KR890000226B1 - Process for preparing 1-sulfo-2-oxoazetidine derivatives - Google Patents

Abstract

Azetidine derivs. (I)[X=H, MeO; R1=H2N with optional protective gps.; R=org. gps. were prepd. Thus, 159.2mg pyridine-SO3 complex was added to a soln. of 201.9mg cis-3-[(benzyloxy) carboxamido -4- carbamoyl-2-azetidine-4-carboxylic acid methyl ester (syn-isomer) in DMF and the mixt. stirred at room temp. for 5 days, addnl. pyridine- SO3 added, the filtrate treated with Dowex 50W Na-type resins to give cis-syn-(I) Na [X=H; R1=2-(2chloroacetamido-4-thiazoyl)-2- methoxyimidoacetoimido; R=MeO2Cl (I) are effective antibacterials at 20-200 mg/kg per day in adults.

Description

Method for preparing 1-sulfo-2-oxoazetidine derivative

The present invention relates to a process for the preparation and use of novel 1-sulfo-2-oxoazetidine derivatives having good flavor and β-lactase inhibitory activity.

Up to now, various 2-oxoazetidine derivatives have been synthesized, and tetrahedron, 34 (1978), 1731 to 1767; Chemical review 76 (1976), 113-346; Synthesis (1973), 327-346, and the like. However, no 2-oxoazetidines with sulfo groups at the 1st position and substituents at the 4th position are yet known.

The present invention relates to a method for preparing a novel 1-sulfo-2-oxoazetidine derivative of formula (I) or a pharmaceutically acceptable salt or ester thereof.

(Wherein R is an organic residue attached to the azetidine ring via a carbon atom therein; R ¹ is an amino group which may optionally be acylated or protected; X is hydrogen or methoxyl).

The present inventors can sulfonate a compound of formula (II) or a salt or ester thereof to obtain 1-sulfo-2-oxoazetidine derivative (I), and the resulting compound (I) has excellent antimicrobial action and It has been found that it has β-lactase inhibitory activity, and the present invention has been accomplished based on this finding.

(Wherein R, R ¹ and X are as defined above).

In the above formulas (I) and (II), R is the organic residue attached to the 2-oxoazetidine nucleus at the fourth position through the carbon atom among the organic residues, that is, by removing one hydrogen atom attached to its carbon atom. Organic residues derived from organic compounds.

Such organic residues include, for example, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl, heterocyclic groups, etc., which may be optionally substituted by one or more substituents. In this specification, the group which may be optionally substituted from now on will be represented by "*" mark. For example, an optionally substituted alkyl group will be designated as "alkyl ^* ". In such cases, the number of substituents is not limited to one, but several substituted groups may have two or more substituents which may be the same or different. Alkyl has 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc. Or branched lower alkyl is preferred. Cycloalkyl is preferably 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and the like. Alkenyl C2-C6 straight or branched lower alkenyl is preferable, and vinyl, allyl, isopropenyl, 2-metall, 2-butenyl, 3-butenyl, etc. belong.

Alkynyl is preferably a straight or branched chain lower alkynyl having 2 to 6 carbon atoms such as ethynyl, 1-propynyl, 2-propynyl and the like. Cycloalkenyl includes 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexen Cycloalkenyl having 3 to 8 carbon atoms, such as cenyl, 1-cycloheptenyl, 1,4-cyclohexadienyl and the like, belongs. Among these, cycloalkenyl having 4 to 6 carbon atoms is preferable. Examples of aryl include phenyl, α-naphthyl, β-naphthyl, biphenyl, anthryl and the like.

Among them, phenyl and naphthyl are usually advantageous. Heterocyclic groups include, for example, heterocycles having one or more heteroatoms such as nitrogen (including N-oxides), oxygen and sulfur, as well as corresponding fused rings having an effective bonding site to their carbon atoms. As such, usually advantageous heterocycle groups include 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolidinyl, 2-, 3- or 4-pyridyl , N-oxido-2-, 3- or 4-pyridyl, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-pyranyl, 2-, 3- or 4-thiopyra Nyl, pyrazinyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isothiazolyl, 3-, 4- or 5-isoxazolyl , 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 3- or 4-pyridazinyl, N-oxido-3- or 4-pyridazinyl, 2-, 4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, piperazinyl, 4- or 5- (1, 2, 3-thiadiazolyl), 3- or 5- (1, 2, 4-thiadiazolyl), 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 4- or 5- (1, 2, 3-oxadiazolyl) , 3- or 5- (1, 2, 4-oxadiazolyl), 1, 3, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 3- or 1, 2, 4 Triazole 1, 1H- or 2H-tetrazolyl, pyrido- [2, 3-d] pyrimidyl, benzopyranyl, 1, 8-, 1, 5-, 1, 6-, 1, 7-, 2, 7 Or 2, 6-taphthyridyl, quinolyl, thieno [2, 3-b] pyridyl and the like. Among them, 5- or 6-membered heterocycles such as thienyl, thiazolyl, thiadiazoleyl, triazolyl, tetrazolyl and the like having 1 to 4 heteroatoms selected from nitrogen and sulfur are preferable.

Among these groups, alkyl, alkenyl and alkynyl groups are, for example, cycloalkyl ^* , cycloalkenyl ^* , aryl ^* , heterocycle group ^* , alkoxycarbonyl, acyl, oxo, halogen, cyano, hydroxy, alkoxy , Aryl ^* -oxy, acyloxy, carbamoyloxy, hydroxysulfonyloxy, alkynsulfonyloxy, aryl ^* -sulfonyloxy, nitro, amino, carboxy, aminocarbonyl, alkylthiocarbonyl, mercapto, Substituents such as alkylthio, aminoalkylthio, acylaminoalkylthio, aralkyl ^* -thio, aryl ^* -thio, heterocycle ^* -thio, quaternary ammonium ^* and the like. Examples of the substituted alkyl group include groups of the following formula (A):

Wherein n is an integer from 0 to 3; R ² and R ^{3, which} may be the same or different, represent hydrogen, alkyl, cycloalkyl ^* , aralkyl ^* , aryl ^* , heterocycle group ^* , alkoxycarbonyl or acyl, or R ² and R ³ taken together Oxo;

R ⁴ is hydrogen, alkyl, cycloalkyl ^* , aryl ^* , heterocycle group ^* , halogen, cyano, hydroxy, alkoxy, aryl ^* -oxy, aralkyl ^* -oxy, acyloxy, carbamoyloxy, hydroxy Sisulfonyloxy, alkylsulfonyloxy, aryl ^* -sulfonyloxy, sulfoxy, nitro, amino, azido, carboxy, alkoxycarbonyl, alkoxycarbonylalkyloxy, aminocarbonyl, alkylthiocarbonyl, acyl, mer Capto, alkylthio, aminoalkylthio, acylaminoalkylthio, aralkyl ^* -thio, aryl ^* -thio, heterocycle ^* -thio or quaternary ammonium ^* and the like.

의 기(여기서, W는 수소, 알킬, 카르바모일, 카르복실, 술포 또는 알콕실임) 및 퀴놀리늄이 속한다. 이들 4차 암모늄은 술포기와 함께 2-옥소아제티딘 핵의 1위에서 분자내 염을 형성할 수 있다. 아실기에는, 예를들어, 포르밀, 알킬카르보닐, 아릴^*-카르보닐, 아르알킬^*-카르보닐, 헤테로사이클^*-아세틸 등 뿐 아니라 하기에 언급된 R¹의 아실기등이 속한다.Substituents for alkyl, alkenyl and alkynyl groups and groups represented by R ² , R ³ or R ⁴ include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec- Preference is given to linear or branched lower alkoxy having 1 to 6 carbon atoms such as butoxy, t-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy and the like. Aralkyl includes benzyl, phenethyl, phenylpropyl, naphthyl methyl and the like. Halogens include fluorine, chlorine, bromine and iodine. Quaternary ammonium groups include, for example, pyridine, carbamoyl-substituted pyridine (e.g. nicotinamide, isonicotinad, etc.), carboxyl-substituted pyridine (e.g. nicotinic acid, iso-nicotinic acid), sulfo-substituted pyridine (e.g. Formulas that can be derived from pyridine derivatives such as

To which W is hydrogen, alkyl, carbamoyl, carboxyl, sulfo or alkoxyl and quinolinium. These quaternary ammonium, together with sulfo groups, can form intramolecular salts at the top of the 2-oxoazetidine nucleus. Examples of the acyl groups include formyl, alkylcarbonyl, aryl ^* -carbonyl, aralkyl ^* -carbonyl, heterocycle ^* -acetyl and the like, as well as acyl groups of R ¹ mentioned below.

Among them, for example, C _1-6 alkylcarbonyl (e.g., acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl, n-hexanoyl), or benzoyl which may be substituted (e.g., Benzoyl, 4-hydroxybenzoyl, 4-methoxybenzoyl), _optionally substituted C _{7-9 aralkylcarbonyl} (eg phenylacetyl, 4-hydroxyphenylacetyl, 4-methoxyphenylacetyl), oxygen, A 5-membered heterocycle group containing at least one of nitrogen and sulfur and optionally substituted (eg, 2-thienylcarbonyl, 2-furylcarbonyl, 2-, 4- or 5-thiazolylacetyl, 2- Or 3-thienylacetyl, 2- or 3-furylacetyl, 2-amino-4- or 5-thiazolylacetyl). And alkyl molecules of alkylsulfonyloxy, alkylthiocarbonyl, alkylthio, aminoalkylthio, acylaminoalkylthio and alkoxycarbonyl alkyloxy; Alkoxyl molecules of alkoxycarbonyl and alkoxycarbonylalkyloxy; And acyl molecules of acyloxy and acylaminoalkylthio have the same meanings as described above. Substituents that may be present on cycloalkyl, cycloalkenyl, aralkyl, aryl, heterocycle and quaternary ammonium groups include, for example, alkyl, alkoxy, alkenyl, aryl, aralkyl, mercapto, alkylthio, aryl Thio, aralkylthio, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, trihaloalkyl, hydroxy, oxo, thioxo, halogen, nitro, amino, cyano, carbamoyl, carboxy, acyl, acyl Oxy, acylamino, hydroxyalkyl, carboxyalkyl, haloalkyl, mono- or dialkylaminoalkyl and the like, wherein alkyl, alkoxy, alkenyl, aryl, aralkyl, acyl and halogen are the same as exemplified above This belongs.

When the organic residue attached to the azetidine ring via a carbon atom in the ring contains an amino group, the amino group may be substituted or protected, and if so, the carboxyl and hydroxyl groups may be protected. Substituents which may be present on the amino group include, but are not limited to, acyl at R ¹ mentioned below, as well as alkyl, alkoxy, hydroxyalkyl, aralkyl ^* , aryl ^* , heterocycle group ^* , sulfo, alkylsulfonyl, aralkyl ^* - Sulfonyl, aryl ^* -sulfonyl, alkoxycarbonyl, aralkyl ^* -oxycarbonyl, aryl ^* -oxycarbonyl and the like, wherein alkyl, alkoxy, aralkyl ^* , aryl ^* and heterocycle groups ^* are exemplified above Bar's). Amido groups taken with such substituents may optionally form cyclic amino groups such as pyrrolidino, piperidino, morpholino, piperazino and the like. Amino protecting groups include, for example, those exemplified below as "amino protecting groups" for R ¹ . Examples of the carboxyl protecting group include ester residues (e.g., methyl, ethyl, n-propyl, isopropyl, t-butyl, t-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, Phenacyl, phenyl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, acetoxymethyl, pivaloyloxymethyl, β-methylsulfonylethyl, β-trimethylsilylethyl, methylthiomethyl, tri Methyl, β, β, β-trichloroethyl, β-iodoethyl, trimethylsilyl, dimethylsilyl, acetylmethyl, p-nitrobenzoylmethyl, p-mesylbenzoylmethyl, phthalimidomethyl, propionyloxymethyl, 1, 1-dimethylpropyl, 3-methyl-3-butenyl, succinimidomethyl, 3, 5-di-t-butyl-4-hydroxybenzyl, mesylmethyl, benzenesulfonylmethyl, phenylthiomethyl, dimethylaminoethyl, Β-lactam and the like, such as pyridine-1-oxido-2-methyl, methylsulfinylmethyl, bis (p-methoxyphenyl) methyl, 2-cyano-1, 1-dimethylethyl, etc.) and silyl Groups can usually be used as carboxyl protecting group in the group field it belongs to any chemical which one.

Examples of the hydroxy protecting group include ester residues (e.g., acetyl, chloroacetyl, etc.), esterified carboxyl groups (e.g., β, β, β-trichloroethoxycarbonyl, β-trimethylsilylethoxycarbonyl), and ether residues (e.g. , t-butyl, benzyl, p-nitrobenzyl, trityl, methylthiomethyl, β-methoxyethoxymethyl, and the like, silyl ether residues (e.g. trimethylsilyl, t-butyldimethylsilyl, etc.), acetal residues And 2-tetrahydropyranyl, 4-methoxy-4-tetrahydropyranyl, and the like), which are commonly used as hydroxy-protecting groups in β-lactam and other organic chemistry. The choice of hydroxy protecting groups described above is not limited in the present invention, as in the case of amino and carboxy protecting groups.

Preferred examples of the organic residue R is the group represented by the formula (A), formula (A) is R ² and R ³ is a hydrogen or R ⁴ is a group other than hydrogen or a straight chain alkyl group; Or when one of R ² and R ³ is hydrogen and the other is a straight chain alkyl group and n is 0, R ⁴ may be other than hydrogen. Of the groups (A), groups of the following formula (B) can be effectively used.

(Wherein n is as defined above and R ^{2 '} and R ^{3', which} may be the same or different, each represent hydrogen or alkyl, or R ^{2 '} and R ^3' taken together represent oxo, R ^{4 ′} is hydrogen, alkyl, aryl ^* , halogen, cyano, hydroxyl, alkoxyl, aralkyl ^* -oxy, acyloxy, carbamoyloxy, alkylsulfonyloxy, sulfo-oxy, amino, azido, Carboxyl, alkoxycarbonyl, alkoxycarbonylalkyloxy, alkylthio, heterocycle ^* -thio or quaternary ammonium ^* groups, wherein the amino groups may be optionally substituted or protected and the carboxyl groups are R ² , R ³ and R Optionally protected under the conditions described in paragraph ⁴ ). Among the groups (A) and (B), the more advantageous

(1) when R ² and R ³ taken together, R ^{2 ′} and R ^{3 ′} represent oxo, and R ⁴ , R ^{4 ′} are substituted or protected amino groups, ie, the group of the following formula (C),

In the above formula, Q ³ and Q ⁴ may be the same or different, and each hydrogen; Alkyl ^* ; Alkoxy; Aralkyl ^* ; Aryl ^* ; Heterocycle ^* group; Sulfo; Alkylsulfonyl; Amino; Aralkyl ^* -sulfonyl; Aryl ^* -sulfonyl; Alkoxycarbonyl; Aralkyl ^* -oxycarbonyl, aryl ^* -oxycarbonyl; Acyl or protecting groups as mentioned for R ¹ , preferably

(In the above formula, Q ^{3 '} and Q ^4' may be the same or different, but each hydrogen; C _1-6 alkyl; C _1-6 alkoxyl; amino; carboxy-C _1-6 alkyl; may be substituted with halogen. One C _1-6 alkylcarbonyl; sulfo; phenyl; benzoyl; carbamonyl-C _1-6 alkyl; p-nitrobenzyl oxycarbonyl; or β-C _1-6 alkylsulfonyl-C _1-6 alkoxycarbon Carbonyl, in particular carbamoyl, mono- or di-C _1-6 alkylcarbamoyl, phenylcarbamoyl, sulfocarbamoyl, C _1-6 alkoxycarbamoyl, carboxy-C _1-6 alkylbarba Group, etc.).

⁽²⁾ R 2 and R ^3, R ^{2 'and} R ^3' each represents an oxo, taken together, R ^4, R ^{4 'is} hydroxyl embodiment, alkoxyl, aryl ^* - oxy, aralkyl ^* - oxy or alkoxy When showing a carbonylalkoxy group, ie, group of following formula (D),

[Wherein, Q ⁵ is a hydroxyl group which may be protected; Alkoxyl; Aryloxy which may be substituted; Arkoxy which may be substituted; Or an alkoxycarbonylalkyloxy group, preferably formula -COQ ^{5 '} wherein Q ^5' is C _1-6 alkoxyl, p-nitrobenzyloxycarbonyl or C _1-6 alkoxycarbonyl-C _1-6 Alkyloxy group).

(3) R <^2> and R <^3> , R <^2>' and R <^3'> are all hydrogen, for example, group of following formula (E); In the case of (E), it is the case of the following formula (E) ':

[Wherein m is an integer of 1 to 4, X ¹ is —NH—, —S—, —O— or a direct bond, Q ⁶ is hydrogen; Carbamoyl; Acyl which may be substituted; Alkyl; Heterocycle group which may be substituted; Or a carboxyl group which may be protected, and Q ^{6 '} may be substituted with halogen; C _1-6 alkylcarbonyl; C _1-6 alkyl; Benzoyl; Heterocycle groups containing 5- or 6-membered nitrogen which may be substituted with C _1-6 alkyl groups (e.g. pyrrolyl, thiazolyl, thiadizolyl, diazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, etc.) ); Heterocycle ring is 5- or 6-membered nitrogen containing heterocycle-thioacetyl which may be substituted with C _1-6 alkyl.

Specific examples of the group (C) include carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-sulfocarbamoyl, N-methoxycarbamoyl, N-ethoxycarbamoyl, N-propoxycarbamoyl, N- Isopropoxycarbamoyl, N-hydroxycarbamoyl, N-aminocarbamoyl, [1- (L) -benzyloxycarbonylethyl] aminocarbonyl, [1- (L) -carboxyethyl] amino Carbonyl, N-phenylcarbamoyl, N, N-diphenylcarbamoyl, N- (p-chlorophenyl) carbamoyl, N-benzylcarbamoyl, N, N-dibenzylcarbamoyl, N -Hydroxymethylcarbamoyl, N-hydroxyethylcarbamoyl, N-chloromethylcarbamoyl, N-acetylcarbamoyl, N-propionylcarbamoyl, N-carboxycarbamoyl, N-meth Oxycarbonylcarbamoyl, N-ethoxycarbonylcarbamoyl, N- Phenoxycarbonylcarbamoyl and the like. Specific examples of the group (D) include carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbon Carbonyl, pentoxycarbonyl, benzyloxycarbonyl, phenethyloxycarbonyl, methoxycarbonylmethyloxycarbonyl, ethoxycarbonylmethyloxycarbonyl, phenyloxycarbonyl, p-chlorophenyloxycarbonyl, hydroxide Oxymethyloxycarbonyl, sulfomethyloxycarbonyl and the like.

