazole-2 -Yl) ethyl] -8-oxa-3-azatricyclo [5.4.
0.0 ³ ' ⁶ ] Undeca-1-ene-2-carboxylic acid allyl (B)

[Chemical 57] When 1H-1,2,3-triazole was used in place of the imidazole of Example 9 and the reaction was carried out in the same manner, the title compounds (A) and (B) were obtained as colorless oils. (A) IR (neat): . 2950, 2870, 1785, 1745, 1265 cm -1 1 H-NMR (CDCl 3) δ: 1.41 (3 H, d, J = 6.2 Hz), 1.5-
1.7 (1 H, m), 1.9-2.4 (2 H, m), 2.5-2.8 (1 H, m),
3.7-4.0 (4 H, m), 4.08 (1 H, dd, J = 8.4, 3.8 Hz),
4.2-4.5 (2 H, m), 4.5-4.9 (5 H, m), 5.15 (1 H, qu
int, J = 6.2 Hz), 5.2-5.6 (4 H, m), 7.50 (1 H, d,
. J = 0.8 Hz), 7.67 (1 H, d, J = 0.8 Hz) (B) IR (neat):. 2945, 1785, 1745, 1255 cm -1 1 H-NMR (CDCl 3) δ: 1.41 ( 3 H, d, J = 6.4 Hz), 1.5-
1.7 (1 H, m), 1.9-2.4 (2 H, m), 2.5-2.8 (1 H, m),
3.7-4.0 (4 H, m), 4.03 (1 H, dd, J = 8.4, J = 3.6 H
z), 4.3-4.9 (7 H, m), 5.16 (1 H, quint, J = 6.4 H
z), 5.2-5.6 (4 H, m), 5.8-6.1 (2 H, m), 7.77 (2 H,
s). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (1H-1,2,3-triazol-1-yl) ethyl]
-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-
Sodium ene-2-carboxylate

Embedded image When the compound (A) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3425, 2965, 1760, 1595, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.25 (3 H, d, J = 6.4 Hz), 1.6-1.
8 (1 H, m), 1.9-2.3 (2H, m), 2.5-2.8 (1 H, m), 3.4
8 (1 H, dd, J = 5.2, 3.4 Hz), 3.5-3.7 (1 H, m), 3.8
-4.0 (3 H, m), 4.26 (1 H, qd, J = 6.4, 5.2 Hz), 4.
4-4.6 (2 H, m), 4.6-4.8 (1 H, m), 7.73 (1 H, d, J
= 0.8 Hz), 7.85 (1 H, d, J = 0.8 Hz). (3) (5S, 6S,
7S, 11S) -5-[(R) -1-Hydroxyethyl] -4-oxo-11- [2-
(2H-1,2,3-triazol-2-yl) ethyl] -8-oxa-3-
Azatricyclo [5.4.0.0 ³ ' ⁶ ] sodium undeca-1-ene-2-carboxylate

Embedded image When the compound (B) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3425, 1755, 1600, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.25 (3 H, d, J = 6.4 Hz), 1.5-1.
8 (1 H, m), 1.8-2.4 (2H, m), 2.5-2.9 (1 H, m), 3.4
5 (1 H, dd, J = 5.2, 3.0 Hz), 3.4-3.8 (1 H, m), 3.8
-4.0 (3 H, m), 4.1-4.4 (1 H, m), 4.4-4.7 (2 H, m),
4.6-4.9 (1 H, m), 7.78 (2 H, s). (4) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-oxo-11- [2- (1H-1,2,3-triazol-1-yl) ethyl] -8
1- (Cyclohexyloxycarbonyloxy) ethyl-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid

Embedded image When the compound obtained in (2) was reacted in the same manner as in Example 3 except that the reaction solvent was changed to dimethylacetamide, the title compound was obtained as a colorless oil. IR (neat):. 3415, 1780, 1755 cm -1 1 H-NMR (CDCl 3) δ: 1.1-2.3 (19 H, m), 2.6-2.9 (1
H, m), 3.58 (0.5 H, dd, J = 6.2, 3.6 Hz), 3.60 (0.5
H, dd, J = 5.8, 3.8 Hz), 3.6-4.0 (3 H, m), 4.02
(0.5 H, dd, J = 8.0, 3.6 Hz), 4.06 (0.5 H, dd, J =
8.4, 3.4 Hz), 4.1-4.5 (3 H, m), 4.5-4.8 (2 H, m),
4.89 (0.5 H, q, J = 5.6 Hz), 4.90 (0.5 H, q, J =
5.4 Hz), 7.54 (0.5 H, d, J = 1.0 Hz), 7.55 (0.5 H,
d, J = 0.8Hz), 7.62 (0.5 H, d, J = 0.8Hz), 7.67
(0.5 H, d, J = 1.0 Hz).

Example 16 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (1H-tetrazole)
-1-yl) ethyl] -8-oxa-3-azatricyclo [5.4.0.
0 ³ ' ⁶ ] Undec-1-ene-2-carboxylic acid allyl (A) and
(5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (2H-tetrazol-2-yl) ethyl] -8 -Oxa- ³ -azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid allyl (B)

[Chemical formula 61] When 1H-tetrazole was used in place of the imidazole of Example 9 and the same reaction was performed, the title compounds (A) and (B) were obtained as colorless oils. (A) IR (neat): . 2950, 1785, 1745, 1265 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.5-
1.7 (1 H, m), 1.9-2.4 (2 H, m), 2.5-2.8 (1 H, m),
3.6-4.0 (4 H, m), 4.14 (1 H, dd, J = 8.4, 3.8 Hz),
4.41 (2 H, t, J = 7.0 Hz), 4.5-4.9 (5 H, m), 5.17
(1 H, quint, J = 6.4 Hz), 5.2-5.6 (4 H, m), 5.8-6.
1 (2 H, m), 8.66 (1 H, s) (B) IR (neat):.. 2950, 1790, 1745, 1265 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.5-
1.7 (1 H, m), 1.9-2.2 (1 H, m), 2.2-2.5 (1 H, m),
2.5-2.8 (1 H, m), 3.7-4.0 (4 H, m), 4.12 (1H, dd,
J = 8.4, 3.8 Hz), 4.4-4.9 (7 H, m), 5.16 (1 H, qui
nt, J = 6.4 Hz), 5.2-5.5 (4 H, m), 5.8-6.1 (2 H,
m), 8.48 (1 H, s). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo -11- [2- (1H- tetrazol-1-yl) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene -2
-Sodium carboxylate

Embedded image When the compound (A) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3425, 1755, 1680, 1670, 1605, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.6 Hz), 1.6-1.
8 (1 H, m), 1.9-2.2 (1H, m), 2.2-2.4 (1 H, m), 2.5
-2.8 (1 H, m), 3.53 (1 H, dd, J = 5.2, 3.6Hz), 3.5
-3.7 (1 H, m), 3.8-4.1 (2 H, m), 4.05 (1 H, dd, J
= 8.2, 3.6 Hz), 4.28 (1 H, qd, J = 6.6, 5.2 Hz),
4.53 (2 H, t, J = 6.8 Hz), 4.7-4.9 (1H, m), 9.09
(1 H, s). (3) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo -11- [2- (2H- tetrazol-2-yl) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene -2
-Sodium carboxylate

[Chemical formula 63] When the compound (B) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3430, 1765, 1595, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.5-1.
7 (1 H, m), 1.9-2.2 (1H, m), 2.2-2.5 (1 H, m), 2.6
-2.9 (1 H, m), 3.50 (1 H, dd, J = 5.0, 3.6Hz), 3.4
-3.7 (1 H, m), 3.8-4.1 (3 H, m), 4.28 (1 H, qd, J
= 6.4, 5.0 Hz), 4.7-4.9 (3 H, m), 8.73 (1 H, s).

Example 17 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (5-methyl-1H-tetrazole)
1-yl) ethyl] -4-oxo-8-oxa-3-azatricyclo
[5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl (A) and (5S, 6S, 7S, 11S ) -5 - [(R) -1- ( allyloxycarbonyl) ethyl] -11- [2- (5-methyl--2H- tetrazol-2-yl) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic Allyl acid (B)

[Chemical 64] When the same reaction was performed using 5-methyl-1H-tetrazole instead of imidazole of Example 9, the title compound (A) was obtained.
And (B) were obtained as colorless oils, respectively. (A) IR (neat): . 2945, 1785, 1745, 1720, 1260 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.6 Hz), 1.5-
1.8 (1 H, m), 2.0-2.4 (2 H, m), 2.51 (3 H, s), 2.5-
2.8 (1 H, m), 3.7-4.0 (4 H, m), 4.0-4.4 (3H, m),
4.5-4.9 (5 H, m), 5.17 (1 H, quint, J = 6.6 Hz),
5.2-5.6 (4 H, m), 5.8-6.1 (2 H, m) (B) IR (neat):.. 2945, 1790, 1745, 1265 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.2 Hz), 1.5-
1.7 (1 H, m), 1.9-2.2 (1 H, m), 2.2-2.5 (1 H, m),
2.52 (3 H, s), 2.5-2.8 (1 H, m), 3.7-4.0 (4H, m),
4.11 (1 H, dd, J = 8.6, 3.4 Hz), 4.3-4.9 (7 H, m),
5.16 (1 H, quint, J = 6.2 Hz), 5.2-5.6 (4 H, m),
5.8-6.2 (2 H, m). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -11
- [2- (5-methyl -1H- tetrazol-1-yl) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec
-1-ene-2-carboxylic acid sodium salt

Embedded image When the compound (A) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3330, 2970, 1760, 1595, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.6-1.
8 (1 H, m), 1.9-2.4 (2H, m), 2.52 (3 H, s), 2.5-2.
8 (1 H, m), 3.51 (1 H, dd, J = 5.0, 3.4 Hz), 3.5-
3.7 (1 H, m), 3.8-4.1 (3 H, m), 4.2-4.5 (3 H, m),
4.6-4.9 (1 H, m). (3) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -11- [2- (5-methyl-2H-tetrazole- 2-
Yl) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Sodium undeca-1-ene-2-carboxylate

[Chemical formula 66] When the compound (B) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3425, 2965, 1765, 1595, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.25 (3 H, d, J = 6.2 Hz), 1.6-1.
8 (1 H, m), 1.9-2.3 (2H, m), 2.50 (3 H, s), 2.5-2.
9 (1 H, m), 3.48 (1 H, dd, J = 5.2, 3.6 Hz), 3.5-
3.7 (1 H, m), 3.8-4.1 (3 H, m), 4.27 (1 H, qd, J =
6.2, 5.2 Hz), 4.5-4.9 (3 H, m).

Example 18 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (5-amino-1H-tetrazole)
1-yl) ethyl] -4-oxo-8-oxa-3-azatricyclo
[5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl (A) and (5S, 6S, 7S, 11S ) -5 - [(R) -1- ( allyloxycarbonyl) ethyl] -11- [2- (5-amino -2H- tetrazol-2-yl) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic Allyl acid (B)

Embedded image When 5-amino-1H-tetrazole was used in place of the imidazole of Example 9 and a similar reaction was carried out, the title compound (A) was obtained.
And (B) were obtained as colorless oils, respectively. (A) IR (neat): 3410, 3340, 2940, 1780, 1745, 1725, 164
^{. 0, 1260 cm -1 1 H} -NMR (CDCl 3) δ: 1.40 (3 H, d, J = 6.2 Hz), 1.5-
1.8 (1 H, m), 1.9-2.4 (2 H, m), 2.5-2.8 (1 H, m),
3.7-4.0 (4 H, m), 4.0-4.2 (3 H, m), 4.56 (1H, d, J
= 8.4 Hz), 4.6-4.9 (4 H, m), 5.00 (2 H, brs), 5.1
5 (1 H, quint, J = 6.2 Hz), 5.2-5.6 (4 H, m), 5.8-
6.1 (2 H, m). (B) IR (neat): 3440, 3360, 2945, 1780, 1740, 1625, 154
^{. 5, 1260 cm -1 1 H} -NMR (CDCl 3) δ: 1.41 (3 H, d, J = 6.4 Hz), 1.5-
1.8 (1 H, m), 1.9-2.4 (2 H, m), 2.4-2.7 (1 H, m),
3.7-4.0 (4 H, m), 4.0-4.9 (9 H, m), 4.12 (1H, dd,
J = 8.2, 3.6 Hz), 5.16 (1 H, quint, J = 6.4 Hz),
5.2-5.6 (4 H, m), 5.8-6.1 (2 H, m). (2) (5S, 6S, 7S, 11S) -11- [2- (5-amino-1H-tetrazol-1-yl ) Ethyl] -5-[(R) -1-hydroxyethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca
-1-ene-2-carboxylic acid sodium salt

[Chemical 68] When the compound (A) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3420, 2970, 1760, 1595, 1550, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d J = 6.4 Hz), 1.6-1.8
(1 H, m), 1.9-2.3 (2H, m), 2.4-2.7 (1 H, m), 3.49
(1 H, dd, J = 5.2, 3.4 Hz), 3.5-3.8 (1 H, m), 3.8-
4.2 (5 H, m), 4.27 (1 H, qd, J = 6.2, 5.2 Hz), 4.6
-4.8 (1 H, m). (3) (5S, 6S, 7S, 11S) -11- [2- (5-Amino-2H-tetrazol-2-yl) ethyl] -5-[(R)- 1-hydroxyethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec
-1-ene-2-carboxylic acid sodium salt

[Chemical 69] When the compound (B) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr): 3420, 2970, 2870, 1760, 1595, 1550, 1400
^{. cm -1 1 H-NMR (} D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.6-1.
8 (1 H, m), 1.9-2.4 (2H, m), 2.5-2.8 (1 H, m), 3.4
9 (1 H, dd, J = 5.2, 3.4 Hz), 3.5-3.7 (1 H, m), 3.8
-4.1 (3 H, m), 4.28 (1 H, qd, J = 6.4, 5.2 Hz), 4.
52 (2 H, t, J = 6.6 Hz), 4.6-4.9 (1 H, m).

Example 19 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (2-phenyl Imidazol-1-yl) ethyl] -8-oxa-3-azatricyclo
[5.4.0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate

Embedded image When 2-phenylimidazole was used in place of the imidazole of Example 9 and the same reaction was performed, the title compound was obtained as a colorless oil. IR (neat):. 2940, 1785, 1745, 1720, 1645 cm -1 1 H-NMR (CDCl 3) δ: 1.41 (3 H, d, J = 6.4 Hz), 1.3-
1.6 (1 H, m), 1.7-2.3 (3 H, m), 3.5-4.3 (5 H, m),
3.74 (1 H, dd, J = 6.8, 3.6 Hz), 3.99 (1 H, dd, J =
8.4, 3.6 Hz), 4.16 (1 H, d, J = 8.4 Hz), 4.6-4.9
(4 H, m), 5.17 (1 H, dq, J = 6.8, 6.4 Hz), 5.2-5.6
(4 H, m), 5.8-6.1 (2 H, m), 6.99 (1H, d, J = 1.2 H
z), 7.13 (1 H, d, J = 1.2 Hz), 7.4-7.6 (5 H, m). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl ]-Four-
Oxo-11-[2- (2-phenyl-imidazol-1-yl) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec -
Sodium 1-ene-2-carboxylate

Embedded image When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3420, 2960, 2930, 1765, 1600, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.24 (3 H, d, J = 6.6 Hz), 1.4-1.
6 (1 H, m), 1.8-2.2 (3H, m), 3.3-3.6 (1 H, m), 3.4
6 (1 H, dd, J = 5.0, 3.6 Hz), 3.7-3.9 (2 H, m), 3.8
5 (1 H, dd, J = 8.2, 3.6 Hz), 4.0-4.3 (4 H, m), 7.
28 (1 H, brs), 7.41 (1 H, brs), 7.5-7.8 (5 H, m).

Example 20 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (3,5-dimethyl-1H -1,2,4-triazol-1-yl) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate allyl (A) and (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (3,5-dimethyl
-4H-1,2,4-triazol-4-yl) ethyl] -4-oxo-8-
Oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene
-2-Allyl carboxylate (B)

Embedded image When the same reaction was carried out using 3,5-dimethyl-trimethylsilyl-1,2,4-triazole instead of imidazole of Example 9, the title compounds (A) and (B) were obtained as colorless oils. . (A) IR (neat): . 2945, 1785, 1745, 1265 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.6 Hz), 1.5-
1.7 (1 H, m), 1.8-2.3 (2 H, m), 2.32 (3 H, s), 2.33
(3 H, s), 2.3-2.6 (1 H, m), 3.7-4.1 (5 H, m), 3.78
(1 H, dd, J = 7.0, 3.6 Hz), 4.10 (1 H, dd, J = 8.
0, 3.6 Hz), 4.5-4.9 (5 H, m), 5.17 (1 H, dq, J =
7.0, 6.4 Hz), 5.2-5.5 ( 4 H, m), 5.8-6.1 (2 H, m) (B) IR (neat):.. 2945, 1790, 1745, 1725, 1265 cm -1 1 H- NMR (CDCl ₃ ) δ: 1.43 (3 H, d, J = 6.6 Hz), 1.5-
1.7 (1 H, m), 1.8-2.3 (3 H, m), 2.39 (6 H, s), 3.4-
4.0 (6 H, m), 4.22 (1 H, dd, J = 8.8, 3.6 Hz), 4.5
-5.0 (5 H, m), 5.1-5.6 (5 H, m), 5.8-6.1 (2 H, m). (2) (5S, 6S, 7S, 11S) -11- [2- (3, 5-dimethyl-1H-1,2,4-
Triazol-1-yl) ethyl] -5-[(R) -1-hydroxyethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ '
⁶ ] Undeca-1-ene-2-carboxylate sodium

Embedded image When the compound (A) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3425, 1760, 1640, 1590, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.25 (3 H, d, J = 6.4 Hz), 1.6-1.
8 (1 H, m), 1.9-2.2 (2H, m), 2.29 (3 H, s), 2.31
(3 H, s), 2.3-2.7 (1 H, m), 3.47 (1 H, dd, J = 5.2,
3.2 Hz), 3.8-4.0 (3 H, m), 4.05 (2 H, t, J = 6.4
Hz), 4.27 (1 H, qd, J = 6.4, 5.2 Hz), 4.80 (1 H, d,
J = 8.0 Hz). (3) (5S, 6S, 7S, 11S) -11- [2- (3,5-dimethyl-4H-1,2,4-
Triazol-4-yl) ethyl] -5-[(R) -1-hydroxyethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ '
⁶ ] Undeca-1-ene-2-carboxylate sodium

[Chemical 74] When the compound (B) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3420, 1765, 1635, 1590, 1540, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.4 Hz), 1.6-1.
8 (1 H, m), 1.9-2.4 (3H, m), 2.40 (6 H, s), 3.58
(1 H, dd, J = 5.0, 3.6 Hz), 3.5-4.1 (5 H, m), 4.16
(1 H, dd, J = 8.4, 3.6 Hz), 4.30 (1 H, qd, J = 6.
4, 5.0 Hz), 4.7-4.9 (1 H, m).

