JPS63225379A - Condensed 5-membered cyclic compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is amino which may be acylated or protected; R<2> is hydrocarbon group or heterocyclic group which may be substituted; n is 0-2), its ester or salt. EXAMPLE:(5RS,7S)-3-( 2-acetamidoethylthio )-7-(2-thienylacetamido)-8-oxo-1-azabi cyclo[2,3,0]oct-2-ene-2-carboxylic acid sodium salt. USE:It has antibacterial activity against Gram-positive bacteria and Gram-negative bacteria and is useful as a remedy for infectious diseases of mammals or dis infectant for operation tools and ward. PREPARATION:The compound of formula I can be produced by reacting a compound of formula II (R<1>' is R<1>; X is eliminable group, R<22> is H or carboxylic acid ester) with a compound of formula III (R<2>' is R<2>) and, if necessary, converting R<1>', R<2>' and R<22>.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel fused five-membered ring lactam compounds having antibacterial activity.

Conventional technology Among β-lactam antibiotics, penicillins, cephalosporins, and cephalosporins have been synthesized with various acylamino groups introduced at the 6th and 7th positions in search of more active antibiotics. It has also been revealed that the compound has vague antibacterial activity and I-lactamase inhibitory activity, and various studies have been made on the substituents at the 8th and 6th positions.

In the case of carbapenems, it is interesting to introduce an acylamino group at the 6-position from the viewpoint of enhancing activity, but since the carbapenem skeleton itself is chemically unstable, it is difficult to introduce a carbapenem compound having an acylamino group at the 6-position. The synthesis is
No success so far.

In addition, regarding compounds in which r-raflame has recently been introduced into carbapenem compounds, Tetrahedron Letters ('Tetrahedron Letters) Vol.
Although a report has been made in Vol. 7, No. 30, pp. 8467-3460, there has been very little research in this field.

Conventional carbapenem compounds have unstable basic skeletons, so the number of substituents that can be introduced is limited, and the antibacterial activity is not sufficient or not necessarily satisfactory.

The object of the present invention is to attempt to improve carbapenems and obtain compounds that are structurally stable even after introducing an acylamino group and that have antibacterial activity.

Means for Solving the Problems The present inventors have attempted to make various improvements to carbapenems, while at the same time developing the antibiotic TAN-588 (2-((48) -4
-acetamido-8-oxo-2-inxazolidinyl]
Focusing on the fact that -5-oxo-2-tetrahydro7rancarboxylic acid sodium salt) has an antibacterial effect, we succeeded in introducing a five-membered ring lactam in place of the four-membered ring lactam in the carbapenem skeleton. We developed a synthetic route for a compound having the basic skeleton represented by the following formula (1
), and found that it exists stably and possesses antibacterial activity, completing the present invention. R2 is an optionally substituted hydrocarbon or The present invention relates to a novel fused five-membered lactam lactam conductor or an ester or salt thereof, in which a heterocyclic group is represented by n representing 0, 1 or 2.

In the formula, the acyl group in the acylated amino group (hereinafter sometimes abbreviated as acylamino group) represented by R1 is 6 of the conventionally known penicillin H conductor.
Examples thereof include an acyl group substituted at the amino group at the position amino group, and an acyl group substituted at the amino group KRy4 at the 7-position of a cephalosporin derivative.

Examples of the acylamino group include formula 1% [wherein, R8Fi hydrogen, alkyl1] In the description of each group in this specification, a group marked with * may have a substituent. shows. ), alkeni, -, cycloalkyl -
Aryl-heterocycle-alkoxy 0. aryloxy 0, R4 represents hydrogen, alkyl/I/'', acyl I, and R8 forms a ring with R4.].

R'-NH-CH-CO-NH- [wherein R6 is hydrogen, an amino acid residue-amino group protecting group, or the formula R'-(CH2). −〇(=Z)−(In the formula, R
7 is heterocycle-, alkokino or amido, n is θ~2
, and Z represents 0-strapping S, respectively. ), R-alkyl, aryl0. represents cycloalkenyl or heterocycle 0, respectively. ], a group represented by the formula 1 formula % [wherein R8 is a group represented by the formula n10. ．． -c (wherein RIG is alkyl.

R11 hetero [''or aryl 0, R11 is hydrogen, alkyl*, alkenyl, arylcarbonyl, cycloalkyl 0. heterocycle]@l or the formula -R12R11l (in the formula,
R"ti alkylene 0. cycloalkylene or alkenylene, Rls represents aryl 0. carboxy 0 or its ester or mono- or dialkylamide, respectively. Chemical bond M9 has the formula -CO-Nl
(represents a group represented by -CH- (in the formula, R represents alkyl 9, aryl 0, or heterocycle 0), respectively), a group represented by the formula % formula % [in the formula, R15 is A IJ-/l/', heterocycle 0 or cycloalkenyl, R16 hydroxy, carboxy 1
1 Sulfamoyl, sulfo, sulfoxy, aryl-
represents oxycarbonyl 1 or acyloxy 1, respectively. ], a group represented by the formula % formula % [wherein, R1Tfi alkyl'f, cyan, aryl0
．． Aryloxy alkenylene 9. Heterocycle 0. R18 represents a chemical bond or -S-, respectively. ], respectively.

0-Rll OR11 and R1 of the formula RIG-C-
LO' represents the anti-isomer or a mixture thereof.

The alkyl group in the above formula preferably has 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5ec-butyl, t-butyl, 1,
1-dimethylglopyr.

Examples include n-pentyl, isopentyl, n-hexyl, isohexyl, and the like.

Examples of substituents that the alkyl group may have include halogen, nitro, amine (acyl).

Amidino, aminomethylene, aralkyloxycarbonyl, alkyl, alkenyl, cycloalkyl, or a heterocyclic ring may be substituted as a substituent. ), sulho,
Cyano, hydroxy, carboxy, cycloalkyl, alkoxy (may have amino, hydroxy, carboxy, halogen, acycloalkyl, alkoxy as a substituent), aryl (halogen, alkyl).

alkoxy, alkylamino, amino, carbamoyl,
Sulfo, alkylsulfonyl, cyano, hydroxy, carboxy, nitro, acyloxy.

It may have 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, halogenalkyl, alkylsulfonyl, alkyl, alkoxy, alkylamino, amine, halogen, carbamoyl, hydroxy on the heterocycle, It may have cyan, carboxy, or sulfo as a substituent. ), acyl, acyloxy, alkoxycarbonyl, alkoxycarbonyloxy7, acyloxy-ethoxy, aralkyl (alkyl, alkoxy, halogen, amine, hydroxy,
It may have nitro, cyano, carbamoyl, or sulfamoyl as a substituent. ).

Aralkyloxy (acyloxy, alkyl, alkoxy, halogen, amine, hydroxy, nitro, cyan,
It may have carbamoyl or sulfamoyl as a substituent. ), alkylsulfonyl, aminosulfonyl, arylsulfonyl, alkylsulfinyl, alkylthio (cyan, halogen, carboxy, alkylamino).

It may have imino, carbamoyl, or acylamino as a substituent. ), arylthio.

Heterocyclic groups - thio (cyano, hydroxy, amino.

It may have alkylamino, alkyl, halogen, or oxo as a substituent. ), heterocycle (cyan, hydroxy, amine, alkylamino, alkyl, halogen,
It may have oxo as a substituent. )-alkyl-thio, iminomethylamino, iminoethylamino, silyl (which may have alkyl or aryl as a substituent), alkyloxycarbonyl, arylcarbonyl (acyloxy, halogen, amino, hydroxy,
It may have alkoxy or sulfamoyl as a substituent. ), phthalimide, succinimide, dialkylamino, dialkylaminocarbonyl, arylcarbonylamino, the formulas are the same or different and represent a hydroxyl group or an amino group. ), and the alkyl group may have 1 to 10 of these substituents.

As the alkyl in the mono- or dialkylamide group in the above formula, the above-mentioned alkyl is applied.

The cycloalkyl in the group in the above formula preferably has 8 to 8 carbon atoms, and examples thereof include cycloglovir, cyclobutyl, cyclopentyl, cyclohexyl, cyclohephthyl, /chlorooctyl, and the like.

The cycloalkyl group may have, for example, halogen, nitro, amine (acyl, amidino, aminomethylene) as a substituent.

), hydroxy, sulfo, quano, carboxy, oxo, etc., and may have 1 to 7 of these substituents.

Examples of the alkylene and 7-chloroalkylene in the group in the above formula include those in which the above-mentioned alkyl and cycloalkyl each have another bond.

Aryl in the group in the above formula, arylcarbonyl, aryloxycarbonyl or aryl in aryloxy is, for example, phenyl,
Examples include naphthyl, biphenyl, anthryl, and indenyl.

Examples of substituents that the nuclear Ryl group may have include halogen, 210. Cyanide, amino (which may have alkyl, alkenyl, cycloalkyl, or aryl as a substituent), sulfo, hydroxy, sulfooxy, sulfamoyl.

Examples include alkyl (which may have 7-mino, halogen, hydroxy, cyan as a substituent), alkoxy, aralkyloxy, argylsulfonyl, methylenedioxy, argylsulfonyl, and the like. The aryl group may have 1 to 7 of these substituents. Also, cycloalkyl and fused rings (e.g., tetrahydronaphthyl, indanyl).

acenaphthyl, etc.).

The alkoxy in the group in the above formula has 1 to 1 carbon atoms.
6 is preferred, examples being methoxy, ethoxy, n-propoxy.

i-propoxy, n-butoxy, i-butoxy.

[-phthoxy, n-pentyloxy, n-hexyloxy and the like.

Examples of the substituents that the alkoxy group may have include halogen, nitro, amino, hydroxy, sulfo, cyano, carboxy, aryl, thoro, amine, hydroxy, alkyl, and alkoxy as substituents. good. ), silyl (which may have alkyl, aryl, or aralkyl as a substituent), and may have 1 to 10 of these.

The alkenyl or alkenylene in the group in the above formula preferably has 1 to 4 carbon atoms, such as methylene.

Vinyl, allyl, impropenil,
1-propenyl, 2-butenyl + 1y8-"y" tagenyl, ethylidene, ingropylidene, propenylene,
Vinylene, 3-methyl-8-7'tenyl natoka.

Examples of the substituents that the alkenyl group may have include halogen, nitro, amine (which may have acyl as a substituent), and sulfo.

Cyano, hydroxy, carboxy, carbamoyl.

Examples include sulfamoyl, aryl (arylL acyl, etc.), and may have 1 to 5 of these.

The cycloalkenyl in the group in the above formula preferably has 8 to 8 carbon atoms, and examples thereof include:
For example, 1-cyclopropenyl.

Examples include 1-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 8-cyclohexenyl, l-cycloheptenyl, 14-cyclohexagenyl, and the like.

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

Sulfo, cyano 1. Examples include hydroxy, carboxy, carbamoyl, sulfamoyl, etc., and may have 1 to 5 of these substituents.

Examples of the heterocycle in the group in the above formula or the heterocycle formed by these groups include a 5- to 7-membered heterocyclic group containing one sulfur atom, nitrogen atom, or oxygen atom;
a 5- to 6-membered heterocyclic group containing 1 to 2 nitrogen atoms and 1 to 2 nitrogen atoms and 1 to 1 sulfur or oxygen atom;
Examples include membered heterocyclic groups, which may be fused with a 6-membered ring group containing up to two nitrogen atoms, a benzene ring, or 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, pyridacy/-(3- or 4-yl), hiberazin-1-yl, hibericin-1-yl, piperazole-(1-,8-yl)
or 4-i#), 4H-bi;y-F3-yl, 4H
-fyf? 57-3-yl, thiazole-(2-,4-
or 6-yl) 2inchazole-(a-,4-4 or 5-yl), oxazole-(2-,4- or 5-yl)
yl), inoxazole-(8-,4- or 5-yl), pyrido(2,a-d)pyrimidine-(2-,3-
, 4-, 5- or 7-yl).

Benzo(1,2-b)-4H-bilan-8-yl.

1.8-naphthyridine (2-,8-14-15-16-
or 7-yl), 1,7-naphthyridine-(2-, a
14-15 re- or 7-yl).

1.6-naphthyridine-(2+, 8 +, 4-, 5
−． 7- or 8-ylL1+5-naphthyridine-(2
-, 8-, 4+, 6+, 7- or 8-yl L2+7-
Naphthyridine-('-+3+4-, 5+, 6- or 8
-ylLL6-naphthyridine-(1-,a-,4=r
a-$7- or 8-yl).

Quinoline-<2-. 8-. 4-. 5-, 6-. 7- or 8-yl), Cheno(218b)pyridin-(2- or 8-yl), Tetrazol-(l- or 5-yl L1'+8+5-thiadiazol-(2-t or 4-yl), 1 ,3,6-oxadiazole-(2-also Vl
, 4-yl), triazin-2-yl, 1.2. a-)
Riazole-(4- or 5-yl), 1,8.5-triazole-(2- or 5-yl), Thiophene-(
2- or 8-yl), pyrrole-(1-,2- or a,-yl), furan-(2- or 8-yl).

Pyrrolidin-1-yl, imidazolidine-(1-12-
or 4-yl), dichetan-2-yl.

tetrahydrofuran-(2-,8- or 4-yl),
Tetrahydro7j-(l- or 8-yl), benzo(1,2-b)thiophene-(2-yet 8-yl), indole-(t+, 2- or 8-yl), isoindolizine -(1-,2- or 3-yl), chroman-(2,8,4°6.7,8t or 9-yl), and the like.

Examples of substituents that the heterocyclic group may have include amine (which may have acyl, halogen-substituted alkylacyl, phenyl, or alkyl as a substituent),
Halogen, nitro, sulfo.

Cyano, hydroxy, carboxy, oxo, thio
C1-10 alkyl [may have as a substituent aryl, halogen, amino, hydroxy, carboxy, alkoxy, alkylsulfonyl, dialkylamine, phosphoric acid (which may have alkyl as a substituent) . ], cycloalkyl, alkoxy (halogen, hydroxy may be included as a substituent), acyl having 1 to 4 carbon atoms, aryl (halogen, nitro, alkyl).

