JPS6383082A - Production of tetrahydrofran carboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A 5-oxo-2-tetrahydrofuranecarboxylic acid derivative expressed by formula I (R<1> represents amino group or organic residue bound through N atom; R<2> represents carboxyl or derivative group thereof; n is 1 or 2). EXAMPLE:4-Nitrobenzyl 2-[(3S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl]-5- oxotetrahydrofuran-2-carboxylate. USE:An antimicrobial agent. PREPARATION:A compound expressed by formula II (R<1>' represents organic residue bound through N atom; R<2>' represents group convertible into carboxyl group; R<3> represents hydrocarbon residue) is subjected to cyclization reaction, and, if necessary, further subjected to conversion reaction of group R<1>' and/or group R<2>'.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a tetrahydrofurancarboxylic acid derivative and a novel 5-year-old xo-2-tetrahydrofurancarboxylic acid derivative having antibacterial activity produced by the present invention.

A new type of monocyclic β-lactam antibiotic with a sulfo group has been discovered and reported from nature [Nichi +
- (Nature), Vol. 289, p. 590 (1981
), Vol. 291, p. 489 (1981)].

Furthermore, the synthesis of l-sulfo-2-azetidine derivatives has also been reported (see, for example, JP-A-55-164672, JP-A-56-125362, etc.). Furthermore, the synthesis of monocyclic β-lactams having an acidic group other than a sulfo group at the 1-position has also been reported [for example, W, Durc
Angewandte Hemi International Edition (Angewandte Ch.
emie, International Editorial
on) Vol. 24, p. 180 (1985).

On the other hand, TA, a new antibiotic that exhibits antibacterial activity against Durham-positive and Durham-negative bacteria, was developed from new bacterial species belonging to the genus Enbetobacter and Rhizobacter isolated from soil.
N-588 (hereinafter sometimes abbreviated as rTAN-588J) was discovered. Furthermore, its derivatives were also synthesized,
For example, it is disclosed in RPC Publication No. 0191989.

The antibiotic TAN-588 has a completely new, hitherto unknown skeleton in which 5-oxo-2-tetrahydrofurancarboxylic acid is bonded to the nitrogen atom of the 3-oxoisoxazolidine ring.

Problems to be Solved by the Invention The present invention provides a compound having a completely new skeleton in which a 5-oxotetrahydrofuran ring, which is a partial structure of TAN-588, is introduced at the 1-position of a β-lactam ring or a γ-lactam ring. Regarding the production method, the object is to produce a compound exhibiting antibacterial activity by the production method.

Means for Solving the Problems As a result of extensive research into various compounds having the skeleton of TAN-588 or its partial structure, the present inventors found that
The 5-oxotetrahydrofuran ring of TAN-588,
It has been discovered that a compound introduced into the 1-position of a β-lactam ring or a γ-lactam ring can be chemically produced, and that the compound thus produced has excellent antibacterial activity.
The present invention has now been completed.

That is, the present invention provides formula E in which R'' represents an organic residue via nitrogen, R'' represents a group convertible to a carboxyl group, R3 represents a hydrocarbon residue, and n represents an integer of 1 or 2. ] is subjected to a ring-closing reaction, and optionally R'' and/or R2'
[wherein R1 is an amino group or an organic residue via nitrogen, R2 is a carboxyl group or a group derived therefrom, and n has the same meaning as above] Process for producing the represented compound or its salt, formula [wherein R", R"' and n have the same meanings as above]
The compound represented by R is subjected to a ring-closing reaction, and if desired, R
A method for producing compound (I) or a salt thereof, characterized in that it is subjected to a conversion reaction of I' and (or) R2', and a compound represented by the formula [wherein R1 and R1 have the same meanings as above] or its salt.

In the above formula, examples of organic residues via nitrogen represented by R1 include acylamino, ureido, thioureido, alkenylamino, thioamino, silylamino, phosphoamino, groups represented by the formula -CO-CO-NH-, etc. Examples include amino substituted via carbon.

Examples of the acyl in the above acylamino include the acyl group substituted at the 6-position amino group of conventionally known penicillin derivatives, the acyl group substituted at the 7-position amino group of cephalosporin derivatives, and the like.

Examples of the acylamino group include, for example, the formula % [wherein R4 is hydrogen, alkyl] (In the description of each group in this specification, a group with ' is a substituent, even if it has a substituent. ), alkenyl 1. cycloalkyl 1
．． Aryl 0. Heterocycle 1. alkoxy 1 or aryloxy 7, R5 represents hydrogen or alkyl 1, R4
includes the case where R5 and ring 1 are formed. Group represented by formula % formula % [wherein R8 is hydrogen, amino acid residue 1, protecting group for amino group or formula R''(CHt)n' C (= A)
(In the formula, R@ represents a heterocyclic ring which may have a carbonyl group 1.alkoxy or amino, n' represents 0°1 or 2, and A represents 0 or S, respectively.) , R7 is alkyl 1. Aryl 1° represents cycloalkenyl 1 or heterocycle 1, respectively. The group represented by formula % formula % [wherein R'' is the formula R''-C- (wherein R''(i7'/l
zto -RI M Kyl 1, heterocycle 1 or aryl 0, R'' is hydrogen, alkyl 1. alkenyl 2. cycloalkyl 1゜heterocycle 1
or a group represented by the formula -RIff-RlI (wherein R" represents alkylene", cycloalkylene or alkenylene, and RlI represents aryl 1.carboxy" or its ester or mono- or dialkylamide, respectively), respectively. R
” represents a chemical bond or the formula -Co-NH-CH- (in the formula,
R” is A R” Kill 1. Represents aryl 1 or heterocycle 1. ), respectively. The group represented by ko.

A group represented by the formula % formula % [wherein RlI represents aryl 6, heterocycle 1 or cycloalkenyl, and R1? represents hydrogen, hytomyxyl, sulfamoyl, sulfo, sulfooxy or acyloxy], respectively.

formula %formula% [In the formula, R18 is alkyl", cyano, aryl".

Aryloxy", alkenylene 1 heterocycle 1. amino 1
or a group represented by the formula R"'-C(=S)- (in the formula, RI8' represents alkoxy), Rls represents a chemical bond or -8-, respectively; a group represented by In addition, the ureido or thioureido has the formula [wherein R" and RlI are the same or different and represent hydrogen, alkyl", aryl 1. heterocycle" or cycloalkyl, and A represents O or S, respectively. show. Examples include groups represented by .

In addition, the formula R -C- in R9 is a syn isomer represented by the formula -R1t R<C->, an anti-isomer represented by the formula % Rl l-C-, or 1ff
O represents a mixture thereof.

As an example of the organic residue represented by R1 above, amino substituted through carbon, for example, the formula % formula % [wherein R'''' is alkyl 1. Indicates aryl", alkenyl" or heterocycle 1. ].

Formula [wherein R'' and R'' are the same or different and represent alkyl'', aryl 7 or alkenyl, respectively; R
23 and R″4 together with adjacent nitrogen atoms to form a multi-ring.]

Formula [wherein R'', R'' and R'' are the same or different, alkyl'', aryl1. "alkenyl" respectively, and includes the case where R" and R" or R" together with the adjacent nitrogen atom form a heterocycle 1. Examples include groups represented by .

Examples of alkenylamino as an example of the nitrogen-mediated organic residue represented by R1 include the formula [wherein R1 and R1 are the same or different, hydrogen,
Alkyl1. Aryl 1. cycloalkyl, amino "or heterocycle", including cases where R1 and R" together with adjacent carbon atoms form cycloalkyl 1 or heterocycle 1.

As an example of thioamino as an example of the nitrogen-mediated organic residue represented by R1 above, for example, the formula % formula % [wherein R'' represents alkyl 1 or aryl 1, and n'' represents 0.1 or 2, respectively] show. ] Examples include groups represented by the following.

As an example of silylamino as an example of the nitrogen-mediated organic residue represented by g2R' above, for example, the formula [wherein R'', IN'' and R33 are the same or different and represent alkyl 0 or aryl'', This includes the case where these form a cyclic group.R" represents hydrogen or silyl 1. ] Examples include groups represented by the following.

As an example of amino phosphoric acid as an example of the nitrogen-mediated organic residue represented by R1 above, for example, the formula [wherein R'' and R3I' are the same or different,
Alkyl1. Aryl 1. It represents alkoxy 1 or aryloxy", including the case where R35 and R" form a heterocycle 1. ] Examples include groups represented by the following.

An example of a group represented by the formula -Go-CO-NH- as an example of the nitrogen-mediated organic residue represented by R1 above is:
For example, the formula % formula % [wherein R37 is hydrogen, alkyl", alkoxy", allinoy, aryloxy0. Examples include groups represented by "heterocycle", which represents amino 1.

In the above formula, the nitrogen-mediated organic residue represented by R1 preferably has a molecular weight of up to 500, for example.

The alkyl in the group represented by R1 in the above formula is preferably a linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n
-propyl, isopropyl, n-butyl, isobutyl,
Examples include 5eC-butyl, t-butyl, 1゜l-dimethylbrobyl, n-pentyl, isopentyl, n-hexyl, isohexyl and the like.

Examples of the substituent that the alkyl group may have include halogen, oxo, thioxo, and nitro.

Amino (which may have alkyl, alkenyl, cycloalkyl, aryl, acyl, carbamoyl, N-sulfocarbamoyl as a substituent), sulfo, cyano, hydroxy, carboxy (which may be esterified with alkyl). ), cycloalkyl, cycloalkenyl, alkoxy (which may have amino, hydroxy, carboxy, halogen, aryl, cycloalkyl, alkoxy as a substituent), aryl (halogen, alkyl, alkoxy).

Alkylamino, amino, carbamoyl, sulfo, alkylsulfonyl, cyano. It may have hydroxy, carboxy, nitro, acyloxy, aralkyloxy, or sulfooxy as a substituent. ), arylcarbonyl which may have the same substituent as the above aryl, aryloxy which may have the same substituent as the above aryl, tro, oxo, aryl, alkenylene, halogenoalkyl on the heterocycle , alkylsulfonyl, alkyl, alkoxy, alkylamino, amino, halogen, carbamoyl, hydroxy, cyano, carboxy,
It may have sulfo as a substituent. ), acyl (
It may have arylcarbonylhydrazino as a substituent, which may have hydroxy, halogen, amino, or nitro as a substituent. ) Acyloxy, alkoxycarbonyl, alkoxycarbonyloxy (optionally substituted with halogen), acyloxy-ethoxy, aralkyl (alkyl, alkoxy, halogen, amino, hydroxy, nitro).

It may have cyano, carbamoyl, or sulfamoyl as a substituent. ), aralkyloxy (which may have acyloxy, alkyl, alkoxy, halogen, amino, hydroxy, nitro, cyano, carbamoyl, sulfamoyl as a substituent), hydroxysulfonyloxy, alkylsulfonyloxy, arylsulfonyloxy, alkyl Sulfonyl, aminosulfonyl, alkylsulfinyl, arylsulfonyl, alkylsulfinyl.

Alkylthio (may have cyano, halogen, carboxy, alkylamino, imino, carbamoyl, acylamino as a substituent), arylthio, heterocyclic group-thio (cyano, hydroxy, amino, alkylamino, alkyl, halogen, may have oxo as a substituent), heterocycles (cyano, hydroxy, amino, alkylamino, alkyl).

It may have halogen or oxo as a substituent. )
-alkyl-thio, iminomethylamino, iminoethylamino, silyl (which may have alkyl or aryl as a substituent), silyloxy which may have the same substituent as the above-mentioned silyl.

Alkyloxycarbonyl 1-arylcarbonyl (may have acyloxy, halogen, amino, hydroxy, alkoxy, or sulfamoyl as a substituent)
, phthalimide, succinimide, dialkylamino,
dialkylaminocarbonyl, arylcarbonylamino, carbamoyl, carbamoyloxy, N-sulfocarbamoyloxy, alkylcarbonylcarbamoyloxy (which may be substituted with halogen), and alkoxyimino formula 1 are the same or different and are hydroxyl group or amino group shows. ) and the like.

In the above formula, the alkylene represented by R'' preferably has 1 to 6 carbon atoms, and examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene.

Examples of substituents that the alkylene group may have include halogen, amino, hydroquine, alkoxy, carboxy, carbamoyl, cyano, and nitro.

In the above formula, the cycloalkyl in the group represented by l' (l, the cycloalkyl in cycloalkyloxy, or the cycloalkyl forming a ring) preferably has 3 to 8 carbon atoms, such as cycloalkyl. Examples include propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

Examples of substituents that the cycloalkyl group may have include halogen, nitro, amino, hydroxy, sulfo, cyano, carboxy, oxo, thioxo, and the like.

Examples of the cycloalkylene in the group in the above formula include those in which the above cycloalkyl has another bond.

Aryl in the group represented by R1 in the above formula
Aryl in l), arylcarbonyl, aryloxycarbonyl, aryloxy or arylthio is, for example, phenyl, naphthyl. biphenyl,
Examples include anthryl and indenyl.

Examples of substituents that the aryl group may have include halogen, nitro, cyano, amino (which may have alkyl, alkenyl, cycloalkyl, and aryl as a substituent), sulfo, mercapto, and hydroxy. , carboxy, acyl, sulfoxy, sulfamoyl, carbamoyl, alkyl (which may have amino, halogen, hydroxy, cyano, or carboxy as a substituent), alkoxy, aralkyloxy, alkylsulfonamide.

Examples include methylenedioxy, alkylsulfonyl, and alkylsulfonylamino. Also, cycloalkyl and fused rings (e.g., tetrahydronaphthyl).

indanyl, acenaphthyl, etc.).

The alkoxy in the group represented by R1 in the above formula preferably has 1 to 6 carbon atoms, and examples thereof include:
For example, methoxy, ethoxy-propoxy, I-propoxy, n-butoxy, i-butoxy, t-butoxy,
Examples include n-pentyloxy and n-hexyloxy.

Examples of substituents that the alkoxy group may have include halogen, nitro, amino, hydroxy, sulfo, cyano, carboxy, and aryl having tho, amino, hydroxy, alkyl, and alkoxy as substituents. good. ), silyl (which may have alkyl, aryl, or aralkyl as a substituent), and the like.

The alkylthio in the group represented by R1 in the above formula is preferably one having 1 to 6 carbon atoms, such as methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio. , n-pentylthio, n-hexylthio, and the like. Examples of the substituent which may have the alkylthio group include the same substituents as the alkoxy substituents described above.

The alkenyl in the group represented by RI in the above formula is preferably one having 1 to 6 carbon atoms, such as methylene and vinyl.

Allyl, isopropenyl! -Propenyl.

2-butenyl, 3-methyl-3-butenyl, 1,3-butadienyl,! , 3-pentagenyl, 4-pentaenyl, 1,3-hexagenyl, ethylidene.

Examples include propylidene, isopropylidene, and butylidene.

Examples of the substituents that the alkenyl group may have include halogen, nitro, amino (which may have acyl as a substituent), sulfo, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, aryl ( aryl), acyl, etc.

The alkenylene in the group represented by RI in the above formula preferably has 2 to 6 carbon atoms, such as vinylene, l-propenylene, 2-butenylene, and 2-pentenylene.

Examples include 1,3-hexadienylene.

The substituents that the alkenylene group may have include:
Examples include halogen, cyano, and carbamoyl.