Example 21 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (3-dimethylcarbamoyl-1)
H-1,2,4-triazol-1-yl) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene -2
-Allyl carboxylate

[Chemical 75] N, N-dimethyl-1H-1, in place of the imidazole of Example 9
The same reaction was performed using 2,4-triazol-3-ylcarboxamide to give the title compound as a colorless oil. IR (neat): 2940, 2860, 1785, 1740, 1720, 1640 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 1.39 (3 H, d, J = 6.4 Hz), 1.6-
2.3 (4 H, m), 3.14 (3H, s), 3.30 (3 H, s), 3.7-3.9
(3 H, m), 3.75 (1 H, dd, J = 3.6, 6.2 Hz), 4.05 (1
H, dd, J = 3.6, 8.4 Hz), 4.1-4.3 (2 H, m), 4.6-4.
8 (5 H, m), 5.16 (1 H, dq, J = 6.2, 6.4 Hz), 5.2-
5.5 (4 H, m), 5.8-6.1 (2 H, m), 8.01 (1 H, s). (2) (5S, 6S, 7S, 11S) -11- [2- (3-dimethylcarbamoyl
-1H-1,2,4-triazol-1-yl) ethyl] -5-[(R) -1-hydroxyethyl] -4-oxo-8-oxa-3-azatricyclo
[5.4.0.0 ³ ' ⁶ ] Undeca-1-ene-2-carboxylate sodium

[Chemical 76] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2930, 2860, 1760, 1630, 1595 cm -1 1 H-NMR (D 2 O) δ: 1.25 (3 H, d, J = 6.6 Hz), 1.6-2.
7 (4 H, m), 3.14 (3 H, s), 3.20 (3 H, s), 3.50 (1
H, dd, J = 3.6, 5.0 Hz), 3.5-3.6 (1 H, m), 3.9-4.0
(2 H, m), 4.00 (1 H, dd, J = 3.6, 8.4 Hz), 4.2-4.
4 (3 H, m), 4.75 (1 H, d, J = 8.4 Hz), 8.38 (1 H,
s).

Example 22 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (imidazo [1,2-b ] pyridazin-6-ylthio) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl

Embedded image When 6-mercaptoimidazo [1,2-b] pyridazine was used instead of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine in Example 8 to carry out the same reaction. A mixture of the title compound and triphenylphosphine oxide (43:57) was obtained as a colorless oil. IR (KBr): 3050, 2990, 2940, 1980, 1900, 1785, 1740
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.43 (3 H, d, J = 6.4 Hz), 1.6-
2.4 (4 H, m), 3.13 (2H, t, J = 7.6 Hz), 3.82 (1 H,
dd, J = 3.6, 6.8 Hz), 3.8-3.9 (3 H, m), 4.22 (1
H, dd, J = 3.6, 8.6 Hz), 4.6-4.9 (5 H, m), 5.20 (1
H, dq, J = 6.8,6.4 Hz), 5.2-5.5 (4 H, m), 5.8-6.1
(2 H, m), 6.82 (1 H, d, J = 9.4 Hz). However, the remaining 3 H overlaps with the absorption of PPh ₃ = O. (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -11
-[2- (Imidazo [1,2-b] pyridazin-6-ylthio) ethyl]-
Sodium 4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate

Embedded image When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2930, 2850, 1760, 1600 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.4 Hz), 1.6-2.
4 (4 H, m), 3.1-3.2 (2H, m), 3.57 (1 H, dd, J = 3.
8, 5.0 Hz), 3.6-3.7 (1 H, m), 3.9-4.0 (2 H, m), 4.1
6 (1 H, dd, J = 3.8, 8.4 Hz), 4.31 (1 H, dq, J =
5.0, 6.4 Hz), 4.82 (1 H, d, J = 8.4 Hz), 7.10 (1
H, d, J = 9.4 Hz), 7.6-8.1 (3 H, m).

Example 23 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (1,3 , 4-Thiadiazol-2-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid allyl

Embedded image 2-mercapto-1, in place of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine of Example 8
The same reaction was performed using 3,4-thiadiazole to give the title compound as a colorless oil. IR (neat): 3080, 2930, 2850, 1780, 1740, 1710 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 1.42 (3 H, d, J = 6.2 Hz), 1.6-
2.5 (4 H, m), 3.2-3.4 (2 H, m), 3.8-4.0 (3 H, m),
3.81 (1 H, dd, J = 3.8, 6.6 Hz), 4.22 (1 H, dd, J =
3.8, 8.4 Hz), 4.6-4.9 (5 H, m), 5.18 (1 H, dq, J
= 6.6, 6.2 Hz), 5.2-5.5 (4 H, m), 5.8-6.1 (2 H, m),
9.01 (1 H, s). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (1,3,4-thiadiazol-2-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-
Sodium 1-ene-2-carboxylate

Embedded image When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2930, 2850, 1760, 1600 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.4 Hz), 1.6-2.
4 (4 H, m), 3.1-3.2 (2H, m), 3.57 (1 H, dd, J = 3.
8, 5.0 Hz), 3.6-3.7 (1 H, m), 3.9-4.0 (2 H, m), 4.1
6 (1 H, dd, J = 3.8, 8.4 Hz), 4.31 (1 H, dq, J =
5.0, 6.4 Hz), 4.82 (1 H, d, J = 8.4 Hz), 7.10 (1
H, d, J = 9.4 Hz), 7.6-8.1 (3 H, m).

Example 24 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (1-methyl-1H-tetrazole)
-5-ylthio) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid allyl

[Chemical 81] Instead of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine of Example 8, 5-mercapto-1-
A similar reaction was performed using methyl-1H-tetrazole to give the title compound as a colorless oil. IR (neat):. 2940, 2850, 1785, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ: 1.43 (3 H, d, J = 6.4 Hz), 1.6-
2.5 (4 H, m), 3.1-3.4 (2 H, m), 3.81 (1 H, dd, J =
3.6, 6.6 Hz), 3.8-3.9 (3 H, m), 3.91 (3 H, s), 4.22
(1 H, dd, J = 3.6, 8.4 Hz), 4.6-4.9 (5 H, m), 5.1
8 (1 H, dq, J = 6.6, 6.4 Hz), 5.2-5.5 (4 H, m), 5.8
-6.1 (2 H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -11
-[2- (1-Methyl-1H-tetrazol-5-ylthio) ethyl] -4
Sodium 8-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate

[Chemical formula 82] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2850, 1755, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.4 Hz), 1.6-2.
4 (4 H, m), 3.1-3.4 (2H, m), 3.57 (1 H, dd, J = 3.
6, 5.0 Hz), 3.6-3.7 (1 H, m), 3.9-4.0 (2 H, m), 3.9
9 (3 H, s), 4.18 (1 H, dd, J = 3.6, 8.4 Hz), 4.30
(1 H, dq, J = 5.0, 6.4 Hz), 4.81 (1 H, d, J = 8.4 H
z). (3) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -11
-[2- (1-Methyl-1H-tetrazol-5-ylthio) ethyl] -4
-Oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl

[Chemical 83] When the compound obtained in (2) was reacted in the same manner as in Example 3, the title compound was obtained as a white solid. IR (neat):. 2930, 2850, 1780, 1750 cm -1 1 H-NMR (CDCl 3) δ: 1.2-2.6 (14 H, m), 1.31 (1.5 H,
d, J = 6.4 Hz), 1.32 (1.5 H, d, J = 6.4 Hz), 1.61
(1.5 H, d, J = 5.4 Hz), 1.63 (1.5 H, d, J = 5.4 H
z), 3.2-3.4 (2 H, m), 3.65 (0.5 H, dd, J = 3.6, 5.
8 Hz), 3.65 (0.5H, dd, J = 3.6, 5.8 Hz), 3.7-3.9
(3 H, m), 3.91 (1.5 H, s), 3.91 (1.5 H, s), 4.21
(1 H, dd, J = 3.6, 8.4 Hz), 4.2-4.4 (1 H, m), 4.5-
4.7 (1 H, m), 4.75 (0.5 H, d, J = 8.4 Hz), 4.76
(0.5 H, d, J = 8.4 Hz), 6.89 (0.5 H, q, J = 5.4 H
z), 6.89 (0.5 H, q, J = 5.4 Hz).

Example 25 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (benzothiazol-2-ylthio) Ethyl] -4-oxo-8-oxa-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate

[Chemical 84] When the reaction was performed in the same manner by using 2-mercaptobenzothiazole instead of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine in Example 8, the title compound was obtained as a colorless oil. Was obtained. IR (neat):. 2920, 2850, 1780, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.43 (3 H, d, J = 6.4 Hz), 1.6-
2.5 (4 H, m), 3.2-3.4 (2 H, m), 3.8-3.9 (3 H, m),
3.81 (1 H, dd, J = 3.6, 6.8 Hz), 4.22 (1 H, dd, J =
3.6, 8.4 Hz), 4.6-4.9 (5 H, m), 5.20 (1 H, dq, J
= 6.8, 6.4 Hz), 5.2-5.5 (4 H, m), 5.8-6.1 (2 H, m),
7.2-7.5 (2 H, m), 7.7-7.9 (2 H, m). (2) (5S, 6S, 7
S, 11R) -11- [2- (Benzothiazol-2-ylthio) ethyl]-
5 - [(R) -1- hydroxyethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylate

Embedded image When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2950, 2920, 2850, 1760, 1595 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.6-2.
4 (4 H, m), 3.1-3.3 (2H, m), 3.55 (1 H, dd, J = 3.
6, 5.0 Hz), 3.6-3.7 (1 H, m), 3.8-3.9 (2 H, m), 4.1
3 (1 H, dd, J = 3.6, 8.4 Hz), 4.30 (1 H, dq, J =
5.0, 6.4 Hz), 4.73 (1 H, d, J = 8.4 Hz), 7.3-7.6
(2 H, m), 7.8-8.0 (2 H, m).

Example 26 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (3-methyl-1,2 , 4-Thiadiazol-5-ylthio) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid allyl

[Chemical 86] Instead of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine in Example 8, 5-mercapto-3-
The same reaction was performed using methyl-1,2,4-thiadiazole to give the title compound as a colorless oil. IR (neat):. 2920, 2850, 1785, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.43 (3 H, d, J = 6.4 Hz), 1.6-
2.4 (4 H, m), 2.61 (3H, s), 3.17 (2 H, t, J = 7.7
Hz), 3.82 (1 H, dd, J = 3.6, 6.6 Hz), 3.8-4.0 (3
H, m), 4.21 (1 H, dd, J = 3.6, 8.4 Hz), 4.6-4.9 (5
H, m), 5.19 (1H, dq, J = 6.6, 6.4 Hz), 5.2-5.5 (4
H, m), 5.8-6.1 (2 H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -11
-[2- (3-Methyl-1,2,4-thiadiazol-5-ylthio) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ]
Undeca-1-ene-2-carboxylate sodium

[Chemical 87] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2920, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.4 Hz), 1.6-2.
5 (4 H, m), 2.57 (3 H, s), 3.21 (2 H, t, J = 7.3 H
z), 3.58 (1 H, dd, J = 3.6, 5.0 Hz), 3.6-3.7 (1 H,
m), 3.9-4.0 (2 H, m), 4.20 (1 H, dd, J = 3.6, 8.4
Hz), 4.31 (1 H, dq, J = 5.0, 6.4 Hz), 4.84 (1 H, d,
J = 8.4 Hz). (3) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -11- [2
-(3-Methyl-1,2,4-thiadiazol-5-ylthio) ethyl]
4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl

Embedded image When the compound obtained in (2) was reacted in the same manner as in Example 3, the title compound was obtained as a colorless amorphous substance. IR (neat):. 2930, 2850, 1780, 1755 cm -1 1 H-NMR (CDCl 3) δ: 1.2-2.5 (14 H, m), 1.30 (1.5 H,
d, J = 6.4 Hz), 1.31 (1.5 H, d, J = 6.2 Hz), 1.61
(1.5 H, d, J = 5.4 Hz), 1.63 (1.5 H, d, J = 5.4 H
z), 2.61 (3 H, s), 3.16 (1 H, t, J = 8.2 Hz), 3.17
(1 H, t, J = 8.2 Hz), 3.6-4.0 (4 H, m), 4.19 (1
H, dd, J = 3.6, 8.8 Hz), 4.2-4.4 (1 H, m), 4.5-4.7
(1 H, m), 4.69 (1 H, d, J = 8.8 Hz), 6.90 (1 H, q,
J = 5.4Hz).

Example 27 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (1,2 , 3-Thiadiazol-5-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid allyl

[Chemical 89] Instead of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine of Example 8, 5-mercapto-1,
The same reaction was performed using 2,3-thiadiazole to give the title compound as a colorless oil. IR (neat):. 2930, 2850, 1780, 1740 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.6-
2.4 (4 H, m), 2.9-3.1 (2 H, m), 3.7-4.0 (3 H, m),
3.82 (1 H, dd, J = 3.6, 6.6 Hz), 4.20 (1 H, dd, J =
3.6, 8.4 Hz), 4.58 (1 H, d, J = 8.4 Hz), 4.6-4.9
(4 H, m), 5.19 (1 H, dq, J = 6.6, 6.4 Hz), 5.2-5.5
(4 H, m), 5.8-6.1 (2 H, m), 8.44 (1H, s). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl]- Four-
Oxo-11- [2- (1,2,3-thiadiazol-5-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-
Sodium 1-ene-2-carboxylate

[Chemical 90] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2920, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.4 Hz), 1.6-2.
4 (4 H, m), 3.14 (2 H, t, J = 7.1 Hz), 3.57 (1 H, d
d, J = 3.6, 5.0 Hz), 3.6-3.7 (1 H, m), 3.9-4.0 (2
H, m), 4.18 (1 H, dd, J = 3.6, 8.4 Hz), 4.30 (1 H,
dq, J = 5.0, 6.4 Hz), 4.79 (1 H, d, J = 8.4 Hz),
8.66 (1 H, s). (3) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (1,2,3-thiadiazol-5-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-
1-ene-2-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl ester

Embedded image When the compound obtained in (2) was reacted in the same manner as in Example 3, the title compound was obtained as a colorless amorphous substance. IR (KBr):. 2940, 2850, 1780, 1750 cm -1 1 H-NMR (CDCl 3) δ: 1.2-2.4 (14 H, m), 1.30 (1.5 H,
d, J = 6.4 Hz), 1.32 (1.5 H, d, J = 6.2 Hz), 1.62
(1.5 H, d, J = 5.6 Hz), 1.63 (1.5 H, d, J = 5.6 H
z), 2.9-3.2 (2 H, m), 3.66 (0.5 H, dd, J = 3.6, 6.
0 Hz), 3.67 (0.5H, dd, J = 3.6, 6.0 Hz), 3.7-4.0
(3 H, m), 4.1-4.4 (2 H, m), 4.59 (1 H, d, J = 8.6 H
z), 4.6-4.7 (1 H, m), 6.91 (1 H, q, J = 5.6 Hz),
8.44 (0.5H, s), 8.45 (0.5H, s). (4) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (1,2,3-thiadiazol-5-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-
1-ene-2-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl

Embedded image When 1-iodoethyl isopropyloxycarboxylate was used in the same reaction instead of 1-iodoethyl cyclohexyloxycarboxylate used in (3), the title compound was obtained as a colorless amorphous substance. IR (KBr):. 2960, 2920, 2850, 1780, 1750 cm -1 1 H-NMR (CDCl 3) δ: 1.2-1.4 (9 H, m), 1.61 (1.5 H,
d, J = 5.4 Hz), 1.63 (1.5 H, d, J = 5.4 Hz), 1.6-
2.4 (4 H, m), 2.9-3.2 (2 H, m), 3.65 (0.5 H, dd, J
= 3.6, 5.8 Hz), 3.66 (0.5 H, dd, J = 3.6, 5.8 Hz),
3.7-4.0 (3 H, m), 4.19 (1 H, dd, J = 3.6, 8.8 H
z), 4.2-4.4 (1 H, m), 4.60 (1 H, d, J = 8.8 Hz), 4.
8-5.0 (1 H, m), 6.90 (1 H, q, J = 5.4 Hz), 8.44
(0.5 H, s), 8.45 (0.5 H, s). (5) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (1,2,3-thiadiazol-5-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-
1-ene-2-carboxylic acid 1- (ethoxycarbonyloxy) ethyl

Embedded image When 1-iodoethyl ethoxycarboxylate was used instead of 1-iodoethyl cyclohexyloxycarboxylate used in (3) and a similar reaction was conducted, the title compound was obtained as a colorless amorphous substance. IR (KBr):. 2950, 2920, 2850, 1780, 1755 cm -1 1 H-NMR (CDCl 3) δ: 1.2-1.4 (6 H, m), 1.62 (1.5 H,
d, J = 5.4 Hz), 1.64 (1.5 H, d, J = 5.4 Hz), 1.6-
2.4 (4 H, m), 2.9-3.2 (2 H, m), 3.6-4.0 (4 H, m),
4.1-4.4 (4 H, m), 4.60 (1 H, d, J = 8.8 Hz), 6.91
(1 H, q, J = 5.4Hz), 8.44 (0.5 H, s), 8.46 (0.5 H,
s). (6) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (1,2,3-thiadiazol-5-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-
1-ene-2-carboxylic acid pivaloyloxymethyl

Embedded image When iodomethyl pivalate was used instead of 1-iodoethyl cyclohexyloxycarboxylate used in (3) and a similar reaction was performed, the title compound was obtained as a colorless oil. IR (neat):. 2970, 2930, 2860, 1780, 1740 cm -1 1 H-NMR (CDCl 3) δ: 1.21 (9 H, s), 1.30 (3 H, d, J
= 6.4 Hz), 1.6-2.4 (4H, m), 2.8-3.2 (2 H, m), 3.66
(1 H, dd, J = 3.6, 5.8 Hz), 3.7-4.0 (3 H, m), 4.21
(1 H, dd, J = 3.6, 8.6 Hz), 4.2-4.4 (1 H, m), 4.6
1 (1 H, d, J = 8.6 Hz), 5.92 (2 H, ABq, J = 5.4 H
z), 8.47 (1 H, s). (7) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (1,2,3-thiadiazol-5-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-
Acetoxymethyl 1-ene-2-carboxylate

Embedded image When bromomethyl acetate was used in place of 1-iodoethyl cyclohexyloxycarboxylate used in (3) and a similar reaction was performed, the title compound was obtained as a colorless amorphous substance. IR (neat):. 2920, 2850, 1770, 1730 cm -1 1 H-NMR (CDCl 3) δ: 1.31 (3 H, d, J = 6.4 Hz), 1.6-
2.4 (4 H, m), 2.14 (3H, s), 2.9-3.2 (2 H, m), 3.67
(1 H, dd, J = 3.6, 5.8 Hz), 3.7-4.0 (3 H, m), 4.20
(1 H, dd, J = 3.6, 8.6 Hz), 4.2-4.4 (1 H, m), 4.6
1 (1 H, d, J = 8.6 Hz), 5.91 (2 H, ABq, J = 5.6 H
z), 8.46 (1 H, s).

