KR930001405B1 - Process for preparing 2-(4-substituted amino-3-oxo-isoxazolydin-5-oxo)-tetra hydrofuran carboxyl acid derivatives - Google Patents

Abstract

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Description

Method for preparing 2- (4-substituted amino-3-oxo-isoxazolidinyl) -5-oxo-2-tetrahydrofurancarboxylic acid derivative

The present invention provides a novel 2-84-substituted amino-3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofurancarboxylic acid derivative which exhibits antibacterial and β-lactamase inhibitory activity, and preparation thereof. It relates to methods and uses.

Recently, novel antibiotics TAN-588 (hereinafter also abbreviated as "TAN-588"), which exhibit antimicrobial activity against Gram- and Gram-negative bacteria, have been separated from soil by Empedobacter and Rizobacter ( Lysobacter) was collected from a new species of microorganism.

The present inventors conducted a study to identify the chemical structure of the antibiotic TAN-588, and as a result, the antibiotic TAN-588 has 5-oxo-2-tetrahydrofurancarboxylic acid bonded to a nitrogen atom. It was found to have a unique backbone composed of oxoisoxazolidine rings.

So far, the synthesis of compounds having 3-oxoisoxazolidine rings in which 1-methylacetic acid groups have been introduced to their nitrogen atoms has been reported [Tsuji and Yamana; Heterocycles, 8, 153 (1977). However, it has been reported that this compound having 1-methylacetic acid value does not exhibit antimicrobial activity.

The present inventors synthesized a derivative of the antibiotic TAN-588 showing antimicrobial activity, and found that the above derivative has excellent antimicrobial activity. Further study of this finding has led to the completion of the present invention.

The present invention (1) the compound of formula (I) or a salt thereof

Wherein R ¹ is an organic residue bound via amino or nitrogen; R ² is carboxy or a group derived from carboxy; X is hydrogen, methoxy or formylamino; When R ¹ is acetylamino or amino and X is hydrogen, R ² is not para-nitrobenzyloxycarbonyl or benzhydryloxycarbonyl),

(2) A method for producing a compound of formula (II), wherein the compound of formula (III) is reacted with a compound capable of introducing a group that forms an organic residue bound through nitrogen.

(Wherein R ¹ ′ is an organic residue bonded through nitrogen; X and R ² are as defined above),

(3) The following general formula (IV) is characterized in that the compound of formula (V) is reacted with a compound capable of introducing a group which forms a group bonded to a carbon or oxygen atom of carboxy which can be derived from a carboxy group. Method for preparing the compound.

Wherein R ¹ and X are as defined above; R ² ′ is a group derivable from a carboxy group; when R ¹ is acetylamino or amino and X is hydrogen, R ² ′ is para-nitro Not benzyloxycarbonyl or benzhydryloxy carbonyl),

(4) A process for producing a compound of formula (VI), wherein the compound of formula (VII) is subjected to methoxy-formation or formmil amination reaction.

(Wherein R ¹ and R ² are as defined above; X 'is methoxy or formylamino), and (5) an antimicrobial agent containing compound (I).

In the general formula described herein, examples of the organic residue bound through nitrogen represented by R ¹ or R ¹ ′ are for example acylamino, amino substituted via carbon, alkenylamino, thioamino, silylamino, phospho Amino and general groups -CO-CO-NH-.

Acyl in the acylamino is a known acyl group such as, for example, an acyl group substituted with a 6-amino group of a penicillin derivative and an acyl group substituted with a 7-amino group of a cephalosporin derivative.

Examples of the acylamino group are, for example, general formula

Wherein R ³ is hydrogen, alkyl ^* , alkenyl ^* , cycloalkyl ^* , aryl ^* , hetero ring ^* , alkoxy ^* or aryloxy ^* ; R ⁴ is hydrogen or alkyl ^* and R ⁴ is or together with R ³ Can form a ring ^* .

[Wherein R ⁵ is hydrogen, an amino residue ^* , an aminoprotecting group or a general formula R ^7- (CH ₂ ) _n -C (= Z)-{wherein R ⁷ is hetero ring ^* , alkoxy) or amino ^* , n Is 0.1 or 2, Z is O or S} and R ⁶ is alkyl ^* , aryl ^* , cycloalkenyl ^* or heterocycle ^* ; General formula

R ⁸ -R ⁹ -CO-NH-

식중, R¹⁰은 알킬^*, 헤테로고리^*또는 아릴^*이고 R¹¹은 수소, 알킬^*, 알케닐^*, 시클로알킬^*, 헤테로고리^*또는 일반식 -R¹²-R¹³ [Wherein R ⁸ is a general formula

Wherein R ¹⁰ is alkyl ^* , heterocycle ^* or aryl ^* and R ¹¹ is hydrogen, alkyl ^* , alkenyl ^* , cycloalkyl ^* , heterocycle ^* or general formula -R ¹² -R ¹³

(식중, R¹⁴는 알킬^*, 아릴^*또는 헤테로고리^*이다)의 기이다]의 기; 일반식Wherein R ¹² is alkylene ^* , cycloalkylene or alkenylene; R ¹³ is aryl ^* , carboxy ^* or its ester or mono- or dialkylamide); R ⁹ is a chemical bond or a general formula

Wherein R ¹⁴ is an alkyl ^* , aryl ^* or heterocyclic ^* group; General formula

[Wherein, R ¹⁵ is aryl ^* , heterocyclic ^* or cycloalkenyl ^* ; R ¹⁶ is hydroxy, sulfamoyl, sulfo, sulfoxy or acyloxy ^* ; General formula

R ¹⁷ -R ¹⁸ -CH ₂ -CO-NH-

[Wherein, R ¹⁷ is alkyl ^* , cyano, aryl ^* , aryloxy ^* , alkenylene ^* , heterocyclic ^* , amino ^* or general formula R ^17′- C (═S) — (where R ^{17 ′} is alkoxy Is a group; R ¹⁸ is a chemical bond or -S-; And general formula

[Wherein R ¹⁹ and R ²⁰ are the same or different and each represents hydrogen, alkyl ^* , aryl ^* , heterocyclic ^* or cycloalkyl; Z is O or S].

In each description of the groups used herein, a group having a "*" sign is defined as a group which may have a substituent.

의 기는 일반식

의 신이성질체 및 일반식

의 안티 이성질체 또는 그의 혼합물을 나타낸다.General formula representing R ⁸

Creeper of the general formula

Isomers and general formulas of

The anti isomer of or mixture thereof.

Examples of amino substituted via carbon exemplifying organic residues bonded via nitrogen represented by R ¹ are, for example, general formula

R ²¹ -NH-

Wherein R ²¹ is alkyl ^* , aryl ^* , alkenyl ^* or heterocycle ^* ; General formula

(Wherein R ²² and R ²³ are the same or different and each represent alkyl ^* , aryl ^* or alkenyl ^* and can also form a heterocycle with adjacent nitrogen atoms); And general formula

Wherein R ²⁴ , R ²⁵ and R ²⁶ are the same or different and each represents alkyl ^* , aryl ^* or alkenyl ^* and may form a heterocycle ^* with adjacent nitrogen atoms.

Examples of alkenylamino exemplified by the group represented by R ¹ are, for example, a general formula

Wherein R ²⁷ and R ²⁸ are the same or different and each represents hydrogen, alkyl ^* , aryl ^* , cycloalkyl, amino ^* or heterocycle ^* , and R ²⁷ and R ²⁸ together with the adjacent nitrogen atoms are cycloalkyl ^* or Heterocycle ^* may be formed).

Examples of thioamino exemplifying a group represented by R ¹ are, for example, a general formula

R ²⁹ -SO _n -NH-

Wherein R ²⁹ is alkyl ^* or aryl ^* ; n is 0.1 or 2.

Examples of silylamino illustrating the group represented by R ¹ are, for example, a general formula

Wherein R ³⁰ , R ³¹ and R ³² are the same or different and each represents an alkyl ^* or an aryl ^* and also they form a cyclic group; R ³³ is hydrogen or silyl ^* .

Examples of phosphoamino exemplifying a group represented by R ¹ are, for example, a general formula

Wherein R ³⁴ and R ³⁵ are the same or different and each represents alkyl ^* , aryl ^* , alkoxy ^* or aryloxy ^* , and R ³⁴ and R ³⁵ form a heterocycle ^* .

Examples of groups represented by R ¹ are general formula

R ³⁶ -CH-CO-NH-

Wherein R ³⁶ is hydrogen, alkyl ^* , alkoxy ^* , aryl ^* , aryloxy ^* , heterocyclic ^* or amino ^* .

In the above general formula, the organic residue bonded through nitrogen represented by R ¹ or R ¹ ′ preferably has a molecular weight of 500 or less.

In the formulas described herein, groups which can be derived from the carboxy represented by R ² or R ² ′, for example

COOR ³⁷

In which R ³⁷ is alkyl ^* , alkenyl ^* , aryl ^* , cycloalkyl ^* , heterocyclic ^* or silyl ^* ; And general formula

Wherein R ³⁸ and R ³⁹ are the same or different and are each represented by hydrogen, alkyl ^* , aryl ^* , cycloalkyl ^* , alkenyl ^* or heterocycle ^* and R ³⁸ and R ³⁹ together with adjacent nitrogen atoms May form a ring ^* ).

In the above general formula, the group derivable from the carboxy represented by R ² and R ² ′ has a molecular weight of 500 or less.

In the above general formula, alkyl in R ³ , R ⁴ , R ⁶ , R ¹⁰ , R ¹¹ , R ¹⁴ , R ¹⁷ and R ¹⁹ to ³⁹ preferably has 1 to 6 carbon atoms, for example methyl . Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 1,1-dimethylpropyl, n-pentyl, isopentyl, n-hexyl and isohexyl.

Substituents which the alkyl group may have may have, for example, halogen, oxo, thioxo, nitro, amino (substituent alkyl, alkenyl, cycloalkyl, aryl, acyl, carbamoyl or n-sulfocarbamoyl). ), Sulfo, cyano, hydroxy, carboxy (can be esterified with alkyl), cycloalkyl, cycloalkenyl, alkoxy (with substituents amino, hydroxy, carboxy, halogen, aryl, cycloalkyl or alkoxy) Aryl (substituents may have halogen, alkyl, alkoxy, alkylamino, amino, carbamoyl, sulfo, alkylsulfonyl, cyano, hydroxy, carboxy, nitro, acyloxy, allalkyloxy or sulfoxy) Arylcarbonyl (which may have substituents similar to those described for aryl), aryloxy (which may have substituents similar to those described for aryl), heterocycles (as substituents nitro, oxo, aryl, alkenyl, Halogenoalkyl, alkylsulfonyl, alkyl, alkoxy, alkylamino, amino, halogen, carbamoyl, hydroxy, cyano, carboxy or sulfo), acyl (with substituents hydroxy, halogen, amino or nitro Arylcarbonylhydrazino which may have substituents), acyloxy, alkoxycarbonyl, alkoxycarbonyloxy (which may have halogen as substituent), acyloxy-ethoxy, aralkyl (alkyl as substituent) , Alkoxy, halogen, amino, hydroxy, nitro, cyano, carbamoyl or sulfoyl), aralkyloxy (substituted as acyloxy, alkyl, alkoxy, halogen, amino, hydroxy, nitro, Cyano, carbamoyl or sulfamoyl), hydroxysulfonyloxy, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonyl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl , Alkyl O (which may have cyano, halogen, carboxyl, alkylamino, amino, carbamoyl or asiamino as a substituent), arylthio, heterocyclic-thio (cyano as a substituent, hydroxy, amino, alkylamino, Alkyl, halogen or oxo), heterocycle (substituent may have cyano, hydroxy, amino, alkylamino, alkyl, halogen or oxo), alkylthio, aminomethylamino, iminoethylamino, Silyl (which may have alkyl or aryl as substituent), alkyloxycarbonyl, arylcarbonyl (which may have acyloxy, halogen, amino, hydroxy, alkoxy or sulfamoyl as substituent), phthalimido, succinimi Also, dialkylamino, dialkylaminocarbonyl, arylcarbonylamino, carbamoyl, carbamoyloxy, N-sulfocarbamoyloxy, alkylcarbonylcarbamoyloxy (which may have a halogen as a substituent) ), Alkoxyamino and general formula

Wherein R ⁴⁰ and R ⁴¹ are the same or different and each represents a hydroxyl or amino group.

The alkylene represented by R ¹² in the general formula above preferably has 1 to 6 carbon atoms, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene.

Substituents which the alkylene group may have are, for example, halogen, amino, hydroxy, alkoxy, carboxy, carbamoyl, cyano and nitro.

In the above general formula, the cycloalkyl formed at or by R ³ , R ¹¹ , R ¹⁹ , R ²⁰ , R ²⁷ , R ²⁸ , R ³⁷ , R ³⁸ and R ³⁹ preferably has 3 to 8 carbon atoms, for example, Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Substituents which the cycloalkyl group may have are, for example, halogen, nitro, amino, hydroxy, sulfo, cyano, carboxy, oxo and thioxo.

Cycloalkylene represented by R ¹² is, for example, a bond added to the cycloalkyl.

Said general ^{formula, R 3, R 6, R} 10, R 13 ~ 17, an aryl represented by R ^{19 ~ 32,} and R ^{34 ~ 39,} aryl from carbonyl, aryloxycarbonyl or aryloxy radicals, for example, Phenyl, naphthyl, biphenyl, anthryl and indenyl.

Substituents which the aryl group may have include, for example, halogen, nitro, cyano, amino (which may have alkyl, alkenyl, cycloalkyl or aryl as substituents), sulfo, mercapto, hydroxy, carboxy, acyl, sulf Foxy, sulfamoyl, carbamoyl, alkyl (which may have amino, halogen, hydroxy, cyano or carboxy as substituents), alkoxy, aralkyloxy, alkylsulfonamido, methylenedioxy, alkylsulfonyl and alkyl Sulfonyl amino. They may also form fused rings (eg tetrahydronaphthyl, indanyl, acenaphthyl, etc.) with cycloalkyl.

In the above general formula, R ³ , R ⁷ , R ¹⁷ ′ and alkoxy represented by R ^{34 to 36} preferably have 1 to 6 carbon atoms, for example methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentyloxy and n-hexyloxy.

Substituents which the alkoxy group may have include, for example, halogen, nitro, amino, hydroxy, sulfo, cyano, carboxy, aryl (substituents may have nitro, amino, hydroxy, alkyl or alkoxy) and silyl (substituents). May be alkyl, aryl or aralkyl).

In the above general formula, alkenyl represented by R ³ , R ¹¹ 1, R ^21-26 and R ^37-39 preferably has 1 to 6 carbon atoms, for example, methylene, vinyl, allyl, isopro Phenyl, 1-propenyl, 2-butenyl, 3-methyl-3-butphenyl, 1,3-butadienyl, 1,3-pentadienyl, 4-pentaenyl, 1,3-hexadienyl , Ethylidene, propylidene, isopropylidene and butylidene.

Substituents which the alkylene group may have are, for example, halogen, nitro, amino (which may have acyl as a substituent), sulfo, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, aryl and acyl.

In the general formula, alkenylene represented by R ¹² and R ¹⁷ preferably has 2 to 6 carbon atoms, and examples thereof include vinylene, 1-propenylene, 2-butenylene, 2-pentenylene, and 1,3- Hexadienylene.

Substituents which the alkenylene group may have are, for example, halogen, cyano and carbamoyl.

In the general formula, cycloalkenyl represented by R ⁶ and R ¹⁵ preferably has 3 to 8 carbon atoms, for example, 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl and 1,4-cyclohexadienyl. Substituents which the cycloalkenyl group may have are, for example, halogen, nitro, amino, sulfo, cyano, hydroxy, carboxy, carbamoyl and sulfamoyl.

Said general ^{formula, R 3, R 6, R} 7, R 10, R 14, R 15, R 17, heterocycle, heterocycle formed by those represented by R ^{19 ~ 28,} and R ^{34 ~ 39,} for example 5- to 7-membered heterocyclic groups containing sulfur, nitrogen or oxygen atoms, 5- to 6-membered heterocyclic groups containing 2 to 4 nitrogen atoms, 1 to 2-nitrogen atoms and sulfur or oxygen atoms It is a 5-membered to 6-membered heterocyclic group containing a heterocyclic group, these heterocyclic groups can be fused to a 6-membered cyclic group containing 2 or less nitrogen atoms, a benzene ring or a 5-membered cyclic group containing a sulfur atom .

Specific examples of the heterocycle include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyridinyl, pyridazinyl, piperazinyl, piperidyl, pyrazolyl, pyranyl , Thiopyranyl, pyrimidyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrido [2,3-d] pyrimidyl, benzopyranyl, 1,8-naphthyridyl, 1,5-naphthyridyl, 1,6-naphthyridyl, 1,7-naphthyridyl, 2,7-naphthyridyl, 2,6-naphthyridyl, quinolyl, thieno [2,3- d] pyridyl, tetrazolyl, thiadiazolyl, oxa-diazolyl, triazinyl, triazolyl, thienyl, pyrrolyl, furyl, pyrrolidinyl, imidazolyldinyl, dithiethane, tetrahydropyranyl, tetrahydro Furanyl, benzothienyl, pyranyl, hexahydro-1H-azinyl, indolyl, isoindoleyl and chromamanyl.

Substituents which the heterocyclic group may have include, for example, amino (which may have acyl, halogen-substituted alkylacyl, phenyl or alkyl as the substituent), halogen, nitro, sulfone, cyano, hydroxy, carboxy, oxo, thi Oxo, C _1-10 -alkyl [with substituent aryl, halogen, amino, hydroxy, carboxy, alkoxy, alkylsulfonyl, dialkylamino or phosphono (which may have alkyl as substituent)], cyclo Alkyl, alkoxy (which may have halogen or hydroxy as substituent), acyl having 1 to 4 carbon atoms, aryl (which may have halogen, nitro, alkyl, alkoxy, amino, sulfo, hydroxy or cyano as substituent) , oxo, thioxo, amino acid residue-thio (examples of the amino acid residues are similar moieties as described below), C ¹ _{~ 10-alkyl-thio} [as a substituent aryl, halogen, amino, hydroxy, carboxy, alkoxy, alkylsulfonyl Ponyl, Dialkyla Mino, or phosphono (which may have alkyl as substituent)], heterocycle (alkyl, alkoxy, halogen, nitro, cyano, carboxy, formyl or alkylsulfonyl as substituent) and general formula R ⁴² -CH = N-, wherein R ⁴² is a heterocycle (substituent may have alkyl, alkoxy, halogen, nitro, cyano, hydroxy, carboxy, formyl or alkylsulfonyl).

In the above general formula, the cyclic group represented by R ⁴ formed together with R ³ is for example a cyclic group having phthaloyl, succinyl, maleoyl, citraconoyl, glutaryl and adipoyl and 2,2-dimethyl -5-oxo-4-phenylamidazolidine.

Substituents which the cyclic group may have are, for example, halogen, nitro, amino, hydroxy, sulfo, cyno and carboxy.

In the above general formula, acyloxy acyl represented by R ¹⁶ preferably has 1 to 4 carbon atoms, for example, formyl, acetyl, propionyl, butyryl and isobutyryl, and examples thereof Is for example alkyl (which may have amino, halogen, cyano, alkoxy, carboxy or hydroxy as substituent).

In the above general formula, the amino acid residue represented by R ⁵ is, for example, glycyl, alanyl, valelyl, leucil, isoleucyl, seryl, threonyl, cysteinyl, cytyl, methionyl, α- or β-aspar Gil, α- or γ-glutamyl, lysyl, arginyl, phenylalanyl, phenylgreeyl, tyrosyl, histidyl, tryptophanyl and prolyl.

Substituents which the amino acid residue may have are, for example, halogen, hydroxy, sulfo, carboxy, cyano, alkylamino, aralkyloxycarbonyl, aralkyloxy and guanidino.

In the above general formula, as the protecting group of the amino group represented by R ⁵ , for example, those used for this purpose in the field of β-lactam and peptide synthesis are suitably used. Examples thereof include, for example, aromatic acyl groups such as phthaloyl, 4-nitrobenzoyl, 4-t-butylbenzoyl, 4-t-butylbenzenesulfonyl, benzenesulfonyl and toluenesulfonyl; Aliphatic acyl groups such as formyl, acetyl, propionyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methanesulfonyl, ethanesulfonyl, trifluoroacetyl, malonyl and succinyl; Methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, 2-cyanoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, Such as 4-nitrobenzoyloxycarbonyl, 4-methoxybenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, isobornyloxycarbonyl and phenyloxycarbonyl Esterified carboxyl group; Methylene groups such as (hexahydro-1H-azin-1-yl) methylene; Sulfonyl groups such as 2-amino-2-carboxyethylsulfonyl; And amino protecting groups other than acyl groups such as trityl, 2-nitrophenylthio, benzylidene, 4-nitrobenzylidene, di- or tri-alkylsilyl, benzyl and nitrobenzyl. The choice of this protecting group is not limited to the present invention, but monochloroacetyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl are preferred.

In the above general formula, the substituent of the carboxyl group which may have a substituent represented by R ¹³ may be, for example, alkyl (which may have halogen, cyano or hydroxy as substituent), aryl (alkyl, alkoxy, halogen, hydroxy as substituent) , Acyloxy, sulfo, cyano or sulfamoyl), silyl (may have alkyl, aryl or aralkyl as substituent), heterocycle (amino as alkyl, alkylamino, sulfamoyl, carbamoyl, Halogen, cyano or nitro).

In the above general formula, the ester group in the ester of the carboxyl represented by R ¹³ preferably has 1 to 6 carbon atoms, and examples thereof include methyl ester, ethyl ester, propyl ester, n-butyl ester, isobutyl ester and t-butyl ester.

In the above general formula, the substituent of amino which may have a substituent represented by R ⁷ , R ¹⁷ , R ²⁷ , R ²⁸ and R ³⁶ is for example amidine, iminomethyl, imino- (aryl-substituted) -methyl , Guanidylcarbonyl, heterocycle (which may have substituents similar to those described above as substituents for the heterocycle), imino- (heterocycle-substituted) -methyl, arylcarbonyl, hydroxyalkyl and alkyl.

In the above general formula, the substituents of the silyl group which may have substituents represented by R ³³ and R ³⁷ are, for example, alkyl, aryl and aralkyl.

R ³⁰ , R ³¹ and R ³² together with R ³³ may form a cyclic group, for example, 2,5-disylylazacyclopentyl, and may have substituents such as alkyl and aryl. have.

Halogens as the above substituents are, for example, chlorine, bromine, fluorine and iodine.

Alkyl in the description of the substituents preferably has 1 to 10, more preferably 1 to 6, most preferably 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, i-propyl , n-butyl, i-butyl, t-butyl, s-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, heptyl, octyl, nonyl and decyl.

Cycloalkyls preferably have from 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Preferably, alkoxy has 1 to 4 carbon atoms, for example methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy and t-butoxy .

Aryl is for example phenyl and naphthyl.

Heterocycles are similar to those described for R ³ .

Acyl is preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovalenyl, pevalo One and hexanoyl.

Aralkyl is for example benzyl, phenethyl and phenyl-propyl.

Alkenyl is similar to, for example, alkenyl as described for R ³ .

The amino acid residue is similar to the amino acid residue described for example in R ⁵ .

It is preferable that 1-3 of said each substituent exists.

In particular, general formula

기(식중, Q³는 H 또는 알킬^*이다)이다]의 기는 R¹으로 표시되는 아실아미노의 아실기로 바람직하다. 상기의 알킬, 알킬^*및 알케닐은 상기에서 설명한 바와 같다.[Wherein Q ¹ is an amino or protected amino group, Q ² is an H, alkyl, alkenyl, —CH ₂ COOQ ³ group or

The group of the group wherein Q ³ is H or alkyl ^* is preferably an acyl group of acylamino represented by R ¹ . Alkyl, alkyl ^* and alkenyl are as described above.