In the above formula, R? The cycloalkenyl represented by , RI II is preferably one having 3 to 8 carbon atoms, such as, for example! -Cyclopropenyl,! -Cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl.

l-cyclohecymonyl. 2-Cyclohecimonyl. Examples include 3-cyclohexenyl, ■-cyclohebutenyl, and 1°4-cyclohexagenyl.

Examples of the substituents that the cycloalkenyl group may have include halogen, nitro, and amino.

Examples include sulfo, cyano, hydroxy, carboxy, carbamoyl, and sulfamoyl.

The heterocycle in the group represented by R1 in the above formula or the heterocycle formed by these groups includes, for example, a 5- to 7-membered heterocyclic group containing one sulfur atom, nitrogen atom, or oxygen atom; a 5- to 6-membered heterocyclic group containing 4 nitrogen atoms,
Examples include 5- to 6-membered heterocyclic groups containing 1 to 2 nitrogen atoms and 1 sulfur atom or oxygen atom, and these heterocyclic groups include 6-membered cyclic groups containing 2 or less nitrogen atoms, benzene rings, Alternatively, it may be fused with a 5-membered ring group containing one sulfur atom.

Specific examples of the above-mentioned heterocyclic groups include pyridine-(2-, 3- or 4-yl), pyrimidine-(2-
, 4- or 5-yl), pyrazin-2-yl, pyridazin-(3- or 4-yl), piperazin-1-yl, piperidin-1-yl, pyrazol-(1-, 3- or 4-yl) ), 4H-pyran-3-yl, 4H-thiopyran-3-yl, thiazole-(2-, 4- or 5
-yl), isothiazol-(3-,4- or 5-yl), oxazol-(2-94- or 5-yl),
isoxazole-(3-04- or 5-yl), pyrido[2,3-d]pyrimidine-(2-,3-,4-,
5- or 7-yl).

Benzo[1,2-b]-4H-pyran-3-yl, I.

8-naphthyridine (2-,3-,4-,5-,6- or 7-yl), l,7-naphthyridine-(2-,3-,
4-,5-,6- or 7-yl), 1,6-naphthyridine-(2-,3-,4-,5-,7- or 8-yl), 1,5-naphthyridine-(2- , 3-, 4-.

6-17- or 8-yl), 2,7-naphthyridine-
(1-, 3-, 4-, 5-, 6- or 8-yl).

2.6-naphthyridine-(1-,3-,4-,5-,7
- or 8-yl), quinoline-(2-,3-,4+.

5-. 6-. 7- or 8-yl), Cheno[2,3-
b] Pyridazine (2- or 3-yl), tetrazol-(1- or 5-yl), 1,3.5-thiadiazole-(2- or 4-yl), 1,3.5-thiadiazole-( 2- or 4-yl), triazin-2-yl, l, 2.3-) lyazol-(4- or 5-yl), 1,3.5-) lyazol-(2- or 5-yl), Thiophene-(2- or 3-yl), pyrrole-
(1-, 2- or 3-yl), furan-(2- or 3-yl), pyrrolidin-1-yl, imidazolidine-
(1-, 2- or 4-yl), dichetan-2-yl, tetrahydrofuran-(2-, 3- or 4-yl)
, tetrahydrofuran-(l- or 3-yl), benzo[1,2-b]thiophene=(2- or 3-yl)
, indole-(l-12- or 3-yl), isoindolizin-(l-92- or 3-yl), and the like.

Examples of substituents that the heterocyclic group may have include amino (which may have acyl, halogen-substituted alkylacyl, phenyl, or alkyl as a substituent);
Halogen, nitro, sulfo, cyano, hydroxy, carboxy, oxo, thioxo + Cl-1° alkyl [aryl, halogen, amino, hydroxy.

It may have carboxy, alkoxy, alkylsulfonyl, dialkylamino, or phosphoric acid (which may have alkyl as a substituent) as a substituent. ], cycloalkyl, alkoxy (halogen.

It may have hydroxy as a substituent. ).

Acyl, aryl having 1 to 4 carbon atoms (halogen, nitro,
Alkyl, alkoxy, amino, sulfo, hydroxy,
It may have cyano as a substituent. ).

oxo, thioxo, amino acid residue-thio (examples of amino acid residues include those mentioned below), CI-+oacyl-thio [aryl;

Halogen, amino, hydroxy, carboxy, alkoxy, alkylsulfonyl, dialkylamino.

Phosphoric acid (may have alkyl as a substituent)
may have as a substituent. Co, heterocyclic ring (may have alkyl, alkoxy, halogen, nitro, cyano, carboxy, formyl, alkylsulfonyl as a substituent) 1 formula R40-CH=N- [wherein r(
” stands for heterocycle (alkyl, alkoxy, halogen, nitro, cyano, hydroxy).

It may have carboxy, formyl, or alkylsulfonyl as a substituent. ) is shown. ] and the like.

In the above formula, examples of the ring formed by R4 together with R5 include phthaloyl, succinyl, maleoyl, and cytotheconoyl. Examples of the ring formed with glutaryl, adipoyl, etc. include 2.2.
-dimethyl-5-oxo-4-phenyl-imidazolidine and the like can also be mentioned.

Examples of substituents that the cyclic group may have include halogen, nitro, amino, hydroxy, sulfo, cyano, and carboxy.

The acyl in acyloxy in the group represented by R1 in the above formula preferably has 1 to 4 carbon atoms, and examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, etc., and the substituents thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, etc. Examples include alkyl (which may have amino, halogen, cyano, alkoxy, carboxy, or hydroxy as a substituent).

In the above formula, the amino acid residue represented by R8 includes, for example, glycyl, alanyl, valyl, leucyl, isoleucyl, seryl, threonyl, cysteinyl, cystyl,
Examples include methionyl, α- or β-asparagyl, α- or γ-glutamyl, lysyl, arginyl, phenylalanyl, phenylglycyl, tyrosyl, hisdecyl, tryptophanyl, prolyl, and the like.

Examples of substituents that the amino acid residue may have include halogen, hydroxy, sulfo, carboxy, cyano, alkylamino, aralkyloxycarbonyl,
Examples include aralkyloxy and guanidino.

In the above formula, the protecting group for the amino group represented by R8 is:
For example, those used for this purpose in the field of β-lactam and peptide synthesis are conveniently employed. For example, phthaloyl, 4-nitrobenzoyl, 4-tert-butylbenzoyl, 4-tert-butylbenzenesulfonyl, benzenesulfonyl.

Aromatic acyl groups such as toluenesulfonyl, such as formyl, acetyl, propionyl, monochloroacetyl,
Dichloroacetyl, trichloroacetyl.

Aliphatic acyl groups such as methanesulfonyl, ethanesulfonyl, trifluoroacetyl, malonyl, succinyl, e.g. methoxycarbonyl, ethoxycarbonyl, t
-butoxycarbonyl, isopropoxycarbonyl, 2
-cyanoethoxycarbonyl, 2°2.2-)dichloroethoxycarbonyl. benzyloxycarbonyl, 4-
Nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl. Esterified carboxyl groups such as acetylmethyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, (hexahydro-IH-azepin-l-yl)
Methylene groups such as methylene, sulfonyl groups such as 2-amino-2-carboxyethylsulfonyl.

Furthermore, for example, trityl, 2-nitrophenylthio,
Protecting groups for amino groups other than acyl groups include benzylidene, 4-nitrobenzylidene, di- or trialkylsilyl, benzyl, and 4-nitrobenzyl. The selection of the protecting group is not particularly limited in the present invention, but monochloroacetyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, and 4-nitrobenzyloxycarbonyl are particularly preferred.

Examples of the substituent in the carboxy group which may have a substituent in the group represented by R1 in the above formula include alkyl (which may have halogen, cyano, or hydroxy as a substituent).

), aryl (which may have alkyl, alkoxy, halogen, hydroxy, acyloxy, sulfo, cyano, or sulfamoyl as a substituent), silyl (which may have alkyl, aryl, or aralkyl as a substituent). ), heterocycle (which may have amino, alkylamino, sulfamoyl, carbamoyl, halogen, cyano, or nitro as a substituent).

Amino (alkyl, aryl, cycloalkyl, sulfo or aralkyl may be present as a substituent. Also, together with nitrogen in the amino group, a 5- to 6-membered heterocycle may be formed). It will be done.

In the above formula, examples of the ester of carboxy represented by R14 include alkyl esters having 1 to 6 carbon atoms, and specific examples thereof include methyl ester, ethyl ethyl, propyl ester, n
-butyl ester, isobutyl ester, tert-
Examples include butyl ester.

Examples of substituents in amino which may have a substituent in the group represented by R1 in the above formula include:
Amidine, iminomethyl, imino (aryl-substituted) methyl, guanidylcarbonyl, heterocycle (which may have the same substituents as the above heterocycle), imino (which may be substituted with a heterocycle) ) Methyl, alkylcarbonyl, arylcarbonyl, hydroxyalkyl, alkyl, etc.

Examples of the substituent on the silyl which may have a substituent in the group represented by R1 in the above formula include alkyl, aryl, aralkyl, and the like.

The above R'', R'', and R'' may form a cyclic group with R34, such as 2,5-disilylazacyclopentyl, which is substituted with alkyl, aryl, etc. It may have a group.

Examples of the halogen in the above description of the substituent include chlorine, bromine, fluorine, and iodine.

Unless otherwise specified, the alkyl in the above description of the substituents preferably has 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms, such as methyl, ethyl, and n-propyl.

i-propyl, n-butyl, i-butyl, t-butyl.

5ec-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, heptyl, octyl, nonyl.

Examples include decyl.

The cycloalkyl as the above-mentioned substituent is preferably one having 3 to 6 carbon atoms unless otherwise specified, examples of which include cyclopropyl, cyclobutyl, cyclopentyl,
Examples include cyclohexyl.

The alkoxy as the above-mentioned substituent preferably has 1 to 4 carbon atoms unless otherwise specified, and examples include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, X-butoxy, t -Butoxy and the like.

Examples of the aryl as the above-mentioned substituent include phenyl, naphthyl, and the like.

Examples of the heterocycle as the above-mentioned substituent include those similar to the above-mentioned heterocycles.

The above-mentioned acyl as a substituent preferably has 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms, unless otherwise specified, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc. .

Examples of aralkyl as the above-mentioned substituent include benzyl, phenethyl, phenyl-propyl, and the like.

Examples of the alkenyl as the above-mentioned substituent include the same alkenyls as described above.

The amino acid residues as the above-mentioned substituents include the above-mentioned R
Examples include amino acid residues similar to those shown by 8.

Examples of the 5- to 6-shell heterocycle formed with the nitrogen in the amino group as the substituent include piperidine, pyrrolidine, imidazolidine, morpholine, and piperazine.

The number of substituents in each of the above groups is preferably 1 to 3.

In the above acyl group, specific examples of the acylamino group represented by the formula R'-GO-N- include, for example, 3-(
2,6-dichlorophenyl)-5-methylisoxazol-4-yl-carbonylamino, 4-ethyl-2,3
-Dioxo-1-piperazinocarbonylamino, 3-phenyl-5-methylisoxazol-4-yl-carbonylamino.

3-(2-chlorophenyl)-5-methylisoxazol-4-yl-carbonylamino, 3-(2-chloro-
6-Fluorophenyl)-5-methylisoxazole-
4-yl-carbonylamino, nicotinylamino, benzoylamino, 4-bromobenzoylamino, 2.6-
Cymethoxybenzoylamino, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino.

pivaloylamino, methoxycarbonylamino, benzyloxycarbonylamino, 1-amino-cyclohexylcarbonylamino, 2-amino-cyclohexylcarbonylamino, 3-ethoxynaphthoylamino, 2-(
2-amino-4-thiazolyl)-2-ethylidene-acetylamino, 2-(2-amino-4-thiazolyl)-2
-Chloromethylene-acetylamino, phthalimide, succinimide, 1,2-cyclohexanedicarboximide.

2-(trimethylsilyl)ethoxycarbonylamino,
2.2-Dimethyl-5-oxo-4-phenyl-imidazolidine, 4-(carbamoylcarboxymethylene)-
Examples include 1,3-dicetan-2-yl-carbonylamino.

Specific examples of the acylamino group represented by the formula 1't6-NH-CI-Co-NH- include D-
Alanylamino, benzyl N-carbobenzoxy-γ-
D-glutamyl-D-alanylamino, D-phenylglycyl-D-alanylamino, N-carbobenzoxy-
D-alanylamino.

N-carbobenzoxy-D-phenylglycylamino,
D-alanyl-D-phenylglycylamino, γ-D-
Glutamyl-〇-alanylamino, 2-(4-ethyl-
2,3-dioxo-1-piperazinocarboxamide)-
2-phenylacetylamino, 2-(4-cyclohexyl-2,3-dioxo-1-piperazinocarboxamide)-2-phenylacetylamino, 2-(4-ethyl-
2,3-dioxo-1-piperazinocarboxamide)-
2-(4-sulfoxyphenyl)acetylamino, N-
(4-ethyl-2,3-dioxo-1-piperazinocarbonyl)-D-alanylamino, N-(4-ethyl-2
,3-dioxo-1-piperazinocarbonyl)-D-phenylglycylamino, 2-(2-amino-4-thiazolyl)-2-(4-ethyl-2゜3-dioxo-1-piperazino carboxamide) acetylamino, 2-(4-
Hydroxy-6-methylnicotinamide)-2-phenylacetylamino, 2-(4-hydroxy-6-methylnicotinamide)-2-(4-hydroxyphenyl)acetylamino, 2-(5,8-dihydro-2 -(4-formyl-1-piperazinyl)-5-oxopyrido[2°3-d]pyrimidine-6-carboxamide)-2-phenylacetylamino, 2-(3,5-dioxo-1,2
,4-triazine-6-carboxamide)-2-(4-
hydroxyphenyl) acetylamino.