Example 28 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (1H-1 Allyl 2,2,4-triazol-3-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid

[Chemical 96] Instead of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine in Example 8, 3-mercapto-1H-
A similar reaction using 1,2,4-triazole gave a mixture of the title compound and triphenylphosphine oxide.
(3: 2) was obtained as a colorless oil. IR (neat):. 2920, 2850, 1785, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.40 (3 H, d, J = 6.2 Hz), 1.6-
2.4 (4 H, m), 3.0-3.1 (2 H, m), 3.7-3.9 (3 H, m),
3.79 (1 H, dd, J = 3.6, 6.4 Hz), 4.15 (1 H, dd, J =
3.6, 8.6 Hz), 4.6-4.9 (5 H, m), 5.16 (1 H, dq, J
= 6.4, 6.2 Hz), 5.2-5.5 (4 H, m), 5.8-6.1 (2 H, m),
8.02 (1 H, s). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo -11- [2- (1H-1,2,4- triazol-3-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid sodium

Embedded image The compound (145 mg) having a purity of 60% obtained in (1) was dissolved in dichloromethane (4 ml), and dimethylaminotrimethylsilane (0.11 ml) and tetrakis (triphenylphosphine) palladium (0) ( 13 mg) was added, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into 0.07N hydrochloric acid (10 ml), and the ether (1
It was washed with 0 ml). The obtained aqueous solution was applied to a column (10 ml) using Dowex 50W (Na type) as a carrier and eluted with water. The solution obtained by concentrating to about 5 ml under reduced pressure was subjected to CHP-20P column chromatography (40 ml), washed with water and 2% ethanol, and then eluted with 5-10% ethanol. The eluate was concentrated under reduced pressure and freeze-dried to give the title compound (7.2 mg) as a white solid. IR (KBr):. 2920, 2850, 1760, 1690 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.6 Hz), 1.4-2.
3 (4 H, m), 3.04 (2 H, t, J = 7.3 Hz), 3.55 (1 H, d
d, J = 3.6, 5.2 Hz), 3.5-3.6 (1 H, m), 3.8-4.0 (2
H, m), 4.16 (1 H, dd, J = 3.6, 8.0 Hz), 4.29 (1 H,
dq, J = 5.2, 6.6 Hz), 4.74 (1 H, d, J = 8.0 Hz),
8.36 (1 H, s).

Example 29 (5S, 6S, 7S, 11R) -11- [2- (1-Carboxymethyl-1H-tetrazol-5-ylthio) ethyl] -5-[(R) -1-hydroxyethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ]
Undeca-1-ene-2-carboxylate sodium

Embedded image The compound of Example 19 (2) of Japanese Unexamined Patent Publication No. 5-86062 (100
triphenylphosphine (93 mg), (5-mercapto-1H-tetrazol-1-yl) acetic acid (50 mg), diethyl azodicarboxylate (46 mg) in tetrahydrofuran (3 ml). (μl) were added successively, and the mixture was stirred under ice cooling for 1 hour. The reaction solution was diluted with dichloromethane (3 ml) and mixed with 2-ethylhexanoic acid (34.2 mg) and sodium 2-ethylhexanoate (39.4 mg) in a dichloromethane-tetrahydrofuran mixed solution (1: 1, 1.6 ml) and tetrakis (tri). Phenylphosphine) palladium (0) (36 mg) was added, and the mixture was stirred at room temperature for 1.5 hours. Water (30 ml) was added to the reaction solution, and the mixture was washed with ether (30 ml × 2). The solution obtained by concentrating under reduced pressure to approx. 10 ml is C
HP-20P column chromatography (40 ml), water-5
Elute with% ethanol. Concentrate the eluate, freeze-dry,
The title compound (23 mg) was obtained as a white solid. IR (KBr):. 2960, 2930, 2850, 1760, 1630 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.4 Hz), 1.4-2.
4 (4 H, m), 3.22 (2 H, t, J = 7.3 Hz), 3.56 (1 H, d
d, J = 3.6, 5.2 Hz), 3.6-3.7 (1 H, m), 3.9-4.0 (2
H, m), 4.19 (1 H, dd, J = 3.6, 8.4 Hz), 4.30 (1 H,
dq, J = 5.2, 6.4 Hz), 4.81 (1 H, d, J = 8.4 Hz),
5.00 (2 H, s).

Example 30 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (1H-tetrazole)
-5-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.
0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate

Embedded image When 5-mercapto-1H-tetrazole was used in place of the imidazole of Example 9 and the same reaction was performed, the title compound was obtained as a colorless oil. IR (neat):. 2940, 2850, 1740 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.2 Hz), 1.6-
2.4 (4 H, m), 3.20 (2H, t, J = 7.4 Hz), 3.7-3.9 (3
H, m), 3.81 (1 H, dd, J = 3.6, 6.4 Hz), 4.21 (1
H, dd, J = 3.6, 8.4 Hz), 4.6-4.9 (5 H, m), 5.18 (1
H, dq, J = 6.4,6.2 Hz), 5.2-5.5 (4 H, m), 5.8-6.1
(2 H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (1H-tetrazol-5-ylthio) ethyl] -8
- oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylate

[Chemical 100] The compound (120 mg) obtained in (1) was dissolved in dry tetrahydrofuran (3 ml), and tributyltin hydride (0.26 ml) and tetrakis (triphenylphosphine) palladium (0) (18 mg) were added at -78 ° C. The mixture was stirred under ice cooling for 2 hours.
The reaction mixture was diluted with ether (30 ml) and extracted with aqueous sodium hydrogen carbonate (19 mg) solution (10 ml). Extraction solution under reduced pressure
After concentrating to 5 ml, CHP-20P column chromatography (40
ml) and eluted with water-5% ethanol. The eluate was concentrated and lyophilized to give the title compound (9 mg) as a white solid. IR (KBr):. 2960, 2930, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.6 Hz), 1.6-2.
2 (4 H, m), 2.97 (3 H, t, J = 7.3 Hz), 3.53 (1 H, d
d, J = 3.6, 5.0 Hz), 3.5-3.6 (1 H, m), 3.8-3.9 (2
H, m), 4.16 (1 H, dd, J = 3.6, 8.4 Hz), 4.29 (1 H,
dq, J = 5.0, 6.6 Hz), 4.63 (1 H, d, J = 8.4 Hz).

Example 31 (1) (5S, 6S, 7S, 11S) -11- [2- [4- (allyloxycarbonylamino) -2H-1,2,3-triazol-2-yl] ethyl] -Five
- [(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec
Allyl-1-ene-2-carboxylate

[Chemical 101] Using 4- (allyloxycarbonylamino) -1H-1,2,3-triazole instead of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine of Example 8. When the reaction was performed in the same manner, the title compound was obtained as a colorless oil. IR (neat):. 3305, 1790, 1740, 1580, 1260 cm -1 1 H-NMR (CDCl 3) δ: 1.41 (3 H, d, J = 6.2 Hz), 1.5-
1.7 (1 H, m), 1.9-2.6 (3 H, m), 3.76 (1 H, dd, J =
7.0, 3.6 Hz), 3.7-3.9 (3 H, m), 4.06 (1 H, dd, J =
8.6, 3.6 Hz), 4.1-4.4 (2 H, m), 4.57 (1 H, d, J =
8.6 Hz), 4.5-4.8 (6 H, m), 5.15 (1 H, dq, J = 7.0,
6.2 Hz), 5.2-5.5 (6 H, m), 5.8-6.1 (3 H, m), 7.10
(1 H, brs), 7.75 (1 H, brs). (2) (5S, 6S, 7S, 11S) -11- [2- (4-amino-2H-1,2,3-triazole-2- Iyl) ethyl] -5-[(R) -1-hydroxyethyl]
Sodium 4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate

Embedded image When the compound obtained in (1) was reacted in the same manner as in Example 30- (2), the title compound was obtained as a white solid. IR (KBr):. 3400, 1760, 1595, 1550, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.25 (3 H, d, J = 6.4 Hz), 1.6-1.
8 (1 H, m), 1.9-2.3 (2H, m), 2.5-2.8 (1 H, m), 3.4
6 (1 H, dd, J = 5.0, 3.6 Hz), 3.5-3.7 (1 H, m), 3.8
-4.1 (3 H, m), 4.1-4.4 (3 H, m), 4.6-4.8 (1 H, m).

Example 32 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- [1- (2-hydroxyethyl) ) -1
H- tetrazol-5-ylthio] ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2
Allyl carboxylate

Embedded image Instead of the imidazole of Example 9, 5-mercapto-1- (2-
A similar reaction was performed using (hydroxyethyl) -1H-tetrazole to give the title compound as a colorless oil. IR (neat):. 2930, 2850, 1780, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.2 Hz), 1.6-
2.6 (4 H, m), 3.26 (2H, t, J = 7.1 Hz), 3.79 (1 H,
dd, J = 3.6, 6.6 Hz), 3.8-3.9 (3 H, m), 4.0-4.2
(2 H, m), 4.21 (1 H, dd, J = 3.6, 8.6 Hz), 4.3-4.4
(2 H, m), 4.6-4.9 (5 H, m), 5.18 (1 H, dq, J = 6.
6, 6.2 Hz), 5.2-5.5 (4 H, m), 5.8-6.1 (2 H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl ] -11
-[2- [1- (2-Hydroxyethyl) -1H-tetrazol-5-ylthio] ethyl] -4-oxo-8-oxa-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Sodium undeca-1-ene-2-carboxylate

[Chemical 104] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2930, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.4 Hz), 1.6-2.
4 (4 H, m), 3.1-3.4 (2H, m), 3.57 (1 H, dd, J = 3.
4, 5.0 Hz), 3.6-3.7 (1 H, m), 3.9-4.0 (2 H, m), 4.0
1 (2 H, t, J = 5.2 Hz), 4.17 (1 H, dd, J = 3.4, 8.
4 Hz), 4.29 (1H, dq, J = 5.0, 6.4 Hz), 4.50 (2 H,
t, J = 5.2 Hz), 4.80 (1 H, d, J = 8.4 Hz).

Example 33 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (imidazol-2-ylthio)
Ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0
^{3 '6]} undec-1-ene-2-carboxylic acid allyl

Embedded image When 2-mercaptoimidazole was used in place of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine in Example 8 to carry out a similar reaction, the title compound and triphenylphosphine oxide were obtained. The mixture (1: 1) was obtained as a colorless oil. IR (neat):. 2920, 2850, 1780, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.41 (3 H, d, J = 6.2 Hz), 1.6-
2.1 (4 H, m), 2.8-3.1 (2 H, m), 3.78 (1 H, dd, J =
3.6, 6.6 Hz), 3.8-4.0 (3 H, m), 4.13 (1 H, dd, J =
3.6, 8.4 Hz), 4.56 (1 H, d, J = 8.4 Hz), 4.6-4.9
(4 H, m), 5.17 (1 H, dq, J = 6.6, 6.2 Hz), 5.2-5.5
(4 H, m), 5.8-6.1 (2 H, m), 7.05 (2H, s). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl]- 11
- [2- (imidazol-2-ylthio) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene -2
-Sodium carboxylate

[Chemical formula 106] When the compound obtained in (1) was reacted in the same manner as in Example 30- (2), the title compound was obtained as a white solid. IR (KBr):. 2960, 2920, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.5-2.
2 (4 H, m), 2.8-3.0 (2H, m), 3.56 (1 H, dd, J = 3.
6, 5.2 Hz), 3.5-3.7 (1 H, m), 3.8-4.0 (2 H, m), 4.1
3 (1 H, dd, J = 3.6, 8.4 Hz), 4.29 (1 H, dq, J =
5.2, 6.4 Hz), 4.67 (1 H, d, J = 8.4 Hz), 7.25 (2
H, brs).

Example 34 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (1H-1 Allyl 2,2,3-triazol-5-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate

[Chemical formula 107] 5-Mercapto-1,2,3 instead of the imidazole of Example 9
The same reaction was performed using -1H-triazole to give the title compound as a colorless oil. IR (neat):. 2920, 2850, 1780, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.43 (3 H, d, J = 6.4 Hz), 1.6-
2.2 (4 H, m), 2.8-3.0 (2 H, m), 3.79 (1 H, dd, J =
3.6, 7.2 Hz), 3.8-3.9 (3 H, m), 4.17 (1 H, dd, J =
3.6, 8.6 Hz), 4.58 (1 H, d, J = 8.6 Hz), 4.6-4.9
(4 H, m), 5.18 (1 H, dq, J = 7.2, 6.4 Hz), 5.2-5.5
(4 H, m), 5.8-6.1 (2 H, m), 7.62 (1H, s). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl]- Four-
Oxo -11- [2- (1H-1,2,3- triazol-5-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid sodium

[Chemical 108] When the compound obtained in (1) was reacted in the same manner as in Example 30- (2), the title compound was obtained as a white solid. IR (KBr):. 2960, 2920, 2850, 1755, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.6-2.
2 (4 H, m), 2.82 (3 H, t, J = 7.4 Hz), 3.5-3.6 (1
H, m), 3.54 (1 H, dd, J = 3.6, 5.0 Hz), 3.8-3.9 (2
H, m), 4.12 (1 H, dd, J = 3.6, 8.4 Hz), 4.29 (1
H, dq, J = 5.0, 6.4 Hz), 4.66 (1 H, d, J = 8.4 H
z), 7.97 (1 H, s).

Example 35 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (imidazol-2-yloxy) ethyl ] -4-Oxo-8-oxa-3-azatricyclo [5.4.
0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate

[Chemical 109] When the same reaction was performed using 1,3-bis (trimethylsilyl) -2-oxo-2,3-dihydro-1H-imidazole instead of the imidazole of Example 9, the title compound was obtained as a colorless oil. IR (neat):. 2950, 1790, 1745, 1725 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.5-
1.8 (1 H, m), 1.9-2.4 (3 H, m), 3.79 (1 H, dd, J =
6.6, 3.8 Hz), 3.8-4.0 (3 H, m), 4.11 (1 H, dd, J =
8.2, 3.8 Hz), 4.2-4.4 (2 H, m), 4.5-4.9 (5 H, m),
5.17 (1 H, dq, J = 6.6, 6.4 Hz), 5.2-5.5 (4 H, m),
5.8-6.1 (2 H, m), 6.60 (2 H, s). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -11
-[2- (Imidazol-2-yloxy) ethyl] -4-oxo-8-
Oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene
-2-Sodium carboxylate

[Chemical 110] When the compound obtained in (1) was reacted in the same manner as in Example 30- (2), the title compound was obtained as a white solid. IR (KBr):. 3410, 2965, 1765, 1645, 1590, 1570 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.6-1.
8 (1 H, m), 1.9-2.2 (2H, m), 2.2-2.5 (1 H, m), 3.5
7 (1 H, dd, J = 5.0, 3.6 Hz), 3.6-3.8 (1 H, m), 3.9
-4.1 (2 H, m), 4.15 (1 H, dd, J = 8.4, 3.6 Hz), 4.
2-4.5 (3 H, m), 4.7-4.9 (1 H, m), 6.78 (2 H, brs).

Example 36 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (1-methylimidazole-2-
Yloxy) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl

[Chemical 111] 1-Methyl-2-oxo-instead of the imidazole of Example 9.
The same reaction was performed using 2,3-dihydro-1H-imidazole to obtain the title compound as a colorless oil. IR (neat): 2950, 1790, 1745, 1720, 1540, 1260 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.6-
1.8 (1 H, m), 1.9-2.5 (3 H, m), 3.36 (3 H, s), 3.79
(1 H, dd, J = 7.0, 3.6 Hz), 3.8-4.0 (3 H, m), 4.10
(1 H, dd, J = 8.4, 3.6 Hz), 4.34 (2 H, t, J = 6.4
Hz), 4.5-4.9 (5 H, m), 5.17 (1 H, dq, J = 7.0, 6.4
Hz), 5.2-5.5 (4 H, m), 5.8-6.1 (2H, m), 6.48 (1
H, d, J = 1.8 Hz), 6.57 (1 H, d, J = 1.8 Hz). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -11
-[2- (1-Methylimidazol-2-yloxy) ethyl] -4-
Oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylate

[Chemical 112] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3420, 1765, 1600, 1540, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J
= 6.4 Hz), 1.6-1.8 (1 H,
m), 1.9-2.3 (2H, m), 2.3.
-2.5 (1 H, m), 3.42 (3 H, m
s), 3.56 (1 H, dd, J =
5.0, 3.6 Hz), 3.6-3.8 (1
H, m), 3.9-4.1 (2 H, m),
4.12 (1 H, dd, J = 8.2,
3.6 Hz), 4.2-4.4 (3 H,
m), 4.7-4.9 (1 H, m), 6.6
5 (1 H, d, J = 1.6 Hz),
6.77 (1 H, d, J = 1.6 Hz).

Example 37 (1) (5S, 6S, 7S, 11S) -5-[(R)-
1- (allyloxycarbonyloxy) ethyl] -11- [2-
(4-methyl-5-oxo-4,5-dihydro-1H-triazole-1-
Yl) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate

[Chemical 113] The compound (210 mg) obtained by the method of Example 19- (2) of JP-A-5-86062 was dissolved in dry dichloromethane (2 ml), and diisopropylethylamine (0.13 ml) and anhydrous trifluoromethanesulfonic acid were added at -78 ° C. (0.10 ml) were sequentially added, and the mixture was stirred at -78 ° C for 10 minutes (solution A). Meanwhile, add sodium hydride (20 mg) to dry dimethylformamide (1 ml).
4-Methyl-5-oxo-4,5-dihydro-1H-triazole (50 mg) was added, and the mixture was stirred at room temperature for 30 minutes, cooled to -15 ° C, and solution A was added. After stirring at -15 ° C for 30 minutes, ether (20 ml) was added to the reaction mixture and pH 7 phosphate buffer (15 ml
× 3), washed successively with saturated saline (20 ml), and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel, 7 g, developing solvent: ethyl acetate-hexane, 1: 2 →
Purified with 1: 1 → ethyl acetate) to give the title compound (13 mg)
Was obtained as a colorless oil. IR (neat):. 2945, 1785, 1745, 1705, 1260 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.5-
1.8 (1 H, m), 1.8-2.2 (2 H, m), 2.2-2.5 (1 H, m),
3.45 (3 H, s), 3.61 (2 H, t, J = 7.2 Hz), 3.6-4.0
(3 H, m), 3.79 (1 H, dd, J = 6.8, 3.6 Hz), 4.15 (1
H, dd, J = 8.4,3.6 Hz), 4.5-4.9 (5 H, m), 5.18 (1
H, dq, J = 6.8, 6.2 Hz), 5.2-5.6 (4 H, m), 5.8-6.1
(2 H, m), 7.39 (1 H, s). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -11
-[2- (4-Methyl-5-oxo-4,5-dihydro-1H-triazol-1-yl) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca -1-ene-2-carboxylic acid sodium salt

[Chemical 114] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr): 3430, 2955, 1760, 1690, 1600, 1560, 1400
^{. cm -1 1 H-NMR (} D 2 O) δ: 1.27 (3 H, d, J = 6.6 Hz), 1.6-1.
8 (1 H, m), 1.9-2.2 (2H, m), 2.2-2.5 (1 H, m), 3.4
4 (3 H, s), 3.53 (1 H, dd, J = 5.0, 3.6 Hz), 3.5-
3.7 (1 H, m), 3.7 (2 H, t, J = 7.0 Hz), 3.8-4.0 (2
H, m), 4.09 (1H, dd, J = 8.0, 3.6 Hz), 4.29 (1 H,
qd, J = 6.6, 5.0 Hz), 4.7-4.9 (1 H, m), 7.78 (1 H,
s).