It may have alkoxy, amine, sulfo, hydroxy, or cyan as a substituent. ), oxo.

Thioquine, amino acid residue - thio (Examples of amino acid residues include those similar to those described below.) +
Cl-1°alkyl-thio [aryl, halogen, amine, hydroxy, carboxy, alkoxy, alkylsulfonyl, dialkylamino.

Phosphoric acid (may have alkyl as a substituent)
may have as a substituent. ], heterocycle (alkyl, alkoxy, halogen, nitro.

It may have cyan, carboxy, formyl, or alkylsulfonyl as a substituent. )1 formula R21-CH=
=-N- (wherein, RU represents a heterocycle (which may have an alkyl, alkoxy, halogen, nitro, cyan, hydroxy, carboxy, formyl, or alkylsulfonyl as a substituent))] The heterocyclic group may have 1 to 6 of these substituents.

The acyl in the group in the above formula or the acyl in acyloxy is preferably one having 1 to 4 carbon atoms, such as formyl, acetyl,
Propionyl, pf').

Examples include isobutyryl, and its substituents include, for example, alkyl (amine, halogen, cyano, etc.).

Alkoxy, carboxy, or hydroxy may be substituted with R. ), etc., and the acyl group is
It may have 1 to 6 of these substituents.

As the acyl represented by 14 in the above formula, for example, 1
(8 and cyclic form phthaloyl, succinyl.

Male oil, citraconoyl, glutaryl, adipoyl, etc. are included. Examples of the substituents that the acyl group may have include halogen, nitro, amino, hydroxy, sulfo, cyano, and carboxy.

Examples of the amino acid residue represented by 15 in the above formula include glycyl, alanyl, valyl, and leucyl.

inleucyl, seryl, threonyl, cysteinyl, cystinyl, methionyl, α-mataha β-asparagyl,
α- or γ-glutamyl, lysyl.

Arginyl, phenylalanyl, phenylcrisyl, thi・□rosyl, histidyl, tryptophanyl.

Examples include prolyl.

The above-mentioned amino acid residues include not only the 9-configuration but also the L-configuration.

If substituents that the amino acid residue may have include:
For example, halogen, hydroxy, and sulfo.

Examples include carboxy, cyan, alkylamino, aralkyloxycarbonyl, aralkyloxy, and guanidino, and may have 1 to 5 of these substituents.

In the above formula, the protecting group for the amino group represented by R6 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 trienesulfonyl, such as formyl, acetyl, globionyl, monochloroacetyl,
dichloroacetyl, trichloroacetyl, methanesulfonyl, ethanesulfonyl, trifluoroacetyl, malonyl, succinyl, etc.) aliphatic acyl groups, for example methoxycarbonyl.

Ethoxycarbonyl, t-butoxycarbonyl.

Ingloboxycarbonyl, 2-cyanoethoxycarbonyl, 2,2.2-)lichloroethoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxy Carbonyl.

Esterified carboxyl groups such as acetylmethyloxycarbonyl, inbornyloxycarbonyl, and phenyloxycarbonyl, methylene groups such as (hexahydro-IH-azepine-l)methylene, 2-amino-
Sulfonyl groups such as 2-carboxyethylsulfonyl, and further examples include trityl, 2-nitrophenylthio, benzylidene, 4-nitrobenzylidene, di- or trialkylsilyl, benzyl, 2,4-dimethoxybenzyl, 4-nitrobenzyl Protecting groups for amino groups other than acyl groups are mentioned. 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 on the carboxy group which may have a substituent in the group in the above formula include H, alkyl (
It may have halogen, cyano, or hydroxyl as a substituent. ), aryl (alkyl, alkoxy, halogen, hydroxy, acyloxy, sulfo, cyano,
It may have sulfamoyl as a substituent. ),
Silyl (which may have alkyl, aryl, or aralkyl as a substituent), heterocycle (which may have amino, alkylamino, sulfamoyl, carbamoyl, halogen, cyan, or nitro as a substituent). ), amine (which may have alkyl, aryl, cycloalkyl, sulfo or aralkyl as a substituent) may also be coprecipitated with the regular form in the amino group to form a 5- to 6-membered heterocycle. )22 etc., and these substituents are 1-
8 may be included.

Examples of the substituent in the amine which may have a substituent in the group in the above formula include amidine, iminomethyl, imino(aryl-substituted)methyl, guanidylcarbonyl, and heterocycle (similar to the above-mentioned heterocycle). (It may have a substituent.)

Imino (heterocycle-substituted) methyl, alkylcarbonyl, arylcarbonyl, hydroxyalkyl.

Examples include alkyl.

Examples of the group in which R and R form a cyclic group include 2,2-dimethyl-5-oxo-4-phenylimidazolidine.

Alkyl, alkeni, cycloalkyl, aryl, heterocycle, heterocycle as each substituent in the group that may have a substituent in the above formula, or as a further substituent in such a substituent; -Heterocycle in thio, heterocyclic alkyl in thio, aryl in arylsulfonyl, aryl in aryl-thio, alkyl in alkylthio, alkoxy, alkyl in alkylamine, alkyl in alkylsulfonyl, alkyl in alkylsulfinyl Alkyl, alkenylene, alkyl in halogenoalkyl, alkoxy in alkoxycarbonyl, alkyl in alkylcarbonyloxy, arylcarbonyl, aryl in arylcarbonylamino, alkyl in dialkylamino, alkyl in dialkylaminocarbonyl, alkyl in alkylsulfonamide, halogen-substituted alkylacyl Regarding the alkyl and acyl in , acyloxy, alkyl in di- or trialkylsilyl, alkyl and acyl in halogen-substituted alkylacyl, and acyl in acylamino, unless otherwise specified, the groups in the above formula are explained and exemplified. Each applies as is.

In addition, aralkyl as each substituent in the group that may have a substituent in the above formula or as a substituent of such a substituent, aralkyl in aralkyloxy, and aralkyl in aralkyloxycarbonyl, Examples include benzyl, phenylethyl, methylbenzyl, naphthylmethyl, naphthylethyl, and the like.

As the azilamino group represented by the above formula R-Co-N-, for example, R is aryl (halogen, alkyl,
Alkoxy, alkylamino.

May have amino, carbamoyl, nitro, etc. as a substituent 14. ) i or heterocycle (nitro, oxo,
It may have halogen, alkyl, alkoxy, alkylamino, amine, carboxy, hydroxy, etc. as a substituent. ), the case where R4 is hydrogen is particularly preferred.

Specific examples of the acylamino group represented by the formula R''-CO-N- include 8-(2,6-dichlorophenyl)-5-methylinxasol-4-yl-carbonylamino, 4-ethyl-2, 3-dioxo-1・-
Piperazinocarbonylamino.

3-phenyl-5-methylisoxazol-4-yl-
Carbonylamino, 8-(2-chlorophenyl)-5-
) f lysoxazol-4-yl-carbonylamino,
8-(2-Rio6-fluorophenyl)-6-methylinxacy-4-yl-carbonylamino, 2,
6-Simethoxypenzoylamino, formylamino, acetylamino, globionyl agunobutyrylamino,
imbutyrylamino, piparoylamino, methoxycarbonylamino, benzylox7carponylamino, p-
Nitrobenzyloxycarbonylamino, 1-amino-
Cyclohexylcarbonylamino, 2-aminocyclohexylcarbonylamino, 3-ethoxynaphthoylamino, 2-(2-amino-4-thiazolyl)-2-ethylidene-acetylamino, 2-(2-amino-4-thiazolyl) )-2-chloromethylene-acetylamino, phthalimide, succinimide, 1,2-cyclohexanedicarboximide, 2-()limethylsilyl)ethoxycarbonylamino, 2,2-dimethyl-5-oxo-4-
Phenyl-imidazolidine.

Examples include 4-(carbamoylcarboxymethylene)-1°8-dicetan-2-yl-carbonylamino.

Specific examples of the acylamino group represented by the formula R'-NH-CH-CO-NH- include D-alanylamino, benzyl Na-carbobenzoxy-r-υ-glutamyl-D-alanylamino, and D-phenylglylamino. Cyl-D-alanylamino, N-carbobenzoxy-D-alanylamino, N-carbobenzoxy-D-phenylglycylamine.

D-7 Rani-D-phenylglycylamino, r-D-
Glutamyl-D-alanylamino, 2-(4-ethyl-
2,8-dioxo-1-piperazinocarboxamide)-
2-phenylacetylamino.

2-(4-cyclohexyl-2,8-dioxo-1-biperazinocarboxamide)-2-phenylacetylamine, 2-(4-ethyl, 2-(4-ethyl-2,.8)
-dioxo-1-piperazinocarboxamide), -2-
(4-sulfoxyphenyl)acetylamino, N-(4
-ethyl-2,3-dioxo-1-piperazinocarbonyl)-D-alanylamino, N-(4-ethyl-2,8
-dioxo-1-piperazinocarbonyl)-D-phenylglycylamino, 2-(2-amino-4-thiazolyl)-2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide) Acetylamino.

2-(4-hydroxy-6-methylnicotinamide)-
2-phenylacetylamide, 2-(4-hydroxy-
6-methylnicotinamide)-2-(4-hydroxyphenyl)acetylamino, 2-(6,8-dihydro-2
-(4-formyl-1-piperazinyl)-5-oxopyrido(2,8-d], pyrimidine-6-carboxamide)-2-phenylacetylamide, 2-(8,5-dioxo-1,2,4- triazine-6-carboxamide)
-2-(4-hydroxyphenyl)acetylamino, 2
-(8-furfrideneamino-2-oxoimidazolidine-1-carboxamide)-2-phenylacetylamino, 2-(coumarin-8-carboxamide)-2-phenylacetylamino.

2-(4- and 7-methyl-1,8-naphthylidene-8-carboxamide)-2-phenylacetylamine, 2-(4-hydroxy-7-dofluoromethylquinoline-8-carboxamido)- 2-phenylacetylamino, N-(2-(2-amino-4-thiazolyl)acetyl)-1)-phenylglycylamine, 2-(
e-promo l-ethyl-1,4-dihydro-4-oxocheno(z,ab]pyridine-3-carboxamide)-2-phenylacetylamine, 2-(4-ethyl-
2,8-dioquine-1-piperazinocarboxamide)-
2-chenylacetylamino, 2-(4-n-benzene-2,3-dioxo-1-piperazinocarboxamide)
-2-thhenylacetylamino, 2-(4-n-octyl-2,3-dioxo-1-piperazinocarboxamide)-2-thhenylacetylamino, 2-(4-cyclohexyl-2,8 -dioxo-1-piperazinocarboxamide)-2-chenylacetylamino, 2-(4-(2
-phenylethyl)-2,8-dioxo-1-piverazinorupoxamide]-2-chenylacetylamino, 2
-(8-Methylsulfonyl-2-oxoimidazolidine-1-carboxamide)-2-phenylacetylamino, 2-(8-furfridenamino-2-oxoimidazolidine-1-carboxamide)-2-(4-hydroxy phenyl)acetylamino, 2-(4-ethyl-2゜3
-dioxo-1-piperazinocarboxamide)-2-(
4-benzyloxyphenyl)acetylamino, 2-(
4-ethyl-2,8-dioxo-1-piperazinocarboxamide)-2-(4-methoxyphenyl)acetylamino, 2-(8-hydroxy-1,5-cathyridine-
7-carboxamide)-2-phenylacetylamino,
2-(2-amino-4-thiazolyl)-2-formamidoacetylamino, 2-(2-amino-4-thiazolyl)-2-7cetamidoacetylamino, 2-phenyl-
2-ureidoacetylamino, 2-phenyl-2-sulfouridoamino, 2-thenyl-2-ureidoacetylamino, 2-amino-8-sulfamoylglopionylamino, 2-amino-2-(IH-indole) -8-
yl) acetylamino, 2-amino-2-(8-benzo(b)chenyl)acetylamino, 2-amino-2-(
2-naphthyl)acetylamino, D-phenylglycylamine, D-2-amino-(4-hydroxyphenyl)
Acetylamino, D-2-amino-2-(1゜4-cyclohexagenyl)acetylamino, D-2-amino-
2-(1-cyclohexenyl)acetylamino, D-2
-amino-2-(8-chloro-4-hydroxyphenyl)acetylamino.

2-Hydroxymethylamino-2-phenylacetylamine, 2-(1-cyclohexenyl)-2-(4-ethyl-2,3-dioxo-1-piverazinolupoxamide)acetylamino, N-(2-( 4-ethyl-2,
8-dioxo-1-piperazinocarbonyl))-D-threonylamino, 2-guanylcarboxamide-2-phenylacetylamine, 2-(4-ethyl-2,8-dioquine-1-piperazinocarboxamide-2- (8,4
-dihydroxyphenyl)acetylamino, 2-(4-
Carboxy-5-imidazolylcarboxamide)-2-
Examples include phenylacetylamino, 2-ami/-2-(8-methylsulfonamidophenyl)acetylamino, and the like.

As an acylamino group represented by the formula R'-R'-Co-NH-, R8 is the formula R1o-C- (wherein R10 is ()
-R11 is 0 heterocyclic group or aryl group, R11 is 0 alkyl group
represents. ), in which R39 is a chemical bond, is particularly preferred. Specific examples of the acylamino group represented by R8-R9-C0NH- 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-ethoxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2-impropoxyiminoacetylamino/12-(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-thiazolyl)-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-6-bromo-4-thiazolyl)-2
-methoxyiminoacetylamino, 2-(2-amino-
4-thiazolyl)-2-oxyiminoacetylamino,
2-chenyl-2-methoxyiminoacetylamino, 2
-furyl-2-methoxyiminoacetylamino+2-(
1+2+4-thiadiazol-8-yl)-2-methoxyiminoacetylamino, 2-(1,2,4-thiadiazol-5-yl)-2-methoxyiminoacetylaminot2(1+8+4-thiadiazolyl)-
2-methoxyiminoacetylamino, 2-(4-hydroxyphenyl)-2-methoxyiminoacetylamino,
2-phenyl-2-methoxyiminoacetylamino, 2
-phenyl-2-oxyiminoacetylamino, 2-(
4-(r-D-glutamyloxy)phenyl2-
Oxyiminoacetylamino, 2-(4-(8-amino-8-carboxypropoxy)phenyl-2-oxyiminoacetylamino, 2-chenyl-2-oxyiminoacetylamino, 2-(5-amino-1゜2) .4-thiadiazol-8-yl)-2-methoxyiminoacetylamino, 2-(5-amino-1,2,4-thiadiazol-8-yl)-2-ethoxyiminoacetylamino, 2-(5-amino -1,2,4-thiadiazole-8
-yl)-2-carboxymethyloxyiminoacetylamino, 2-(5-amino-1,2,4-thiadiazol-8-yl)-2-((1-methyl-1-rupoxyethyl)oxyiminocoacetyl amino.