Specific examples of the group (E) include acylaminoalkyl (eg, acetylaminomethyl, propionylaminomethyl, n-butyrylaminomethyl, isobutyrylaminomethyl, acetylaminoethyl, propionylaminoethyl, acetylaminopropyl, acetyl Aminobutyl, benzoylaminomethyl; benzoylaminoethyl, benzoylaminopropyl, formylaminomethyl, phenylacetylaminomethyl, 4-hydroxyphenylacetylaminomethyl, 2-thienylcarbonylaminomethyl, 2-furylcarbonylaminomethyl , Thiethylacetylaminomethyl, 2-amino-4-thiazolylacetylaminomethyl, etc.), carbamoylaminoalkyl (eg, carbamoylaminomethyl, carbamoylaminoethyl, carbamoylaminopropyl, etc.), acyl Oxyalkyl (e.g. acetoxymethyl, propionyloxymethyl, isopropionyloxymethyl, acetoxyethyl, 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-methoxyiminoa Cetoxyme , 2- (2-amino-4-thiazolyl)-(Z) -2-methoxyiminoacetoxymethyl, 2-thienylacetoxymethyl, 2-furylacetoxymethyl, thiazolylacetomethoxymethyl, 2-amino-4-thiazolylacetoxymethyl, benzoyloxymethyl, benzoyloxyethyl, 4-hydroxybenzoyloxymethyl, 4-methoxybenzoyloxymethyl, monochloroacetoxymethyl, trichloroethoxycarbonyloxymethyl , Acetoacetoxymethyl, (1-methyl-1H-tetrazol-5-yl) thioacetoxymethyl, (1-N, N-dimethylaminoethyl-1H-tetrazol-5-yl) thioacetoxymethyl, (2-methylthiadiazol-5-yl) thioacetoxymethyl, (2-methyloxadiazol-5-yl) thioacetoxymethyl, carbamoyloxyalkyl (e.g. carbamoyloxymethyl, carba Moyloxyethyl, carbamoyloxypropyl, carbamoyloxyisopropyl, etc.), heterocycle-thioalkyl (e.g. thienylthiomethyl, thienylthioethyl, thienylthiopropyl, furylthiomethyl, Rylthioethyl, thiazolylthiomethyl, thiazolylthioethyl, 2-aminothiazolylthiomethyl, 2-aminothiazolylthioethyl, 2-aminothiazolylthioisopropyl, (2-methyl-thiadiazole-5- Yl) thiomethyl, (2-methyloxadiazol-5-yl) thiomethyl, oxazolylthiomethyl, (1-methyl-1H-triazol-5-yl) thiomethyl, (1-methyl-1H-tetra Zol-5-yl) thiomethyl, (1-N, N-dimethylaminoethyl-1H-tetrazol-5-yl) thiomethyl, (1-carboxymethyl-1H-tetrazol-5-yl) thiomethyl, (1-methyl-1H-tetrazol-5-yl) thioethyl, (1-methyl-1H-tetrazol-5-yl) thiopropyl, etc.), alkylthioalkyl (e.g. methylthiomethyl, methylthioethyl, Methylthiopropyl, methylthioisopropyl, ethylthiomethyl, ethylthioethyl, propylthiomethyl, propylthioethyl, isopropylthiomethyl, n-butylthiomethyl, isobutylthiomethyl, sec-butylthiomethyl, etc.), carboxy Or esterified carboxyalkyl groups (eg Carboxymethyl, carboxyethyl, carboxypropyl, carboxyisopropyl, carboxy-n-butyl, carboxyisobutyl, carboxy-sec-butyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, propoxy Carbonylmethyl, isopropoxycardylmethyl, phenoxycarbonylmethyl, phenoxycarbonylethyl, benzyloxycarbonylmethyl, benzyloxycarbonylethyl, p-hydroxybenzyloxycarbonylmethyl, p-methoxybenzyl Oxycarbonylmethyl, carboxymethyloxycarbonylmethyl and the like).

In the above formulas (I), (II) and (III), R ¹ is an amino group which may be optionally acylated or protected, and the acyl group in the acylated amino group may be a known phenylsilin derivative and cephalosporin derivative, respectively. Conventional acyl groups on the 6- and 7-amino groups belong to any group. Examples of the acyl group include group (i) of formula (F), group (ii) of formula (G), group (iii) of formula (H), group (iv) of formula (I), and Group (v) of formula (J), etc. belong.

[R¹¹이 알킬^*, 헤테로사이클^*기 또는 페닐^*이고 R¹²가 수소, 저급알킬, 저급알케닐 또는 기-R¹³-R¹⁴(R¹³이 저급알킬렌 또는 저급알케닐렌이고 R¹⁴가 페닐^*, 카르복실 또는 그의 에스테르임)], 또는 모노- 또는 디(저급알킬)아미노이고, R¹⁰은 직접결합 또는 기

(R¹⁵는 저급알킬, 페닐^*, 또는 티아졸일^*임)이고, R¹⁶은 히드록시, 히드록시술포닐옥시, 카르복시, 우레이도^*, 술파모일^*, 술포, 페녹시^*카르보닐 또는 포르밀옥시이고, R¹⁷은 수소, 저급알킬, 저급알콕시, 할로겐, 니트로 또는 히드록시이고, R¹⁸은 시아노, 페닐^*, 페녹시^*, 저급알킬^*, 알케닐렌^*또는 헤테로사이클^*기이고, 그리고 R¹⁹는 직접결합 또는 -S-임].[Wherein R ⁵ is a lower alkyl or heterocycle ^* group, R ⁶ is a hydrogen, an amino acid residue, an aminoprotecting group or a R ⁶ heterocycle ^* group and n ₁ is an integer from 0 to 2 groups R ^8- (CH ₂ ) n1-CO-, R ⁷ is a lower alkyl, phenyl ^* , heterocycle ^* -carbonylamino or heterocycle group, and R ⁹ is a group

[R ¹¹ is alkyl ^* , heterocycle ^* group or phenyl ^* and R ¹² is hydrogen, lower alkyl, lower alkenyl or group-R ¹³ -R ¹⁴ (R ¹³ is lower alkylene or lower alkenylene and R ¹⁴ is phenyl ^* , Carboxyl or ester thereof), or mono- or di (lower alkyl) amino, R ¹⁰ is a direct bond or a group

(R ¹⁵ is lower alkyl, phenyl ^* , or thiazolyl ^* ) and R ¹⁶ is hydroxy, hydroxysulfonyloxy, carboxy, ureido ^* , sulfamoyl ^* , sulfo, phenoxy ^* carbonyl or formyl Oxy, R ¹⁷ is hydrogen, lower alkyl, lower alkoxy, halogen, nitro or hydroxy, R ¹⁸ is cyano, phenyl ^* , phenoxy ^* , lower alkyl ^* , alkenylene ^* or heterocycle ^* group, and R ¹⁹ is a direct bond or -S-.

In the symbols from R ⁵ to R ¹⁹ , alkyl, heterocycle, alkoxy and halogen belong to those exemplified for R above. The amino acid residues are, for example, glycyl, alanyl, valeyl, leusil, isoleucyl, seryl, threonyl, cysteinyl, cisyl, methionyl, α- or β-asparyl, α- or γ-glu Tiles, lysyl, arginyl, phenylalanyl, phenylglycyl, tyrosyl, histidyl, tritopanyl, pyrrolyl and the like. Examples of the amino protecting group include those exemplified as "amino protecting group" for R ¹ . The alkylene is preferably a linear or branched lower alkylene having 1 to 3 carbon atoms, for example, methylene, ethylene, propylene, isopropylene, and the like. Alkenylene is preferably a linear or lower alkenylene having 2 to 4 carbon atoms, such as vinylene, propenylene and the like. The lower alkyl esters having 1 to 6 carbon atoms belong to the carboxylic acid esters, which are the aforementioned alkyl molecules such as methyl ester, ethyl ester, propyl ester, n-butyl ester, isobutyl ester, t-butyl ester and the like. Substituents on heterocycle ^* groups, phenyl ^* , thiazolyl ^* , phenoxy ^* carbonyl and phenoxy ^* include the substituents on heterocycle ^* groups and aryl ^* described above for R, and the like. In addition, substituents on thiazolyl ^* may, for example, belong to acylamino having 2 to 4 carbon atoms substituted with alkyl, alkoxy, halogen, hydroxy, amino, and the like, and to heterocycle ^* gaseous substituents, for example. And phenyl substituted in an appropriate amount, such as sodium or potassium. Substituents on ureido ^* include, for example, sulfo in the form of a salt with a suitable cation such as sodium or potassium; Carbamoyl; Sulfamoyl; Amidino; And alkyl having 1 to 3 carbon atoms. Substituents on sulfamoyl ^* include, for example, lower alkyl having 1 to 3 carbon atoms, amidino and the like. Substituents on lower alkyl ^* include, for example, halogen, hydroxy, cyano, trifluoromethyl and the like. Substituents on alkenylene ^* include, for example, carboxy and cyano.

는 syn 이성체

또는 anti 이성체

또는 그들의 혼합물로 나타내진다.Formula for R ⁹

Syn isomer

Or anti isomer

Or mixtures thereof.

Among them, the preferred form of group (G) is the group of the histograms:

(Wherein, R ^{6 'is} an amino protecting group or R ⁸ is heterocyclic ^* group and n ₁ is an integer of 0 to 2 groups R ⁸ - and _{(CH 2) -n 1 -CO-,} R 7' is phenyl ^* or Heterocycle ^* group); Preferable form of group (H) is group of the following formula;

(Wherein R ^{11 '} is a heterocycle ^* group or phenyl ^* , R ^12' is hydrogen, lower alkyl, or a group -R ¹³ -R wherein R ¹³ is as defined above and R ^{14 '} is a carboxyl or esterified carboxyl group) ^{14 '} ); Is the preferred form of the group (J) is a group of the _{^{formula: R 18 '-R 19 -CH 2}} -CO- ( wherein, R ^18' is a heterocyclic ^* group, R ¹⁹ is as defined Electric).

In particular, the group of the following formula is more useful as an acyl molecular sieve of an acylated amino group with respect to R ¹ in view of antibiotic activity.

이고, COOQ⁹은 카르복실 또는 에스테로화 카르복실기임).Wherein Q ⁷ is an amino or protected amino group and Q ⁸ is lower alkyl, lower alkenyl, a group-CH ₂ COOQ ⁹ or a group

And COOQ ⁹ is a carboxyl or esterified carboxyl group.

In the above-mentioned acyl group, examples of the acyl group R ⁵ -CO- include 3- (2, 6-dichlorophenyl) -5-methylisoxa-4--4-carbonyl, 4-ethyl-2, 3-di Oxo-1-piperazino carbonyl and the like.

의 예로는, D-알라닐, 벤질-Nα-카르보벤족시-γ-D-글루타밀-D-알라닐, D-페닐글리실-D-알라닐, N-카르보벤족시-D-알라닐, N-카르보벤족시-D-페닐글리실, D-알라닐-D-페닐글리실, γ-D-글루타밀-D-알라닐, 2-(4-에틸-2, 3-디옥소-1-피페라지노카르복사미도)-2-페닐아세틸, 2-(4-에틸-2, 3-디옥소-1-피페라지노카르복사미도)-2-(4-술폭시페닐)아세틸, N-(4-에틸-2, 3-디옥소-1-피페라지노 카르보닐)-D-알라닐, N-(4-에틸-2, 3-디티오옥소-1-피페라지카르보닐)-D-페닐글리실, 2, 2-비스(4-에틸-2, 3-디옥소-1-피페라지노카르복사미도)-아세틸, 2-(2-아미노-4-티아졸일)-2-(4-에틸-2, 3-디옥소 1-피페라지노카르복사미도)아세틸, 2-(4-히드록시-6-메틸니코틴아미도)-2-페닐아세틸, 2-(4-히드록시-6-메틸니코틴아미도)-2- (4-히드록시페닐)아세틸, 2-{5, 8-디히드로-2-(4-포르밀-1-피페라지닐)-5-옥소피리도-[2, 3-d]피리미딘-6-카르복사미도}-2-페닐아세틸, 2-(3, 5-디옥소-1, 2, 4-트리아진-6-카르복사미도)-2-(4-히드록시페닐)아세틸, 2-(3-푸르푸리덴아미노-2-옥소이미다졸리딘-1-카르복사미도)-2-페닐아세틸, 2-(코우마린-3-카르복사미도)-2-페닐아세틸, 2-(4-히드록시-7-메틸-1, 8-나프티리딘-3-카르복사미도)-2-페닐아세틸, 2-(4-히드록시-7-트리플루오로메틸퀴놀린-3-카르복사미도)-2-페닐아세틸, N-[2-(2-아미노-4-티아졸일)아세틸]-D-페닐글리실, 2-(6-브로모-1-에틸-1, 4-디히드로-4-옥소티에노[2, 3-b]피리딘-3-카르복사미도-2-페닐아세틸, 2-(4-에틸-2, 3-디옥소-1-피페라지노카르복사미도)-2-티에틸아시틸, (2-4-n-페닐-2, 3-디옥소-1-피페라지노 카르복사미도)-2-티에닐아세틸, 2-(4-n-옥틸-2, 3-디옥소-1-피페라지노 카르복사미도)-2-티에틸아세틸, 2-(4-시클로헥실-2, 3-디옥소-1-피페라지노 카르복사미도)-2-티에닐아세틸, 2-[4-(2-페닐에틸)-2, 3-디옥소-1-피페라지노 카르복사미도]-2-티에닐아세틸, 2-(3-메틸술포닐-2-옥소이미다졸리딘-1-카르복사미도)-2-페닐아세틸, 2-(3-푸르푸리덴아미노-2-옥소이미다졸리도)-2-(4-벤질옥시페닐)아세틸, 2-(4-에틸-2, 3-디옥소-1-피페라지노카르복사미도)-2-(4-메톡시페닐)아세틸, 2-(8-히드록시-1, 5-나프티리딘-7-카르복사미도)-2-페닐아세틸, 2-(2-아미노-4-티아졸일)-2-포름아미도아세틸, 2-(2-아미노-4-티아졸일)-2-아세타미도 아세틸등이 속한다.Acyl

Examples of D-alanyl, benzyl-Nα-carbobenzoxoxy-γ-D-glutamyl-D-alanyl, D-phenylglycyl-D-alanyl, N-carbobenzoxoxy-D- Alanyl, N-carbobenzoxy-D-phenylglycidyl, D-alanyl-D-phenylglycyl, γ-D-glutamyl-D-alanyl, 2- (4-ethyl-2, 3- Dioxo-1-piperazinocarboxamido) -2-phenylacetyl, 2- (4-ethyl-2,3-dioxo-1-piperazinocarboxamido) -2- (4-sulphophenyl ) Acetyl, N- (4-ethyl-2, 3-dioxo-1-piperazino carbonyl) -D-alanyl, N- (4-ethyl-2, 3-dithiooxo-1-piperage Carbonyl) -D-phenylglycidyl, 2, 2-bis (4-ethyl-2, 3-dioxo-1-piperazinocarboxamido) -acetyl, 2- (2-amino-4-thiazolyl ) -2- (4-ethyl-2, 3-dioxo 1-piperazinocarboxamido) acetyl, 2- (4-hydroxy-6-methylnicotinamido) -2-phenylacetyl, 2- ( 4-hydroxy-6-methylnicotinamido) -2- (4-hydroxyphenyl) acetyl, 2- {5, 8-dihydro-2- (4-formyl-1-piperazinyl) -5 Oxopyrido- [2, 3-d] pyrimidine-6-carboxamido} -2-phenylacetyl, 2- (3, 5-dioxo-1, 2, 4-triazine-6-carboxamido) -2- (4- Hydroxyphenyl) acetyl, 2- (3-furfurydenamino-2-oxoimidazolidine-1-carboxamido) -2-phenylacetyl, 2- (coumarin-3-carboxamido) -2 -Phenylacetyl, 2- (4-hydroxy-7-methyl-1, 8-naphthyridine-3-carboxamido) -2-phenylacetyl, 2- (4-hydroxy-7-trifluoromethylquinoline -3-carboxamido) -2-phenylacetyl, N- [2- (2-amino-4-thiazolyl) acetyl] -D-phenylglycyl, 2- (6-bromo-1-ethyl-1 , 4-dihydro-4-oxothieno [2, 3-b] pyridine-3-carboxamido-2-phenylacetyl, 2- (4-ethyl-2, 3-dioxo-1-piperazino Carboxamido) -2-thiethylacetyl, (2-4-n-phenyl-2, 3-dioxo-1-piperazino carboxamido) -2-thienylacetyl, 2- (4-n -Octyl-2, 3-dioxo-1-piperazino carboxamido) -2-thiethylacetyl, 2- (4-cyclohexyl-2, 3-dioxo-1-piperazino carboxy Samido) -2-thienylacetyl, 2- [4- (2-phenylethyl) -2, 3-dioxo-1-piperazino carboxamido] -2-thienylacetyl, 2- (3- Methylsulfonyl-2-oxoimidazolidine-1-carboxamido) -2-phenylacetyl, 2- (3-furfurydeamino-2-oxoimidazolido) -2- (4-benzyloxy Phenyl) acetyl, 2- (4-ethyl-2, 3-dioxo-1-piperazinocarboxamido) -2- (4-methoxyphenyl) acetyl, 2- (8-hydroxy-1, 5 -Naphthyridine-7-carboxamido) -2-phenylacetyl, 2- (2-amino-4-thiazolyl) -2-formamidoacetyl, 2- (2-amino-4-thiazolyl) -2 -Acetami also belongs to acetyl.

Examples of the acyl group R ⁹ -R ¹⁰ -CO- include N- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl] -D-alanyl, N- [2- (2 -Amino-4-thiazolyl) -2-methoxyiminoacetyl] -D-phenylglycyl, 2- (2-amino-4-thiazolyl) -2- [2- (2-amino-4-thiazolyl ) -2-methoxyiminoacetamido] acetyl, 2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2 -Methoxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2-propoxyiminoacetyl, 2- (2 -Amino-4-thiazolyl) -2-butoxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2-benzyloxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2 -Allyloxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2-[(1-methyl-1-carboxyethyl) oxyimino] acetyl, 2- (2-amino-4-thiazolyl)- 2-carboxymethyloxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2-carboxyvinyloxy Minoacetyl, 2- (2-amino-5-chloro-4-thiazolyl) -2-methoxyiminoacetyl, 2- (2-amino-5-chloro-4-thiazolyl) -2-methoxyiminoacetyl , 2- (2-amino-4-thiazolyl) -2-oxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2-carboxyethyloxyiminoacetyl, 2- (2-amino-4- Thiazolyl) -2-methoxycarbonylethyloxyiminoacetyl, 2-thienyl-2-methoxyiminoacetyl, 2-furyl-2-methoxyiminoacetyl, 2- (1,2,4-thiadiazole -3-yl) -2-methoxyiminoacetyl, 2- (1,2,4-thiadiazol-5-yl) -2-methoxyiminoacetyl, 2- (1,3,4-thiadiazolyl ) -2-methoxyiminoacetyl, 2- (4-hydroxyphenyl) -2-methoxyiminoacetyl, 2-phenyl-2-methoxyiminoacetyl, 2-phenyl-2-oxyiminoacetyl, 2- [ 4- (γ-D-glutamyloxy) phenyl] -2-oxyiminoacetyl, 2- [4- (3-amino-3-carboxypropoxy) phenyl] -2-oxyiminoacetyl, and the like.

의 예로는, α-술포페닐아세틸, α-히드록시페닐아세틸, α-우레이도페닐아세틸, α-술포우레이도 페닐아세틸, α-술파모일페닐아세틸, α-페녹시카르보닐 페닐아세틸, α-(p-톨일옥시카르보닐)페닐아세틸, α-포르밀옥시페닐아세틸 등이 속한다.Acyl

Examples include α-sulfophenylacetyl, α-hydroxyphenylacetyl, α-ureidophenylacetyl, α-sulfoureido phenylacetyl, α-sulfamoylphenylacetyl, α-phenoxycarbonyl phenylacetyl, α -(p-tolyloxycarbonyl) phenylacetyl, α-formyloxyphenylacetyl, and the like.

Examples of the acyl group R ¹⁸ -R ¹⁹ -CH ₂ -CO- include cyanoacetyl, phenylacetyl, phenoxyacetyl, trifluoromethylthioacetyl, cyanomethylthioacetyl, 1H-tetrazolyl-1-acetyl, Thienylacetyl, 2- (2-amino-4-thiazolyl) acetyl, 4-pyridylthioacetyl, 2-thienylthioacetyl, 3, 5-dichloro-1, 4-dihydro-4-oxopyridine- 1-acetyl, β-carboxyvinylthioacetyl, 2- (2-aminomethylphenyl) acetyl and the like.

Among the acyl groups exemplified above, the amino, carboxyl and / or hydroxyl groups may be protected by a protecting group.

Amino protecting groups belong to those described below as "amino protecting groups".

Carboxyl or hydroxyl protecting groups belong to those described above for R.

As the amino protecting group for R ¹ , which may be optionally protected, any of those used in the field of β-lactam or peptide synthesis for this purpose can be used as well. Examples of such amino protecting groups include aromatic acyls such as phthalolyl, p-nitrobenzoyl, pt-butylbenzoyl, pt-butylbenzenesulfonyl, benzenesulfonyl, toluenesulfonyl, and the like, formyl, acetyl, propionyl, monochloro Aliphatic acyl groups such as acetyl, dichloroacetyl, trichloroacetyl, methanesulfonyl, ethanesulfonyl, trifluoroacetyl, maleyl, succinyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl , Isopropoxycarbonyl, 2-cyanoethoxycarbonyl, β, β, β-trichloroethoxycarbonyl, β-trimethylsilylethoxycarbonyl, β-metalsulfoylethoxycarbonyl, benzyloxy Carbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, isoboroxycarbonyl, phenyloxycarbonyl Same esterified carboxyl groups As trityl, 2-nitrophenyl thio, benzylidene, 4-knit Robben tired Den, trialkylsilyl, benzyl, p- nitrobenzyl, proton, such as non-acyl amino-protecting group that belongs. The choice of amino protecting group is not limited in the present invention.