Example 38 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (5-oxo -4,5-Dihydro-1H-triazol-1-yl) ethyl] -8-oxa-3-
Azatricyclo [5.4.0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate

[Chemical 115] When bis (trimethylsilyl) -5-oxo-4,5-dihydro-1H-triazole was used in place of the imidazole of Example 9 and the same reaction was carried out, the title compound was obtained as a colorless oil. IR (neat): 3150, 2945, 1785, 1745, 1705, 1260 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 1.42 (3 H, d, J = 6.2 Hz), 1.5-
1.7 (1 H, m), 1.9-2.2 (2 H, m), 2.3-2.5 (1 H, m),
3.63 (2 H, t, J = 7.2 Hz), 3.7-4.0 (4 H, m), 4.16
(1 H, dd, J = 8.2, 3.6 Hz), 4.6-4.9 (5 H, m), 5.17
(1 H, quint, J = 6.2 Hz), 5.2-5.6 (4 H, m), 5.8-6.
1 (2 H, m), 7.43 (1 H, d, J = 1.0 Hz), 9.20 (1 H,
brs). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (5-oxo-4,5-dihydro-1H-triazol-1-yl) ethyl] -8-oxa-3-azatricyclo [5.4.0.
0 ³ ' ⁶ ] Sodium undeca-1-ene-2-carboxylate

[Chemical formula 116] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3410, 1760, 1695, 1590, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.6 Hz), 1.6-1.
8 (1 H, m), 1.9-2.2 (2H, m), 2.3-2.6 (1 H, m), 3.5
4 (1 H, dd, J = 5.0, 3.4 Hz), 3.5-3.7 (1 H, m), 3.7
1 (2 H, t, J = 7.0 Hz), 3.8-4.0 (2 H, m), 4.10 (1
H, dd, J = 8.0, 3.4 Hz), 4.29 (1 H, qd, J = 6.6,
5.0 Hz), 4.7-4.9 (1 H, m), 7.77 (1 H, s). (3) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (5-oxo-4,5-dihydro-1H-triazol-1-yl) ethyl] -8-oxa-3-azatricyclo [5.4.0.
0 ³ ' ⁶ ] Undec-1-ene-2-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl

[Chemical 117] When the compound obtained in (2) was reacted in the same manner as in Example 3 except that the reaction solvent was changed to dimethylacetamide, the title compound was obtained as a colorless oil. IR (KBr):. 3375, 2940, 1780, 1755, 1700, 1260 cm -1 1 H-NMR (CDCl 3) δ: 1.1-2.2 (19 H, m), 2.3-2.7 (2
H, m), 3.5-4.0 (6 H, m), 4.1-4.4 (2 H, m), 4.5-4.8
(2 H, m), 6.8-7.0 (2 H, m), 7.42 (1 H, m), 9.93
(0.5 H, brs), 10.02 (0.5 H, brs).

Example 39 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (2-oxo 2,3-dihydro-1,3,4-oxadiazol-3-yl) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene -2
-Allyl carboxylate

[Chemical 118] When the same reaction was performed using 1,3,4-oxadiazol-2 (3H) -one instead of imidazole of Example 9, the title compound was obtained as a colorless oil. IR (neat):. 2945, 1785, 1745 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.5-
1.7 (1 H, m), 1.9-2.4 (3 H, m), 3.5-4.0 (6 H, m),
4.16 (1 H, dd, J = 8.4, 3.6 Hz), 4.5-4.9 (5H, m),
5.17 (1 H, quint, J = 6.4 Hz), 5.2-5.5 (4 H, m),
5.8-6.1 (2 H, m), 7.54 (1 H, s). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl) ethyl] -8-oxa-3-azatricyclo
[5.4.0.0 ³ ' ⁶ ] Undeca-1-ene-2-carboxylate sodium

[Chemical formula 119] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3430, 1765, 1640, 1585, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.2 Hz), 1.6-1.
8 (1 H, m), 1.9-2.2 (2H, m), 2.2-2.5 (1 H, m), 3.5
3 (1 H, dd, J = 5.2, 3.4 Hz), 3.5-3.7 (1 H, m), 3.7
6 (2 H, t, J = 7.0 Hz), 3.9-4.1 (2 H, m), 4.13 (1
H, dd, J = 8.0, 3.4 Hz), 4.30 (1 H, qd, J = 6.4,
5.2 Hz), 4.7-4.9 (1 H, m), 8.03 (1 H, s). (3) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl) ethyl] -8-oxa-3-azatricyclo
[5.4.0.0 ³ ' ⁶ ] Undec-1-ene-2-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl

[Chemical 120] When the compound obtained in (2) was reacted in the same manner as in Example 38- (3), the title compound was obtained as a colorless oil. IR (neat): 3480, 2940, 1785, 1765, 1450, 1260 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 1.1-2.4 (20 H, m), 3.6-4.0 (6
H, m), 4.15 (1 H, dd, J = 8.4, 3.8 Hz), 4.2-4.4 (1
H, m), 4.5-4.8 (2 H, m), 6.88 (0.5 H, q, J = 5.2 H
z), 6.89 (0.5 H, q, J = 5.4 Hz), 7.55 (0.5 H, s),
7.57 (0.5 H, s).

Example 40 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (4-methyl-5-thioxo -4,5-
Dihydro-1H-1,2,4-triazol-1-yl) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca
Allyl-1-ene-2-carboxylate

[Chemical 121] 3-mercapto-4-instead of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine of Example 8
A similar reaction was performed using methyl-4H-1,2,4-triazole to obtain a mixture (3: 2) of the title compound and triphenylphosphine oxide as a colorless oil. IR (neat):. 2930, 2850, 1780, 1760, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.41 (3 H, d, J = 6.2 Hz), 1.6-
2.6 (4 H, m), 3.57 (3H, s), 3.7-3.8 (1 H, m), 3.78
(1 H, dd, J = 3.6, 6.8 Hz), 3.8-3.9 (2 H, m), 4.16
(1 H, dd, J = 3.6, 8.2 Hz), 4.1-4.3 (2 H, m), 4.6
-4.9 (5 H, m), 5.17 (1 H, dq, J = 6.8, 6.2 Hz), 5.2
-5.5 (4 H, m), 5.8-6.1 (2 H, m). (Waste 1H is PPh ₃ =
Overlaps with O. ) (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -11
-[2- (4-Methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4. 0.0 ³ ' ⁶ ] Undeca-1-ene-2-carboxylate sodium

[Chemical formula 122] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2850, 1760, 1595 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.2 Hz), 1.6-2.
6 (4 H, m), 3.52 (1 H, dd, J = 3.4, 5.0 Hz), 3.57
(3 H, s), 3.5-3.6 (1 H, m), 3.9-4.0 (2 H, m), 4.10
(1 H, dd, J = 3.4, 8.2 Hz), 4.18 (2 H, t, J = 7.2
Hz), 4.29 (1 H, dq, J = 5.0, 6.2 Hz), 4.87 (1 H,
d, J = 8.2 Hz), 8.25 (1 H, s).

Example 41 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (2,5-dihydro-6) -Methoxy-
2-Methyl-5-oxo-1,2,4-triazin-3-ylthio) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ]
Undeca-1-ene-2-carboxylic acid allyl

[Chemical 123] When the same reaction was carried out using 2,5-dihydro-3-mercapto-6-methoxy-2-methyl-1,2,4-triazin-5-one instead of the imidazole of Example 9, the title compound was colorless. Obtained as an amorphous material. IR (KBr):. 2950, 2850, 1785, 1740 cm -1 1 H-NMR (CDCl 3) δ: 1.44 (3 H, d, J = 6.4 Hz), 1.6-
2.5 (4 H, m), 3.0-3.4 (2 H, m), 3.81 (1 H, dd, J =
3.6, 6.4 Hz), 3.82 (3 H, s), 3.8-3.9 (3 H, m), 3.97
(3 H, s), 4.30 (1 H, dd, J = 3.6, 8.2 Hz), 4.6-4.
9 (5 H, m), 5.19 (1 H, quint, J = 6.4 Hz), 5.2-5.5
(4 H, m), 5.8-6.1 (2 H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -11
-[2- (2,5-Dihydro-6-methoxy-2-methyl-5-oxo-1,
2,4-triazine-3-ylthio) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2
Sodium carboxylate

[Chemical formula 124] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2950, 2850, 1760, 1730, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J
= 6.4 Hz), 1.6-2.4 (4 H,
m), 3.0-3.3 (2H, m), 3.5
6 (1 H, dd, J = 3.6, 5.2
Hz), 3.6-3.7 (1 H, m), 3.
88 (3 H, s), 3.9-4.0 (2
H, m), 3.99 (3 H, s), 4.1
7 (1 H, dd, J = 3.6, 8.4
Hz), 4.30 (1 H, dq, J = 5.
2, 6.4 Hz), 4.78 (1 H, d,
J = 8.4 Hz).

Example 42 (1) (5S, 6S, 7S, 11R) -5-[(R)-
1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (1,2,5-thiadiazol-3-ylthio) ethyl]-
8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl

Embedded image 3-mercapto-1, in place of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine of Example 8
The same reaction was performed using 2,5-thiadiazole to give the title compound as a colorless oil. IR (neat):. 2930, 2850, 1780, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.43 (3 H, d, J = 6.4 Hz), 1.6-
2.4 (4 H, m), 3.18 (2H, t, J = 7.7 Hz), 3.81 (1 H,
dd, J = 3.6, 6.6 Hz), 3.8-3.9 (3 H, m), 4.19 (1
H, dd, J = 3.6, 8.6 Hz), 4.6-4.9 (5 H, m), 5.19 (1
H, dq, J = 6.6,6.4 Hz), 5.2-5.5 (4 H, m), 5.8-6.1
(2 H, m), 8.26 (1 H, s). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (1,2,5-thiadiazol-3-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-
Sodium 1-ene-2-carboxylate

[Chemical formula 126] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2950, 2930, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.4 Hz), 1.6-2.
4 (4 H, m), 3.1-3.3 (2H, m), 3.56 (1 H, dd, J = 3.
6, 5.0 Hz), 3.6-3.7 (1 H, m), 3.9-4.0 (2 H, m), 4.1
8 (1 H, dd, J = 3.6, 8.4 Hz), 4.30 (1 H, dq, J =
5.0, 6.4 Hz), 4.82 (1 H, d, J = 8.4 Hz), 8.49 (1
H, s).

Example 43 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (1,2 , 4-Thiadiazol-5-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid allyl

Embedded image Instead of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine of Example 8, 5-mercapto-1,
The same reaction was performed using 2,4-thiadiazole to give the title compound as a colorless oil. IR (neat):. 2930, 2850, 1785, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.43 (3 H, d, J = 6.6 Hz), 1.6-
2.5 (4 H, m), 3.22 (2H, t, J = 7.7 Hz), 3.7-4.0 (3
H, m), 3.81 (1 H, dd, J = 3.6, 6.6 Hz), 4.21 (1
H, dd, J = 3.6, 8.6 Hz), 4.6-4.9 (5 H, m), 5.19 (1
H, quint, J = 6.6 Hz), 5.2-5.5 (4 H, m), 5.8-6.1
(2 H, m), 8.45 (1 H, s). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (1,2,4-thiadiazol-5-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-
Sodium 1-ene-2-carboxylate

[Chemical 128] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2930, 2850, 1760, 1600 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.4 Hz), 1.6-2.
5 (4 H, m), 3.26 (2 H, t, J = 7.2 Hz), 3.58 (1 H, d
d, J = 3.6, 5.0 Hz), 3.6-3.7 (1 H, m), 3.9-4.0 (2
H, m), 4.20 (1 H, dd, J = 3.6, 8.4 Hz), 4.30 (1 H,
dq, J = 5.0, 6.4 Hz), 4.84 (1 H, d, J = 8.4 Hz),
8.56 (1 H, s). (3) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (1,2,4-thiadiazol-5-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-
1-ene-2-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl ester

[Chemical formula 129] When the compound obtained in (2) was reacted in the same manner as in Example 3, the title compound was obtained as a colorless oil. IR (KBr):. 2930, 2850, 1780, 1750 cm -1 1 H-NMR (CDCl 3) δ: 1.2-2.5 (14 H, m), 1.31 (1.5 H,
d, J = 6.2 Hz), 1.32 (1.5 H, d, J = 6.4 Hz), 1.61
(1.5 H, d, J = 5.6 Hz), 1.63 (1.5 H, d, J = 5.6 H
z), 3.21 (1 H, t, J = 7.8 Hz), 3.22 (1 H, t, J =
7.8 Hz), 3.66 (0.5 H, dd, J = 3.6, 5.8 Hz), 3.66
(0.5 H, dd, J = 3.6, 5.8 Hz), 3.7-4.0 (3H, m), 4.2
0 (1 H, dd, J = 3.6, 8.8 Hz), 4.2-4.4 (1 H, m), 4.
5-4.7 (1 H, m), 4.69 (1 H, d, J = 8.8 Hz), 6.91 (1
H, q, J = 5.6 Hz), 8.45 (1 H, s).

Example 44 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (thiazole-2 -Ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ '
⁶ ] Allyl undec-1-ene-2-carboxylate

Embedded image A similar reaction was carried out using 2-mercaptothiazole in place of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine in Example 8 to obtain the title compound as a colorless oil. Was given. IR (neat):. 2940, 2860, 1790, 1740 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.5-
2.4 (4 H, m), 3.14 (2H, t, J = 7.6 Hz), 3.7-3.9 (3
H, m), 3.79 (1 H, dd, J = 3.6, 6.8 Hz), 4.17 (1
H, dd, J = 3.6, 8.4 Hz), 4.6-4.9 (5 H, m), 5.18 (1
H, dq, J = 6.8,6.4 Hz), 5.2-5.5 (4 H, m), 5.8-6.1
(2 H, m), 7.21 (1 H, d, J = 3.2 Hz), 7.65 (1 H, d,
J = 3.2 Hz). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11-[2- (thiazol-2-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2
Sodium carboxylate

[Chemical 131] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2970, 2930, 2850, 1760, 1600 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.6 Hz), 1.6-2.
4 (4 H, m), 3.12 (2 H, t, J = 7.5 Hz), 3.56 (1 H, d
d, J = 3.6, 5.0 Hz), 3.6-3.7 (1 H, m), 3.9-4.0 (2
H, m), 4.16 (1 H, dd, J = 3.6, 8.2 Hz), 4.30 (1 H,
dq, J = 5.0, 6.6 Hz), 4.76 (1 H, d, J = 8.2 Hz),
7.54 (1 H, d, J = 3.5 Hz), 7.72 (1 H, d, J = 3.5 H
z). (3) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11-[2- (thiazol-2-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2
Carboxylic acid 1- (cyclohexyloxycarbonyloxy)
ethyl

[Chemical 132] When the compound obtained in (2) was reacted in the same manner as in Example 3, the title compound was obtained as a colorless amorphous substance. IR (KBr):. 2930, 2850, 1780, 1750 cm -1 1 H-NMR (CDCl 3) δ: 1.2-2.4 (14 H, m), 1.30 (1.5 H,
d, J = 6.2 Hz), 1.32 (1.5 H, d, J = 6.2 Hz), 1.61
(1.5 H, d, J = 5.4 Hz), 1.63 (1.5 H, d, J = 5.4 H
z), 3.0-3.2 (2 H, m), 3.6-3.9 (4 H, m), 4.17 (1 H,
dd J = 3.6, 8.4 Hz), 4.2-4.4 (1 H, m), 4.5-4.7 (1
H, m), 4.67 (1 H, d, J = 8.4 Hz), 6.91 (1 H, q, J =
5.4 Hz), 7.21 (1 H, d, J = 3.4 Hz), 7.65 (1 H, d,
H = 3.4 Hz).

Example 45 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (thiazole-5 -Ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ '
⁶ ] Allyl undec-1-ene-2-carboxylate

Embedded image A similar reaction was carried out using 5-mercaptothiazole in place of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine in Example 8 to obtain the title compound as a colorless oil. Was given. IR (neat):. 2930, 2850, 1780, 1760 cm -1 1 H-NMR (CDCl 3) δ: 1.41 (3 H, d, J = 6.4 Hz), 1.5-
2.2 (4 H, m), 2.6-2.9 (2 H, m), 3.7-3.9 (3 H, m),
3.79 (1 H, dd, J = 3.6, 6.6 Hz), 4.14 (1 H, dd, J =
3.6, 8.6 Hz), 4.50 (1 H, d, J = 8.6 Hz), 4.6-4.9
(4 H, m), 5.17 (1 H, dq, J = 6.6, 6.4 Hz), 5.2-5.5
(4 H, m), 7.84 (1 H, s), 8.85 (1 H, s). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4 -
Oxo-11-[2- (thiazol-5-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2
Sodium carboxylate

Embedded image When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2920, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.6-2.
2 (4 H, m), 2.7-2.9 (2H, m), 3.54 (1 H, dd, J = 3.
4, 5.2 Hz), 3.5-3.6 (1 H, m), 3.8-3.9 (2 H, m), 4.1
1 (1 H, dd, J = 3.4, 8.4 Hz), 4.28 (1 H, dq, J =
5.2, 6.4 Hz), 4.65 (1 H, d, J = 8.4 Hz), 7.89 (1
H, s), 9.04 (1 H, s).

Example 46 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (4-pyridylthio) )
Ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl

[Chemical 135] When 4-mercaptopyridine was used instead of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine in Example 8 to carry out the same reaction, the title compound and triphenylphosphine oxide were obtained. A mixture with and (1: 1) was obtained as a colorless solid. IR (KBr):. 2930, 2850, 1785, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.6-
2.3 (4 H, m), 2.8-3.1 (2 H, m), 3.81 (1 H, dd, J =
3.6, 6.6 Hz), 3.8-4.0 (3 H, m), 4.18 (1 H, dd, J =
3.6, 8.4 Hz), 4.58 (1 H, d, J = 8.4 Hz), 4.6-4.9
(4 H, m), 5.18 (1 H, dq, J = 6.6, 6.4 Hz), 5.2-5.5
(4 H, m), 5.8-6.1 (2 H, m), 7.0-7.1 (2 H, m), 8.3-
8.4 (2 H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11-[2- (4-pyridylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylate

[Chemical 136] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2920, 2850, 1760, 1580 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.6-2.
4 (4 H, m), 3.03 (2 H, t, J = 7.3 Hz), 3.56 (1 H, d
d, J = 3.6, 5.2 Hz), 3.6-3.7 (1 H, m), 3.9-4.0 (2
H, m), 4.15 (1 H, dd, J = 3.6, 8.4 Hz), 4.29 (1 H,
dq, J = 5.2, 6.4 Hz), 4.78 (1 H, d, J = 8.4 Hz),
7.3-7.4 (2 H, m), 8.2-8.4 (2 H, m). (3) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11-[2- (4-pyridylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl

[Chemical 137] When the compound obtained in (2) was reacted in the same manner as in Example 3, the title compound was obtained as a colorless amorphous substance. IR (KBr):. 2930, 2850, 1780, 1750 cm -1 1 H-NMR (CDCl 3) δ: 1.2-2.3 (14 H, m), 1.29 (1.5 H,
d, J = 6.2 Hz), 1.31 (1.5 H, d, J = 6.2 Hz), 1.61
(1.5 H, d, J = 5.4 Hz), 1.63 (1.5 H, d, J = 5.4 H
z), 2.7-3.1 (2 H, m), 3.65 (0.5 H, dd, J = 3.8, 5.
8 Hz), 3.66 (0.5H, dd, J = 3.8, 5.8 Hz), 3.7-4.0
(3 H, m), 4.18 (1 H, dd, J = 3.8, 8.8Hz), 4.2-4.4
(1 H, m), 4.5-4.7 (1 H, m), 4.61 (1 H, d, J = 8.8
Hz), 6.92 (1 H, q, J = 5.4 Hz), 7.0-7.1 (2 H, m),
8.3-8.4 (2 H, m).