로 표시되는 아실아미노기의 특정예로는 예를들면 3-(2,6-디클로로페닐)-5-메틸이속사졸-4-일-카르보닐아미노, 4-에틸-2,3-디옥소-1-피페라지노-카르보닐아미노, 3-페닐-5-메틸이속사졸-4-일-카르보닐아미노, 3-(2-클로로페닐)-5-메틸이속사졸-4-일-카르보닐아미노, 3-(2-클로로-6-플루오로페닐)-5-메틸이속사졸-4-일-카르보닐아미노, 니코티닐아미노, 벤조일아미노, 4-브로모벤조일아미노, 2,6-디메톡시벤조일아미노, 포르밀아미노, 아세틸아미노, 프로피오닐아미노, 부티릴아미노, 이소부티릴아미노, 피발로일아미노, 메톡시카르보닐아미노, 벤질옥시카르보닐아미노, 1-아미노-시클로헥실카르보닐아미노, 2-아미노-시클로헥실카르보닐아미노, 3-에톡시나프토일아미노, 2-(2-아미노-4-티아졸릴)-2-에틸리덴아세틸아미노, 2-(2-아미노-4-티아졸릴)-2-클로로메틸렌아세틸아미노, 프탈아미노, 숙신이미도, 1,2-시클로헥산디카르복시미드, 2-(트리메틸실릴)에톡시카르보닐아미노, 2,2-디메틸-5-옥소-4-페닐이미다졸리딘 및 4-(카르바모일카르복시메틸렌)-1,3-디티에탄-2-일-카르보닐아미노가 있다.The protecting group of the protected amino group is as described above. In the acyl group, a general formula

Specific examples of the acylamino group represented by, for example, 3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl-carbonylamino, 4-ethyl-2,3-dioxo- 1-piperazino-carbonylamino, 3-phenyl-5-methylisoxazol-4-yl-carbonylamino, 3- (2-chlorophenyl) -5-methylisoxazol-4-yl-car Bonylamino, 3- (2-chloro-6-fluorophenyl) -5-methylisoxazol-4-yl-carbonylamino, nicotinylamino, benzoylamino, 4-bromobenzoylamino, 2,6- Dimethoxybenzoylamino, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pivaloylamino, methoxycarbonylamino, benzyloxycarbonylamino, 1-amino-cyclohexylcarbonyl Amino, 2-amino-cyclohexylcarbonylamino, 3-ethoxynaphthoylamino, 2- (2-amino-4-thiazolyl) -2-ethylideneacetylamino, 2- (2-amino-4-thia Zolyl) -2-chloromethyleneacetyl Mino, phthalamino, succinimido, 1,2-cyclohexanedicarboximide, 2- (trimethylsilyl) ethoxycarbonylamino, 2,2-dimethyl-5-oxo-4-phenylimidazolidine and 4 -(Carbamoylcarboxymethylene) -1,3-dithiethan-2-yl-carbonylamino.

로 표시되는 아실아미노기의 특정예로는 예를들면 D-알라닐아미노, 벤질-N-카르보벤족시-γ-D-글루타밀-D-알리닐아미노, D-페닐글리실-D-알라닐아미노, N-카르보벤족시-D-알라닐아미노, N-카르보벤족시-D-페닐글리실아미노, D-알라닐-D-페닐글리실아미노, γ-D-글루타밀-D-알라닐아미노, 2-(4-에틸-2,3-디옥소-1-피페라지노카르복사미도)-2-페닐아세틸아미노, 2-(4-시클로헥실-2,3-디옥소-1-피페라지노카르복사미도)-2-페닐아세틸아미노, 2-(4-에틸-2,3-디옥소-1-피페라지노카르복사미도)-2-(4-술폭시페닐)아세틸아미노, N-(4-에틸-2,3-디옥소-1-피페라지노카르보닐)-D-알라닐아미노, N-(4-에틸-2,3-디옥소-1-피페라지노카르보닐)-D-페닐글리실아미노, 2-(2-아미노-4-티아졸릴)-2-(4-에틸-2,3-디옥소-1-피페라지노카르복사미도)아세틸아미노, 2-(4-히드록시-6-메틸니코틴아미도)-2-페닐아세틸아미노, 2-(4-히드록시-6-메틸니코틴아미도)-2-(4-히드록시페닐)아세틸아미노, 2-{5,8-디히드로-2-(4-포르밀-1-피페라지닐)-5-옥소피리도[2,3-d]피리미딘-6-카르복사미도}-2-페닐아세틸아미노, 2-(3,5-디옥소-1,2,4-트리아진-6-카르복사미도)-2-(4-히드록시페닐)아세틸아미노, 2-(3-푸르푸릴리덴아미노-2-옥소이미다졸리딘-1-카르복사미도)-2-페닐아세틸아미노, 2-(쿠마린-3-카르복사미도)-2-페닐아세틸아미노, 2-(4-히드록시-7-메틸-1,8-나프틸리딘-3-카르복사미도)-2-페닐아세틸아미노, 2-(4-히드록시-7-트리플루오로메틸퀴놀린-3-카르복사미도)-2-페닐아세틸아미노, N-[2-(2-아미노-4-티아졸릴)아세틸]-D-페닐글리실아미노,2-(6-브로모-1-에틸-1,4-디히드로-4-옥소티에노[2,3-b]피리딘-3-카르복사미도)-2-페닐아세틸아미노, 2-(4-에틸-2,3-디옥소-1-피페라지노카르복사미도)-2-티에닐아세틸아미노, 2-(4-n-펜틸-2,3-디옥소-1-피페라지노카르복사미도)-2-티에닐아세틸아미노, 2-(4-n-옥틸-2,3-디옥소-1-피페라지노카르복사미도)-2-티에닐아세틸아미노, 2-(4-시클로헥실-2,3-디옥소-1-피페라지노카르복사미도)-2-티에닐아세틸아미노, 2-[4-(2-페닐에틸)-2,3-디옥소-1-피페라지노카르복사미도]-2-티에닐아세틸아미노, 2-(3-메틸술포닐-2-옥소이미다졸리딘-1-카르복사미도)-2-페닐아세틸아미노, 2-(3-푸르푸릴리덴아미노-2-옥소이미다졸리딘-1-카르복사미도)-2-(4-히드록시페닐)아세틸아미노, 2-(4-에틸-2,3-디옥소-1-피페라지노카르복사미도)-2-(4-벤질옥시페닐)아세틸아미노, 2-(4-에틸-2,3-디옥소-1-피페라지노카르복사미도)-2-(4-메톡시페닐)아세틸아미노, 2-(8-히드록시-1,5-나프틸리덴-7-카르복사미도)-2-페닐아세틸아미노, 2-(2-아미노-4-티아졸릴)-2-포름아미도아세틸아미노, 2-(2-아미노-4-티아졸릴)-2-아세토아미도아세틸아미노, 2-페닐-2-우레이도아세틸아미노, 2-페닐-2-술포우레이도아미노, 2-티에닐-2-우레이도아세틸아미노, 2-아미노-3-술파모일프로피오닐아미노, 2-아미노-2-(1H-인돌-3-일)아세틸아미노, 2-아미노-2-(3-벤조[b]티에닐)아세틸아미노, 2-아미노-2-(2-나프틸)아세틸아미노, D-페닐글리실, D-2-아미노-(4-히드록시페닐)아세틸아미노, D-2-아미노-2-(1,4-시클로헥사디에틸)아세틸아미노, D-2-아미노-2-(1-시클로헥세닐)아세틸아미노, D-2-아미노-2-(3-클로로-4-히드록시페닐)아세틸아미노, 2-히드록시메틸아미노-2-페닐아세틸아미노, 2-(1-시클로헥세닐)-2-(4-에틸-2,3-디옥소-1-피페라지노카르복사미도)아세틸아미노,N-[2-(4-에틸-2,3-디옥소-1-피페라지노카르보닐)]-D-트레오닐아미노, 2-구아닐카르복사미도-2-페닐아세틸아미노, 2-(4-에틸-2,3-디옥소-1-피페라지노카르복사미도-2-(3,4-디히드록시페닐)아세틸아미노, 2-(4-카르복시-5-이미다졸릴카르복사미도)-2-페닐아세틸아미노 및 2-아미노-2-(3-메틸술폰아미도페닐)아세틸아미노가 있다.General formula

Specific examples of the acylamino group represented by: D-alanylamino, benzyl-N-carbobenzoxoxy-γ-D-glutamyl-D-alanylamino, D-phenylglysil-D-alla Nylamino, N-carbobenzoxoxy-D-alanylamino, N-carbobenzoxoxy-D-phenylglycosylamino, D-alanyl-D-phenylglycosylamino, γ-D-glutamyl-D -Alanylamino, 2- (4-ethyl-2,3-dioxo-1-piperazinocarboxamido) -2-phenylacetylamino, 2- (4-cyclohexyl-2,3-dioxo- 1-piperazinocarboxamido) -2-phenylacetylamino, 2- (4-ethyl-2,3-dioxo-1-piperazinocarboxamido) -2- (4-sulfoxyphenyl) acetyl Amino, N- (4-ethyl-2,3-dioxo-1-piperazinocarbonyl) -D-alanylamino, N- (4-ethyl-2,3-dioxo-1-piperazinoca Levonyl) -D-phenylglycosylamino, 2- (2-amino-4-thiazolyl) -2- (4-ethyl-2,3-dioxo-1-piperazinocarboxamido) acetylamino, 2- (4-hydroxy-6-methylnicotinamido) -2-phenyla Tylamino, 2- (4-hydroxy-6-methylnicotinamido) -2- (4-hydroxyphenyl) acetylamino, 2- {5,8-dihydro-2- (4-formyl-1 -Piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxamido} -2-phenylacetylamino, 2- (3,5-dioxo-1,2,4- Triazine-6-carboxamido) -2- (4-hydroxyphenyl) acetylamino, 2- (3-furfurylideneamino-2-oxoimidazolidine-1-carboxamido) -2- Phenylacetylamino, 2- (coumarin-3-carboxamido) -2-phenylacetylamino, 2- (4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxamido) -2 -Phenylacetylamino, 2- (4-hydroxy-7-trifluoromethylquinoline-3-carboxamido) -2-phenylacetylamino, N- [2- (2-amino-4-thiazolyl) acetyl ] -D-phenylglycosylamino, 2- (6-bromo-1-ethyl-1,4-dihydro-4-oxothieno [2,3-b] pyridine-3-carboxamido) -2 -Phenylacetylamino, 2- (4-ethyl-2,3-dioxo-1-piperazinocarboxamido) -2-thienyl ace Amino, 2- (4-n-pentyl-2,3-dioxo-1-piperazinocarboxamido) -2-thienylacetylamino, 2- (4-n-octyl-2,3-dioxo -1-piperazinocarboxamido) -2-thienylacetylamino, 2- (4-cyclohexyl-2,3-dioxo-1-piperazinocarboxamido) -2-thienylacetylamino, 2- [4- (2-phenylethyl) -2,3-dioxo-1-piperazinocarboxamido] -2-thienylacetylamino, 2- (3-methylsulfonyl-2-oxoimida Zolidine-1-carboxamido) -2-phenylacetylamino, 2- (3-furfurylideneamino-2-oxoimidazolidine-1-carboxamido) -2- (4-hydroxyphenyl ) Acetylamino, 2- (4-ethyl-2,3-dioxo-1-piperazinocarboxamido) -2- (4-benzyloxyphenyl) acetylamino, 2- (4-ethyl-2,3 -Dioxo-1-piperazinocarboxamido) -2- (4-methoxyphenyl) acetylamino, 2- (8-hydroxy-1,5-naphthylidene-7-carboxamido) -2 -Phenylacetylamino, 2- (2-amino-4-thiazolyl) -2-formamidoacetylamimi , 2- (2-amino-4-thiazolyl) -2-acetoamidoacetylamino, 2-phenyl-2-ureidoacetylamino, 2-phenyl-2-sulphoureidoamino, 2-thienyl- 2-ureidoacetylamino, 2-amino-3-sulfamoylpropionylamino, 2-amino-2- (1H-indol-3-yl) acetylamino, 2-amino-2- (3-benzo [b] Thienyl) acetylamino, 2-amino-2- (2-naphthyl) acetylamino, D-phenylglycyl, D-2-amino- (4-hydroxyphenyl) acetylamino, D-2-amino-2 -(1,4-cyclohexadiethyl) acetylamino, D-2-amino-2- (1-cyclohexenyl) acetylamino, D-2-amino-2- (3-chloro-4-hydroxyphenyl ) Acetylamino, 2-hydroxymethylamino-2-phenylacetylamino, 2- (1-cyclohexenyl) -2- (4-ethyl-2,3-dioxo-1-piperazinocarboxamido) Acetylamino, N- [2- (4-ethyl-2,3-dioxo-1-piperazinocarbonyl)]-D-threonylamino, 2-guanylcarboxamido-2-phenylacetylamino, 2- (4-ethyl-2, 3-dioxo-1-piperazinocarboxamido-2- (3,4-dihydroxyphenyl) acetylamino, 2- (4-carboxy-5-imidazolylcarboxamido) -2-phenylacetyl Amino and 2-amino-2- (3-methylsulfonamidophenyl) acetylamino.

Specific examples of the acylamino group represented by general formula R ⁸ -R ⁹ -CO-NH- include, for example, N- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl] -D -Alanylamino, N- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl] -D-phenylglycosylamino, 2- (2-amino-4-thiazolyl) -2 -[2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] acetylamino, 2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetyl Amino, 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetylamino, 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetylamino, 2- (2-amino -4-thiazolyl) -2-isopropoxyiminoacetylamino, 2- (2-amino-4-thiazolyl) -2-butoxyiminoacetylamino, 2- (2-amino-4-thiazolyl)- 2-cyclopropylmethyloxyaminoacetylamino, 2- (2-amino-4-thiazolyl) -2-benzyloxyiminoacetylamino, 2- (2-amino-4-thiazolyl) -2-allyloxyimino Acetylamino, 2- (2-amino-4-thiazolyl) -2-[(1-methyl-1-carboxyethyl) oxyimino] acetylamino, 2- (2-amino-4-thiazolyl) -2- [(1-methyl-1-methoxycarbonylethyl) oxyimino] acetylamino, 2- (2-amino-4-thiazolyl) -2-carboxymethyloxyiminoacetylamino, 2- (2-amino-4 -Thiazolyl) -2-carboxyvinyloxyiminoacetylamino, 2- (2-amino-4-thiazolyl) -2-carboxyethyloxyiminoacetylamino, 2- (2-amino-4-thiazolyl) -2 -Methoxycarbonylethyloxyiminoacetylamino, 2- (2-amino-5-chloro-4-thiazolyl) -2-methoxyiminoacetylamino, 2- (2-amino-5-bromo-4- Thiazolyl) -2-methoxyiminoacetylamino, 2- (2-amino-4-thiazolyl) -2-oxyiminoacetylamino, 2-thienyl-2-methoxyiminoacetylamino, 2-furfuryl- 2-methoxyiminoacetylamino, 2- (1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetylamino, 2- (1 , 2,4-thiadiazol-5-yl) -2-methoxyiminoacetylamino, 2- (1,3,4-thiadiazolyl) -2-methoxyiminoacetylamino, 2- (4-hydrate Oxyphenyl) -2-methoxyiminoacetylamino, 2-phenyl-2-methoxyiminoacetylamino, 2-phenyl-2-oxyiminoacetylamino, 2- [4- (γ-D-glutamyloxy) phenyl ] -2-oxyiminoacetylamino, 2- [4- (3-amino-3-carboxypropoxy) phenyl] -2-oxyiminoacetylamino, 2-thienyl-2-oxyiminoacetylamino, 2- ( 5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetylamino, 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 -Ethoxyiminoacetylamino, 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-? 2: oxymethyloxyiminoacetylamino, 2- (5-amino-1, 2,4-thiadiazol-3-yl) -2-[(1-methyl-1-carboxyethyl) oxyimino] acetylamino, 2- (2-amino-4-thiazolyl) -2- (2- Amino-2-carboxy) ethyloxyiminoacetylamino, 2- (2-a Mino-4-thiazolyl) -2- (dimethylamidomethyloxyimino) acetylamino, 2- (2-amino-4-thiazolyl) -2- (3,4-diacetoxybenzoyloxyimino) acetylamino , 2- (2-amino-4-thiazolyl) -2- (1-carboxycyclopropyloxyimino) acetylamino, 2- (2-amino-4-thiazolyl) -2- (1-carboxycyclobutyloxy Mino) acetylamino, 2- (2-amino-4-thiazolyl) -2- (2-imidazolylmethyloxyimino) acetylamino, 2- (2-amino-4-thiazolyl) -2- (2 -Methyl-4-nitro-1-imidazolylethyloxyimino) acetylamino, 2- (2-amino-4-thiazolyl) -2- (3-pyrazolylmethyloxyimino) acetylamino, 2- (2 -Amino-4-thiazolyl) -2- (1H-tetrazol-5-yl-methyloxyimino) acetylamino, 2- (2-amino-4-thiazolyl) -2- (2-oxo-3- Pyrrolidinyloxyimino) acetylamino, 2- [2- (2-amino-2-carboxyethylthio)]-4-thiazolyl-2-methoxyiminoacetylamino and 2- (2-thioxo-4- tea Jolly pyridinyl) a mino-2-methoxy-acetylamino toksiyi.

으로 표시되는 아실아미노기의 특정예로는 예를들면 2-페닐-2-술포아세틸아미노, 2-히드록시-2-페닐아세틸아미노, 2-페닐-2-술파모일아세틸아미노, 2-카르복시-2-페닐아세틸아미노, 2-(4-히드록시페닐)-2-카르복시아세틸아미노, 2-페녹시카르보닐-2-페닐아세틸아미노, 2-페닐-2-톨릴옥시카르보닐아세틸아미노, 2-(5-인다닐옥시카르보닐)-2-페닐아세틸아미노, 2-포르밀옥시-2-페닐아세틸아미노, 2-알라닐옥시-2-페닐아세틸아미노, 2-카르복시-2-티에닐아세틸아미노, 2-(2-메틸페녹시카르보닐)-2-티에닐아세틸아미노, 2-(2-아미노-4-티아졸릴)-2-히드록시아세틸아미노 및 2-[4-(2-아미노-2-카르복시에톡시카르복사이미도)페닐]-2-히드록시아세틸아미노가 있다.General formula

As a specific example of the acylamino group represented by, for example, 2-phenyl-2-sulfoacetylamino, 2-hydroxy-2-phenylacetylamino, 2-phenyl-2-sulfamoylacetylamino, 2-carboxy-2 -Phenylacetylamino, 2- (4-hydroxyphenyl) -2-carboxyacetylamino, 2-phenoxycarbonyl-2-phenylacetylamino, 2-phenyl-2-tolyloxycarbonylacetylamino, 2- ( 5-indanyloxycarbonyl) -2-phenylacetylamino, 2-formyloxy-2-phenylacetylamino, 2-alanyloxy-2-phenylacetylamino, 2-carboxy-2-thienylacetylamino, 2- (2-methylphenoxycarbonyl) -2-thienylacetylamino, 2- (2-amino-4-thiazolyl) -2-hydroxyacetylamino and 2- [4- (2-amino-2 -Carboxyethoxycarboxamido) phenyl] -2-hydroxyacetylamino.

Specific examples of the acylamino group represented by the general formula R ¹⁷ -R ¹⁸ -CH ₂ -CO-NH- include, for example, cyano acetylamino, phenyl acetylamino, phenoxyacetylamino, trifluoromethylthioacetylamino, Cyanomethylthio, acetylamino, difluoromethylthioacetylamino, 1H-tetrazolyl-1-acetylamino, thienylacetylamino, 2- (2-amino-4-thiazolyl) acetylamino, 4-pyridyl Thioacetylamino, 2-thienylthioacetylamino, 3,5-dichloro-1,4-dihydro-4-oxopyridine-1-acetylamino, β-carboxyvinylthioacetylamino, 2- (2-aminomethylphenyl ) Acetylamino, 2-chloroacetylamino, 3-aminopropionylamino, (2-amino-2-carboxy) ethyl thioacetylamino, 4-amino-3-hydroxybutyrylamino, 2-carboxyethylthioacetylamino , 2-benzyloxycarbonyl aminoacetylamino, β-carbamoyl-β-fluor Vinylthio acetylamino, 2- (1-isopropylamino-1-isopropyliminomethylthio) acetylamino, 2- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl-thio] Acetylamino, 2- (1-methyl-1,3,5-triazol-2-yl) acetylamino and 2- (4-cyano-3-hydroxy-5-isothiazolylthio) acetylamino .

로 표시되는 기의 특정예로는 예를들면 카르바모일아미노, 메틸아미노카르보닐 아미노, 에틸아미노카르보닐아미노, t-부틸아미노카르보닐아미노, 이소부틸아미노카르보닐아미노, 디메틸아미노카르보닐아미노, 2-메틸페닐아미노카르보닐아미노, 페닐아미노카르보닐아미노, 3-클로로페닐아미노카르보닐아미노, 4-니트로페닐아미노카르보닐아미노, 4-브로모페닐아미노카르보닐아미노, 티오카르바모일아미노, 메틸아미노티오카르보닐아미노, 에틸아미노티오카르보닐아미노, 페닐아미노티오카르보닐아미노, 디메틸아미노카르보닐아미노 및 3-플루오로페닐아미노카르보닐아미노가 있다.General formula

Specific examples of the group represented by, for example, carbamoylamino, methylaminocarbonyl amino, ethylaminocarbonylamino, t-butylaminocarbonylamino, isobutylaminocarbonylamino, dimethylaminocarbonylamino, 2-methylphenylaminocarbonylamino, phenylaminocarbonylamino, 3-chlorophenylaminocarbonylamino, 4-nitrophenylaminocarbonylamino, 4-bromophenylaminocarbonylamino, thiocarbamoylamino, methylamino Thiocarbonylamino, ethylaminothiocarbonylamino, phenylaminothiocarbonylamino, dimethylaminocarbonylamino and 3-fluorophenylaminocarbonylamino.

Specific examples of the group represented by the general formula R ²¹ -NH- include, for example, methylamino, ethylamino, allylamino, cyclohexylamino, cyclohexylmethylamino, benzylamino, 4-chlorobenzyl amino, phenylamino, 2 Iminazolylamino, 1-methyl-2-imidazolylamino, 2- (2-amino-4-thiazolyl) -2-methoxyaminothioacetylamino, 1-benzyl-4-pyridiniumamino and 2 Acetyl-1-methylvinylamino.

로 표시되는 알킬아미노기의 특정예로는 예를들면 디메틸아미노, 디에틸아미노, 디프로필아미노, 디벤질아미노, 디시클로헥실아미노, N-벤질-N-메틸아미노, 디알릴아미노, N-페닐-N-메틸아미노는, 피롤리디닐, 피페리디닐, 피페라지닐 및 모르폴리닐이 있다.General formula

Specific examples of the alkylamino group represented by are, for example, dimethylamino, diethylamino, dipropylamino, dibenzylamino, dicyclohexylamino, N-benzyl-N-methylamino, diallylamino, N-phenyl- N-methylamino includes pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

로 표시되는 알킬아미노기의 특정예로는 예를들면 트리메틸암모늄, 트리에틸암모늄, 트리벤질암모늄, 벤질디메틸암모늄, 메틸피롤리디늄 및 메틸피페리디늄이 있다.General formula

Specific examples of the alkylamino group represented by include trimethylammonium, triethylammonium, tribenzylammonium, benzyldimethylammonium, methylpyrrolidinium and methylpiperidinium.

으로 표시되는 알케닐아미노기의 특정예로는 예를들면 디메틸아미노 메틸렌아미노, 1-디메틸아미노 에틸리덴아미노, 헥사히드로-1H-아제핀-1-일-메틸렌아미노, 1-(N-벤질-N-메틸아미노)에틸리덴아미노, 4-디메틸아미노벤질리덴아미노, (P-니트로)벤질리덴아미노 및 벤질리덴아미노가 있다.General formula

Specific examples of the alkenylamino group represented by, for example, dimethylamino methyleneamino, 1-dimethylamino ethylideneamino, hexahydro-1H-azin-1-yl-methyleneamino, 1- (N-benzyl-N -Methylamino) ethylideneamino, 4-dimethylaminobenzylideneamino, (P-nitro) benzylideneamino and benzylideneamino.