The objective compound (I) of the present invention may have a 1-sulfo group and a carboxyl group or groups in R and / or R ¹ in free form. Alternatively, non-toxic anions such as sodium, potassium and the like; Basic amino acids such as arginine, ornithine, lysine, histidine and the like; It may be in the form of a salt with a polyhydroxyalkylamine such as N-methylglucamine, diethanolamine, triethanolamine, trisidoxymethylaminomethane, or the like. When R and / or R ¹ comprise a basic group, compound (I) may be an organic acid such as acetic acid, tartaric acid, methanesulfonic acid, or the like; Inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like; It may be in the form of a salt with an acidic amino acid such as arginine, aspartic acid, glutamic acid or the like. In addition, when R and / or R ¹ comprise a carboxyl group, compound (I) can be converted to biologically active ester derivatives which help to increase blood concentration and sustain in vivo activity. Efficient ester groups in such cases are, for example, α-alkoxy-α-substituted-methyl groups (e.g., methoxymethyl, ethoxymethyl, isopropoxymethyl, α-methoxyethyl, α-ethoxyethyl, etc.). Alkoxymethyl or α-alkoxyethyl), methylthiomethyl, ethylthiomethyl, alkylthiomethyl such as isopropylthiomethyl, pivaloyloxymethyl, acyloxymethyl such as α-acetoxybutyl or α-acyloxy-α-substituted -Alkoxycarbonyloxy-alpha-substituted-methyl groups, such as -methyl group, ethoxycarbonyloxymethyl, and (alpha) -ethoxycarbonyloxyethyl, etc. belong.

Compounds (I) of the present invention may exist as various stereoisomers (e.g., cis, trans, syn, anti and optically active isomers) as in the case of starting compound (II) described below, and the present invention It is understood that these individual isomers as well as mixtures thereof are included. These isomers may be used alone or as a medicament in the form of a mixture.

Thus, the form of the stereoisomers of the compound (I) of the present invention can be represented, for example, by the formula:

(Wherein R, R ¹ (β-array) and X (α-array) are as defined above, and dashed lines refer to trans or cis array of R groups for R ¹ groups in the 3rd position).

Compounds listed below belong to the objective compound (I) of the present invention.

Among these, especially preferable objective compound (I) of this invention is a compound represented by following formula, or its salt or ester.

(Wherein Q ^{3 '} , Q ^4' , Q ⁷ , Q ⁸ and dashed lines are as defined previously).

In the above formula, when Q ⁷ is an amino group, the compound of the formula may be in the form of a molecular salt of the amino group of Q ^{7 and} the sulfo period in the first place.

The target compound (I) and salts or esters thereof are valuable as antibiotic activators for various Gram-positive or Gram-negative bacteria, used as medicaments for humans and livestock, and infectious diseases caused by Gram-positive or Gram-negative bacteria Safely used as an antimicrobial agent for the treatment of In addition, the antimicrobial agents of the present invention are added to the rations of animals as a disinfectant for the protection of materials.

Antibiotics may also be used to inhibit the growth of harmful bacteria in, for example, medical and dental equipment, or to inhibit the growth of harmful bacteria in industrial aqueous media such as aqueous paints or paper mill white water. As antimicrobial agents, it can be used in the form of an aqueous formulation having a concentration of 0.1 to 100 ppm (ie 0.1 to 100 parts of antibiotic per million parts of solution).

The desired compound (I) and salts or esters thereof, alone or in combination with one or more active ingredients, can be used in any pharmaceutical preparation such as solutions, suspensions and elixirs as well as capsules, tablets and powders. These preparations can be administered orally, intravenously or intramuscularly.

Oral tablets include, for example, binders such as syrup, gum arabic, gelatin, sorbitol, tracant rubber or polyvinylpyrrolidone; Fillers such as lactose and other sugars, corn starch, calcium phosphate, sorbitol or glycine; Lubricants such as magnesium stearate, talc, polyethylene glycol or silica; Disintegrants such as corn starch; Or conventional excipients such as effective wetting agents such as sodium lauryl sulfate. Tablets may be coated by well known methods. Oral liquid dosage forms can be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, and the like, or in the form of lyophilizers for immediate dissolution in water or a suitable solvent. These liquid preparations include suspensions such as sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hafoxyethyl-cellulose, carboxymethyl-cellulose or aluminum stearate gel; Hydrogenated edible oils such as almond oil, coconut oil fractions, oily esters, propylene glycol or ethyl alcohol; Or preservatives such as methyl or propyl p-hydroxy benzoate or sorbic acid. Suppositories may contain conventional suppository bases such as theobroma oil or other glycerides.

Injectable compositions can be used in unit containers with ampoules or preservatives added. These compositions may be in the form of suspensions, solutions or emulsions of oily or aqueous excipients and may contain suitable auxiliaries or auxiliaries such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form that can be re-used in a suitable solvent such as sterile pyrogen-free water prior to use.

The active ingredient may also be formulated in a form that can be absorbed through the mucous membranes or bronchial tissues of the nose and throat, such as powders, liquid sprays or inhalants, sugar tablets, cervical paints, and the like. For use in ophthalmology or pediatrics, it may be administered as a liquid or semisolid capsule or drop. It may be formulated in the form of ointments, creams, lotions, paints, powders and the like with the addition of a hydrophobic or hydrophilic pharmaceutical base to prepare pharmaceutical preparations for external use.

In addition to the carrier, these preparations may contain other ingredients such as stabilizers, binders, antioxidants, preservatives, lubricants, suspending agents, rheology modifiers or flavoring agents and the like. Moreover, other active ingredients or ingredients can be combined with the composition to obtain a broader antimicrobial spectrum.

For administration to livestock, the active ingredient of the present invention may be formulated with a time-release medium to obtain a mammary gland adjuvants.

Compound (I) of the present invention can be used in mammals as a therapeutic agent for microbial infections in the treatment of, for example, respiratory infections, urinary tract infections, purulent infections, bile duct infections, intestinal infections, gynecological infections, surgical infections, and the like. have. The daily dosage varies with the condition of the patient to be treated, the weight of the host, the route and the frequency of administration, and unique parenteral or oral methods suitable for general infection are used for enteric infection.

Generally, the daily oral amount is made up of one or more active ingredients in an amount of about 15 to 600 mg per kg body weight of the patient. The daily dose suitable for administration to an adult is about 10 to 200 mg / kg / weight as an active ingredient, and is preferably administered 2 to 4 times at 2.5 to 100 mg / kg each by a method other than oral.

Pharmaceutical compositions containing compound (I) can be administered, for example, in the form of oral ingestible units in various solid or liquid forms. The liquid or solid composition contains 0.5 to 99% of the active ingredient. Preferred concentrations of the active ingredient are about 10 to 60%. The composition generally contains 15 to 1500 mg of active ingredient per unit, preferably using a unit in the range of about 250 to 1000 mg as the active ingredient.

In addition to the above-mentioned uses, the compound (I) of the present invention or a salt or ester thereof can be used in combination with a β-lactam antibiotic having β-lactase inhibitory activity. Examples of such β-lactam antibiotics include penicillin antibiotics such as benzyl penicillin, phenoxymethylpenicillin, carbenicillin, ampicillin, amoxicillin, sulfenicillin, cephaloridine, cephalotin, cephazoline, cephalin Cephalosporin antibiotics such as lexin, cephacithin, cephacetyl, cephamandol, cefmenoxime, ceftsulodine, cytothiam, cephataxime, cephapyrin, ceftizone, cepradine, cephaloclysin The back belongs.

The 1-sulfo-2-oxoazetidine derivative (I) which is the target compound of the present invention can be produced, for example, by sulfonating compound (II).

Compound (II) can be used as starting material in the process of the invention in the form of salts with various acids or bases, or esters or silyl derivatives. Compounds (II) include cis- and trans-isomers because they have substituents on 3- and 4-positions. In addition, since the 3- and-4-carbon atoms are subsidiary carbons, in theory, a total of four or more stereoisomers exist. These stereoisomers may be used alone or in the form of mixtures. This is also the case when R or R ¹ comprise sub-carbons, wherein the resulting stereoisomers are also used alone or in the form of mixtures.

As salts and esters of compound (II), for example, those described above for compound (I) can be used. Compound (II) may also be silylated by silylating agents. The silylating agent may be a compound of the formula: P ¹ P ² P ³ .Si.Hal

[Wherein P ¹ , P ² and P ³ are each lower alkyl having 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, etc.) or an aryl group (eg, phenyl, tolyl) And Hal is halogen, preferably chlorine or bromine, at least one of P ¹ , P ² and P ³ is halogen, preferably chlorine or bromine, and one of P ¹ , P ² and P ³ is Hydrogen may be used].

In addition, hexa-alkyl (C ₁ -C ₄ ) cyclotrisilazane, octa-alkyl (C ₁ -C ₄ ) cyclotetrasilazane, trialkyl (C ₁ -C ₄ ) silylacetamide, bis-tri- Alkyl (C ₁ -C ₄ ) silylacetamide can be used as the silylating agent. Preferred silylating agents are groups of the formula

Wherein Y represents a reactive group to be liberated from the silyl compound, Y ¹ and Y ² each represent a lower (C ₁ -C ₄ ) alkyl, phenyl, benzyl or lower (C ₁ -C ₄ ) alkoxy group, and Y ³ Represents a t-butyl or isopropyl group).

As lower alkyl represented by Y ¹ and Y ² , methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl and the like can be mentioned, and as lower alkoxy represented by Y ¹ and Y ² , Oxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and the like can be mentioned.

Examples of the reactive group to be liberated from the silyl compound include halogen (eg, chloro, bromo); N- (trialkylsilyl) trifluoroacetimidoyloxy group; N- (trialkylsilyl) acetimidoyloxy group; Acylamino groups such as formylamino, acetylamino, propionylamino, butylylamino or trifluoroacetylamino; (Trialkylsilyl) amino groups such as (tri-t-butyldimethylsilyl) amino, isopropyldimethylsilylamino or (chloromethyldimethylsilyl) amino; Alkylamino groups such as methylamino, ethylamino or propylamino; N, N-dimethylamino, N-chloromethyl-N-methylamino, N, N-diethylamino, N, N-dipropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino Or N, N-dialkylamino groups such as N-ethyl-N-propylamino; Or heticycle groups such as imidazolyl. It is preferable to have 1-4 carbon atoms as an alkyl molecular body in the above-mentioned reactor, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, etc. are mentioned. Specific examples of the silyl compound described above include N, O-bis (t-butyldimethylsilyl) trifluoroacetamide, N, O-bis (isopropyldimethylsilyl) acetamide, and bis (dimethylisopropylsilyl) acetate. Cetamide, isopropyldimethylsilylacetamide, bis (dimethyl-t-butylsilyl) acetamide, N-methyl-Nt-butyldimethylsilylacetamide, N-methyl-N-isopropyldimethylsilyltrifluoroa Cetamide, Nt-butyldimethylsilyldiethylamine, 1, 3-bis (chloromethyl) -1, 1, 3, 3, -tetra-t-butyldimethyldisilazane, N-isopropyldimethylsilylimidazole , t-butyldiphenylchlorosilane, isopropyldiethylchlorosilane, isopropylmethyldichlorosilane, t-butyldimethylchlorosilane, isopropyl dimethylchlorosilane, t-butyldiethylchlorosilane, and the like.

Among them, t-butyldimethylchlorosilane or isopropyldimethyl chlorosilane is preferred. This silylation reaction follows the conventional method. The reaction temperature of the silylation is about 0 ° to 50 ° C., preferably 38 ° C. or less, usually room temperature (about 20 ° C.), and the reaction time is a few minutes (about 10 minutes) to about 24 hours. The reaction is, for example, ethyl acetate, dioxane, tetrahydrofuran, N, N-dimethylacetamide, N, N-dimethylformamide, dichloromethane, chloroform, benzene, toluene, acetone, methyl ethyl ketone or acetonitrile It is carried out in a good manner or in a mixture of any of them selected or in other solvents which are inert to the reaction. This reaction also includes inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate or potassium carbonate or trialkylamines such as triethylamine, tributylamine; Triaralkylamines such as tribenzylamine; Organic tertiary amines such as N-methylmorpholine, N-methylpiperidine, N, N-dialkylaniline, N, N-dialkylbenzylamine, pyridine, picoline or rutadine; Or in the presence of an organic base such as 1, 5-diazabicyclo 2, 2, 2, -octane or 1, 8-diazabicyclo 5, 4, 4, undeken-7, when the base is liquid, It can also be used as a solvent. The silyl derivatives of the compound (II) thus obtained can be used as starting materials in the present sulfonation reaction after being separated and purified in the form of a reaction mixture or by the conventional methods described below.

The sulfonation reaction means that the sulfo group is introduced in the 1-position of compound (II), and is made by reacting compound (II) with, for example, sulfuric anhydride or a reactive derivative thereof. As a reactive derivative of sulfate anhydride, for example, sulfate anhydride-base (for example, sulfate anhydride-pyridine, sulfate anhydride-trimethylamine, sulfate anhydride-picoline, sulfate anhydride-lutidine, etc.), sulfate anhydride-N, N And its adducts such as dimethylformamine, sulfate anhydride-dioxane, sulfate anhydride-chlorosulfonic acid and the like.

For this reaction, about 1 to 10 moles, preferably 1 to 5 moles of sulfate anhydride or reactive derivatives thereof are used per mole of compound (II). The reaction temperature is about -78 ° to 80 ° C, preferably -20 ° to 60 ° C. The reaction can be carried out in the presence of a solvent. In such cases, water, dioxane, tetrahydrofuran, ethyrs such as diethyl ether, ethyl acetate, esters such as ethyl formate, chloroform, halogenated hydrocarbons such as dichloromethane, benzene, toluene and n-hexane Conventional organic solvents to which hydrocarbons, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like belong can be used alone or in the form of a mixture.

The reaction is usually completed within minutes to several hours depending on the unique starting compound (II), sulfonating agent, reaction temperature and solvent used, but in some cases it may take several days to complete the reaction. After completion of the reaction, the reaction mixture can be suitably used known purification and separation methods such as solvent extraction, recrystallization, chromatography, etc. to obtain pure target compound (I).

Alternatively, the objective compound (I) of the present invention can be prepared by acylating the compound of formula (III).

Wherein R and X are as previously defined.

Acylation according to the method is achieved by reacting compound (III) (including its various salts, esters and silyl derivatives) with at least 1 mole, preferably 1.2 to 4 moles of acylating agent per mole of compound (III). do. The acylating agent used in this reaction is an organic carboxylic acid wherein R ¹ is an acyl group [R ⁰ COOH, wherein R ⁰ CO is an acyl group such as the acyl group of the acylated amino group defined in R ¹ ] or its reactivity in the carboxyl group. It may be a derivative.

Examples of the reactive derivative of the organic carboxylic acid include acid anhydrides, active amides, and active esters as illustrated below.

1) Acid anhydrides: Acid anhydrides include, for example, halogenated acids (e.g. hydrochloric acid, hydrobromic acid, etc.), monoalkylcarboxylic acids, aliphatic carboxylic acids (e.g. acetic acid, pivalic acid, valeric acid, isovaltic acid, triclo) Roacetic acid, etc.) and mixed acid anhydrides with aromatic carboxylic acids (eg, benzoic acid, etc.), as well as symmetric acid anhydrides, and the like.

2) Active Amides: Examples of active amides include amides with pyrazole, imidazole, 4-substituted imidazole, dimethyl pyrazole, benzotriazole and the like.

3) Active esters: Examples of active esters include methyl, ethyl, methoxymethyl, propargyl, 4-nitrophenyl, 2, 4-dinitrophenyl, trichlorophenyl, pentachlorophenyl and mesylphenyl esters. In addition to esters, esters of the aforementioned carboxylic acids such as 1-hydroxy-1H-2-pyridone, N-hydroxysuccinimide, N-hydroxy phthalimide and the like belong to the above.

The choice of reactive derivatives of organic carboxylic acids depends on the particular acid used. When the acylating agent used is an organic carboxylic acid, the reaction is preferably carried out in the presence of a condensing agent. Examples of such condensing agents include N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N '-(4-diethyl Aminocyclohexyl) carbodiimide, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide and the like.

Acylation is usually carried out in a solvent. Solvents include water, acetone, dioxane, acetonitrile, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, pyridine and reactions And other conventional organic solvents which do not have the same. Among them, the hydrophilic solvent can be used in combination with water.

Acylation also includes alkali metal carbonates, trialkylamines (eg, trimethylamine, triethylamine, tributylamine, N-methylmorpholine and N-methylpiperidine, etc.), N, N-dialkylaniline, N, N-dialkylbenzylamine, pyridine, picoline, lutidine, 1, 5-diazabicyclo [4, 3, 0] nonan-3-ene, 1, 4-diazabicyclo [2, 2, 2] octane , 1,8-diazabicyclo [5, 4, 4] -undec-7 and the like. Among these bases and the condensates described above, liquid compounds can also act as solvents. The reaction temperature is not limited, and the reaction is usually performed at cooling to room temperature and is completed in a few minutes to several tens of hours. The resulting compound (I) can be isolated and purified by known methods such as concentration, acidity to basic or vice versa liquid phase conversion, solvent exchange, solvent extraction, crystallization, recrystallization, fractional distillation, chromatography and the like. have.

If the starting compound (III) or salt thereof and / or acylating agent used in the acylation contains a subsidiary carbon in the molecule, the stereoisomers may be used alone or in combination. If the acylation produces two or more stereoisomers, each stereoisomer can be separated by conventional methods such as column chromatography, recrystallization, etc., if necessary.

The group R in the target compound (I) may be modified with another group while the compound (I) has a 1-sulfo group capable of producing another target compound of the present invention. For example, when R is acetoxymethyl, methanesulfonyloxymethyl, iodomethyl and the like, it can be transformed into another desired group by reaction with a nucleophilic agent. Nucleophilic agents that can be used include, for example, alkyl ^* - thiols, aryl ^* - thiols, heterocycle ^* - thiols, pyridines ^* belongs the like, they R is a substituted thiomethyl, a quaternary ammonium ^* -methyl The target compound (I) which is etc. can be provided. Alkyl ^* , aryl ^* , heterocycle ^* groups and quaternary ammonium ^* of these nucleophiles are as previously defined. The reaction is preferably carried out in an aqueous solution or in a water miscible solvent such as acetone, acetonitrile, or N, N-dimethylformamide, or a mixture of water and such a water miscible solvent. In some cases it is advantageous to add alkali carbonates or alkali phosphates. The reaction is usually carried out at a temperature of 20 ° to 100 ° C. The resulting compound (I) can be isolated and purified by known methods as in the case of compounds obtained in sulfonation or acylation.

When the target compound (I) thus obtained has a protecting group, the protecting group can be removed if necessary. Such protecting groups can be removed by conventional methods such as methods consisting of acids, bases or hydrazines, reductions, and iminohalogenating agents, followed by iminoesterifying agents, if necessary, hydrolysis again. The choice of this method depends on the specific protecting group to be removed. When the protecting group is removed by an acid, usable acids include, but are not limited to, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and the like, as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Resins, etc. The choice of acid depends on the specific protecting group and other conditions. In the case where the protecting group is removed with a base, bases that can be used include inorganic bases such as alkali metals (eg, sodium, potassium, etc.) or alkaline earth metals (eg, calcium, magnesium, etc.) hydroxides, carbonates and the like, and metal alkoxides Basic ion-exchange resins, as well as organic bases such as organic amines, quaternary ammonium salts, and the like, are selected. The choice of base depends on unique protecting groups and other conditions.

When the protecting group is carried out in a solvent in which the acid or base is removed, a hydrophilic organic solvent, water or a mixed solvent is generally used.

When the protecting group is removed by reduction, for example, reduction by mixing a metal such as tin or zinc or a metal compound such as chromium chloride or chromium acetate with an organic or inorganic acid such as acetic acid, propionic acid or hydrochloric acid, or the presence of a metal hydrogenation catalyst Catalytic reduction and the like can be used according to unique protecting groups and other conditions. Catalysts that can be used for catalytic reduction include, for example, platinum catalysts such as platinum wire, platinum sponge, platinum lumps, platinum oxides, colloidal platinum, etc., palladium sponges, palladium black, palladium oxide, palladium sulfate, palladium-carbonate Palladium catalysts such as barium, palladium-charcoal, palladium-silica gel, colloidal palladium, and the like, nickel catalysts such as reduced nickel, nickel oxide, raninickel, and urushihara nickel, and the like.

In the case of reduction with metals and acids, metal compounds of metals such as iron or chromium and inorganic acids such as hydrochloric acid or organic acids such as formic acid, acetic acid or propionic acid are used. Removal of the protecting group by reduction is usually carried out in a solvent. Examples of the solvent conveniently used for catalytic reduction include methanol, ethanol, propyl alcohol, alcohols such as isopropyl alcohol, and ethyl acetate. Reduction with metals and acids is conveniently carried out in water or acetone, but if the acid is liquid, it can also act as a solvent.