(4) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-oxo-11- [2- (4-pyridylthio) ethyl] -8
- oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid 1- (isopropoxycarbonyloxy)
ethyl

[Chemical 138] When 1-iodoethyl isopropyloxycarboxylate was used in the same reaction instead of 1-iodoethyl cyclohexyloxycarboxylate used in (3), the title compound was obtained as a colorless amorphous substance. IR (KBr):. 2960, 2920, 2850, 1780, 1755 cm -1 1 H-NMR (CDCl 3) δ: 1.2-1.4 (9 H, m), 1.61 (1.5 H,
d, J = 5.4 Hz), 1.63 (1.5 H, d, J = 5.4 Hz), 1.6-
2.3 (4 H, m), 2.7-3.1 (2 H, m), 3.65 (0.5 H, dd, J
= 3.6, 6.0 Hz), 3.66 (0.5 H, dd, J = 3.6, 6.0 Hz),
3.7-4.0 (3 H, m), 4.19 (1 H, dd, J = 3.6, 8.8 H
z), 4.2-4.4 (1 H, m), 4.61 (1 H, d, J = 8.8 Hz), 4.
8-5.0 (1 H, m), 6.92 (1 H, q, J = 5.4 Hz), 7.0-7.1
(2 H, m), 8.3-8.5 (2 H, m). (5) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11-[2- (4-pyridylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid 1- (ethoxycarbonyloxy) ethyl

[Chemical 139] When 1-iodoethyl ethoxycarboxylate was used instead of 1-iodoethyl cyclohexyloxycarboxylate used in (3) and a similar reaction was conducted, the title compound was obtained as a colorless amorphous substance. IR (KBr):. 2960, 2930, 2850, 1780, 1760 cm -1 1 H-NMR (CDCl 3) δ: 1.2-1.4 (6 H, m), 1.62 (1.5 H,
d, J = 5.4 Hz), 1.64 (1.5 H, d, J = 5.4 Hz), 1.6-
2.4 (4 H, m), 2.8-3.1 (2 H, m), 3.6-4.0 (4 H, m),
4.1-4.4 (4 H, m), 4.62 (1 H, d. J = 8.8 Hz), 6.93 (1
H, q, J = 5.4 Hz), 7.1-7.2 (2 H, m), 8.4-8.5 (2
H, m).

Example 47 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (2-pyridylthio) )
Ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl

[Chemical 140] When 2-mercaptopyridine was used instead of the imidazole of Example 9 and the same reaction was performed, the title compound was obtained as a colorless oil. IR (neat):. 2930, 2850, 1785, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ: 1.43 (3 H, d, J = 6.4 Hz), 1.6-
2.4 (4 H, m), 3.0-3.2 (2 H, m), 3.80 (1 H, dd, J =
3.6, 6.8 Hz), 3.8-3.9 (3 H, m), 4.19 (1 H, dd, J =
3.6, 8.4 Hz), 4.6-4.9 (5 H, m), 5.19 (1 H, dq, J =
6.8, 6.4 Hz), 5.2-5.5 (4 H, m), 5.8-6.1 (2 H, m),
6.9-7.0 (1 H, m), 7.1-7.2 (1 H, m), 7.4-7.5 (1 H,
m), 8.3-8.4 (1 H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11-[2- (2-pyridylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylate

[Chemical 141] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2930, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.6 Hz), 1.4-2.
4 (4 H, m), 3.06 (2 H, t, J = 7.3 Hz), 3.56 (1 H, d
d, J = 3.6, 5.2 Hz), 3.5-3.7 (1 H, m), 3.8-4.0 (2
H, m), 4.16 (1 H, dd, J = 3.6, 8.4 Hz), 4.30 (1 H,
dq, J = 5.2, 6.6 Hz), 4.77 (1 H, d, J = 8.4 Hz),
7.2-7.3 (1 H, m), 7.39 (1 H, d, J = 8.0 Hz), 7.7-
7.8 (1 H, m), 8.3-8.4 (1 H, m).

(3) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-oxo-11- [2- (2-pyridylthio) ethyl] -8
1- (Cyclohexyloxycarbonyloxy) ethyl-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid

[Chemical 142] When the compound obtained in (2) was reacted in the same manner as in Example 3, the title compound was obtained as a colorless amorphous substance. IR (KBr):. 2920, 2850, 1780, 1750 cm -1 1 H-NMR (CDCl 3) δ: 1.2-2.4 (14 H, m), 1.31 (1.5 H,
d, J = 6.4 Hz), 1.32 (1.5 H, d, J = 6.2 Hz), 1.61
(1.5 H, d, J = 5.4 Hz), 1.63 (1.5 H, d, J = 5.4 H
z), 3.0-3.2 (2 H, m), 3.6-3.9 (4 H, m), 4.18 (1 H,
dd, J = 3.6, 8.4 Hz), 4.2-4.4 (1 H, m), 4.5-4.7
(1 H, m), 4.72 (1 H, d, J = 8.4 Hz), 6.92 (1 H, q,
J = 5.4 Hz), 6.9-7.0 (1 H, m), 7.1-7.2 (1 H, m),
7.4-7.5 (1H, m), 8.3-8.4 (1H, m).

Example 48 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (pyrazinylthio)
Ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl

[Chemical 143] When mercaptopyrazine was used instead of the imidazole of Example 9 and the same reaction was performed, the title compound was obtained as a colorless oil. IR (neat):. 2920, 2850, 1780, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.43 (3 H, d, J = 6.4 Hz), 1.6-
2.4 (4 H, m), 3.09 (2H, t, J = 7.8 Hz), 3.80 (1 H,
dd, J = 3.6, 6.6 Hz), 3.8-3.9 (3 H, m), 4.19 (1
H, dd, J = 3.6, 8.4 Hz), 4.6-4.9 (5 H, m), 5.19 (1
H, dq, J = 6.6,6.4 Hz), 5.2-5.5 (4 H, m), 8.20 (1
H, d, J = 2.6 Hz), 8.32 (1 H, dd, J = 1.6, 2.6 H
z), 8.42 (1 H, d, J = 1.6 Hz). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11-[2- (pyrazinylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylate

[Chemical 144] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2930, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.4 Hz), 1.6-2.
5 (4 H, m), 3.0-3.2 (2H, m), 3.56 (1 H, dd, J = 3.
6, 5.2 Hz), 3.6-3.7 (1 H, m), 3.9-4.0 (2 H, m), 4.1
7 (1 H, J = 3.6, 8.2 Hz), 4.30 (1 H, dq, J = 5.2,
6.4 Hz), 4.81 (1 H, d, J = 8.2 Hz), 8.28 (1 H, d, J
= 2.8 Hz), 8.44 (1 H, dd, J = 1.6,2.8 Hz), 8.51
(1 H, d, J = 1.6 Hz).

Example 49 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (3-pyridylthio) )
Ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl

[Chemical 145] When 3-mercaptopyridine was used in place of the imidazole of Example 9 and the same reaction was performed, the title compound was obtained as a colorless oil. IR (neat):. 2930, 2850, 1780, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.5-
2.3 (4 H, m), 2.7-3.0 (2 H, m), 3.7-4.0 (3 H, m),
3.79 (1 H, dd, J = 3.6, 6.6 Hz), 4.16 (1 H, dd, J =
3.6, 8.4 Hz), 4.54 (1 H, d, J = 8.4 Hz), 4.6-4.9
(4 H, m), 5.18 (1 H, dq, J = 6.6, 6.4 Hz), 5.2-5.5
(4 H, m), 5.8-6.1 (2 H, m), 7.2-7.3 (1 H, m), 7.6-
7.7 (1 H, m), 8.45 (1 H, dd, J = 1.6, 4.8 Hz), 8.5
-8.6 (1H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11-[2- (3-pyridylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylate

[Chemical 146] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2920, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.6-2.
2 (4 H, m), 2.9-3.0 (2H, m), 3.55 (1 H, dd, J = 3.
4, 5.0 Hz), 3.5-3.7 (1 H, m), 3.8-4.0 (2 H, m), 4.1
2 (1 H, dd, J = 3.4, 8.4 Hz), 4.29 (1 H, dq, J =
5.0, 6.4 Hz), 4.67 (1 H, d, J = 8.4 Hz), 7.43 (1
H, dd, J = 4.8, 7.6 Hz), 7.89 (1 H, dt, J = 8.4,
2.0 Hz), 8.3-8.6 (2 H, m).

Example 50 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (4-pyridyl) oxy) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl

[Chemical 147] When 4-hydroxypyridine was used in place of the imidazole of Example 9 and the same reaction was performed, the title compound was obtained as a colorless oil. IR (neat):. 2920, 2850, 1780, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.6-
2.4 (4 H, m), 3.81 (1H, dd, J = 3.6, 6.8 Hz), 3.9-
4.1 (5 H, m), 4.17 (1 H, dd, J = 3.6, 8.6 Hz), 4.5
-4.8 (5 H, m), 5.18 (1 H, dq, J = 6.8, 6.4 Hz), 5.
2-5.5 (4 H, m), 5.8-6.1 (2 H, m), 6.7-6.8 (2 H, m),
8.3-8.5 (2 H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (4-pyridyloxy) ethyl] -8-oxa-3-
Azatricyclo [5.4.0.0 ³ ' ⁶ ] sodium undeca-1-ene-2-carboxylate

Embedded image When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2860, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.6-2.
5 (4 H, m), 3.56 (1 H, dd, J = 3.6, 5.2 Hz), 3.6-3.
8 (1 H, m), 3.9-4.0 (2 H, m), 4.13 (1 H, dd, J =
3.6, 8.4 Hz), 4.1-4.2 (2 H, m), 4.29 (1 H, dq, J =
5.2, 6.4 Hz), 4.84 (1 H, d, J = 8.4 Hz), 7.10 (2
H, brs), 8.39 (2 H, brs). (3) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (4-pyridyloxy) ethyl] -8-oxa-3-
Azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate 1- (cyclohexyloxycarbonyloxy) ethyl

[Chemical 149] When the compound obtained in (2) was reacted in the same manner as in Example 3, the title compound was obtained as a colorless amorphous substance. IR (KBr):. 2930, 2850, 1780, 1750 cm -1 1 H-NMR (CDCl 3) δ: 1.2-2.4 (14 H, m), 1.30 (1.5 H,
d, J = 6.4 Hz), 1.31 (1.5 H, d, J = 6.4 Hz), 1.49
(1.5 H, d, J = 5.4 Hz), 1.57 (1.5 H, d, J = 5.4 H
z), 3.65 (0.5 H, dd, J = 3.6, 6.0 Hz), 3.66 (0.5
H, dd, J = 3.6, 6.0 Hz), 3.8-4.1 (5 H, m), 4.17 (1
H, dd, J = 3.6, 8.6 Hz), 4.27 (0.5 H, dq, J = 6.0,
6.4 Hz), 4.28 (0.5 H, dq, J = 6.0, 6.4 Hz), 4.5-
4.7 (1 H, m), 4.67 (1 H, d, J = 8.6 Hz), 6.7-6.8
(2 H, m), 6.84 (0.5 H, q, J = 5.4 Hz), 6.86 (0.5 H,
q, J = 5.4 Hz), 8.3-8.4 (2 H, m).

Example 51 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (1-methyl-2-imidazoline -
2-ylthio) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl

[Chemical 150] When 1-methylimidazolidine-2-thione was used in place of the imidazole of Example 9 and the same reaction was performed, the title compound was obtained as a colorless oil. IR (neat):. 2930, 2850, 1780, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.6-
2.4 (4 H, m), 2.77 (3H, s), 2.9-3.1 (2 H, m), 3.3-
3.4 (2 H, m), 3.7-3.9 (5 H, m), 3.79 (1 H, dd, J =
3.6, 6.8 Hz), 4.15 (1 H, dd, J = 3.6, 8.2 Hz), 4.6
-4.9 (5 H, m), 5.18 (1 H, dq, J = 6.8, 6.4 Hz), 5.2
-5.5 (4 H, m), 5.8-6.1 (2 H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -11
-[2- (1-Methyl-2-imidazolin-2-ylthio) ethyl] -4-
Oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylate

Embedded image When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2850, 1760, 1580 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.4 Hz), 1.6-2.
4 (4 H, m), 3.06 (3 H, s), 3.1-3.3 (2 H, m), 3.59
(1 H, dd, J = 3.6, 5.0 Hz), 3.6-3.7 (1 H, m), 3.8-
4.0 (6 H, m), 4.18 (1 H, dd, J = 3.6, 8.4 Hz), 4.3
0 (1 H, dq, J = 5.0, 6.4 Hz), 4.82 (1 H, d, J = 8.4
Hz).

Example 52 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (2-thiazoline -2-
Ilthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0
^{3 '6]} undec-1-ene-2-carboxylic acid allyl

[Chemical 152] When 2-mercapto-2-thiazoline was used in place of the imidazole of Example 9 and the same reaction was performed, the title compound was obtained as a colorless oil. IR (neat):. 2920, 2850, 1780, 1730 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.2 Hz), 1.6-
2.4 (4 H, m), 2.9-3.1 (2 H, m), 3.39 (2 H, t, J =
8.0 Hz), 3.7-3.9 (3 H, m), 3.79 (1 H, dd, J = 3.6,
6.8 Hz), 4.15 (1 H, dd, J = 3.6, 8.4 Hz), 4.20 (2
H, t, J = 8.0 Hz), 4.6-4.9 (5 H, m), 5.18 (1 H, d
q, J = 6.8, 6.2 Hz), 5.2-5.5 (4 H, m), 5.8-6.1 (2
(H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11-[2- (2-thiazoline-2-ylthio) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene -2
-Sodium carboxylate

[Chemical 153] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2930, 2850, 1760, 1585 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.4 Hz), 1.6-2.
4 (4 H, m), 3.02 (2 H, t, J = 7.3 Hz), 3.45 (2 H,
t, J = 8.0 Hz), 3.56 (1 H, dd, J = 3.6, 5.2Hz), 3.
5-3.7 (1 H, m), 3.9-4.0 (2 H, m), 4.17 (2 H, t, J
= 8.0 Hz), 4.18 (1 H, dd, J = 3.6, 8.6 Hz), 4.30 (1
H, dq, J = 5.2, 6.4 Hz), 4.83 (1 H, d, J = 8.6 H
z).

Example 53 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- (isooxazol-3-yloxy) Ethyl] -4-oxo-8-oxa-3-azatricyclo
[5.4.0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate

Embedded image A similar reaction was carried out using 3-hydroxyisoxazole instead of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine in Example 8, to give the title compound as a colorless oil. Was obtained. IR (neat): 2990, 2940, 2850, 1780, 1740, 1700 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 1.42 (3 H, d, J = 6.3 Hz), 1.6-
2.4 (4 H, m), 3.79 (1H, dd, J = 3.6, 6.8 Hz), 3.8-
4.0 (3 H, m), 4.14 (1 H, dd, J = 3.6, 8.5 Hz), 4.2
-4.3 (2 H, m), 4.6-4.9 (5 H, m), 5.17 (1 H, dq, J
= 6.8, 6.3 Hz), 5.2-5.5 (4 H, m), 5.8-6.1 (2 H, m),
5.91 (1 H, d, J = 1.7 Hz), 8.11 (1H, d, J = 1.7 H
z). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -11
- [2- (isoxazol-3-yloxy) ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec -1
-Sodium ene-2-carboxylate

[Chemical 155] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2860, 1760, 1580 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.4 Hz), 1.6-2.
4 (4 H, m), 3.55 (1 H, dd, J = 3.6, 5.2 Hz), 3.6-3.
8 (1 H, m), 3.9-4.0 (2 H, m), 4.14 (1 H, dd, J =
3.6, 8.4 Hz), 4.2-4.4 (3 H, m), 4.83 (1 H, d, J =
8.4 Hz), 6.15 (1H, d, J = 1.9 Hz), 8.33 (1 H, d, J
= 1.9 Hz).

Example 54 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (2-pyridyl) oxy) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl (A) and (5S, 6S, 7
S, 11S) -5-[(R) -1- (Allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- [2 (1H) -oxopyridin-1-yl] ethyl] -8- oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl (B)

[Chemical 156] When 2-hydroxypyridine was used in place of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine in Example 8 to carry out the same reaction, the title compounds (A) and (B Each) was obtained as a colorless oil. (A) IR (neat): . 2930, 2850, 1780, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.2 Hz), 1.6-
2.4 (4 H, m), 3.79 (1H, dd, J = 3.6, 6.8 Hz), 3.8-
4.0 (3 H, m), 4.13 (1 H, dd, J = 3.6, 8.4 Hz), 4.3
0 (2 H, t, J = 6.6 Hz), 4.5-4.8 (5 H, m), 5.17 (1
H, dq, J = 6.8,6.2 Hz), 5.2-5.5 (4 H, m), 5.8-6.1
(2 H, m), 6.6-6.7 (1 H, m), 6.8-6.9 (1 H, m), 7.5-
7.6 (1 H, m), 8.1-8.2 (1 H, m). (B) IR (neat): 2940, 2860, 1780, 1740, 1715, 1655 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 1.41 (3 H, d, J = 6.4 Hz), 1.6-
2.6 (4 H, m), 3.7-4.0 (5 H, m), 3.78 (1 H, dd, J =
3.6, 7.0 Hz), 4.14 (1 H, dd, J = 3.6, 8.4 Hz), 4.6
-4.9 (5 H, m), 5.16 (1 H, dq, J = 7.0, 6.4 Hz), 5.
2-5.5 (4 H, m), 5.8-6.1 (2 H, m), 6.13 (1 H, dt, J
= 1.6, 6.6 Hz), 6.5-6.6 (1 H, m), 7.2-7.4 (2 H,
m).

(2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-oxo-11- [2- (2-pyridyloxy) ethyl]
-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-
Sodium ene-2-carboxylate

[Chemical 157] When the compound (A) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2860, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.6-2.
5 (4 H, m), 3.53 (1 H, dd, J = 3.6, 5.2 Hz), 3.6-3.
8 (1 H, m), 3.9-4.1 (2 H, m), 4.11 (1 H, dd, J =
3.6, 8.4 Hz), 4.2-4.4 (3 H, m), 4.81 (1 H, d, J =
8.4 Hz), 6.84 (1H, d, J = 8.4 Hz), 7.0-7.1 (1 H,
m), 7.7-7.9 (1 H, m), 8.0-8.1 (1 H, m). (3) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4 -
Oxo-11- [2- [2 (1H) -oxopyridin-1-yl] ethyl]-
Sodium 8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate

[Chemical 158] When the compound (B) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2920, 2860, 1760, 1650, 1580 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.2 Hz), 1.6-2.
6 (4 H, m), 3.49 (1 H, dd, J = 3.4, 5.4 Hz), 3.6-3.
7 (1 H, m), 3.8-4.1 (5 H, m), 4.27 (1 H, dq, J =
5.4, 6.2 Hz), 4.74 (1 H, d, J = 8.0 Hz), 6.49 (1
H, dt, J = 1.2, 6.8 Hz), 6.62 (1 H, d, J = 8.2 H
z), 7.5-7.7 (2 H, m).