Specific examples of the thioamino group represented by general formula R ²⁹ -SO _n -NH- include, for example, benzenesulfonylamino, 4-methylbenzenesulfonylamino, 4-methoxybenzenesulfonylamino, 2,4,6 -Trimethylbenzenesulfonylamino, benzylsulfonylamino, 4-methylbenzylsulfonylamino, trifluoromethylsulfonylamino, phenacylsulfonylamino, methylsulfonylamino, ethylsulfonylamino, 4-fluorobenzenesul Phenylamino, benzenesulfonylamino, 2-nitrobenzenesulfinylamino, 2,4-dimethylbenzenesulfinylamino, 4-chlorobenzenesulfinylamino, 4-methoxybenzenesulfinylamino, phenylthioamino, 2,4 Dinitrophenylthioamino, triphenylmethylthioamino and 2-nitro-4-methoxyphenylthio amino.

로 표시되는 실릴아미노기의 특정예로는 예를들면 트리메틸실릴아미노, 트리에틸실릴아미노, t-부틸디메틸실릴아미노, t-부틸디페닐실릴아미노, 이소프로필디메틸실릴아미노, 트리페닐실릴아미노, 트리이소프로필실릴아미노, 트리벤질실릴아미노, (트리페닐메틸)디메틸실릴아미노 및 2,2,5,5-테트라메틸-2,5-디실릴아자시클로펜탄이 있다.General formula

Specific examples of the silylamino group represented by are, for example, trimethylsilylamino, triethylsilylamino, t-butyldimethylsilylamino, t-butyldiphenylsilylamino, isopropyldimethylsilylamino, triphenylsilylamino and triiso Propylsilylamino, tribenzylsilylamino, (triphenylmethyl) dimethylsilylamino and 2,2,5,5-tetramethyl-2,5-dissilylazacyclopentane.

로 표시되는 기의 특정예로는 예를들면 디메틸포스포아미노, 디에틸포스포아미노, 디페닐포스포아미노, 디벤질포스포아미노 및 디-4-클로로페닐 포스포아미노가 있다.General formula

Specific examples of the group represented by include, for example, dimethylphosphoamino, diethylphosphoamino, diphenylphosphoamino, dibenzylphosphoamino and di-4-chlorophenyl phosphoamino.

Specific examples of the group represented by the general formula R ³⁶ -CO-CO-NH- include, for example, methoxalylamino, ethoxalylamino, phenoxalylamino, benzyloxalylamino, pyruboylamino, ethyl oxalylamino, Oxamoylamino, benzylaminooxalylamino, thienyloxalylamino, 2-amino-4-thiazolyl oxalylamino and ethylaminooxalylamino.

Specific examples of the group represented by the general formula -COOR ³⁷ include, for example, methyl ester, ethyl ester, n-propyl ester, isopropyl ester, t-butyl ester, t-amyl ester, benzyl ester, 4-bromobenzyl Ester, 4-nitrobenzyl ester, 2-nitrobenzyl ester, 3,5-dinitrobenzyl ester, 4-methoxybenzyl ester, benzhydryl ester, penacyl ester, 4-bromophenacyl ester, phenyl ester, 4 -Nitrophenyl ester, methoxymethyl ester, methoxyethoxymethyl ester, ethoxymethyl ester, benzyloxymethyl ester, acetoxymethyl ester, pivaloyloxymethyl ester, 2-methylsulfonylethyl ester, 2-trimethyl Silylethyl ester, methylthiomethyl ester, trityl ester, 2,2,2-trichloroethyl ester, 2-iodoethyl ester, cyclohexyl ester, cyclopentyl ester, allyl S Tere, cinnamil ester, 4-picolinyl ester, 2-tetrahydropyranyl ester, 2-tetrahydrofuranyl ester, trimethylsilyl ester, t-butyldimethylsilyl ester, t-butyldiphenylsilyl ester, acetylmethyl Ester, 4-nitrobenzoylmethyl ester, 4-mesylbenzoylmethyl ester, phthalimidomethyl ester, propionyloxymethyl ester, 1,1-dimethylpropyl ester, 3-methyl-3-butenyl ester, succinimidomethyl ester, 3,5-di-t-butyl-4-hydroxybenzyl ester, mesylmethyl ester, benzenesulfonylmethyl ester, phenylthiomethyl ester, iminomethylaminoethyl ester, 1-iminoethylamino ethyl ester, dimethylamino Ethyl ester, pyridine-1-oxido-2-methyl ester, methylsulfinylmethyl ester, bis- (4-methoxyphenyl) methyl ester, 2-cyano-1,1-dimethylethyl ester, t-butyloxy Ka Bonyl methyl ester, benzoylaminomethyl ester, 1-acetoxyethyl ester, 1-isobutyryloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, phthalide ester, 4-t-butylbenzyl ester, 5-inda Nylesters, 5-methyl-2-oxo-1,3-dioxolen-4-yl-methylester and 5-t-butyl-2-oxo-1,3-dioxolen-4-ylmethylester.

로 표시되는 기의 특정예로는 예를들면 디메틸아미드, 디에틸아미드, 디프로필아미드, 디벤질아미드, 디시클로헥실아미드, N-벤질-N-메틸아미드, 디알릴아미드, N-페닐-N-메틸아미드, 피롤리딘아미드, 피페리딘아미드, 피페라진아미드, 모르폴린아미드, 카르복시메틸아미드 및 1-카르복시에틸아미드가 있다.General formula

Specific examples of the group represented by, for example, dimethylamide, diethylamide, dipropylamide, dibenzylamide, dicyclohexylamide, N-benzyl-N-methylamide, diallylamide, N-phenyl-N -Methylamide, pyrrolidineamide, piperidineamide, piperazineamide, morpholinamide, carboxymethylamide and 1-carboxyethylamide.

The reaction of reacting compound (III) with a compound capable of introducing the organic residues bound through nitrogen is, for example, acylated, ureated (thiouraidated), alkylated, alkenylated, thioated, silylated and It is a phosphorylation reaction.

[Acylated]

Acylation of amino groups can be carried out by reacting the starting material with an acylating agent containing an acylation in the R ¹ group, such as a reactive derivative of carboxylic acid in a solvent. Reactive derivatives of carboxylic acids include, for example, acid halides, acid anhydrides, amide compounds, active esters or active thioesters. Specific examples of such reactive derivatives are described below.

1) acid halides:

Acid halides used here are, for example, acid chlorides or acid bromide.

2) acid anhydride:

Acid anhydrides used herein include, for example, monoalkyl carboxylic acid mixed acid anhydrides, mixed acid anhydrides containing aliphatic carboxylic acids (e.g. acetic acid, pivalic acid, valeric acid, isovaleric acid, trichloroacetic acid, etc.), aromatic Mixed acid anhydrides or symmetric acid anhydrides containing carboxylic acids such as benzoic acid.

3) Amide Compounds:

Amide compounds used herein include compounds having an acyl group attached to a nitrogen group of the ring, such as pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole and benzotriazole.

4) Active Ester:

Active esters are, for example, methyl esters, ethyl esters, methoxymethyl esters, propargyl esters, 4-nitrophenyl esters, 2,4-dinitrophenyl esters, trichlorophenyl esters, pentachlorophenyl esters and mesylphenyl esters. Esters such as and esters formed with 1-hydroxy-1H-2-pyrrolidone, N-hydroxysuccinimide or N-hydroxyphthalimide and the like are used.

5) Active Thioesters:

As the active thioesters, thioesters formed with heterocyclics such as 2-pyridylthiol or 2-benzothiazolylthiol are used.

Various reactive derivatives mentioned above are selected according to the kind of carboxylic acid.

This reaction is in some cases carried out in the presence of a base, and suitable bases include, for example, aliphatic tertiary amines (eg trimethylamine, triethylamine, tripropylamine, tri-n-butylamine, etc.), N-methylpy Tertiary amines such as ferridine, N-methylpyrrolidine, cyclohexyldimethylamine and N-methylmorpholine, alkylamines such as di-n-butylamine, diisobutylamine and dicyclohexylamine, pyridine, ruti Aromatic amines such as dine and γ-collidine, hydroxides or carbonates of alkali metals such as lithium, sodium and potassium, or hydroxides or carbonates of alkaline earth metals such as calcium and magnesium, and the like.

In this reaction, the reactive derivative of carboxylic acid is used in about 1 mole ratio with respect to 1 mole of compound (III), but it can be used in excess if it does not adversely affect the reaction. When using a base, the amount of base is used in an amount of about 1 to 30 moles, preferably about 1 to 10 moles per 1 mole of compound (III), and the reactivity of the starting compound (III) and carboxylic acid used is It may vary depending on the type of derivative and other reaction conditions. This reaction is usually carried out in a solvent. Known solvents may be used alone or in mixtures, for example, ethers such as dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether, propylene oxide and butylene oxide, ethyl acetate and ethyl Esters such as formate, chloroform, dichloromethane, halogenated hydrocarbons such as 1,2-dichloroethane and 1,1,1-trichloroethane, hydrocarbons such as benzene, toluene and n-hexane, N, N-dimethylformamide And amides such as N, N-dimethylacetamide or nitriles such as acetonitrile. Among the bases mentioned above, liquid bases can be used for dual purposes of bases and solvents.

The reaction temperature is not particularly limited as long as the reaction proceeds, but is usually performed at about -50 ° C to 150 ° C, preferably at about -30 ° C to 80 ° C. The reaction ends in several tens of minutes to several tens of hours and can vary depending on the type of starting compound and base used, the reaction temperature and the type of solvent, in some cases about 10 days.

[Ureido Formation (Tioureido Formation)]

(식중, R¹⁹, R²⁰및 Z는 상기에 정의한 바와 같다)로 표시되는 기를 함유한 치환된 이소시아네이트 또는 이소티오시아네이트와 반응시킴으로써 수행된다. 상기 치환된 이소시아네이트로는 예를들면 메틸이소시아네이트, 에틸이소시아네이트, 페닐이소시아네이트 또는 P-브로모페닐이소시아네이트가 사용되며, 치환된 이소티오시아네이트로는 예를들면 메틸이소티오시아네이트 또는 페닐이소티오시아네이트가 사용된다. 이 반응에서 치환된 이소시아네이트 또는 치환된 이소티오시아네이트는 보통 1몰의 화합물(Ⅲ)에 대해 약 1몰 비율로 사용되나, 반응에 역효과를 주지 않는다면 과량으로 사용될 수 있다. 적당한 용매로는 예를들면 테트라히드로푸란, 디에틸에테르, 에틸아세테이트, 클로로포름, 디클로로메탄 또는 톨루엔이 사용된다. 반응 온도는 약 -20℃∼50℃의 범위이며, 반응시간은 보통 약 10분∼5시간이다.The reaction for converting an amino group to a ureide or thioureido group is carried out by the general formula

It is carried out by reacting with a substituted isocyanate or isothiocyanate containing a group represented by wherein R ¹⁹ , R ²⁰ and Z are as defined above. As the substituted isocyanate, for example, methyl isocyanate, ethyl isocyanate, phenyl isocyanate or P-bromophenyl isocyanate is used, and as substituted isothiocyanate, for example, methyl isothiocyanate or phenyl isothiocyanate Is used. In this reaction, substituted isocyanates or substituted isothiocyanates are usually used in an amount of about 1 mole relative to 1 mole of compound (III), but may be used in excess if it does not adversely affect the reaction. Suitable solvents are, for example, tetrahydrofuran, diethyl ether, ethyl acetate, chloroform, dichloromethane or toluene. The reaction temperature is in the range of about -20 ° C to 50 ° C, and the reaction time is usually about 10 minutes to 5 hours.

[Alkylation]

The reaction of the amino group of compound (III) with a group bonded via carbon is described below as alkylation.

Alkylation derivatives of compound (III) can be prepared by reacting compound (III) with an alkylating agent containing a group in which the R ¹ group is bonded to nitrogen via carbon. Alkylating agents are, for example, halogenated alkyl compounds such as propyl chloride, butyl chloride, benzyl chloride, butyl bromide, benzyl bromide, allyl bromide, methyl iodide, ethyl iodide and propyl iodide, dimethyl sulfate and diethyl sulfate Substituted sulfonate compounds or dihalogenated alkyl compounds such as dialkyl sulfate compounds, methyl mesylate, ethyl mesylate, methyl tosylate and ethyl tosylate (e.g. 1,5-dichloropentane, 1,4-dichlorobutane, etc.) There is. This reaction is usually carried out in a solvent, examples of the solvent which can be used are, for example, water, methanol, benzyl alcohol, benzene, dimethylformamide, tetrahydrofuran or acetonitrile. The temperature of this reaction is about 20 degreeC-200 degreeC, and reaction time is about 30 minutes-50 hours. This reaction can optionally prepare secondary, tertiary amine or quaternary amine compounds by changing reaction conditions such as the molar ratio of compound (III) to alkylating agent. It is also possible to introduce other substituents to the nitrogen by carrying out the reaction stepwise. The reaction for introducing the bonded group through carbon other than the alkyl group may be carried out by a process similar to that described above.

The alkylation can also be carried out by reacting compound (III) with a carbonyl compound in the presence of a reducing agent. Examples of reducing agents used in this reaction include lithium aluminum hydride, sodium borohydride, sodium borohydride, sodium, sodium amalgam and a combination of zinc and acid. This reaction can also be carried out via catalytic reduction using, for example, palladium, platinum and rhodium as catalysts.

A reaction for converting an amino group to a group represented by the general formula R ²¹ -NH- (amino-substituted alkylamino, alkylamino-substituted alkylamino or substituted guanidino group): amino group to amino-substituted alkylamino group or alkylamino-substituted group The conversion of the alkylamino group is carried out by reacting the starting material with an imido ester in a solvent such as dioxane, tetrahydrofuran, dimethylformamide, chloroform, acetone, acetonitrile and water. Suitable imidoesters are, for example, methyl formimidate, ethyl formimate, benzylformimate, methylacetoimate, ethylacetoimidate, methylphenylacetoimidate, ethyl N-methylformimidate, methyl N-ethyl Formimidate or methyl N-isopropylformimidate are used.

The reaction temperature is in the vicinity of 0 ° C to 25 ° C, and the reaction time is usually 1 to 6 hours. The reaction for converting an amino group to a guanidino group involves the starting compound in a solvent such as water, dimethylformamide and hexamethylphosphoramide, with 0-alkyl- or 0-arylshudorea or S-alkyl- or S-arylshudothiourea. It is carried out by reacting with. As the above pseudourea, for example, O-methyl pseudourea, O-2,4-dichlorophenyl pseudourea or ON, N-trimethyl pseudourea are used. As the pseudothiourea, for example, Sp-nitro Phenylshudothiourea is used. The reaction temperature is around 0 ° C to 40 ° C, and the reaction time is usually 1 to 24 hours.

Alkenylation

Alkenylation (amination) of compound (III) can be carried out by decompression of compound (III) with a carbonyl compound. This reaction is carried out in the absence of solvent, but can be carried out in a solvent. Acids or bases are used as catalysts in some cases. The desired compound can be prepared by heating the compound (III) and the carbonyl compound in the presence of a dehydrating agent or under reflux using a dehydrating group such as Dean-Stark. Solvents that can be used for this reaction are, for example, benzene, toluene, dichloromethane or ethanol. Reaction temperature is about 0 degreeC-200 degreeC, and reaction time is about 1 hour-20 hours. Acids used as catalysts are for example benzenesulfonic acid, methanesulfonic acid, sulfuric acid, boron trifluoride and zinc chloride, and bases are for example potassium hydroxide and sodium carbonate. Useful dehydrating agents for this reaction are, for example, molecular sieves, silica gel, anhydrous magnesium sulfate and anhydrous sodium sulfate.

[Thiolation:]

The thiolation reaction of compound (III) is a halogenated thio compound containing a group represented by the formula R ²⁹ -SO _n- (wherein R ²⁹ and n are as defined above) in a solvent in the presence of base (III). (E.g., sulfonyl halide, sulfinyl halide, sulfonyl halide, etc.). Solvents used in this reaction are, for example, water, acetone, dioxane, dimethylformamide, benzene, tetrahydrofuran, dichloromethane or solvent mixtures thereof. Bases used are, for example, organic bases such as pyridine, picoline, triethylamine, isopropylamine and N-methylmorpholine and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and potassium carbonate. This reaction is usually used in an amount of about 1 to 10 equivalents of a base based on compound (III) of a halogenated thio compound, with a reaction temperature of about -20 ° C to 80 ° C and a reaction time of 15 minutes to 10 hours.

This reaction is also carried out using thioacid anhydrides (e.g. toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.) in place of the halogenated thio compounds. This reaction also reacts the starting compound with a thiolating agent such as N-sulfonyl-N-methyl pyrrolidinium, N-sulfonylimidazolide or N-sulfonyl-1H-1,2,4-triazolide Can be carried out.

또는 R³³(식중, R^30∼33은 상기에 정의한 바와같다)의 기를 함유한 할로겐화 실릴화합물(예. 실릴클로라이드화합물, 실릴브로마이드 화합물 등)과 반응시킴으로써 수행될 수 있다. 상기의 염기는 예를 들면 피리딘, 피콜린, 트리에틸아민, 디이소프로필아민 및 N-메틸모르폴린과 같은 유기염기이다. 반응은 바람직하게는 용매중에서 수행되며, 용매는 예를 들면 아세톤, 디옥산, 디메틸포름아미드, 벤젠, 테트라히드로푸란 및 디클로로메탄이다. 반응온도는 약 -20℃∼사용된 용매의 비점 또는 -20℃∼80℃이며, 반응시간은 15분∼20시간이다.Silylation: The silylation of compound (III) is carried out in the presence of a base in compound (III).

Or R ³³ can be performed by a halogenated silyl compound (eg, silyl chloride compounds, silyl bromide compounds, etc.) containing a group of reaction: (wherein, R ^30~33 are as defined above). The base is, for example, an organic base such as pyridine, picoline, triethylamine, diisopropylamine and N-methylmorpholine. The reaction is preferably carried out in a solvent, for example acetone, dioxane, dimethylformamide, benzene, tetrahydrofuran and dichloromethane. The reaction temperature is about -20 ° C to the boiling point of the solvent used or -20 ° C to 80 ° C, and the reaction time is 15 minutes to 20 hours.

(식중, R³⁴및 R³⁵는 상기에 정의한 바와 같다)로 표시되는 기를 함유한 포스포릴클로라이드(예. 디메틸포스포릴클로라이드, 디에틸포스포릴클로라이드, 디페닐포스포릴클로라이드, 디벤질포스포릴클로라이드 등)거의 등몰량의 반응시킴으로써 수행된다. 염기로는 예를 들면 피리딘, 피콜린, 트리에틸아민 및 N-메틸모르폴린과 같은 유기염기, 및 수산화나트륨, 수산화칼륨, 탄산수소나트륨 및 탄산나트륨과 같은 무기염기가 사용된다. 용매로는 예를 들면, 물, 아세톤, 아세토니트릴, 디옥산, 디메틸포름아미드, 테트라히드로푸란 및 디클로로메탄을 단독으로 또는 용매 혼합물로 사용한다. 반응온도는 약 -20℃∼80℃이며, 반응시간은 15분∼15시간이다.Phosphorylation: Phosphorylation of compound (III) is usually carried out in a solvent in the presence of an approximately equal molar amount or excess base of compound (III).

A phosphoryl chloride containing a group represented by (wherein R ³⁴ and R ³⁵ are as defined above) (e.g., dimethylphosphoryl chloride, diethylphosphoryl chloride, diphenylphosphoryl chloride, dibenzylphosphoryl chloride, etc.) It is carried out by reacting in almost equimolar amounts. As the base, for example, organic bases such as pyridine, picoline, triethylamine and N-methylmorpholine, and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate are used. As the solvent, for example, water, acetone, acetonitrile, dioxane, dimethylformamide, tetrahydrofuran and dichloromethane are used alone or in a solvent mixture. The reaction temperature is about -20 ° C to 80 ° C and the reaction time is 15 minutes to 15 hours.

Methoxylation reaction and formylaminoation reaction of compound (iii) are demonstrated below.

Methoxylation: In the methoxylation of compound (VII), a 6-position or 7-position methoxylation method commonly used in the field of penicillyl or cephalosporin may be used. Methoxylation of penicillin or cephalosporin is described, for example, in E. M. Gordon, R. B. Cykes, et al., "Chemical and Biology of β-lactam Antibiotic" Vol. (1) Diazo intermediates, (2) alkylimine intermediates, (3) keteneimines or related imine intermediates, (4) quinoidoimine intermediates, (5) Methods of methoxylation via sulfenimine intermediates, (6) enimine intermediates, and the like are described. These methods can be used to prepare the desired compound, and as a representative example, the method of methoxylation via acylimine intermediates is described.

The methoxylation reaction of compound (VII) is carried out by reacting the alkali metal salt of methanol and the halogenating agent with compound (VII) in the presence of methanol. As alkali metal salts of methanol, for example, lithium methoxide, sodium methoxide and potassium methoxide are used, and as the halogenating agent, for example, t-butyl hypochloride, N-chlorosuccinimide, N-bromosuccinimide , N-chloroacetamide, N-bromoacetamide, N-chlorobenzenesulfonamide, chlorine and bromine are used. This reaction is carried out in a solvent, for example tetrahydrofuran, dioxane, dichloromethane, chloroform, acetonitrile, methanol and dimethylformamide are used. This reaction is preferably carried out by dissolving or suspending compound (iii) in the above-mentioned solvent and proceeding the reaction by adding an alkali metal salt of methanol, methanol and a halogenating agent to the solution or suspension. In this case, it is preferable to add 1 mol or more of methanol, alkali metal salt of about 1 to 3.5 mol of methanol, and about 1 to 2 mol of halogenating agent with respect to 1 mol of compound (i) to advance reaction. The reaction proceeds at about -80 ° C to 30 ° C and is suspended by acidifying the reaction system. As the acid used in the suspension of the reaction, formic acid, acetic acid or trichloroacetic acid is used, for example. After completion of the reaction, the excess halogenating agent is removed by treatment with a reducing agent such as sodium thiosulfate and trialkylester of phosphoric acid.

Formyl Amination: Formyl Amination is a general formula of Compound

Wherein R ^{1 ″} is a molecular sieve other than nitrogen in the organic residue (R ^{1 ′} ) bonded through nitrogen; R ² is as defined above; and the imine derivative is converted to an imine derivative. Nucleophilic derivatives of formamide are, for example, N-silyl, N-stanyl and N-phosphorylformamide derivatives, among which N, N-bis (trimethylsilyl) formamide The formyl amidation reaction is carried out in a solvent under an inert atmosphere such as nitrogen and argon, and the reaction temperature is about -100 ° C to -20 ° C, preferably about -80 ° C to -50 ° C, The reaction time is about 10 minutes to 8 hours, preferably about 15 minutes to 2 hours The solvent used may be any aprotic solvent, for example tetrahydrofuran, dimethylformamide, hexamethylphosphoramide or Dioxane, followed by acid The formyl amide group can be prepared by base hydrolysis or metal ion treatment such as mercury, silver, thallium or copper ions. It can be prepared by a similar method.

The above-mentioned method of reacting compound (V) with a compound capable of introducing a group which forms a group bonded to a carbon or oxygen atom of carboxy which can be derived from carboxy is a general formula

Wherein R ¹ is an organic residue bound via amino or nitrogen, R ^{2 ′} is a group derivable from carboxy, and X is hydrogen, methoxy or formylamino.

The reaction of compound (V) with a compound capable of introducing a group bonded to a carbon or oxygen atom of carboxy which can be derived from carboxy is carried out, for example, by esterifying or amidating both compounds.

[Esterification of Carboxylic Acid]

Esterification is performed by the following process, for example.

1) Compound (V) was dissolved in diazomethane, phenyldiazomethane and diphenyl in a solvent such as tetrahydrofuran, dioxane, ethyl acetate and acetonitrile for about 2 minutes to 2 hours at reflux temperature of the solvent. React with diazoalkanes such as diazomethane.