2-(2-amino-4-thiazolyl)-2-(2-amino-2-carboxy)ethyloxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2-(N,
N-dimethylcarbamoylmethyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-2-
(8,4-diacetoxy-benzoyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-
2-(1-carboxycycloprobyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-
2-(1-carboxycyclobutyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-2
-(2-imidazolylmethyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-2-(2
-Methyl-4-nitro-1-imidazolylmethyloxyimino)acetylamine, 2-(2-amino-4-thiazolyl)-2-(8-pyrazolylmethyloxyimino)
Acetylamino, 2-(2-amino-4-thiazolyl)
-2-(IH-tetrazol-6-yl-methyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-2-(2-oxo-8-pyrrolidinyloxyimino)acetylamino, 2 -(:2-(2-amino-
2-carboxyethylthio)-4-thiazolyl-2-
Methoxyiminoacetylamino, 2-(2-thioquine-
Examples include 4-thiazolidinyl)-2-methoxyiminoacetylamino.

Specific examples of the acylamino group represented by the formula R''-CH-Co-NH- include 2-phenyl-2-sulfoacetylamino, 2-hydroxy-2-phenylacetylamino, and 2-phenyl-2-sulfamoyl. Acetylamine, 2-carboxy-2-phenylacetylamine, 2-(4-hydroxyphenyl)-2-carboxyacetylamine, 2-phenoxycarbonyl-2-phenylacetylamino, 2-phenyl-2-tolyloxycarbonylacetylamino , 2-(5-imidanyloxycarbonyl)-2-phenylacetylamine, 2-formyloxy-2-phenylacetylamine, 2-alanyloxy-2-phenylacetylamine, 2-carboxy-2-chenylacetylamino , 2-(2-methylphenoxycarbonyl)-2-chenylacetylamino,
Examples include 2-(2-amino-4-thiazolyl)-2-hydroxyacetylamino, 2-(4-(2-amino-2-carboxyethoxycarboxamide) phenyl-2-hydroxyacetylamino), and the like.

Specific examples of the acylamino group represented by the formula R17-R18-CH2-Co-NH- include cyanoacetylamino and phenylacetylamino.

Phenoxyacetylamino, trifluoromethylthioacetylamino, cyanmethylthioacetylamino, difluoromethylthioacetylamino.

lH-tetrazolyl-1-acetylamino, chenylacetylamine, 2-(2-amino-4-thiazolyl)acetylamino, 4-pyridylthioacetylamino, 2-
Chenylthioacetylamine.

8.5-dichloro-1,4-dihydro-4-oxopyridi7-1-acetylamino, β-carboxyvinylthioacetylamino, 2-(2-aminomethylphenyl)acetylamine, 2-chloroacetylamino, 8- Aminopropionylamino.

(2-amino-2-carboxy)ethylthioacetylamine, 4-amino-8-hydroxybutyrylamino, 2
-carboxyethylthioacetylamino, 2-benzyloxycarbonylamino-acetylamino, /-carbamoyl-β-fluorovinylthioacetylamino, 2-
(1-impropylamino-l-impropyliminomethylthio)acetylamino, 2-(1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl-thiocoacetylamino, 2-(1-methyl- 1,3゜5-
triazol-2-yl)acetylamino.

Examples include 2-(4-cyano-a-hydroxy-5-isothiazolylthio)acetylamino.

In formula (1), examples of the hydrocarbon group represented by R2 include alkyl, cycloalkyl, and alkenyl.

Examples include aryl groups. Specific examples of these are:
Alkyl similar to the group listed as a substituent for the acyl group in the acylated amino group shown in R1 above,
Cycloalkyl, alkenyl.

Zero aryl groups are mentioned. In addition, the heterocyclic group represented by R may have a substituent, and specific examples thereof include:
The same heterocyclic groups as those mentioned above as the substituent for the acyl group in the acylated amine 7 group represented by R1 can be mentioned.

Specific examples of the ester of formula (1) include methyl ester, ethyl ester, n-7'lopyl ester,
inglobilmostel, [-butyl ester, t-amyl ester, benzyl ester.

4-bromobenzyl ester, 4-nitrobenzyl ester, 2-nitrobenzyl ester, 8°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, acetoxymethyl ester, pivaloyloxymethyl ester, 2-methylsulfonylethyl ester 12-) IJ methylsilylethyl ester, methylthiomethyl ester.

Trityl ester r 2 t 212-F' -chloroethyl ester, 2-iodoethyl ester, cyclohexyl ester, cyclopentyl ester, allyl ester, cinnamyl ester, 4-picolyl ester, 2
-Tetrahydropyranyl ester.

2-tetrahydrofuranyl ester, trimethylsilyl ester, t-7' methyldimethylsilyl ester, t
-butyldiphenylsilyl ester, acetyl methyl ester, 4-nitrobenzoyl methyl ester, 4-mesylbenzoyl methyl ester, phthalimidomethyl ester, propionyloxymethyl ester, l, 1-
Dimethylpropyl ester, 8-methyl-8-butenyl ester, succinimidomethyl ester, 8,6-
Di-t-butyl-4-hydroxybenzyl ester.

Mesyl methyl ester, benzenesulfonyl methyl ester, phenylthiomethyl ester, iminomethylaminoethyl ester, 1-iminoethylaminoethyl ester, dimethylaminoethyl ester, pyridine-1-
Oxide-2-methyl ester, methylsulfinyl methyl ester.

Bis-(4-methoxyphenyl)methyl ester.

2-cyano-1,1-dimethylethyl ester.

t-7' tyloxycarbonyl methyl ester, beacylaminomethyl ester, l-acetoxyethyl ester, benzoylaminomethyl ester, l-acetoxyethyl ester, 1-inbutyryloxyethyl ester, 1-ethoxycarboxyloxyethyl ester ester,
7-thallide ester, 4-t-butylbenzyl ester, 6-indanyl ester, 5-methyl-2-oxo-
1゜8-Dioxolen-4-ylmethyl ester, 5-
1-Butyl-2-oxo-1,8-dioxolene-4-
Examples include yl methyl ester.

Examples of the carboxylic acid salt of formula (1) include sodium, potassium, lithium, calcium, magnesium,
Examples include inorganic bases such as ammonia, organic bases such as pyridine, collidine, triethylamine, triethanolamine, and the like.

In addition, when R1 or R8 contains a basic group,
Salts with organic acids such as acetic acid, tartaric acid, methanesulfonic acid, e.g. hydrochloric acid, hydrobromic acid.

Salts with inorganic acids such as sulfuric acid and phosphoric acid, for example salts with acidic amino acids such as arginine, aspartic acid, and glutamic acid, may be formed and used.

The compound of the present invention or its ester or salt can be produced by the reaction sequence shown in FIG.

(In the figure, R1' is an amine group that may be acylated or protected like R1, X is a leaving group, and R22 is hydrogen or a carboxylic acid ester of (1) and a group of M.

2F represents an optionally substituted hydrocarbon or heterocyclic group similar to R2, and n has the same meaning as above. ) The first step is to react the compound represented by (II) or its salt with the compound represented by (1) or its salt (
1') or a salt thereof.

1/ in formula (II)K is the same optionally acylated or protected amine group as defined and explained as R1 above. The leaving group X in formula (II) may be any group as long as it can substitute for the R'8(0)n group of compound (1). For example, a sulfonyloxy group having a halogen (e.g., bromo, chromium), a substituent (alkyl group such as methyl, ethyl, propyl, or aryl group such as phenyl which may be substituted with methyl, nitro group, etc.) (e.g., p-trienesulfonyloxy, p-nitrophenylsulfonyloxy, methanesulfonyloxy), and di-substituted phosphoryloxy groups substituted with the same substituents as substituted sulfonyloxy (
For example, diphenylphosphoryloxy.

(diethylsulfolyloxy), etc.

As the salts of compound (1) and compound (1'), those mentioned above for the salt of (1) can be used. Compound value) may be used in its free form, but it may also be subjected to the reaction as a salt, such as an alkali metal salt such as lithium, sodium, potassium, etc., or an alkaline earth metal salt such as calcium, magnesium, etc. . Compound (1) or its salt 1-1 per mol of compound 1) or its salt
0 mol, preferably 1 to 5 mol is reacted. Usually the reaction is carried out in a solvent. As a solvent, for example, dichloromethane.

Preferably used are chloroformed hydrocarbons such as chloroform, nitriles such as acetonitrile, ethers such as dimethoxyethane and dihydrofuran, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, and the like. Addition of base favors the reaction. Such bases include, for example, sodium hydrogen carbonate,
Potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium amide,
Preferred are sodium methoxide, triethylamine, diisopropylethylamine, pyridine, and the like. Also,
In this reaction, instead of using a base, compound (1) may be converted into an alkali metal salt, alkaline earth metal salt, etc. as described above, and this may be reacted with compound (1) or its salt. The amount of the base used varies depending on the type of compound (distillate (1)) and solvent used and other reaction conditions, but is usually 1 to 10 mol, preferably 1 to 6 mol, per 1 mol of compound (H). The reaction temperature is about -50°C to 40°C, preferably -80°C to 20°C.The reaction time depends on the type of compound (11) or its salt,
Although it varies depending on the type of compound (1) or its salt, the reaction temperature, etc., it is from 1 to 72 hours, preferably from 1 to 24 hours. The obtained target product (+')-* or its salt can be obtained by means known per se, such as concentration, liquid conversion, dissolution, solvent extraction,
It can be isolated and purified by crystallization, recrystallization, chromatography, etc. For example, adding a water-immiscible organic solvent such as ethyl acetate and water to the reaction mixture;
It can be obtained by separating the organic solvent layer, washing it with water, drying it with a desiccant, and then distilling off the solvent.

Compound (1') thus obtained can be further purified, if necessary, by conventional methods such as preparative thin layer chromatography, force chromatography, and recrystallization.

The compound (1') obtained in this way is also the target compound (
1), but the second step is (R1- in one).
This is a step in which R2' and R22 are converted as necessary. For example, if one of them has a protecting group, that protecting group can be removed if necessary.

Depending on the type of the protecting group, methods for removing the protecting group include an acid method, a base method, a reduction method, a method using an iminohalogenating agent, and then an iminoetherifying agent. This can be carried out by appropriately selecting a conventional method, such as a method in which the reaction mixture is allowed to react and then hydrolyzed as necessary. In the case of a method using an acid, the acid may be, for example, hydrochloric acid, sulfuric acid,
In addition to inorganic acids such as phosphoric acid, organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, heninsulfonic acid, and p-toluenesulfonic acid, acidic ion exchange resins and the like are used. In the case of a method using a base, it depends on the type of protecting group and other conditions, but as a base, for example, sodium,
In addition to inorganic bases such as hydroxides and carbonates of alkali metals such as potassium or alkaline earth metals such as calcium and magnesium, organic bases such as metal alkoxides, organic amines, and quaternary ammonium salts, as well as basic Ion exchange resin etc. are 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 method by reduction, it differs depending on the type of compound and other conditions, but for example, metals such as soot and zinc or metal compounds such as chromium dichloride and chromium acetate, and acetic acid, propionic acid, hydrochloric acid, etc. Examples include a method using acids such as organic and inorganic acids, and a method of reduction in the presence of a metal catalyst for catalytic reduction. Examples of catalysts used in the catalytic reduction method include platinum cotton, platinum sponge, Platinum catalysts such as platinum black, platinum oxide, colloidal platinum, palladium black cotton, palladium black,
Examples include palladium catalysts such as palladium oxide, palladium barium sulfate, palladium barium carbonate, palladium on carbon, palladium silica gel, and colloidal palladium, reduced nickel, nickel oxide, Raney nickel, and urushihara nickel. In addition, in the case of a reduction method using metals and related compounds, metal compounds such as iron and chromium, inorganic acids such as hydrochloric acid, and organic acids such as formic acid, acetic acid, and propionic acid are used. The reduction method is usually carried out in a solvent, and for example, in the catalytic reduction method, alcohols such as methanol, ethanol, propyl alcohol, inpropyl alcohol, ethyl acetate, etc. are often 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, base method, and reduction method is generally -50 to 80°C. ·Also,
Examples of the iminohalogenating agent used in the method of removing the protecting group by acting with an iminohalogenating agent and then an iminoetherifying agent and then hydrolyzing if necessary include phosphorus octachloride, Phosphorus pentachloride, phosphorus octabromide, phosphorus oxychloride, thionyl chloride, phosgene, etc. are used.

This reaction temperature is not limited to %, but is usually -50 to 50%.
It is often carried out at ℃. Alcohols or metal alkoxides are used as iminoetherifying agents that act on the reactive acid organisms obtained in this way.
Alcohols include alkanols such as methanol, ethanol, gropanol, isopropanol, n-butanol, and tert-butanol, or compounds in which the alkyl moiety of these is substituted with an alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc. Examples of the metal alkoxides include alkali metal alkoxides such as sodium alkoxide and potassium alkoxide derived from the above-mentioned alcohols, and alkaline earth metal alkoxides such as calcium alkoxide and barium alkoxide. is used. For example, if the protecting group is a residue of an organic carboxylic acid, a free amino group, hydroxyl group, mercapto group, carboxyl group, etc. on the carbon adjacent to the carbonyl group,
When a substituent such as a sulfonic acid group is present, it is advantageous to perform a treatment to further enhance the adjacent group effect of these groups to increase the reactivity of the carbonyl group and remove the protective group.