2-(3-furfrideneamino-2-oxoimidazolidine-1-carboxamide)-2-phenylacetylamino, 2-(coumarin-3-carboxamide)-2-phenylacetylamino, 2-(4-hydroxy-7 -Methyl-1,8-naphthylidene-3-carboxamide)-
2-phenylacetylamino, 2-(4-hydroxy-
7-Dolifluoromethylquinoline-3-carboxamide)-2-phenylacetylamino, N-[2-(2-amino-4-thiazolyl)acetyl]-D-phenylglycylamino, 2-(6-bromo-! -Ethyl 1゜4-
Dihydro-4-oxocheno[2,3-b]pyridine-
3-carboxamide)-2-phenylacederamino,
2-(4-ethyl-2,3-dioxo=1-piperazinocarboxamide)-2-chenylacetylamino, 2-
(4-n-pentyl-2,3-dioxo-1-piperazinocarboxamide)-2-chenylacetylamino, 2
-(4-n-octyl-2,3-dioxo-I-piperazinocarboxamide)-2-chenylacetylamino,
2-(4-cyclohexyl-2,3-dioxo-1-piperazinocarboxamide)-2-chenylacetylamino, 2-[4-(2-phenylethyl)-2,3-dioxo-1- piperazinocarboxamide]-2-thhenylacetylamino, 2-(3-methylsulfonyl-2-oxoimidazolidine-!-carboxamide)-2-7enylacetylamino, 2-(3-furfrideneamino-
2-oxoimidazolidine-1-carboxamide)-2
-(4-hydroxyphenyl)acedelamino, 2-(
4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-(4-benzyloxyphenyl)acetylamino, 2-(4-ethyl-2,3-dioxo-1)
-piperazinocarboxamide)-2-(4-methoxyphenyl)acetylamino, 2-(8-hydroxy-1,
5-naphthyridine-7-carboxamido)-2-phenylacetylamino, 2-(2-amino-4-thiazolyl)-2-formamidoacetylamino, 2-(2-amino-4-thiazolyl)-2-acetamidoacetylamino , 2-phenyl-2-ureidoacetylamino, 2-
Phenyl-2-sulfouridoamino, 2-chenyl-
2-ureitoacedylamino, 2-amino-3-sulfamoylpropionylamino, 2-amino-2-(IH
-indol-3-yl)acetylamino, 2-amino-2-(3-benzo[b]chenyl)acetylamino,
2-amino-2-(2-naphthyl)acedelamino, D
-phenylglycyl, D-2-amino-(4-hydroxyphenyl)acetylamino, D-2-amino-2-(
1,4-cyclohexagenyl)acetylamino, D-
2-amino-2-(l-cyclohexenyl)acetylamino, D-2-amino-2-(3-chloro-4-hydroxyphenyl)acetylamino, 2-hydroxymethylamino-2-phenylacetylamino, 2 -(1-cyclohexenyl)-2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)acetylamino, N
-[2-(4-ethyl-2,3-dioxo-1-piperazinocarbonyl)]-]D-threonylamino 2-guanylcarboxamide-2-phenylacetylamino, 2
-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide-2-(3,4-dihydroxyphenyl)
Acetylamino.

2-(4-carboxy-5-imidazolylcarboxamide)-2-phenylacetylamino, 2-amino-2-
(3-methylsulfonamidophenyl)acetylamino and the like.

Specific examples of the acylamino group represented by the formula R11-R"-Co-NH- include, for example, N-[2-(2-
amino-4-thiazolyl)-2-methoxyiminoacetyl]-D-alanylamino, N-[2-(2-amino-
4-thiazolyl)-2-methoxyiminoacetyl]-D
-Phenylglycylamino.

2-(2-amino-4-thiazolyl)-2-[2-(2
-amino-4-thiazolyl)-2-methoxyiminoacetamidocoacetylamino, 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetylamino, 2-'(2-amino-4-thiazolyl)- 2-
Methoxyiminoacetylamino, 2-(2-amino-4
-thiazolyl)-2-ethoxyiminoacederamino,
2-(2-amino-4-thiazolyl)-2-isopropoxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2-butoxyiminoacetylamino, 2-
(2-amino-4-thiazolyl)-2-cyclopropylmethyloxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2-benzyloxyiminoacetylamino, 2-(2-amino-4-thiazolyl) )-2-
Allyloxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2-[(1-methyl-1-carboxyethyl)oxyiminocoacetylamino, 2-(2
-amino-4-deazolyl)-2-[(1-methyl-1
-methoxycarbonylethyl)oxyiminocoacetylamino, 2-(2-amino-4-thiazolyl)-2-carboxymethyloxyiminoacetylamino, 2-(2
-amino-4-thiazolyl)-2-carboxyvinyloxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2-carboxyethyloxyiminoacetylamino, 2-(2-amino-4-thiazolyl)- 2-
Methoxycarbonylethyloxyiminoacetylamino, 2-(2-amino-5-chloro-4-thiazolyl)-
2-methoxyiminoacetylamino, 2-(2-amino-5-bromo-4-thiazolyl)-2-methoxyiminoacetylamino, 2-(2-amino-4-thiazolyl)
-2-oxidium acetylamino, 2-thenyl-2
-Methoxyiminoacetylamino, 2-furyl-2-methoxyiminoacetylamino, 2-(1,2゜4-thiadiazol-3-yl)-2-methoxyiminoacetylamino, 2-(1,2,4-thiadiazole) -5-yl)-2-methoxyiminoacetylamino, 2-(1,3
, 4-thiadiazolyl)-2-methoxyiminoacetylamino, 2-(4-hydroxyphenyl)-2-methoxyiminoacetylamino, 2-phenyl-2-methoxyiminoacetylamino, 2-phenyl-2-oxyiminoacetylamino , 2-[4-(γ-D-glutamyloxy)phenyl]-2-oxyiminoacetylamino,
2-[4-(3-amino-3-carboxypropoxy)
Phenyl-2-oxyiminoacetylamino, 2-thenyl-2-oxyiminoacetylamino, 2-(5-
Amino-1,2,4-thiadiazol-3-yl)-2
-methoxyiminoacetylamino, 2-(5-amino-
1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetylamino, 2-(5-amino-1,2,
4-thiadiazol-3-yl)-2-carboxymethyloxyiminoacetylamino, 2-(5-amino-!
, 2゜4-thiadiazol-3-yl)-2-[(1-
Methyl-1-carboxyethyl)oxyiminocoacetylamino, 2-(2-amino-4-thiazolyl)-2-
(2-amino-2-carboxy)ethyloxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-
2-(dimethylamidomethyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-2-(3
, 4-diacetoxy-benzoyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-2-
(r-carboxy-cycloprobyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-2
-(1-carboxy-cyclobutyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-2
-(2-imidazolylmethyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-2-(2
-Methyl-4-nitrol-imidazolylethyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-2-(3-pyrazolylmethyloxyimino)
Acetylamino, 2-(2-amino-4-thiazolyl)
-2-(IH-tetrazol-5-yl-methyloxyimino)acedelamino, 2-(2-amino-4-thiazolyl)-2-(2-oxo-3-pyrrolidinyloxyimino)acetylamino, 2- [2-(2-amino-2
-carboxyethylthio)]-]4-thiazolyl-2-
Methoxyiminoacetylamino 2-(2-thioxo-4
-diazolidinyl)-2-methoxyiminoacetylamino, and the like.

Specific examples of the R'' acylamino group represented by the formula R''-CH-CON H- include 2-phenyl-2-sulfoacetylamino, 2-hydroxy-2-phenylacetylamino, 2-phenyl-2-sulfa Moylacetylamino, 2-carboxy-2-phenylacetylamino, 2-(4-hydroxyphenyl)-2-
Carboxyacetylamino, 2-phenoxycarbonyl-2-phenylacetylamino, 2-phenyl-2-tolyloxycarbonylacetylamino, 2-(5-indanyloxycarbonyl)-2-phenylacetylamino, 2-formyloxy-2 -phenylacetylamino, 2-alanyloxy-2-phenylacetylamino,
2-carboxy-2-chenylacetylamino, 2-(
2-methylphenoxycarbonyl)-2-chenylacetylamino, 2-(2-amino-4-thiazolyl)-2
-hydroxyacetylamino, 2-[4-(2-amino-2-carboxyethoxycarboxamide) phenyl-io2-hydroxyacetylamino, and the like.

Specific examples of the acylamino group represented by the formula 1N"R"CHtCoNH- include cyanoacetylamino and phenylacetylamino.

Phenoxyacetylamino, trifluoromethyldioacetylamino, cyanomethylthioacetylamino, difluoromethylthioacetylamino, I-tetrazolyl-1-acetylamino, chenylacetylamino, 2
-(2-amino-4-thiazolyl)acetylamino, 4
-pyridylthioacetylamino, 2-thenylthioacetylamino, 3,5-dichloro-1,4-dihydro-4
-Oxopyridine-1-acetylamino, β-carboxyvinylthioacetylamino, 2-(2-aminomethylphenyl)acetylamino, 2-chloroacetylamino.

3-aminopropionylamino, (2-amino-2-carboxy)ethylthioacetylamino, 4-amino-3
-Hydroxybutyrylamino, 2-carboxyethylthioacetylamino, 2-benzyloxycarbonylamino-acetylamino, β-carbamoyl-β-fluorovinylthioacetylamino, 2-(1-isopropylamino-!-isopropyliminomethylthio) Acetylamino, 2-[1-(2-dimethylaminoethyl)-1H
-tetrazol-5-yludiocoacedylamino, 2
-(l-methyl-1,3,5-triazol-2-yl)acetylamino, 2-(4-cyano-3-hydroxy-5-isothiazolylthio)acetylamino, and the like.

Specific examples include carbamoylamino.

Methylaminocarbonylamino, ethylaminocarbonylamino, t-butylaminocarbonylamino, isobutylaminocarbonylamino, dimethylaminocarbonylamino, 2-methylphenylaminocarbonylamino, phenylaminocarbonylamino, 3-chlorophenylaminocarbonylamino, 4-nitro Phenylaminocarbonylamino, 4-bromophenylaminocarbonylamino, thiocarbamoylamino, methylaminothiocarbonylamino, ethylaminothiocarbonylamino, phenylaminothiocarbonylamino.

Examples include dimethylaminocarbonylamino, 3-fluorophenylaminocarbonylamino, and the like.

Specific examples of the group represented by the formula R"NH- include methylamino, ethylamino, allylamino, cyclohexylamino, cyclohexylmethylamino, benzylamino, 4-chlorobenzylamino, phenylamino, 2-imidazolylamino .

l-methyl-2-imidazolylamino, 2-(2-amino-4-thiazolyl)-2-methoxyimino-thioacetylamino, l-benzyl-4-pyridiniumamino,
Examples include 2-acetyl-1-methylvinylamino.

Specific examples include dimethylamino, diethylamino, dipropylamino, and dibenzylamino. dicyclohexylamino, N-benzyl-N-methylamino,
Examples include diallylamino, N-phenyl-N-methylamino, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like.

Specific examples of the group include trimedelammonium, triethylammonium, tribenzylammonium, benzyldimethylammonium, methylpyrrolidinium, methylpiperidinium, and the like.

Specific examples of the mino group include dimethylaminomethyleneamino,! -dimethylaminoethylideneamino, hexahydro-IH-azepin-l-ylmethyleneamino 1.1-(N-benzyl-N-methylamino)ethylideneamino, 4-dimethylaminobenzylideneamino, (
p-nitro)benzylidene amino, benzylidene amino, and the like.

Specific examples of the thioamino group represented by the formula R"-5on"-NH- include benzenesulfonylamino,
4-Methylbenzenesulfonylamino, 4-methoxybenzenesulfonylamino, 2°4.6-trimethylbenzenesulfonylamino.

Benzylsulfonylamino, 4-methylbenzylsulfonylamino, trifluoromethylsulfonylamino, phenacylsulfonylamino, methylsulfonylamino,
Ethylsulfonylamino, 4-fluorobenzenesulfonylamino, benzenesulfinylamino, 2-nitrobenzenesulfinylamino, 2,4-dimethylbenzenesulfinylamino, 4-chlorobenzenesulfinylamino.

Examples include 4-methoxybenzenesulfinylamino, phenylthioamino, 2,4-dinitrophenylthioamino, triphenylmethylthioamino, and 2-nitro-4-methoxyphenylthioamino.

Specific examples of the R group include trimethylsilylamino, triethylsilylamino, t-butyldimethylsilylamino, [-butyldiphenylsilylamino, isopropyldimethylsilylamino, triphenylsilylamino, triisopropylsilylamino, tribenzylsilyl Examples include amino, (triphenylmethyl)dimethylsilylamino, 2,2,5.5-tetramethyl-2,5-disilylazacyclobencune, and the like.

Examples include amino dimethylphosphate, amino diethylphosphate, amino diphenylphosphate, amino dibenzylphosphate, amino di-4-chlorophenylphosphate, and the like.

A specific example of the group represented by the formula R''-CO-CO-NH- is, for example, methoxarylamino.

Ethoxarylamino, phenoxarylamino, benzyloxarylamino, bilboylamino, ethyloxarylamino, oxamoylamino, benzylaminooxarylamino, thenyloxarylamino, 2-amino-
Examples include 4-thiazolyl-oxarylamino and ethylaminooxarylamino.

Among the organic residues with nitrogen as l'(+) explained above, the formula R'-Co-N-.

R8-NH-CH-CO-Nl-1-, R”-R”-C
A group represented by R" such as O-NH-, R"-CH-C0NH-, etc. is preferable, R4 is aryloxy etc., R5 is hydrogen etc., R8 is a group represented by the formula R"
t)n'C(=A), etc., R7 is preferably aryl, R'' is a chemical bond, R'' is aryl, heterocycle, etc., and R'7 is preferably hydrogen.

In particular, R4 is aryloxy, R8゜R''
is hydrogen, and R8 is 4-alkyl-2,3-
Dioxo-1-piperazinecarbonyl is phenyl as R7, 2-(2-aminothiazol-4-yl)-(Z)-2-methoxyimino is R''-R10, R
'' is preferably benzyl or 2-dienylmethyl.

As the organic residue via nitrogen as R-weight, the above-mentioned R
Examples include organic residues via nitrogen as 1 and groups that can be derived into primary amino groups (for example, benzyloxycarbonyl) if desired.

Groups derived from the carboxyl group represented by R" in the above formula include esters, amides, etc. Examples of esters include -COOR" [wherein R38 is alkyl", alkenyl", aryl 1. cycloalkyl, heterocycle 1 or silyl. Examples include compounds having a group represented by the following.

The group represented by -cOoR'' above preferably has a molecular type of up to 500.

In the above formula, R'' represents alkyl3.alkenyl0°aryl'', cycloalkyl1. As for the explanations and exemplifications of each group of "heterocycle 1 or silyl", the explanations and exemplifications of the corresponding groups described above regarding R' apply as they are.

Specific examples of the group represented by the formula -〇〇OR'' include methyl ester, ethyl ester, low propyl ester, isopropyl ester, 1-butyl ester,
t-amyl ester, benzyl ester, 4-bromobenzyl ester, 4-nitrobenzyl ester, 2-nitrobenzyl ester.

3.5-Dinitrobenzyl ester, 4-methoxybenzyl ester, benzhydryl ester, phenacyl ester, 4-bromo-phenacyl ester, phenyl ester, 4-nitrophenyl ester, methoxymethyl ester, methoxyethoxymethyl ester, ethoxymethyl ester, benzyloxymethyl ester, acetoxymethylneester, pivaloyloxymethyl ester, 2-methylsulfonyl ethyl ester, 2-trimethylsilylethyl ester, methylthiomethyl ester, trityl ester, 2.2.2-trichloroethyl ester, 2 -Iodoethyl ester. Cyclohexyl ester 9 cyclopentyl ester, allyl ester,
Cinnamyl ester, 4-picolyl ester.

2-tetrahydropyranyl ester, 2-tetrahydrofuranyl ester, trimethylsilyl ester, t-butyldimethylsilyl ester, t-butyldiphenylsilyl ester, acetyl methyl ester, 4-nitrobenzoyl methyl ester, 4-mesylbenzoyl methyl ester, phthalimidomethyl ester , propionyloxymethyl ester, ■, 1-dimethylpropyl ester, 3-methyl-3-butenyl ester, succinimidomethyl ester, 3,5-di-t-butyl-4-hydroxybenzyl ester, mesylmethyl ester, benzenesulfonyl Methyl ester, phenylthiomethyl ester, iminomethylaminoethyl ester, l-iminoethylaminoethyl ester, dimethylaminoethyl ester, pyridine-l-oxide-2-methyl ester, methylsulfinylmethyl ester, bis-(4
-methoxyphenyl) methyl ester, 2-cyano-1
, 1-dimethylethyl ester, t-butyloxycarbonylmethyl ester, benzoylaminomethyl ester.