2) Alkali metal salts of compound (V) with activated alkyl halides such as methyl iodide, benzyl bromide, p-nitrobenzyl bromide, m-phenoxybenzyl bromide, pt-butylbenzylbroamide and pivaloyloxymethyl chloride React. Given the appropriate reaction conditions, the reaction proceeds in a solvent such as dimethylformamide, dimethyl sulfoxide or hexamethylphosphoramide and at about 0 ° C. to 60 ° C. for about 2 minutes to 4 hours. There is no adverse effect of coexistence of triethylamine and the like on the reaction solution.

3) Compound (V) is reacted with alcohols such as methanol, ethanol and benzyl alcohol. This reaction is carried out in the presence of a carbodiimide binder such as dicyclohexylcarbodiimide at about 0 ° C. to about 15 minutes to 18 hours at the reflux temperature of the solvent used. As the solvent, for example, chloroform, dichloromethane and dichloro ethane are used.

4) The acid anhydride of compound (V) formed by reacting compound (V) with acid chlorides such as ethylchloroformate and benzylchloroformate is reacted with the alcohol described in 3) under the reaction conditions of 3) above. Acid anhydrides can be obtained by reacting compound (V) with acid chloride in solvents such as tetrahydrofuran and dichloromethane at 25 ° C. to reflux for about 15 minutes to 10 hours.

5) Compound (V) is reacted with a silylating agent such as trimethylsilyl chloride and t-butyl-dimethylsilyl chloride for about 15 minutes to 16 hours at about 0 ° C. to reflux temperature, for example in the presence of triethylamine.

Amidation of Carboxylic Acids: Amidation of carboxylic acids can be accomplished by compound (V) and acid chlorides (e.g. trimethylacetylchloride, ethylchloroformate and benzylchloroformate) or acid anhydrides (e.g. acetic anhydride and trifluoro Acetic anhydride) to synthesize an acid anhydride of compound (V) and react with, for example, the alkyl-, dialkyl-, aralkyl- or heterocyclic amines described above. The reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran and dimethylformamide and at about 0 ° C. to reflux for 15 minutes to 16 hours. The above-mentioned reaction can produce the target compound of the following general formula (I ').

Wherein R ¹ is an organic residue bound via amino or nitrogen, R ² is a carboxy or group derivable therefrom, and X is hydrogen, methoxy or formylamino)

Deprotection reaction: When the target compound (I ') thus obtained has a protecting group, the protecting group can be removed if necessary. As the method for removing the protecting group, a known method such as an acid treatment, a base treatment, a hydrazine treatment or a reducing treatment may be selected and performed according to various types of protecting groups. When treating with acid, acidic ion exchange resins can be used as the acid, as well as inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid or organic acids such as formic acid, acetic acid, trifluoroacetic acid and propionic acid, depending on the type of protecting group and other conditions. Can be changed. When treated with bases, bases include inorganic bases such as hydroxides and carbonates of alkali metals (e.g. sodium and potassium) and alkaline earth metals (e.g. calcium and magnesium) and organic bases such as metal alkoxides, organic amines and quaternary ammonium salts. In addition, basic ion exchange resins may be used and may vary depending on the type of protecting group and other conditions. When the solvent is used in the above-described acid or base treatment, a hydrophilic organic solvent, water or a solvent mixture is used.

When treated by Korean Won, methods of using metals such as tin or zinc or metal compounds such as chromium dichloride and chromium acetate and acids such as organic and inorganic acids exemplified by acetic acid, propionic acid and hydrochloric acid and metal catalysts for catalytic reduction A method of reducing in the presence of the present invention may be adopted, and may vary depending on the type of protecting group and other conditions. Catalysts used in the process by catalytic reduction include, for example, platinum lead, platinum sponge, platinum black, platinum catalysts such as platinum oxide and colloidal platinum, palladium sonic, palladium black, palladium oxide, barium palladium sulfate, barium palladium carbonate Palladium catalysts such as palladium carbon, palladium silica gel and colloidal palladium, reduced nickel, nickel oxide, ranickel, urushibara nickel and the like. For the reduction with metals and acids, metals such as iron and chromium and inorganic acids such as hydrochloric acid or organic acids such as formic acid, acetic acid and propionic acid are used. The process by reduction is usually carried out in a solvent, in the case of catalytic reduction, for example alcohols such as methanol, ethanol, propyl alcohol and isopropyl alcohol, ethyl acetate and the like are commonly used. In the case of methods using metals and acids, water, acetone, and the like are commonly used, and when the acid is in liquid form, the acid itself can be used as a solvent.

In the case of a method using an acid, a method using a base and a method by reduction, the reaction is usually carried out at a reaction temperature under cooling or warming.

R ¹ is an amino of the formula (Ⅰ ') of the compound (Ⅲ) is R ¹ is the organic residue of general formula (Ⅰ bonded through nitrogen other than amino, similar reaction and deprotection reaction described above the compound of the) It can be prepared by performing.

Compound (III) is useful as a starting material, i.e., an intermediate for preparing a compound of formula (I ') wherein R ¹ ′ is an organic residue bonded through nitrogen other than amino. R ² is of the formula (Ⅰ ') a carboxyl compound (Ⅴ) of the resulting formula (Ⅰ that R ² is derivable from a carboxyl group, be prepared by performing a) the reaction similar to the deprotection reaction described above for the compounds of Can be.

In the process of the invention, the antibiotic TAN-588, ie 2-[(4S) -4-acetamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofurancarboxylic acid , Salts thereof, p-nitrobenzyl esters, benzhydryl esters thereof, or N-deacetyl derivatives thereof can be used as starting materials.

The antibiotic TAN-588 used as a starting material in the method of the present invention was cultured in a culture medium for antibiotic TAN-588 producing microorganism belonging to the genus Empedobacter or Rizobacter to release and accumulate antibiotic TAN-588 in the culture broth. It can be manufactured by recovering. Such microorganisms include, for example, Emphadobacter lactamgenus YK-258 and Lazobacter albus sp. nov. YK-422 strain.

The microorganisms described above have been deposited in the Osaka Osaka Fermentation Research Institute (IFO, 17085, Yokogawa Chuo Honmachi, Osaka, Japan) as follows.

In addition, the microorganisms above were deposited in the following FERM P-accession number to the Japan Institute of Commerce, Industry and Technology Institute of Microbial Industrial Technology Research Institute (FRI, 1-3 Yadabecho Hagashi, Ibaragi-chan, Japan). Is converted to a deposit under the Budapest Convention and stored in the FRI under the following FERM BP-number.

In addition, the microorganisms have been deposited with the following accession number at KAIST (39-1, Hawolgok-dong, Seongbuk-gu, Seoul).

As described in detail in the Reference Examples below, the N-deacetyl derivative of TAN-588 is a p-nitrobenzyl ester or benzhydryl ester by introducing a p-nitrobenzyl or benzhydryl group into TAN-588 or a salt thereof. It can be prepared by preparing a derivative, deacetylating the above ester derivative to prepare p-nitrobenzyl ester or benzhydryl ester derivative of N-deacetyl TAN-588, and then removing each ester group.

The desired compound (I ′) thus obtained can be separated and purified by known methods such as concentration, solvent extraction, lyophilization, crystallization, recrystallization, fractional distillation and chromatography.

Four stereoisomers exist due to two asymmetric carbons in the basic skeleton of the desired compound (I '), and each of these stereoisomers and mixtures thereof is also included in the scope of the present invention. Similarly, stereoisomers may be present due to the asymmetric carbons of the groups represented by the R ¹ and R ² groups, and each of these stereoisomers and mixtures thereof is also within the scope of the present invention. When the above-mentioned reaction produces stereoisomers in the form of a mixture, each of these stereoisomers may be separated by known methods such as various chromatographic methods and recrystallization if necessary.

Compound (I ′) of the present invention may in some cases act with a base to form salts. Bases are, for example, inorganic bases such as sodium, potassium, lithium, calcium, magnesium and ammonia and organic bases such as pyridine, collidine, triethylamine and triethanolamine.

When prepared in free form, compound (I ') can form salts by known methods, and compound (I') obtained in the form of salts can be converted to free forms by known methods.

Compounds (I) also in some cases form intramolecular salts, which are included within the scope of the invention.

The stereoisomers of compound (I ') can be used in the medicament alone or in mixture.

Compound (I ′) thus obtained is useful as a medicament having antimicrobial activity against Gram-positive and Gram-negative bacteria.

The biological activity of compound (I ') is demonstrated below. Representative compounds of Compound (I ′) show antimicrobial spectra against the different microorganisms shown in Table 1 below.

TABLE 1

*: Medium, amount of trypticase soy agar inoculated bacterium, 10 ⁸ CFU / mL

**: It is number which compound added in the Example.

Compound (R-4) is a compound obtained in Reference Example 4. In any case, when the compound (I ') of the present invention (I') obtained in Example 21 (b) having R ¹ = -NHCOH, R ² = -COONa and X = H was administered to the mouse at a dose of 400 mg / kg, Mice do not die. Therefore, compound (I ') or salts thereof are very low in toxicity.

As described above, the compound (I ') and salts thereof of the present invention exhibit antimicrobial activity against gram-positive and gram-negative bacteria and are also less toxic. As a result, the compounds of the present invention are bacterial infections of mammals (eg, mice, mice, dogs, cows, pigs, humans, etc.) due to bacterial infections (eg respiratory infections, urinary tract infections, purulent diseases, bile duct infections, testicular infections). , Gynecological infection, surgical infection, etc.) can be used as an antimicrobial or therapeutic agent.

The daily dose of compound (I ') or its salt is about 2-100 mg / kg, preferably about 5-40 mg / kg of compound (I').

For administering compound (I '), compound (I') or a pharmaceutically acceptable salt thereof is formulated by known methods together with a pharmaceutically acceptable carrier, excipient and diluent suitable for oral administration. Injectable solutions can be prepared in dosage forms such as granules, capsules or elixirs or by combining sterile carriers prepared by known methods for parenteral administration.

In the preparation of oral pharmaceuticals such as the tablets described above, binders (e.g., hydroxylpropyl cellulose, hydroxypropylmethylcellulose, macrogol, etc.), disintegrants (e.g. starch, calcium carboxymethylcellulose, etc.), excipients (e.g. Lactose, starch, etc.), lubricants (eg magnesium stearate, activity, etc.) may be suitably used.

Parenteral preparations, such as injectable solutions, include, but are not limited to, isotonic agents (e.g. glucose, D-sorbicol, D-mannitol, sodium chloride, etc.), preservatives (e.g. benzyl alcohol, chlorobutanol, methyl p-oxybenzoate, Propyl p-oxybenzoate, etc.), a buffer (e.g., a phosphate buffer, sodium benzoate buffer, etc.) etc. can be used suitably.

The following Reference Examples and Examples will be described in more detail the present invention, but the present invention is not limited thereto. "Percent" is "weight / volume" unless otherwise indicated.

In the resin used, those indicated by abbreviations are defined as follows.

CHP-20: Dion CHP-20 (manufactured by Mitsubishi Chemical Corporation, Japan)

HP-20: Dion HP-20 (manufactured by Mitsubishi Chemical Corporation, Japan)

LH-20: Sephadex LH-20 (made in Sweden Pharmacia)

XAD-2: Amberlite XAD-2 (product made in the United States Rom & Haas)

SP-207: Dion SP-207 (made by Mitsubishi Chemical Corporation, Japan)

Abbreviations used in the examples are defined as follows.

rt: room temperature

h: hour

Me: Methyl

Ac: Acetyl

DMA: Dimethyl Acetamide

Reference Example 1

(1) 2% glucose, 3% soluble starch, 1% raw soy flour in the strains of Empedobacter lactamgenus YK-258 (IFO 14322, FERM BP-699, KAIST 850211-15511) grown on slopes of nutrient agar Inoculate a 2 L saga gucci flask containing 500 ml of medium mixed with 0.5% polypeptone (produced by Daigo Nutrition Chemicals, Japan) and 0.3% sodium chloride (pH 7.0) with 0.5% precipitated calcium carbonate, Shake incubation for 48 hours at 24 ℃ in a rotary shaker. The resulting culture broth of total volume was inoculated into a 50 liter tank containing 30 liters of medium in which the above medium was mixed with 0.05% actucol (Tadayaku Hingyo Kogyo Co., Ltd.), aerated at 50 liters per minute and 200 r.pm. Incubate at 24 ° C. for 48 hours under stirring conditions. 6 liters of this broth were mixed with 120 liters of medium containing 3% dextrin, 1.5% raw soy flour, 1.5% corn gluten powder, 0.2% polypeptone, and 0.1% sodium thiosulfate in an aqueous solution (pH 6.5) mixed with 0.05% actchol. Incubate in a 200 L tank and perform incubation for 66 h at 17 ° C. under 200 L / min aeration and agitation conditions of 150 r.pm.

This incubation is repeated twice, and the culture broth (230 L) is adjusted to pH 8, followed by filtration using 9 kg of Hyflosurusel (manufactured by Johns Manville, USA). The filtrate (200 L) was adjusted to pH 6 and chromatographed on a column of Amberlite IRA-402 (10 L of Cl type, manufactured by Rohm and Haas, USA). The antibiotics are eluted with a 2% aqueous sodium chloride solution, the eluate (53 L) is adjusted to pH 6, and chromatographed on activated carbon (5 L, manufactured by Tadaya Chemical Co., Ltd.). The antibiotic was eluted with 8% aqueous isobutanol and the eluate (14 L) was concentrated under reduced pressure to a total volume of 5 L. The concentrate is adjusted to pH 6 and extracted with 2% tri-n-octylammonium chloride / dichloromethane solution (2.5 L × 2). The extract is treated with 1.6% aqueous sodium iodide (2.5 L) and the antibiotic is transferred to the aqueous phase. The aqueous layer is concentrated and the concentrate is chromatographed on activated carbon (500 mL) and eluted with 8% aqueous isobutanol. The eluate is concentrated and lyophilized to yield 1.41 g of crude powder. Crude powder (1.4 g) was dissolved in water (100 mL), the solution was chromatographed on a column of 200 L of QAE-Sepadex A-25 (type Cl, Swedish Pharmaciase), eluted with 0.03 M aqueous sodium chloride solution and Fractionate. Fractions (600 mL) were collected, adjusted to pH 5.1, desalted via activated carbon chromatography, and the eluate was concentrated and lyophilized to give a powder (384 mg). The powder is dissolved in water, the solution is preparative HPLC using YMC-PACK SH-343 (Yamamura Chemical Laboratory, Japan), and then eluted with 0.01 M phosphate buffer. The eluate containing antibiotics was collected, desalted through activated carbon chromatography, and the eluate was concentrated and lyophilized to give a white powder (141 mg) of TAN-588 sodium salt.

The TAN-588 sodium salt (equilibrium mixture of isomers A and B) obtained above exhibits the physico-chemical properties shown below.

1) Appearance: White powder

-19.0°±10°(c=0.5, 물)2) Specific Radiance:

-19.0 ° ± 10 ° (c = 0.5, water)

3) for compounds containing C, H, N, O and Na elements

Elemental Analysis (%): Samples dried at 40 ° C. on phosphorus pentoxide for 6 hours.

Found (%): C; 38.5 ± 2.0, H; 4.5 ± 1.0, N; 9.1 ± 1.5, Na; 6.9 ± 1.5

Calculated ^* (%): C; 39.61, H; 3.99, N; 9.24, O; 39.58, Na; 7.58

(*: Calculated under the assumption that it contains 0.5 moles of adherent water)

4) Content of adhered water: 3.0 ± 1.5% (heat weight measuring method)

5) Buzaion peak obtained by SIMS method:

m / z 611 (2M + Na) ⁺ , 317 (M + Na) ⁺ , 295 (M + H) ⁺

6) Molecular formula: C ₁₀ H ₁₁ N ₂ O ₇ Na

, 쇼울더)7) UV absorption (UV) spectrum (water): λ max 216 nm (

, Shoulder)

8) Infrared absorption (IR) spectrum (KBr purification method):

The main absorbance (wavelength) measured in KBr tablets is as follows.

3450, 1780, 1730, 1660, 1550, 1385, 1320, 1290, 1260, 1200, 1120, 1040, 980, 910, 810, 770, 690, 600, 540 cm ^-1

9) ¹³ C-nuclear magnetic resonance (NMR) spectrum (100 MHz, heavy water): The following signal is observed:

182.02 (s), 177.30 (s), 173.79 (s), 173.30 (s), 173.25 (s), 172.58 (s), 96.97 (s), 96.92 (s), 74.27 (t), 72.63 (t), 55.57 (d), 55.34 (d), 31.92 (t), 31.08 (t), 30.98 (t), 24.58 (q) ppm

(Where the abbreviations are: s; singlet, d; doublet, t; triplet, q; quartet).

10) Circular dichroism (CD) spectrum (water): A negative cotton effect appears at 232 ± 3 nm.

11) Solubility:

Soluble: Water, Dimethylsulfoxide

Difficulty: ethyl acetate, chloroform, diethyl ether

12) Color Reaction:

Positive: ninhydrin reaction

Negative: Grag-Lieback reaction, Sarcas Gucci reaction, Erlich reaction, Barton reaction and Dragendorf reaction

13) Amino Acid Analysis: Hydrolysis of 6N hydrochloric acid at 105 ° C. for 20 hours yields serine detected with known amino acids.

14) Stability: Stable in aqueous solution at pH 5: Slightly stable at pH 3 and pH 7; Unstable at pH 9.

15) Thin layer chromatography (TLC) (cellulose f, product of Toko Kasei Co., Ltd.)

16) Distinguish between acidic, neutral and basic: neutral

17) High performance liquid chromatography (HPLC) (carrier: YMCA-312, Yamamura Chemical Laboratory, Japan; mobile phase; 4% methanol / 0.01 M phosphate buffer (pH 6.3), 2 ml / min): Rt = 4.3 and 4.8 ( minute)

(2) Rizobacter albus sp. nov. Using YK-422 (IFO 14383, FERM BP-698, KAIST 850211-15411), incubation and purification were carried out by a method similar to that described above for the antibiotic TAN-588 sodium salt (620 g) (from both isomers A and B Mixtures).

In the examples described below, the TAN-588 sodium salt obtained above (a mixture of two isomers A and B) may be abbreviated as "Compound (R-)".

Reference Example 2

After dissolving 58.8 g of benzophenone hydrazone, 42 ml of 1,1,3,3-tetramethylguanidine and 150 mg of iodine in 500 ml of dichloromethane, the mixed solution was cooled to 0--5 캜. , 74 g of m-chloroperbenzoic acid (70% purity) was added, and stirred at 0 ° C for 40 minutes. The reaction solution is washed with water, dried over sodium sulfate and the solvent is distilled off to obtain diphenyldiazomethane.

31 g of TAN-588 sodium salt (mixture of both isomers A and B) are suspended in tetrahydrofuran and the total amount of diphenyldiazomethane obtained above is dissolved in 150 ml of tetrahydrofuran and added to the suspension. The mixed solution is cooled at 0 ° C. and 60 ml of 2N HCl is added dropwise, followed by stirring at room temperature for 1 hour. 10 mL of 2N HCl is added and after stirring for an additional hour, 3 L of dichloromethane is added. The resulting solution was washed with water and concentrated, and ether was added to the residue to give 28 g of a white crystalline powder of TAN-588 benzhydryl ester (a mixture of isomers A and B).

The mixture (1.8 g) was chromatographed on a column of silica gel (180 mL), eluting the compound isomer B first by eluting with a solvent system of chloroform: methanol (97: 3) and eluting the compound isomer A later. . Each fraction was concentrated to give isomer A (433 mg), isomer B (400 mg) and a mixture of isomers A and B (476 mg) of TAN-588 benzhydryl ester to give a colorless crystalline form.

In the examples described below, the TAN-588 benzhydryl ester (mixture of isomers A and B) obtained above may be abbreviated as "Compound (R-2)".

The TAN-588 benzhydryl ester (mixture of isomers A and B) obtained above exhibits the physico-chemical properties described below.

1) Appearance: Colorless Crystal

2) Melting Point: 153 ~ 155 ℃ (Decomposition)

+9.2°±5°(c0.52, CHCl₃)3) Specific Radiance:

+ 9.2 ° ± 5 ° (c0.52, CHCl ₃ )

4) Molecular weight: m / z, 438 (M ⁺ ) (EI-MS method)

5) Elemental Analysis:

Calculated (%): C; 63.01, H; 5.06, N; 6.39, 0; 25.54

Found (%): C; 62.83, H; 5.32, N; 6.28

6) Molecular formula: C ₂₃ H ₂₂ N ₂ O ₇

7) UV Spectrum: Methanol

, 쇼울더) 및 250∼260㎚(

, 쇼울더)λmax 220 ± 2 nm

, Shoulder) and 250-260 nm (

, Shoulder)

8) IR Spectrum: KBr Method

3380, 3080, 3050, 2960, 1800, 1780, 1750, 1705, 1690, 1600, 1590, 1540, 1500, 1460, 1380, 1310, 1280, 1190, 1110, 1060, 980, 920, 880, 750, 710, 700, 650, 630, 610, 570, 550, 470 cm ^-1

9) ¹ H-NMR spectrum: 90 MHz, CDCl ₃ , δ ppm m (㎐), 1.97 (3H, s), 2.1 to 3.5 (4H, m), 3.8 to 4.2 (1H, m), 4.5 to 5.1 (2H, m), 6.1-6.4 (1H, b), 6.97 (1H, s), 7.3-7.4 (10H, m).

(Where the abbreviations are: m; polyline, b; broad, H; proton)

10) TLC: Conditional Rf values as described below, 0.58 and 0.65

11) Distinguish between acidic, neutral and basic: neutral

The TAN-588 benzhydryl ester (isomer A) and TAN-588 benzhydryl ester (isomer B) obtained above exhibit the properties described below.

Isomer A

1) Appearance: Colorless Crystal

2) Melting Point: 97 ~ 135 ℃ (Decompose the compound by slowly bubbling or bubbling)

+44.2°±10°(c=0.505, CHCl₃)3) Specific Radiance:

+ 44.2 ° ± 10 ° (c = 0.505, CHCl ₃ )

4) Molecular weight: Molecular ion peak m / z 438 (M ⁺ ) by EI-MS method

5) Elemental Analysis:

Calculated (%): C; 63.01, H; 5.06, N; 6.39, 0; 25.54

Found (%): C; 62.62, H; 5.06, N; 6.32

6) Molecular formula: C ₂₃ H ₂₂ N ₂ O ₇

7) UV spectrum (methanol):

, 쇼울더) 및 250∼260㎚(

, 쇼울더)λmax 220 ± 2 nm

, Shoulder) and 250-260 nm (

, Shoulder)

8) IR spectrum: KBr method

3380, 3080, 3050, 1800, 1780, 1760, 1685, 1540, 1500, 1450, 1380, 1310, 1280, 1190, 1110, 1050, 980, 920, 880, 750, 710, 650, 610, 550 cm ^-1

9) Nuclear Magnetic Resonance ( ¹ H-NMR) Spectrum: 100 MHz, CDCl ₃ -d ₆ -DMSO Mixture, δppm J (㎐), 1.98 (3H, s), 2.2 ~ 3.4 (4H, m), 4.10 (1H , dd, J = 8.10), 4.4 to 5.0 (2H, m), 6.93 (1H, s), 7.3 to 7.5 (10H, m), 8.27 (1H, d, J = 7).