As an example of such a case, for example, when the substituent on the carbon adjacent to the above carbonyl group is a free amino group, the free 7-mino group is converted to a thioureido group and then deacylated. Methods include a method of removing a protecting group by applying a known method used for decomposing a peptide bond. The temperature of this reaction is not particularly limited and is appropriately selected depending on the type of a-retaining group, the method of elimination, etc., but it is preferably carried out under mild conditions such as cooling or heating.

Specifically, when the protecting group for the carboxyl group in the target compound (1') is a halogenoalkyl group, an aralkyl group, a benzhydryl group, etc., it is achieved by contacting it with a reducing agent. Reducing agents used in this reaction include 2,2-dibromoethyl,
Zinc and acetic acid are preferred when the protecting group is a halogenoalkyl group such as 2,2.2-)lychloroethyl, and when the protecting group is an aralkyl group or benzhydryl group such as benzyl, p-nitrobenzyl, etc. hydrogen and platinum oxide, platinum black, platinum sponge, palladium
Catalytic reduction catalysts such as carbon, palladium black, palladium-barium sulfate, palladium-barium carbonate, reduced nickel, Raney nickel, Urushihara nickel, or alkali metal sulfides such as sodium sulfide or potassium sulfide are suitable. Further, in the case of an 0-nitrobenzyl group, removal can be performed by light irradiation, and in the case of a p-methoxybenzyl group, removal can be performed by electrolytic reduction. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, and ethers such as tetrahydrofuran and dioxane are used. , fatty acids such as acetic acid, and mixed solvents of these organic solvents and water are suitable. The reaction temperature is usually around 0 to 40°C, and the reaction time varies depending on the raw material compound and the type of reducing agent, but is usually 5 molecules &J1 to 12 hours. ``Also, the protecting group for the amine 7 group in the target compound (1') is, for example, a p-nitrobenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a benzyloxycarbonyl group. etc., it is removed by the carboxyl group protecting group removal reaction.

As the second step, keep it like this! Compound (1') from which the I group has been removed (e.g., R1' is an amino group, C00R
Specific examples include a process in which 22 is a carboxyl group or an ester) or a salt thereof.
(R" is an amino group, COOR" is a carboxyl group, or an ester) or a salt thereof and an acylating agent containing an acyl group in the group R1, such as carboxylic acid σ? When the acyl group to be introduced as 1 is RCO, the carboxylic acid is represented by RCOOH. ) or a reactive derivative thereof.

Examples of reactive derivatives of carboxylic acids include reactive acid halides, acid-free *'4 paper active injection amides, active esters,
Specific examples of such reactive derivatives in which active thioesters and the like are used are as follows.

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

2) Acid anhydride: Here, the acid anhydride includes, for example, monoalkyl carbonic acid mixed acid anhydride, aliphatic carboxylic acid (for example, acetic acid, pivalic acid, valeric acid, invaleric acid, trichloroacetic acid, etc.). Mixed acid anhydrides, mixed acid anhydrides consisting of aromatic carboxylic acids (eg, benzoic acid, etc.), and usually symmetrical acid anhydrides are used.

8) Active amide: Here, as the amide compound, 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 tester: Examples of active esters include the above-mentioned carboxylic acids and, for example, methyl ester, ethyl ester, methoxymethyl ester, clopargyl ester.

4-nitrophenyl ester, 2,4-dinitrophenyl ester s') chlorophenyl ester.

In addition to esters such as pentachlorophenyl ester and mesylphenyl ester, 1-hydroxy-1H-2-pyridone and N-hydroxysuccinimide. N-hydroxyphthalimide, ester with 1-hydroxybenzotriazole, etc. are used.

6) Active thioester: As the active thioester, a thioester of the above-mentioned carboxylic acid and a heterocyclic thiol such as 2-pyri, dilthiol, 2-be/zthiazolylthiol, etc. is used here.

Incidentally, the compound (■') or its salt can also be acylated using the carboxylic acid itself, but in this case, c, for example, 1. This is carried out in the presence of a dehydrating agent such as N,N'-dicyclohedylpodiimide, but in this case as well, the acylation reaction proceeds via a reactive derivative produced from the carboxylic acid and the dehydrating agent.

The various reactive derivatives described above are appropriately selected according to the 8i class of carboxylic acids.

When this reaction is carried out in the presence of a base, S
The bases used include, for example, aliphatic tertiary amines (
tertiary amines such as di-n-butylamine, diisobutylamine.

Dialkyl amines such as di-chlorhydramine, aromatic amines such as pyridine, rutidi-7,7-collidine, 4-dimethylaminopyridine, alkali metals such as lithium, sodium, potassium, alkaline earths such as calcium, magnesium, etc. Hydroxides or carbonates of similar metals are used.

In this method, the reactive derivative of carboxylic acid is usually used in an amount equivalent to that of compound (+')K, but it can also be used in excess without causing any hindrance to the reaction.

When using a base, the amount of the base used varies depending on the raw material compound (1') used, the type of reactive derivative of carboxylic acid, and other reaction conditions, but it is usually about equivalent to 80 equivalents relative to the compound (i9). , preferably from about equivalents to 10 equivalents. This reaction is usually carried out in a solvent. Examples of the solvent include ethers such as dioxane, tet, lahydrofuran, diethyl ether, diisopropyl ether, propylene oxide, and butylene oxide; Esters such as ethyl acetate, ethyl formate, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane+1tl+1-)9chloroethane, such as benzene.

Hydrocarbons such as toluene and n-hexane, such as N
, N-dimethylformamide, N,N-dimethylacetamide, and other amides; for example, nitriles such as acetonitrile; and other conventional organic solvents may be used alone or in combination. Moreover, among the above-mentioned bases, liquid ones can also be used as a solvent. Although the reaction temperature is not particularly limited, the reaction temperature is generally -50°C to 100°C, preferably about -80°C to 40°C. The reaction time varies depending on the raw materials used, the base, the reaction temperature, and the type of solvent, but the reaction is usually completed in several tens of minutes to several tens of hours, but it may sometimes take several tens of days.

In the second step, if the acylated amino group in %R''K has a 7-mino group in the acyl group, or if it has an amino group in the substituent represented by ng/, the Amide the amino group.

Step 1 of converting into ureido, amidino, and guanidino groups.
Alternatively, when they have a hydroxyl group, specific examples include a step of converting the hydroxyl group into an acyloxy group or a halogen atom. Furthermore, when n is 0, a step of oxidizing a sulfur atom to 1 or 2 is also included. Such a reaction is carried out in a manner known per se.

The compounds obtained by distillation, salts thereof, or esters thereof can be prepared by methods known per se, such as concentration.

It can be isolated and purified by liquid conversion, dissolution, solvent extraction, freeze drying, crystallization, recrystallization, chromatography, etc. For example, by adding a water-immiscible organic solvent such as ethyl acetate and water to the reaction mixture, separating the organic solvent layer, washing it with water, drying it with a desiccant, and then distilling off the solvent. Can be done. Compound (1) or its salt or ester obtained in the same manner as above may be processed by conventional methods, such as preparative thin layer chromatography, if necessary.
It can be further purified by column chromatography, recrystallization, etc. Compound (+) or its salt or ester may be a stereoisomer (e.g., D-isomer, L-isomer,
-isomers, diastereomers, syn-anti isomers, etc.)
may exist. In this case, each of these isomers and mixtures thereof are also included in the present invention.

These isomers can be used as medicines either alone or as a mixture.

In addition, when these isomers are obtained as a mixture,
If necessary, each isomer can be isolated by conventional methods such as various chromatography and recrystallization.

Compound (n) used as a raw material compound in the method of the present invention is a new compound, and can be produced, for example, by the reaction sequence shown in FIG. 2.

Aspartic acid (IV) (V
) (It) Figure 2 (In the figure, R", R", and X have the same meanings as above. B1
1" represents a carboxyl group-protecting group, and R represents a () group-protecting group. The carboxyl group-protecting group represented by R22' is a β-lactam or a carboxyl-protecting group normally used in organic chemistry. For the acylamino group represented by R1, examples include the substituents for the carboxyl group.Also, as the protecting group for the amino group represented by R23,
Those explained and exemplified as the protecting group for the amino group represented by R5 above can be applied as is.

As a starting material, a known compound (IY) derived from aspartic acid is used. For the compound QV), for example Oiemische Berichte
icllte), Vol. 97, p. 1789 (1964). The first step is to subject QV) to a carburizing reaction, and (
V). This step is carried out in the same manner as the fifth step described later.

The second step is a step in which (V) is reacted with a protected amine (vl) to obtain a five-membered ring 2cutam (2). This step is commonly used to protect (V) amines (e.g. benzylamine).

2,4-dimethoxybenzylamine) under heating. The amount of amine used is from 1 to 10 equivalents, and the reaction temperature is from 20"C to aOOC, preferably from 100 to 200C. This reaction is first carried out under normal pressure in a solvent that does not participate in the reaction, such as toluene. A method is preferably used in which the reaction is carried out by heating at the reaction temperature and then the ring is closed by further heating to the above reaction temperature under reduced pressure.The reaction time is usually 5 minutes to 10 hours, preferably 10 minutes to 2 hours.

(2) is usually obtained as a mixture of isomers regarding double bonds. Both can be isolated individually and subjected to the next step, but they can also be used as a mixture.

The 8th step is to remove the protecting group of the nitrogen in the ring (2)
This is the process of A known reaction for removing the protecting group for the amino group can be applied to this step, for example, the reaction for removing the protecting group for the amino group in the above-mentioned compound (1')K can be applied. For example, when R'' is a 2,4-dimethoxybenzyl group, it is reacted with an oxidizing agent such as cerium ammonium nitrate (hereinafter abbreviated as CAN).This reaction is performed in a solvent (e.g., methanol, acetone).
medium, -1θ℃ to 40℃ (usually l to 20℃ for IK)
This is done by reacting an equivalent amount of oxidizing agent. Furthermore, when R2s is a group that can be removed by a reductive reaction, such as a benzyl group, if a group that can be removed reductively is used as R1, the following fourth step can also be carried out at once.

The fourth step is a step of saturating the double bond in (2) and further removing the carboxyl group protecting group R22'.

The double bond in (2) is easily saturated by K in a reduction reaction (for example, a catalytic reduction reaction). The reaction for removing the a-protecting group R1 of the carboxyl group can be carried out by a known method, for example, by applying the method for removing the protecting group of the carboxyl group in compound (1') described above. When Hd is a group that can be removed reductively (eg, benzyl group), W can be obtained by saturating the 2f bond and removing the protecting group R1 at once. In this step, a reduction reaction using, for example, palladium-carbon is preferably used. Furthermore, when there is a group that is reductively removed in R1/substituted component in (2) (e.g., R'' is a benzyloxycarbonylamino group)
is R11 by introducing the same or different substituents again.
It's good as well.

The fifth step is to activate the carboxyl group of the button and then extend two carbon atoms to obtain (X).

To carry out the reaction of this step, the button is first dissolved in a solvent such as THF, dimethoxyethane, etc., in an amount of 1 to 2 mol per 001 mol, such as 1,1'-carbonyldiimidazole or 1,1'- carbonyl bis(
(2-methylimidazole) etc. at 0°C to 50°C to give the imidazolide, and then without isolating the imidazolide, the following formula % formula of 1 to 8 moles per mole of (IK) %( ) [wherein R4 has the same meaning as defined above] The reaction is carried out by reacting with a magnesium salt of a malonic acid derivative represented by the following formula at 0°C to 60°C for 1 to 48 hours.

The sixth step is a step of diazotizing α) to form ω).

The diazotization reaction is carried out in a solvent such as acetonitrile, dichloromethane, THF, etc. in the presence of a base such as triethylamine, diethylamine, pyridine, etc. per 1 mole of K(X), such as 1 to 2 moles of p-carboxybenzene. Sulfonide azide, p-toluenesulfonyl azide.

This is accomplished by reaction with an azide such as methanesulfonyl azide. The reaction temperature is about -10℃ to 40℃,
The reaction time is usually 1 to 48 hours.

The seventh step is a step of cyclizing (Xl) to obtain (2).

In this cyclization reaction, for example, benzene, toluene,
For example, sulfuric acid steel, copper powder in a solvent such as THF.

This is carried out by cyclization in the presence of a catalyst such as rhodium acetate, palladium-acetate, etc.

The reaction temperature is from 50°C to 110°C, and the reaction time is 1 to 6°C.
It takes a long time and is usually carried out in an atmosphere of an inert gas such as nitrogen or argon. In addition, this cyclization reaction (Xl
) for example benzene.

This can be carried out by irradiating a solvent such as THF, carbon tetrachloride, diethyl ether, etc. at a temperature of about -10°C to 40°C for 0.5 to 2 hours.

The eighth step is a step of activating the others with an activating agent to obtain (n). Examples of the activator include "Pegtide Synthesis" by Nobuo Izumiya, Tetsuo Kato, Motonori Ohno, and Higashihiko Seyanagi,
The reagent described in K. (Maruzen), published in 1975, pages 117 to 158, is used. More specifically, these activators include, for example, thionyl chloride, thionyl bromide, sulfuryl chloride, oxyphosphorus chloride, oxalyl chloride, chlorine, bromine or carbon tetrachloride and halogenated compounds such as triphenylphosphine. agents, such as anhydrous p
-) liensulfone, anhydrous 2 s 41 s -F liisopropylphenyl sulfone, anhydrous meta/sulfone rRt p -) sulfonylating agents such as lienesulfonyl chloride + p-chlorobenzenesulfonyl chloride,
For example, diphenylphosphorus chloride.

Examples include phosphorylating agents such as dimethyl phosphoryl chloride and diethyl phosphoryl chloride.