1-acetoxyethyl ester, ■-isobutyryloxyethyl ester, l-ethoxycarbonyloxyethyl ester, phthalide ester, 4-t-butylbenzyl ester, 5-indanyl ester, 5-methyl-
Examples include 2-oxo-1,3-dioxolen-4-ylmethyl ester, 5-t-butyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, and the like.

In the compound of the present invention, the carboxyl group of R3 may be used in its free form, but it can also be used in the form of a pharmacologically acceptable salt by a method known per se. Non-toxic cations such as sodium, potassium, etc., such as arginine, ornithine.

Basic amino acids such as lysine and histidine, such as N-
It may be used by forming a salt with a polyhydroxyalkylamine such as methylglucamine, jetanolamine, triethanolamine, or trishydroxymethylaminomethane. In addition, R1 has a basic group (for example, an amino group)
For example, salts with organic acids such as acetic acid, tartaric acid, methanesulfonic acid, etc., salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., such as arginine, aspartic acid, etc. It may also be used by forming a salt with an acidic amino acid such as glutamic acid.

n! As an amide as a group derived from a carboxyl group represented by the formula [wherein R'' and R40 are the same or different, hydrogen, alkyl'', aryl'', cycloalkyl''.

represents alkenyl 1 or heterocycle 7, R39 and R”
This includes the case where ``heterocycle'' is formed together with the adjacent nitrogen atom.

For example, dimethylamide, diethylamide,
Dipropylamide, dibenzylamide, zinclohexylamide, N-benzyl-N-methylamide, diallylamide, N-phenyl-N-methylamide, pyrrolidineamide, piperidineamide.

piperazinamide, morpholinamide, carboxymethylamide. Examples include l-carboxyethylamide.

In the above formula, the group that can be converted into a carboxyl group as R1' includes a group derived from a carboxyl group as R2, and varanitrobenzyl, benzyl, benzhydryl, etc., which are known as carboxyl group protecting groups, Particular preference is given to using valanitrobenzyl.

In the above formula, examples of the hydrocarbon residue represented by R3 include alkyl 1. Alternatively, examples include aryl 1 (alkyl and aryl include the same substituents as mentioned above for R1), and lower alkyl of C1-1 (e.g., methyl, ethyl, propyl, etc.) is particularly advantageously used. be done.

The production method of the present invention involves subjecting compound (n) or compound (I [I) to a ring-closing reaction as described above, and formula [wherein R'',
rt'' and n have the same meanings as defined above], and if desired, R'' and/or R1'
Compound (1) is obtained by subjecting it to the conversion reaction.

The conversion reaction from compound (II) to compound (I") can be carried out by adding mercuric chloride, mercuric nitrate, silver nitrate, or thallium nitrate in a solvent to convert a metal such as mercury, silver, or thallium into a solvent. The reaction is carried out in the presence of ions.Reaction solvents include methanol, ethanol, tetrahydrofuran, dichloromethane, ethyl acetate, chloroform, N, N
- Dimethylformamide etc. are mentioned as a specific example,
The reaction temperature is usually about -78°C to about 50°C, but the reaction may be carried out at other temperatures.

Alternatively, compound (III) may be subjected to a ring-closing reaction to form compound (I
Compound (I) can also be produced by converting compound (■'') into R'' and/or R'', if desired.

The conversion reaction from compound (I[I) to compound (I'') is
This is usually carried out by treating the compound ([1)] with a dehydrating agent. The reaction is preferably carried out in a solvent. As the dehydrating agent, for example, a combination of triphenylphosphine and diethyl azodicarboxylate is used. As the solvent, common solvents such as dichloromethane, chloroform, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylacetamide, and dimethylformamide are used. In this reaction, the dehydrating agent is usually used in an amount equivalent to that of compound (II[), but it can be used in excess as long as it does not interfere with the reaction. The reaction temperature is usually about -20°C to 1
The reaction time is usually about 5 minutes to 3 minutes.
It is 0 hours.

By further subjecting the thus obtained compound (■'') to a conversion reaction of R'' and R1', if necessary,
Compound (1) or its ester or, for example, acyl cleavage reaction, deprotection reaction, acylation reaction, ureidation (thioureidation) reaction, alkylation reaction, alkenylation reaction, thiolation reaction, silylation reaction by iminoether method, Examples include phosphorylation reaction, esterification reaction, and amidation reaction.

The acyl cleavage reaction using the iminoether method is performed on the compound (■
''), R'' represents a moiety other than nitrogen, R'''-C-NH-.] is reacted with phosphorus pentachloride, phosgene, phosphorus trichloride, phosphorus oxychloride, etc. It is preferable to use the above reaction reagent in an amount of about 1 to 5 equivalents, more preferably about 1.5 to 3 equivalents.

The reaction is, for example, methylene chloride. Conveniently this is carried out in the presence of a solvent such as dichloroethane, chloroform, carbon tetrachloride, trichloroethane or the like. To accelerate the reaction, for example, pyridine, N,N-dimethylaniline, in an amount of, for example, about 3 to 20 equivalents, more preferably about 5
~IO equivalent is preferably used.

The acyl cleavage reaction is carried out at a reaction temperature of about -30°C to 0°C, more preferably -15°C to -5°C, and a reaction time of about 1.
It is preferable to carry out the treatment for 5 minutes to 8 hours, more preferably for about 30 minutes to 2 hours. The reaction is conveniently carried out under stirring.

In order to convert iminochloride produced as an intermediate into iminoether, excess methanol was added to the reaction solution.
About -30°C to 0°C, preferably about -15°C to -5°C, about 1
The mixture is stirred for 5 minutes to 2 hours, preferably about 30 minutes to 1 hour, and further stirred at about 10°C to 40°C, preferably about 20°C to 30°C, for about 30 minutes to 2 hours to complete the reaction. Furthermore, dilute hydrochloric acid is added to the reaction solution to cleave the C--N bond. The reaction temperature is about 10°C to 40°C, preferably about 20°C to
At 30°C, the reaction time is about 15 minutes to 2 hours, preferably about 30 minutes to 1 hour.

The reaction solution thus obtained is neutralized with, for example, sodium hydrogen carbonate, and the product is extracted with a water-immiscible organic solvent such as methyl cyclolide, diethyl ether, ethyl acetate, or the like.

The above deprotection reaction can be carried out by appropriately selecting a commonly used method such as an acid method, a base method, a hydrazine method, or a reduction method depending on the type of the protecting group. In the case of a method using an acid, the acid may be an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., or an organic acid such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, etc., depending on the type of protecting group and other conditions. In addition, acidic ion exchange resins and the like are used. In the case of the base method,
Although it varies depending on the type of protecting group and other conditions, examples of bases include hydroxides of alkali metals such as sodium and potassium, or alkaline earth metals such as calcium and magnesium, inorganic bases such as carbonates, metal alkoxides,
In addition to organic bases such as organic amines and quaternary ammonium salts,
A basic ion exchange resin or the like is used. When a solvent is used in the above acid or base method, a hydrophilic organic solvent, water or a mixed solvent is often used.

In the case of the reduction method, it depends on the type of protecting group and other conditions, but for example, a metal such as tin or zinc or a metal compound such as chromium dichloride or chromium acetate, and acetic acid,
Methods using acids such as organic and inorganic acids such as propionic acid and hydrochloric acid, methods of reduction in the presence of a metal catalyst for catalytic reduction, etc. are used, and the catalysts used in the method by catalytic reduction include, for example. Platinum wire, platinum sponge, platinum black, platinum oxide.

Platinum catalysts such as colloidal platinum, palladium sponge, palladium black, palladium oxide, palladium barium sulfate, palladium barium carbonate, palladium carbon.

Examples include palladium catalysts such as palladium silica gel and colloidal palladium, reduced nickel, nickel oxide, Raney nickel, and urushihara nickel. Also, iron in the case of reduction methods using metals and acids.

Metals such as chromium and inorganic acids such as hydrochloric acid or organic acids such as formic acid, acetic acid, and propionic acid are used. Reduction methods are usually carried out in a solvent; for example, in catalytic reduction methods, methanol, ethanol, propyl alcohol,
Alcohols such as isopropyl alcohol, ethyl acetate, etc. are frequently used.

Furthermore, in the method using a metal and an acid, water, acetone, etc. are often used, but when the acid is liquid, the acid itself can also be used as a solvent.

The reaction temperature in the acid method, the base method, and the reduction method is usually carried out under cooling or heating.

Furthermore, the protective groups in each group of the obtained compound can be removed by the same method as above. In short, the deprotection reaction can be carried out by a method known per se.

By subjecting the compound (■'') to a deprotection reaction, a compound (1-1) in which R1 is an amino group and R2 is an ester in compound (1), or an organic residue in which RI is nitrogen-mediated in compound (I) can be obtained. A compound in which R2 is an ester (
I-2) can be produced, and by further subjecting these compounds to a deprotection reaction, compound (I-3) in which R1 is an amino group and R2 is carboxyl in compound (I) can be produced. can.

Alternatively, compound (■'') can be subjected to a deprotection reaction to yield compound (T-3).

Further, the compound (1-1) can be subjected to, for example, acylation, ureidation (thioureidation), alkylation, alkenylation,
It can also be converted to compound (1-2) by subjecting it to reactions such as thiolation, silylation, and phosphorylation. Next, the reaction will be explained in detail.

Acylation of the acylated amino group is carried out in a solvent using the starting compound and the group R1.
This can be carried out by reacting an acylating agent containing an acyl group, such as a reactive derivative of a carboxylic acid. Examples of reactive derivatives of carboxylic acids that can be used include acid halides, acid anhydrides, amide compounds, active esters, and active thioesters.Specific examples of such reactive derivatives are as follows.

l) Acid halide: As the acid halide, for example, acid chloride, acid bromide, etc. are used.

2) Acid anhydride The acid anhydride here includes, for example, monoalkyl carbonic acid mixed acid anhydride, aliphatic carboxylic acid (for example, acetic acid,
Mixed acid anhydrides consisting of pivalic acid, valeric acid, isovaleric acid, trichloroacetic acid, etc.), mixed acid anhydrides consisting of aromatic carboxylic acids (eg, benzoic acid, etc.), symmetrical acid anhydrides, etc. are used.

3) Amide Compound: As the amide compound, for example, a compound in which an acyl group is bonded to the nitrogen in the ring such as pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole, benzotriazole, etc. is used.

4) Active ester: Examples of the active ester include methyl ester, ethyl ester, methoxymethyl ester, propargyl ester, 4-nitrophenyl ester, 2.4-
In addition to esters such as dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, and benzotriazolyl ester, esters with l-hydroxy-IH-2-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, etc. etc. are used.

5) Active thioester: As the active thioester, for example, a thioester with a heterocyclic thiol such as 2-pyridylthiol or 2-benzthiazolylthiol is used.

The various reactive derivatives described above are appropriately selected depending on the type of carboxylic acid.

This reaction may be carried out in the presence of a base, and the bases used include, for example, aliphatic tertiary amines (e.g., trimethylamine, triethylamine, tripropylamine, tri-n-butylamine, etc.), N-methylpiperidine, N- tertiary amines such as methylpyrrolidine, cyclohexyldimethylamine, N-methylmorpholine, dialkylamines such as di-n-butylamine, diisobutylamine, dicyclohexylamine;
For example, aromatic amines such as pyridine, lutidine, and γ-collidine, hydroxides or carbonates of alkali metals such as lithium, sodium, and potassium, and alkaline earth metals such as calcium and magnesium are used.

In this method, the reactive derivative of carboxylic acid is usually used in an amount equivalent to that of compound (1-1), but it can be used in excess as long as it does not interfere with the reaction. When using a base, the amount of the base used depends on the raw material compound (I-1) used.
Although it varies depending on the type of reactive derivative of carboxylic acid and other reaction conditions, it is usually about equivalents to 30 equivalents, preferably about equivalents to 10 equivalents, relative to compound (1-1). This reaction is usually carried out in a solvent. Examples of the solvent include ethers such as dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether, propylene oxide, butylene oxide, esters such as ethyl acetate and ethyl formate, chloroform, dichloromethane, 1°2-dichloroethane, l
, halogenated hydrocarbons such as l,1-trichloroethane, hydrocarbons such as benzene, toluene, n-hexane, e.g. N,N-dimethylformamide,
Common organic solvents such as amides such as N,N-dimethylacetamide and nitriles such as acetonitrile are used alone or in combination. Moreover, among the bases mentioned above, liquid ones can also be used as a solvent.

The reaction temperature is not particularly limited as long as the reaction proceeds, but is usually -50°C to 150°C, preferably about -30°C.
The temperature is between 80°C and 80°C. The reaction usually completes in several tens of minutes to several tens of hours, although it varies depending on the raw materials, base, reaction temperature, and type of solvent used, but it may sometimes take several tens of days.

Ureidation (Thioureidation) The conversion reaction of an amino group into a ureido group or a thioureido group can be carried out, for example, by adding the formula R''-N to a raw material compound in the presence of a solvent.
=C=A (wherein R'' and A have the same meanings as above). Isocyanate, phenyl isocyanate, p-bromophenyl isocyanate, etc.
As the substituted isothiocyanate, for example, methyl isothiocyanate, phenyl thiocyanate, etc. are used. In this reaction, the substituted isocyanate or substituted isothiocyanate is usually used in about an equivalent amount to compound (I-1), but it can also be used in excess as long as it does not hinder the reaction. Examples of the solvent used include tetrahydrofuran, diethyl ether, ethyl acetate, chloroform, dichloromethane, and toluene. The reaction temperature is about -20°C to around 50°C, and the reaction time is usually about 10 minutes to 5 hours.

The reaction for obtaining a compound having an alkyl group as a group bonded to the amino group of the alkylated compound (1-1) via carbon will be described below as alkylation.

Alkylation of compound (I-1) can be produced by reacting compound (1-1) with an alkylating agent containing a group bonded to the nitrogen of group R1 via carbon. Examples of alkylating agents include halogenated alkyl compounds such as propyl chloride, butyl chloride, benzyl chloride, butyl bromide, benzyl bromide, allyl bromide, methyl iodide, ethyl iodide, propyl iodide, etc., such as dimethyl sulfate, diethyl sulfate, etc. Dialkyl sulfate compounds, substituted sulfonic acid ester compounds such as methyl mesylate, ethyl mesylate, methyl tosylate, ethyl tosylate, dihalogenated alkyl compounds (
For example, 1,5-dichloropenkune, [,4-dichlorobutane, etc.] are used. This reaction is usually carried out in a solvent, and the solvents used are water, methanol, ethanol, and benzyl alcohol.

Examples include benzene, N,N-dimethylformamide, tetrahydrofuran, and acetonitrile.

The temperature of this reaction is about 20°C to 200°C, and the reaction time is about 30 minutes to 50 hours. In this reaction, a secondary amine compound, a tertiary amine compound, or a quaternary ammonium compound can be selectively produced by changing reaction conditions 1, for example, the molar ratio of compound (1-1) and the alkylating agent. In addition, by performing the reaction in stages,
It is also possible to introduce different substituents on the nitrogen. Reactions that introduce groups that bond through carbon other than alkyl also include
This can be done in the same way as above.

The alkylation can also be carried out by combining compound (1-1) and a carbonyl compound in the presence of a reducing agent. Examples of the reducing agent used in this reaction include lithium aluminum hydride, sodium cyanoborohydride, sodium borohydride, sodium, sodium amalgam, and a combination of zinc and acid. Also palladium and platinum.