10) Thin layer chromatography (TLC): a carrier and silica gel (manufactured by West Germany Merk). Developing solvent, ethyl acetate, Rf value. 0.58

11) Distinguish between acidic, neutral and basic: neutral

Isomer B

1) Appearance: Colorless Crystal

2) Melting Point: 157 ~ 160 ℃ (Decomposition)

-28.8°○10°(c=0.5, CHCl₃)3) Specific Radiance:

-28.8 ° ○ 10 ° (c = 0.5, CHCl ₃ )

4) Molecular weight: m / z 438 (M ⁺ ) (EI-MS method)

5) Elemental Analysis:

Calculated: C; 63.01, H; 5.06, N; 6.39, 0; 25.54

Found: C; 63.11, H; 5.13, N; 6.30

6) Molecular Weight: C ₂₃ H ₂₂ N ₂ O ₇

7) UV Spectrum: Methanol

, 쇼울더) 및 250∼260㎚(

, 쇼울더)λmax 22 ± 2 nm (

, Shoulder) and 250-260 nm (

, Shoulder)

8) IR spectrum: KBr method

3400, 3080, 3050, 1815, 1780, 1735, 1705, 1540, 1460, 1380, 1290, 1265, 1190, 1060, 980, 920, 880, 760, 715, 610, 550 cm ^-1

9) ¹ H-NMR spectrum: 100 MHz, CDCl ₃ , δ ppm J (㎐), 1.98 (3H, s), 2.2 to 2.3 (4H, s), 4.03 (1H, dd, J = 8.10), 4.6 to 5.2 (2H, m), 6.32 (1H, d, J = 5), 6.96 (1H, s), 7.2-7.5 (10H, m).

10) TLC: (the same conditions as described for Isomer A): Rf, 0.65

11) Distinguish between acidic, neutral and basic: neutral

Reference Example 3

Suspend 26 g (59 mmol) of TAN-588 benzhydryl ester (mixture of isomers A and B) in 1.2 L of dichloromethane and cool the suspension to -20 ° C. 49 ml of pyridine and 37.6 g of phosphorus chloride are added and stirred at -10 ° C to -15 ° C for 50 minutes. The mixed solution is cooled to −30 ° C., 180 ml of methanol is added, followed by stirring at −5 ° C. to −15 ° C. for 30 minutes and further stirring at room temperature for 1 hour. 100 mL of 1N HCl was added to the mixture, stirred at room temperature for 45 minutes, and then 100 mL of 5% aqueous sodium phosphate and 2N sodium hydroxide (Ca. 500 mL) were added to the reaction solution to adjust the pH of the aqueous layer to 8.0. The aqueous layer was separated from the dichloromethane layer and extracted with dichloromethane (600 mL), then the combined organic layers were concentrated and ether was added to the residue to give benzhydryl ester of N-deacetyl TAN-588 (mixture of isomers A and B) white. 17.9 g of powder are obtained.

In the examples below, the benzhydryl esters of N-decenyltyl TAN-588 (mixture of isomers A and B) obtained above are abbreviated as "Compound (R-3)".

Benzhydryl ester of N-deacetyl TAN-588 (mixture of isomers A and B) obtained above exhibits the following physical-chemical properties.

1) Appearance: White powder

-15.2±5°(c=0.5, CHCl₃)2) Specific Radiance:

-15.2 ± 5 ° (c = 0.5, CHCl ₃ )

3) Molecular weight: m / z, 396 (M ⁺ ) (EI-MS method)

4) Elemental Analysis

Calculated: C; 63.63, H; 5.09, N; 7.08, 0; 24.22

Found: C; 63.63, H; 5.05, N; 7.02

5) Molecular weight: C ₂₁ H ₂₀ N ₂ O ₆

6) UV Spectrum: Methanol

, 쇼울더) 및 250∼260㎚(

, 쇼울더)λmax 220 ± 2 nm

, Shoulder) and 250-260 nm (

, Shoulder)

7) IR spectrum: KBr method

3400, 3050, 2970, 1800, 1780, 1740, 1600, 1500, 1460, 1305, 1270, 1190, 1110, 1060, 980, 920, 880, 850, 750, 710, 650, 620, 605 cm ^-1

8) ¹ H-NMR spectrum: 90MHz, CDCl ₃ , δppm J (㎐)

2.2 to 3.5 (4H, m), 3.7 to 4.0 (2H, m), 4.4 to 4.6 (1H, m), 6.97 (1H, s), 7.2 to 7.4 (10H, m).

9) HPLC:

Apparatus, Model 6000A / 660/440 (US Waters Associate) Carrier, YMC-Pack A-312 (from Yamamoto Chemical Laboratory, Japan) Mobile Phase, 65% Methanol / 0.01 M Phosphate Buffer (pH 6.3) Flow Rate, 2 ml Per minute, Rt, 5.3 and 5.6 minutes.

10) Color Reaction:

Positive: ninhydrin reaction

Negative: ferric chloride

11) The distinction between acidic, neutral and basic:

A basic substance

Reference Example 4

396 mg of N-deacetyl TAN-588 benzhydryl ester (mixture of isomers A and B) is suspended in 10 ml of dichloromethane and the suspension is cooled to -20 ° C. 434 μl of anisole and 924 μl of trifluoroacetic acid are added to the suspension and stirred at −20 to −10 ° C. for 40 minutes. It was added to 280 mL of dichloromethanol reaction solution and extracted with 0.1MH ₃ PO _{4 to} Na ₂ HPO ₄ solution (pH 7.3) (40 mL). The extract is adjusted to pH 5.5 and concentrated, and the concentrate is passed through a column packed with Diaion HP-20 (50-100 mesh, 100 mL). The column is washed with water and eluted with 40% aqueous methanol. Fractions showing antimicrobial activity were collected, concentrated and lyophilized to yield 143 mg of white powder of N-deacetyl TAN-588 (mixture of isomers A and B).

N-deacetyl TAN-588 (mixture of isomers A and B) obtained above exhibits the physico-chemical properties described below.

1) Appearance: White powder

2) Specific Radiance:

-11°±5°(c=0.1, 물)

-11 ° ± 5 ° (c = 0.1, water)

3) Molecular Weight:

m / z, 231 (M + H) ⁺ (FD-MS method)

4) Elemental Analysis

Found (%): C; 40.42, H; 4.36, N; 11.65.

Calculated ^* (%): C; 40.17, H; 4.64, N; 11.71, 0; 43.48.

(*; Calculated assuming 0.5 moles of adherent water)

5) Molecular Formula:

C ₈ H ₁₀ N ₂ O ₆ (0.5H ₂ O)

6) UV spectrum: water

)λ _max 221 ± 2 nm

)

7) IR spectrum: KBr method

The main peak is as follows:

3450, 3220, 2960, 2900, 1800, 1760, 1740, 1670, 1580, 1420, 1390, 1370, 1310, 1250, 1200, 1120, 1050, 1030, 980, 950, 920, 810, 770, 720, 690, 610, 540 cm ⁺¹

8) ¹ H-NMR spectrum: 400MHz, D ₂ O. The following signals are observed. δppm J (㎐)

2.52 (1H, m), 2.27 (1H, m), 2.91 (1H, m), 3.08 (1H, m), 4.34 (1H, m), 4.56 (1H, m), 4.80 (1H, m).

9) Circularly polarized dichroism (CD) spectrum: water

A negative cotton effect is seen at 233 ± 3 nm.

10) Solubility:

Soluble: Water

Difficulty: Dimethyl sulfoxide, ethyl acetate, diethyl ether

11) HPLC: The device, carrier and flow rate are as described for the benzohydryl ester of N-deacetyl TAN-588 (mixture of isomers A and B).

Mobile phase, 0.01 M phosphate buffer (pH 6.3)

Rt: 3.1 and 3.3 minutes

12) Color Reaction:

Positive: ninhydrin, iodine

Negative: ferric chloride

13) The distinction between acidic, neutral and basic:

Amphoteric substances

In the examples below, N-deacetyl TAN-588 (a mixture of isomers A and B) is sometimes abbreviated as "Compound (R-4)".

Reference Example 5

100 mg of N-deacetyl TAN-588 (a 1: 1 mixture of isomers A and B) was dissolved in water, and the solution was left at 7 ° C. overnight to separate colorless crystals. The separated crystals are recovered by filtration to give 40 mg of crystalline N-deacetyl TAN-588 (Isomer A).

The crystals of N-deacetyl TAN-588 obtained above exhibit the physico-chemical properties as described below.

1) Appearance:

Colorless crystals

2) Melting Point:

177 to 181 ° C (decomposition)

3) Specific Radiance:

+124°±20°(c=0.1, 물)

+ 124 ° ± 20 ° (c = 0.1, water)

4) Molecular weight: m / z 231 (M + H) ⁺ (FD-MS method)

5) Elemental Analysis:

Found (%): C; 41.57, H; 4.39, N; 12.11.

Calculated (%): C; 41.75, H; 4.38, N; 12.17, O; 41.71.

6) Molecular formula: C ₈ H ₁₀ N ₂ O ₆

7) UV Spectrum: Water

)λ _max 221 ± 2 nm

)

8) IR Spectrum: KBr Method

The main absorption peaks are as follows.

3450, 3220, 2950, 2900, 1800, 1735, 1660, 1580, 1440, 1420, 1400, 1360, 1340, 1310, 1280, 1200, 1160, 1110, 1050, 1025, 980, 940, 920, 810, 770, 710, 690, 600, 540 cm ⁺¹

9) ¹ H-NMR spectrum: 400 MHz, D ₂ O, The following signal is observed. δppm J (㎐)

2.52 (1H, m), 2.72 (1H, m), 2.91 (1H, m), 3.08 (1H, m), 4.34 (1H, m), 4.55 (1H, m), 4.78 (1H, m).

10) CD spectrum: water

A negative cotton effect is observed at 238 ± 3 nm.

11) Solubility:

Soluble: Water

Difficulty: dimethyl sulfoxide, ethyl acetate, chloroform, diethyl ether

12) HPLC: The conditions are as described for the mixture of isomers A and B.

Rt, 3.3 min

13) The distinction between acidic, neutral and basic:

Amphoteric substances

Reference Example 6

657 mg of TAN-588 benzhydryl ester (isomer B) was reacted and treated by the method of Reference Example 3 to obtain 200 mg of benzhydryl ester (isomer B) of N-deacetyl TAN-588. 180 mg of the compound is dissolved in 18 ml of aqueous tetrahydrofuran (1: 1), 90 mg of 10% palladium-carbon is added to this solution, followed by stirring under hydrogen stream. After filtering off the catalyst, the filtrate was concentrated, the aqueous layer was washed with diethyl ester, and then concentrated and dried to obtain 77 mg of N-deacetyl TAN-588 (isomer B) powder.

The powder of N-deacetyl TAN-588 obtained above exhibits the following physical-chemical properties.

1) Appearance: White powder

2) Molecular Weight:

m / z 231 (M + H) ⁺ (FD-MS method)

3) Elemental Analysis

Found (%): C; 40.98, H; 4.88, N; 12.17.

Calculated ^* (%): C; 40.17, H; 4.64, N; 11.71, 0; 43.48.

(*: Calculated assuming 0.5 mole of adhering water)

4) Molecular formula: C ₈ H ₁₀ N ₂ O ₆

5) UV Spectrum: Water

)λ _max 221 ± 2 nm

)

6) IR Spectrum: KBr Method

The main peaks are as follows.

3440, 2980, 1800, 1760, 1670, 1570, 1520, 1390, 1290, 1250, 1190, 1090, 1050, 990, 920, 810, 760, 720, 690 cm ⁺¹

7) ¹ H-NMR spectrum: 400 MHz, D ₂ O, The following signal is observed. ppm J (dl).

2.52 (1H, m), 2.72 (1H, m), 2.90 (1H, m), 3.08 (1H, m), 4.44 (1H, m), 4.68 (1H, m), 4.86 (1H, m).

8) CD spectrum: water

A negative cotton effect is observed at 224 ± 2 nm.

9) Solubility:

Soluble: Water

Poorly soluble: dimethyl sulfoxide, ethyl acetate, chloroform, diethyl ether.

10) HPLC: The conditions are as described for the mixture of isomers A and B.

Rt, 3.1 min

11) The distinction between acidic, neutral and basic:

Amphoteric substances

Reference Example 7

TAN-588 sodium salt (400 mg) was dissolved in DMF (4 mL), triethylamine (10 μL) and p-nitrobenzylbromide (800 mg) were added to the solution, followed by stirring at room temperature for 3 hours. 0.1 M phosphate buffer (pH 6.3, 50 mL) was added to the reaction solution, and extraction was performed twice with ethyl acetate (50 mL). The extracts were washed with water and concentrated, and the resulting oily substance was treated with ethyl acetate-petroleum benzine and converted into a powder (507 mg) to convert TAN-588 p-nitrobenzylester (isomer A) and TAN-588 p-nitrobenzyl ester ( A mixture of isomers B) is obtained. The resulting powder was chromatographed on a column of Sephadex LH-20 using ethyl acetate: methanol = 19: 1 as a mobile phase, and TAN-588 p-nitrobenzyl ester (isomer A) (105 mg), TAN-588 p- Nitrobenzyl ester (isomer B) (67 mg) and mixtures thereof (280 mg) are obtained.

The p-nitrobenzyl ester of TAN-588 (mixture of isomers A and B) obtained above exhibits the following physical-chemical properties.

1) Appearance: White powder

2) non-radiation:

+16.3°±5°(c=0.485, CHCl₃)

+ 16.3 ° ± 5 ° (c = 0.485, CHCl ₃ )

3) Molecular weight: 407 (SIMS method)

4) Elemental Analysis

Calculated (%): C; 50.13, H; 4.21, N; 10.32, O; 35.35.

Found (%): C; 50.26, H; 4.32, N; 10.31.

5) Molecular formula: C ₁₇ H ₁₇ N ₃ O ₉

6) UV Spectrum:

=262±2(281+20), 214±2(278±20, 쇼울더)

= 262 ± 2 (281 + 20), 214 ± 2 (278 ± 20, shoulder)

7) IR spectrum: KBr method

3400, 3080, 2960, 1805, 1760, 1680, 1610, 1520, 1450, 1380, 1350, 1270, 1180, 1105, 1050, 1015, 970, 905, 850, 740, 690, 600, 540 cm ⁺¹ .

8) ¹ H-NMR spectrum: 90MHz, CDCl ₃ , ppm J (㎐)

2.05 (3H, s), 2.3 to 3.3 (4H, m), 4.10 (1H, m), 4.5 to 5.1 (2H, m), 5.35 (2H, s), 6.25 (1H, d, like), 7.55 ( 2H, dd, like), 8.27 (2H, d, like).

9) TLC:

Carrier: Silica gel (manufactured by West Germany Merck)

Electrosolvent: Chloroform: Methanol (19: 1)

Rf values, 0.25 and 0.32

10) The distinction between acidic, neutral and basic:

Neutral

The TAN-588 p-nitrobenzyl ester (isomer A) obtained above exhibits the following physical-chemical properties.

1) Appearance: White powder

2) Specific Radiance:

+97.3°±15°(c=0.48, CHCl₃)

+ 97.3 ° ± 15 ° (c = 0.48, CHCl ₃ )

3) Molecular weight: 407 (SIMS method)

4) Elemental Analysis

Calculated (%): C; 50.13, H; 4.21, N; 10.32, O; 35.35.

Found (%): C; 50.20, H; 4.22, N; 10.13.

5) Molecular formula: C ₁₇ H ₁₇ N ₃ O ₉

6) UV Spectrum:

=262±2㎚(280±30), 241±2㎚(276±30, 쇼울더)

= 262 ± 2 nm (280 ± 30), 241 ± 2 nm (276 ± 30, shoulder)

7) ¹³ C-NMR spectrum: (100MHz, CDCl ₃ )

173.70 (s), 171.53 (s), 170.72 (s), 165.09 (s), 148.06 (s), 141.38 (s), 128.86 (d), 123.91 (d), 91.82 (s), 71.60 (t), 67.29 (t), 53.00 (d), 29.09 (t), 27.49 (t), 22.64 (q) ppm.

8) IR Spectrum: KBr Method

3400, 3080, 2950, 1805, 1775, 1760, 1680, 1610, 1530, 1450, 1380, 1350, 1300, 1275, 1190, 1105, 1060, 1020, 980, 910, 850, 740, 700, 600, 540 cm ⁺¹ .

9) TLC:

Carrier: Silica gel (manufactured by West Germany Merck)

Developing Solvent: Chloroform: Methanol (19: 1)

Rf value, 0.25

10) The distinction between acidic, neutral and basic:

Neutral

The TAN-588 p-nitrobenzyl ester (isomer B) obtained above exhibits the following physical-chemical properties.

1) Appearance: White powder

2) Specific Radiance:

-64.5°±15°(c=0.50, CHCl₃)

-64.5 ° ± 15 ° (c = 0.50, CHCl ₃ )

3) Molecular weight: 407 (SIMS method)

4) Elemental Analysis

Calculated (%): C; 50.13, H; 4.21, N; 10.32, O; 35.35.

Found (%): C; 50.10, H; 4.21, N; 10.15.

5) Molecular formula: C ₁₇ H ₁₇ N ₃ O ₉

6) UV Spectrum:

=262±2㎚(282±30), 214±2㎚(280±30, 쇼울더)

= 262 ± 2 nm (282 ± 30), 214 ± 2 nm (280 ± 30, shoulder)

7) ¹³ C-NMR spectrum: (100MHz, CDCl ₃ )

173.59 (s), 170.86 (s), 170.61 (s), 165.06 (s), 148.12 (s), 141.24 (s), 128.96 (d), 123.96 (d), 91.69 (s), 74.60 (t), 67.39 (t), 51.94 (d), 29.11 (t), 127.38 (t), 22.67 (q), ppm.

8) IR Spectrum: KBr Method

3400, 3090, 2950, 1805, 1760, 1680, 1610, 1530, 1450, 1380, 1355, 1270, 1180, 1105, 1055, 1015, 965, 910, 855, 740, 695, 600, 540 cm ⁺² .

9) TLC: The conditions are the same as described for TAN-588 p-nitrobenzyl ester (This Property A).

Rf value, 0.32

10) The distinction between acidic, neutral and basic:

Neutral

Example 1

Sodium 2-{(4S) -4- [2- (2-amino-4-thiazolyl)-(Z) -2- (methoxyimino) acetamido] -3-oxo-2-isoxazolidinyl } -5-Oxo-2-tetrahydrofuran carboxylate [Compound (Ic)]

(a) Diphenylmethyl 2-{(4S) -4- [2- (2-chloroacetamido-4-thiazolyl)-(Z) -2- (methoxyimino) acetamido] -3- Preparation of oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (Ia)]:

Diphenylmethyl 2-[(4S) -4-amino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofurancarboxylate obtained in Reference Example 3 [Compound (R-3 )] Is dissolved in dimethylformamide (DMF) 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-methoxyiminoacetic acid, 1-hydroxybenzotriazole (HOBT) and To a solution of dicyclohexylcarbodiimide (DCC) was added under ice-cooling and stirred for 1 hour.

Ethyl acetate is added to the reaction solution, and the separated precipitate is filtered off, and the filtrate is washed successively with aqueous sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was chromatographed on silica gel, and then eluted with ethyl acetate-hexane (2: 1) to obtain compound (1a) as a colorless foamy substance.

(b) diphenylmethyl 2-{(4S) -4- [2- (2-amino-4-thiazolyl)-(Z) -2- (methoxyimino) acetamido] -3-oxo-2 Preparation of Isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (1b)]:

Compound (1a) obtained above is dissolved in a mixed solution of tetrahydrofuran and water, sodium N-methyldithiocarbamate is added to the solution little by little, and then stirred at room temperature for 1 hour. THF is distilled off and the residue is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The extract is separated from the solvent and the residue is chromatographed on silica gel and then eluted with ethyl acetate to give compound 1b as a colorless foamy material.

(c) Preparation of the target compound (Ic):

Anisole and trifluoroacetic acid are added to a dichloromethane solution of compound (1b) under a nitrogen atmosphere at -10 to -15 ° C, and stirred for 5.5 hours. The reaction solution was cooled and added to a pH 7.0 phosphate buffer (8 ml) containing sodium hydrogen carbonate (220 mg), and the aqueous layer was separated while extracting the organic layer with a pH 7.0 buffer solution (4 ml). The combined aqueous layers are washed with dichloromethane and concentrated under reduced pressure. The concentrate is chromatographed on HP-20, eluted with water, and the eluate is lyophilized to give the title compound (Ic) as colorless powder.

Example 2

Sodium 2-{(4S) -4- [D-2- (4-ethyl-2,3-dioxo-1-piperazinocarboxamido) -2-phenylacetamido] -3-oxo-2 Preparation of Isoxazolidinyl} -5-oxo-2-tetrahydrofurancarboxylate [Compound (2b)]:

(a) Preparation of the diphenylmethyl ester of the compound (2a) and the target compound (2b):

Compound (2a) by the method of Example 1 (a) from compound (R-3) and N- (4-ethyl-2,3-dioxo-1-piperidinylcarbonyl) -D-phenylglycine; Diphenylmethyl ester of the target compound (2b) is obtained.

(b) Preparation of the target compound (2b):

Compound (2a) obtained above was dissolved in THF (10 mL) and a pH 6.86 buffer (5 mL), and 5% palladium-carbon (141 mg) was added to the solution, followed by stirring for 20 minutes under hydrogen atmosphere and ice cooling. do. The catalyst is filtered off and the filtrate is evaporated under reduced pressure to remove THF. The remaining solution is washed with ethyl acetate, the aqueous layer is concentrated under reduced pressure, chromatographed on a column of XAD-2 and eluted with 20% aqueous ethanol. The eluate is concentrated under reduced pressure, and the concentrate is lyophilized to give the title compound (2b) as a colorless powder.

Example 3

Sodium 2-{(4S) -4- [D-2- (3-methylsulfonyl-2-oxoimidazolidine-1-carboxamido) -2-phenylacetamido] -3-oxo-2 Preparation of Isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (3b)]:

Compound (3a), the objective by the method of Example 1 (a) from compound (R-3) and N- (3-methylsulfonyl-2-oxoisoxazolidinyl-1-carbonyl) -D-phenylglycine Diphenyl methyl ester of compound (3b) was obtained, and target compound (3b) was obtained by the method of Example 2.

Example 4

Sodium 2-{(4S) -4- [D-2- (3-furfurylideneamido-2-oxoimidazolidine-1-carboxamido) -2-phenylacetamido] -3- Preparation of oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofurancarboxylate [Compound (4b)]:

Compound (R-3) was acylated by the method of Example 1 (a) to give the diphenylmethyl ester of the compound (4a) and the target compound (4b). The target compound (4b) was obtained by the method of Example 2. ).

Example 5

Sodium 2-{(4S) -4- (2-thienylacetamido) -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofurancarboxylate [Compound (5b)] Preparation of:

Dimethylformamide and 2-thiophene acetyl chloride are added to a dichloromethane solution of compound (R-3) under ice-cooling, and stirred for 10 minutes and at room temperature for 20 minutes. Ethyl acetate is added to the reaction solution, and the organic layer is washed successively with aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and ether was added to the residue to obtain a diphenylmethyl ester of the compound (5a) or the target compound (5b) as a colorless powder. Compound (5a) was treated by the method of Example 1 (c) to give the target compound (5b).

Example 6

Sodium 2-[(4S) -4- (2-cyanoacetamido) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofurancarboxylate [Compound (6b)] Preparation of:

Using compound (R-3) and cyanoacetic acid, the diphenylmethyl ester of the compound (6a) and the target compound (6b) was obtained by the method of 1 (a), and the method of Example 2 (b) was obtained. To obtain the target compound (6b).

Example 7

Sodium 2-{(4S) -4-[(1H) -tetrazolylacetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofurancarboxylate [Compound (7b Production of]]:

Diphenylmethyl ester of compound (7a) and target compound (7b) was obtained by the method of Example 1 (a) using compound (R-3) and (1H) -tetrazolyl acetic acid. The process of b) is carried out to obtain the target compound (7b).

Example 8

Sodium 2-[(4S) -4- (2,6-dimethoxybenzamido) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofurancarboxylate [Compound (8b Production of]]:

Using the compound (R-3) and 2,6-dimethoxybenzoyl chloride, the diphenylmethyl ester of the compound (8a) and the target compound (8b) was obtained by the method of Examples 5 and 2 (b). Compound (8b) is prepared.