Example 55 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (4-pyridazinylthio) ) Ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ]
Undeca-1-ene-2-carboxylic acid allyl

[Chemical 159] By performing the same reaction by using 4-mercaptopyridazine instead of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine of Example 8, the title compound was obtained as a colorless oil. Was given. IR (neat):. 2930, 2850, 1780, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3 H, d, J = 6.4 Hz), 1.6-
2.3 (4 H, m), 2.8-3.2 (2 H, m), 3.7-4.0 (3 H, m),
3.82 (1 H, dd, J = 3.6, 6.4 Hz), 4.20 (1 H, dd, J =
3.6, 8.4 Hz), 4.5-4.9 (5 H, m), 5.19 (1 H, quint,
J = 6.4 Hz), 5.2-5.5 (4 H, m), 5.8-6.1 (2 H, m),
7.19 (1 H, dd, J = 2.7, 5.7 Hz), 8.9-9.0 (2 H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -Four-
Oxo-11- [2- (4-pyridazinylthio) ethyl] -8-oxa-
Sodium 3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate

[Chemical 160] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2920, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.2 Hz), 1.6-2.
4 (4 H, m), 3.09 (2 H, t, J = 7.2 Hz), 3.58 (1 H, d
d, J = 3.6, 5.2 Hz), 3.6-3.7 (1 H, m), 3.9-4.0 (2
H, m), 4.17 (1 H, dd, J = 3.6, 8.4 Hz), 4.30 (1 H,
dq, J = 5.2, 6.2 Hz), 4.81 (1 H, d, J = 8.4 Hz),
7.60 (1 H, dd, J = 2.6, 5.8 Hz), 8.86 (1 H, dd, J =
1.0, 5.8 Hz), 9.02 (1 H, dd, J = 1.0, 2.6 Hz).

(3) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-oxo-11- [2- (4-pyridazinylthio) ethyl] -8-oxa- 3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-
1-ene-2-carboxylate 1- (cyclohexyloxycarbonyloxy) ethyl (2) The compound (50 mg) obtained with 1-iodoethyl cyclohexyloxycarboxylate (51 mg) was reacted in the same manner as in Example 3. The title compound (42 mg) was obtained as a colorless amorphous substance. IR (KBr):. 2940, 2860, 1780, 1750 cm -1 1 H-NMR (CDCl 3) δ: 1.2-2.4 (14H, m), 1.30 (1.5H,
d, J = 6.4 Hz), 1.31 (1.5H, d, J = 6.2 Hz), 1.62
(1.5H, d, J = 5.4 Hz), 1.63 (1.5H, d, J = 5.4 Hz),
2.8-3.1 (2H, m), 3.66 (0.5H, dd, J = 3.6 and 5.8 H
z), 3.67 (0.5H, dd, J = 3.6 and 5.8 Hz), 3.7-4.0
(3H, m), 4.1-4.4 (2H, m), 4.5-4.7 (1H, m), 4.63 (1
H, d, J = 8.8 Hz), 6.91 (1H, q, J = 5.4 Hz), 7.23
(1H, dd, J = 2.6 and 5.6 Hz), 8.91 (1H, d, J = 5.6
Hz), 8.9-9.0 (1H, m). (4) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (4-pyridazinylthio) ethyl] -8-oxa-
3-Azatricyclo [5.4.0.0 ³ ' ⁶ ] 1- (isopropoxycarbonyloxy) ethyl undeca-1-ene-2-carboxylic acid Compound (50 mg) obtained with (2) and 1-iodoethyl isopropoxycarboxylic acid (43.5 mg) was reacted in the same manner as in Example 3 to obtain the title compound (41 mg) as a colorless amorphous substance. IR (KBr):. 2980, 2930, 2860, 1780, 1755 cm -1 1 H-NMR (CDCl 3) δ: 1.2-1.4 (9H, m), 1.61 (1.5H, d,
J = 5.4 Hz), 1.63 (1.5H, d, J = 5.4 Hz), 1.6-2.4
(4H, m), 2.8-3.1 (2H, m), 3.6-4.0 (3H, m), 4.1-4.4
(2H, m), 4.63 (1H, d, J = 8.8 Hz), 4.8-5.0 (1H,
m), 6.91 (1H, q, J = 5.4 Hz), 7.2-7.3 (1H, m), 8.91
(1H, d, J = 5.4 Hz), 9.0-9.1 (1H, m). (5) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (4-pyridazinylthio) ethyl] -8-oxa-
3-Azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid 1- (ethoxycarbonyloxy) ethyl compound (50 mg) obtained with (2) and ethoxycarboxylic acid
1-Iodoethyl (42 mg) was reacted in the same manner as in Example 3 to obtain the title compound (38 mg) as a colorless amorphous substance. IR (KBr):. 2960, 2930, 2860, 1780, 1760 cm -1 1 H-NMR (CDCl 3) δ: 1.2-2.4 (6H, m), 1.62 (1.5H, d,
J = 5.4 Hz), 1.64 (1.5H, d, J = 5.4 Hz), 1.6-2.4
(4H, m), 2.8-3.1 (2H, m), 3.66 (0.5H, dd, J = 3.8 a
nd 5.6 Hz), 3.67 (0.5H, dd, J = 3.8 and 5.6 Hz),
3.7-4.0 (2H, m), 4.1-4.4 (4H, m), 4.63 (1H, d, J =
8.6 Hz), 6.92 (1H, q, J = 5.4 Hz), 7.2-7.3 (1H,
m), 8.91 (1H, d, J = 5.6 Hz), 8.99 (1H, m).

Example 56 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (3-pyridyl oxy) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl

[Chemical 161] A similar reaction was carried out using 3-hydroxypyridine in place of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine in Example 8 to obtain the title compound as a colorless oil. Was given. IR (neat):. 2930, 2860, 1780, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ: 1.43 (3 H, d, J = 6.4 Hz), 1.6-
2.5 (4 H, m), 3.81 (1H, dd, J = 3.6, 6.8 Hz), 3.9-
4.1 (5 H, m), 4.17 (1 H, dd, J = 3.6, 8.4 Hz), 4.5
-4.8 (5 H, m), 5.18 (1 H, dq, J = 6.8, 6.4 Hz), 5.
2-5.5 (4 H, m), 5.8-6.1 (2 H, m), 7.0-7.3 (2 H, m),
8.2-8.3 (2 H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (3-pyridyloxy) ethyl] -8-oxa-3-
Azatricyclo [5.4.0.0 ³ ' ⁶ ] sodium undeca-1-ene-2-carboxylate

[Chemical 162] The compound obtained in (1) is reacted in the same manner as in Example 2, u
\ The title compound was obtained as a white solid. IR (KBr):. 2960, 2860, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3 H, d, J = 6.4 Hz), 1.6-2.
5 (4 H, m), 3.55 (1 H, dd, J = 3.6, 5.2 Hz), 3.6-3.
8 (1 H, m), 3.9-4.0 (2 H, m), 4.1-4.2 (3 H, m), 4.2
9 (1 H, dq, J = 5.2, 6.4 Hz), 4.83 (1 H, d, J = 8.
4 Hz), 7.3-7.5 (2 H, m), 8.1-8.3 (2 H, m).

Example 57 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (3-pyridazinylthio) ) Ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ]
Undeca-1-ene-2-carboxylic acid allyl

[Chemical formula 163] A similar reaction was carried out by using 3-mercaptopyridazine in place of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine in Example 8 to obtain the title compound as a colorless oil. Was given. IR (neat):. 2920, 2850, 1780, 1760 cm -1 1 H-NMR (CDCl 3) δ: 1.43 (3 H, d, J = 6.4 Hz), 1.6-
2.5 (4 H, m), 3.1-3.4 (2 H, m), 3.81 (1 H, dd, J =
3.6, 6.6 Hz), 3.8-3.9 (2 H, m), 4.24 (1 H, dd, J =
3.6, 8.4 Hz), 4.6-4.9 (5 H, m), 5.19 (1 H, dq, J =
6.6, 6.4 Hz), 5.2-5.5 (4 H, m), 5.8-6.1 (2 H, m),
7.22 (1 H, dd, J = 4.4, 8.6 Hz), 7.30 (1 H, dd, J
= 1.8, 8.6 Hz), 8.88 (1 H, dd, J = 1.8, 4.4 Hz). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4- Oxo-11- [2- (3-pyridazinylthio) ethyl] -8-oxa-3-
Azatricyclo [5.4.0.0 ³ ' ⁶ ] sodium undeca-1-ene-2-carboxylate

[Chemical 164] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 2960, 2920, 2850, 1760, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 6.4 Hz), 1.6-2.
4 (4 H, m), 3.1-3.3 (2H, m), 3.56 (1 H, dd, J = 3.
6, 5.2 Hz), 3.6-3.7 (1 H, m), 3.9-4.0 (2 H, m), 4.1
7 (1 H, dd, J = 3.6, 8.4 Hz), 4.30 (1 H, dq, J =
5.2, 6.4 Hz), 4.81 (1 H, d, J = 8.4 Hz), 7.59 (1
H, dd, J = 4.8, 8.8 Hz), 7.70 (1 H, dd, J = 1.5,
8.8 Hz), 8.91 (1 H, dd, J = 1.5, 4.8 Hz).

Example 58 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2-[(1-methylimidazole-2 -
Yl) thio] ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl

[Chemical 165] 2-mercapto-1-instead of N, N-dimethyl-2- (5-mercapto-1H-tetrazol-1-yl) ethylamine of Example 8
A similar reaction was performed using methylimidazole to obtain the title compound as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 4.44 (3 H, d, J = 6.4 Hz), 1.6-
1.68 (1 H, m), 1.95-2.38 (3 H, m), 2.99 (2 H, t, J
= 6.2 Hz), 3.61 (3 H, s), 3.81 (1 H, dd, J = 3.6,
6.6 Hz), 3.75-3.88 (3 H, m), 4.17 (1 H, dd, J = 3.
6, 8.4 Hz), 4.64-4.9 (5 H, m), 5.13-5.51 (5 H, m),
5.86-6.08 (2 H, m), 6.96 (1 H, d, J = 1.2 Hz), 7.0
6 (1 H, d, J = 1.2 Hz). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -11
-[2-[(1-Methylimidazol-2-yl) thio] ethyl] -4-
Oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylate

[Chemical 166] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3433, 1763, 1593, 1400 cm -1 1 H-NMR (D 2 O) δ: 1.28 (3 H, d, J = 6.4 Hz), 1.57-
2.2 (4 H, m), 2.87 (2 H, t, J = 6.8 Hz), 3.56 (1
H, dd, J = 3.4, 5.2 Hz), 3.51-3.59 (1 H, m), 3.73
(3 H, s), 3.88-3.93 (2 H, m), 4.13 (1 H, dd, J =
3.4, 8.4 Hz), 4.24-4.34 (1 H, m), 4.66 (1 H, d, J
= 8.4 Hz), 7.12 (1 H, brs), 7.27 (1 H, brs).

Example 59 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (2-pyrimidylthio) ) Ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid allyl

[Chemical 167] When 2-mercaptopyrimidine was used in place of the imidazole of Example 9 and the same reaction was performed, the title compound was obtained as a colorless oil. IR (KBr):. 3427, 1785, 1601, 1400 cm -1 1 H-NMR (CDCl 3) δ: 1.43 (3 H, d, J = 6.4 Hz), 1.6-
2.4 (4 H, m), 3.09 (2H, t, J = 7.8 Hz), 3.8 (1 H,
dd, J = 3.6, 6.8 Hz), 3.78-3.88 (4 H, m), 4.18 (1
H, dd, J = 3.6, 8.4 Hz), 4.61-4.8 (5 H, m), 5.21-
5.49 (5 H, m), 5.87-6.09 (1 H, m), 6.97 (1 H, t, d
= 5 Hz), 8.5 (2 H, d, J = 5 Hz). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (2-pyrimidylthio) ethyl] -4-oxo-8-
Oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene
-2-Sodium carboxylate

[Chemical 168] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3425, 1761, 1589, 1574, 1385 cm -1 1 H-NMR (D 2 O) δ1.29 (3 H, d, J = 6.4 Hz), 1.64-2.3
5 (4 H, m), 3.12 (3 H, m), 3.58 (1 H, dd, J = 3.6,
5.2 Hz), 3.65 (1 H, m), 3.95 (2 H, m), 4.19 (1 H, d
d, J = 3.6, 8.2 Hz), 4.31 (1 H, m), 4.86 (1 H, d,
J = 8.2 Hz), 7.24 (1 H, t, J = 5 Hz), 8.59 (2 H,
d, J = 5 Hz).

Example 60 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2-[(2-oxazoline-2- (Ill)
Thio] ethyl] -4-oxo-8-oxa-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate

[Chemical 169] Oxazolidine-2-in place of the imidazole of Example 9
The same reaction was carried out using thione to give the title compound as a colorless oil. IR (neat):. 1788, 1745, 1608, 1259 cm -1 1 H-NMR (CDCl 3) δ: 1.4 (3 H, d, J = 6.4 Hz), 1.57-
1.65 (1 H, m), 1.92-2.35 (3 H, m), 2.85 (2 H, t, J
= 7.2 Hz), 3.77 (1 H, dd, J = 3.6, 6.8 Hz), 3.7-3.
87 (3 H, m), 3.86 (2 H, t, J = 9.2 Hz), 4.14 (1 H,
dd, J = 3.6, 8.2), 4.33 (2 H, t, J = 9.2 Hz), 4.5
9-4.85 (5 H, m), 5.09-5.47 (5 H, m), 5.82-6.08 (2
H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -11
-[2-[(2-Oxazolin-2-yl) thio] ethyl] -4-oxo-
Sodium 8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate

[Chemical 170] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3427, 1785, 1601, 1400 cm -1 1 H-NMR (D 2 O) δ1.26 (3 H, d, J = 6.2 Hz), 1.57-1.7
(1 H, m), 1.9-2.32 (3H, m), 2.93 (2 H, t, J = 7.4
Hz), 3.55 (1 H, dd, J = 3.8, 5 Hz), 3.53-3.62 (1
H, m), 3.83 (2 H, t, J = 9.2 Hz), 3.91-3.97 (2 H,
m), 4.17 (1 H, dd, J = 3.8, 8.4 Hz), 4.22-4.34 (1
H, m), 4.44 (2 H, t, J = 9.2 Hz), 4.86 (1 H, d, J
= 8.4 Hz).

Example 61 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] -4-oxo-11- [2- (1H -1,2,4-Triazol-1-yl) ethyl] -8-oxa-3-azatricyclo
[5.4.0.0 ³ ' ⁶ ] Undec-1-ene-2-carboxylic acid allyl (A) and (5S, 6S, 7S, 11S) -5-[(R) -1- (tert-butyldimethylsilyloxy) Ethyl] -4-oxo-11- [2- (4H-1,2,4-
Triazol-4-yl) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid allyl (B)

[Chemical 171] Example 19 of JP-A-5-86062 used in Example 13
-In the same manner as above, using the compound obtained by the method of Reference Example 30 instead of the compound obtained in (2), the title compound (A) was obtained as a colorless oil, and (B) was obtained as a white solid. It was obtained as a thing. (A) IR (neat): . 1780, 1720 cm -1 1 H-NMR (CDCl 3) δ 0.08 (3 H, s), 0.09 (3 H, s), 0.
90 (9 H, s), 1.19 (3 H, d, J = 6.2 Hz), 1.5-1.65
(2 H, m), 1.95-2.3 (2 H, m), 2.4-2.65 (1 H, m), 3.
56 (1 H, dd, J = 4.4, 3.6 Hz), 3.65-3.95 (3 H, m),
4.1-4.25 (2 H, m), 4.12 (1 H, dd, J = 8.4, 3.6 H
z), 4.29 (1 H, qd, J = 6.2, 4.4 Hz), 4.58 (1 H, d,
J = 8.4 Hz), 4.7-4.8 (2 H, m), 5.2-5.55 (2 H, m),
5.85-6.1 (1H, m), 7.93 (1 H, s), 8.04 (1 H, s) (B) IR (KBr):.. 1785, 1720 cm -1 1 H-NMR (CDCl 3) δ 0.086 (3 H, s), 0.093 (3 H, s),
0.90 (9 H, s), 1.19 (3H, d, J = 6.2 Hz), 1.5-1.65
(1 H, m), 1.9-2.5 (3 H, m), 3.62 (1 H, t, J = 3.9 H
z), 3.70-4.1 (5 H, m), 4.21 (1 H, dd, J = 8.8, 3.9
Hz), 4.31 (1H, qd, J = 6.2, 3.9 Hz), 4.58 (1 H,
d, J = 8.8 Hz), 4.7-4.8 (2 H, m), 5.2-5.6 (2 H,
m), 5.8-6.1 (1 H, m), 8.21 (2 H, s).

(2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-oxo-11- [2- (1H-1,2,4-triazole-1) -
Iyl) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ]
Undeca-1-ene-2-carboxylic acid allyl

[Chemical 172] To a tetrahydrofuran solution (1.8 ml) of the compound (A) (61 mg) obtained in (1) was added a tetrahydrofuran solution of 1 M tetrabutylammonium fluoride and 3 M acetic acid (0.6 ml) at 0 ° C, and the mixture was stirred at room temperature. Stir for 55 hours. Ethyl acetate was added to the reaction solution, which was washed successively with pH 7 phosphate buffer and saturated saline, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is subjected to flash column chromatography (carrier: silica gel, 10
g, a developing solvent: methanol-dichloromethane, 1:40) to give the title compound (23.8 mg) as a colorless oil. IR (neat):. 3380, 1775, 1715 cm -1 1 H-NMR (CDCl 3) δ 1.31 (3 H, d, J = 6.2 Hz), 1.5-
2.3 (3 H, m), 2.45-2.7 (1 H, m), 3.63 (1 H, dd, J =
6.2, 3.6 Hz), 3.65-3.95 (3 H, m), 4.1-4.25 (2 H,
m), 4.12 (1 H, dd, J = 8.4, 3.6 Hz), 4.28 (1 H, qu
int, J = 6.2 Hz), 4.62 (1 H, d, J = 8.4 Hz), 4.65-
4.9 (2 H, m), 5.25-5.55 (2 H, m), 5.85-6.1 (1 H,
m), 7.95 (1 H, s), 8.05 (1 H, s). (3) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (4H-1,2,4-triazol-4-yl) ethyl]
-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-
Allyl ene-2-carboxylate

[Chemical 173] When the compound (B) obtained in (1) was reacted in the same manner as in (2), the title compound was obtained as a white solid. IR (KBr):. 3400, 1780, 1715 cm -1 1 H-NMR (CDCl 3) δ 1.31 (3 H, d, J = 6.2 Hz), 1.5-
1.8 (1 H, m), 1.95-2.2 (2 H, m), 2.3-2.55 (1 H, m),
3.64 (1 H, dd, J = 6.2, 3.6 Hz), 3.7-4.1 (5H, m),
4.22 (1 H, dd, J = 8.6, 3.6 Hz), 4.29 (1 H, quin
t, J = 6.2 Hz), 4.63 (1 H, d, J = 8.6 Hz), 4.65-4.9
(2 H, m), 5.25-5.55 (2 H, m), 5.85-6.1 (1 H, m),
8.23 (2 H, s).