In any method using acids or bases or reductions, the reaction is usually performed under cooling to warming.

If the protecting group is removed by reacting an aminohalogenating agent, followed by an iminoesterifying agent and, if necessary, further hydrolysis, iminohalogenating agents that can be used include, for example, phosphorus trichloride, phosphorus pentachloride, 3 Phosphorous bromide, phosphorus oxychloride, thionyl chloride, phosgene and the like. The reaction temperature is not limited, but the reaction is usually carried out from room temperature to cooling. The resulting half product is reacted with an iminoesterifying agent comprising an alcohol and a metal alkoxide. Alcohols include alkanols such as methanol, ethanol, propanol, isopropanol, n-butanol, t-butanol and the like, and alkyl molecules of the above-mentioned alcohols include methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. The compounds substituted by the same alkoxy group belong. Examples of the metal alkoxides include alkali metal alkoxides such as sodium alkoxides and potassium alkoxides, and alkaline earth metal alkoxides such as potassium alkoxides derived from the above-mentioned alcohols and barium alcohol seeds.

For example, if the protecting group is a residue of an organic carboxylic acid and the free amino, hydroxyl, mercapto, carboxyl or sulfo group is attached to a carbon atom adjacent to the carmoyl of the carboxylic acid residue, before deprotecting the reaction. In order to increase the reactivity of the carbonyl group, it is advantageous to carry out a pretreatment to improve the effect of adjacent groups of such substituents. This will be explained, for example, when the substituent on the carbon adjacent to carbonyl is a free amino group. In such a case, the protecting group can be removed by modifying the amino group with a thioureido group followed by deacylation or by other known methods of breaking peptide bonds. Although it is preferable to carry out the reaction under mild conditions such as cooling to warming, the temperature at which the reaction is carried out is not limited and is selected according to unique protecting groups and deprotection methods.

In the above reactions, if R or R ¹ and R are carboxyl-containing groups, derivatives at the carboxyl groups can be converted to the corresponding free carboxyl compounds and the present invention naturally includes such cases.

The deprotected compound (I) thus obtained can be converted into the desired salt by conventional methods as described above.

Compounds (I) comprising sulfo groups can generally react with bases to form salts. Therefore, compound (I) can be obtained as a salt, and the salt thus obtained can be further converted into a free form or another salt. Compound (I) obtained in free form can be converted into its salt. Compound (I) obtained in the form of a salt can, for example, be converted to the free form using an acid. As the acid, for example, inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids such as formic acid, acetic acid or p-toluenesulfonic acid are advantageously used depending on unique salts and other conditions. Alternatively, an acidic ion-exchange resin or the like may be used. As the solvent, organic solvents such as acetone, tetrahydrofuran, methanol, ethanol, dioxane and the like, water or a mixed solvent are generally used. The reaction is usually carried out at room temperature, but may be carried out under cooling or warming. The reaction time depends on the unique acid and solvent used and the reaction temperature chosen, and in general the reaction is preferably completed in a short period of time. Compound (I) produced in free form can be separated by known methods as described above.

The starting compound (II) used in the present invention can be prepared, for example, by the following method or a similar method.

Wherein Ac is acetyl, Et is ethyl, Me is methyl, iso-Pr is isopropyl, Ar is aryl, R ¹ is an acylated or protected amino group, DBU is 1, 3-diazabicyclo 5, 4, 0 -7-undecene, and DCC is dicyclohexylcarbodiimide.

As a starting material used in said method 1) -17), for example, cis-3-amino-1- (2, 4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid Methyl ester [described in the American Chemical Society, 99, 2352 (1977)], cis-1- (2, 4-dimethoxybenzyl) -3-phthalimido-2-oxoazetidine-4-carboxylic acid methyl Ester (XIV) [described in Japanese Laid-Open Patent Publication No. 136694/1976], cis-3-azido-4-phenyl-2-oxoazetidine (XXI) [organic paper, 34 1477 (1969)] ], Cis-3-azido-1- (2, 4-dimethoxybenzyl) -4- (2, 2-dimethoxyethyl) -2-oxoazetidine (XXIV) [American Chemical Society, 101, 4730 (1979)], cis-1- (3, 4-dimethoxybenzyl) -3-phenoxycetamido-4-phenyl-2-oxoazetidine (XXXI) [synthesis (1979), 543 Base material], and the like. The starting material is not limited to these examples, and any compound consistent with the object of the present invention can be used. Examples of such starting materials will be given in the Reference Examples below.

The present invention will be described in more detail in the following examples and reference examples, but the examples are to be understood only as illustrative and not to limit the invention, and many variations are possible without departing from the spirit and scope of the invention. .

In the following Reference Examples and Examples, elution in column chromatography is performed by measurement of TLC (Thin Layer Chromatography). In TLC, the same developing solvent as the eluent used in column chromatography and Merck precoated TLC plate 60F254 and UV detector are used. Fractions containing the desired compound with spots that change to red violet by ninhydrin when sprayed with 48% HBr and then heated for hydrolysis are collected.

When two kinds of solvents are used as the developing solvent, the first described solvent is for eluting and removing by-products from the column, and the second described solvent is for eluting the desired product, except as specifically stated. . Drying of the compound is carried out on anhydrous magnesium sulfate unless otherwise specified. Except as specifically described in the Examples and Reference Examples, as an eluent for purification by column chromatography using the resin "Amberlite" or "Sepadex", an aqueous ethanol solution is first used while increasing the concentration. .

The resin "Amberlite" is manufactured by Rhom & Hass in the United States. "Dowex" is from Dow Chemical and "Sephadex" is from Pharmacia fine chemical. All temperatures are not accurate and the percentages are by weight except for solvents. In this case, percentages are based on volume. The NMR spectra given here are measured using a Barian model EM 390 (90 MHz) or T60 (60 MHz) spectrometer using tetramethylsilane as internal or external reference, all δ values are in ppm. The symbol s is singlet, d is doublet, q is quadruple, ABq is quadruplet, t is triplet, dd is doublet, m is multiplet, sh is shoulder, br is broad and J is coupling Represents a constant. The symbols in the embodiment and the reference example have the following meanings, respectively.

Experiment

The tables given below show the minimum inhibitory concentrations (MIC) of some exemplary compounds (I) of the invention as obtained in the basic examples.

Way

The minimum inhibitory concentration of the test compound is determined by agar dilution. That is, 1.0 ml of the test compound aqueous solution diluted by the serial dilution method is poured into a test petri dish, and then 9.0 ml of trypticase agar is poured into the dish and mixed. Streaks one loop of bacterial suspension of the test microorganisms on a mixed agar plate. After overnight incubation at 37 ° C., the lowest concentration of test microorganism that completely inhibits the growth of the test microorganism is taken as the minimum inhibitory concentration.

Test microorganism

(1) Enterobacter cloacae IFO 12937

(2) Klipsiela pneumoniae TN 1711

result

Example 1

201.9 mg cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn -Isomer) is added to 159.2 mg of pyridine-sulfate anhydride complex to a solution of 3.5 ml of N, N-dimethylformamide and the mixture is stirred at room temperature for 5 days. Then add 80 mg of pyridine-sulfuric anhydride complex and continue stirring for 2 days. Adding 50 ml of ether to the reaction mixture results in solidification of the insolubles. The ether layer supernatant is tilted and another ether is added to wash insolubles. The ether layer is decanted again to dissolve the remaining insoluble solid in 5 ml of water. The resulting solution is filtered and the filtrate is passed through a column of Dowex 50 W resin (Na-type). The effluent was lyophilized to dissolve the lyophilisate in a minimum amount of water, purified by column chromatography of Amberlite XAD-II resin and lyophilized again to give sodium cis-3- [2- (2-chloroacetamido). 4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 2

85 mg of sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarbonyl-2-oxoa under ice cooling and stirring To 2 ml aqueous solution containing zetidine-1-sulfonate (syn-isomer) 23.85 mg sodium monomethyldithio carbamate is added. Stirring was continued for 40 minutes at room temperature, and 7 mg of sodium monomethyldithiocarbamate was further added. Stir for another 30 minutes. The reaction mixture is then filtered and the filtrate is washed with ether. The aqueous layer was purified by column chromatography of Amberlite XAD-II and lyophilized to give sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4- Methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 3

41.8 mg of cis-4-acetoxymethyl-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine (syn-isomer ) Is dissolved in 3 ml of N, N-dimethylformamide, 318 mg of pyridine-sulfuric anhydride complex is added and the mixture is stirred at room temperature for 24 hours. 150 mg of pyridine-sulfuric anhydride complex is further added and further stirred for 48 hours, then a second 159 mg complex is further added and stirring is continued for 70 hours. Then, ether is added to the reaction mixture to solidify the insolubles. The ether is decanted, another ether is added to wash insolubles, and then collected by filtration. The collected crystals are dissolved in 5 ml of water and the solution is filtered. The filtrate is passed through a column of Dowex 50 W resin (Na-type). The lyophilisate of the effluent from the column was dissolved in 5 ml of water, then purified by column chromatography of Amberlite XAD-II and lyophilized to give sodium cis-4-acetoxymethyl-3- [2- (2-chloro Acetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 4

Under ice-cooling and stirring, 41 mg of sodium monomethyldithiocarbamate was dissolved in 150 mg of sodium cis-4-acetoxymethyl-3- [2- (2-chloroacetamido-4-thiazolyl) -2-medium. It is added to 4 ml of aqueous solution containing oxyiminoacetamido] -2-oxoazetidine-1-sulfonate (syn-isomer). The mixture is stirred at rt for 30 min and further 10 mg sodium monomethyldithiocarbamate are added. Stirring is continued for another 30 minutes and the reaction mixture is filtered. The filtrate was washed with ether, purified by Amberlite XAD-II column chromatography and freeze-dried, sodium cis-4-acetoxymethyl-3- [2- (2-amino-4-thiazolyl) -2- Methoxyiminoacetamido] -2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 5

150 mg of cis-3-benzyloxycarboxamido-4- (1-methyl-5-tetrazolylthiomethyl) -2-oxoazetidine in a solution of 2 ml of N, N-dimethylformamide, 137 mg Pyridine-sulfate anhydride complex is added and the mixture is stirred at room temperature for 24 hours. 70 mg of pyridine-sulfate anhydride complex is added and stirring is continued for another 2 hours. after that. Addition of ether to the reaction mixture results in solidification of the insolubles. The ether is decanted, another ether is added to wash the insolubles, and then collected by filtration. The collected crystals are dissolved in 15 ml of water and filtered. The filtrate is passed through a column of Dowex 50 W resin (Na-type). The effluent was lyophilized and the lyophilisate was dissolved in 5 ml of water, purified by column chromatography of Amberlite XAD-II, and then lyophilized. Sodium cis-3-benzyloxycarboxamido-4- (1-methyl -5-tetrazolylthiomethyl) -2-oxoazetidine-1-sulfonate is obtained.

Example 6

202 mg of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (anti- 159 mg of pyridine-sulfuric anhydride complex is added to a solution of isomers) in 3.5 ml of N, N-dimethylformamide, and the mixture is stirred at room temperature for 4 days. 80 mg of pyridine-sulfate anhydride complex is added and stirring is continued for 1 day. Then, 50 ml of ether is added to produce an insoluble on syrup. The ether layer supernatant is tilted and more ether is added to wash out the insolubles. The ether layer is decanted again and the remaining syrup insoluble is dissolved in 6 ml of water. After filtration, the filtrate is passed through Dowex 50 W resin (Na-type). The lyophilisate of the effluent from the column was dissolved in a minimum amount of water, then purified by column chromatography of Amberlite XAD-II and lyophilized to give sodium cis-3- [2- (2-chloroacetamido-4- Thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (anti-isomer) is obtained.

Example 7

85 mg of sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminosaetamido] -4-methoxycarbonyl-2-jade under ice cooling and stirring 21 mg of sodium monomethyldithiocarbamate is added to a 2 ml aqueous solution containing pediatric zetidine-1-sulfonate (anti-isomer). The mixture is stirred for 1 hour at room temperature and further 7 mg of sodium monomethyldithiocarbamate are added. Stirring is continued for another hour, then the reaction mixture is filtered and the filtrate is washed with ether. The aqueous layer was purified by column chromatography of Amberlite XAD-II and lyophilized to give sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-meth Oxycarbonyl-2-oxoazetidine-1-sulfonate (anti-isomer) is obtained.

Example 8

To a solution of 112 mg of cis-3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester in 3.5 ml of N, N-dimethylformamide, 159 mg of pyridine-sulfuric anhydride complex was added. The mixture is stirred for 5 days at room temperature. Add 80 mg of pyridine-sulfate anhydride complex and continue stirring for 1 more day. Then, 50 ml of ether is added to the reaction mixture to produce a syrupy precipitate. Further ether is added to tilt the ether and to wash the precipitate on the syrup. The ether is decanted again and the precipitate on syrup is dissolved in 5 ml of water. After the solution is filtered, the filtrate is passed through a Dowex 50 W resin (Na-type). The lyophilisate of the effluent from the column was dissolved in a minimum amount of water, then purified by column chromatography of Amberlite XAD-II and lyophilized to give sodium cis-4-methoxycarbonyl-3-phenylacetamido-2. Oxoazetidine-1-sulfonate is obtained.

Example 9

To a solution of 30 mg of cis-4-acetamidomethyl-3-phenylacetamido-2-oxoazetidine in 0.7 ml of N, N-dimethylacetamide, 52 mg of pyridine-sulfuric anhydride complex was added The mixture is stirred at room temperature for 69 hours. 35 ml of ether is then added to the reaction mixture to form a syrupy precipitate. Decant the ether and add ether again to wash out the precipitate. The ether is decanted again to dissolve the remaining syrupy precipitate in 1 ml of water. After filtering the solution, the filtrate is passed through a column of Dowex 50 W resin (Na-type). The lyophilisate of the effluent from the column was dissolved in a minimum amount of water, then purified by column chromatography of Amberlite XAD-II and lyophilized to give sodium cis-4-acetamidomethyl-3-phenylacetamido-2. Oxoazetidine-1-sulfonate is obtained.

Example 10

250 mg cis-3- [2- (chloroacetamido-4-thiazolyl) -2-ethoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn-isomer) To a solution dissolved in 2 ml of N, N-dimethylformamide, 190.4 mg of sulfuric anhydride-pyridine complex was added, and the mixture was stirred at room temperature for 24 hours. 95 mg of anhydrous sulfate-pyridine complex is further added to the mixture, followed by further stirring for 24 hours. 20 ml of ether is added to the mixture to solidify the insolubles. Discard the ether layer floating on it. 20 ml of fresh ether is added to the residue to wash the solids. Repeat the similar procedure to discard the ether layer and suspend insolubles in 20 ml of water. To the suspension is added 12 ml of Dow's 50 W (Na-type) resin and the mixture is stirred at room temperature for 2 hours. The resin is removed by filtration and the filtrate is lyophilized. The resulting powder is dissolved in 20 ml of water and then purified by column chromatography of Amberlite XAD-II. The purified product was lyophilized to give sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-ethoxyiminoacetamido] -4-methoxycarbonyl-2- Oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 11

110 mg sodium cis-3- [2- (chloroacetamido-4-thiazolyl) -2-ethoxyiminoacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate To the solution of (syn-isomer) in 8 ml of water, 30 mg of sodium monomethyldithiocarbamate was added under ice cooling. The mixture is stirred at room temperature for 1 hour, followed by further addition of 10 mg sodium mono methyldithiocarbamate. After the mixture is stirred for an additional hour, the resulting mixture is filtered and the filtrate is washed with ether. The aqueous layer was purified by column chromatography of Amberlite XAD-II and lyophilized to give sodium cis-3- [2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetamido] -4- Methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 12

In the same manner as in Example 10, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2- (n-propoxyimino) acetamido] -4-methoxycarbonyl 2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 13

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2- (n-propoxyimino) acetamido] -4-methoxycarbonyl-2- Oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 14

In the same manner as in Example 10, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-isopropoxyimino acetamido] -4-methoxycarbonyl-2- Oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 15

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-isopropoxyiminoacetamido] -4-methoxycarbonyl-2-oxoazeti Dean-1 -sulfonate (syn-isomer) is obtained.

Example 16

In the same manner as in Example 10, sodium cis-3- [2- (2-chloroacetamido-4-4-thiazolyl) -2- (n-butoxyimino) acetamido] -4-methoxy Carbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 17

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2- (n-butoxyimino) acetamido] -4-methoxycarbonyl-2- Oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 18

In the same manner as in Example 10, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-benzyloxyimidoacetamido] -4-methoxycarbonyl-2-jade Pediazetidine-1-sulfonate (syn-isomer) is obtained.

Example 19

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-benzyloxyiminoacetamido] -4-methoxycarbonyl-2-oxoazetidine -1-sulfonate (syn-isomer) is obtained.

Example 20

In the same manner as in Example 10, sodium cis-3- [2- (5-chloro-2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarbonyl 2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 21

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-5-chloro-4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarbonyl-2- Oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 22

In the same manner as in Example 10, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (n-butoxycarbonyl) 2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 23

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4- (n-butoxycarbonyl) -2- Oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 24

180 mg of trans-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn- Isomer) in a solution of 1.8 ml of N, N-dimethylformamide, 142 mg of pyridine-sulfuric anhydride complex and the mixture is stirred at room temperature. After 2 days and 4 days, 142 mg of pyridine-sulfuric anhydride complex is replenished and the mixture is stirred for a total of 6 days. 50 ml of ether is added to the reaction mixture. The ether layer is removed from the ramp. This process is performed three times. The resulting syrup-like material, which is insoluble in ether, is dissolved in a small amount of water and the solution is passed through a Dowex 50 W resin (Na-type). The lyophilisate of the effluent was dissolved in a small amount of water, purified by column chromatography of Amberlite XAD-II, and then freeze-dried. Sodium trans-3- [2- (2-chloroacetamido-4-thiazolyl) -2 -Methoxyiminoacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 25

320 mg of cis-3- [2- (2-chloroacetamido-4-thiazolyl) acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester in 2 ml of N, N-dimethylform To the solution in amide is added 282.3 mg of pyridine-sulfuric anhydride complex and the mixture is stirred at room temperature for 48 hours. Add 141 mg of pyridine-yellow anhydride complex and then continue stirring for 24 hours. Then 30 ml of ether is added and the ether layer is removed by ramping. This process is performed twice. The resulting syrupy material insoluble in ether is dissolved in 10 ml of water, the insolubles are removed by filtration and the filtrate is passed through a column of Dowex 50 W resin (Na-type). The effluent was concentrated under reduced pressure to a volume of 10 ml, purified by column chromatography of Amberlite XAD-II and lyophilized to give sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl ) Acetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate is obtained.

Example 26

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) acetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate Obtained.

Example 27

169 mg β-form, cis-3- {D-2- [4- (n-butyl) -2,3-dioxo-1-piperazinecarboxamido] -2-phenylacetamido} -2- To a solution of oxoazetidine-4-carboxylic acid methyl ester (Reference Example 39) in 1 ml of N, N-dimethylformamide, 114 mg of pyridine-sulfuric anhydride complex is added and the mixture is stirred at room temperature. After 10 days and another week, 57 mg of pyridine-sulfuric anhydride complex is further added and the mixture is stirred for a total of 12 days. Then 20 ml of ether is added to the mixture. The ether layer is removed from the ramp. This process is performed twice. The remaining insolubles are dissolved in 25 ml of water. To the suspension, Dow's 50 W (Na-type) resin is added and the mixture is stirred at room temperature for 1.5 hours. The resin is removed by filtration and the filtrate is lyophilized to form a powdery substance which is dissolved in a small amount of water. The aqueous solution was purified by column chromatography of Amberlite XAD-II and frozen. Sodium cis-3- {D-2- [4- (n-butyl) -2, 3-dioxo-1-piperazinecarbox Mido] -2-phenylacetamido} -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (β-type) is obtained.

Example 28

In the same manner as in Example 27, β- and α-type sodium cis-3- {D-2- [4- (n-butyl) -2, 3-dioxo-1-piperazinecarboxamido]- 2- (2-thienyl) acetamido} -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate is obtained.