Example 9

Sodium 2-[(4S) -4- (5-methyl-3-phenyl-2-isoxazolin-4-carboxamido) -3-oxo-2-isoxazolidinyl] -5-oxo-2- Preparation of Tetrahydrofurancarboxylate [Compound (9b)]:

Diphenyl of compound (9a) and target compound (9b) by the method of Example 5 using compound (R-3) and 5-methyl-3-phenyl-2-isoxazolyl-4-carbonylchloride Methyl ester is obtained and the target compound 9b is obtained by performing the method of Example 2 (b).

Example 10

Sodium 2-[(4S) -4- (2-ethoxynaphthalenyl-1-carboxamido) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofurancarboxylate Preparation of [Compound (10b)]:

Diphenylmethyl ester of compound (10a) and target compound (10b) was obtained by the method of Example 5 using compound (R-3) and 2-ethoxynaphthalenyl-1-carbonyl chloride. The method of Example 2 (b) was carried out to obtain the target compound 10b.

The reaction conditions of Examples 1 to 10 and the yields and representative physico-chemical properties of the compounds obtained are shown below.

Example 11

Sodium 2-[(4S) -4- (2-cyanomethylthio acetamide) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (11b) Manufacturing of

Using the compound (R-3) and cyanomethylthioacetyl chloride, the diphenylmethyl ester of the compound (11a) and the target compound (11b) was obtained by the method of Example 5, and the method of Example 1 (c) Is carried out to obtain the target compound (11b).

Example 12

Sodium 2-[(4S) -4- (2-difluoromethylthio acetamide) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (12b Production of]]:

Compound (12a) and diphenylmethyl ester of target compound (12b) were obtained by the method of Example 5 using compound (R-3) and difluoromethylthioacetyl chloride, and the compound of Example 1 (c) The method is carried out to obtain the target compound 12b.

Example 13

Sodium 2-{(4S) -4-[(R) -2- (4-cyclohexyl-2,3-dioxo-1-piperazinocarboxamido-2-phenyl acetamido] -3-oxo -2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (13b)]

Compound (R-3) and N- (4-cyclohexyl-2,3-dioxo-1-piperazinylcarbonyl) -D-phenylglycine using the compound of Example 2 (a) 13a) (chromatography on silica gel separates stereoisomers A and B associated with the 2-position) to give the diphenylmethyl ester of the desired compound (13b). The desired compound (13b) is obtained by the method of Example 2 (b) using isomers A and B of compound (13a).

Example 14

Preparation of Sodium 2-((4S) -4-chloroacetamide-3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofuran carboxylate [Compound (14b)]:

To the dichloromethane solution of compound (R-3) is added quenching propylene oxide at -10? -20 占 폚, chloroacetyl chloride is added dropwise to the mixture and stirred at the same temperature for 1 hour. The reaction solution is poured into an aqueous sodium hydrogen carbonate solution (10 ml), the organic layer is separated, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was chromatographed on a column of silica gel, and then eluted with dichloromethane: ethyl acetate: hexane (1: 1: 1) to diphenylmethyl of crystalline compound (14a) and target compound (14b). Obtain an ester.

Compound 14a was subjected to deprotection reaction by the method of Example 1 (c) to obtain target compound 14b.

Example 15

Sodium 2-{(4S) -4- [2- (4-pyridylthio) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [ Preparation of Compound (15b)]

Reaction with 4-pyridine thiol using compound (14a) obtained in Example 14 to obtain diphenylmethyl ester of compound (15a) and target compound (15b) was carried out. To give the desired compound (15b).

The reaction conditions of Examples 11-15 and the yields and representative physico-chemical properties of the compounds obtained are shown below.

Example 16

Preparation of Methyl 2-[(4S) -4-acetamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (16)]:

Sodium 2-[(4S) -4-acetamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate obtained in Reference Example 1 [Compound (R-1 )] Is dissolved in DMF, methyl iodide is added to this solution and stirred for 5 hours at room temperature under sun protection. The reaction solution is concentrated and 50 ml of water is added to the concentrate, followed by extraction with 20 ml of dichloromethane. The extract is concentrated and the residue is crystallized with ethyl acetate-ether to give crystals (1.36 g). Crystals (mixture of isomers A and B, 1 g) are chromatographed on silica gel (50 g) and fractional elution is carried out with a solvent system of chloroform-methanol (30: 1). The fraction which first flowed out of the column was concentrated and crystallized to give the target compound (isomer B of 16), and then the fraction from the column was concentrated and crystallized to give the target compound (isomer A of 16) in crystalline powder.

Example 17

Preparation of pivaloyloxymethyl 2-[(4S) -4-acetamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (17)] :

Compound (R-1) is dissolved in DMF, chloromethyl pivalate is added to the solution, followed by stirring. Water is added to the reaction solution, and the mixture is extracted with 150 ml of ethyl acetate. The extract is concentrated and the resulting residue is powdered with petroleum ether. 140 mg of the resulting powder was chromatographed in Sephadex LH-20 (500 mL) and eluted with ethyl acetate-methanol (19: 1). The corresponding fractions are treated to give crystalline target compound (isomer B of 17) and compound (isomer A of 17), respectively.

Example 18

3,5-Dinitrobenzyl 2-[(4S) -4-acetamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (18)] Preparation of:

Compound (R-1) is dissolved in DMF, 3,5-dinitro benzyl chloride is added to the solution, and then stirred. Water is added to the reaction system and the mixture is extracted with ethyl acetate. The extract is concentrated and the residue is powdered from petroleum ether. 624 mg of the product powder was crystallized with acetone-hexane to obtain the crystal of compound (Isomer A of 18). The mother liquor is also crystallized with the same solvent to obtain crystals of the target compound (Isomer B of 18).

Example 19

p-bromophenacyl2-[(4S) -4-acetamido-3-oxo-2-isoxazolidinyl)]-5-oxo-2-tetrahydrofuran carboxylate of [Compound (19)] Produce :

Compound (R-1) is dissolved in DMF, and p-bromophenacyl bromide is added to the solution, followed by stirring. Water is added to the reaction solution and the mixture is extracted with ethyl acetate. The extract is concentrated and petroleum benzine is added to the residue to give 410 mg of powder. The powder is chromatographed in Sephadex LH-20 (500 mL) and fractional elution is carried out using a solvent system of ethyl acetate-methanol (19: 1). The fraction from the first column obtains a powder of the desired compound (isomer B of 19), and the fraction from the column finally obtains a powder of the compound (isomer A of 19), the intermediate from the fraction from the column (19 isomer of 19). Powder of A and B).

Example 20

Preparation of p-bromobenzyl 2-[(4S) -4-acetamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (20)] :

Compound (R-1) is dissolved in DMF, triethylamine and p-bromobenzyl bromide are added to the solution, followed by stirring. 100 ml of 0.1 M phosphate buffer (pH 6.3) is added to the reaction solution, and the mixture is extracted with ethyl acetate. The extract is concentrated and 562 mg of powder are obtained by adding chloroform and petroleum benzine to the residue to convert to a powder. The powder is chromatographed on a column of Sephadex LH-20 and eluted with ethyl acetate-methanol (19: 1). Crystals of the desired compound (isomer B of 20) are obtained from the fraction from the first column, crystals of the compound (isomer A of 20) are obtained from the fraction from the last, and from compound (isomer A of 20) And a mixture of B).

The reaction conditions of Examples 16 to 20 and the yields and representative physical-chemical properties of the compounds obtained are shown below.

Example 21

Preparation of Sodium 2-[(4S) -4-formylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (21b)]:

(a) of diphenylmethyl 2-[(4S) -4-formylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (21a)] Produce :

Compound (R-3) is dissolved in dichloromethane, and a mixed solution of pyridine, acetic anhydride and formic acid is added to the solution, followed by stirring. The reaction solution is washed successively with N-hydrochloric acid and 2% aqueous sodium hydrogen carbonate solution, the organic layer is dried and concentrated, and ether is then added to the residue to obtain a powder of compound 21a.

(b) Preparation of the target compound (21b):

10% palladium-carbon is suspended in THF, and compound (21a) is added to the suspension, followed by stirring under hydrogen stream. After filtration of the catalyst, the filtrate is concentrated and water is added to the concentrated residue, which is then adjusted to pH6. The aqueous layer is washed with ether and chromatographed over activated carbon. Fractional elution is carried out using a solvent system of 8% isobutanol / 0.02N aqueous ammonia and the eluted fractions are concentrated. The residue is treated with acetone and converted to a powder to give a powder of the desired compound (21b).

Example 22

Preparation of Sodium 2-[(4S) -4-n-butyrylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (22b)]:

(a) of diphenylmethyl 2-[(4S) -4-n-butyrylamino-3-oxo-2-isoxazolidinyl] -5-oxo-tetrahydrofuran carboxylate [Compound (22a)] Produce :

Compound (R-3) is dissolved in dichloromethane, N, N-dimethylacetamide (DMA) and n-butyrylchloride are added to the solution and stirred. The reaction solution is treated by the method of Example 21 (a) to give a powder of compound 22a.

(b) Preparation of the target compound (22b):

10% palladium-carbon is suspended in THF and 0.1M phosphate buffer (pH 7.0), and compound (22a) is added to the suspension, followed by stirring under hydrogen stream. After filtration of the catalyst, THF is distilled off, the aqueous layer is washed with ether and then chromatographed on a column of Diion HP-20. Elution with water is carried out, and the active fractions are concentrated and dried to obtain a powder of the target compound (22b).

Example 23

Preparation of Sodium 2-[(4S) -4-methoxycarbonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (23b)]:

(a) Diphenylmethyl 2-[(4S) -4-methoxycarbonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (23a) Manufacturing of

Compound (R-3) is dissolved in THF, triethyl amine and methylchlorocarbonate are added to the solution, followed by stirring. The reaction solution is treated by the method of Example 21 (a) to give a powder of compound 23b.

(b) Preparation of the target compound (23b):

Compound (23a) is reacted similarly to Example 22 (b), and the reaction solution is treated by the method of Example 21 (b) to obtain a powder of the target compound (23b).

Example 24

Sodium 2-[(4S) -4- (N-benzyloxycarbonyl) gylsilamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (24b Production of]]:

(a) Diphenylmethyl 2-[(4S) -4- (N-benzyloxycarbonyl) glycidylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxyl Preparation of the rate [Compound (24a)]:

Methylchlorocarbonate, N-benzyloxycarbonylglycine (Z-glycine) and triethylamine are added to THF, and a suspension of compound (R-3) dissolved in THF is added to the solution and stirred. The reaction solution is treated by the method of Example 21 (a) to give crystals of compound 24a.

(b) Preparation of the target compound (24b):

Compound (24a) was reacted in a similar manner to Example 22 (b) and treated by the method of Example 21 (b) to obtain a powder of the desired compound (24b).

Example 25

Preparation of Sodium 2-[(4S) -4-benzoylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (25b)]:

(a) Preparation of diphenylmethyl 2-[(4S) -4-benzoylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (25a)] :

Compound (R-3) is dissolved in dichloromethane, DMA and benzoyl chloride are added to the solution, followed by stirring. The reaction solution is treated by the method of Example 21 (a) to give crystals of compound 25a.

(b) Preparation of the target compound (25b):

Compound (25a) was reacted in a similar manner to Example 22 (b), and after treatment, the residue was chromatographed on a column of Diaion HP-20, eluted with 40% aqueous methanol to give the powder of target compound (25b). To obtain.

Example 26

Preparation of Sodium 2-[(4S) -4-phenylacetylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (26b)]:

(a) of diphenylmethyl 2-[(4S) -4-phenylacetylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (26b)] Produce :

Compound (R-3) is dissolved in dichloromethane, DMA and phenylacetylchloride are added to the solution, followed by stirring. The reaction solution is treated by the method of Example 21 (a) to give crystals of compound 26a.

(b) Preparation of the target compound (26b).

Compound (26a) is reacted and treated in a similar manner to Example 25 (b) to give a powder of the desired compound (26b).

Example 27

Preparation of Sodium 2-[(4S) -Nicotinylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (27b)]:

(a) of diphenylmethyl 2-[(4S) -4-nicotinylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (27a)] Produce :

Compound (R-3) is dissolved in dichloromethane, DMA and nicotinylchloride hydrochloride are added to the solution, followed by stirring. The reaction solution is treated by the method of Example 21 (a) to give crystals of compound 27a.

(b) Preparation of the target compound (27b):

Compound (27a) is reacted and treated in a similar manner as in Example 22 to give the desired compound (27b) in powder form.

Example 28

Of pivaloyloxymethyl 2-[(4S) -4-phenoxyacetylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (28c)] Produce :

(a) Diphenylmethyl 2-[(4S) -4-phenolcyacetylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (28a)] Preparation of:

Compound (R-3) is dissolved in dichloromethane, DMA and phenoxyacetylchloride are added to the solution, followed by stirring. The reaction solution is treated by the method of Example 21 (a) to give crystals of compound 28a.

(b) Preparation of sodium 2-[(4S) -4-phenoxyacetylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (28b)] :

Compound 28a was reacted in a similar manner to Example 25 (b) to obtain a powder of the desired compound 28b.

(c) Preparation of the target compound (28c):

Compound (28b) is dissolved in DMF, chloromethyl pivalate is added to the solution, and then stirred. Water is added to the reaction solution and the mixture is extracted with ethyl acetate. The extract is concentrated and hexane is added to the residue. The mixture is decanted twice and decanted twice with petroleum benzine. The residue is dried through a vacuum pump to afford the desired compound 28c.

Example 29

Sodium 2-[(4S) -4- (P-toluenesulfonyl) amino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (29b)] Produce :

(a) Diphenylmethyl 2-[(4S) -4-P-toluene sulfonyl amino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (29a Production of]]:

Compound (R-3) is dissolved in pyridine and P-toluene sulfonyl chloride is added to the solution, followed by stirring. Dichloromethane and water are added to the reaction solution, and the organic layer is washed successively with dilute hydrochloric acid and dilute aqueous sodium hydrogen carbonate, and then concentrated. Ether is added to the concentrate to give a powder of compound 29a.

(b) Preparation of the target compound (29b):

Compound (29a) is reacted in a similar manner to Example 25 (b) to obtain a powder of the target compound (29b).

Example 30

Diphenylmethyl 2-[(4S) -4- (P-bromobenzoyl) amino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (30a) Manufacturing of

Compound (R-3) is dissolved in dichloromethane, DMA and P-bromobenzoyl chloride are added to the solution, followed by stirring. The reaction solution is reacted in a similar manner to Example 25 (b) to give 528 mg of crude material of compound 30a. This product is chromatographed on silica gel (50 g), and eluted with a solvent system of ethyl acetate-hexane (2: 3). The eluate is concentrated to give crystals of the target compound (30a).

Example 31

Diphenylmethyl2-[(4S) -4- (N-benzyloxycarbonyl-D-alanyl) amino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxyl Preparation of the rate [Compound (31a)]:

N-benzyloxycarbonyl-D-alanine and triethyl amine are added to a THF solution of methylchlorocarbonate, and a solution of Compound (R-3) dissolved in THF is gradually added, followed by stirring. The reaction is carried out according to the method of Example 21 (a), to obtain a powder of the target compound 31a.

The reaction conditions of Examples 21 to 31 and the yields and representative physico-chemical properties of the compounds obtained are shown below.

Example 32

Preparation of 2-[(4S) -4-dimethylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxysilane [Compound No. (32b)]:

(a) Preparation of diphenylmethyl 2-[(4S) -4-dimethylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (32a)] :

Compound (R-3) is dissolved in acetonitrile, formaldehyde, sodium cyanoborohydride and acetic acid are added to the solution, followed by stirring. After adding water to the reaction solution, acetonitrile was distilled off, and the aqueous layer was extracted with ethyl acetate. The extract is washed with 2% aqueous sodium hydrogen carbonate solution and concentrated, then the concentrate is mixed with THF and 2N hydrochloric acid and stirred overnight at room temperature. The organic layer is concentrated, water is added to the concentrate, and then adjusted to pH 10 with diluted aqueous sodium hydroxide solution. The aqueous layer is extracted with ethyl acetate and the extract is concentrated to give a powder of compound 32a.

(b) Preparation of the target compound (32b):

Compound 32a was reacted in the same manner as in Example 25 (b) to obtain a powder of the target compound 32b.

The reaction conditions of Example 32 and the yield and representative physicochemical properties of the target compound are shown below.

Example 33

Sodium 2-{(4S) -4- [2- (2-amino-4-thiazolyl) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofurancar Preparation of Cyxlate [Compound (33c)]:

(a) diphenylmethyl 2-{(4S) -4- [2- (2-chloroacetamido-4-thiazolyl) acetamido] -3-oxo-2-isoxazolidinyl} -5- Preparation of oxo-2-tetrahydrofuran carboxylate [Compound (3a)]:

Compound 33a is obtained by the method of Example 5 using compound (R-3) and 2- (2-chloroacetamido-4-thiazolyl) acetylchloride.

(b) diphenylmethyl 2-{(4S) -4- [2- (2-amino-4-thiazolyl) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2 Preparation of Tetrahydrofuran Carboxylate [Compound (33b)]:

Compound (33a) obtained above was reacted in a similar manner to Example 1 (b) to give compound (33b).

(c) Preparation of the target compound (33c):

(33b) obtained above was reacted in a similar manner to Example 1 (c) to give the target compound 33c.

The reaction conditions of Example 33 and the yield and physico-chemical properties of the obtained compound are shown below.

Example 34

Sodium 2- [4-methoxy-4- (2-thienylacetamido) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (34b) Manufacture of

Compound (5a) obtained in Example 5 was dissolved in THF, a methanol solution of t-butyl hypochloride and lithium methoxide was added while cooling with dry ice-acetone, followed by stirring for 5 minutes. One drop of acetic acid is added, the reaction solution is diluted with ethyl acetate, and the organic layer is washed successively with aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is chromatographed on a column of silica gel to give the diphenyl methyl ester of the compound (34a) and the target compound (34b). Subsequently, it is dissolved in THF of compound (34a), and a pH 7.0 buffer, palladium-black and palladium oxide are added to the solution, followed by stirring under hydrogen stream. After filtering off the catalyst, the filtrate is concentrated under reduced pressure, and the aqueous layer is washed and concentrated with ether. Column chromatography of concentrate XAD-2 is eluted with 10% ethanol. The eluate was concentrated under reduced pressure and lyophilized to yield the desired compound 34b as an off-white powder.

Example 35

Disodium 2-{(4S) -4- [2- (2-amino-4-thiazolyl)-(Z) -2- (carboxymethyloxyimino) acetamido] -3-oxo-2-isoxazole Preparation of Ridinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (35d)]:

(a) Diphenylmethyl 2-{(4S) -4- [2- (2-chloroacetamido-4-thiazolyl)-(Z) -2- (4-nitrobenzyl oxycarbonylmethyloxyimino) Acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (35a)] Preparation of:

Compound (R-3) is suspended in dimethylchloromethane, butylene oxide and 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2- (4-nitrobenzyloxycarbonylme Toxyimino) acetyl chloride hydrochloride was added to the suspension under ice-cooling and the reaction was allowed to proceed for 1 hour. Ethyl acetate is added and the organic layer is washed successively with aqueous sodium bicarbonate solution and aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure to obtain compound 35a as a foamy material.

(b) diphenylmethyl 2-{(4S) -4- [2- (2-amino-4-thiazolyl)-(Z) -2- (4-nitrobenzeneoxycarbonyl methoxyimino) acetamido -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (35b)] Preparation of:

Compound 35a obtained above was reacted and treated in a similar manner to Example 1 (b) to give compound 35b.

(c) sodium 2 {(4S) -4- [2- (2-amino-4-thiazolyl)-(Z) -2- (4-nitrobenzyloxycarbonimethoxyimino) acetamido] -3- Preparation of oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (35c)]:

Compound 35b obtained above was reacted and treated in a similar manner to Example 1 (c) to give compound 35c.

(d) Preparation of the target compound (35d).

The compound 35c obtained above was reacted and treated in a similar manner to Example 2 (b) to obtain the target compound 35d.

The reaction conditions of Examples 34 and 35 and the yields and representative physico-chemical properties of the compounds obtained are shown below.

Example 36

Tablets are prepared by known methods using the following ingredients:

30 mg of compound (1c) obtained in Example 1

Corn starch 50mg

Lactose 28mg

Hydroxypropyl Cellulose L 20mg

Magnesium Stearate 2mg

400mg per tablet

Four to eight tablets are given to adults daily after meals (three times a day).

Example 37

Tablets are prepared by known methods using the following ingredients:

300 mg of the compound (35d) obtained in Example 35

Corn starch 50mg

Lactose 28mg

Hydroxypropyl Cellulose L 20mg

Magnesium Stearate 2mg

400mg per tablet

Four to eight tablets are given to adults daily after meals (three times a day).

Example 38

2-{(4S) -4- [2- (2-aminomethyl) phenylacetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylic acid [compound (38b)] Preparation:

(a) Diphenylmethyl 2-{(4S) -4- [2- (2-benzyloxycarbonylaminomethyl) phenylacetamido] -3-oxo-2-isoxazolidinyl} -5-oxo- Preparation of 2-tetrahydrofuran carboxylate [Compound (38a)]:

Compound 38a is obtained by the method of Example 1 (a) using compound (R-3) and 2-benzyloxycarbonylaminomethylphenyl acetic acid.

(b) Preparation of the target compound (38b): The compound (38a) was reacted and treated in a similar manner to Example 2 (B) to give the target compound (38b).

Example 39

Sodium 2-[(4S) -4- (4-fluorobenzenesulfonylamino) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (39b) Manufacture of

(a) Diphenylmethyl 2-[(4S) -4- (4-fluorobenzene sulfonylamino) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate Preparation of [Compound (39a)]:

Compound (R-3) and 4-fluorobenzenesulfonyl chloride and propylene oxide were stirred in DMA under ice-cooling for 1 hour and treated in a similar manner to Example 1 (a) to give compound 39a.

(b) Preparation of the target compound 39b. The compound 39a was catalytically reduced using palladium black and treated by the method of Example 2 (b) to obtain the target compound 39b.

Example 40

Sodium 2-{(4S) -4- {2- [1- (2-dimethylaminoethyl) -1H-5-tetrazolylthio] acetamido] -3-oxo-2-isoxazolidinyl} -5 Preparation of oxo-2-tetrahydrofuran carboxylate [Compound (49b)] Example 15 using compound (14a) and 1- (2-dimethylaminoethyl) -5-mercapto-1H-tetrazole The diphenylmethyl ester of the compound (40a) and the target compound (40b) was obtained by the method of, followed by formation of the target compound (40b).

Example 41

Sodium 2-{(4S) -4- [2- (4-methyl-4H-1,2,4-triazolyl-3-ylthio) acetamido] -3-oxo-2-isoxazolidinyl} Preparation of -5-oxo-2-tetrahydrofuran carboxylate [Compound (41b)]:

Diphenylmethyl ester of compound (41a) and target compound (41b) was obtained by the method of Example 15 using compound (14a) and 3-mercapto-4-methyl-4H-1,2,4-triazole. Obtained and the target compound (41b) are formed.

Example 42

Sodium 2-{(4S) -4-[(2S, 3S) -2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3-formyloxybutylamido]- Preparation of 3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (42b)]:

The method of Example 5 using compound (R-3) and (2S, 3S) -2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3-formyloxybutyric acid This yields the diphenylmethyl ester of the compound (42a) and the target compound (42b) to form the target compound (42b).

Example 43

Disodium 2-[(4S) -4- (2-phenyl-2-sulfoacetamido) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [ Preparation of Compound (43)]:

Compound (4-4) obtained in Reference Example 4 was dissolved in water, and an ether solution of sodium hydrogencarbonate and phenylsulfoacetyl chloride was added to the solution while stirring under ice-cooling. After the reaction proceeds for 1 hour, the aqueous layer is separated, washed with ethyl acetate and concentrated, and the concentrate is chromatographed on a column of XAD-2. The fraction eluted with water was lyophilized to give the title compound (43) as colorless powder.