Catalytic reduction using rhodium or the like as a catalyst may also be used.

Reaction to convert an amino group into a compound represented by R''-NH- (imino group-substituted alkylamino group, alkylimino group-substituted alkylamino group, or substituted guanidino group) Niamino group imino group-substituted alkylamino group, alkylimino group-substituted alkyl group The reaction for converting into an amino group is dioxane, tetrahydrofuran, N,N-dimethylformamide, chloroform, and acetone.

This is carried out, for example, by reaction with imidoesters in a solvent such as acetonitrile or water. Suitable imidoesters include, for example, methylformimidate, ethylformimidate, benzylformimidate, methylacetimidate, ethylacetimidate, methylphenylacetimidate, ethyl N
-Methylformimidate, methyl N-ethylformimidate, methyl N-isopropylformimidate, etc. are used. The reaction temperature is around 0℃ to 25℃,
The reaction time is usually about 1 to 6 hours. The conversion reaction of an amino group to a guanidino group uses water.

For example, by reaction with 0-alkyl or 0-aryl pseudoureas or S-alkyl or S-aryl pseudothioureas in a solvent such as N,N-dimethylformamide or hexamethylene phosphoramide. It will be done. The above pseudoureas include:
0-methylpseudourea, S-methylpseudourea, O
-2,4-') chlorophenyl pseudourea, 0-N,
As the pseudothioureas such as N-)limethylbusoidurea, 5-p-nitrophenyl pseudothiourea and the like are used. The reaction temperature is from 0℃ to around 40℃,
The reaction time is usually 1 hour to 24 hours.

Alkenylation (Imination) Alkenylation (Imination) of Compound (I-1) can be carried out by dehydration condensation of Compound (1-1) and a carbonyl compound (eg, propionaldehyde, diethyl ketone). Although this reaction proceeds without a solvent, it can also be carried out in a solvent. Acids or bases may also be used as catalysts. It can also be produced by heating and refluxing compound (1-1) and a carbonyl compound in the presence of a dehydrating agent or using a dehydrating apparatus such as Dean-Stark. Examples of the solvent used in this reaction include benzene.

Toluene, dichloromethane, ethanol, etc. are used, the reaction temperature is about 0°C to 200°C, and the reaction time is about 1 hour to 20 hours. Examples of acids used as catalysts include benzenesulfonic acid.

Examples of bases include methanesulfonic acid, sulfuric acid, boron trifluoride, and zinc chloride. Examples of bases include potassium hydroxide and sodium carbonate. Examples of the filtration and dehydrating agent used in this reaction include Molecule sieves, silica gel, anhydrous magnesium sulfate, and anhydrous sodium sulfate.

The thiolation reaction of thiolated compound (1-1) is usually carried out with compound (I-
1) and a halogenated thio compound (e.g., , sulfonyl halide, sulfinyl halide, sulfenyl halide) in a solvent in the presence of a base.

Examples of the solvent used in this reaction include water, acetone, dioxane, N,N-dimethylformamide, benzene, tetrahydrofuran, dichloromethane, and a mixed solvent thereof.

Bases include pyridine, picoline, and triethylamine. Organic bases such as diisopropylethylamine and N-methylmorpholine, or inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and potassium carbonate are used. This reaction usually involves adding about 1 equivalent of a halogenated thio compound to compound (r-1).
The base is used in an amount of about 1 equivalent to 10 equivalents, and the reaction temperature is about -
The temperature is 20°C to 80°C, and the reaction time is 15 minutes to 10 hours.

This reaction can also be carried out using a thioic anhydride (eg, toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.) instead of the halogenated thio compound. Also, for example, N-sulfonyl-N-methylpyrrolidinium, N
-Sulfonylimidazolide or N-sulfonyl-I
It can also be carried out by reacting with a thiolating reagent such as H-1,2,4-triazolide.

The silylation reaction of the silylated compound (I-1) is usually carried out with the compound R''-
Y (wherein R31-3s has the same meaning as above, R" represents silyl 1, and Y represents halogen, respectively.

) with a halogenated silyl compound (eg, silyl chloride compound, silyl bromide compound) in the presence of a base. Examples of the base include organic bases such as pyridine, picoline, triethylamine, diisopropylethylamine, and N-methylmorpholine. The reaction is preferably carried out in a solvent, such as acetone, dioxane, N.

Examples include N-dimethylformamide, benzene, tetrahydrofuran, and dichloromethane. The reaction temperature is about -20°C to the boiling point of the solvent, or about -20°C to 80°C, and the reaction time is about 15 minutes to 20 hours.

The phosphorylation reaction of phosphorylated compound (1-1) is usually carried out using compounds R'', R
" has the same meaning as above.) (e.g., dimethyl phosphoryl chloride, diethyl phosphoryl chloride, diphenyl phosphoryl chloride, dibenzyl phosphoryl chloride, etc.) and about an equivalent to an excess amount of a base in a solvent. The base used includes organic bases such as pyridine, picoline, triethylamine, and N-methylmorpholine, and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, and sodium carbonate. Examples of solvents include water, acetone, acetonitrile, dioxane, N, N-
Dimethylformamide, tetrahydrofuran, dichloromethane, or a mixed solvent thereof is used.

The reaction temperature is about -20°C to 80°C, and the reaction time is 15 minutes to 15 hours.

Compound (I-3) is subjected to, for example, acylation, ureidation (thioureidation), alkylation, and alkenylation.

It can be converted to compound (I-2) by subjecting it to reactions such as thiolation, silylation, and phosphorylation. The conversion reaction converts the above-mentioned compound (I-1) to the compound (
It can be carried out in the same manner as the conversion reaction to 1-2).

Compound (I-2) can also be converted to compound (I') or (1-1) by subjecting it to, for example, a carboxylic acid esterification reaction or a carboxylic acid amidation reaction. Next, the reaction will be explained.

Esterification of carboxylic acid Esterification of carboxylic acid is carried out, for example, by the following method.

■) A raw material compound is mixed with a diazoalkane such as diazomethane, phenyldiazomethane, diphenyldiazomethane, etc. and a solvent such as tetrahydrofuran or dioxane.
The reaction is carried out in ethyl acetate, acetonitrile, etc. at about 0° C. to reflux temperature for about 2 minutes to 2 hours.

2) Activate the alkali metal salt of the raw material compound with an alkyl halide, such as methyl iodide, benzyl bromide, p-
React with nitro-benzyl bromide, m-phenoxybenzyl bromide, pt-butylbenzyl bromide, pivaloyloxymethyl chloride, etc. Appropriate reaction conditions include using a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphoramide, and reacting at about 0°C to 60°C for about 2 minutes to 4 hours. let Even if triethylamine or the like is present in this reaction solution, it will not interfere with the progress of the reaction.

3) The raw material compound is reacted with an alcohol of the formula R"-OH [where R38 has the same meaning as above. This reaction is carried out using a carbodiimide condensing agent. ,for example,
This is carried out in the presence of DCC, etc. The reaction is carried out at about 0°C to reflux temperature for about 15 minutes to 18 hours, and the solvent used is chloroform, dichloromethane, dichloroethane, etc.

4) The acid anhydride of the starting compound obtained by reacting the starting compound with an acid chloride, such as ethyl chlorocarbonate, benzyl chlorocarbonate, etc., is reacted with an alcohol, such as those listed in 3), as described in 3). React under conditions. This anhydride is prepared by combining the starting compound with an acid chloride and a solvent such as tetrahydrofuran.

dichloromethane, etc. at 25°C to reflux temperature,
It is obtained by reacting for about 15 minutes to 10 hours.

5) The raw material compound is coexisted with a silylating agent such as trimethylsilyl chloride, t-butyl-dimethylsilyl chloride, and triethylamine, etc., in a solvent such as dichloromethane, chloroform, tetrahydrofuran, etc. at about 0°C to reflux temperature for about 15 minutes to 16 minutes. Allow time to react.

Amidation of carboxylic acids is performed by synthesizing the acid anhydride of the starting compound with an acid chloride, such as ethyl chlorocarbonate, benzyl chlorocarbonate, pivalic acid chloride, or an acid anhydride, such as acetic anhydride or trifluoroacetic anhydride. , ammonia or a selected amine, such as the alkyl-, dialkyl-, aralkyl- or heterocyclic amines mentioned above. Alternatively, the reaction may be carried out by reacting a carboxylic acid and the above-mentioned amines in the presence of a condensing agent such as DCC or N-3-dimethylaminopropyl-N-ethylcarbodiimide.

The above reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, etc.
The reaction is carried out at a temperature of from °C to reflux for about 15 minutes to 16 hours.

The target compound thus obtained can be isolated and purified by means known per se, such as concentration, liquid conversion, dissolution, solvent extraction, lyophilization, crystallization, recrystallization, 8-fraction distillation, and chromatography.

Since the target compound has two or more asymmetric carbon atoms in its basic skeleton, there are theoretically four or more types of stereoisomers, and each of these isomers and mixtures thereof are also included in the present invention.

In addition, in the case where the group represented by R1 has an asymmetric carbon or in the case of an ester, 100OR'' at the 2-position of the basic skeleton [in the formula,
When the group represented by "R" has the same meaning as above] has an asymmetric carbon, stereoisomers also occur, and each of these isomers and mixtures thereof are also included in the present invention. If a mixture of these isomers is produced in the reaction, each isomer can be isolated by conventional methods such as various chromatography and recrystallization, if necessary.

Compound (I) of the present invention may react with a base to form a salt. Examples of such salts include salts with inorganic bases such as sodium, potassium, lithium, calcium, magnesium, and ammonium salts.

For example, pyridine, collidine, triethylamine.

Examples include salts with organic bases such as triethanolamine.

When the compound of the present invention is obtained in a free form, it may be formed into a salt using a conventional method, or the compound obtained as a salt may be converted into a free form using a conventional method.

Further, the target compound may form an inner salt, and this case is also included in the present invention.

The stereoisomers of the target compound can be used as medicines either singly or as a mixture.

Compound (II) used as a starting compound in the method of the present invention can be produced, for example, by the following method. In addition, R'', R'', R'' and n in the formula have the same meanings as above.

Method for producing compound (n) This step consists of a compound of the formula [wherein R4' represents a group that can be derived into a carboxyl group]. n'', R''', R3 and n have the same meanings as above. ] or the compound (IV) represented by the general formula [wherein R1', R1', R3, R41 and n have the same meanings as above. X represents a leaving group. ] Compound (
V) is subjected to a ring-closing reaction to obtain a compound (Vl) represented by the general formula [wherein R", R", R', n, and R" have the same meanings as above.] This is a step for producing compound (II) by converting R4+ into a carboxyl group or, if necessary, subjecting R'' and R2 to a conversion reaction such as deprotection.

R'' in the above formulas (IV), (V), and (VI) is, for example, a carboxylic acid such as t-butyloxycarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, 4-nitrobenzyloxycarbonyl, or aryloxycarbonyl. Examples include esters.

In the above formula, the leaving group represented by X is compound (V)
Any substance may be used as long as it can replace the hydrogen of the NH group. Examples include, for example, halogens (e.g. bromo, chloro), substituents (e.g. alkyl, aryl) (
Examples of alkyl and aryl include the same substituents as mentioned above for R1. ) (specific examples thereof include p-toluenesulfonyloxy).

p-nitrophenylsulfonyloxy, methanesulfonyloxy), disubstituted phosphoryloxy (eg, diphenylphosphoryloxy, diethylphosphoryloxy), and the like.

The conversion reaction from compound (IV) to compound (Vr) is carried out in a solvent in the presence of a dehydrating agent such as triphenylphosphine and diethyl azodicarboxylate. Examples of the solvent include dichloromethane, chloroform, tetrahydrofuran, dioxane, ethyl acetate, diethyl ether, benzene, and toluene.

Common solvents such as acetonitrile, N,N-dimethylformamide are used.

The conversion reaction from compound (V) to compound (Vl) is usually carried out by treating compound (I[I) with a base. The reaction is preferably carried out in a solvent. As the base, for example, triethylamine.

tripropylamine, tri-n-butylamine,
Sopropylethylamine, triethylenediamine, 1.
4-diazabicyclo[2,2,2]octane (hereinafter DA
(sometimes abbreviated as BCO), 1,8-diazabicyclo[5,4,0]-7-undecene (sometimes abbreviated as DBU hereinafter), N-methylnarforine. N-methylpiperidine, N-methylpyrrolidine, 3,4-dihydro-2[1-pyridro, 2-a]pyrimidin-2-one,
4-dimethylaminopyridine, pyridine, lutidine, γ
- Organic amines such as collidine, alkali metals such as lithium, sodium, potassium, and cesium, alkaline earth metals such as magnesium and calcium, or their hydrides, hydroxides, carbonates, or alcoholades are used. . Examples of solvents include dichloromethane, chloroform, tetrahydrofuran, dioxane, benzene, and toluene.

Common solvents such as acetonitrile, dimethylacetamide, dimethylformamide are used. Moreover, among the above-mentioned bases, liquid ones can also be used as a solvent. In this reaction, the base is usually used in an approximately equivalent amount to compound (I[I), but it can also be used in excess as long as it does not interfere with the reaction. The reaction temperature is usually about -20°C to 100°C, and the reaction time is usually about 5 minutes to 30 hours.

Production of compound (V) In this step, the compound represented by general formula (■) is reacted with a halogenating agent, a sulfonylating agent, or a phosphorylating agent in a solvent to produce a compound represented by general formula (V). It is a process. Specific examples include thionyl chloride, thionyl bromide, sulfuryl chloride, phosphorus oxychloride, oxalyl chloride, chlorine, bromine or carbon tetrachloride, and halogenating agents such as triphenylphosphine, such as anhydrous p-toluenesulfonic acid, p-Nitrobenzenesulfonic anhydride, 2,4,6-triisobrobylphenylsulfonic anhydride, methanesulfonic anhydride, p-
Examples include sulfonylating agents such as toluenesulfonyl chloride and p-chlorobenzenesulfonyl chloride, and phosphorylating agents such as diphenylphosphoryl chloride, dimethylphosphoryl chloride, and diethylphosphoryl chloride.

Any solvent may be used as long as it does not affect the reaction, but common solvents such as dichloromethane, chloroform, tetrahydrofuran, dioxane, diethyl ether, ethyl acetate, benzene, toluene, n-hexane, acetonitrile, and diethylformamide can be used. is used.

Production of Compound (Ill) This step is carried out using the general formula [wherein R1', R1', R3, R41 and n have the same meanings as above. ] Compound (IV) represented by the general formula [wherein R'', R'', R3 and n have the same meanings as above. ] is obtained, and the compound is subjected to a ring-closing reaction to produce compound (I).

The conversion reaction from compound (IV) to compound (■) is related to the method for producing (1) from (do), and R'' and R
The conversion reaction of 3' is carried out by subjecting it to the deprotection reaction described above. For example, when R41 is t-butyloxycarbonyl or diphenylmethyloxycarbonyl, the reaction is carried out with trifluoroacetic acid in the presence of anisole. In the case of benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, this is carried out by a catalytic reduction reaction.

The conversion reaction from compound (■) to compound (II) is carried out by adding mercuric chloride, mercuric nitrate, silver nitrate or thallium nitrate in a solvent.