Beta

Alpha type

Example 29

261 mg of β-form, cis-3- {D-2- [4- (n-octyl) -2, 3-dioxo-1-piperazinecarboxamido] -2- (2-thienyl) -ace 155 mg of pyridine-sulfuric anhydride complex was added to a solution of tamido} -2-oxoazetidine-4-carboxylic acid methyl ester (Reference Example 39) in 2 ml of N, N-dimethyl formamide, and the mixture was allowed to stand at room temperature. Stir for 5 days. 20 ml of ether is added to the reaction mixture, and the ether layer is removed by decantation. This process is performed three times. Solid insoluble in ether is suspended in 50 ml of water. To the suspension, Dow's 50 W (Na-type) resin is added and the mixture is stirred at room temperature for 2 hours. The resin is removed by filtration and the filtrate is lyophilized. The resulting powdery substance was dissolved in a small amount of water, the solution was purified by column chromatography of Amberlite XAD-II and lyophilized to give sodium cis-3- {D-2- [4- (n-octyl)- 2,3-dioxo-1-piperazinecarboxamido] -2- (2-thienyl) -acetamido} -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (β -Form) is obtained.

-형이 수득된다.As mentioned above,

-Form is obtained.

Example 30

330 mg of β-form, trans-3- {D-2- [4- (n-octyl) -2, 3-dioxo-1-piperazinecarboxamido] -2- (2-thienyl) -ace 196 mg of pyridine-sulfuric anhydride complex was added to a solution of tamido} -2-oxoazetidine-4-carboxylic acid methyl ester (Reference Example 39) in 2 ml of N, N-dimethyl formamide, and the mixture was allowed to stand at room temperature. Stir at. 20 ml of ether is added to the reaction mixture, and the ether layer is removed by decantation. This process is performed twice. To a rubbery material insoluble in the resulting ether is added 15 ml of water and 15 ml of Dow's 50W (Na-type) resin and the mixture is stirred at room temperature for 1.5 hours. The resin is removed by filtration and the filtrate is lyophilized to form a powdery substance that is dissolved in a small amount of water. The aqueous solution was purified by column chromatography of Amberlite XAD-II and lyophilized, followed by sodium trans-3- {D-2- [4- (n-octyl) -2,3-dioxo-1-piperazinecarbox Mido] -2- (2-thienyl) -acetamido} -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (β-form) is obtained.

As mentioned above, the corresponding α-form is obtained.

Example 31

625 mg of cis-4-acetamidomethyl-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine (syn-isomer ) Is dissolved in 6 ml of N, N-dimethyl formamide, 477 mg of pyridine-sulfuric anhydride complex is added and the mixture is stirred at 27-28 ° C. for 28 hours. 90 ml of ether is added to the reaction mixture, and the ether layer is removed by decantation. This process is performed twice. The remaining syrupy material is dissolved in 90 ml of water. To the solution is added 70 ml Dow's 50 W (Na-type) resin and the mixture is stirred at room temperature for 3 hours. The resin was filtered off, the filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography of Amberlite XAD-II, followed by freeze drying. Sodium cis-4-acetamidomethyl-3- [2- (2- Chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 32

In the same manner as in Example 11, sodium cis-4-acetamidomethyl-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine -1-sulfonate (syn-isomer) is obtained.

Example 33

In the same manner as in Example 31, sodium cis-4-benzamidomethyl-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-jade Pediazetidine-1-sulfonate (syn-isomer) is obtained.

Example 34

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-benzamidomethyl-2-oxoazetidine -1-sulfonate (syn-isomer) is obtained.

Example 35

In the same manner as in Example 31, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-methoxyiminoacetamido] -4- [2- ( 2-Chloroacetamido-4-thiazolyl- (Z) -2-methoxyiminoacetoxymethyl] -2-oxoazetidine-1-sulfonate is obtained.

Example 36

221 mg sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-methoxyiminoacetamido] -4- [2- (2-chloroacetamido 85 mg of sodium mono by ice-cooling stirring in a solution of -4-thiazolyl)-(Z) -2-methoxyiminoacetoxymethyl] -2-oxoazetidine-1-sulfonate in 10 ml of water Methyldithiocarbamate is added. The mixture is stirred at rt for 1 h before 40 mg of sodium mono methyldithiocarbamate is added. The mixture is stirred for another 1 hour at room temperature. The reaction mixture is washed with ethyl acetate and ether followed by concentration under reduced pressure. The concentrate was purified by column chromatography of Amberlite XAD-II and freeze-dried to give sodium cis-3- [2- (2-amino-4-thiazolyl)-(Z) -2-methoxyiminoacetamido. ] -4- [2- (2-amino-4-thiazolyl)-(Z) -2-methoxyiminoacetoxymethyl] -2-oxoazetidine-1-sulfonate is obtained.

Example 37

In the same manner as in Example 30, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (2-thienylacetoxymethyl ) -2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 38

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-thienylacetoxymethyl] -2-oxoazeti Dean-1 -sulfonate (syn-isomer) is obtained.

Example 39

In the same manner as in Example 30, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (1-methyl-1H-tetra A sol-5-ylthiomethyl) -2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 40

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4- (1-methyl-1H-tetrazol-5 -Ylthiomethyl) -2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 41

In the same manner as in Example 10, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methylthiomethyl-2-oxoa Zetidine-1-sulfonate (syn-isomer) is obtained.

Example 42

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-methylthiomethyl-2-oxoazetidine- 1-sulfonate (syn-isomer) is obtained.

Example 43

In the same manner as in Example 10, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methyl-2-oxoazetidine -1-sulfonate (syn-isomer) is obtained.

Example 44

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-methyl-2-oxoazetidine-1- Sulfonates (svn-isomers) are obtained.

Example 45

500 mg of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (4-chlorophenyl) -2-oxoazetidine (syn -Isomer) is added 353 mg of pyridine-sulfuric anhydride complex to a solution of 12 ml of N, N-dimethylformamide, and the mixture is left at room temperature for 18 days. 150 ml of ether is added to the reaction mixture, and the ether layer supernatant is discarded. To the residue is added 30 ml of water, 30 ml of ethyl acetate and 10 ml of tetrahydrofuran and shake the mixture. The organic layer is reextracted with 30 ml of water. The water layer is combined and 20 ml Dow's 50W (Na-type) resin is added thereto, followed by stirring at room temperature for 30 minutes. The resin is filtered off and the filtrate is concentrated under reduced pressure on a bath having a temperature of 30 ° C. or lower. The concentrate was purified by column chromatography of Amberlite XAD-II and freeze-dried to give sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido]. 4- (4-chlorophenyl) -2-oxoazetidine-1-sulfonate- (syn-isomer) is obtained.

Example 46

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4- (4-chlorophenyl) -2-oxoa Zetidine-1-sulfonate (syn-isomer) is obtained.

Example 47

In the same manner as in Example 10, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (N, N-dimethylcarba Moyl) -2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 48

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4- (N, N-dimethylcarbamoyl)- 2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 49

To a solution of 278 mg of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester in 2.8 ml of N, N-dimethylformamide was added 320 mg of pyridine-sulfate anhydride complex The mixture is stirred for 2 days at room temperature. 120 mg of pyridine-sulfuric anhydride complex is further added to the reaction mixture, followed by further stirring for 1 day. 50 ml of ether is added to the reaction mixture, and the resulting powdery precipitate is collected by filtration and washed with ether. The powdery product is dissolved in 5 ml of water and the solution is passed through a column of Dow's 50 W (Na-type) resin. The lyophilisate of the effluent is dissolved in a small amount of water and then purified by column chromatography of Amberlite XAD-II. Lyophilization of this purified product yields sodium cis-3-benzyloxycarboxamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate.

Example 50

190 mg of 10% palladium-carbon in a solution of 190 mg of sodium cis-3-benzyloxycarboxamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (monohydrate) in 10 ml of water After adding, catalytic reduction is performed for 1 hour at ambient temperature under atmospheric pressure. The reaction mixture is passed through a celite bed to filter the catalyst. Lyophilization of the filtrate affords sodium cis-3-amino-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate.

Example 51

In the same manner as in Example 30, sodium cis-3- (2-thienylacetamido) -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate is obtained.

Example 52

807 mg in a solution of 380 mg of cis-3- (1H-tetrazol-1-ylacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester in 3 ml of N, N-dimethylacetamido Pyridine-sulfuric acid anhydride complex was added. The mixture is stirred at 70 ° C. for 4 hours and then 50 ml of ether is added. Discard the ether layer. 50 ml of ether is added again to the residue. Similar procedure is performed twice. The insolubles are dissolved in 5 ml of water and the aqueous solution is passed through a column filled with 40 ml of Amberlite IR-120 (SO3Na-type) resin and purified by column chromatography of Amberlite XAD-II. The desired fractions were lyophilized, purified by column chromatography on Sephadex LH-20, and lyophilized again to give sodium cis-3- (1H-tetrazol-1-yl-acetamido) -4-methoxycarba. Bonyl-2-oxoazetidine-1-sulfonate is obtained.

Example 53

Sodium cis-3- (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyl) by the same method as in Example 52, on the condition that the reaction time was shortened to 1 hour. Din-3-ylcarbonylamino) -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate is obtained.

Example 54

409 mg of cis-3- (2-chloroacetyloxy-2-phenylacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester was dissolved in 2 ml of N, N-dimethylacetamide. 549 mg of pyridine-sulfate anhydride complex is added and the mixture is stirred at 70 ° C. for 1 hour. Add 50 ml of ether to the mixture, stir and discard the ether layer. Do this procedure two more times. 15 ml of 1M aqueous sodium hydrogen carbonate solution is added to the remaining insolubles to form a solution. The solution is stirred at room temperature for 1 hour and the reaction solution is passed through a column of 40 ml of Amberlite IR-120 (SO 3 Na-type) resin. The desired fractions are purified twice by column chromatography of Amberlite XAD-II and then further by column chromatography of Sephadex LH-20. The purified product was lyophilized to prepare the diastereomer as a mixture of sodium cis-3- (2-hydroxy-2-phenylacetamido) -4-methoxycarbonyl-2-oxoazetidine-1- Sulfonates are obtained.

Example 55

100 mg of cis-3- (D-2-sulfo-2-phenylacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester sodium salt was dissolved in 1.5 ml of N, N-dimethylformamide. To the solution, under ice-cooling and stirring, 1.2 ml of sulfuric anhydride-N, N-dimethylformamide complex (1.2M) is added, and the mixture is left at 5 ° C. for 24 hours. 0.5 ml of pyridine is added to the reaction mixture, the mixture is stirred for 5 minutes, and then 30 ml of ether is added. Discard the ether layer, add 30 ml of ether again and discard the ether layer again. The remaining insoluble was dissolved in 2 ml of 1M aqueous sodium hydrogen carbonate solution and the solution was passed through a column of Amberlite IR-120 (SO3Na-type) resin followed by column chromatography of Amberlite XAD-II and Sephadex LH-20. Purification by graphy and freeze-drying resulted in a mixture of diastereomers, cis-3- (D-2-sulfo-2-phenylacetamido) -4-methoxycarbonyl-1-sulfo-2-oxoazeti Dean. Sodium salt is obtained.

Example 56

In the same manner as in Example 53, as a mixture of diastereomers, sodium cis-3- (2-benzyloxycarbonyl-2-phenylacetamido) -4-methoxycarbonyl-2-oxoazetidine- 1-sulfonate is obtained.

Example 57

In 6 ml of 80% ethanol, 106 mg of sodium cis-3- (2-benzyloxycarbonyl-2-phenylacetamido) -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate, 106 ml 5% palladium-carbon and 16.8 mg sodium bicarbonate are added and the mixture is vigorously stirred in a hydrogen atmosphere for 3.5 h at ambient temperature under atmospheric pressure. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The concentrate was purified by column chromatography of Amberlite XAD-II and freeze-dried to give a mixture of diastereomers, cis-3- (2-carboxy-2-phenylacetamido) -4-methoxycarbonyl- 1-sulfo-2-oxoazetidine. A sodium salt is obtained.

Example 58

480 mg of pyridine-sulfate anhydride complex was dissolved in a solution of 360 mg of sodium cis-3-cyanomethyl carboxamido-2-oxoazetidine-4-carboxylic acid methyl ester in 3 ml of N, N-dimethylformamide. The mixture is stirred and left to stand at room temperature for 6 days. 20 ml of ether is added to the reaction mixture, followed by stirring and discarding the ether layer. Again, 10 ml of ether was added to the residue, and the ether layer was discarded. The remaining oil is dissolved in 10 ml of water. 10 ml of Dow's 50 W (Na-type) resin is added to the aqueous solution, and the mixture is stirred at room temperature for 30 minutes. The resin is filtered off and the filtrate is washed four times with 10 ml of water each. The filtrate and washings are mixed and lyophilized. The freeze-dried material was dissolved in a small amount of water, purified by column chromatography of Amberlite XAD-II, followed by Sephadex LH-20, and then freeze-dried. Sodium cis-3-cyanomethylcarboxamido-4 -Methoxycarbonyl-2-oxoazetidine-1-sulfonate is obtained.

Example 59

341 mg sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyimino acetamido] -2-oxoazetidine-4-carboxylic acid P-nitrobenzyl To a solution of esters dissolved in 3 ml of N, N-dimethylformamide, 258 mg of pyridine-sulfate anhydride complex was added, and 103 mg of pyridine-sulfate anhydride complex was added to the mixture, followed by further stirring for 38 hours. 45 ml of ether is added to the reaction mixture, and the ether layer is removed by decantation. This process is performed twice. The remaining syrupy material is suspended in 45 ml of water. 20 ml of Dow's 50 W (Na-type) resin is added to the suspension and the mixture is stirred at room temperature for 1.5 hours. The resin is filtered off and the filtrate is concentrated under reduced pressure. The concentrate was purified by column chromatography of Amberlite XAD-II and lyophilized to yield a colorless powder. After dissolving this powder in 16 ml of water, 68 mg of sodium monomethyldithio carbamate was added under ice-cooling and stirring. The mixture is stirred for an additional hour at room temperature before 68 mg of sodium monomethyldithio carbamate is added as a supplement. The mixture is stirred for an additional hour and then washed with ethyl acetate. The aqueous layer was purified by column chromatography of Amberlite XAD-II and lyophilized to give sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyimino acetamido] -4- (4-nitrobenzyloxycarbonyl) -2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 60

155 mg of sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyimino acetamido] -4- (4-nitrobenzyloxy in a mixture of 10 ml tetrahydrofuran and 10 ml water Carbonyl) -2-oxoazetidine-1-sulfonate (syn-isomer) is dissolved. 145 mg of 10% palladium-carbon is added to the solution, and the mixture is subjected to catalytic reduction at ambient temperature under atmospheric pressure with stirring. After 3 hours, 10 ml of an aqueous solution of 25 mg of sodium bicarbonate was added to the reaction mixture. The catalyst is filtered off and the filtrate is washed with ethyl acetate and concentrated under reduced pressure. The concentrate was purified by column chromatography of Amberlite XAD-II and freeze-dried to give cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyimino acetamido] -4-carboxy 1-Sulfo-2-oxoazetidine. 2 Sodium salt (syn-isomer) is obtained.

Example 61

462 mg of methyl cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxycarbonylmethyloxyimino acetamido] -2-7 ml of N, N-dimethylformamide The oxoazetidine-4-carboxylate (syn-isomer) is dissolved, cooled to -78 ° C and sulfuric anhydride -N, N-dimethylformamide complex solution (3 mmol) is added. The mixture is stirred at 4 ° C. for 18 hours, then pyridine (3 mmol) is added and the mixture is stirred for another hour. Adding 100 ml of ether crystallizes the insolubles. Discard the mother liquor and wash the crystals twice with 30 ml of ether. After dissolving the crystals in 10 ml of water, 23 ml of Dow's 50 W (Na-type) resin is added and the mixture is stirred at room temperature for 2 hours. Filter off the resin and add 300 ml of water to the filtrate. The suspension thus produced is chromatographed with Amberlite XAD-II, the column is washed with 350 ml of water and eluted with 15% ethanol. The eluate (200 ml) was concentrated under reduced pressure and freeze dried to yield 420 mg of a colorless powder.

This powder is rechromatized with an Amberlite XAD-II column. The column is washed with 1 L of water and eluted with 100 ml of 15% ethanol. The eluate was concentrated under reduced pressure and lyophilized to yield colorless powdered sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxycarbonylmethyloxyimino acetamido] -4 -Methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 62

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxycarbonylmethyloxyimino acetamido] -4-methoxycarbonyl-2- Oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 63

1.35 g cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2- (P-nitrobenzyloxycarbonyl methyloxyimino) acetate in 20 ml of anhydrous N, N-dimethylformamide Tamido] -4-methoxy carbonyl-2-oxoazetidine (syn-isomer), cooled to -78 ° C, and 4.11 ml sulfuric anhydride -N, N-dimethylformamide complex solution (1.69 M) is added. The mixture is stirred at 4 ° C. for 72 hours, then 0.57 ml of pyridine is added and the mixture is stirred for another 1 hour. After adding 500 ml of ether, the mixture is left overnight in the refrigerator. Discard the above ether layer and wash the residue twice with 50 ml each ether. 50 ml of water is added to dissolve some of the insoluble fraction of the serum phase and a rubbery product is obtained. 50 ml of Dow's 50 W (Na-type) resin was added to the product and the mixture was stirred at room temperature for 2 hours. After removal of the resin (about 200 ml), the mother suspension is washed with a column of 1 L of water chromatographed with an Amberlite XAD-II column, eluting with 200 ml of 30% ethanol. The eluate was concentrated under reduced pressure and lyophilized to remove sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2- (P-nitrobenzyloxycarbonyl methyloxyimino) acetamido]. 4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 64

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2- (P-nitrobenzyloxycarbonylmethyloxyimino) acetamido] -4-methoxy Carbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 65

500 mg of sodium cis-3- [2- (2-amino-4-thiazolyl) -2- (P-nitrobenzyloxycarbonylmethyloxyimino) acetamido in a mixture of 25 ml of water and 25 ml of tetrahydrofuran ] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is dissolved and then 500 mg of 10% palladium-carbon is added. The mixture is stirred for 1 hour in a hydrogen atmosphere. 25 ml of sodium hydrogen carbonate (66 mg) solution is added and the catalyst is filtered off. The filtrate is washed with 30 ml of ethyl acetate and concentrated to 10 ml under reduced pressure. The concentrate is chromatographed with Amberlite XAD-II and eluted with water. Discard the first 130 ml fractions and freeze-dry the 40 ml fractions subsequently followed by cis-3- [2- (2-amino-4-thiazolyl) -2-carboxymethyloxy imino acetamido] -4 -Methoxycarbonyl-2-oxoazetidine-1-sulfonic acid disodium (syn-isomer) is obtained.

Example 66

In a mixture of 20 ml of water and 20 ml of tetrahydrofuran, 950 mg of sodium cis-3-benzyloxycarboxamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate obtained in Example 49 was added. After dissolution, 950 mg of 10% palladium-carbon is added. After the mixture is stirred at room temperature for 1 hour in a hydrogen atmosphere, the catalyst is filtered off and washed with 40 ml of water-tetrahydrofuran (1: 1). The filtrate and washings are mixed, and on ice cooling and stirring, 504 mg of sodium bicarbonate and 1.55 g of 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2- [1-methyl-1- (P-nitrobenzyloxycarbonyl) ethyloxyimino acetylchloride. Apply HCL. The mixture is stirred for 40 minutes under ice-cooling and then concentrated under reduced pressure. The residue was chromatographed on an Amberlite XAD-II column and lyophilized to give colorless powdery sodium cis-3- {2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1 -(P-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido} -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 67

1.158 g of sodium cis-3- {2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (P-nitrobenzyloxycarbonyl) ethyloxyimino in 30 ml of water ) Acetamido} -4-methyloxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is dissolved, and 241 mg of sodium monomethyldithio carbamate is added under ice cooling and stirring. do. After stirring for 1 hour at room temperature in the mixture, 241 mg of sodium monomethyldithio carbamate is further added. The mixture is stirred for an additional hour. The reaction mixture is then washed with ether and concentrated under reduced pressure. The residue was chromatographed on an Amberlite XAD-II column and lyophilized to give colorless powdery sodium cis-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (P -Nitrobenzyloxycarbonyl) ethyloxyimino] acetamido} -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 68

500 mg of sodium cis-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (P-nitrobenzyloxycarbonyl) in a mixture of 25 ml of water and 25 ml of tetrahydrofuran ) Ethyloxyimino] acetamido} -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is added and then 500 mg of 10% palladium-carbon is added. The mixture is stirred for 1 hour at room temperature in a hydrogen atmosphere. After adding 25 ml of aqueous sodium hydrogen carbonate (62 mg) solution, the catalyst was filtered off, and the filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue was chromatographed on an Amberlite XAD-II column and lyophilized to give cis-3- [2- (2-amino-4-thiazolyl) -2- [1-methyl-1-carboxyethyloxyimino) acetate. Tamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid disodium salt (syn-isomer) is obtained.