Example 44

Sodium 2-{(4S) -4- [2- (2-amino-4-thiazolyl)-(E) -2-methoxyiminoacetamido] -3-oxo-2-isoxazolidinyl} Preparation of -5-oxo-2-tetrahydrofuran carboxylate [Compound (44c)]:

(a) Diphenylmethyl 2-{(4S) -4- [2- (2-chloroacetamido-4-thiazolyl)-(E) -2-methoxyiminoacetamido] -3-oxo -2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (44a)] Preparation: Compound (R-3) and 2- (2-chloroacetamido-4-thia Reaction and treatment in a similar manner to Example 1 (a) using zolyl)-(E) -2-methoxyiminoacetic acid yielded compound 44a.

(b) diphenylmethyl 2-{(4S) -4- [2- (2-amino-4-thiazolyl)-(E) -2-methoxyiminoacetamido] -3-oxo-2- Preparation of Isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (44b)]: Compound (44b) was obtained by the method of Example 1 (b) using compound (44a). do.

(c) Preparation of the target compound (44c): The target compound (44c) was obtained by treating the compound (44b) by the method of Example 1 (c).

Example 45

Sodium 2-[(4S) -4- (2-trimethylsilyl) ethoxycarbonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (45b )] Butylene oxide and trimethylsilyl ethoxycarbonyl chloride are added to a dichloromethane suspension of compound (R-3) and stirred for 2 hours. The solvent is distilled off, and the powder separated when hexane is added is collected by filtration to obtain the diphenylmethyl ester of the compound (45a) and the target compound (45b). This product is treated by the method of Example 2 (b) to afford the desired compound 45b.

Example 46

Preparation of 2-[(4S) -4- (1-aminocyclohexylcarbonylamino) -3-oxo-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylic acid [Compound (46b)] : By the method of Example 1 (a) using compound (R-3) and 1-benzyloxycarbonylamino cyclohexanecarboxylic acid, diphenylmethyl 2-[(4S) -4- (1- Benzyloxycarbonylamino cyclohexyl carbonylamino) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (46a)] is obtained. This product was treated by the method of Example 2 (b) to afford the target compound 46b.

Example 47

2-{(4S) -4- [3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarbonylamino] -3-oxo-2-isoxazolidinyl} -5-oxo Preparation of 2-tetrahydrofuran carboxylate [Compound (47b)]: Compound (R-3) and 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolicarbonyl chloride By the method of Example 5, diphenylmethyl ester of the compound (47a) and the target compound (47b) was obtained. This product is treated by the method of Example 1 (c) to afford the desired compound (47b).

Example 48

Sodium 2-{(4S) -4- [2- (2-pyridylio) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [ Compound (48b)]: Diphenylmethyl ester of compound (48a) and compound (48b) was obtained by the method of Example 15 using compound (14a) and 2-pyridine thiol, and target compound (48b). To form.

Example 49

Sodium 2-{(4S) -4- [2- (4-pyridylmethylthio) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate Preparation of [Compound (49b)] Using compound (14a) and 4-pyridylmethanethiol, diphenylmethyl ester of compound (49a) and target compound (49b) was obtained by the method of Example 15. Compound 49b is formed.

Example 50

Sodium 2-{(4S) -4- [2- (2-pyrimidinylthio) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate Preparation of [Compound (50b)] Using compound (14a) and 2-pyrimidinethiol, diphenylmethyl ester of compound (50a) and target compound (50b) was obtained by the method of Example 15. 50b is formed.

Example 51

Sodium 2-{(4S) -4- {2-[(E) -2- (acetamido vinyl) thio] acetamido} -3-oxo-2-isoxazolidinyl} -5-oxo-2 Preparation of Tetrahydrofuran Carboxylate [Compound (51b)]: Compound (14a) and (E) -2-acetamidovinylthiol were prepared by the method of Example 15 using a salt, Diphenylmethyl ester of the compound (51b) is obtained, and the target compound (51b) is formed.

Example 52

Preparation of Sodium 2-[(4S) -4-cyclopropylcarbonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (52b)]: Compound Compound (52a) and the diphenylmethyl ester of the target compound (52b) were obtained by the method of Example 1 (a) using (R-3) and cyclopropane carboxylic acid. The target compound (52b) is formed by the method.

Example 53

Preparation of Sodium 2-[(4S) -4-Methoxalylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (53b)]: Compound (R -3) and methyloxalyl chloride were used to obtain the diphenylmethyl ester of the compound (53a) and the target compound (53b) by the method of Example 2 (b), and by the method of Example 2 (b) The target compound (53b) is formed.

Example 54

Preparation of Sodium 2-[(4S) -4-acrylamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (54)]: Compound (R -3) is suspended in tetrahydrofuran, water and 5% palladium-carbon are added to the suspension, followed by stirring under ice cooling and hydrogen stream. After filtration of the catalyst, the filtrate is washed with water, the filtrate and wash are combined and concentrated under reduced pressure. The concentrate is washed with ethyl acetate, the aqueous layer is separated and then mixed with a tetrahydrofuran solution of sodium bicarbonate and acryloyl chloride with stirring under ice cooling. The reaction solution is washed with ethyl acetate and the aqueous layer is concentrated. The concentrate is chromatographed on a column of HP-20 and the fraction eluted with water is lyophilized to afford the desired compound (54).

Example 55

Sodium 2-{(4S) -4- [2- (2-chloro-4-pyridylthio) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran Preparation of carboxylate [Compound (55b)]: Diphenylmethyl ester of compound (55a) and target compound (55b) by the method of Example 15 using compound (14a) and 2-chloro-4-pyridinethiol. To obtain the desired compound (55b).

Example 56

Sodium 2-[(4S) -4- (2-acetamido-5-oxo-2-tetrahydrofuran carbonylamino) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetra Preparation of Hydrofuran Carboxylate [Compound (56b)]: Method of Example 1 (a) using Compound (R-3) and 2-acetamido-5-oxo-2-tetrahydrofuran carboxylate The diphenylmethyl ester of the compound (56a) and the target compound (56b) is obtained by this, and the target compound (56b) is formed by the method of Example 2 (b).

Example 57

Sodium 2-{(4S) -4- [2- (1-pyrazolyl) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (57b)] Preparation: A diphenylmethyl ester of the compound (57a) and the target compound (57b) was obtained by the method of Example 1 (a) using compound (R-3) and pyrazolyl acetic acid. The target compound 57b is formed by the method of Example 2 (b).

Example 58

Sodium 2-{(4S) -4- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-ethoxyiminoacetamido] -3- Preparation of oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [compound (58b)]: compound (R-3) and 2- (5-amino-1,2,4 The diphenylmethyl ester of the target compound (58a) and the target compound (58b) was prepared by the method of Example 1 (a) using -thiadiazol-3-yl)-(Z) -2-ethoxyiminoacetic acid. Obtained and formed the target compound 58b by the method of Example 1 (c).

Example 59

Sodium 2-{(4S) -4- [2- (3-pyridazinylthio) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate Preparation of [Compound (59b)] Using compound (14a) and 3-pyridazinethiol lithium salt, diphenylmethyl ester of compound (59a) and target compound (59b) was obtained by the method of Example 15. The target compound (59b) is formed.

Example 60

Preparation of Sodium 2-[(4S) -4-dichloroacetamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (60b)]: Compound ( The diphenylmethyl ester of the compound (60a) and the target compound (60b) was obtained by the method of Example 14 using R-3) and dichloroacetyl chloride to form the target compound (60b).

Example 61

Sodium 2-{(4S) -4-[(2R, 3S) -2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3-hydroxybutyramid] -3 Preparation of oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (61b)]: Compound (R-3) and (2R, 3S) -2- (4- Diphenyl of compound (61a), target compound (61b) by reaction similar to Example 1 (a) using ethyl-2,3-dioxo-1-piperazinecarboxamido) -3-hydroxybutyric acid Methyl ester is obtained, and the target compound (61b) is formed by catalytic reduction using palladium black.

Example 62

Sodium 2-{(4S) -4- [2- (5-trifluoromethyl-1,3,4-thiadiazol-2-ylthio) acetamido] -3-oxo-2-isoxazolidi Preparation of Nyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (62b)]: Compound (14a) and 5-trifluoromethyl-1,3,4-thiadiazole-2-thiol The diphenylmethyl ester of the compound (62a) and the target compound (62b) is obtained by the method of Example 15, and the target compound (62b) is formed.

Example 63

Disodium 2-{(4S) -4- {2- [1-ethoxy (hydroxy) phosphinylmethyl-1H-5-tetrazolylthio] acetamido} -3-oxo-2-isoxazolidinyl } -5-Oxo-2-tetrahydrofuran carboxylate [Compound (63b)] Preparation: Compound (14a) and 1- [ethoxy (hydroxy) phosphinylmethyl] -1H-tetrazol-5-thiol The diphenylmethyl ester of the compound (63a) and the target compound (63b) was obtained by the method of Example 15 using an O, S-disodium salt to form the target compound (63b).

Example 64

Sodium 2-{(4S) -4- {2- [5- (2-diethoxyphosphinylethylthio) -1,3,4-thiadiazolylthio] acetamido} -3-oxo-2-iso Preparation of Sazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (64b)]: Compound (14a) and 5- (2-diethoxyphosphinylethylthio) -1,3,4- The diphenylmethyl ester of the compound (64a) and the target compound (64b) was obtained by the method of Example 15 using thiadiazole-2-thiol to form the target compound (64b).

Example 65

Sodium 2-{(4S) -4- [2- (1-dimethylamino-1H-5-tetrazolylthio) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2- Preparation of tetrahydrofuran carboxylate [Compound (65b)]: Compound (65a), target compound by the method of Example 15 using compound (14a) and 1-dimethylamino-1H-tetrazol-5-thiol The diphenylmethyl ester of (65b) is obtained, and the target compound (65b) is formed.

Example 66

Sodium 2-{(4S) -4- [2- (4,5-dimethyl-2-thiazolylthio) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetra Preparation of hydrofuran carboxylate [Compound (66b)]: Compound (66a) and target compound (66b) by the method of Example 15 using compound (14a) and 4,5-dimethyl-2-thiazolthiol. Diphenylmethyl ester of was obtained to form the target compound (66b).

Example 67

Sodium 2-{(4S) -4- [2- (4,5-dimethyl-2-oxazolylthio) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetra Preparation of hydrofuran carboxylate [Compound (67b)]: Compound (67a), target compound (67b) by the method of Example 15 using compound (14a) and 4,5-dimethyl-2-oxazolthiol. The diphenyl methyl ester of was obtained to form the target compound (67b).

Example 68

Sodium 2-{(4S) -4- [2- (5-methoxymethyl-1,3,4-thiadiazol-2-ylthio) acetamido] -3-oxo-2-isoxazolidinyl } -5-Oxo-2-tetrahydrofuran carboxylate [Compound (68b)] Preparation: Using compound (14a) and 5-methoxymethyl-1,3,4-thiadiazole-2-thiol By the method of Example 15, diphenylmethyl ester of compound (68a) and target compound (68b) was obtained, and target compound (68b) was formed.

Example 69

Sodium 2-{(4S) -4- [2- (5-methylsulfonylmethyl-1,3,4-thiadiazol-2-ylthio) acetamido] -3-oxo-2-isoxazolidi Preparation of Nyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (69b)]: Compound (14a) and 5-methylsulfonylmethyl-1,3,4-thiadiazole-2-thiol The diphenylmethyl ester of the compound (69a) and the target compound (69b) is obtained by the method of Example 15, to form the target compound (69b).

Example 70

Sodium 2-{(4S) -4- [2- (4-ethyl-4H-1,2,4-triazol-3-ylthio) acetamido] -3-oxo-2-isoxazolidinyl} Preparation of -5-oxo-2-tetrahydrofuran carboxylate [Compound (70b)]: Example using compound (14a) and 4-ethyl-4H-1,2,4-triazole-3-thiol By the method of 15, diphenylmethyl ester of the compound (70a) and the target compound (70b) is obtained, and the target compound (70b) is formed.

Example 71

Disodium 2-{(4S) -4- [2- (5-carboxymethyl-1,3,4-thiadiazol-2-ylthio) acetamido] -3-oxo-2-isoxazolidinyl } -5-Oxo-2-tetrahydrofuran carboxylate [Compound (71b)] Preparation: Using compound (14a) and sodium 2-mercapto-1,3,4-thiadiazol-5-ylacetate The diphenylmethyl ester of the compound (71a) and the target compound (71b) was obtained by the method of Example 15 to form the target compound (71b).

Example 72

Sodium 2-{(4S) -4- {2- [1- (2-hydroxyethyl-1H-5-tetrazolylthio) acetamido} -3-oxo-2-isoxazolidinyl} -5- Preparation of oxo-2-tetrahydrofuran carboxylate [Compound (72b)]: Method of Example 15 using compound (14a) and 1- (2-hydroxyethyl) -1H-tetrazol-5-thiol This yields diphenylmethyl ester of compound (72a) and target compound (72b) to form target compound (72b).

Example 73

Sodium 2-{(4S) -4- {2- [1- (3-dimethylaminopropyl) -1H-5-tetrazolylthio] acetamido} -3-oxo-2-isoxazolidinyl} -5 Preparation of -Oxo-2-tetrahydrofuran carboxylate [Compound (73b)]: Example 15 using compound (14a) and 1- (3-dimethylaminopropyl) -1H-tetrazol-5-thiol By the method, diphenylmethyl ester of compound (73a) and target compound (73b) is obtained, and target compound (73b) is formed.

Example 74

2-[(4S) -4- (2-amino-3-sulfamoylpropionamido) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylic acid [compound ( 74b)] Preparation: Compound (74a), target compound (74b) by the method similar to Example 1 (a) using compound (R-3) and 2-benzyloxycarbonylamino-3-sulfamoylpropionic acid Diphenylmethyl ester of was obtained and catalytically reduced using palladium-black as a catalyst to form the target compound (74b).

Example 75

Sodium 2-{(4S) -4- [2- (4-cyano-3-hydroxy-5-isothiazolylthio) acetamido] -3-oxo-2-isoxazolidinyl} -5- Preparation of oxo-2-tetrahydrofuran carboxylate [Compound (75b)] Example 1 (a) using compound (R-3) and 4-cyano-3-hydroxy-5-isothiazolylacetic acid In a similar manner to), diphenylmethyl ester of compound (75a) and target compound (75b) is obtained, to form target compound (75b).

Example 76

Sodium 2-{(4S) -4- [2- (2-amino-4-thiazolyl) -2-oxoacetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2- Preparation of Tetrahydrofuran carboxylate [Compound (76b)]: Similar to Example 1 using compound (R-3) and 2- (2-chloroacetamido-4-thiazolyl) -2-oxoacetic acid Diphenylmethyl (4S) -2- {4- [2- (2-chloroacetamido-4-thiazolyl) -2-oxoacetamido] -3-oxo-2-isoxazolidinyl } -5-oxo-2-tetrahydrofuran carboxylate [Compound (76a)] was obtained, and this product was converted into the diphenylmethyl ester of the compound (76b) and the target compound (76c), followed by the desired compound ( 76c).

Example 77

Sodium 2-{(4S) -4- [2- (2-amino-4-thiazolyl)-(Z) -2-isopropoxyiminoacetamido] -3-oxo-2-isoxazolidinyl } -5-Oxo-2-tetrahydrofuran carboxylate [Compound (77c)] Preparation of compound (R-3) and 2- (2-chloroacetamido-4-thiazolyl- (Z) -2 -Diphenylmethyl 2-{(4S) -4- [2- (2-chloroacetamido-4-thiazolyl)-(Z)-by a similar method as in Example 1 using isopropoxyiminoacetic acid 2-isopropoxyiminoacetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (77a)] to obtain a product (77b) After conversion to diphenylmethyl ester of the target compound (77c), the target compound (77c) is obtained.

Example 78

Preparation of Sodium 2-[(4S) -4-trifluoroacetamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (78b)]: The compound (R-3) and trifluoroacetic anhydride are stirred in dichloromethane under ice-cooling, the reaction solution is poured into water, and extracted with ethyl acetate. The organic layer is washed successively with aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, and dried (MgSO ₄ ). The solvent was distilled off and the residue was chromatographed on a silica gel column to obtain the diphenylmethyl ester of the compound (78a) and the target compound (78b), and then reacted and treated similarly to Example 2 (b) to obtain the target compound ( 78b).

Example 79

Disodium 2-{(4S) -4- [2- (2-amino-4-thiazolyl)-(Z) -2- (1-carboxy-1-methylethoxyimino) acetamido] -3- Preparation of oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (79d)]: (a) Diphenylmethyl 2-{(4S) -4- {2- ( 2-chloroacetamido-4-thiazolyl)-(Z) -2- [1-methyl-1- (4-nitrobenzyloxycarbonyl) ethoxyimino] acetamido} -3-oxo-2- Preparation of Isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (79a)]: Compound (R-3) and 2- (2-chloroacetamido-4-thiazolyl)- Compound (79a) is obtained by the method of Example 1 (a) using (Z) -2 [1-methyl-1- (4-nitrobenzyloxycarbonyl) ethoxyimino] acetic acid.

(b) diphenylmethyl 2-{(4S) -4- {2- (2-amino-4-thiazolyl)-(Z) -2- [1-methyl-1- (4-nitrobenzyloxycarbonyl ) Ethoxyimino] acetamido} -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (79b)] Preparation of Compound (79a) Treatment by the method of 1 (b) affords compound (79b).

(c) to sodium 2-{(4S) -4- {2- (2-amino-4-thiazolyl)-(Z) -2- [1-methyl-1- (4-nitrobenzyloxycarbonyl) Preparation of Toxyimino] acetamido} -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (79c)]: Compound (79b) was prepared in Example 1 ( Treatment according to c) affords compound 79c.

(d) Preparation of the target compound (79d): The compound (79c) was treated by the method of Example 2 (b) to obtain the target compound (79d).

Example 80

Sodium 2-{(4S) -4- [2- (2-amino-4-thiazolyl)-(Z) -2- (hydroxyimino) acetamido] -3-oxo-2-isoxazolidinyl } -5-Oxo-2-tetrahydrofuran carboxylate [Compound (80b)] Preparation: (a) Diphenylmethyl 2-{(4S) -4- {2- (2-tritylamino-4- Thiazolyl)-(Z) -2- (trityloxyimino) acetamido} -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (80a) Preparation of 2- (2-tritylamino-4-thiazolyl)-(Z) -2- in which a solution of compound (R-3) dissolved in N, N-dimethylformamide was dissolved in tetrahydrofuran. (Trityloxyimino) acetic acid 2-benzothiazolylthio ester solution is added and stirred at room temperature for 16 hours. The reaction solution is diluted with ethyl acetate, washed successively with aqueous sodium bicarbonate solution and water, and dried (Na ₂ SO ₄ ). The solvent is distilled off and the residue is chromatographed on a silica gel column to give compound 80a.

(b) Preparation of the target compound (80b): Formic acid (> 98%) is added to a dichloromethane solution of compound (80), and the mixture is stirred at room temperature for 1 hour. After distilling off the solvent under reduced pressure, the residue was dissolved in dichloromethane, pH 7.0 phosphate buffer (10 mL) containing sodium hydrogencarbonate (400 mg) was added, and the solution was shaken to separate the aqueous layer. The organic layer is further extracted with pH 7.0 phosphate buffer (5 mL), the aqueous layers are combined, and concentrated under reduced pressure. The concentrate is chromatographed on a column of HP-20 and lyophilized to afford the desired compound (80b).

Example 81

Preparation of Sodium 2-[(4S) -4-isobutyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (81b)]: (a) Sodium diphenylmethyl 2-[(4S) -4-isobutyloxy carbonylamino-3-oxo-2-isoxazolidinyl-5-oxo-2-tetrahydrofuran carboxylate [Compound (81a )] Preparation: Compound 81a is obtained by the method of Example 23 (a) using compound (R-3) and isobutyl chlorocarbonate.

(b) Preparation of the target compound (81b): The compound (81a) was treated by the method of Example 23 (b) to obtain the target compound (81b).

Example 82

Diphenylmethyl 2-{(4S) -4- [N- (4-nitrobenzyl oxycarbonyl) glycyamino] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran Preparation of carboxylate [Compound (82)] by the method of Example 24 (a) using compound (R-3), methylchlorocarbonate and N- (4-nitrobenzyloxycarbonyl) glycine The desired compound (82) is obtained.

Example 83

Diphenylmethyl 2-{(4S) -4- [N- (2,2,2-trichloromethoxycarbonyl) phenylglycylamino] -3-oxo-2-isoxazolidinyl} -5-oxo- Preparation of 2-tetrahydrofuran carboxylate [Compound (83)]: Using compound (R-3), methylchlorocarbonate and N- (2,2,2-trichloroethoxycarbonyl) phenylglycine To obtain the target compound (83) by the method of Example 24 (a).

Example 84

Sodium {(4S) -4- [N- (benzyloxycarbonyl) -D-phenylglycosylamino] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate Preparation of [Compound (84b)]: (a) Diphenylmethyl 2-{(4S) -4- [N- (benzyloxycarbonyl) -D-phenylglycosylamino] -3-oxo-2-isoxazole Preparation of Ridinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (84a)] Example 1 using Compound (R-3) and N-benzyloxycarbonyl-D-phenylglycine Compound 84a is obtained by the method of a).

(b) Preparation of the target compound 84b. The compound 84a was treated by the method of Example 2 (b) to obtain the target compound 84b.

Example 85

Preparation of 2 [(4S) -4-L-phenylglycylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylic acid [Compound (85b)]: (a ) Diphenylmethyl 2-{(4S) -4- [N- (4-methoxybenzyloxycarbonyl) -L-phenylglycylamino] -3-oxo-2-isoxazolidinyl} -5-oxo Preparation of 2-tetrahydrofuran carboxylate [Compound (85a)] Example 1 (a) using compound (R-3) and N- (4-methoxybenzyloxycarbonyl) -L-phenylglycine Compound 85a is obtained by the method of

(b) Preparation of the target compound (85b): The compound (85a) was treated by the method of Example 1 (c) to obtain the target compound (85b).

Example 86

Preparation of 2-{(4S) -4-D-phenylglyciylamino-3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofuran carboxylic acid [Compound (86b)]: ( a) diphenylmethyl 2-{(4S) -4- [N- (4-methoxybenzyloxycarbonyl) -D-phenylglycosylamino] -3-oxo-2-isoxazolidinyl} -5- Preparation of oxo-2-tetrahydrofuran carboxylate [Compound (86a)]: Example 1 using compound (R-3) and N- (4-methoxybenzyloxycarbonyl) -D-phenylglycine Compound (86a) is obtained by the method of a).

(b) Preparation of the target compound (86b). The target compound (86b) was obtained by the method of Example 1 (c).

Example 87

Sodium 2-{(4S) -4-[(2S)-(2-hydroxy-2-phenylacetamido] -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran Preparation of carboxylate [Compound (87b)]: (a) Diphenylmethyl 2-{(4S) -4-[(2S)-(2-hydroxy-2-phenyl) acetamido] -3-oxo Preparation of 2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (87a)] Example 1 (a) using compound (R-3) and S-mandelic acid Compound (87a) is obtained by the method of.

(b) Preparation of the target compound (87b): The compound (87a) was treated by the method of Example 2 (b) to obtain the target compound (87b).

Example 88

Sodium 2-{(4S) -4-[(2R)-(2-hydroxy-2-phenyl) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydro Preparation of furan carboxylate [Compound (88b)]: Compound (88a) and diphenylmethyl ester of the target compound (88b) were prepared by the method of Example 87 using compound (R-3) and R-mandelic acid. Obtained and formed the target compound (88b).

Example 89

Sodium 2-{(4S) -4- [2- (4-chlorophenyl) -2-hydroxyacetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran Preparation of carboxylate [Compound (89b)]: Compound (89a), diphenyl of target compound (89b) by the method of Example 87 using compound (R-3) and 4-chloro-DL-mandelic acid. Methyl ester is obtained, and the target compound (89b) is formed.