It is carried out in the presence of metal ions such as silver or thallium. Reaction solvents are methanol, ethanol, tetrahydrofuran, dichloromethane, and ethyl acetate.

Chloroform, N,N-dimethylacetamide, N.

Specific examples include N-dimethylformamide, and the reaction temperature is usually about -78°C to about 50°C, but it may be carried out at other temperatures.

(Margin below) Production of compound (IV) Compound (IV) is produced by the following reaction scheme.

(■) (IX) (X)(
XI) (X[[) (XI
II) (XV) (XVI) In the above formula, R", R'', R3, R" and n have the same meanings as above. R" is the same as the explanation and specific examples of R" mentioned above. .R43 represents alkyl or aryl 1, which may be the same or different from R3. R44 represents halogenoacetyl.

The above reaction formula will be explained.

The conversion reaction from compound (■) to compound (IX) is carried out using compound (■) in a solvent with a catalyst (for example, palladium-carbon,
A catalytic reduction reaction is carried out in the presence of palladium black or platinum oxide).

The conversion reaction from compound (IX) to compound (X) is carried out by reacting compound (IX) with a mixed anhydride prepared from formic acid and acetic anhydride or a formic acid-DCC system.

The conversion reaction from compound (X) to compound (XI) is carried out by selectively hydrolyzing compound (X) in the presence of a base (eg, sodium hydroxide, potassium hydroxide).

The conversion reaction from compound (xl) to compound (Xl[) is
The reaction is carried out by applying the specific example described above for the esterification reaction of carboxylic acid of compound (I-2) to compound (XI).

The conversion reaction from compound (■) to compound (XIII) is
This is carried out by reacting compound (Xl) with phosgene, diphosgene or phosphorus oxychloride in a solvent.

The conversion reaction from compound (XII[) to compound (XV) is carried out by mixing compound (XII[) with compound (1') in a solvent,
It is carried out by reacting in the presence of a base. Examples of solvents include ether, tetrahydrofuran,
Examples include dioxane, ethyl acetate, N,N-dimethylformamide, and the like. Examples of bases include hydrides and carbonates of alkali metals such as lithium, sodium, and potassium, lithium salts of secondary amines such as diisopropylamine, methylisopropylamine, and dicyclohexylamine, and tertiary amines such as triethylamine and DBU. Can be mentioned. The reaction temperature ranged from -78°C to 5°C.
It can be done within the range of 06C.

The conversion reaction from compound (XV) to compound (XVI) is
This is carried out by reacting compound (XV) with an acid. Examples of acids include p-)luenesulfonic acid,
Examples include hydrochloric acid.

The conversion reaction from compound (XVI) to compound (XW) is
This reaction is carried out by reacting compound (XW) with a reactive derivative of compound (XW) in the presence of a base.

The explanation and specific examples of this reaction will be explained using the above-mentioned compound (I-1
) is applied.

The conversion reaction from compound (XW) to compound (IV) is carried out by treating compound (XW) with an aqueous sodium hydrogen carbonate solution in a solvent.

Preparation of Compound (■) This step consists of compound (XIX) represented by the formula [wherein R" has the same meaning as above] [R" is t-butyloxycarbonyl, M, Itoh , Chemical Pharmaceutical Bulletin (Chem, Pharm, B
ull, ).

17, 1672 (1969). ] is produced by applying the specific example described for the esterification reaction of carboxylic acid of compound (1-1).

Production of compound (XW) In this step, compound (XX) represented by the general formula [wherein R'' and n have the same meanings as above] is reacted with halogenoacetyl chloride (for example, chloracedel chloride, bromoacetyl chloride, etc.).It is produced by reacting with chloride.Solvents include, for example, water, ethyl acetate, chloroform, dichloromethane,
Ether, tetrahydrofuran, dioxane, N, N
-dimethylformamide, N,N-dimethylacetamide, and the like. As the base, the specific examples explained for the acylation of compound (1-1) above are applicable.

Each intermediate compound thus obtained can be isolated by means known per se, such as concentration, liquid conversion, dissolution, solvent extraction, freeze-drying, crystallization, recrystallization, one-fraction distillation, and chromatography.

Compounds (n) and (II[) thus obtained
is a new substance and is useful, for example, as a raw material compound for producing compound (1).

Effect Compound (I) or its ester or salt obtained as described above is useful as a medicine, and has antibacterial activity against certain types of Durum-positive and Durum-negative bacteria, for example.

Compound (I) has low toxicity.

Thus, compound (I) is effective against certain types of Durum-positive bacteria.
It exhibits antibacterial activity against Durham-negative bacteria, so it can be used in mammals (e.g. mice, rats, dogs, etc.) that have been infected with bacteria.
Treatment of bacterial infections (e.g., respiratory infections, urinary tract infections, purulent diseases, biliary tract infections, intestinal infections, obstetric and gynecological infections, surgical infections, etc.) in pigs, cows, etc. It can be used as a treatment for bacterial infections or as an antibacterial agent.

To administer compound (1), it is mixed with an appropriate pharmacologically acceptable carrier, excipient, or diluent, and then administered orally in the form of a tablet, granule, capsule, drop, etc. Alternatively, it can be formulated into, for example, an injection by conventional means, formulated into a sterile carrier prepared by conventional means, and administered parenterally.

The daily dosage of the compound of the present invention is, for example, about 2 to 100 mg/Kg of compound (1) when administered as an injection.
, more preferably about 5 to 40 mg/Kg.

When manufacturing the above oral preparations, such as tablets, a binder (
(e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol, etc.), disintegrants (e.g., starch, calcium carboxymethylcellulose, etc.), excipients (e.g., lactose, starch, etc.), lubricants (e.g., magnesium stearate, talc, etc.) can be blended as appropriate.

In addition, when manufacturing parenteral preparations, such as injections,
Isotonic agents (eg, glucose, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (eg, benzyl alcohol, chlorobutanol).

Methyl paraoxybenzoate, propyl paraoxybenzoate, etc.), buffers (eg, phosphate buffer, sodium acetate buffer, etc.), etc. can be appropriately blended.

Examples The present invention will be further explained in detail in the following examples and reference examples, but these examples are not intended to limit the present invention.
Further, changes may be made without departing from the scope of the present invention.

Unless otherwise specified, elution in column chromatography for Examples and Reference Examples was performed using TLC (ThinLayer C).
chromatography, thin layer chromatography)
It was carried out under the observation of In TLC observation,
60 manufactured by Merck as a TLC plate.
The solvent used as the elution solvent in column chromatography was used as the developing solvent, and the detection method was O
A v-detector was adopted. In addition, the phenomenon in which 48% HBr is sprayed onto a spot on a TLC plate, heated to hydrolyze it, then ninhydrin reagent is sprayed, and the color changes from red to reddish purple when heated again is also used as a detection method. Containing elution fractions were identified and collected.

Regarding developing solvents, the numbers shown in parentheses indicate the volume mixing ratio of each mixed solvent.If two types of developing solvents are used, unless otherwise specified, the numbers shown in parentheses indicate the volume mixing ratio of each mixed solvent. The by-product was eluted with a solvent of the same ratio, and the target product was then eluted with a solvent with a volumetric mixing ratio indicated after the arrow in parentheses. “Amber light (Am?erlite) X A
In the column chromatography purification using D-2'', water was first used as the developing solvent, and then an aqueous ethanol solution was used while gradually increasing the concentration, unless otherwise specified in the Examples and Reference Examples.

“Amberlight” is manufactured by Rohm and Haas (Rohm & Haas)
hm & 1laas Co, in U, S, A). Unless otherwise specified, Wako Gel C-300 (200 to 300 mesh) manufactured by Wako Pure Chemical Industries, Ltd. was used as the silica gel for the column, and the method described in Journal of the Organic Chemistry, Ushi-3, 2923 (1978) was used. and subjected to flash chromatography. NMR spectra were performed using VARIANEM type 390 (
90MHz) was measured with a spectrometer, and the total δ value was calculated as p
Shown in pm. Mass spectra marked as FDMS are field desorption mass spectra (FDMS).
Mass Spectrum)
Measurements were made using a -80A spectrometer.

Note that "room temperature" usually means 0°C to 40°C. Further, unless otherwise specified, % indicates weight percentage. When mixed solvents are used, the numbers in parentheses indicate the volumetric mixing ratio of each solvent. The symbols in Examples and Reference Examples have the following meanings.

S: singlet d: doublet t Nitribulet (tr
iplet)q: quartet
ABq: AB type qua
rtet) dd: double doublet (double d)
oublet)m: multiplet
let) sh: Shoulder (sho Vlder) br=
Broad J: Coupling constant
stunt) mg: milligram
g ; gram d : milliliter ρ
:liter ppm :part per million
ion) 1[z: llerz DMSO dimethylsulfoxide (dimethyls
ulfoxide) D, O: Heavy water Reference Example 1 (2S)-2-Benzoloxycarbonylaminoglutaric acid l-methyl-4-(t-butyl) diester [Preparation of compound (1) (2S)-2-benzyl Oxycarbonylaminoglutaric acid 5-(t-butyl) ester [M, Itoh.

Chem, Pharm, Bull,, ↓7
．． 1672 (1969) 5.00g of ethyl acetate
The solution was dissolved in 100% water, and an ether solution of diazomethane was added thereto. After adding acetic acid to the reaction mixture to decompose excess diazomethane, the mixture was washed with a 5% aqueous sodium hydrogen carbonate solution and then with saturated brine, dried (MgSO, ), and the solvent was distilled off under reduced pressure. The residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and hexane (1:3). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the title compound (1) as an oil.
．． Obtained 39g.

r n v "tcm-': 3340.1729.1
525.1250°aX 1213,115O NMR (90MIIZ, CDCl5) δ: 1.43
(9H, s), 1.75-2.43 (411, m),
3.74 (3H, s), 4.40 (1!I, m),
5.10 (211, s), 5.40 (In, b, s
), 7.34 (5H, s) Reference Example 2 Production of (2S)-2-formylaminoglutaric acid 1-methyl-5-(t-butyl) diester [Compound (2)] Compound obtained in Reference Example 1 (1) 4.72g methanol 8
0.74 g of formic acid and 0.25 g of palladium black were added thereto, and the mixture was stirred at room temperature under a hydrogen stream for 4 hours. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the crude product (2S)-2-aminoglutaric acid l-methyl-4-Q
-butyl) diester was obtained as an oil. This was dissolved in dichloromethane GOd, and 3.33 g of dicyclohexylcarbodiimide (DCC) was added thereto and stirred at room temperature for 15 hours. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure.

The residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and hexane (1:l). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the title compound (2) as an oil.
．． Obtained 06g.

Reference Example 3 2-Incyanoglutaric acid l-methyl-5-(t-butyl) diester [Preparation of Compound (3) 3.06 g of Compound (2) obtained in Reference Example 2 was dissolved in 50 turns of dichloromethane, - Cool to 45-40°C. A dichloromethane solution containing 3.03 g of triethylamine and 1.23 g of diphosgene was added dropwise thereto, and the mixture was stirred at the same temperature for 30 minutes. After heating the reaction solution to 0°C for 20 minutes,
Wash with water, then 5% sodium hydrogen carbonate aqueous solution, and dry (
MgS04). The solvent was distilled off under reduced pressure, and the residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and hexane (1:4). Fractions containing the target product were collected and concentrated under reduced pressure to obtain the compound (3). 2.56 g of oil was obtained.

I Rv noatcm-': 2147.1?62.
1730.1155aX NMR (90MIIZ, CDC13) δ: 1
, 45 (9H, s), 1.95-2.60 (4H, m
), 3.42(311,s), 4.44(lIl,
dd, J = 5Hz.

7Hz) Reference Example 4 Production of 2-isocyano-2-methylthioglutarate l-methyl-5-(t-butyl) diester [Compound (4)] 2.56 g of Compound (3) obtained in Reference Example 3 was dried with N .

The mixture was dissolved in 30 d of N-dimethylformamide, 1.70 g of water-cooled potassium carbonate and 1.56 g of methyl methanethiosulfonate were added thereto, and the mixture was stirred at the same temperature for 2 hours.

The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was taken, washed with water, dried (MgSO, ), and the solvent was distilled off under reduced pressure. The residue was passed through a silica gel column and eluted with a mixture of acetic acid and hexane (1:10). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain compound (4) as an oil with a concentration of 2.9
I got 9g.

I Rv "tc+n-': 2120.1745.1
730.1245°ax NMR (90MIIZ, CDCl δ: 1.4
7 (911,3), 2.28 (3+1°s), 2.
30-2.80 (4H, m), 3.85 (311, s
) Reference example 5 2-amino-2-methylthioglutaric acid 1-methyl-
Production of 5-(t-butyl) diester [compound (5)] 0.181 g of p-toluenesulfonic acid monohydrate was dissolved in chloroform at 13:00, and the compound (4) obtained in Reference Example 4 was added to the solution under water cooling. 0.186 g was added and stirred at the same temperature for 1 hour. The reaction solution was washed with a 5% aqueous sodium hydrogen carbonate solution, dried (MgS O4), and then the solvent was distilled off under reduced pressure. The residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and hexane (l:2-t:t). Fractions containing the target product were collected and concentrated under reduced pressure to obtain compound (5) as an oil. 0.085g was obtained.

I Rv "tcm-': 3400.1728.11
50ax NMR (90MH2, CDCl5) δ: 1.4
3 (9i1.s), 1.95 (2[1°s), 2.
07 (3H, s), 1.9 (1-2, 70 (41 (,
m), 3.77 (311°S) Reference Example 6 2-Formylaminoglutaric acid 1-(4-nitro)benzyl-5-(t-butyl) diester [Compound (6)
] 1.0 g of compound (2) obtained in Reference Example 2 was mixed with 10 g of methanol.
Dissolve in zJ and cool with water! Normal sodium hydroxide 6
．． After dropping 1d, the mixture was stirred at the same temperature for 1 hour. Methanol was distilled off under reduced pressure, 30 degrees of ethyl acetate was added thereto, and then 6°Id of 1N hydrochloric acid was added under water cooling. The organic layer was separated, and the aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. The combined organic layers were dried (MgSO, ) and the solvent was distilled off under reduced pressure to obtain 2-formylaminoglutaric acid 5-(shi-butyl) ester as a crude product as an oil. Dissolve this in 15d of dichloromethane, add 0.625g of 4-nitrobenzyl alcohol, 1.0g of DCC and N
, 0.025 g of N-dimethylaminopyridine was added, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure, 50% ethyl acetate was added to the residue, and insoluble matter was filtered off. 5 filtrate
After washing with % aqueous sodium hydrogen carbonate solution and then saturated brine and drying (MgSO4), the solvent was distilled off under reduced pressure. The residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and hexane (1:l). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain 1.2 g of compound (6) as an oil. Obtained.

I RvKBrcm-': 3310.1?40.17
03.1680゜aX 1523, 1352.1192 NMR (90MIIz, CDC1t) δ: 1
．． 41 (98, s), 1.97-2.40 (411
, m), 4.73 (IH, m), 5.25 (2t
l, s), 6.47 (IIf, d, J=8Hz),
7.53 (211, d, 'J=9Hz), 8.25
(ill, s).