When X in (II) is a substituted sulfonyloxy group, (X
V) 1 to 8 mol per mole of anhydrous p-toluenesulfone Mr p-nitrophenylsulfonic anhydride, 2.4-)liisopropylphenylsulfonic anhydride, mwater methanesulfone EL p-toluenesulfonyl chloride r p -7' romophenyl sulfonyl chloride, etc., for example, dichloromethane,
Chloroform, acetonitrile, dimethoxyethane, T
For example triethylamine, in a solvent such as HF etc.
The reaction is carried out in the presence of a base such as diisopropylethylamine, pyridine, or 4-dimethylaminopyridine. Usually, the reaction temperature is -20°C to 40°C, and the reaction time is 0.5 to 5 hours.

When X in (fl) is a halogen, a halogenating agent (eg, oxalyl chloride) can be used instead of the sulfonylating agent in the reaction when X is a substituted sulfonyloxy group.

(CaH2)s PC'''z, (C6H5)II P
B'2 , (C6H50) aPB r z + thionyl chloride, etc.) can be reacted under the same conditions to convert (O\). Also when X in (ff) is a di-substituted phosphoryloxy group, the above In the case of a substituted sulfonyloxy group, the substitute for the sulfonylating agent in the reaction is a phosphorylating agent (e.g., diphenyl phosphoryl chloride, dimethyl phosphoryl chloride).

(e.g., diethyl phosphate chloride) under similar conditions.

After the reaction is completed, the target compound (U) of this step is collected from the reaction mixture according to a conventional method. For example, a water-immiscible organic solvent such as ethyl acetate and water are added to the reaction mixture, the organic solvent layer is separated, washed with water, dried with a desiccant, and then the solvent is distilled off. be able to. Moreover, (II) can be directly subjected to the next step reaction without performing the above-mentioned isolation operation.

The above examples do not limit the starting material (II);
Any starting compound (n) can be used as long as it meets the purpose of the present application.

The salt or ester of Compound (1) thus obtained is useful as a medicine, and has, for example, antibacterial activity against certain Gram-positive and Gram-negative bacteria.

Compound (1) of the present invention, its salt or its ester, can be used, for example, in mammals infected with the above-mentioned bacteria (
e.g., mice, rats, humans, etc.).

The salt of the compound (I)t of the present invention or its ester can be used as a therapeutic agent for bacterial infections, for example, in the above-mentioned mammals, such as respiratory tract infections, urinary tract infections, corticosteroid diseases, biliary tract infections, intra-internal infections, etc. It can be used to treat obstetric and gynecological infections, surgical infections, etc.

The compound of the present invention (i) containing its salt or its ester can also be used, for example, as a disinfectant for surgical instruments and in hospital rooms. For example, a surgical instrument may be immersed in this solution for 1 to 8 days and dried aseptically. Compound (1) or a physiologically acceptable salt may be prepared in a conventional manner into tablets, capsules, drops, etc. It can be administered orally in a dosage form such as, or it can be formulated into an injection by conventional means, formulated into a sterile carrier prepared by conventional means, and administered parenterally.

Examples The present invention will be further explained in detail in the following examples and reference examples, but these examples are merely illustrative and do not limit the present invention, and changes may be made without departing from the scope of the present invention. You may let them.

Unless otherwise specified, the elution in column chromatography m= of Examples and Reference Examples was performed using TLC (Th1nLayer).
The analysis was carried out under observation using chromatography (thin layer chromatography). In the TLC observation, Merck's 60FII64 was used as the TLC plate, the solvent used as the elution solvent in column chromatography was used as the developing solvent, and a UV detector was used as the detection method. Another detection method is to spray 48% HBr onto a spot on a TLC plate, heat it to hydrolyze it, spray it with ninh-ydrin reagent, and then heat it again to change the color from red to reddish-purple. The elution fractions containing the target product were confirmed and collected.

Regarding developing solvents, the numbers shown in () (2) represent the volume mixing ratio of each mixed solvent. If two types of developing solvents are used, unless otherwise specified, the volume shown first in parentheses Elute the by-products with a mixed ratio of solvents, and then ()
The target product was eluted with the solvent at the volume mixing ratio shown after the arrow inside.

“Amber light (＾-berlite) X A D
In column chromatography purification using -2”,
Unless otherwise specified in the examples, water was first used as the developing solvent, and then an aqueous ethanol solution was used while gradually increasing the concentration.

“Amberlight” is manufactured by Rohm and Haas (Rohm & Haas)
hs & Haas Co, in U,S,
A).

Unless otherwise specified, silica gel for columns is manufactured by Merck.
ck) manufactured by 1. Silica gel 60 (Silica g
et60) (70-230 mesh s) was used. As the Floriseal, Floriseal (100-200 mesh) manufactured by Floridin was used.

NMR spectra were performed using a VARIAN EM 390 model (90 MHz) or JEOL JNM-GX40 using tetramethylsilane as an internal or external reference.
It was measured with a 0FT (400 sets 1z) spectrometer, and the δ value was expressed in ppm. Note that "room temperature" usually means 0°C to 40°C. Also, 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: Triblet q: Quartet dt: Double triplet ABq: AB type quartet dd: Double double doublet dddd: Double double double doublet 1m = multiplet 8h: Shoulder br = Broad J: Coupling constant (Coupling const
ant) mg: milligram
) g, nigerum (gram) ml: milliliter (milliliter) l:
Leak (1ter) Hz: to/l/7 (Herz) CDC#s: heavy chloroform DMSO:tme'j, II/s/l/hoxito (dim
ethylsulfoxide) Reference Example 1 (28)-2-Pendyloxine luponylamino-4-
Oxoadipic acid l-be/syl-6-methyl ester malonic acid monomethyl ester potassium acid 12.08.
A suspension of 9 and 2.61 g of magnesium chloride in 100 ml of anhydrous tetrahydrofuran was stirred at 50° C. for 16 hours under a nitrogen atmosphere. On the other hand, 9.91 of 1,1'-carbonyldiimidazole was added to a solution of 18 Jl of L-N-benzyloxycarbonyl aspartic acid α-benzyl ester in 100×# of anhydrous tetrahydrofuran, and after stirring at room temperature for 1 hour,
Added to the above suspension. This mixture was heated at room temperature for 16 hours.
After stirring, two tetrahydrofurans were distilled off. Ethyl acetate was added to the residue, which was washed successively with 8N hydrochloric acid and aqueous sodium bicarbonate brine, dried (Na 2804 ), and then the solvent was distilled off. Inglovir ether was added to the residue and crystallized to obtain the above compound as colorless crystals. Melting point 100-102°C.

I RuKBras-': 8280.1740.1
715°ax 1690.1585.1800.126ONMR(90
MHz, CD (Js) J: Ll 2-8.80
C2H, m), 8.40 (2H, l.

8.68 (8H, S), 4.48-4.80 (IH'
.

m), 5.10+5.15 (2HX2.SX2
).

5.72 (IH, d, J-8H2), 7.82 (10
H,s) [α]p+18.7°(C-0,805,CHC
4's) Elemental analysis value: Cg*H+5NOy Calculated value: C, 68,92iH, 5,61; N, 8.89
Actual value: C, s 8. ? 7;H,5,52;N,
a, e 9 Reference Example 2 (,88)-8-benzyloxycarbonylamino-1
-(2,4-diphthoquinbenzyl)-6-medoxycarponylmethlidene-2-pyrrolidone Compound 18 obtained in Reference Example 1. A solution of 50 ml of toluene containing 5.269 of Of and 2.4-i;/methquin benzylamine was heated under reflux for 40 minutes, and then the toluene was distilled off.

The residue was stirred with an aspirator under reduced pressure (20-25 mmHg) for 40 minutes while heating at 160°C.

After cooling, the reaction mixture was purified by column chromatography using silica gel. Hequinane-ethyl acetate (2:
1→2:8), fractions containing the target product were collected, and concentrated under reduced pressure to obtain compound 9.849 as colorless crystals. Melting point 169-170℃ IRuKBrcys-': 1
1820.1750.1690゜ax 1610.1275.114O NMR (9GMHz, CDCA's) J: 2.90
(IH, dd, Jm1.7Hz), 8.18 (IH
.

dd, JR2, 7Hz), 8.68.8-'I
6 +8.88 (ai-ixa, sxa), 4.2
9 (IH, dt.

J-7, 9Hz), 4.68 (2H,s),
5.12(2H,S)t 5.8G-5,48(I
H, m).

6.40 (IH, d, Jm9H1, 6, 80-6, 49
,6,98-7,11(8H,m),? , 82 (5H,
S) [α] ”LIs-100,2° (c = 0.455
．． CH (Jm) elemental analysis value: C14HzsNxOy calculated value: C, 68, 48iH, 5, 77iN, 6.16
Actual measurement value: C, 68,68iH, 5,76iN, 6.
06 Reference Example 8 (28)-2-benzyloxycarbonylamino-4-
Oxoadipic acid dibenzyl ester L-N-benzyloxycarbonyl aspartic acid α-benzyl ester 10. 5.849 ml of 1,1'-carbonyldiimidazole was added to a solution of 180 ml of anhydrous tetrahydrofuran and stirred at room temperature for 2 hours. To this solution was added 6.469 g of malonate monopendyl ester magnecum salt, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off, and ethyl acetate was added to the residue, which was washed successively with 8N hydrochloric acid, aqueous sodium bicarbonate, and brine, dried (Nag 5o4), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and hexane-ethyl acetate (2:1-
After elution (1:1), fractions containing the target product were collected and concentrated under reduced pressure to obtain compound 11.29 as colorless crystals. Melting point 82-86°C KBr-(.

Engineering RJ/maxcat, 8800, 1745.1?
20°1695.151'15,129O NMR (90MHz, CD, (Js) I: 8.
18 (2H, t, Jz5Hz), 8.48 (2H, S
).

4.74-4.78 (IH, m), 5.10 (2H.

S), 5.12 (2HX2.S), 5゜7
0 (IH.

d, Jm9H2), '1.80 (15H,s)
(α) p + 1156 ('=0.585.CHC
Js) Elemental analysis value: CzsHgyNOy Calculated value: C, 68,70iH, 5,56iN, 2.
86 actual measurement value: C168, 52iH, 5,57iN,
2.87 Reference Example 4 (aS)-a-benzyloxycarbonylamino-5
-penzyloxycarbonylmethylidene-1-(2,4
-i;/methquinbenzyl)-2-pyrrolidone A toluene 60j+1 solution of 11.0 g of the compound obtained in Reference Example 8 and 8.76 f of 2,4-dimethoxybenzylamine was heated under reflux for 80 minutes, and then the toluene was distilled off.

Remove the residue using an aspirator (20-25mmH5F)
Heated at 1fiO-160°C for 1 hour. After cooling, the reaction mixture was subjected to chromatography using silica gel, eluted with hequinane-acetic acid (8:1-1:1), and fractions containing the target product were collected and concentrated under reduced pressure to obtain the compound listed above. 6.
2g was obtained. Colorless crystal. Melting point 15B-164°C.

IRI/KBras-': 1l1840, 1740,
1695°ax 1610.1145.118O NMR (90MHz, CD (Js), l: 2
．． 8G-8, 21 (IH, m), 8.72, 8.80 (
8Hx2.5X2), 8.96-4.48 (IH, m)
.

5.0? , 5.10 (2HX2.SX2), 5.40
(,tH,S), 5.46 (IH,d,J=8Hz
).

6.80-6.48, 6.92-7.14 (8H, m)
.

7.80 (5H, 8) [α] D -88,6° (Csw Q, 89, C
HCJa) Elemental analysis value: Cs0H8,N! 07 Calculated value: C, 67, 91iH, 5, 70iN, 5.28
Actual measurement value: C, es, i 1 iH, 5, 65iN, 5
．． 11 Reference Example 5 (aS)-a-benzyloxycarbonylamino-6-
Pendyloxinemeteridene-2-pyrrolidone 1.5 g of the compound obtained in Reference Example 4 was added to a solution of 50 liters of methanol and 150 liters of acetone under ice cooling, and 50 ml of water was added to 4.589 ml of the compound obtained in Reference Example 4. Add the solution under stirring. After stirring for 80 minutes, CAN4.58f was added and stirred for 1 hour. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate (1G (1+t).The extract was washed with 9 brine, and then dried with CM98
0+)L, the solvent was distilled off.

The residue was subjected to column chromatography using silica gel, eluted with hexane-ethyl acetate (2:1-2:8), and fractions containing the target compound were collected and concentrated under reduced pressure to obtain 200 η of the two isomers of the title compound. and E isomer 540W9 were obtained as colorless oils. They were crystallized by adding ether.

E isomer (small R value): Melting point 165-168℃ Punishment "-1・ IRu　　　3　. 1740.1700.169G.

ax 154G, 1265.1185 NMR (9oMHz, CDC15) J: 8.
04 (IH, ddd, J-1, 7, 19Hz), 8
．． 77 (IH, dd, J-10, 19Hz), 4.0
84.88 (IH, m), 5.09, 5.11 (2HX
2.5X2), 5.86 (IH,br), 5゜64
(IH, d, J, = 7H1, ?, 25. 7.28 (5
HX2,5X2), 8.60-8.88 (IH.

br) [al”g-1aa, oo(C-0,88, CHgC0
0C2HI elemental analysis 11 [:CgtHgoNgOs calculation at:c, 66.81; H, 5, 8 (1BN, 7.8
6 Actual measurement value: c, 66.28 iH, 5, 28iN, 7.
282 isomer (large Rf value); melting point 105-107°C I RuKBrag-': 1760.16g5.1
645゜ax 1580.1265.120O NMR (90MHz, CDCJ@)J:2.80
(IH, ddd, J-1, 7, 16H2), 8.2
6 (IH, dd, J-9, 16H1, 4, 10-4, 4
8 (IH, m), 4.68 (IH, br)t5.10
, 5.14 (2HX2, 5X2), 5.55 (IH, d
, J-6H1),? , 80. 7.82 (6HX2,5
X2), 9.85-10.10 (IH, br) (α) T-4r, 5° (Cj 0.415, 01
80000gH6) Reference Example 6 (88,5R,S)-8-(p-nitrobenzyloxycarbonylamino)-6-carpoquinemethyl-2-pyrrolidone Compound obtained in Reference Example 6 (Z, E mixture)5. (1051 palladium carbon 2.
6 g was added and hydrogenated at 50° C. for 6 hours under normal pressure. The catalyst was filtered off and washed with ethanol, then the filtrate 1 and the washing liquid were combined and the solvent was distilled off. The residue (add 25 liters of diwater and 25 ml of tetrahydrofuran, and add 8.81 liters of sodium hydrogen carbonate.
9 and p-nitropendyloquine carbonyl cucride 2.
889 was added and stirred at room temperature for 2 hours. Tetrahydrofuran was distilled off. 50 ml of water was added to the LA@condensed liquid, and the mixture was washed with ether. The aqueous layer was acidified with 8N hydrochloric acid and extracted with ethyl acetate. After washing the extract with water and drying (MfSO4), the solvent was distilled off and ether was added to the residue to obtain the compound 2. (
1 was obtained as a colorless powder.