Example 69

85 mg of sodium cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-methoxycarbonyl in 4 ml of cold water The 2-oxoazetidine-1-sulfonic acid disodium salt (syn-isomer) is dissolved and the solution is chromatographed with a column of Dows 50 W (H-type) resin (10 ml) and eluted with water. Fractions that absorb UV are collected and concentrated under reduced pressure, and the residue is chromatographed with Sephadex LH-20 and lyophilized to give a colorless powder of cis-3- [2- (2-amino-4-thiazolyl) -2. -(1-methyl-1-carboxyethyloxyimino) acetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn-isomer) is obtained.

Example 70

550 mg of cis-3-2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (P-nitrobenzyloxycarbonyl) in 3 ml of N, N-dimethylformamide Ethyloxyimino] acetamido-4-methoxycarbonyl-2-oxoazetidine (syn-isomer) was dissolved, cooled to -78 ° C, and 1.6 ml of sulfuric anhydride -N, N-dimethylformamide Complex solution (1.67 M) is added. The mixture is stirred for 24 h at 3-5 ° C. and then 0.22 ml of pyridine is added. Adding 75 ml of ether separates the syrupy material. The ether layer is discarded and the syrup insoluble in ether is washed twice with 50 ml of ether and suspended in 25 ml of water. After adding 20 ml of Dow's 50 W (Na-type) resin, the mixture is stirred at room temperature for 1.5 hours. The resin is filtered off and the filtrate is concentrated under reduced pressure. The residue was chromatographed on an Amberlite XAD-II column and lyophilized to give colorless powdery sodium cis-3- {2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1 -(P-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido} -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained. In IR and NMR spectra, this product is consistent with the compound obtained in Example 66.

Elemental _{analysis: C 23 H 22 ClN 6 NaO} 13 S 2 · H 2 O

Calculated Value: C; 37.79%, H; 3.31%, N; 11.50%

Found: C; 37.50%, H; 3.42%, N; 11.69%

The amino- and carboxy-protecting groups on this resulting compound can be removed by the methods described in Examples 67 and 68, respectively.

Example 71

In the same manner as in Example 10, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-allyloxyiminoacetamido] -4-methoxycarbonyl-2-jade Pediazetidine-1-sulfonate (syn-isomer) is obtained.

Example 72

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-allyloxyiminoacetamido] -4-methoxycarbonyl-2-oxoazetidine -1-sulfonate (syn-isomer) is obtained.

Example 73

To 2 ml of water, 50 mg of sodium trans-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyaminoacetamido] -4-methoxycarbonyl obtained in Example 24 After dissolving the 2-oxoazetidine-1-sulfonate (syn-isomer), 15 mg of sodium monomethyldithio carbamate is added under ice water cooling and stirring. The mixture is stirred for 30 minutes at room temperature, then 15 mg of sodium monomethyldithio carbamate is further added and the mixture is stirred for 30 minutes. The reaction mixture is filtered and the filtrate is washed with ether. The aqueous layer was chromatographed with an Amberlite XAD-II column and lyophilized to give sodium trans-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarb Bonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 74

In the same manner as in Example 10, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-chloromethyl-2-oxoazeti Dean-1 -sulfonate (syn-isomer) is obtained.

Example 75

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-chloromethyl-2-oxoazetidine-1 -Sulfonates (syn-isomers) are obtained.

Example 76

In the same manner as in Example 10, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methylsulfonyloxymethyl-2- Oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 77

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-methylsulfonyloxymethyl-2-oxoazeti Dean-1 -sulfonate (syn-isomer) is obtained.

Example 78

In the same manner as in Example 10, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-azidomethyl-2-oxoa Zetidine-1-sulfonate (syn-isomer) is obtained.

Example 79

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-azidomethyl-2-oxoazetidine- 1-sulfonate (syn-isomer) is obtained.

Example 80

In the same manner as in Example 3, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-benzoyloxymethyl-2-oxoa Zetidine-1-sulfonate (syn-isomer) is obtained.

Example 81

In the same manner as in Example 4, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-benzoyloxymethyl-2-oxoazetidine- 1-sulfonate (syn-isomer) is obtained.

Example 82

In the same manner as in Example 1, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-acetyl-2-oxoazetidine -1-sulfonate (syn-isomer) is obtained.

Example 83

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-acetyl-2-oxoazetidine-1- Sulfonates (syn-isomers) are obtained.

Example 84

172 mg of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-hydroxymethyl-2 in 2 ml of N, N-dimethylformamide After dissolving oxoazetidine (syn-isomer), 318 mg of sulfuric anhydride-pyridine complex is added. After the mixture is stirred at room temperature for 24 hours, 159 mg of sulfuric anhydride-pyridine complex are added and the mixture is further stirred for 106 hours. When ether is added to the reaction mixture, syrupy material is separated out. Discard the ether layer and wash the insolubles with ether. Repeat this once more and discard the ether layer and dissolve the insoluble matter in 20 ml of water. After adding 40 ml of Dow's 50 W (Na-type) resin, the mixture is stirred at room temperature for 2 hours and the resin is filtered off. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on an Amberlite XAD-II column and freeze-dried to give 2 sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-meth Toxyiminoacetamido] -4-sulfonatoitooxymethyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 85

In the same manner as in Example 1, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-chloroacetoxymethyl-2-jade Pediazetidine-1-sulfonate (syn-isomer) is obtained.

Example 86

70 mg sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-chloroacetoxymethyl-2-oxoazeti in 2 ml of water Dean-1-sulfonate (syn-isomer) is dissolved and 39 mg of sodium monomethyldithio carbamate are added under ice-cooled light stirring. The mixture is stirred at rt for 1 h. After addition of 10 mg sodium monomethyldithio carbamate, the mixture is stirred for 30 minutes. The reaction mixture is filtered off and the filtrate is washed with ether. The aqueous layer was chromatographed with an Amberlite XAD-II column and lyophilized to give sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-hydroxymethyl 2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 87

In the same manner as in Example 31, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (2-methylsulfonylethoxy Carbonylaminomethyl) -2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 88

In the same manner as in Example 10, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-trifluoroacetylaminoethyl-2 Oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 89

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-trifluoroacetylaminomethyl-2-oxoa Zetidine-1-sulfonate (syn-isomer) is obtained.

Example 90

416 mg cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (P-nitro) in 3.5 ml of N, N-dimethylformamide After dissolving benzyloxycarbonylaminomethyl) -2-oxoazetidine (syn-isomer), 239 mg of sulfuric anhydride-pyridine complex are added. The mixture is stirred at rt for 48 h. After adding 119 mg of sulfuric anhydride-pyridine complex, the mixture is further stirred for 72 hours. 55 ml of ether is added to the reaction mixture to separate the syrupy material. Discard the upper ether layer and wash the insolubles with ether. Repeat the same procedure once more and discard the ether layer. The insoluble in syrup is suspended in 50 ml of water, then 25 ml of Dow's 50W (Na-type) resin is added and the mixture is stirred at room temperature for 2 hours. The resin is filtered off and the filtrate is concentrated under reduced pressure.

Chromatography of the residue with an Amberlite XAD-II column yielded 404 mg of a colorless powder. The powder is dissolved in 15 ml of water, and 87 mg of sodium monomethyldithio carbamate are added under ice cooling and stirring. The mixture is stirred for 1 hour at room temperature before 5 ml of water, 5 ml of tetrahydrofuran and 87 mg of sodium monomethyldithio carbamate are added. The mixture is stirred for an additional hour. The reaction mixture was washed with ethyl acetate, chromatographed on an Amberlite XAD-II column and lyophilized to give sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido. ] -4- (P-nitrobenzyloxycarbonylaminomethyl) -2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 91

203 mg of sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4- (p-nitrobenzyl in a mixture of 15 ml of water and 15 ml of tetrahydrofuran Oxycarbonylaminomethyl) -2-oxoazetidine-1-sulfonate (syn-isomer) is dissolved and then 190 mg of 10% palladium-carbon is added. The mixture is stirred for 3 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off, the filtrate is washed with ethyl acetate and concentrated under reduced pressure. Chromatography of the residue with an Amberlite XAD-II column yields a colorless powder. The powder was lyophilized by rechromatography with a Sephadex LH-20 column to give cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-aminomethyl- 2-oxoazetidine-1-sulfonic acid (syn-isomer) is obtained.

Example 92

In the same manner as in Example 27, beta and alpha type sodium cis-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido ] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate is obtained.

Example 93

In the same manner as in Example 27, beta and alpha types of sodium cis-3- [D-2-(-4-ethyl-2, 3-dioxo-1-piperazinecarboxamido) -2-phenylacetami 4-acetoxymethyl-2-oxoazetidine-1-sulfonate is obtained.

Example 94

In the same manner as in Example 27, beta and alpha types of sodium cis-3- [D-2- (furan-2-aldomino) -2-oxo-1-imidazolidinecarboxamido] -2-phenyl Acetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate is obtained.

Example 95

In the same manner as in Example 27, beta and alpha type sodium cis-3- [D-2- (3-thiophene-2-aldimido) -2-oxo-1-imidazolidinecarboxamido]- 2-phenylacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate is obtained.

Example 96

In 10 ml of methylene chloride, 0.8 g of methyl cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylate was dissolved in the same manner as in Reference Example 3, followed by ice cooling. And 0.4 ml of triethylamine were added under stirring, followed by dropwise addition of 0.6 g of a methylene chloride solution of 2- (2-methyl-4-thiazolyl) -2-methoxyiminoacetylchloride. The mixture is stirred under ice cooling for 20 minutes and at room temperature for 1.5 hours. Water is added to the reaction mixture, and the methylene chloride layer is separated. This layer is dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is cooled to −10 ° C. and 1.75 ml of sulfuric anhydride —N, N-dimethylformamide complex solution (1.58 M) are added. The mixture is left for 3 days at 5 ° C. in the stopper flask. 0.29 ml of pyridine is added to the reaction mixture, the mixture is poured into 100 ml of ether and stirred. Discard the supernatant and dissolve the residue in 2 ml of water. After adding 30 ml of Dow's 50 W (Na-type) resin, the mixture is stirred at room temperature for 30 minutes. Filter off the resin and concentrate the filtrate to 20 ml. The concentrate was chromatographed on an Amberlite XAD-II column and lyophilized to give sodium cis-3- [2- (2-methyl-4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarba Bonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 97

1.9 ml of 499 mg of methyl cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-diethylphosphonoacetamido] -2-oxoazetidine-4-carboxylate Anhydrous sulfate-N, N-dimethylformamide complex solution (1.58M) was added at 10 ° C, and the mixture was left at 5 ° C in a stopper flask for 3 days. 0.32 ml of pyridine is added to the reaction mixture, the mixture is poured into 100 ml of ether and stirred. Discard the supernatant and dissolve the residue in 20 ml of water. After adding 15 ml of Dow's 50 W (Na-type) resin, the mixture is stirred at room temperature for 30 minutes. The resin is filtered off and the filtrate is concentrated to 20 ml. The concentrate was chromatographed with an Ambertite XAD-II column and lyophilized to give sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-diethylphosphonoacetamido] -4 -Methoxycarbonyl-2-oxezetidine-1-sulfonate is obtained.

Example 98

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-diethylphosphonoacetamido] -4-methoxycarbonyl-2-oxoazeti Dean-1 -sulfonate is obtained.

Example 99

In the same manner as in Example 97, sodium cis-3- (2-triethylsilylethylcarboxamido) -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate is obtained.

Example 100

In the same manner as in Example 97, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4- (2-phenylethyl) -2-oxoa Zetidine-1-sulfonate (syn-isomer) is obtained.

Example 101

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4- (2-phenylethyl) -2-oxoa Zetidine-1-sulfonate (syn-isomer) is obtained.

Example 102

In the same manner as in Example 97, sodium cis-3- [2- (2-hydroxy-4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarbonyl-2-oxoazeti Dean-1 -sulfonate (syn-isomer) is obtained.

Example 103

In the same manner as in Example 10, the following compound is obtained. Sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-ethoxycarbonyl-2-oxoazetidine-1-sulfonate Of syn- and anti-isomers

Example 104

In the same manner as in Example 11, the following compound is obtained: sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-ethoxycarbonyl 2-oxoazetidine-1-sulfonate is syn- and anti-isomer.

Example 105

In the same manner as in Example 1, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-phenylcarbamoyl-2-jade Pediazetidine-1-sulfonate (syn-isomer) is obtained.

Example 106

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-phenylcarbamoyl-2-oxoazetidine -1-sulfonate (syn-isomer) is obtained.

Example 107

In the same manner as in Example 10, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-ethoxycarbonylmethyloxycarbonyl 2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 108

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-ethoxycarbonylmethyloxycarbonyl-2- Oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 109

630 mg of trans-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-acetoxymethyl- in 3 ml of anhydrous N, N-dimethylformamide Dissolve 2-oxoazetidine (syn-isomer). After cooling the solution to −78 ° C., 2.68 ml of anhydrous sulfate-N, N-dimethylformamide complex solution (1.69 M) was added thereto. The mixture is left at 4 ° C. for 12 h and 358 mg of pyridine, followed by 40 ml of ether, are cooled to 0 ° C. Discard the supernatant and wash the precipitate three times with 30 ml of ether. After the ether was removed, 10 ml of water and 20 ml of Dow's 50 W (Na-type) resin were added and the mixture was stirred for 2 hours. The resin was filtered off, the filtrate was concentrated and chromatographed with Amberlite XAD-II column to give sodium trans-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoaceta. Mido] -4-acetoxymethyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 110

In the same manner as in Example 11, sodium trans-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-acetoxymethyl-2-oxoazetidine- 1-sulfonate (syn-isomer) is obtained.

Example 111

In the same manner as in Example 109, sodium trans-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methyl-2-oxoazetidine -1-sulfonate (syn-isomer) is obtained.

Example 112

To 3 ml of water, 300 mg of lyophilized sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarbonyl obtained in Example 2 The 2-oxoazetidine-1-sulfonate (syn-isomer) is dissolved and the mixture is stirred briefly, whereby a white turbid solution gives crystals. After cooling the mixture overnight, 10 ml of ethanol are added and the mixture is further cooled for 3 hours. When the resulting crystalline precipitate was diluted by filtration and dried, 241 mg of monohydrate of the compound described above was obtained as colorless crystals. Melting point 235-245 캜 (decomposition).

Example 113

To 3 ml of 1N HCL, 86 mg of sodium cis-3- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -4-methoxycarbonyl-2-azetidinone 1-Sulfonate (syn-isomer) is dissolved and the solution is stirred under ice cooling. Then 500 mg of zinc powder are all added simultaneously. After the mixture is stirred for 5 minutes, the reaction mixture is filtered. The filtrate is chromatographed with Amberlite XAD-II column and developed with water. Fractions containing the desired product are put together and lyophilized to yield cis-3- [DL-2- (2-aminothiazol-4-yl) -2-ammonioacetamido] -4-methoxycarbonyl-. 2-azetidinone-1-sulfonate is obtained.

Example 114

The procedure of Example 113 is repeated until zinc powder reduction and filtration are obtained. 500 mg of sodium cyanide is added to the filtrate, and the mixture is stirred at 45 ° C for 30 minutes. The reaction mixture is ice-cooled, the pH is adjusted to 1 with 1N HCl and then the pH is adjusted to 7 with 1N sodium hydrogen carbonate. The mixture is chromatographed in order of Amberlite XAD-II and Sephadex LH-20 column using water as the developing solvent. Fractions containing the desired compounds were collected and lyophilized to yield sodium cis-3- [DL-2- (2-aminothiazol-4-yl) -2-katbamoylaminoacetamido] -4-methoxy. Carbonyl-2-azetidinone-1-sulfonate is obtained.

Example 115

60 mg cis-3- [DL-2- (2-aminothiazol-4-yl) -2-ammonioacetamido] -4-methoxycarbonyl-2-azetidinone-1-sulfonate, 45 mg Of a mixture of diisopropylethylamine, 1 ml of dichloromethane and 3 ml of acetone was stirred under ice-cooling, 77 µl of 1-chloroformyl-2, 3-dioxo-4-ethyl-1, 4-piperazine, Next, 1 ml of water is added. The mixture is stirred vigorously for 30 minutes, and then the organic solvent is distilled off under reduced pressure. The residue is chromatographed in the order of Amberlite IR-200 (Na-type), Amberlite XAD-II and Sephadex LH-20 using water as eluent. The fractions containing the desired product were collected and lyophilized to give sodium cis-3- [DL-2- (2-aminothiazol-4-yl) -2- (2, 3-dioxo-4-ethyl-1 , 4-piperazin-1-yl) carbonylaminoacetamido] -4-methoxycarbonyl-2-azetidinone-1-sulfonate is obtained.

Example 116

40 mg of cis-3- [DL-2- (2-aminothiazol-4-yl) -2-ammonioacetamido] -4-methoxycarbonyl-2-azetidinone-1 in 2 ml of acetonitrile After the sulfonate is suspended, the suspension is stirred under ice-cooling and 150 μl of acetic formic anhydride is added. After the mixture was stirred for 5 minutes, a solution of 20 mg of sodium bicarbonate dissolved in 2 ml of water was added. The mixture is stirred for 30 minutes and concentrated to one third of the original volume. To the residue is added 1 ml of sodium hydrogen carbonate solution (1M) and the resulting mixture is chromatographed in the order of Amberlite XAD-II and Sephadex LH-20 using water as eluent. The fractions containing the desired product were collected and lyophilized to yield sodium cis-3- [DL-2- (2-aminothiazol-4-yl) -2-formamidoacetamido] -4-methoxycarb. Bonyl-2-azetidinone-1-sulfonate is obtained.

Example 117

40 mg of cis-3- [DL-2- (2-aminothiazol-4-yl) -2-ammonioacetamido] -4-methoxy in a mixture of 1 ml acetonitrile and 0.5 ml dimethylacetamide Carbonyl-2-azetidinone-1-sulfonate is dissolved and stirred at −20 ° C., 50 μl of methanesulfonyl chloride and 100 μl of diisopropylethylamine are added. The mixture is stirred at the same temperature for 10 minutes and at 0 ° C. for 20 minutes. The reaction mixture is cooled to -50 ° C, then ether is added and shaken (30 ml x 3). Insoluble matter on the resulting syrup is separated and 5 ml of water is added thereto. The solution is chromatographed in the order of Amberlite IR-120 (Na-type) and Amberlite XAD-II columns using water as eluent. The fractions containing the desired product were collected and lyophilized to give sodium cis-3- [DL-2- (2-aminothiazol-4-yl) -2-methanesulfonylaminoacetamido] -4-methoxy Carbonyl-2-azetidinone-1-sulfonate is obtained.

Example 118

80 mg of cis-3- [DL-2- (2-aminothiazol-4-yl) -2-ammonioacetamido] -4-methoxycarbonyl-2-azetidinone-1 in 3 ml of acetonitrile -Sulfonate is suspended and, under ice-cooling and stirring, 38ul of benzoyl chloride and then 1ml of 1N sodium hydrogen carbonate are added. After the mixture was stirred for 30 minutes, 10 ml of water and 15 ml of ethyl acetate were added. After shaking, the aqueous layer is taken and chromatographed with Amberlite XAD-II column using water as eluent. The fractions containing the desired product are combined and lyophilized to give sodium cis-3- [DL-2- (2-aminothiazol-4-yl) -2-benzoylaminoacetamido] -4-methoxycarbonyl 2-acetidinone-1-sulfonate is obtained.

Example 119

80 mg of cis-3- [DL-2- (2-aminothiazol-4-yl) -2-ammonioacetamido] -4-methoxycarbonyl-2-azetidinone in 1 ml dimethylacetamide 1-Sulfonate is suspended and 50 mg P-toluenesulfonyl chloride is added followed by 120 μl of diisopropylethylamine under ice-cooling and stirring. The mixture is stirred for 30 minutes. The reaction mixture is stirred for 2 more hours at room temperature, then ether is added and shaken (30 ml x 3). The resulting insoluble syrup is chromatographed in the order of Amberlite IR-120 (Na-type), Amberlite XAD-II and Sephadex LH-20 columns eluting with water. The fractions containing the desired product were collected and lyophilized to give sodium cis-3- [DL-2- (2-aminothiazol-4-yl) -2-P-toluenesulfonylaminoacetamido] -4- Methoxycarbonyl-2-acetidinone-1-sulfonate is obtained.