8.25 (2H, d, J = 9 Hz) Reference Example 7 2-isocyanoglutaric acid 1-(4-nitro)benzyl-5-(t-butyl) diester [Preparation of compound (7) in Reference Example 6 5.29 g of the obtained compound (6) was dissolved in 150 g of dichloromethane, 4.14 g of triethylamine was added thereto while cooling at -50° to -45°C, and then a diphosgene solution in dichloromethane was added! Added 0 turns. 30 at the same temperature
After stirring for a minute, the temperature was raised to 0°C. Wash the reaction solution with water and then with saturated saline.

Dry (MgSO4). The solvent was evaporated under reduced pressure, and the residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and hexane (1:3). Fractions containing the target product were collected and concentrated under reduced pressure to obtain the compound (7) as an oil with 4.53
I got g.

I Rv noatcm-': 2147.1?63.
1729.1525°ax 1350, 1154 NMR (90MIIZ, CDC13) δ: 1.
45 (911, s), 2.00-2.60 (411
, m), 4.55 (III, m), 5J3 (211
, s), 7.58 (211, d, J=911z),
8.28 (211, d, J=911z) Reference Example 8 2-isocyano-2-methylthioglutaric acid 1-(4-
nitro)benzyl-5-(t-butyl)diester [Preparation of Compound (8) 4.53 g of Compound (8) obtained in Reference Example 7 was dissolved in 25 d of N,N-dimethylformamide, and methylmethanethiosulfonate was added to the solution. 2.15g and potassium carbonate 2.35g
was added and stirred at room temperature for 2 hours. Add 11 ethyl acetate to the reaction solution.
50 d and 100 d of water were added to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, and dried (MgS
O,) I did. The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and hexane (1:4). Fractions containing the target product were collected and concentrated under reduced pressure to obtain 4.51 g of compound (8) as an oil.

neatcm-': 2115.175'0.1729
．． 1524°■RI=maX 1347, 1155 NMR (90 MllZ, CDC13) δ: 1.
47 (9H, s), 2.21 (311°s), 2.
45 (4tl, m), 5.34 (2[1,s), 7
．． 55 (211, d, J=911z), 8.25 (2
)1. d, J=9Hz) Reference Example 9 2-amino-2-methylthioglutaric acid! = (4-nitro)benzyl-5-(thi-butyl) diester [Preparation of compound (9) 0.237 g of p-toluenesulfonic acid l hydrate was dissolved in chloroform + 5 d, and the solution was dissolved in water-cooled reference example 7. A chloroform solution 3- containing 0.30 g of the compound (7) obtained in step 3 was added, and the mixture was stirred at the same temperature for 50 minutes.

Wash the reaction solution with a 5% aqueous sodium hydrogen carbonate solution.

After drying (NatSO4), the solvent was distilled off under reduced pressure.

The residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and hexane (1:2). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the compound (9) as an oil with a 0.
112g was obtained.

I R1/""tcm-': 3415.1738.1
728.1523°1118 to 1348, 1176, 1153 N M R (90 MIlz, CDCl+) δ: 1.
43 (9+1.S), 2.00 (3+1°s), 2
．． 10-2.70 (411, m), 5.30 (2H,
s), 7.55 (211°d, J=9112), 8
．． 21 (211, d, J=9112) Reference Example 10 (2S)-2-benzyloxycarbonylamino-4-
Production of chloroacetyloquinobutyric acid [compound (10)] (2S)-2-benzyloxycarbonyl-4-hydroxybutyric acid t-butyl ester [J, Nikawaan
d T, 5hiba, Chem, Letters
, 981 (1979). ]
4. Dissolve Og in 50 g of dichloromethane, add 1.82 g of triethylamine under water cooling, and then dissolve 107 g of dichloromethane containing 2.03 g of chloroacetyl chloride.
I1. added.

After stirring for 40 minutes under water cooling, the reaction solution was washed with water and a 5% aqueous sodium bicarbonate solution, dried (MgSO,), and the solvent was distilled off under reduced pressure. The residue was passed through a column of silica gel and treated with a mixture of ethyl acetate and hexane (1:4-1:3).
The fractions containing the target product were collected and concentrated under reduced pressure.
4.97 g of a crude product of butyl ester of S)-2-benzyloxycarbonylamino-4-chloroacetylobutyric acid was obtained as an oil. To this, 2 d of anisole and 20 d of trifluoroacetic acid were added under water cooling, and the mixture was stirred for 3.5 hours. The residue obtained by evaporating the solvent under reduced pressure was washed with hexane, passed through a silica gel column, and eluted with a mixture of ethyl acetate, chloroform, and methanol (3:3·I). Fractions containing the target product were collected and concentrated under reduced pressure to obtain 4.20 g of the compound (lO) as an oil.

I Rneatcm-': 3500-3100.17
30~1700°ax 1527, 1197N? vI R (90MHz, CDC13) δ:
2.13 (2H, m), 3.94 (2H.

s), 4.08-4.60 (311, m), 5
．． 07 (211, s), 5.91 (LH.

d, J=Illllz), 7.29(511,s)
, 10.39 (ill, s) Reference Example 11 2-[(2S)-2-benzyloxycarbonylamino-4-chloroacetyloxybutyrylcoamino-2-methylthioglutaric acid 1-(4-nitro)benzyl-5
-Production of (t-butyl) diester [compound (11)] 181 mg of the compound (9) obtained in Reference Example 9 was dissolved in dichloromethane 5y=e, and the compound (9) obtained in Reference Example IO was dissolved in this.
10) 125 mg of N,N-dimethylaminopyridine and 125 mg of DCC were added and stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and 20% of ethyl acetate was added to the residue.
d was added and insoluble matter was filtered off. The filtrate was washed with 1N hydrochloric acid, then with 5% aqueous sodium bicarbonate solution, and dried (MgSO
,)did. The solvent was distilled off under reduced pressure, and the residue was passed through a silica gel column. A mixture of ethyl acetate and hexane (l:
2→2:3), fractions containing the target product were collected and concentrated under reduced pressure to obtain 81 mg of the compound (11) as an oil.

neat -1°I Rcm, 3315. 1730. 162
2. 1347°118X 1247.1155 N! vl R (90MH2, CDCl5) δ: 1
．． 42 (9H, s), 1.92 (3H.

s), 1.80-2.36 (411, m), 2.
58 (2B, m), 4.02 (2H.

s), 4.27 (311, m), 5.10 (211
, s), 5.30 (211, s).

5.61 (ill, d, J=8Hz), 7.33 (6
H, s), 7.53 (211, d, J-911z),
8.20 (2H, d, J = 9Hz) Reference Example 12 2-[(2S)-2-benzyloxycarbonylamino-4-hydroxybutyrylcoamino-2-methylthioglutaric acid 1-(4-nitro)benzyl- Production of 5-(t-butyl) diester [compound (12)] 1.243 g of compound (11) obtained in Reference Example 11 was dissolved in 10y4 of tetrahydrofuran, and to this was added 207 g of methanol, 7 g of water, and sodium hydrogen carbonate under cooling with water. 225 mg was added and stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, 40 J of ethyl acetate and 20 turns of saturated brine were added, and the organic layer was dried (MgSO-).

The residue obtained by evaporating the solvent under reduced pressure was passed through a silica gel column and eluted with a mixture of ethyl acetate and hexane. Fractions containing the target compound were collected and concentrated under reduced pressure to obtain Jiki compound (12).
905 mg of was obtained as a powder.

I Rν""tcm-': 3300.1730.17
18.1690°ax 1515, 1343 N M n (90MHz, CDCl5) δ: 1.
42 (9H, s), 1.96 (311°s), 1.
80-2.05 (411, m), 2.62 (211,
m), 3.01 (III.

bs), 3.74 (2H, m), 4.43 (11L
m), 5.11 (2!l, s).

5.30 (28, s), 5.92 (III, dj=7
11z), 7.32 (5H, s).

7.42 and 7.46 (III, N11), 7
．． 54 (2H, d, J=9Hz).

8.21 (211, d, J=911z) Reference Example 13 2-[(3S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-■-yl]-2-medyldioglutaric acid 1-( 4-nitro)benzyl-5-(t-
Production of Compound (H) Diester [Compound (H)] 81 mg of Compound (12) obtained in Reference Example 12 was dissolved in acetonitrile ld, and 0% carbon tetrachloride was added to the solution under a nitrogen stream.
．． After adding Id, 41 mg of triphenylphosphine, and 17 mg of triethylamine and stirring at room temperature for 1.5 hours,
Furthermore, 34 mg of triphenylphosphine and 34 mg of triethylamine were added and stirred for 3.5 hours. The solvent was distilled off under reduced pressure, the resulting residue was passed through a silica gel column, and a mixture of ethyl acetate and hexane (1:2-2:3) was added.
It was eluted. Fractions containing the target product were collected and concentrated under reduced pressure to obtain 55 mg of the compound (13) as an oil.

I Rv noatcm-': 3390.1735.
1725.1693°aX 1520, 1346 NMR (90 MIlz, CDC13) δ: 1.
43 (911, s), 2.02 (3HxL, s),
2.05 (3tl×+), 1.75-2.90 (al
l, m).

3.60 (18, m), 4.00-4.60 (2H,
m), 5.11(2[1,s).

5.25 (211xL, s), 5.29 (2Hx+
, s), 5.42 (IHXL, d, J = 811z)
, 5.47 (IHx +, d, J = 8Hz), 7
．． 34 (5H, s), 7.52 (2+1.d, J=9
H2), 8.20 (2H, d, J = 9Hz) Reference Example 14 2-[(2S)-2-benzyloxycarbonylamino-4-hydroxybutyrylcoamino-5-oxotetrahydrofuran-2-carboxylic acid 4- Production of nitrobenzyl ester [compound (14)] 85 mg of the compound (12) obtained in Reference Example I2 was added with 0.1-0.1% of anisole under water cooling.
and trifluoroacetic acid IM1. was added and stirred at the same temperature for 80 minutes. The solvent was distilled off under reduced pressure, carbon tetrachloride was added to the residue, and the mixture was again concentrated under reduced pressure, which was repeated twice. After washing the resulting residue three times with hexane, it was washed with N,N-
Dissolved in dimethylformamide ty. After adding 0.371112 of N,N-dimethylformamide containing 48 mg of mercury acetate to this at -50°C under a nitrogen stream, the reaction temperature was raised to -20°C over 20 minutes. Add 11 ethyl acetate to the reaction solution.
After adding 50% of the mixture and 8% of water, insoluble materials were filtered off, and the organic layer was separated. After washing the organic layer with water and drying (MgSO,), the solvent was distilled off under reduced pressure. The residue was passed through a column of silica gel and treated with a mixture of ethyl acetate and hexane (10:l).
It was eluted. Fractions containing the target product were collected and concentrated under reduced pressure to obtain 57 mg of the compound (14) as an oil.

I n vnea"cm-': 3350.1?80
．． 1750.1692°aX 1515, 1343 N M R (90 MIIz, CDCl5) δ: 1.
92 (211, m), 2.57 (5H.

m), 3.67 (2tl, m), 4.43 (LH,
m), 5.07 (211, s).

5.30 (2H, s), 6.00 (18, d, J=7
Hz), 7.33 (511,s).

7.48 (211, d, J=9Hz), 8.19 (2
0, d, J=911z), 8.43 (IH, s) Reference Example 15 2-[(3S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl]-2-methylthioglutaric acid 1 Production of -(4-nitro)benzyl ester [compound (15)] Compound (13) obtained in Reference Example 13
0.2 g of anisole and 2 g of trifluoroacetic acid were added to 126 mg under water cooling, and after stirring for 20 minutes, the solvent was distilled off under reduced pressure.

After adding carbon tetrachloride to the residue and condensing under reduced pressure twice, the residue was washed three times with hexane and dried under reduced pressure to obtain the crude compound (15). Honjima was used as a raw material in Example 1 without being purified.

Reference example 16 (2S)-2-benzyloxycarbonylamino-3-
Chloroacetyloxypyropionic acid [Compound (16)]
Production of (2S>-2-benzyloxycarbonylamino-3-
To a 60% solution of N,N-dimethylacedeamide containing 11.96 g of hydroxypropionic acid, 7.34 g of chloroacetyl chloride was added under water cooling.

After stirring for 15 minutes under water cooling and then 45 minutes at room temperature, the reaction solution was poured into water and extracted with ethyl acetate.

After washing the organic layer with water and drying (MgSO4), the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixture of isopropyl ether and hexane to obtain 88 g of I 2 O as white crystals.

Melting point: 75.0-75.58C I RvKBrcm-': 3350.2950.17
60.1720゜aX 1640.1540.121O NMR (90MH2, CDC13) δ: 3.9
5(211,s), 4.20~4.85(3[1,m
), 5.10 (211, s), 5.93 (1) 1. d,
J=6. Old (z), 7.30 (5H, s), 1
0.45 (lH, s) Reference Example 17 2-[(2S)-2-benzyloxycarbonylamino-3-chloroacetyloxypyropionylcoamino-2
-Preparation of methylthioglutaric acid 1-(4-nitro)bentu-5-(t-butyl) diester [compound (17)] Dissolve 0.5-N,N-dimethylformamide in 30-dichloromethane and add to the solution at -10°C. 594 mg of diphosgene was added to the mixture under cooling, and the mixture was stirred at the same temperature for 20 minutes. The reaction solution was cooled to -70°C, and a solution of 0.53d of pyridine and the compound obtained in Reference Example (17) (9N, 77g dissolved in 30d of dichloromethane) was added, and the mixture was heated to -60° to -50°C.
Stir at ℃ for 1 hour. Add pyridine to the reaction solution at -70°C.
．． 53m12 and 1.81g of compound (9) obtained in Reference Example 9
After adding a solution of 20°C in dichloromethane, the temperature was gradually raised and the mixture was stirred at 0°C for 1 hour. Add 1N hydrochloric acid to the reaction solution.

It was washed with a 5% aqueous sodium hydrogen carbonate solution and a homogeneous saline solution, and dried (MgS O). The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and hexane (1:3).

Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the compound (17).
) was obtained as an oil.

I Rv "tcm-': 3330.1730.15
20.1350aX NMR (90MH2, CDC13) δ: 1.4
2 (911, s), 1.93 (3H.

s), 2.0-2.9 (411, m), 4.03 (
2H, s), 4.1-4.8 (311, m), 5.
14 (211,s), 5.31 (211,s), 5
．． 62 (III, d, J=6.311z), 7.33
(ell, m), 7.89 (411, ABQ, J=9
11z) Reference Example 18 2-[(2S)-2-benzyloxycarbonylamino-3-hydroxypropionylcoamino-2-methylthioglutaric acid 1-(4-nitro)benzyl-5-(t
-butyl) diester [compound (18)] 1.82 g of the compound (18) obtained in Reference Example 18 was mixed with 60 g of methanol and 41 n1. To this was added an aqueous solution containing 355 mg of sodium hydrogen carbonate, and the mixture was stirred at room temperature for 1 hour.

The solvent was distilled off under reduced pressure, and the resulting aqueous solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried (MgSO,
)did. The residue obtained by distilling off the solvent under reduced pressure was passed through a silica gel column, and a mixture of ethyl acetate and hexane (
1:I). Fractions containing the target product were collected and concentrated under reduced pressure to obtain 1.54 g of the compound (18) as an oil.

I Rv neatcm-': 3300.1720.
1520.1350°ax 25O NMR (90MIIZ, CDC13) δ: 1.
40 (9tl, s), 1.91 (3H.

s), 1.80-2.90 (411, m), 3.1
0-4.40 (411, m).