Example 90

Sodium 2-{(4S) -4- [2-hydroxy-2- (4-hydroxyphenyl) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydro Preparation of furan carboxylate [Compound (90b)]: Compound (90a) and target compound (90b) by the method of Example 87 using compound (R-3) and 4-hydroxy-DL-mandelic acid Diphenylmethyl ester is obtained, and the target compound (90b) is formed.

Example 91

Sodium 2-[(4S) -4- (2-hydroxypropionamido) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (91b)] Preparation of the compound (91a) and the diphenylmethyl ester of the target compound (91b) by the method of Example 87 using compound (R-3) and DL-lactic acid to form the target compound (91b). .

Example 92

Disodium 2-[(4S) -4- (2-carboxy-2-phenylacetamido) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (92b)] Preparation: Bis (diphenylmethyl ester) of compound (92a) and target compound (92b) by the method of Example 87 using compound (R-3) and monodiphenylmethyl DL-phenyl malonate To obtain the desired compound (92b).

Example 93

Preparation of Sodium 2-[(4S) -4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (93b)]: Compound Compound (93a) and diphenylmethyl ester of target compound (93b) were obtained by the method of Example 5 using (R-3) and benzyloxycarbonyl chloride to form target compound (93b).

Example 94

Preparation of Sodium 2-((4S) -4-pyruvamido-3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofuran carboxylate [Compound (94b)]: Compound (R -3) and pyruvic acid were used to obtain the diphenylmethyl ester of the compound (94a) and the target compound (94b) by the method of Example 87 to form the target compound (94b).

Example 95

Pivaloyloxymethyl 2-{(4S) -4-[(2R)-(2-hydroxy-2-phenyl) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo- Preparation of 2-tetrahydrofuran carboxylate [Compound (95)]: Compound (95) is formed by the method of Example 28 (c) using compound (88b) and chloromethyl pyrrolate.

Example 96

Diphenylmethyl 2-[(4S) -4- (4-nitrobenzylinen) amino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (96) Preparation: Molecular sieve 4A is added to a dichloromethane solution of compound (R-3) and 4-nitrobenzaldehyde and stirred at room temperature for 8 hours. The molecular sieves are filtered off and the filtrate is concentrated to dryness under reduced pressure. Ether is added to the residue and converted to a powder to afford the desired compound (96).

Example 97

Sodium 2-{(4S) -4- [2- (3-chloro-6-pyridazinylthio) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydro Preparation of furan carboxylate [Compound (97b)]: Compound (97a) and target compound (97b) were obtained by the method of Example 15 using compound (14a) and 3-chloro-6-pyrididizinthiol sodium salt. Diphenylmethyl ester is obtained, and the target compound (97b) is formed.

Example 98

Sodium 2-[(4S) -4- (2-phenylthioacetamido) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (98b)] Preparation: Using the compound (R-3) and phenylthioacetic acid, the diphenylmethyl ester of the compound (98a) and the target compound (98b) was obtained by the method of Example 1 (a). The target compound (98b) is formed by the method of.

Example 99

Sodium 2-[(4S) -4- (2-ethoxydithiocarbonyl acetamido) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound ( 99b)] Preparation: A diphenylmethyl ester of the compound (99a) and the target compound (99b) was obtained by the method of Example 15 using compound (14a) and potassium ethyl acrylate, and the target compound (99b) was obtained. Form.

The reaction conditions of Examples 38-99 and the yields and representative physico-chemical properties of the compounds obtained are shown below.

Example 100

Sodium 2-{(4S) -4- [2- (2-amino-4-thiazolyl)-(Z) -2- (ethoxyimino) acetamido] -3-oxo-2-isoxazolidinyl Preparation of -5-oxo-2-tetrahydrofuran carboxylate [Compound (100)]:

(a) Compound (R-3) is dissolved in a mixed solvent of ethyl acetate and phosphate buffer (pH 7.0) with addition of 10% palladium-carbon. The resulting solution is stirred for 1.5 h in a hydrogen air stream under ice cooling. The catalyst is filtered off and rinsed with water, the filtrate and the antibacterial liquid are combined and the aqueous layer is separated. Tetrahydrofuran was added to the aqueous layer with sodium bicarbonate and 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-ethoxyiminoacetylchloride hydrochloride, and the resulting solution was cooled on ice for 30 minutes. Stir. Tetrahydrofuran is evaporated under reduced pressure and the resulting aqueous layer is rinsed with ethyl acetate.

(b) Tetrahydrofuran and sodium N-methyl dithio carbamate are added to the aqueous layer, and the resulting solution is stirred at room temperature for 30 minutes. Tetrahydrofuran is evaporated under reduced pressure. After rinsing with ethyl acetate, the resulting concentrate is column chromatographed on HP-20. The fractions are concentrated in 10% ethanol, concentrated and lyophilized to yield compound 100.

Example 101

Sodium 2-{(4S) -4- [2- (2-amino-5-chloro-4-thiazolyl)-(Z) -2- (methoxyimino) acetamido] -3-oxo-2- Preparation of Isoxazolidinyl} -5-oxo-2-tetra hydrofuran carboxylate [Compound (101)]:

In a reaction similar to Example 100 using compound (R-3) and 2- (5-chloro-2-chloroacetamido-4-thiazolyl)-(Z) -2-methoxyiminoacetyl chloride hydrochloride To yield compound (101).

Example 102

Sodium 2-{(4S) -4- [2-4-ethyl-2,3-dioxo-1-piperazino carboxamido) -2-thienylacetamido] -3-oxo-2-iso Preparation of Sazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (102b)]:

(a) Preparation of Diphenylmethyl Ester [Compound (102a)] of Compound (102b):

Compounds by the method of Example 1 (a) using compound (R-3) and 2- (4-ethyl-2,3-dioxo-1-piperazinyl carboxamido) -2-thienyl acetic acid Obtain 102a.

(b) Preparation of Compound 102b:

Compound 102a is reacted in a similar manner to Example 1 (c) to afford compound 102b.

Example 103

Preparation of Sodium 2-[(4S) -4-ureido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (103b)]:

(a) Preparation of Diphenyl Methyl Ester [Compound (103a)] of Compound (103b):

An aqueous potassium isocyanate solution is added to an acetic acid solution of compound (R-3), and the obtained solution is stirred at room temperature for 2 hours. The obtained reaction solution is added to water and extracted with ethyl acetate. The organic layer is washed with water, aqueous sodium bicarbonate solution and saturated salt solution and then dried (Na ₂ SO ₄ ). After evaporation of the solvent, the residue is subjected to column chromatography on silica gel to give compound 103a.

(b) Preparation of Compound (103b):

Compound 103b is reacted by a method similar to Example 2 (b) to give compound 103b.

Example 104

Preparation of Sodium 2-((4S) -4-phenylureylene-3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofuran carboxylate [Compound 104b]:

(a) Preparation of Diphenylmethyl Ester [Compound 104a] of Compound 104b:

Phenyl isocyanate is added to a dichloromethane solution of compound (R-3) and stirred at room temperature for 10 minutes. Evaporate the solvent. The residue is column chromatographed on silica gel to give compound 104a.

(b) Preparation of Compound 104b:

Compound 104a is reacted by a method similar to Example 2 (b) to give compound 104b.

Example 105

Sodium 2-{(4S) -4- [2- (pyridyl) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [Compound (105 )] Manufacture of:

Compound 105 is obtained by a method similar to Example 100 (a) using compound (R-3) and 2-pyridylacetylchloride hydrochloride.

Example 106

Sodium 2-{(4S) -4- [2- (4-chlorophenyl) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofurancarboxylate [Compound 106] Preparation of:

Compound 106 is obtained by a method similar to Example 100 (a) using compound (R-3) and 4-chlorophenylacetyl chloride.

Example 107

Sodium 2-{(4S) -4-[(2-chloro-2-phenyl) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [ Preparation of Compound (107)]

Compound 107 is obtained by a method similar to Example 100 (a) using compound (R-3) and 2-chloro-2-phenyl acetyl chloride.

Example 108

Sodium 2-{(4S) -4- [2- (3-pyridylthio) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [ Preparation of Compound 108b]

Treatment with compound 14a and sodium 3-pyridine thiol in a similar manner to Example 15 affords diphenylmethyl ester of compound 108b [compound 108a], the method of Example 1 (c) Further treatment to give compound 108b.

Example 109

Sodium 2-{(4S) -4- [2- (4-chlorophenylthio) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate [ Compound (109b)]

Diphenyl methyl ester [Compound 109a] of compound 109b was obtained by a method similar to Example 15 using compound 14a and sodium 4-chlorophenylthiol, to obtain compound 109b.

Example 110

Sodium 2-[(4S) -4- (2-isopropyl phenoxy carbonylamino) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (110b )] Manufacture of:

Diphenylmethyl ester of compound 110a, compound 110b was obtained by a method similar to Example 5 using compound (R-3) and 2-isopropyl phenoxycarbonyl chloride, and Example 2 (b) Compound (110b) is obtained by similar method).

Example 111

Preparation of Sodium 2-((4S) -4-difluoroacetamido-3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofuran carboxylate [Compound (111b)]:

Diphenyl methyl ester [Compound (111a)] of Compound (111b) was obtained by a method similar to Example 1 (a) using Compound (R-3) and difluoro acetic acid, and Example 2 (b). Compound (111b) is obtained by similar method as above.

Example 112

Sodium 2- [4 (s) -4- (3-chloro) propionamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (112)] Preparation of:

Compound 112 is obtained by a method similar to Example 100 (a) using compound (R-3) and 3-chloropropionyl chloride.

Example 113

Of pivaloyloxymethyl 2-((4S) -4-chloroacetamido-3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofuran carboxylate [Compound (113)] Produce :

Compound 113 is obtained by a method similar to Example 17 using compound 14b and chloromethyl pivalate.

Example 114

Pivaloyloxymethyl 2-[(4S)-(2-phenylthioacetamido) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (114 )] Manufacture of:

Compound 114 is obtained by a method similar to Example 17 using compound 98b and chloromethyl pivalate.

Example 115

Preparation of Sodium 2-((4S) -4-propionamido-3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofuran carboxylate [Compound (115b)]:

Diphenyl methyl ester of compound 115b [Compound 115a] was obtained by a method similar to Example 5 using compound (R-3) and propionyl chloride, and in a method similar to Example 2 (b) To yield compound 115b.

Example 116

Pivaloyloxy methyl 2-((4S) -4-benzyloxy carbonylamino-3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofuran carboxylate [Compound (116)] Preparation of:

Compound (116) is obtained by a method similar to Example 17 using compound (93b) and chloromethyl pivalate.

Example 117

Pivaloyloxymethyl 2-((4S) -4-bromo acetamido-3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofuran carboxylate [Compound (117)] Preparation of:

Compound 116 is dissolved in ethyl acetate with 5% palladium-carbon added. The resulting solution is stirred for 1 hour under ice-cooling in a hydrogen stream. The catalyst is filtered off, DMA and bromoacetyl bromide are added, and the solution is stirred under ice cooling for 0.5 hour. The organic layer is washed with water, then dried (Na ₂ SO ₄ ) and the solvent is evaporated. The residue is subjected to silica gel column chromatography to give compound (117).

Example 118

Pivaloyl oxy methyl 2-[(4S) -4- (2,4-hexadiene) amido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [ Preparation of Compound (118)]

Compound 116 is catalytically reduced in a similar manner as in Example 117. After filtering off the catalyst, the filtrate is concentrated to dryness. The obtained residue is dissolved in DMF, sorbic acid, DCC and HOBT are added, and then the solution is stirred at room temperature for 1 hour. Ethyl acetate is added to the obtained reaction mixture, and the separated crystals are filtered off. The organic layer is rinsed with water and dried (Na ₂ SO ₄ ). Evaporate the solvent. The residue is column chromatographed on silica gel to give compound (118).

Example 119

Pivaloyloxymethyl 2-[(4S) -4- (2-thienyl) acetamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound 119] Preparation:

Compound 119 is obtained by a method similar to Example 117 using compound 116 and thienylacetyl chloride. Examples 100 to 119 below show the reaction conditions and the yield and physico-chemical properties of the obtained compound.

Example 120

Pivaloyloxymethyl 2-[(4S) -4- (hexahydro-1H-azin-1-yl) methyleneamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydro Preparation of furan carboxylate [Compound (120)]:

Compound 116 is catalytically reduced in a similar manner to Example 117. After the catalyst was filtered off, 1-hexamethyleneimine carboxy aldehyde dimethyl acetal and a catalytic amount of boron trifluoride were added to the filtrate under ice-cooling, and the mixture was stirred at room temperature for 20 hours. The solvent is evaporated off under reduced pressure and the residue is purified by Florisil column chromatography to give the desired mixture 120.

Example 121

Of diphenylmenyl 2-[(4S)-(t-butyldimethylsilyl) amino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (121)] Produce :

T-butyl dimethylsilyl chloride and triethylamine are added to a dimethylformamide solution of compound (R-3), and the mixture is stirred at room temperature for 1 hour. The reaction solution is added to water-ethyl acetate and the mixture is shaken. The organic layer is recovered, washed with water and dried (Na ₂ SO ₄ ). The solvent is evaporated off under reduced pressure to afford the target compound (121).

Example 122

Diphenyl methyl 2-[(4S) -4-t-butyldiphenylsilyl) amino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (122) Manufacturing of

The desired compound 122 is obtained by the method of Example 121 using compound (R-3) and t-butyl-diphenylsilyl chloride.

Example 123

Preparation of Sodium 2- [4 (S) -3-diphenylphosphoryl amino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (123b)]:

To the dimethylformamide solution of compound (R-3), diphenyl phosphorochlorate was added under ice cooling, and the mixture was stirred for 1 hour. The reaction solution is added to water and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried (Na ₂ SO ₄ ). The solvent is evaporated off under reduced pressure, and the residue is purified by silica gel chromatography to obtain diphenylmethyl ester of the compound (123a) and the target compound (123b). Compound (123a) thus obtained was treated by the method of Example 2 (b) to obtain the target compound (123b).

Example 124

Preparation of diphenylmethyl 2- [4 (S) -4-dimethylphosphoryl amino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (124)] :

Using compound (R-3) and dimethyl phosphorochlorate, the desired compound 124 is obtained according to the method of Example 123.

Example 125

Preparation of Sodium 2 [(4S) -4-ethylsulfonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (125b)]:

To the dichloromethane solution of compound (R-3) ethane sulfonyl chloride and triethyl amine were added under ice cooling. The mixture is stirred at 0 ° C. for 30 minutes and at room temperature for 90 minutes. The reaction mixture is washed with water and dried (Na ₂ SO ₄ ). The solvent is evaporated off under reduced pressure, and the residue is purified by silica gel chromatography to give compound (125a) and target compound (125b) to obtain diphenyl ester. The obtained compound 125a is treated by the method of Example 2 (b) to obtain the target compound 125b.

Example 126

Preparation of Sodium 2-[(4S) -4-vinylsulfonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (126)]:

The desired compound 126 is obtained by the method of Example 125 and Example 1 (c) using compound (R-3) and 2-chloroethane sulfonyl chloride.

Example 127

Preparation of 2- [4 (S) -thienylacetamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carbonylanilide [Compound (127)]:

To a suspension of compound (5b) suspended in dichloromethane is added trimethyl acetyl chloride at 0 ° C. and the mixture is stirred at 0 ° C. for 1 hour. Aniline is added to the product and the mixture is stirred at room temperature for 1 hour. The reaction mixture is washed with water and dried (Na ₂ SO ₄ ). The solvent is evaporated off under reduced pressure and the residue is purified by Florisil column chromatography to give compound 127 as a colorless oily product.

Example 128

Preparation of 2- [4 (S) -4-benzyloxycarbonyl amino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carbonyl anilide [Compound (128)]:

Using compound (93b) and aniline, the desired compound (128) as colorless crystals was obtained by the method of Example 127.

Example 129

2- [4 (S) -4-benzyloxy carbonyl amino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carbonyl pyrrolidine amide [Compound (129)] Produce :

Compound (93b) and pyrrolidine to give the desired compound (129) as a colorless oily product by the method of Example 127.

Example 130

2- [4 (S) -4-thienylacetamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carbonyl pyrrolidine amide [Compound (130)] Produce :

Compound 5b and pyrrolidine gave the desired compound 130 as a colorless oily product by the method of Example 127.

Example 131

Preparation of 2-[(4S) -4-thienylacetamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carbonyl propylamine [Compound (131)]:

Compound 5b and propyl amine were used to give the title compound 131 as a colorless oily product by the method of Example 127.

Example 132

Preparation of Sodium 2-[(4S) -γ-D-glutamylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carbonylate [Compound 132]:

The desired compound 132 is obtained by the method of Example 1 (a) and Example 2 (b) using compound (R-3) and α-benzyl N-carbobenzoxy-D-glutamate.

Example 133

Sodium 2-[(4S) -4- (2-hydroxy) -isobutyryl amino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [Compound (133 )] Manufacture of:

The desired compound 133 is obtained by the method of Examples 1 (a) and 2 (b) using compound (R-3) and 2-hydroxy isobutyric acid.

The reaction conditions of Examples 120-133, and the yields and representative physico-chemical properties of the compounds obtained are shown below.

Claims (19)

The compound of formula (III) is selected from the group of acylamino, amino, alkenylamino, thioamino, silylamino, phosphoamino, and A process for producing a compound of formula (II), characterized by reacting with a compound which can be introduced.

Wherein R ¹ ′ is an organic moiety selected from the group of acylamino, amino, alkenylamino, thioamino, silylamino, phosphoamino, and groups of the formula -CO-CO-NH- substituted via carbon X is hydrogen, methoxy or poromyl amino; R ² is a carboxyl group which may be esterified or amidated). The method of claim 1, wherein R ¹ ′ is acyl amino. The acyl amino group according to claim 2, wherein the acyl amino group is

Wherein R ³ is hydrogen, alkyl which may have 1 to 3 substituents, alkenyl which may have 1 to 3 substituents, cycloalkyl which may have 1 to 3 substituents, aryl which may have 1 to 3 substituents, Hetero ring which may have 1 to 3 substituents, alkoxy which may have 1 to 3 substituents or aryloxy which may have 1 to 3 substituents, R ⁴ is hydrogen or alkyl which may have 1 to 3 substituents, R ⁴ may form a ring which may have 1 to 3 substituents together with R ³ ); General formula

Wherein R ⁵ is hydrogen, an amino acid residue which may have 1 to 3 substituents, an aminoprotecting group or the general formula R ^7- (CH ₂ ) _n -C (= Z)-{wherein R ⁷ is a 1 to 3 substituent A heterocyclic ring which may have, alkoxy which may have 1 to 3 substituents or amino which may have 1 to 3 substituents, n is 0, 1 or 2 and Z is O or S.}, R ⁶ Is an alkyl which may have 1 to 3 substituents, an aryl which may have 1 to 3 substituents, a cycloalkenyl which may have 1 to 3 substituents or a hetero ring which may have 1 to 3 substituents); General formula R ⁸ -R ⁹ -CO-NH- [Wherein R ⁸ is a general formula

Wherein R ¹⁰ is alkyl which may have 1 to 3 substituents, hetero ring which may have 1 to 3 substituents or aryl which may have 1 to 3 substituents, and R ¹¹ may be hydrogen, 1 to 3 substituents where alkyl, cycloalkyl, heterocycle, or the general formula which may have 1 to 3 substituents, which may have an alkenyl, 1 to 3 substituents, which may have 1 to 3 substituents -R ¹² -R ¹³ (wherein, R ¹² is Alkylene, cycloalkylene or alkenylene which may have 1 to 3 substituents, R ¹³ is aryl which may have 1 to 3 substituents, carboxy which may have 1 to 3 substituents or esters thereof or mono- or di- Alkyl amide), and R ⁹ is a chemical bond or a general formula

(Wherein R ¹⁴ is an alkyl which may have 1 to 3 substituents, an aryl which may have 1 to 3 substituents or a hetero ring which may have 1 to 3 substituents). General formula

Wherein R ¹⁵ is aryl which may have 1 to 3 substituents, a hetero ring which may have 1 to 3 substituents or haloalkenyl which may have 1 to 3 substituents, and R ¹⁶ is hydroxy, sulfamoyl, sulfo , An acyloxy which may have sulfoxy or 1-3 substituents); General formula R ¹⁷ -R ¹⁸ -CH ₂ -CO-NH- [Wherein R ¹⁷ is alkyl which may have 1 to 3 substituents, cyano, aryl which may have 1 to 3 substituents, aryl oxy which may have 1 to 3 substituents, alkenylene which may have 1 to 3 substituents , A hetero ring which may have 1 to 3 substituents, an amino which may have 1 to 3 substituents or a group of the general formula R ¹⁷ '-C (= S)-(wherein R ¹⁷ ' is alkoxy), R ¹⁸ Is a chemical bond or -S-; Or general formula

Wherein R ¹⁹ and R ²⁰ are the same or different and each is hydrogen, alkyl which may have 1 to 3 substituents, aryl which may have 1 to 3 substituents, heterocyclic or cycloalkyl which may have 1 to 3 substituents And Z is O or S.). The acyl group of acyl amino according to claim 2, wherein

[Wherein Q ¹ is an amino or protected amino group and Q ² is H, alkyl, alkenyl, —CH ₂ COOQ ³ or

(Wherein Q ³ is H or alkyl which may have 1 to 3 substituents). The method of claim 1 wherein X is hydrogen. The method of claim 1, wherein R ² is carboxy. The method of claim 1, wherein R ² is a group that can be derived from carboxy. 8. The group according to claim 7, wherein the group derivable from carboxy may be selected from the general formula —COOR ³⁷ wherein R ³⁷ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, cyclo alkyl, The optionally substituted hetero ring or optionally substituted silyl). 8. A group according to claim 7, wherein the group derivable from carboxy is a general formula

Wherein R ³⁸ and R ³⁹ are the same or different and each is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted A heterocyclic ring, and R ³⁸ and R ³⁹ may form an optionally substituted hetero ring together with adjacent nitrogen atoms. The compound of claim 1, wherein the target compound is 2-[(4S) -4- (2-thienylacetamido) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofurancar Acid. The compound of claim 1, wherein the target compound is 2-{(4S) -4- [2- (2-amino-4-thiazolyl)-(Z) -2- (carboxymethyloxyimino) acetamido] -3 -Oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylic acid. The compound of claim 1, wherein the target compound is 2-{(4S) -4- [2- (2-chloro-4-pyridylthio) acetamido] -3-oxo-2-isoxazolidinyl} -5 -Oxo-2-tetrahydrofuran carboxylic acid. The compound of claim 1, wherein the target compound is 2-{(4S) -4- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-ethoxyimino Acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylic acid. The compound of claim 1, wherein the target compound is 2-{(4S) = 4- [2- (2-amino-4-thiazolyl)-(Z) -2- (1-carboxy-1-methyl ethoxyimino). Acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylic acid. The compound of claim 1, wherein the target compound is 2-{(4S) -4- [2- (2-amino-4-thiazolyl)-(Z) -2- (hydroxyimino) acetamido] -3- Oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylic acid. The compound of claim 1, wherein the target compound is 2-{(4S) -4- [2- (2-amino-4-thiazolyl)-(Z) -2- (ethoxyimino) acetamido] -3- Oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylic acid. The compound of claim 1, wherein the target compound is pivaloyloxymethyl 2-[(4S) -4- (2-thienyl) acetamido-3-oxo-2-isoxazolidinyl] -5-oxo-2 -Tetrahydrofuran carboxylate. A process for preparing a compound of formula (IV), characterized in that the compound of formula (V) is esterified or amidated.

Wherein R ¹ is an organic residue bonded through nitrogen; X is hydrogen, methoxy or formylamino; R ² ′ is an ester or amidated carboxy group; R ¹ is acetylamino or amino, When X is hydrogen, R ² ′ is not para-nitrobenzyloxy carbonyl or benzhydryloxy carbonyl.) A process for preparing a compound of formula (VI), wherein the compound of formula (VII) is subjected to methoxylation or formyl amination.

(Wherein R ¹ is an organic residue bound via amino or nitrogen; R ² is carboxy or a group derivable therefrom; X ′ is methoxy or formyl amino.)