Example 120

80 mg of cis-3- [DL-2- (2-aminothiazol-4-yl) -2-ammonioacetamido] -4-methoxycarbonyl-2-azetidinone in 1 ml of dimethyl acetamide 1-Sulfonate is suspended and 20 μl of 2-methoxyacetyl chloride is added under ice-cooling and stirring. The mixture is stirred at room temperature for 2 hours, then ice-cooled and 300 mg of 1N sodium hydrogen carbonate is added. The mixture is further stirred for 20 minutes, then ethyl ether is added and shaken (30 ml x 3). The resulting insoluble syrup is chromatographed in the order of Amberlite XAD-II and Sephadex LH-20 columns using water as eluent. The fractions containing the desired product were collected and freeze dried to obtain sodium cis-3- [DL-2- (2-aminothiazol-4-yl) -2- (2-methoxyacetamido) acetamido]. 4-methoxycarbonyl-2-azetidinone-1-sulfonate is obtained.

Example 121

80 mg of cis-3- [DL-2- (2-aminothiazol-4-yl) -2-ammonioacetamido] -4-methoxycarbonyl-2-azetidinone-1 in 2 ml acetonitrile -Sulfonate is suspended and the suspension is ice cooled and stirred. 200 μl of acetic anhydride, 60 mg of sodium acetate and 2 ml of water are added to the suspension, and the mixture is stirred for 10 minutes. The mixture is stirred for another 1 hour at room temperature, after which 3.6 ml of sodium hydrogen carbonate solution (1M) is added. The resulting mixture is chromatographed with a column of Amberlite XAD-II, then Sephadex LH-20, using water as eluent. The fractions containing the desired product were collected and lyophilized to yield sodium cis-3- [DL-2- (2-aminothiazol-4-yl) -2-acetamidoacetamido] -4-methoxycarb. Bonyl-2-azetidinone-1-sulfonate is obtained.

Example 122

402 mg of cis-3-2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methylcarbamoyl-2- in 20 ml anhydrous NN-dimethylformamide After suspending oxoazetidine (syn-isomer), 320 mg of anhydrous sulfate-pyridine complex is added. After the mixture is stirred for 24 hours, 40 ml of anhydrous N.N-dimethylformamide and 320 mg of sulfuric anhydride-pyridine complex are added and then the mixture is stirred for 72 hours. The reaction mixture is poured into 500 ml of ethanol and the insolubles are collected by filtration, washed with ether and suspended in 500 ml of water. After adding 30 ml of Dow's 50W (Na-type) resin, the suspension is stirred for 3 hours. The filtrate is lyophilized by filtering the resin to give a colorless powder. The powder was dissolved in water and the aqueous solution was chromatographed with an Amberide XAD-II column and lyophilized to give sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyimine. Noacetamido] -4-methylcarbamonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 123

Sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-methylcarbamoyl-2-oxoazetidine- in the same manner as in Example 11 1-sulfonate (syn-isomer) is obtained.

Example 124

In the same manner as in Example 70, ethyl was dissolved in sodium trans-3- {2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (P-nitrobenzyl oxycarbonyl) Oxiimino] acetamido} -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate is obtained.

Example 125

In the same manner as in Example 67, sodium trans-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1 (P-nitrobenzyloxycarbonyl) ethyloxyimino] acetami 4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 126

In the same manner as in Example 68, trans-3- [2- (2-amino-4-thiazolyl) -2- (1-carboxy-1-methylethoxyimino) acetamido] -4-methoxycarb Bonyl-2-oxoazetidine-1-sulfonic acid-2 sodium salt (syn-isomer) is obtained.

Example 127

In the same manner as in Example 61, sodium cis-3- [2- (2-coloacetamido] -4-thiazolyl) -2- (1-methoxycarbonyl-2-oxoazetidine-1 -Sulfonates (syn-isomers) are obtained.

Example 128

In the same manner as in Example 62, sodium cis-3- {2- (2-amino-4-thiazolyl) -2- (1-methoxycarbonyl-1-methylethoxyimino) acetamido} -4 -Methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 129

In the same manner as in Example 61, to sodium cis-3- {2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (1-trimethylsilylethoxycarbonyl) Toxyimino acetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 130

In the same manner as in Example 62, sodium cis-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (2-trimethylsilylethoxycarbonyl) ethoxyimino] Acetamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 131

630 mg of cis-3- {2- (2-chloroacetamido-4-thiazolyl) -2- {1-methyl-1- (P-nitro) obtained at 166 in 2 ml of anhydrous NN-dimethylformamide Benzyloxycarbonyl) ethyloxyimino] acetamido} -4-katbamoyl-2-oxoazetidine (syn-isomer) is dissolved. Then, 1.69 ml of sulfuric anhydride -N, N-dimethylformamide complex solution (1.56 M) was added at -78 ° C. The mixture is left overnight at 40 ° C. in the refrigerator. 208 mg of pyridine and then 30 ml of ether are added to the reaction mixture under ice-cooling, and the resulting syrup-like precipitate is washed with ether by decantation (20 ml x 3). The precipitate is dissolved in 15 ml of water, and then 15 ml of Dodec's 50 W (Na-type) resin is added and the mixture is stirred at room temperature for 2 hours. The resin is filtered off and the filtrate is concentrated under reduced pressure. The residue is chromatographed with an Ambolite XAD-II column and subsequently eluted with water and 10-20% ethanol to give the disulfo compound (Example 134) which is further eluted with 40% ethanol. Lyophilization of 40% ethanol nuclei containing desired compounds resulted in sodium cis-3- {2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1-(-nitrobenzyl Oxycarbonyl) ethyloxyimino] acetamido} -4-carbamoyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 132

280 mg of sodium cis-3--3-2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (P-nitrobenzyloxycarbonyl) obtained in Example 131 in 20 ml of water ) Ethyloxyimino] acetamido} -4-carbamoyl-2-oxoazetidine-1-sulfonate (syn-isomer), 104 mg of sodium monomethyldithiocarba under ice cooling and stirring Add a mate. The mixture is stirred for 1.5 hours at room temperature. The reaction mixture is washed twice with ether, then eluted with water and chromatographed with Amberlite XAD-II (40 g) column eluting with 20% ethanol. When the nucleus containing the desired product is combined and lyophilized, sodium cis-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (P-nitrobenzyloxycarbonyl) Ethyloxyimino] acetamido} -4-carbamoyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 133

In 10 ml of water, 200 mg of sodium cis-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (P-nitrobenzyloxycarbonyl) ethyloxy After dissolving mono] acetamido} -4-carbamoyl-2-oxoazetidine-1-sulfonate (syn-isomer), 200 mg of 10% palladium-carbon is added. The mixture is stirred at hydrogen atmosphere for 1 hour at room temperature. The catalyst is filtered off and ice-cooled to add 27 mg of sodium hydrogen carbonate. The mixture is stirred for 5 minutes and washed with ethyl acetate. 20 ml of Dow's 50 W (H-type) resin was added to the aqueous worm, and the mixture was stirred for 1.5 hours. Filter off the resin and concentrate the filtrate to half its volume. The residue is chromatographed with Amber followed by Ambernet's XAD-II (40 g) column, eluting with 15% ethanol. The fractions containing the desired product were combined and lyophilized to yield cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido]- 4-Carbamoyl-2-oxoazetidine-1-sulfonic acid (syn-isomer) is obtained.

Example 134

Lyophilization of the 10-20% ethanol eluate fraction obtained from the Amberlite XAD-II column in Example 131 gave a colorless powder of cis-3- {2- (2-chloroacetamido-4-thiazolyl) -2. -[1-Methyl-1- (P-nitrobenzyloxycarbonyl) -ethyloxyimino] aceramid} -4-sulfoaminocarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn-isomer) Is generated. Removing the amino and carboxyl protecting groups from this product in the same manner as in Examples 132 and 133, respectively, cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1 -Carboxyethyloxyimino) acetamido] -4-sulfoaminocarbonyl-2-oxoazetidine-1-sulfonic acid triammonium salt (syn-isomer) is obtained.

Example 135

When cis-4-acetoxymethyl-3-benzyloxycarboxamido-2-oxoazetidine obtained in Reference Example 7 is reacted in the same manner as in Reference Example 91, cis-3- {2- (2- Chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (P-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido} -4-acetoxymethyl-2-oxoazetidine (syn-isomer) is obtained. Melting Point 120-123 ° C

The above product is sulfonated in the same manner as in Example 70. The procedure of Example 67 was then performed to remove the amino protecting group, followed by sodium cis-3-2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (P-nitrobenzyloxy Carbonyl) ethyloxyamino] acetamido} -4-acetoxymethyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 136

In the same manner as in Example 68, cis-3- [2- (2-amino-4-thiazolyl) -2- [1-methyl-1-carboxyethyloxyimino) acetamido] -4-acetoxymethyl 2-oxoazetidine-1-sulfonic acid disodium salt (syn-isomer) is obtained.

[137]

The procedure of Reference Example 3 was carried out to remove the -3-amino protecting group from cis-3-benzyloxycarboxamido-4-carbamoyloxymethyl-2-oxoazetidine obtained in Reference Example 167. The corresponding 3-amino compound of the phase is obtained.

When acylated the above product in the same manner as in Reference Example 4, colorless crystalline cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4 -Carbamoyloxymethyl-2-oxoazetidine (syn-isomer) is obtained.

When the above product was sulfonated in the same manner as in Example 1, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-carbohydrate Barmoyloxymethyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 138

In the same manner as in Example 2, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-carbamoyloxymethyl-2-oxoazeti Dean-1 -sulfonate (syn-isomer) is obtained.

Example 139

Dissolve 1.08 g of cis-3-benzyloxycarboxamido-4-iodomethyl-2-oxoazetidine obtained in Reference Example 12 in 3 ml of N, N-dimethylformamide, and at -78 ° C, 5.8 ml (1.5 6M) of sulfuric anhydride-N, N-dimethylformamide complex solution are added. The mixture is stirred at 3-5 ° C. for 17 hours, then 0.73 ml of pyridine and 95 ml of ether are added continuously. The solid phase is collected by filtration, washed with ether and suspended in 50 ml of water. After adding 30 ml of Dow's 50 W (Na-type) resin, the suspension is stirred for 2 hours at room temperature. The resin is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by Amberlite XAD-II column chromatography eluting with 10-20% ethanol. The eluate is concentrated and lyophilized to give a colorless powder of sodium cis-3-benzyloxycarboxamido-4-iodomethyl-2-oxoazetidine-1-sulfonate.

Example 140

In 30 ml and pyridine is suspended 320 mg of sodium cis-3-benzyloxycarboxamido-4-iodomethyl-2-oxoazetidine-1-sulfonate and the suspension is heated under reflux for 9 hours. The pyridine is distilled off under reduced pressure and 50 ml of ether is added to the residue to separate the syrupy material. Discard the ether layer and wash the insolubles twice with ether.

Subsequently, 50 ml of water is added, the insoluble matter is considered, and the filtrate is concentrated under reduced pressure. The residue is purified by Amberlite XAD-2 column chromatography and eluted with 20% ethanol. The eluate is concentrated and lyophilized to give a colorless powder of cis-3-benzyloxycarboxamido-4-pyridiniomethyl-2-oxoazetidine-1-sulfonate.

Example 141

Suspension of 1.537 g of cis-3-benzyloxycarboxamido-4-carbamoyl-2-oxoazetidine obtained in Reference Example 165 in 12 ml of anhydrous N, N-dimethylformamide was cooled to -78 ° C. Then, sulfuric anhydride-N, N-dimethylformamido complex solution (10.51 mmol) is added. The mixture is left in the refrigerator for 3 days, ice-cooled, 0.85 ml of pyridine and then 40 ml of ether are added. The insolubles are washed three times with 50 ml of ether, and the ether is distilled off under reduced pressure. To the residue is added 10 ml of water and 40 ml of Dow's 50 W (Na-resin) and the mixture is stirred at room temperature for 2 hours. The resin was filtered off and the filtrate was purified by Amberlite XAD-2 column (eluent: water) chromatography and lyophilized. Sodium cis- [3-benzyloxycarboxamido-4-carbamoyl-2-oxoazeti Din] -1-sulfonate is obtained.

Sodium trans-3-benzyloxycarboxamido-4-cart while reacting the trans-3-benzyloxycarboxamido-4-carbamoyl-2-oxoazetidine obtained in Reference Example 168 in the same manner as described above. Bamoyl-2-oxoazetidine-1-sulfonate is obtained. This product is a hygroscopic powder and is used immediately for the next reaction.

Example 142

When sodium cis-3-benzyloxycarboxamide-4-carbamoyl-2-oxoazetidine-1-sulfonate is reacted in the same manner as in Example 66, sodium cis-3- {2- (2- Chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (P-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido} -4-carbamoyl-2-oxoazetidine -1-sulfonate (syn-isomer) is obtained. The product is eluted through the Amberlite XAD-II column with 40% ethanol. The IR and NMR spectra of this product are the same as those of the product obtained in Example 131.

Example 143

Sodium trans-3-benzyloxycarboxamido-4-carbamoyl-2-oxoazetidine-1-sulfonate is first reduced and acylated, as in Example 66. Then, as in Example 67, the chloro acetyl group was removed, and sodium trans-3-2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (P-nitrobenzyloxycarbonyl) Ethyloxyimino] acetamido} -4-carbamoyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 144

In the same manner as in Example 133, trans-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-carbamoyl 2-oxoazetidine-1-sulfonic acid (syn-isomer) is obtained.

Example 145

When cis-4-acetamidomethyl-3-benzyloxycarboxamido-2-oxoazetidine obtained in Reference Example 50 is reacted in the same manner as in Reference Example 91, cis-3-2- (2-chloroacetate Tamido-4-thiazoyl) -2- [1-methyl-1- (P-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido-4-acetamidomethyl-2-oxoazetidine (syn Isomers) are obtained.

When the above product was sulfonated as in Example 70, sodium cis-3 {2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (P-nitrobenzyloxycarbine) Bonyl) ethyloxyimino] acetamido} -4-acetamidoethyl-2-oxoazeridine-1-sulfonate (syn-isomer) is obtained.

Example 146

In the same manner as in Example 67, sodium cis-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (P-nitrobenzyloxycarbonyl) ethyloxyimino] acene Tamido} -4-acetamidomethyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 147

In the same manner as in Example 133, cis-3-2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido-4-acetamidoethyl- 2-oxoazetidine-1-sulfonic acid (syn-isomer) is obtained.

Example 148

260 mg of cis-3-amino-4-isopropyl-2-oxoazetidine is dissolved in a mixture of 15 ml of tetrahydrofuran and 15 ml of water and, under ice-cooling and stirring, 438 mg of sodium bicarbonate and 1.0 g of 2- (2-Chloroacetamido-4-thiazolyl) -2- (Z)-[1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetyl chloride hydrochloride is added. The mixture is stirred at room temperature for 2 hours, and the reaction mixture is concentrated under reduced pressure. The residue is shaken with 30 ml of water and 50 ml of ethyl acetate. The ethyl acetate layer is taken, washed with aqueous sodium bicarbonate solution and water in that order and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure. The residue was dissolved in 2 ml of N, N-dimethylformamide and sulfonated as in Example 70 to give sodium cis-3- {2- (2-chloroacetamido-4-thiazolyl) -2- [1 -Methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido} -4-isopropyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 149

In the same manner as in Example 67, sodium cis-3-2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetami 4-isopropyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 150

In the same manner as in Example 133, cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-isopropyl- 2-oxoazetidine-1-sulfonic acid (syn-isomer) is obtained.

Example 151

In the same manner as in Example 148, sodium cis-3- {2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (p-nitro benzyloxycarbonyl) ethyloxy Mino] acetamido} -4-methylcarbamoyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 152

In the same manner as in Example 67, sodium cis-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (p-nitro benzyloxycarbonyl) ethyloxyimino] acene Tamido} -4-methylcarbamoyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 153

In the same manner as in Example 133, cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-methylcarba Moyl-2-oxoazetidine-1-sulfonic acid (syn-isomer) is obtained.

Example 154

240 mg of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (E) -sty in 2 ml of N, N-dimethylformamide Dissolves yl-1- (P-butyldimethylsilyl) -2-oxoazetidine (Syn-isomer) and 0.83 ml (1.58 M) sulfuric anhydride-N, N-dimethylformamide complex at -10 ° C. Add solution. Under sealing, the reaction mixture is left at 5 ° C. for 2 days. 0.136 ml of pyridine is added to this solution followed by 100 ml of ether. The ether layer was discarded and the insolubles were dissolved in a mixture of 20 ml of water and 10 ml of ethanol, and 10 ml of Dow's 50W (Na-type) resin was added to the solution and stirred for 20 minutes. The resin was filtered off and the filtrate was concentrated to about 20 ml, purified by chromatography using Amberlite XAD-2 column (eluent: 10% EtOH), and lyophilized. Sodium cis-3- [2- (2- Chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (E) -styryl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 155

In the same manner as in Example 11, sodium cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4- (E) -styryl-2-oxoa Zetidine-1-sulfonate (syn-isomer) is obtained.

Example 156

Suspension 145 mg of cis- and trans-mixture (1: 4) of 3-azido-4-methoxycarbonylmethyl-2-oxoazetidine in 10 ml of methanol was added, followed by addition of 100 mg of 10% palladium-carbon. do. The suspension is stirred for 30 minutes at room temperature in a hydrogen atmosphere. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue was dissolved in 20 ml of tetrahydrofuran and 0.35 ml of triethylamine was added followed by 332 mg of 2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetylchloride hydrocloid It is added with ice cooling and stirring. The mixture is stirred under ice cooling for 15 minutes and then at room temperature for 1.5 hours. Tetrahydrofuran is distilled off under reduced pressure and the residue is shaken with ethyl acetate and water. The ethyl acetate layer is taken, washed with water and dried over anhydrous sodium sulfate. Then, concentrated under reduced pressure to dryness, the powdery 3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarbonylmethyl- A cis- and trans-mixture (1: 4) of 2-oxoazetidine (syn-isomer) is obtained.

When the above product was sulfonated in the same manner as in Example 109, sodium 3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarb A cis- and trans-mixture (1: 4) of carbonylmethyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

The above product was treated as in Example 11 to remove the amino protecting group. Sodium 3- [2- (2-amino-4-thiazolyl) -2-methoxyaminoacetamido] -4-methoxycarbonylethyl-2-oxoazetidine-1-sulfonate by this procedure A cis- and trans-mixture (1: 4) of (syn-isomer) is obtained.

Example 157

When sulfonate trans-3-azido-4-methoxycarbonylmethyl-2-oxoazetidine obtained in Reference Example 177 was treated according to the procedure of Example 141, sodium trans-3-azido-4-me Oxycarbonyl methyl-2-oxoazetidine-1-sulfonate is obtained.

Example 158

After dissolving 266 mg of sodium-trans-3-azido-4-methoxycarbonylmethyl-2-oxoazetidine-1-sulfonate in 5 ml of N, N-dimethylformamide, 150 mg of 10% palladium Add carbon. The mixture is stirred for 45 minutes at room temperature in a hydrogen atmosphere. The catalyst is separated by filtration and washed with 5 ml of N, N-dimethylformamide. After mixing the filtrate and the wash, 284 mg of 2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl- (t-butoxycarbonyl) acetyloxyimino] acetic acid, 110 mg of N , N-hydroxybenzotriazole beard and 150 mg of dicyclohexylcarbodiimide are added. The mixture is allowed to stir at room temperature for 4 hours and then left overnight at 50 ° C. After 20 ml of water is added, the insolubles are separated by filtration and washed with 5 ml of water. The filtrate and washes are mixed and sodium monomethyldithiocarbamate is added. When the mixture was reacted as in Example 11, sodium trans-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (t-butoxycarbonyl) ethyloxyimino ] Acetamido} -4-methoxycarbonylethyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Under ice-cooling and stirring, 84 mg of the product cord is added to 2 ml of trifluoro acetic acid and the mixture is stirred for 3 hours. The reaction mixture is concentrated to dryness under reduced pressure. The residue is dissolved in 5 ml of water and purified by Amberlite XAD-II (eluent; water, then 10% ethanol) and then Sephadex LH-20 column (eluent: water) chromatography. The lyophilisate is dissolved in 5 ml of water and stirred for 10 minutes with 2 g of Dow's 50 W (H-type) resin. The resin was filtered off and the filtrate was lyophilized to give trans-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4- Methoxycarbonylmethyl-2-oxoazetidine-1-sulfonic acid (syn-isomer) is obtained.

Example 159

When the sulfonate cis-3-benzyloxycarboxamido-4-methoxyaminocarbonyl-2-oxoazetidine obtained in Reference Example 178 was treated according to the procedure of Example 141, sodium cis-3-benzyloxycarboxa Mido-4-methoxyaminocarbonyl-2-oxoazetidine-1-sulfonate is obtained.