5.10 (2H, s), 5.30 (2fl, s),
5.90 (lH, d, J=6.911z), 7.31
(511, s), 7.54 (III, s), 7.8
5 (411, ABqj=9oz) Reference Example 19 2-[(3S)-3-benzyloxycarbonylamino-2-oxoazedecine-! -yl]-2-methyldioglutaric acid 1-(4-nitro)benzyl ester [Compound (19)] Compound (18) obtained in Reference Example 18
Dissolve 513 mg in 12d of tetrahydrofuran,
To this, 445 mg of triphenylphosphine was added under a nitrogen stream.
and 296 mg of diethyl azodicarboxylate were added and stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and hexane (2+5). Fractions containing the target product were collected and concentrated under reduced pressure to obtain 1-(4-nitro)benzyl-5-(t -butyl) diester and by-produced N, N-
663 mg of a mixture with jetoxycarbonylhydrazine was obtained as an oil. This was dissolved in a mixture of 1.5 volumes of anisole and I5 trifluoroacetic acid under water cooling and stirred for 1.5 hours. An operation of adding carbon tetrachloride to the residue obtained by concentrating the solvent under reduced pressure and reducing the pressure to J5'm was performed twice. The resulting residue was washed twice with hexane and dried under reduced pressure to obtain the crude compound (19) as an oil. The crystal was used as a raw material in Example 6 without being purified.

Example 1 2-[(3S)-3-benzyloxycarbonylamino-2-xopyrrolidin-1-yl]-5-oxotetrahydro afuran-2-carboxylic acid 4-nitrobenzyl ester [Compound (20) ] The crude product of compound (15) obtained in Reference Example 15 was dissolved in 1°2-dimethoxyethane, and 87 mg of mercury acetate was added thereto under a nitrogen stream.
Stir at room temperature for 2 hours. The solvent was distilled off under reduced pressure, 5 d of ethyl acetate was added to the resulting residue, and insoluble matter was filtered off.

The filtrate was concentrated under reduced pressure, the resulting residue was passed through a silica gel column, and a mixture of ethyl acetate and chloroform (1:
It eluted with I). Fractions containing the target product were collected and concentrated under reduced pressure to obtain 71 mg of the compound (20) as an oil.

neat - meaning.

I 12cm, 3310. 1790. 17
48. 169g.

aX 1518.1343 NMR(90Mllz, CDCl*)δ: 2.
0? (Ill, m), 2.40-3.00 (511,
n+), 3.28-3.93 (211, m), 4.
48 (IH.

m), 5.03 (2Hx+, s), 5.08 (21
1xL, s), 5.24 (2114, s), 5.
30 (211x+, s), 6.00 (III, d, J
=811z), 7.30 (511X", S), 7
．． 32 (5HX+, S).

7.45 (211xi, d, J=9Hz), 7.4
8 (211x+, d, J=911z), 8.18 (2
+1XL, d, J=9H2), 8.21 (211X
'−.

d, J=911z) Example 2 2-[(3S)-3-benzyloxycarbonylamino-2-oxopyrrolidine-■-ylco-5-oxotetrahydrofuran-2-carboxylic acid 4-nitrobenzyl ester [Compound (20) ] 33 mg of compound (14) obtained in Reference Example 14 was added to anhydrous tetrahydrofuran ld.
34 +++ g of triphenylphosphine and 2 g of diethyl azodicarboxylate were added to this in a stream of nitrogen over water cooling.
2 mg was added and stirred at the same temperature for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and chloroform (1:l).

Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the compound (2).
26 mg of 0) was obtained as an oily substance. This compound was completely identical to the compound obtained in Example 1.

Example 3 2-[(3S)-3-[2-(2-aminothiazole-
4-yl)-(Z)-2-methoxyiminoacetamidoco-2-oxopyrrolidin-1-ylco-5-oxotetrahydrofuran-2-carboxylic acid-sodium salt [Compound (21)] Obtained in Example 1 Compound (20)
Dissolve 105 mg in ethyl acetate and add pl-
I7. 5 d of 0.1 molar phosphate buffer and 50 mg of 10% palladium-carbon were added, and stirred for 1 hour while cooling with water and passing hydrogen gas through the mixture. After removing the catalyst by filtration and separating the aqueous layer, the organic layer was extracted with water. Combine the aqueous layers and add ethyl acetate
After washing with
d. 54 mg of sodium hydrogen carbonate and 85 mg of hydrochloride of 2-(2-chloroacetamidodeazol-4-yl)-(Z)-methoxyiminoacetic acid chloride were added, and the mixture was stirred at the same temperature for 30 minutes. After distilling off tetrahydrofuran from the reaction solution under reduced pressure, the aqueous layer was mixed with ethyl acetate (51.5%). Washed with fl. Tetrahydrofuran 51nQ and N
-49 mg of sodium methyldithiocarbamate was added and stirred at room temperature for 75 minutes. Tetrahydrofuran was distilled off from the reaction solution under reduced pressure, and the resulting aqueous layer was diluted with 10 ml of ethyl acetate.
After washing with water, add Amberlite XAD-2 to the column.

The mixture was then passed through a column of Sephadex L) (-20) and eluted with water. Fractions containing the target compound were collected and lyophilized to obtain 38 mg of the compound (21) as a powder.

Elemental analysis value (C+sr(+eNsNaO?S ” 3I
-r, o ) Calculated value C, 36, 96, 1 (, 4, 55
; N, 14,37°S, 6.58 Actual value C, 37,10; H, 4,34; N, 14
, 52°S, 6.78 I n νK"'cm-'+ 3330.1770.
1695.1632°aX NMr((90MH2,D,O): 2.30(IH
, m), 2.40-3.15 (511, m), 3.
75 (211, m), 4.04 (311, s), 4
．． 60 (lIl, m).

7.17(III,S) Example 4 2-[(3S)-3-[(2R)-2-(4-ethyl-
2,3-dioxo-! -Piperazinecarboxamide) Phenylacetamidogo 2-xopisolysine-1-ylro 5-oxotetrahydrofuran-2-carboxylic acid-sodium [Compound (22)] 125 mg of Compound (20) obtained in Example 1 was dissolved in acetic acid. Dissolve in ethyl 2- and add 41n1 of 0.1 molar phosphate buffer with pi-I7.0. and 1θ% palladium-carbon 60
mg was added thereto, and the mixture was stirred for 1 hour while cooling with water and passing hydrogen gas through the mixture. After filtering off the catalyst and separating the aqueous layer, the Ja layer was mixed with 2 ml of water.
Extracted with water. The aqueous layers were combined and washed with 5 ml of ethyl acetate, followed by 4 ml of tetrahydrofuran. n1. and 127 mg of sodium hydrogen carbonate were added.

(2rL)-2-(4-ethyl-2,3-dioxo-1
-piperazine carboxamide) phenylacetic acid 240 mg
was dissolved in diluted methylene chloride, 76 mg of 11-edylamine and 157 mg of phosphorus pentachloride were added to the solution under water cooling, and the mixture was stirred for 50 minutes and then stirred at room temperature for 10 minutes. After evaporating the solvent under reduced pressure and washing the residue three times with 5d hexane,
The mixture was dissolved in tetrahydrofuran, and insoluble matter was filtered off.

The filtrate was added dropwise to the previously prepared solution under water cooling, and stirred at the same temperature for 2 hours. Tetrahydrofuran was distilled off from the reaction solution under reduced pressure, and the resulting aqueous layer was passed through an Amberlite XAD-2 column and eluted with 5% ethanol. Fractions containing the target product were collected and freeze-dried to obtain 36 mg of the compound (22) as a powder.

Elemental analysis value (CtnHzNaOa'4.5H20
) Calculation fa C, 45, 57, H, 5, 58, N, 1
1.07 actual value C, 45, 46; II, 5.11;
N, 11.16T RvKBrcm-': 3440
．． 1772.1713.1678°aX NMR (90MIIz, D, O): 1.27 (3H
, tj=7H2), 2.04(Ill, m), 2.4
0-3.20 (5H, m), 3.58 (211, AB
Q, J-711z), 3.75 (411, m),
4.07 (211, m), 4.73 (III, m),
5.56 (III, s), 7.56 (511,
s) Example 5 2-4(3S)-3-chenylacetamido-2-oxopyrrolidin-1-ylco-5-oxote!・Rahydrofuran-2-carboxylic acid-sodium salt [Compound (23
)] 97 mg of the compound (20) obtained in Example I was dissolved in 2+J ethyl acetate, and 41n1. and 10% palladium-carbon 50mg
was added and stirred for 1 hour while passing hydrogen gas over water cooling. The catalyst was filtered off, the aqueous layer was separated, and the organic layer was extracted with two portions of water. The aqueous layers were combined and washed with 5 portions of ethyl acetate, followed by 4 Tn of tetrahydrofuran and 6 Tn of sodium hydrogen carbonate.
4 mg was added. To this, 2 ml of tetrahydrofuran solution containing 80 mg of chenyl acetate chloride was added dropwise under water cooling.
Stir at the same temperature for 1 hour. Tetrahydrofuran was distilled off from the reaction solution under reduced pressure, and the resulting aqueous layer was transferred to Amberlite
It was passed through an AD-2 column and eluted with water. Fractions containing the target product were collected and lyophilized to obtain 35 mg of the compound (23) listed above as a powder.

I n vKBrcm-': 3400.1773.1
770.1635ax NMR (90MIIZ, D20): 2.13 (IH
, m), 2.40-3.23 (511, m), 3.7
0 (211, m), 3.94 (211, s), 4.
70 (III, +n).

7.12 (2H, m), 7.46 ('ill, m) Example 6 2-[(3S)-3-benzyloxycarbonylamino-2=oxoazedecin-1-yl-5-oxotetrahydrofuran-2-carvone Acid 4-nitrobenzyl ester [Preparation of Compound (24) J The crude product of Compound (19) obtained in Reference Example 19 was mixed with a ratio of 2 to nometquinethane 5 t
270 mg of mercury acetate was added thereto, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure (11), 10 d of ethyl acetate was added to the residue, insoluble materials were filtered off, and the filtrate was distilled off under reduced pressure. The resulting residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and hexane (1:1). Fractions containing the target product were collected and concentrated under reduced pressure to obtain 247 mg of the compound (24) as an oil.

[αco25=,9° (c=0.305. MeOH
) FDMS m/z: 484 (MH”) I n v
C""13cm-': 3430.1?98.1773
．． 1725°aX 1513, 1347 NMR (90MHz, CDCl5): 2.3-2.
9(6H,+n), 4.6-4.9(1)1. m),
5.08 (2H, s), 5.33 (211, s),
5.79 (18°d, J=7.8), 7.30 (5
tl, s), 7.4-'8.3 (41Lm) Example 7 2-[(3S)-3-[2-(2-aminothiazole-
Production of sodium salt [compound (25)] obtained in Example 6 Compound (24)
Dissolve 149 mg in ethyl acetate and adjust the pH to 7.
, 0, and 133 mg of 10% palladium-carbon were added thereto, and the mixture was stirred at room temperature for 45 minutes while passing hydrogen gas. After removing the catalyst by filtration and separating the aqueous layer, the organic layer was extracted with water. Combine the aqueous layers and add ethyl acetate
125 mg of sodium bicarbonate and 122 mg of 2-(2-chloroacetamidothiazol-4-yl)-(Z)-methoxyiminoacetic acid chloride hydrochloride were added to the mixture under water cooling, and the mixture was heated at the same temperature. and stirred for 20 minutes. After adding 71 mg of sodium N-methyldithiocarbamate to the reaction solution and stirring at room temperature for 1 hour, tetrahydrofuran was distilled off under reduced pressure. The obtained aqueous layer was passed through an Amberlite XAD-2 column and then a Sephadex LH-20 column, and eluted with water. Fractions containing the target product were collected and lyophilized to obtain 56 mg of the compound (25) as a powder.

mp 226° (dec,), [α]”3=+1.
2° (c=0.43°Summer]!0) Elemental analysis value (C+4H+4NsO9SNa・3HtO)
Calculated value C, 35, 52, H, 4, 26, N, 14.7
9°S, 6.77 Actual measurement C, 35, 66: H, 4,03, N, 14.
76;S, 6.95 I Rv KBrcm-': 3400.1760.1
540.1030ax NMR (90MHz, DtO): 2.4-3.5 (
411, m), 3.73 (IH.

m), 3.90 (LH, m), 4.06 (31
1, s), 5.11 (IH, m).

7.05 (IH,s) Example 8 2-4(3S)-3-chenylacetamido-2-oxoazetidin-1-yl]-5-oxotetrahydrofuran-2-carboxylic acid-sodium salt [Compound (26)
163 mg of the compound (24) obtained in Example 6 was dissolved in ethyl acetate, and mixed with 0.1 molar phosphate buffer of pi-17.0 and 10% palladium-carbon 135II.
1 g was added, and the mixture was stirred for 1.5 hours while cooling with water and passing hydrogen gas through the mixture. After removing the catalyst by filtration and separating the aqueous layer, the organic layer was extracted with two portions of water. Combine the aqueous layers with 5M ethyl acetate. After washing with water, add 6 ml of tetrahydrofuran, 140 mg of sodium bicarbonate and 10 ml of dienylacetic acid chloride under water cooling.
8 mg was added and stirred at the same temperature for 30 minutes. Tetrahydrofuran was distilled off from the reaction solution under reduced pressure, and the resulting aqueous layer was passed through a column of Amberlite XAD-2 and eluted with water. Fractions containing the target compound were collected and lyophilized to obtain 85 mg of the compound mentioned above as a powder.

mp 136℃ (dec,), [αkoku3=+
4.9° (c=0.51°1 [zO) Elemental analysis value (CI4813N to lls Na-
1/2Hto) Calculated value C, 43, 41, H, 4, 1
6, N, 7.23°S, 8.28 Actual value C, 43,60; H, 4,29, N, 7.2
3°S, 8.59 I RshiKBrcm-': 3420.1780.26
40.1371) max NMR (90MIIz, D, O): 2.2-3.4
(4H, m), 3.62 (ill.

m), 3.78 (IH, m), 3.93 (2H
, s), 4.93 (III, m).

7.09 (211, m), 7.47 (IH, m) Effects of the Invention The compound (T) produced by the present invention has excellent antibacterial activity and can be advantageously used as a pharmaceutical or the like.

Claims (3)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1' is an organic residue via nitrogen, R^2' is a group that can be converted to a carboxyl group, and R^3 is a hydrocarbon. residue, n represents an integer of 1 or 2] is subjected to a ring-closing reaction, and optionally subjected to a conversion reaction of R^1' and (or) R^2'. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is an amino group or an organic residue via nitrogen, R^2 is a carboxyl group or a group derived therefrom, and n has the same meaning as above. A method for producing a compound represented by or a salt thereof. (2) Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1' is an organic residue via nitrogen, R^2'
is a group that can be converted into a carboxyl group, and n is an integer of 1 or 2] is subjected to a ring-closing reaction, and optionally subjected to a conversion reaction of R^1' and (or) R^2'. There are formulas that are characterized by attaching ▲ mathematical formulas, chemical formulas, tables, etc. n has the same meaning as defined above] or a salt thereof. (3) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 represents an amino group or an organic residue via nitrogen, and R^2 represents a carboxyl group or a group derived therefrom] compound or its salt.