I RvKBras-': 8850.1780-1
680°ax 1520.185O NMR (90MHz, DMSO-d6) I: 2.28
-2.55 (2H, m), 8.50-8.90 (IH.

m), 8.90-4.28 (IH, m), 5.2
0 (2H, S ), 7.61 (2H, d, Jx9Hz
).

7.81 (IH, d, J m7Hz), 8.2
2(2H, d, J-9I-1z) Reference Example 7 (as, 5R8)-8-(1)-nitrobenzyloxycarbonylamino)-5-[4-(p-nitrobenzyloxycarbonyl)-2- :txobrovir]-2-pyrrolidone To a solution of 1.7 g of the compound obtained in Reference Example 6 (q-position isomer mixture) in 20 ml of anhydrous tetrahydrofuran was added 1.1' under water cooling.
- Add 9.819% of carbonyldiimidazole and 2.0% at room temperature.
Stir for hours. To this solution was added malonic acid monobenzyl ester magnecum salt 1.261F, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off, and diacetate was added to the residue.
Potassium hydrogen sulfate water.

After sequentially washing with sodium bicarbonate water and brine and drying (MfSO4), the solvent was distilled off. The residue was subjected to column chromatography using silica gel.
Elute with chitin-ethyl acetate (1:2) and then ethyl acetate-methanol (5:1), collect fractions containing the target product,
When concentrated under reduced pressure, the compound listed above (5-position isomer mixture) 2.0
1F was obtained as a colorless oil.

I RJ/Ne"am-': 8250.2940
．． 1785-ax 168G, 1520.1145 NMR (90MHz, CD (Js-DMSO-d,) #
:1.60-2.48(2H,m), 2.60-
2.98 (2H, m), 8.57 (2H, 8).

8.87-4. -45 (2H, m), 5.2G, 5.2
5(2HX245X2), 5.80-6.20(-1H
.

br), 7.85-7.65 (4H, m), 8.00-
8.85 (4H, m) Reference Example 8 (5R8,78)-7-CP-nitrobenzyloxycarbonylamino)-1-azobiccyclo(a,s,o)octa,no 8.8-dione-2-carvone Hp -Nitrobenzyl ester To a solution of 2.0 g of the compound obtained in Reference Example 7 and 842 d of toluene-p-sulfonyl azide in 20111 acetonitrile, 482 η of triethylamine was added under water cooling, and the mixture was stirred for 2 hours. Acetonitrile was distilled off, and the residue was dissolved in ethyl acetate (50 ml) and washed with water and brine. After drying the organic layer (MgSO4), the solvent was distilled off to give (88,5R8)-8-(p-nitrobenzyloxycarbonylamino)-5-[8-diazo-4-(p
-nitrobenzyloxycarbonyl)-2-oxopropyl"-2-pyrrolidone was obtained as an oil.

(IRu"quidax-': 214G)ax This oil was dissolved in anhydrous tetrahydrofuran (50s+t) and anhydrous benzene (100gt), and rhodium (If
) 60 Da of acetate was added and heated under reflux for 1.5 hours.

When the solvent is distilled off, the compound mentioned above (mixture of 5-position isomers)2.
Of was obtained as an oil.

IRJ/"qu"3-' :1740-1680(b
road, 4ax Reference Example 9 (3S, 5S)-3-benzyloxycarbonylamino-5-carboxymethyl-2-pyrrolidone In Reference Example 5, 1.8 g of the (suta compound (Z, E mixture)) and 1
1.8 g of 0% palladium-carbon (50% water content) was suspended in a mixture of 10 ml of ethyl acetate and 10 ml of water, and hydrogenated at normal pressure and room temperature for 8 hours. After the solvent was filtered off and the aqueous layer was separated, 10 mQ of tetrahydrofuran, 9 g of sodium bicarbonate, and 969 mg of benzyloxycarbonyl chloride were successively added, and the mixture was stirred at room temperature for 18 hours. After washing this mixture with hexane, it was washed with potassium hydrogen sulfate water.
H2 and extracted with ethyl acetate. After washing the extract with water and drying (M g S O4), the solvent was distilled off, and ether was added to the residue to obtain 1.0 g of the above compound as colorless crystals.

Melting point 169-171"C 1525, 128O NMR (90MHz, DMSOds) δ: 1.30-1.80. 1.90-2.60
(iHX2.s), 2°28-2.70 (2+
1. a), 3.52-3.94 (ill, m),
C94-4゜35(Ill, m), 5.02(
211, s), ? J3(511,s), 7.75(
111,s) [α]2' -23,0° (C=0.33.
EtOH) Elemental analysis value: C1-1-1+sN
*Os calculation value: C, 57, 53, 1+, 5.52
, N, 9.58 Actual value: C, 57, 51, 1+, 5
．． 49; N, 9.43 When the mother liquor from which the above crystals were obtained is concentrated, the compound listed above and its isomer (3S, 51”t)
A mixture of was obtained as an oil.

Poor side 1O (3S, 5S)-3-amino-5-carboxymethyl-
2-pyrrolidone Compound obtained in Reference Example 9 [(3S,5S) form] 100 mg
and 10% palladium-carbon (50% water content) IQOmg were suspended in a mixture of 5m+2 methanol and 5m12 water, and hydrogenated at normal pressure and room temperature for 2 hours. The catalyst was filtered off, washed with methanol-water, the filtrate and the washing liquid were combined, and the solvent was distilled off to obtain 50 mg of the above compound as colorless crystals.

Melting point 245-248℃ (decomposed) [α]'' knee 2a, 4° (C = 0° mouth 5,1 (*O) Elemental analysis value: C6H,.N, 0.・115H,0 Calculated value: C, 44,55; 11,6.48; N, 1
7.32 actual measurements: C, 44, 63, 11, 6, 36,
N, 17.24 Reference Example I+ (39,5S)-3-(p-nitrobenzyloxycarbonylamino)-5-carboxymethyl-2-pyrrolidone Compound obtained in Reference Example 9 [(3S,5S) form] 1 .5 g and 1.5 g of 10% palladium-carbon (50% water content) were suspended in 20 ml of ethyl acetate and 20 ml of water, and hydrogenated at normal pressure and room temperature for 2 hours. After filtering the catalyst and separating the aqueous layer,
Tetrahibi 0 furan 30mQ, sodium hydrogen carbonate 86
2 mg and 1.22 g of p-nitrobenzyloxycarbonyl chloride were added sequentially, and the mixture was stirred at room temperature for 18 hours.

This mixture was washed with ether, adjusted to pI-11 to 2 with aqueous potassium hydrogen sulfate, and extracted with a mixture of ethyl acetate and tetrahydrofuran (3:1). Wash the extract with water and dry it (
After MgSO4), the solvent was distilled off, and ether was added to the residue to obtain 1.56 g of the compound listed above as colorless crystals.

Melting point 200-203℃ 151G, 1350.126O NMR (9Q MJ(z, DMS Od,)6
: 1.31-1.78.2.00-2.60 (111
x2. m), 2.20-2.70 (211,s),
3.55-3.92 (111, m), 3.92-
4゜39 (III, m), 5.20 (211, s)
, 7.80 (III, s), ? , 64°8.25(
211X2. d, J=911z) [α]2'
-31,0° (C=0.2. EtOH) Elemental analysis value: C14H+sN*0? Calculated value: C, 4
9,85; I+, 4.48, N, 12.46 Actual value: C, 49,8g; 11,4.49; N,
12.35 Reference Example 12 (3S,5S)- and (3S,5R)-3-benzyloxycarbonylamino-5-(p-bromobenzyloxycarbonylmethyl)-2-pyrrolidone Compound obtained in Reference Example 5 (Z The crude [(3S,
5S) and (38,5R) mixture] was dissolved in 5ml of DMF, 125mg of p-bromobenzylbromide and potassium carbonate were added, and the mixture was heated at room temperature for 18 hours. Stirred. Ethyl acetate was added to the reaction solution, washed sequentially with water, potassium hydrogen sulfate, and brine, and dried (M
gSO,), and then the solvent was distilled off. The residue was subjected to column chromatography using silica gel, eluting with hexane-ethyl acetate (1:1) and then with ethyl acetate, yielding approximately 10:1 of the listed compounds. 210 mg of a mixture was obtained as a pale yellow oil. A portion was again subjected to column chromatography using silica gel, and hexane-ethyl acetate (1
:1-2=3), the following compound (3S) is obtained.

5S) and (3S, 5R) bodies were each obtained as colorless crystals.

(3S, 5S) body Cnf value large): Melting point 159-160℃ 1290.1260, 1190.108ON MR (
270MIIz, CDC(!, +D-0)δ:
1.61 (III, ddd, J=4.8.6.8.
12.511z).

2.84(ill, drld, J=8.3.9
．． 2. +2.511z).

2.49 (Ill, dd, J=1.7. 16.8
11z), 2.67 (III.

dd, J=8.4. 16.811z), 3.9
0(lit, dddd, J=1.7°4.8.8.
3.8.411z), 4.21(III,,dd,
J=6.8°9.211z), 5.08(/!I
I, s), 5.11 (2H, s), 7.20-7
．． 52 (911, w+) [α]! 3 +5.7' (C=0.21.CI(C
(! 3) Elemental analysis value: C*+Ht+B'r N
tOs calculation value: C, 54, 68, I+, 4.59
, N, 6.07 Actual value: C, 54, 73, 1+, 4
．． 57, N, 6.04 (3S, 5R) body (Rf value
Small): Melting point 123-124℃ 129G, 1250.108O NMR (27108ON, CDCl25+DtO)6
: 2.21(fil, dd, J=8.4,1
3.5112), 2.39 (11°ddd, J=8
．． 3.9.4, 13.511z), 2.57(II
l, dd.

J=5. 17.211z), 2.61(ill,
dd, J=8.6. 17.2Hz), 4.01(
Ill, ddd, J=5.0.8.3.8.611
z), 4.27 (III, dd, J=8.4.9
．． 411z), 5.08 (211,s).

5.11 (211,s), 7.20-7.51 (9
11, Kasumi) [α]2' -22,7° (C=0
．． 2 2. CHCl2 s) Elemental analysis value:
Cz+II*+l[3r NtOs calculation value: C,5
4,611, 11,4°59, N, 6.07 Actual value: C, 54,49, 11,4,48, N, 6.02 Reference example 13 (3S, 5S) -3-(tert-butoxy Carbonylamino)-5-carboxymethyl-2-pyrrolidone Compound obtained in Reference Example 12 [(38,5S) form] 300m
g and 10% palladium-carbon (50% water content) were suspended in a mixture of ethyl acetate lom12 and water at 20 mC, and hydrogenated at normal pressure and room temperature for 3 hours. After filtering the catalyst and separating the aqueous layer, 20ml of tetrahydrofuran was added. 0.3 ml of di-tert-butyl dicarbonate and 1 mQ of triethylamine were added, and the mixture was stirred at room temperature for 18 hours. Tetrahydrofuran was distilled off, and the residue was washed with ether, set to pI (+) using aqueous potassium hydrogen sulfate, and extracted with ethyl acetate. The extract was dried (M g SO ), concentrated,
Ether was added to the residue to obtain 121 mg of the compound listed above as colorless crystals.

Melting point 184-186°C 1675, 1510.1165 NMR (90M1lz, DMSO-da) δ
: 1.35 (911, s), 1.20-1.75.
2.01-2.50 (111X2.m), 2.27
-2.63 (211, m), 3.48-3.85 (I
Il, m), 3.70-4.23 (III, i)
, 6.88(ill, d.

911z), 7.70(ill, s)[α]2'
-11,4” (C=0.21.EtOH)
Elemental analysis value: C, H1aNtos calculation value:
C, 51, 16, 11,? ,02,N,lO,85
Actual value: C, 51,05, II, 7.05, N,
10.77 Reference Example 14 (3s, 5S)-3-(p-nitrobenzyloxycarbonylamino)-5-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-pyrrolidone Reference Example 11 Using 1.45 g of the compound obtained above, the reaction and treatment were carried out in the same manner as in Reference Example 7 to obtain 2.02 g of the compound listed above as a white foamy substance.

NMR(90MIIz, CDCl2*)6
: 1.50-2.80 (211, m), 2.65-
2.97 (2H, s).

3.56 (211,s), 3.55-4.40 (28
, m), 5.16°5.24 (211x2.s),
5.70 (lit, d, J=611z), 6.
6G.

(III, s), 7.35-7.60.8.1O-
842 (411x2.s) Reference Example 15 (3S, 5S)-3-(t-butoxycarbonylamino)-5-[3-(p-nitropenzyloxycarbonyl)-2-oxobropylco-2-pyrrolidone Using 481 mg of the compound obtained in Reference Example 13, Reference Example 7
When reacted and treated in the same manner as above, 408 mg of the compound mentioned above was obtained as a white powder.

Melting point 81-84℃ 1520, 1350.1165 NMI't (90MIIz CDC12-) δ: 1
．． 45 (911, s), 2.63 (IIl, dd,
J=9.1811z).