(4) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-oxo-11- [2- (1H-1,2,4-triazole-1) -
Iyl) ethyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ]
Undeca-1-ene-2-carboxylate sodium

[Chemical 174] Triphenylphosphine (2 mg) was added to a dichloromethane solution (1 ml) of the compound (23.8 mg) obtained in (2). Then, tetrakis (triphenylphosphine) palladium (0) (3.5 mg) and sodium 2-ethylhexanoate (10 mg) in tetrahydrofuran-dichloromethane mixed solution (1: 1, 1 ml) were added dropwise, and the mixture was stirred at room temperature for 30 minutes. did. Ether was added to the reaction mixture, and the mixture was extracted with water. The extract was concentrated under reduced pressure, and the concentrate was chromatographed (carrier: CHP-20P, 20 ml, developing solvent: 5% ethanol-
After purification with water) and lyophilization, the title compound (17 m
g) was obtained as a white solid. The spectral data were completely in agreement with the compound of Example 11- (2). (3) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [2- (4H-1,2,4-triazol-4-yl) ethyl]
-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-
Sodium ene-2-carboxylate

[Chemical 175] When the compound obtained in (3) was reacted in the same manner as in (4), the title compound was obtained as a white solid. The spectral data were completely in agreement with the compound of Example 13- (2).

Example 62 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11-[(R) -2- (1H-Tetrazol-1-yl) propyl] -8-oxa-3-azatricyclo [5.
4.0.0 ³ ' ⁶ ] Allyl undec-1-ene-2-carboxylate (A)
And (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11-[(R) -2- (2H-tetrazol-2-yl ) Propyl] -8-oxa-3-azatricyclo [5.4.
0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate (B)

[Chemical 176] Example 19 of JP-A-5-86062 used in Example 16
-Instead of the compound obtained by the method of (2), Reference Example 2
When the same reaction was performed using the compound obtained by the method 1, the title compound (A) was obtained as a white solid, and (B) was obtained as a colorless oil. (A) IR (KBr): . 1785, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ 1.4-1.6 (1 H, m), 1.42 (3 H, d,
J = 6.2 Hz), 1.65 (3 H, d, J = 6.8 Hz), 1.9-2.1 (1
H, m), 2.4-2.5 (2 H, m), 3.4-3.6 (1 H, m), 3.75-3.
95 (2 H, m), 3.79 (1 H, dd, J = 6.8, 3.6 Hz), 4.16
(1 H, dd, J = 8.4, 3.6 Hz), 4.5-4.7 (1 H, m), 4.59
(1 H, d, J = 8.4 Hz), 4.6-4.8 (4 H, m), 5.17 (1 H,
quint, J = 6.8 Hz), 5.25-5.55 (4 H, m), 5.8-6.1
. (2 H, m), 8.66 (1 H, s) (B) IR (neat):. 1780, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ 1.4-1.6 (1 H, m) , 1.42 (3 H, d,
J = 6.4 Hz), 1.63 (3 H, d, J = 6.8 Hz), 1.9-2.15
(1 H, m), 2.3-2.6 (2 H, m), 3.5-3.65 (1 H, m), 3.7
7 (1 H, dd, J = 6.8, 3.6 Hz), 3.8-3.95 (2 H, m),
4.15 (1 H, dd, J = 8.4, 3.6 Hz), 4.60 (1 H, d, J =
8.4 Hz), 4.6-4.75 (4 H, m), 4.85-5.05 (1 H, m), 5.
16 (1 H, quint, J = 6.6 Hz), 5.2-5.5 (4 H, m), 5.8
-6.05 (2 H, m), 8.48 (1 H, s).

(2) (5S, 6S, 7S, 11S) -5-[(R) -1-Hydroxyethyl] -4-oxo-11-[(R) -2- (1H-tetrazol-1-yl) ) Propyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ]
Undeca-1-ene-2-carboxylate sodium

[Chemical 177] When the compound (A) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3450, 1795, 1770, 1585, 1395 cm -1 1 H-NMR (D 2 O) δ 1.26 (3 H, d, J = 6.4 Hz), 1.5-1.7
(1 H, m), 1.61 (3 H, d, J = 6.8 Hz), 1.85-2.15 (1
H, m), 2.25-2.45 (1 H, m), 2.55-2.75 (1 H, m), 3.2-
3.4 (1 H, m), 3.52 (1 H, dd, J = 5.0, 3.6 Hz), 3.8
5-4.05 (2 H, m), 4.10 (1 H, dd, J = 8.2, 3.6 Hz),
4.28 (1 H, qd, J = 6.4, 5.0 Hz), 4.7-5.0 (2 H, m),
9.06 (1 H, s). (3) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11-[(R) -2- (2H-tetrazol-2-yl) propyl]
-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-1-
Sodium ene-2-carboxylate

[Chemical 178] When the compound (B) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3430, 1760, 1595, 1395 cm -1 1 H-NMR (D 2 O) δ 1.26 (3 H, d, J = 6.4 Hz), 1.5-1.7
(1 H, m), 1.62 (3 H, d, J = 6.6 Hz), 1.85-2.15 (1
H, m), 2.3-2.8 (2 H, m), 3.15-3.35 (1 H, m), 3.50
(1 H, dd, J = 5.0, 3.6 Hz), 3.85-4.05 (2 H, m), 4.
11 (1 H, dd, J = 8.2, 3.6 Hz), 4.29 (1 H, qd, J =
6.4, 5.0 Hz), 4.6-5.1 (2 H, m), 8.73 (1 H, s).

Example 63 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11-[(R) -2- (4H-1,2,4-triazol-4-yl) propyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid allyl (A) and (5S , 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11-[(R) -2- (1H-1,2,
4-Triazol-1-yl) propyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid allyl (B)

[Chemical 179] Example 19 of JP-A-5-86062 used in Example 13
When the reaction was similarly performed using the compound obtained in Reference Example 21 instead of the compound of (2), the title compounds (A) and (B) were obtained as colorless oils. (A) IR (neat): . 1780, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ 1.3-1.6 (1 H, m), 1.42 (3 H, d,
J = 6.6 Hz), 1.54 (3 H, d, J = 6.8 Hz), 1.9-2.45
(3 H, m), 3.5-4.0 (3 H, m), 3.79 (1 H, dd, J = 6.6,
3.6 Hz), 4.1-4.3 (1 H, m), 4.17 (1 H, dd, J = 8.
2, 3.6 Hz), 4.57 (1 H, d, J = 8.2 Hz), 4.6-4.8 (4
H, m), 5.17 (1 H, quint, J = 6.6 Hz), 5.2-5.55 (4
H, m), 5.8-6.1 (2 H, m), 8.24 (2 H, s) (B) IR (neat):.. 1780, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ 1.3 -1.6 (1 H, m), 1.42 (3 H, d,
J = 6.4 Hz), 1.55 (3 H, d, J = 6.6 Hz), 1.85-2.1
(1 H, m), 2.3-2.4 (2 H, m), 3.4-4.0 (3 H, m), 3.77
(1 H, dd, J = 7.0, 3.6 Hz), 4.13 (1 H, dd, J = 8.
2, 3.6 Hz), 4.32 (1 H, sextet, J = 6.6 Hz), 4.59 (1
H, d, J = 8.2 Hz), 4.6-4.8 (4 H, m), 5.17 (1 H, d
q, J = 7.0, 6.4 Hz), 5.2-5.55 (4 H, m), 5.8-6.1 (2
H, m), 7.96 (1 H, s), 8.03 (1 H, s).

(2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-oxo-11-[(R) -2- (4H-1,2,4) -Triazol-4-yl) propyl] -8-oxa-3-azatricyclo [5.4.
0.0 ³ ' ⁶ ] Undeca-1-ene-2-carboxylate sodium

[Chemical 180] When the compound (A) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3430, 1760, 1595, 1395 cm -1 1 H-NMR (D 2 O) δ 1.26 (3 H, d, J = 6.2 Hz), 1.4-1.7
(1 H, m), 1.52 (3 H, d, J = 6.8 Hz), 1.9-2.3 (2 H,
m), 2.4-2.65 (1 H, m), 3.25-3.4 (1 H, m), 3.53 (1
H, dd, J = 5.2, 3.6 Hz), 3.85-4.05 (2 H, m), 4.10
(1 H, dd, J = 8.0, 3.6 Hz), 4.29 (1 H, qd, J = 6.2,
5.2 Hz), 4.3-4.5 (1 H, m), 4.6-5.1 (1 H, m), 8.51
(2 H, s). (3) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11-[(R) -2- (1H-1,2,4-triazol-1-yl) propyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene- 2-carboxylate sodium

[Chemical 181] When the compound (B) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3420, 1760, 1595, 1395 cm -1 1 H-NMR (D 2 O) δ 1.26 (3 H, d, J = 6.6 Hz), 1.4-1.7
(1 H, m), 1.51 (3 H, d, J = 6.6 Hz), 1.9-2.65 (3
H, m), 3.15-3.3 (1 H, m), 3.51 (1 H, dd, J = 5.2,
3.4 Hz), 3.85-4.05 (2 H, m), 4.09 (1 H, dd, J = 7.
8, 3.4 Hz), 4.29 (1 H, qd, J = 6.6, 5.2 Hz), 4.4-5.
3 (2 H, m), 8.07 (1 H, s), 8.28 (1 H, s).

Example 64 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (4H-1 , 2,4-Triazol-4-yl) ethyl] -8-thia-3-azatricyclo [5.4.
0.0 ³ ' ⁶ ] Undeca-1-ene-2-carboxylic acid allyl (A) and (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4- Oxo-11- [2- (1H-1,2,4-triazol-1-yl) ethyl] -8-thia-3-azatricyclo [5.4.0.
0 ³ ' ⁶ ] Allyl undec-1-ene-2-carboxylate (B)

[Chemical 182] Example 19 of JP-A-5-86062 used in Example 13
-Instead of the compound obtained by the method of (2), Reference Example 2
When the reaction was performed in the same manner using the compound obtained by the method of 7, the title compound (A) was obtained as a white solid and (B) was obtained as a colorless oil. (A) IR (neat): . 1780, 1740, 1710 cm -1 1 H-NMR (CDCl 3) δ 1.43 (3 H, d, J = 6.4 Hz), 1.85-
2.35 (4 H, m), 2.50-2.70 (1 H, m), 2.90-3.15 (1 H,
m), 3.59 (1 H, dd, J = 7.0, 2.6 Hz), 3.85-4.05 (3
H, m), 4.25 (1 H, d, J = 9.2 Hz), 4.32 (1 H, dd,
J = 9.2, 2.6 Hz), 4.60-4.90 (4 H, m), 5.12 (1 H, q
uint, J = 6.8 Hz), 5.25-5.55 (4 H, m), 5.80-6.10 (2
H, m), 8.18 (2 H, s) (B) IR (neat):.. 1775, 1740, 1715 cm -1 1 H-NMR (CDCl 3) δ 1.43 (3 H, d, J = 6.2 Hz ), 1.60-
2.70 (5 H, m), 3.00-3.20 (1 H, m), 3.55 (1 H, dd,
J = 7.2, 2.6 Hz), 3.80-4.50 (3 H, m), 4.22 (1 H, d
d, J = 9.0, 2.6 Hz), 4.29 (1 H, d, J = 9.0 Hz), 4.
50-4.90 (4 H, m), 5.11 (1 H, dq, J = 7.2, 6.2 Hz),
5.20-5.60 (4 H, m), 5.80-6.10 (2 H, m), 7.94 (1
H, s), 8.00 (1 H, s).

(2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-oxo-11- [2- (4H-1,2,4-triazole-4) -
Yl) ethyl] -8-thia-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylate

[Chemical 183] When the compound (A) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3420, 1750, 1590, 1385 cm -1 1 H-NMR (D 2 O) δ 1.27 (3 H, d, J = 6.2 Hz), 1.95-2.
20 (3 H, m), 2.25-2.50 (1 H, m), 2.55-2.75 (1 H,
m), 3.10-3.30 (1 H, m), 3.39 (1 H, dd, J = 6.2, 2.
6 Hz), 3.60-3.80 (1 H, m), 4.05-4.20 (3 H, m), 4.2
2 (1 H, quint, J = 6.2 Hz), 4.36 (1 H, d, J = 8.8 H
z), 8.47 (2 H, s). (3) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-oxo-11- [2- (1H-1 , 2,4-Triazol-1-yl) ethyl] -8
-Thia- ³ -azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-
2-carboxylate sodium

Embedded image When the compound (B) obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3420, 1750, 1590, 1390 cm -1 1 H-NMR (D 2 O) δ 1.26 (3 H, d, J = 6.6 Hz), 1.95-2.
20 (3 H, m), 2.35-2.75 (2 H, m), 3.10-3.30 (1 H,
m), 3.37 (1 H, dd, J = 6.0, 2.6 Hz), 3.60-3.75 (1
H, m), 4.08 (1 H, dd, J = 8.8, 2.6 Hz), 4.15-4.30
(3 H, m), 4.34 (1H, d, J = 8.8 Hz), 8.07 (1 H, s),
8.29 (1 H, s).

Example 65 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [2- (1,2 , 3-Thiadiazol-5-ylthio) ethyl] -8-thia-3-azatricyclo
[5.4.0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate

[Chemical 185] Example 19 of JP-A-5-86062 used in Example 27
-Instead of the compound obtained by the method of (2), Reference Example 2
When the reaction was performed in the same manner using the compound obtained by the method of 7, the title compound was obtained as a colorless oil. IR (neat):. 1780, 1740, 1715 cm -1 1 H-NMR (CDCl 3) δ 1.44 (3 H, d, J = 6.2 Hz), 1.80-
2.40 (4 H, m), 2.50-2.70 (1 H, m), 2.85-3.15 (3 H,
m), 3.59 (1 H, dd, J = 7.0, 2.6 Hz), 3.90-4.10 (1
H, m), 4.23 (1 H, d, J = 9.5 Hz), 4.33 (1 H, dd,
J = 9.5, 2.6 Hz), 4.60-4.90 (4 H, m), 5.13 (1 H, d
q, J = 7.0, 6.2 Hz), 5.20-5.60 (4 H, m), 5.80-6.10
(2 H, m), 8.43 (1 H, s). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11-[2- (1,2,3-thiadiazol-5-ylthio) ethyl] -8-thia-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-
Sodium ene-2-carboxylate

[Chemical 186] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3430, 1750, 1590, 1395 cm -1 1 H-NMR (D 2 O) δ 1.28 (3 H, d, J = 6.6 Hz), 1.80-2.
30 (4 H, m), 2.55-2.70 (1 H, m), 3.00-3.25 (3 H,
m), 3.44 (1 H, dd, J = 5.8, 2.6 Hz), 3.65-3.90 (1
H, m), 4.24 (1 H, qd, J = 6.6, 5.8 Hz), 4.29 (1 H,
dd, J = 9.2, 2.6Hz), 4.42 (1 H, d, J = 9.2 Hz),
8.67 (1 H, s). (3) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11-[2- (1,2,3-thiadiazol-5-ylthio) ethyl] -8-thia-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-
En-2-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl

[Chemical 187] When the compound obtained in (2) was reacted in the same manner as in Example 3, the title compound was obtained as a colorless amorphous substance. IR (KBr):. 3450, 1775, 1750 cm -1 1 H-NMR (CDCl 3) δ 1.29 (3/2 H, d, J = 6.2 Hz), 1.3
1 (3/2 H, d, J = 6.2 Hz), 1.61 (3/2 H, d, J = 5.4
Hz), 1.63 (3/2 H, d, J = 5.4 Hz), 1.20-2.30 (14 H,
m), 2.50-2.70 (1 H, m), 2.90-3.15 (3 H, m), 3.43
(1/2 H, dd, J = 5.6, 2.6 Hz), 3.44 (1/2 H, dd, J =
5.8, 2.6 Hz), 3.85-4.05 (1 H, m), 4.15-4.35 (1 H,
m), 4.24 (1 H, d, J = 9.6 Hz), 4.33 (1 H, dd, J =
9.6, 2.6Hz), 4.55-4.75 (1 H, m), 6.90 (1 H, q, J =
5.4 Hz), 8.44 (1/2 H, s), 8.45 (1/2 H, s).

Example 66 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11-[(1,2,3 -Thiadiazol-5-ylthio) methyl] -8-oxa-3-azatricyclo
[5.4.0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate

[Chemical 188] Example 19 of JP-A-5-86062 used in Example 27
-Instead of the compound obtained by the method of (2), Reference Example 1
When the reaction was performed in the same manner using the compound obtained by the method of 4, the title compound was obtained as a colorless oil. IR (neat):. 1785, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ 1.42 (3 H, d, J = 6.6 Hz), 1.75-
1.95 (1 H, m), 2.00-2.25 (1 H, m), 3.33 (1 H, dd,
J = 11.8, 7.8 Hz), 3.42 (1 H, dd, J = 11.8,8.8 H
z), 3.75-4.20 (3 H, m), 3.81 (1 H, dd, J = 6.6, 3.
6 Hz), 4.20 (1 H, dd, J = 8.8, 3.6 Hz), 4.59 (1 H,
d, J = 8.8 Hz), 4.60-4.80 (4 H, m), 5.18 (1 H, qui
nt, J = 6.6 Hz), 5.20-5.50 (4 H, m), 5.80-6.10 (2
H, m), 8.48 (1 H, s). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11 - [(1,2,3-thiadiazol-5-ylthio) methyl] -8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec -
Sodium 1-ene-2-carboxylate

[Chemical 189] When the compound obtained in (1) was reacted in the same manner as in Example 2, the title compound was obtained as a white solid. IR (KBr):. 3425, 1760, 1595, 1395 cm -1 1 H-NMR (D 2 O) δ 1.25 (3 H, d, J = 6.6 Hz), 1.75-1.
90 (1 H, m), 2.00-2.25 (1 H, m), 3.49 (1 H, dd, J =
12.8, 6.6 Hz), 3.58 (1 H, dd, J = 5.2, 3.6 Hz), 3.
64 (1 H, dd, J = 12.8, 10.4 Hz), 3.80-4.00 (3 H,
m), 4.10 (1 H, dd, J = 8.4, 3.6 Hz), 4.28 (1 H, qd,
J = 6.6, 5.2 Hz), 4.79 (1 H, d, J = 8.4 Hz), 8.69
(1 H, s).