2.98 (III, dd, J=4.1811z),
3.54 (211, s).

3.67-4.30 (211, a+), 5.28 (2
11,s), ? , 52.8.25 (211X2.d
, J=911z) [α]2'+11.4' (
C=0.21. Cl4Cl2s) Elemental analysis value: C
*o■I*5NpO*Calculated value: C, 55, 17, 1
1,5,79,N, 9.65 Actual value: C,55,6
2, II, 5.93, N, 10.02 Reference Example 16 (3S, 5R) -3-(tert-butoxycarbonylamino)-5-[4-(p-nitrobenzyloxycarbonyl)-2-oxo Propyl]-2-pyrrolidone reference example! Compound obtained in 2 [(3S,5R) form] 300m
When the reaction and treatment were carried out in the same manner as in Reference Example 13 and Reference Example 15 using g, 181 mg of the compound mentioned above was obtained as colorless crystals.

Melting point 174~! 75°C H2O, 116O N M n (90Ml1 z CDCl23) δ:
1.44 (911,s), 2.00-2.53 (21
+, m), 2.80 (211, d, J=711z
), 3.50 (211,s), 3.80-4.37
(211, m), 5.00-5.20 (1!I, b
), 5.25 (21+, s).

a, l3-6.35 (1+1.b), ? , 52.8
．． 25 (211x2.d.

J=911z) [αko” -14,8° (C=0.1 3 5.
CHCl2 3) Elemental analysis value: C2°H□N, 0.
・I/21-1,0 total Wf/i: C,54,05
, II, 5.90 , N, 9.45 Actual value I C, 5
3,95; II, 5.57, N, 9.44 Reference Example 17 (5S, 7S)-7-(p-nitrobenzyloxycarbonylamino)-1-azabicyclo[3°3.0]octane-3, 8-Dione-2-carboxylic acid p-nitrobenzyl ester Compound 2.01 obtained in Reference Example 14. When the mixture was reacted and treated in the same manner as in Reference Example 8, 2.0 g of the compound mentioned above was obtained as an oily substance.

Reference example! 8 (5S,7S)-7-(t-butoxycarbonylamino)-1-azabicyclo[3,3,0]octane-3,8
-dione-2-carboxylic acid p-nitrobenzyl ester 408 mg of the compound obtained in Reference Example 15 was reacted and treated in the same manner as in Reference Example 8 to obtain 400 mg of the title compound as an oil.

Reference Example 19 (5rt, ?5)-7-(t-butoxycarbonylamino)-1-azabicyclo[3,3,0]octane-3,
8-dione-2-carboxylic acid p-nitrobenzyl ester 180 mg of the compound obtained in Reference Example 16 was reacted and treated in the same manner as in Reference Example 8 to obtain 170 mg of the compound listed above as an oily substance.

Example 1 (5R8,78)-8-(2-acetamidoetetvfo)-7-(1)-nitropenzyloxylponylamino)-8-oxo-1-azabicyclo[8,8,Olocto-2 -ene-2-carboxylic acid p-nitrobenzyl ester Compound 2 obtained in Reference Example 8. Of acetonitrile 50m
1 and diisopropylethylamine 607 under water cooling.
Add ①, then 1.26g of diphenylphosphoric acid chloride
was added and stirred for 80 minutes. To this mixture were added a solution of 560 Da of 2-acetamidoethanethiol in 5 ml of acetonitrile and 607 II g of diisopropylamine, and the mixture was stirred for 2 hours under water cooling. The solvent was distilled off, ethyl acetate was added to the residue, and the mixture was washed successively with water, potassium hydrogen sulfate solution, and sodium bicarbonate monobrine solution. Dry the organic layer (MgSO4)
After that, the residue was subjected to column chromatography using Prolysil, eluted with ethyl acetate and then ethyl acetate-methanol (a:1), and the fractions containing the target compound were collected and concentrated under reduced pressure to obtain the compound mentioned above. 1.719 was obtained as a pale yellow tarry substance.

KBr-1・IRu CM, 8860, 1710(E)r
).

ax 165G, 1605, 1520.114・5NMR (9
0MHz, DMSO-d6) a: 1.80
(l)l,8), 2.6O-178(8H,m).

4.25-4.80 (IH, m), 5.20 (2H.

S), 5.88 (2H, ABq), 7.50-
7.86 (4H, m), 7.95-8.35 (4H, m
) [α] p -41,4° (C-0,21, DMS
O) Example 2 (5R8,78)-1-(2-7 cetamide ether)
-7-[2-(4-ethyl-2,8-dioxo-1-piperazinocarboxamide)-(2R)-2-phenylacetamide]-8-oxo-1-azabicyclo(a,
a, O) Oct-2-ene-2-carboxylic acid sodium salt Compound 20011F obtained in Example 1, ethyl acetate 10m
1 and pH 7,09 phosphate buffer (10 + wl) (
Add 200 g of 21096 Palladium Charcoal 5I,
Hydrogenation was carried out at room temperature under normal pressure for 2 hours. After filtering off the catalyst, the aqueous layer was separated and washed with ethyl acetate. On the other hand, 156 Wg of 2-(4-eftv-2,a-dioxo-1-piperazinocarboxamide)-(2R)-2-phenylacetic acid and 1-
, hydroxybenzotriazole 50 Da tetrahydrogen 0
F2F10 511 g of chlorohexylcarbodiimide 18 was added and stirred at room temperature for 80 minutes. This solution was filtered, and the filtrate was added to the aqueous layer and stirred at room temperature for 2 hours. After washing this mixture with ethyl acetate, the aqueous layer was concentrated and the concentrated solution was subjected to column chromatography using Amberly) XAD-2 (
Water-2096 ethanol) was purified and lyophilized to obtain the above compound as a colorless powder (6611 g).

IRJ/KBram-”: 1l1400, 170
5, 1670.

ax 89O NMR (9GMHz, DMSO-d6)l
: 1.1 4 (2H, t, Jx7Hz), 1.8
0 (3H, s).

2, 60-2.85 42) 1, m), 8.0G-3.
72 (8H, m), +11, 80-4.05 (2H, m
).

4, IQ-4.90 (IH, m), 5.57 (IH.

d, J=7Hz), 7.10-7.60 (5H, m).

8, 42-9.10 (2°H.m), 9.89 (
IH.

d, J=7Hz) [αID-45.8°(C=0.1 9, H2O
) Elemental analysis i[:C27H31N50@SNa°15H
20 Calculated value: c, 47.80 in, 5.59; N,
12.26 Actual value: C, 47.29; H, 5.27
BN, x2. ssMIC (by agar dilution method. 1o'
CFUAt) Test bacteria (μg/Alt) Escherichia coli (E, coli) PGas 12.5 Proteus mirabilis (P, m1rabilis) ATCC211006
, 25 Proteus vulgaris (P, vulgaris) IFO 89886, 25 Pseudomonas aeruginosa (P, aeruginosa) C14112, 5 Alcaligenes faecalis (AI, faecalis) IFO 131116,
25 Example 3 (5R8,78>-8-C2-acetamidoetherthio)
-7-[2-(2-aminothiazol-4-yl)-(
Z)-2-methoxyiminoacetamide]-8-oxo-
1-Azabicyclo (a, a.

O] Oct-2-ene-2-carboxylic acid sodium salt A mixture of 200 Da of the compound obtained in Example 1, 8 ml of ethyl acetate and 8 ml of pH 7,0 phosphate buffer (=1096
200 Da of palladium on carbon was added, and hydrogenation was carried out at room temperature under normal pressure for 2 hours. After filtering off the catalyst, the aqueous layer was separated and washed with ethyl acetate. This aqueous Wll: Tetrahydrofuran 2
pH 7, using sodium bicarbonate salt.
180 Mg of 2-(2-cucroacetamidothiazol-4-yl)-(Z)-2-methoxyiminoacetyl chloride hydrochloride was added while cooling with water and stirring. After stirring for 80 minutes, N-methyldithiocarbamic acid potassium salt 63 was added, and the pH of the reaction solution was adjusted to 8-9 using IN hydrochloric acid. The mixture was stirred at room temperature for 2 hours, washed with ether, and the aqueous layer was concentrated. The concentrated solution was purified by column chromatography (water-596 ethanol) using Amberly) XAD-2 and freeze-dried to obtain the above compound as a colorless powder (84H).

IRνKBrex-': 8400.1690-16
50°ax 1595.1585.189O NMR (90MHz, DMSO-d@)a: 1.
80 (8H, s), 2.05-8.00.8.0
0-8.8 a(,8H,m), 1.84(3H,S)
, 4.15-5.07 (IH,m), 7.0
5-7.80 (2H.

br), 6,? 5, 7.80 (IH, S), 8.7
8゜9.21 (IH, d, J = 9Hz) [α] Sweet 27.4° (C = Q, 185, H, O') Elemental analysis value: CIgH21N6068 HBNa ・2.5
H40 calculated value: C, sa, sa; H, 4, 7? ;N
, 15.29 Actual value: c, a9J8 iH, 4, 64i
N, 15.48 Example 4 (5R8,78)-1-(2-acetamidoethylthio)
−? -(2-chenylacetamide)-8-oxo-1-
Azabicyclo(8,+1.Oloct-2-ene-2-
Carboxylic acid +)ium salt Compound obtained in Example 1 200m
+9. 10 ml of ethyl acetate and G) H7,O! J
Acid buffer IQm/mixture ζ”110% palladium
Carbon 20011F was added and hydrogenated at room temperature under normal pressure for 2 hours. After filtering off the catalyst, the aqueous layer was separated and washed with ethyl acetate. Separately, 1421 Ig of chenyl acetic acid and 248 Ig of N-hydroquine succinimide and 221 g of N-hydroquine succinimide were added, and the mixture was stirred at room temperature for 2 hours. This solution was filtered, and the filtrate was added to the aqueous layer and stirred at 50°C for 1 hour. After washing this mixture with ethyl acetate, the aqueous layer was adjusted to pH 7.5, purified by column chromatography (water → 10% ethanol) using Amberly XAD-2, and freeze-dried to obtain the compound mentioned above. was obtained as a colorless powder (Cape 76).

Phantom juice -! IRJJ (11: 8400, 1680-
1650.

aX , 1590, 14 (10, 1265, 1205, 101
095N (90MHz, DMSO-d6)
a: 1.80 (aH,S), 2.40-2.8
8 (2H, m).

8, 69 (2) (, s), 4.1 0 -4
．． 9 2 (IH.

m), 6.78-7.38(3)1, m), 8.3
6-8.6 7 (IH, m) [α] D - 1 2.7° (C dry 0.275, H20
) Example 5 (5R8.78)-3-(2-acetamidoethylthio)
-7-[(2R)-2-amino-2-phenylacetamide]-8-oxo-1-azabinclo(a, S,
O) Oct-2-ene-2-carboxylic acid Compound aooIIg obtained in Example 1, ethyl acetate 811
and p)17. o Add 1 to the mixture of phosphoric acid solution Logt
0% palladium on dicarbonate aoowl was added and hydrogenated at room temperature under normal pressure for 2 hours. After filtering off the catalyst, separate the aqueous layer,
Washed with ethyl acetate. This solution 1=N-(tert-
Butquin carbonyl)-D-phenylalanine and hydroxybenzotriazole N.

A tetrahydrofuran solution (2 mmo
1 equivalent) was added thereto, and the mixture was stirred at 50°C for 2 hours.

Washing the reaction solution with ether (Amberley) XAD-2
Column chromatography (water = 5096 ethanol) using
The grt-butoxycarbonyl compound was obtained as a colorless powder.To this compound, 2 ml of dichlorothane and 21 mL of anisole were added.
11 was added thereto, and trifluoroacetic acid 21/2 was added at -20°C, and after stirring for 1 hour under water cooling, the solvent was distilled off. Water was added to the residue, the pH was adjusted to 5 with aqueous sodium bicarbonate, and the mixture was washed with ether. Concentrate the aqueous layer and transfer the concentrated H solution to amber chromatography using
1096 ethanol) (:) and lyophilized to obtain the compound listed above as a colorless powder (85#).

) G3r -t IR, cM: J1400, 1690, 1650°a
x 1590.119O NMR (90MHz, DMSO-d6)a: 1.8
0 (an, s), 2.40-115 (6H, m)
.

4.60 (1B, S), 3.60-5.05 (t
H.

m), 7.21-7.54 (5H, m), 8.05-8
．． 40.8.47-8.78 (3H, m) [α] Amase 55.2° (C = 0.28. H2O) Elemental analysis ff
l: C20H24N405S ・2.5H20 calculated value:
C, 50, 30iH, 6, 12iN, 11.73 Actual value: C, 50, 18iH, 5, T 6 iN, 11.5
0 Example 6 (5S,7S)-3-(2-acetamidoethylthio)
-7-(p-nitrobenzyloxycarbonylamino)
-8-oxo-1-azabicyclo[3,3,O-oct-2-ene-2-carboxylic acid p-nitrobenzyl ester Using 2.0 g of the compound obtained in Reference Example 17, react and treat in the same manner as in Example 1. Then, 1.55 g of the compound mentioned above was obtained as yellow crystals.

Melting point 177-180°C I Rv xB'cm-': 3400.1720,
1520.1345ax NMR (400MH2, CDCl23 + DMs
o-do + oto) δ; 1.80-1.88 (IH
, n), 1.98 (3■, s), 2.76-2.8
3 (1B.

l11), 2.81-2.90.2.99-4.05
(IHx 2.m), 3.05-3.1Q (IH, m
), 3.30-347, 3.44-3.48 (lHx
2. m).

3.36-3.42 (IH, ff1), 4.43-4
．． 46 (18, m), 4.60-4.65 (IH, m
), 5.22 (2H, s), 5.27, 5.47 (
lHx2. d.

J=13.411z), 7.52,7.65(2Hx
2. d, J=8.8tlz).

8.21.11.22 (2HX 2.d, J=8.8H
z) [α]24-15.2°(cm0.105.CH
Cl23) Elemental analysis value: C2, Ht7NsOtoS・3
/4) 110 calculated value: C, 51, 71, H, 4, 5
8, N, 11. ．． 17 Actual measurement value: C, 51, 75, H
,4,45:N,11.05Example 7 (5S,7S)-3-(2-acetamidoethylthio)
-7-[2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-(2R)-2-phenylacetamide]-8-oxo-1-azabicyclo[3,3,
0] Oct-2-ene-2-carboxylic acid sodium salt 200 mg of the compound obtained in Example 6 was reacted and treated in the same manner as in Example 2 to obtain 66 mg of the compound listed above as a white powder.

I Rv KBrcta-': 3400,1710,
1675, 1510, 1390°aX N M R (90 MHz, D t O) δ: 1.
35 (3H, t, J=7H2).

2.08 (3H, s), 2.63-3.75 (12H
, m), 3.51-3.88 (LH, m), 3.9
5-4.20 (1B, m), 5.58 (LH, s),
7.59 (5H, s) [αko23 -39.5° (cm0.21.H*
O) Example 8 (55,7S)-3-(2-acetamidoethylthio)=
7-[2-(2-aminothiazol-4-yl)-(Z
)-2-methoxyiminoacetamide]-8=oxo-1
-Azabicyclo[3,3,0 years old ct-2-en-2-
Carboxylic acid sodium salt Compound 200 obtained in Example 6
When the reaction and treatment were carried out in the same manner as in Example 3, 65 mg of the compound mentioned above was obtained as a white powder.

I Rv KBrcm-': 3300,1690,1
650,1595,1530゜ax 1415,139O NMR (90MHZ, DeO) δ: 2
．． 0g(3H,s), 2.6L3.28(411,m
), 3,30. (,60(2tl,m), 4.06
(3H, s).

5.00-5.35 (211, m), 7.25 (IH
,s)[α]23-284°(c=0.205.Ht
O) Elemental analysis value: C+sHt+NaS*Na' 3Ht
O calculated value: C, 3g, 71. H, 4, 87, N
, 15.05 Actual value: C, 39,00, H, 4,6
6, N, 14.67 Example 9 (5S,7S)-3-[2-(+)-nitropenzyloxycarbonylamino)ethylthio] -7-(ter
t-Butoxycarbonylamino)-8-oxo-1-azabicyclo[3,3,O]oct-2-ene-2=carboxylic acid p-nitrobenzyl ester 400 mg of the compound obtained in Reference Example 18 was dissolved in 20% acetonitrile. Then, 133 mg of diisopropylethylamine was added under water cooling, and then 277 mg of diphenylphosphoryl chloride was added.
Stirred for 5 hours.

To this mixture were added 264 mg of 2-(p-nitrobenzyloxycarbonylamino)ethanethiol and 133 mg of diisopropylamine, and the mixture was left standing in a refrigerator for 18 hours. Add ethyl acetate to the reaction solution, and add water.

After sequentially washing with a potassium hydrogen sulfate solution, a sodium hydrogen carbonate solution, and a saline solution, the solution was dried (MgSO, ) and the solvent was distilled off. The residue was subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate (1:2) and then ethyl acetate-methanol (9:1). Fractions containing the target product were collected and concentrated to yield the compound mentioned above. 350 mg was obtained as a yellow powder.

When this product was recrystallized from ethyl acetate, pale yellow crystals were obtained.

Melting point 178-180°C I Rv KBrcm-': 3400,1720,1
690,1670,1520゜ax 1345.1260.116O NMR (400MHz, CD C(ls+DtO)
δ2 1.46 (9H.

s), 1.78 (IH, ddd, J=9.2, 11.
9,11.9Hz), 2.78 (1B, dd, J=1
0.6, 17.1Hz), 3.01 (IH, ddd,
J=6.3°8.9, 11.9Hz), 3.27(I
H, dd, J-9, 4, 17, 1Hz).

2.91, 3.01 (IHX2.dt, J=6.9,1
1.6Hz), 3.38 (2H.

t, J=6.9Hz), 4.40(111,dddd
, J=6.3,9.2,9.4°10.6112),
4.56(1)1. dd, J=8.9.11.9Hz)
, 5.19 (211, s), 5.26, 5.47 (
2H, ABQ, J=13.7Hz), 7.50°7.
65 (2Hx2.d, J=8.9Hz), 8.21(
4H, d, J = 8.9UZ) [a] 24-6.7° (c = 0.075.CHC
l2s) Elemental analysis value: C4゜Hs s N s O+
lS・1/4Ht○ Calculated value: C, 53, 29, H,
4,99,N, 10.36 Actual value: C, 53,24
; H, 4,88; N, 10.29 Example 10 (5R,7S)-3-[2-(p-nitrobenzyloxycarbonylamino)ethylthio] 7-([ert
-butoxycarbonylamino)-8-oxo-1-azabicyclo[3,3,0]oct-2-ene-2-carboxylic acid p-nitrobenzyl ester Using 170 mg of the compound obtained in Reference Example 19, Example 9 When reacted and treated in the same manner, 1 g of compound 185Il was obtained as a yellow powder. When this product was recrystallized from ethyl acetate, pale yellow crystals were obtained.

Melting point 165-167°C I Rv KBrcm-': 3350.1720-1
680.1510,1345゜fiaX 16O NMR (400MH2, CDC&3+D!O) δ:
1.44 (9B.

s), 2.30 (IH, ddd, J=5.8, 7.8
, 13.9Hz), 2.38 (IH, ddd, J=3
．． 3, 6.8, 13.9Hz), 2.73 (1■, d
d, J=11.9.16.5Hz), 3.17(IH
, dd, J-8, 6, 16, 5Hz).

2.91, 3.03 (IHX 2.ddX 2.J=
6.6, 6.9, 13.5) 12).

348 (2H, t, J = 6.7Hz), 4.33 (I
H, dd, J = 3.3, 7.8112), 4.63
(111, dddd, J=5.8, 6.8, 8.6, 1
1.9H2).

5.19 (211, s), 5.26, 5.48 (2
+1. ^Bq, J = 13.9Hz).

7.50, 7.67 (2HX 2.d, J = 8.6
, 8.9■Z), 8.19, 8.21 (2HX2.d
, J=8.6,8.9Hz) [a]24+11.4°(
c=0.07. CHCps) Elemental analysis value: C3083
3NIIOIts-1/2HtO calculation value: C,52
,94,H,5,03;N,10.29 Actual value:
C, 53,05; H, 4,85; N, 9.
99 Example 11 (5s,7S)-3-[2-(p-nitropenzyloxycarbonylamino)ethylthio]-7-[2-(4
-ethyl-2,3-dioxo-1-piperazinocarboxamide)-(2R)-2-phenylacetamide]-8-
Oxo, -1-azabicyclo[3,3,0]oct-2
-ene-2-carboxylic acid p-nitrobenzyl ester 300 mg of the compound obtained in Example 9 was dissolved in dichlorometajiro, and trifluoroacetic acid 6- was added under water cooling. After stirring for 2 hours, the solvent was distilled off under reduced pressure. did. Aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried (N at SO-) and the solvent was distilled off.

On the other hand, 66 mg of 1-hydroxybenzotriazole and N,N '-Dicyclohexylcarbodiimide 111a+g was added and
The mixture was stirred for 0 minutes, and the precipitated crystals were filtered off. The filtrate was added to the above concentrated residue and stirred at room temperature for 18 hours. Add 30 g of ethyl acetate to this mixture and add potassium hydrogen silosulfate solution.

After sequentially washing with sodium bicarbonate water and brine and drying (M g S 04), the solvent was distilled off. Ether was added to the residue to obtain 400 mg of the above mentioned compound as a pale yellow powder. The main island should not be further refined (Example 1)
It was used in the reaction of 3.14.

I Rv KBram-': 3320,1?20,1
680.1625,1515゜ax 35O NMR (400MHz, CD CQs) δ:
1. ．． 21 (3H, t, J=7.2Hz), 1.
53-1.64 (IH, m), 2.65-3.66 (
9H, a).

3.55 (2H, Qj=7.2112), 3.93-
4.17 (28, I), 4.36-4.47 (11,
s), 4.74-4.83 (2B, s), 5.18
(2H, s).

5.24, 5.45 (111x2.d, J=13.6f
lz), 5.46 (IH, d, J=6.4H2),
7.31-7.64 (9H, I), 8.17-8
．． 25 (4H, l).

9.93 (111, d, J=6.4Hz) [α]”
-22,7° (c=0.075. CHCl25) Example 12 (5R,7S)-3-[2-(p-nitrobenzyloxycarbonylamino)ethylthio]-7-[2-(4-
Ethyl-2,3-dioxo-1-piperazinocarboxamide)-(2R)-2-phenylacetamide]-8-oxo-1-azagicyclo[3,3,0]oct-2-ene- 2-Carboxylic acid p-nitrobenzyl ester Using 150 mg of the compound obtained in Example 1O, Example 1
When reacted and treated in the same manner as 1, the compound 1' 85 m
g was obtained as a pale yellow oil. When ether was added to the main island, pale yellow crystals (+1hg) were obtained.

Melting point 135-138°C I Rv KBrcya-': 1400.1715
-1670.1510.1340ax NMR (400MHz, DMS Ods)
δ: 1.08 (3H, t.

J=7.2Hz), 2.85-2.97 (3H, m)
, 3.12-3.40 (7tl, m), 3.52-
3.59 (2H, w), 3.87-3.95 (2H,
m), 4.47-4.63 (2H, m), 5.17
(2H, s), 5.31, 5.46 (IHX2.d.

J=13.9Hz), 5.49(LH,d, J=7.
611z), 7.28-7.77 (9H, m), 8
．． 13-8.25 (4H) [αko24 ±0° (
c=0.15. DMSO) Example 13 (5S,7S)-3-(2-aminoethylthio)-? −
[2-(4-Ethyl-2,3-dioxo-1=piperazinocarboxamide)-(2R)-2-phenylacetamide-8-oxo-1-azabicyclo[3,3,0]oct-2- Ene-2-carboxylic acid 10% palladium-carbon (5
0% water content) was added thereto, and hydrogenation was carried out at room temperature under normal pressure for 2 hours. After filtering off the catalyst, separate the aqueous layer and dilute it with IN hydrochloric acid.
Adjusted to H4. This aqueous solution was washed with ether, concentrated, purified by column chromatography using Amberlite XAD-2 (water → 50% ethanol), and lyophilized to obtain 32 mg of the compound as a white powder. Ta.

I Rv KBrcm-': 3400,1705,1
670, 1500, 1390° ax 18O N MR (90 MHz, D t O) δ: 1.
26 (31f, tj=7H2).

1.70-2.50 (211, m), 2.55-3.
10 (2H, m), 2.98-3.45 (2H, m)
, 3.42-3.90 (4H, m), 3.9O-4
JO (2B.

m), 4.20-5.00 (2H, m), 5.60
(IH, s), 7.58 (5H.

S) [α 40.0° (cm0.07.H
tO) SIMS m/z 559 (M+1), 58
1(M+Na)UVλ””ruIl: 283(ε
=9540)aX Example 14 (5S,7S)-3-(2-aminoethylsulfonyl)
-7-[2-(4-ethyl-2,3-dioxopiperazinocarboxamide)-(2R)-2-phenylacetamidoco-8-oxo-■-azabinclo[33,0]oct-2-ene- Compound 18 of 2-carboxylic acid Example 11
To an aqueous solution of the crude compound prepared from 0 mg by the method of Example 13, sodium hydrogen carbonate 52B and m-chloroperbenzoic acid 107D were added, stirred at room temperature for 3 hours, and then concentrated under reduced pressure. Amberlite XAI)-2
The product was purified by column chromatography (water → 50% ethanol) and freeze-dried to obtain compound 28@g as a white powder.

I RJ/KB'cm-': 3400.1?15
, 1870.1510flaX NMR(90MHZ, D*O)δ: 1
．． 25 (3H, t, J=711z).

2.42-3.15 (2H, +n), 3.43-3.
90 (6H, m), 3.90-4.25 (2H, a+
), 5.58 (IH, s), 7.58 (5H, s)
[αCoD 50.0' Cc=o, 06. H
tO) SIMS a/z: 591(M+1)uv
t ■” +v: 271 (5 = 11800) aX Example 15 (5R,7S)-3-(2-acetamidoethylthio)-
7-[2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-(2R)-2-phenylacetamide]-8-oxo-1-azabicyclo[3,3,0
co-oct-2-ene-2-carboxylic acid sodium salt 140 eg of the compound obtained in Example 12 in ethyl acetate 10-
and 10% in a mixture of pH 7,0 phosphate buffer 10-
280 mg of palladium-carbon (50% water content) was added and hydrogenated at room temperature under normal pressure for 1 hour. After filtering off the catalyst, the aqueous layer was separated, and 2 d of saturated sodium bicarbonate water, 20 ml of tetrahydrofuran, and 0.1 ml of acetic anhydride were added. The mixture was stirred at room temperature for 2 hours, washed with ethyl acetate, and concentrated. The concentrated solution was purified by column chromatography (water-50% ethanol) using Amberlite XAD-2, and lyophilized to obtain 28 mg of the above compound as a white powder.

r RLI KBrCl-': 3400,1710,
1670, 1590, 1390°aX 1365.118O NMR (90MHz, DtO) δ: 1.25 (38
, t, J=7FIz).

2.05 (3B, s), 2.62-3.20 (2H,
m), 3.33-3.88 (411゜m), 3.9
6-4.25 (2H, R1), 5.53 (IH, S)
, 7.58 (511°S) [ff]D-38,4° (cm0.185.HtO)
S I MS ta/z: 623(M+1)U
Vλ threshold nm: 274 (ε=11070) ax Effects of the Invention As stated above, the target compound of the present invention exhibits antibacterial activity and can be used as an antibacterial agent with a new chemical structure.

Claims (1)

[Claims] General formula▲ Numerical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is an optionally acylated or protected amino group, and R^2 is an optionally substituted carbonized group. A fused five-membered lactam compound represented by hydrogen or a heterocyclic group, where n represents 0, 1 or 2, or an ester or salt thereof.