Example 67 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- [3- (4-pyridylthio )
Propyl] -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] Allyl undeca-1-ene-2-carboxylate The compound (200 mg) obtained by the method of Reference Example 8 and 4-mercaptopyridine (61 mg) was reacted in the same manner as in Example 4,
1: 1 between the title compound and triphenylphosphine oxide
A mixture (250 mg) was obtained as a pale yellow solid. IR (KBr):. 3050, 2940, 2860, 1790, 1750, 1720 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3H, d, J = 6.0 Hz), 1.5-
2.2 (6H, m), 2.9-3.1 (2H, m), 3.6-3.8 (1H, m), 3.7
9 (1H, dd, J = 3.6 and 6.6 Hz), 3.8-3.9 (2H, m), 4.
13 (1H, dd, J = 3.6 and 8.4 Hz), 4.57 (1H, d, J =
8.4 Hz), 4.6-4.9 (4H, m), 5.18 (1H, dq, J = 6.6 and
6.0 Hz), 5.2-5.5 (4H, m), 5.8-6.1 (2H, m), 7.0-7.
1 (2H, m), 8.3-8.4 (2H, m). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- [3- (4-pyridylthio) propyl] -8-oxa-3-
Azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylate 50% purity of the compound obtained by the method of (1) a (90 mg) was reacted in the same manner as in Example 2, the title compound (26 mg) was obtained as a white solid. IR (KBr):. 2960, 2930, 2850, 1760, 1580 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3H, d, J = 6.2 Hz), 1.6-2.2
(6H, m), 3.0-3.3 (2H, m), 3.4-3.6 (1H, m), 3.53 (1
H, dd, J = 3.6 and 5.2 Hz), 3.9-4.0 (2H, m), 4.04
(1H, dd, J = 3.6 and 8.2 Hz), 4.28 (1H, dq, J = 5.
2 and 6.2 Hz), 4.75 (1H, d, J = 8.2 Hz), 7.3-7.5 (2
H, m), 8.2-8.4 (2H, m).

Example 68 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- [N-methyl-N- ( Thiazoline-2
- yl) amino] ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} Example undec-1-ene-2-carboxylic acid allyl Hei 5-86062 19- (2 ) In a solution of the compound (100 mg) in dry dichloromethane (3 ml) at -78 ℃ diisopropylethylamine (0.12 ml)
And trifluoromethanesulfonic anhydride (42 μl) were added, and the mixture was stirred under ice cooling for 1 minute and cooled to -78 ° C. A 40% methylamine methanol solution (48 μl) was added to the reaction solution, and the temperature was raised to -30 ° C over 1.5 hours, and then cooled to -78 ° C. Diisopropylethylamine (0.12 ml) and 2-chloroethyl isocyanate (0.13 ml) were added sequentially, and then 1.5
The temperature was raised to 0 ° C over time, and the mixture was stirred under ice cooling for 30 minutes. The reaction solution was diluted with ethyl acetate, washed successively with pH 7 phosphate buffer and saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel, 12 g, developing solvent: ethyl acetate → ethyl acetate-ethanol, 4: 1).
The title compound (25 mg) having a purity of about 50% was obtained as a colorless oil. IR (neat):. 2960, 2970, 1780, 1740, 1715 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3H, d, J = 6.4 Hz), 1.6-
2.5 (4H, m), 3.01 (3H, s), 3.33 (2H, t, J = 7.6 H
z), 3.6-3.9 (1H, m), 3.79 (1H, dd, J = 3.6 and 6.6
Hz), 3.8-3.9 (2H, m), 4.02 (2H, t, J = 7.6 Hz), 4.
1-4.2 (1H, m), 4.6-4.9 (5H, m), 5.17 (1H, dq, J =
6.6 and 6.4 Hz), 5.2-5.5 (4H, m), 5.8-6.1 (2H, m). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl]- 11
-[2- [N-Methyl-N- (thiazolin-2-yl) amino] ethyl]-
4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylate purity of about 25% of the compound obtained by the method of (1) a (140 mg) The reaction was conducted in the same manner as in Example 2 to obtain the title compound (23 mg) as a white solid. IR (KBr):. 2960, 2850, 1760, 1635, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3H, d, J = 6.4 Hz), 1.6-2.4
(4H, m), 3.16 (3H, s), 3.4-3.6 (6H, m), 3.9-4.0
(4H, m), 4.17 (1H, dd, J = 3.4 and 8.2 Hz), 4.30
(1H, dq, J = 5.4 and 6.4 Hz), 4.84 (1H, d, J = 8.2
Hz).

Example 69 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [3- [N-methyl-N- ( Thiazoline-2
-Yl) amino] propyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate allyl Compound obtained by the method of Reference Example 8 (200 mg) in Example 6
The title compound with a purity of about 40% was reacted in the same manner as in 8- (1).
(158 mg) was obtained as a pale yellow oil. IR (neat):. 2930, 2850, 1780, 1760, 1715 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3H, d, J = 6.4 Hz), 1.5-
2.4 (6H, m), 2.97 (3H, s), 3.32 (2H, t, J = 7.6 H
z), 3.6-3.8 (1H, m), 3.78 (1H, dd, J = 3.6 and 6.8
Hz), 3.8-3.9 (2H, m), 4.01 (2H, t, J = 7.6 Hz), 4.
13 (1H, dd, J = 3.6 and 8.2 Hz), 4.5-4.9 (5H, m),
5.17 (1H, dq, J = 6.8 and 6.4 Hz), 5.2-5.5 (4H,
m), 5.8-6.1 (2H, m). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -11
- [3- [N-methyl--N- (thiazoline-2-yl) amino] propyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]}
Sodium undeca-1-ene-2-carboxylate The compound (155 mg) obtained by the method (1) having a purity of about 40% was reacted in the same manner as in Example 2 to give the title compound (41 mg) as a white solid. Got as. IR (KBr):. 2930, 2850, 1760, 1640, 1595 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3H, d, J = 6.4 Hz), 1.5-2.2
(6H, m), 3.18 (3H, s), 3.4-3.7 (6H, m), 3.9-4.0
(2H, m), 4.01 (2H, t, J = 7.6 Hz), 4.17 (1H, dd, J
= 3.4 and 8.4 Hz), 4.30 (1H, dq, J = 5.2 and 6.4 H
z), 4.51 (1H, d, J = 8.4 Hz).

Example 70 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [3- (1-methyl-2-imidazoline -
2-ylthio) propyl] -4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid allyl compound obtained by the method of Reference Example 8 (100 mg ) And 1-methylimidazolidine-2-thione (29 mg) were reacted in the same manner as in Example 1 to obtain the title compound (79 mg) as a pale yellow oil. IR (neat):. 2930, 2850, 1780, 1740, 1715 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3H, d, J = 6.4 Hz), 1.6-
2.1 (6H, m), 2.79 (3H, s), 3.09 (2H, t, J = 6.8 H
z), 3.3-3.4 (2H, m), 3.6-3.9 (6H, m), 4.13 (1H, d
d, J = 3.6 and 8.4 Hz), 4.59 (1H, d, J = 6.4 Hz),
4.6-4.9 (4H, m), 5.17 (1H, dq, J = 6.8 and 6.4 H
z), 5.2-5.5 (4H, m), 5.8-6.1 (2H, m). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -11
-[3- (1-Methyl-2-imidazolin-2-ylthio) propyl]-
4-oxo-8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] sodium undec-1-ene-2-carboxylate The compound (76 mg) obtained by the method of (1) was used in the same manner as in Example 2. To give the title compound (37 mg) as a white solid. IR (KBr):. 2960, 2930, 2850, 1760, 1585 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3H, d, J = 6.4 Hz), 1.6-2.2
(6H, m), 3.06 (3H, s), 3.1-3.3 (2H, m), 3.4-3.6
(1H, m), 3.57 (1H, dd, J = 3.6 and 5.0 Hz), 3.8-4.
0 (6H, m), 4.15 (1H, dd, J = 3.6 and 8.4 Hz), 4.30
(1H, dq, J = 5.0and 6.4 Hz), 4.82 (1H, d, J = 8.4
Hz).

Example 71 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- (4-pyridylthiomethyl) -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undeca-
Allyl 1-ene-2-carboxylate The compound (500 mg) obtained by the method of Reference Example 14 and 4-mercaptopyridine (145 mg) were reacted in the same manner as in Example 1 to give the title compound (420 mg) as a pale yellow color. Obtained as an oil. IR (neat):. 2950, 2850, 1790, 1740, 1720 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3H, d, J = 6.4 Hz), 1.8-
2.2 (2H, m), 3.2-3.4 (2H, m), 3.80 (1H, dd, J = 3.
6 and 6.6 Hz), 3.8-4.1 (3H, m), 4.19 (1H, dd, J =
3.6 and 8.2 Hz), 4.6-4.8 (5H, m), 5.17 (1H, dq, J
= 6.6 and 6.4 Hz), 5.2-5.5 (4H, m), 5.8-6.1 (2H,
m), 7.1-7.2 (2H, m), 8.4-8.5 (2H, m). (2) (5S, 6S, 7S, 11S) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- (4-pyridylthiomethyl) -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate sodium (1) Compound obtained by the method (100) was reacted in the same manner as in Example 2 to obtain the title compound (66 mg) as a white solid. IR (KBr):. 2950, 2920, 2850, 1760, 1580 cm -1 1 H-NMR (D 2 O) δ: 1.25 (3H, d, J = 6.3 Hz), 1.8-2.2
(2H, m), 3.4-3.6 (2H, m), 3.56 (1H, dd, J = 3.6 an
d 5.1 Hz), 3.8-3.9 (1H, m), 3.9-4.0 (2H, m), 4.06
(1H, dd, J = 3.6 and 8.5 Hz), 4.27 (1H, dq, J = 5.
1 and 6.3 Hz), 4.79 (1H, d, J = 8.5 Hz).

Example 72 (1) (5S, 6S, 7S, 11R) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -11- [2- [1- (2-methoxyethyl) ) -2-
Imidazolin-2-ylthio] ethyl] -4-oxo-8-oxa-
3-Azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylic acid allyl compound (100 mg) obtained by the method of Example 19- (2) of JP-A-5-86062 and 1- ( 2-Methoxyethyl) imidazolidine-2-thione (38 mg) was reacted in the same manner as in Example 9 to obtain the title compound (86 mg) as a pale yellow oil. IR (neat):. 2930, 2850, 1780, 1740, 1715 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3H, d, J = 6.2 Hz), 1.6-
2.4 (4H, m), 2.9-3.1 (2H, m), 3.2-3.5 (6H, m), 3.3
7 (3H, s), 3.7-3.9 (6H, m), 4.15 (1H, dd, J = 3.6 a
nd 8.4 Hz), 4.6-4.9 (5H, m), 5.17 (1H, dq, J = 6.6
and 6.2 Hz), 5.2-5.5 (4H, m), 5.8-6.1 (2H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -11
-[2- [1- (2-Methoxyethyl) -2-imidazolin-2-ylthio] ethyl] -4-oxo-8-oxa-3-azatricyclo [5.4.
0.0 ³ ' ⁶ ] Sodium undec-1-ene-2-carboxylate The compound (84 mg) obtained by the method of (1) was reacted in the same manner as in Example 2 to give the title compound (46 mg) as a white solid. Got as. IR (KBr):. 2960, 2930, 2860, 1760 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3H, d, J = 6.4 Hz), 1.6-2.4
(4H, m), 3.0-3.2 (2H, m), 3.41 (3H, s), 3.6-3.8 (6
H, m), 3.8-4.1 (6H, m), 4.18 (1H, dd, J = 3.4 and
8.4 Hz), 4.31 (1H, dq, J = 5.2 and 6.4 Hz), 4.82
(1H, d, J = 8.4Hz).

Example 73 (1) (5S, 6S, 7S, 11S) -5-[(R) -1- (allyloxycarbonyloxy) ethyl] -4-oxo-11- (pyridazin-4-ylthiomethyl) -8-Oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ]
Allyl undeca-1-ene-2-carboxylate The compound (254 mg) obtained by the method of Reference Example 14 and 4-mercaptopyridazine (73 mg) were reacted in the same manner as in Example 9 to give the title compound (202 mg) Was obtained as a pale yellow oil. IR (neat):. 2930, 2860, 1785, 1740 cm -1 1 H-NMR (CDCl 3) δ: 1.42 (3H, d, J = 6.2 Hz), 1.8-
2.2 (2H, m), 3.2-3.5 (2H, m), 3.82 (1H, dd, J = 3.
6 and 6.4 Hz), 3.8-4.2 (3H, m), 4.22 (1H, dd, J =
3.6 and 8.6 Hz), 4.6-4.8 (5H, m), 5.18 (1H, dq, J
= 6.4 and 6.2 Hz), 5.2-5.5 (4H, m), 5.8-6.1 (2H,
m), 7.3-7.4 (1H, m), 8.9-9.0 (2H, m). (2) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- (pyridazin-4-ylthiomethyl) -8-oxa-3
-Azatricyclo [5.4.0.0 ³ ' ⁶ ] sodium undeca-1-ene-2-carboxylate The compound (195 mg) obtained by the method of (1) was reacted in the same manner as in Example 2 to give the title compound (93 mg ) Was obtained as a white solid. IR (KBr):. 2960, 2920, 2850, 1760, 1595 cm -1 1 H-NMR (D 2 O) δ: 1.26 (3H, d, J = 6.6 Hz), 1.8-2.2
(2H, m), 3.4-3.7 (3H, m), 3.8-4.1 (3H, m), 4.14 (1
H, dd, J = 3.6 and 8.8 Hz), 4.29 (1H, dq, J = 5.4 a
nd 6.6 Hz), 4.84 (1H, d, J = 8.8 Hz), 7.6-7.7 (1H,
m), 8.88 (1H, d, J = 5.8 Hz), 9.0-9.1 (1H, m). (3) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl]- Four-
Oxo-11- (pyridazin-4-ylthiomethyl) -8-oxa-3
- azatricyclo [5.4.0.0 ^{3 '6]} undec-1-ene-2-carboxylic acid 1 compound obtained by the method of (cyclohexyloxycarbonyloxy) ethyl (2) (50 mg) and cyclohexyloxy acid 1- Iodoethyl (56 mg) was reacted in the same manner as in Example 3 to obtain the title compound (51 mg) as a white solid. IR (KBr):. 2950, 2870, 1790, 1760 cm -1 1 H-NMR (CDCl 3) δ: 1.2-2.2 (12H, m), 1.29 (1.5H,
d, J = 6.4 Hz), 1.31 (1.5H, d, J = 6.4 Hz), 1.58
(1.5H, d, J = 5.2 Hz), 1.60 (1.5H, d, J = 5.2 Hz),
3.2-3.4 (2H, m), 3.6-4.4 (6H, m), 4.6-4.7 (2H, m),
6.89 (1H, q, J = 5.2 Hz), 7.3-7.4 (1H, m), 8.95 (1
H, d, J = 5.6 Hz), 9.0-9.1 (1H, m).

(4) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-oxo-11- (pyridazin-4-ylthiomethyl) -8-oxa-3-azatricyclo [5.4.0.0 ³ ' ⁶ ] Undeca-
1-Ene-2-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl (2) The compound (50 mg) obtained by the method and 1-iodoethyl isopropoxycarboxylic acid (48 mg) were used in the same manner as in Example 3. The title compound (45 mg) was obtained as a white solid. IR (KBr):. 2980, 2930, 2870, 1790, 1760 cm -1 1 H-NMR (CDCl 3) δ: 1.31 (6H, d, J = 6.0 Hz), 1.57
(1.5H, d, J = 5.2 Hz), 1.60 (1.5H, d, J = 5.2 Hz),
1.6-2.2 (2H, m), 3.3-3.4 (2H, m), 3.6-4.4 (6H, m),
4.65 (1H, d, J = 8.8 Hz), 4.8-5.0 (1H, m), 6.8-6.
9 (1H, m), 7.3-7.4 (1H, m), 8.95 (1H, d, J = 5.6 H
z), 9.0-9.1 (1H, m). (5) (5S, 6S, 7S, 11R) -5-[(R) -1-hydroxyethyl] -4-
Oxo-11- (pyridazin-4-ylthiomethyl) -8-oxa-3
-Azatricyclo [5.4.0.0 ³ ' ⁶ ] undec-1-ene-2-carboxylate 1- (ethoxycarbonyloxy) ethyl (2) The compound (50 mg) obtained by the method and 1-iodoethyl ethoxycarboxylate ( 46 mg) was reacted in the same manner as in Example 3 to obtain the title compound (45 mg) as a white solid. IR (KBr):. 2970, 2880, 1780, 1760 cm -1 1 H-NMR (CDCl 3) δ: 1.2-1.4 (6H, m), 1.58 (1.5H, d,
J = 5.2 Hz), 1.60 (1.5H, d, J = 5.2 Hz), 1.7-2.2
(2H, m), 3.2-3.4 (2H, m), 3.6-4.4 (8H, m), 4.65 (1
H, d, J = 8.7 Hz), 6.88 (1H, q, J = 5.2 Hz), 7.3-
7.4 (1H, m), 8.94 (1H, d, J = 5.5 Hz), 9.0-9.1 (1H,
m). The chemical structural formulas of compounds whose chemical structural formulas are not shown in the examples are as follows.

Embedded image

[Test Example] Minimum inhibitory concentration (MIC) Minimum inhibitory concentration of a test compound [MIC: minimal inh
ibitory concentration) (unit: μg / ml)] was determined by the agar dilution method. That is,
Aqueous solution of test compound diluted by serial dilution method 0.25m
Pour l into a petridish, then pour in 9.75 ml of Muller-Hinton agar and mix. On the mixed agar plate, the suspension of test bacteria
(Approx. 10 ⁶ CFU / ml). Incubate at 37 ℃ overnight (in
After cubation, the lowest concentration of the test compound that completely inhibits the growth of the test strain is defined as MIC. Test bacterium: H. influenzae NN400 Test results:

[Table 1] From the above results, it is clear that the carbapenem compound of the present invention has an excellent antibacterial action against strains clinically regarded as important.

[0123]

INDUSTRIAL APPLICABILITY Since the novel carbapenem compound (I) obtained in the present invention has excellent properties as an antibacterial agent such as having an antibacterial activity having a broad spectrum, the present invention provides a novel clinically useful antibacterial agent. Can be provided.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location A61K 31/44 A61K 31/44 31/495 31/495 31/50 31/50 31/505 31 / 505 31/53 31/53 C07D 495/14 C07D 495/14 F 519/00 301 519/00 301 // (C07D 519/00 487: 04 491: 147)

Claims (6)

[Claims] 1. The formula: [Wherein R ¹ is an optionally substituted lower alkyl group, X is an oxygen atom or a sulfur atom, R is a lower alkylene group, and A is a bond, an oxygen atom, a sulfur atom (mono- or di-oxidized). May be present) or -NR '-(R'
Represents a hydrogen atom or a lower alkyl group), and Q represents an optionally substituted non-quaternized nitrogen-containing heterocyclic group. ] The carbapenem compound represented by these, its ester, or its salt. 2. -RAQ is represented by: The compound according to claim 1, which is 3. R ¹ is The compound according to claim 1, which is 4. The formula: And a compound or an ester or salt thereof represented by the formula: and a compound or an ester or a salt thereof represented by the formula: Q-A-B [wherein, W and B are groups capable of leaving by reacting with each other,
Other symbols have the same meaning as in claim 1.]
The method according to claim 1, wherein the reaction is accompanied by elimination of B, and the protecting group is removed as necessary. 5. A medicine containing the compound according to claim 1. 6. The medicine according to claim 5, which is an antibacterial agent.