Example 160

In the same manner as in Example 143, sodium cis-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acene Tamido} -4-methoxyaminocarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 161

In the same manner as in Example 133, cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-methoxyamino Carbonyl-2-oxoazetidine-1-sulfonic acid (syn-isomer) is obtained.

Example 162

Sulfonate cis-3- {2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] obtained in Reference Example 181] Acetamido} -4-cyano methyl-2-oxoazetidine (syn-isomer) is treated according to the procedure of Example 70. In the same manner as in Example 67, if the amino-protecting group was removed from the product obtained above, sodium cis-3 {2- (2-amino-4-thiazolyl) -2- [1-methyl-1- (p- Nitrobenzyloxycarbonyl) ethyloxyimino] acetamido} -5-4-cyanomethyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 163

In the same manner as in Example 133, cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-cyanomethyl 2-oxoazetidine-1-sulfonic acid (syn-isomer) is obtained.

Example 164

In 20 ml of methylene chloride, 708 mg of 1-methyl-1H-tetrazol-5-ylthioacetic acid obtained in Reference Example 183 was dissolved. Under ice-cooling, 806 mg of thionyl chloride is added and the mixture is heated at reflux for 1 h. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in 10 ml of methylene chloride.

1 g of cis-3- (p-nitrobenzyloxycarboxamido) -4-hydroxymethyl-2-oxoa obtained in Reference Example 182 in a mixture of 50 ml of tetrahydrofuran, 50 ml of methylene chloride and 0.5 ml of pyridine Dissolve zetidine. Then, the solution containing the acid chloride prepared as above is added dropwise at room temperature. The mixture is stirred at rt for 4 h and extracted with ethyl acetate-tetrahydrofuran (3: 1). The extract was washed with 3N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [silica gel: 140 g; Eluent: ethyl acetate and then acetate-methanol (8: 1, next 4: 1)]. When this product was sulfonated in the same manner as in Example 141, sodium cis-3- (p-nitrobenzyloxycarboxamido) -4- (1-methyl-1H-tetrazol-5-yl) thioacetoxymethyl 2-oxoazetidine-1-sulfonate is obtained.

Example 165

1.02 g of sodium cis-3- (p-nitrobenzyloxycarboxamido) -4- (1-methyl-1H-tetrazol-5-yl) thioacetoxymethyl in a mixture of 20 ml of tetrahydrofuran and 20 ml of water After dissolving -2-oxoazetidine-1-sulfonate, 1 g of 10% palladium-carbon is added. The mixture is stirred in a hydrogen atmosphere for 5 hours. The catalyst is filtered off, the filtrate is neutralized with sodium bicarbonate and the ethyl acetate is washed twice. 30 ml of tetrahydrofuran was added to the aqueous layer, and on ice cooling, 356 mg of sodium hydrogen carbonate, and then 1.16 g of 2- (2-chloroacetamido-4-thiazolyl) -2- (1-methyl-1-benzhydroxy Carbonylethyloxyimino) acetyl chloride hydrochloride is added. The mixture is stirred for 1 hour under ice cooling, then 476 mg of sodium monomethyldithiocarbamate is added and the mixture is stirred at room temperature for 1 hour. The reaction mixture is washed twice with ether and concentrated. The residue was purified by chromatography in Amberlite XAD-II column (eluent: water, 20% ethanol, then 30% ethanol) and lyophilized to give sodium cis-3- [2- (2-amino-4-thiazolyl). ) -2- (1-methyl-1-benzhydryloxy-carbonylethyloxyimino) acetamide] -4- (1-methyl-1H-tetrazol-5-yl) thioacetoxymethyl-2- Oxoazetidine-1-sulfonate (syn-isomer) is obtained.

545 mg of the above product was dissolved in 2.5 ml of irisole, cooled to -12 ° C and 12 ml of trifluoroacetic acid was added. The mixture is stirred at -10 to -12 [deg.] C. for 30 minutes before 40 ml of ether and 20 ml of hexane are added. The resulting solid precipitate is washed three times with 60 ml of ether and then dissolved in 40 ml of water. After adding sodium hydrogen carbonate, the mixture is filtered. The filtrate was concentrated, purified by amber light XAD-II column (eluent: water) chromatography, lyophilized, cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1 -Carboxyethyloxyimino) acetamido] -4- (1-methyl-1H-tetrazol-5-yl) thioacetoxymethyl-2-oxoazetidine-1-sulfonic acid 2 sodium salt (syn-isomer) Is obtained.

Example 166

895 mg of hydrogen carbonate after dissolving 2.56 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid obtained in Reference Example 68 in a mixture of 30 ml of tetrahydrofuran and 15 ml of water. Sodium, 2.23 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 3.62 g of alanine benzylester p-toloene sulfonate are added. The mixture is stirred at rt for 12 h. The reaction mixture is extracted with ethyl acetate-tetrahydrofuran (2: 1) and the extract is washed with water, 3N hydrochloric acid (twice), saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was subjected to silica gel column chromatography [silica gel: 450 g; Eluent: chloroform-ethyl acetate (1: 1), then chloroform-ethyl acetate-methanol (20: 20: 1, then 10: 10: 1)], and cis-3-benzyloxycarboxamido-4- [ Diastereomers (beta and alpha forms; Comparative, Reference Example 39) of 1- (L) -benzyloxycarbonylethyl] aminocarbonyl-2-oxoazetidine are obtained.

When this product was sulfonated in the same manner as in Example 141, sodium cis-3-benzyloxycarboxamido-4- [1- (L) -benzyloxycarbonylethyl] aminocarbonyl-2-oxoazetidine Beta and alpha forms of -1-sulfonate are obtained.

Example 167

Beta of sodium cis-3-benzyloxycaroxamido-4- [1- (L) -benzyloxycarbonylethyl] aminocarbonyl-2-oxoazetidine-1-sulfonate in the same manner as in Example 66 And reducing the alpha form yields the beta and alpha forms of sodium cis-3-amino-4- [1- (L) -carboxyethyl] aminocarbonyl-2-oxoazetidine-1-sulfonate. The product was acylated as in Example 66 and the chloroacetyl group was removed as in Example 67. Sodium cis-3- {2- (2-amino-4-thiazolyl) -2- [1-methyl-1 -(p-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido} -4- [1- (L) -carboxyethylaminocarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) Beta and alpha forms of are obtained.

Example 168

In the same manner as in Example 133, cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4- [1- Beta and alpha forms of (L) -carboxyethyl] aminocarbonyl-2-oxoazetidine-1-sulfonic acid (syn-isomer) are obtained.

[Examples 169-173]

Cis-3- [DL-2- (2-aminothiazol-4-yl) -2-ammonioacetamido] -4-methoxycarbonyl-2-azetidinone-1-sulfonate is shown in the table below. When reacted with the indicated acylating agents, the corresponding sodium cis-3- [DL-2-acylamido-2- (2-aminothiazol-4-yl) acetamido] -4-meth as shown in the same table A oxycarbonyl-2-azetidinone-1-sulfonate compound is obtained.

Example 174

In the same manner as in Example 45, sodium cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2- (1-methyl-1-benzhydryloxycarbonylethyloxyimino) acetate Tamido] -4-carbamoyloxymethyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 175

In the same manner as in Example 67, sodium cis-3- [2- (1-amino-4-thiazolyl) -2- (1-methyl-1-benzhydryloxycarbonylethyloxyimino) acetamido] 4-Carbamoyloxymethyl-2-oxoazetidine-1-sulfonate (syn-isomer) is obtained.

Example 176

250 mg of sodium cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-benzhydryloxycarbonylethyloxyimino) acetamido in 1 ml of arisole]- 4-Carbamoyloxymethyl-2-oxoazetidine-1-sulfonate (syn-isomer) is added and 5 ml of trifluoroacetic acid is added dropwise under stirring at -20 占 폚. The mixture is stirred at −15 ° C. for 30 minutes, then 10 ml of ether and 10 ml of petroleum ether are added. The resulting powder is recovered by centrifugation and dissolved in water. To the solution was added dodecane 50W (H-type) resin and stirred. The resin was filtered off and the filtrate was concentrated and purified by chromatography using Amberlite XAD-2 (eluent: water, 100 ml; 100 ml of 10% ethanol; 100 ml of 30% ethanol, then 50 ml of 40% ethanol) to 30% ethanol and Lyophilization of 40% ethanol fractions resulted in cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4- Carbamoyloxymethyl-2-oxoazetidine-1-sulfonic acid (syn-isomer) is obtained.

In the same manner as in the above example, the following compounds are obtained: cis-3- [2- (2-amino-4-thiazolyl) -2-carboxymethyloxyiminoacetamido-4-acetoxymethyl- Disodium salt of 2-oxoazetidine-1-sulfonic acid (syn-isomer).

Cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-acetamidomethyl-2-oxoazetidine 2-sodium salt of 1-sulfonic acid (syn-isomer).

Disodium salt of cis-3- [2- (2-amino-4-thiazolyl) -2-carboxymethyloxyiminoacetamido] -4-acetamidomethyl-2-oxoazetidine-1-sulfonic acid (syn-isomer).

Cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-isopropyl-2-oxoazetidine-1 Disodium salt of sulfonic acid (syn-isomer).

Cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-methoxycarbonylmethyl-2-oxoazeti Disodium salt of din-1-sulfonic acid (syn-isomer).

Cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-methylcarbamoyl-2-oxoazetidine 2-sodium salt of 1-sulfonic acid (syn-isomer).

Reference Example 1

To a solution of 2.94 g of cis-3-amino-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester in 12 ml of methylene chloride, ice-cooled and stirred, 6.7 ml of propylene oxide, followed by 3.24 g of carbobenzoic chloride. The reaction mixture is stirred for 30 minutes at room temperature. The solvent was distilled off in vacuo, then ether was added to the residue and the precipitated crystals were collected by filtration, cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoa Zetidine-4-carboxylic acid methyl ester is obtained. Melting Point 115-116 ° C

Elemental analysis: C ₂₂ H ₂₄ N ₂ O ₇

Calculated Value: C; 61.67%, H; 5.65%, N; 6.54%

Found: C; 61.64%, H; 5.67%, N; 6.49%

Reference Example 2

2.7 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester was dissolved in 150 ml of acetonitrile. Heat to 90-95 ° C. in a nitrogen stream and add 55 ml of an aqueous solution containing 2.73 g of potassium persulfate and 1.65 g of potassium diphosphate. At the end of the dropping, the mixture is stirred for 3 hours at isothermal temperature. Upon cooling, the pH is adjusted to 6-7 with dipotassium phosphate, and then the acetonitrile and water are distilled off in vacuo. The residue is dissolved in chloroform and the solution is washed with water followed by aqueous sodium chloride solution. The chloroform solution is dried over anhydrous sodium sulfate, and then the solvent is distilled off in vacuo. The residue is subjected to silica gel column chromatography. Elution with ethyl acetate gives cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester. Melting point 127-128 ° C

Elemental Analysis: C ₁₃ H ₁₄ N ₂ O ₅

Calculated Value: C; 56.11%, H; 5.07%, N; 10.07%

Found: C; 56.03%, H; 5.01%, N; 9.99%

Reference Example 3

To a suspension of 0.8 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester in 20 ml of ethanol, 0.8 g of 5% palladium-charcoal was added and stirred under atmospheric pressure. Catalytic reduction is performed. After stopping the hydrogen uptake, the catalyst is removed by filtration. The filtrate is concentrated in vacuo and the residual oil is left to cool. Collecting the precipitated crystals by filtration yields 0.38 g (92%) of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester. Melting Point 59 ~ 61 ℃

Elemental Analysis: C ₅ H ₈ N ₂ O ₃

Calculated Value: C; 41.66%, H; 5.59%, N; 19.44%

Found: C; 41.54%, H; 5.59%, N; 19.67%

Reference Example 4

1.18 g of 2- (2-chloro) under ice-cooling and stirring to 6 ml of an aqueous solution containing 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester and 561 mg of sodium hydrogencarbonate. A solution of acetamido-4-thiazolyl) -2-methoxyiminoacetyl chloride (syn-isomer) in 10 ml of tetrahydrofuran is added. The mixture is stirred at room temperature for 2 hours and then the solvent is distilled off in vacuo leaving a solidified residue. Water was added to the solids, filtered and the collected crystals washed continuously with water and ethanol, cis-3- [2- (2--chloroacetamido-4-thiazolyl) -2-methoxyiminoa Setamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn-isomer) is obtained. Melting point 270-275 degreeC (decomposition).

Elemental Analysis: C ₁₃ H ₁₄ ClN ₅ O ₆ S

Calculated Value: C; 38.66%, H; 3.49%, N; 17.35%

Found: C; 38.50%, H; 3.78%, N; 17.25%

Reference Example 5

12 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4 under ice-cooling and stirring in a 250 ml aqueous solution containing 2.65 g of sodium borohydride -A solution of carboxylic acid methyl ester dissolved in 500 ml of tetrahydrofuran is added. The reaction mixture is stirred at room temperature for 5 hours. Tetrahydrofuran was distilled off in vacuo, water was added to the residue, and the precipitated crystals were collected by filtration and dried. 9.8 g (87%) of cis-3-benzyloxycarboxamido-1- (2, 4- Dimethoxybenzyl) -4-hydroxymethyl-2-oxoazetidine is obtained. Melting point 129-131 ° C

Elemental analysis: C ₂₁ H ₂₄ N ₂ O ₆

Calculated Value: C; 62.99%, H; 6.04%, N; 7.00%

Found: C; 62.78%, H; 5.91%, N; 7.05%

Reference Example 6

5.1 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-2-oxoazetidine in a solution of 50 ml of methylene chloride, at 0 ° C Under stirring, 3.8 ml of pyridine and 2.04 ml of acetylchloride are added dropwise. After the reaction mixture is stirred for 30 minutes, the solvent is distilled off in vacuo. Silica gel column chromatography eluting the residue with ethyl acetate gave 5.45 g (96%) of cis-4-acetoxymethyl-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2- Oxoazetidine is obtained. Melting Point 110 ~ 111 ℃

Elemental Analysis: C ₂₃ H ₂₆ N ₂ O ₇

Calculated Value: C; 62.43%, H; 5.92%, N; 6.33%

Found: C; 62.26%, H; 5.68%, N; 6.07%

Reference Example 7

4.862 g of cis-4-acetoxymethyl-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine in 275 ml of acetonitrile was stirred with nitrogen Heated at 80 to 83 ° C. To the solution is added dropwise 110 ml of an aqueous solution containing 4.752 g potassium persulfate and 2.871 g dipotassium phosphate. At the end of the dropping, the mixture is stirred at 90 ° C. for 2.5 hours. Upon cooling, dipotassium phosphate is added to adjust the pH to 6-7 and the acetonitrile and water are distilled off in vacuo. Chloroform is added to the residue and insolubles are collected by filtration, washed with water and chloroform in order to dryness to afford cis-4-acetoxymethyl-3-benzyloxycarboxamido-2-oxoazetidine. Melting point 137-138 ° C

Elemental Analysis: C ₁₄ H ₁₆ N ₂ O ₅

Calculated Value: C; 57.53%, H; 5.52%, N; 9.59%

Found: C; 57.38%, H; 5.43%, N; 9.58%

Reference Example 8

1.46 g of cis-4-acetoxyethyl-3-benzyloxycarboxamido-2-oxoazetidine in 50 ml of ethanol was added 1.5 g of 5% palladium-charcoal and the mixture was stirred at atmospheric pressure. Catalytic reduction at The reaction is complete in 30 minutes. The catalyst was filtered off and the filtrate was concentrated in vacuo to yield 750 mg (95%) of cis-4-acetoxymethyl-3-amino-2-oxoazetidine as a colorless oil.

Reference Example 9

2.36 g of 2- (2-chloroacetami) under ice-cooling and stirring in a 12 ml aqueous solution containing 632 mg of cis-4-acetoxymethyl-3-amino-2-oxoazetidine and 1.122 g of sodium bicarbonate A solution in which do-4-thiazolyl) -2-methoxyiminoacetyl chloride (syn-isomer) is suspended in 20 ml of tetrahydrofuran is added. The mixture is stirred at room temperature for 2 hours and then the solvent is distilled off in vacuo leaving a solid residue. Water is added to the solid residue and filtered. The collected crystals were washed continuously with aqueous sodium hydrogen carbonate solution, water and ether to give cis-4-acetoxymethyl-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyimine Noacetamido] -2-oxoazetidine (syn-isomer) is obtained. Melting point 180-190 ° C. (decomposition).

Elemental Analysis: C ₁₄ H ₁₆ ClN ₅ O ₆ S

Calculated Value: C; 40.24%, H; 3.86%, N; 16.76%

Found: C; 39.89%, H; 3.67%, N; 16.60%

Reference Example 10

To a solution of 4.5 g of cis-3-benzyloxycarboxamido-1- (2,4-dimenoxybenzyl) -4-hydroxymethyl-2-oxoazetidine in 30 ml of pyridine, under ice cooling and stirring 1.94 g of methanesulfonyl chloride are added. The mixture is stirred for 30 minutes at room temperature, 100 ml of ethyl acetate and 50 ml of water are added to the reaction mixture, and then acidified with diluted hydrochloric acid. The precipitated crystals are collected by filtration and the filtrate is separated into an aqueous layer and an organic layer. The organic layer is concentrated in vacuo, water is added to the residue and the resulting crystals are collected by filtration and mixed with the crystals obtained above. The mixed crystals were washed with an aqueous sodium hydrogen carbonate solution, followed by water and ether, followed by drying. 5.0 g (93%) of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4- Methanesulfonyloxymethyl-2-oxoazetidine is obtained. Melting Point 140 ~ 141 ℃

Elemental analysis: C ₂₂ H ₂₆ N ₂ O ₈ S

Calculated Value: C; 55.22%, H; 5.48%, N; 5.85%

Found: C; 55.16%, H; 5.40%, N; 5.61%

Reference Example 11

3.83 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-methanesulfonyloxymethyl-2-oxoazetidine dissolved in 200 ml of acetonitrile was stirred. It is heated at a nitrogen stream of 80 to 83 ° C. To the solution is added dropwise 80 ml of a solution containing 3.46 g of potassium persulfate and 2.09 g of potassium diphosphate. At the end of the dropping, the mixture is stirred at 85 to 90 ° C. for 3 hours. After distilling off the solvent in vacuo, 200 ml of water was added to the residue, the resulting crystals were collected by filtration, washed with water and then ether and dried, cis-3-benzyloxycarboxamido-4-methane Phenyloxymethyl-2-oxoazetidine is obtained. Melting point 132-133 캜

Reference Example 12

To 55 ml of methyl ethyl ketone, 1.4 g cis-3-benzyloxycarboxamido-4-methanesulfonyloxymethyl-2-oxoazetidine and 4.2 g sodium iodide are added and the mixture is stirred at 90 ° C. for 2 hours. After stirring for 12 hours at 60 ℃. The solvent is then distilled off in vacuo. The residue was thoroughly shaken with 100 ml of water and 50 ml of chloroform, the insolubles were collected by filtration, washed with water and chloroform and dried to give cis-3-benzyloxycarboxamido-4-iodinemethyl-2- Oxoazetidine is obtained. Melting point 160 to 162 ° C.

Elemental Analysis: C ₁₂ H ₁₃ IN ₂ O ₃

Calculated Value: C; 40.02%, H; 3.64%, N; 7.78%

Found: C; 40.26%, H; 3.64%, N; 7.93%

Reference Example 13

522 mg of 1-methyl-5-tetrazolylmercaptan is added to a solution of 103.5 mg of sodium in 9 ml of methanol, and the mixture is stirred at room temperature for 15 minutes. The methanol is distilled off in vacuo and 12 ml of N, N-dimethylformamide is added to the residue to dissolve the residue. 900 mg of cis-3-benzyloxycarboxamido-4-iodinemethyl-2-oxoazetidine is added to the resulting solution, and the mixture is stirred at room temperature for 19 hours. 100 ml of water is added to the reaction mixture, and the precipitated crystals are collected by filtration and washed in the order of water and ether. The crystals are then dissolved in ethyl acetate and passed through a small column of silica gel. After the effluent was collected and the solvent was distilled off in vacuo, colorless crystalline cis-3-benzyloxycarboxamido-4- (1-methyl-5-tetrazolylthiomethyl) -2-oxoazetidine 780 mg (90%) ) Is obtained. Melting point 151 to 152 ° C

Elemental Analysis: C ₁₄ H ₁₆ N ₆ O ₃ S

Calculated Value: C; 48.26%, H; 4.63%, N; 24.13%

Found: C; 48.38%, H; 4.65%, N; 23.89%

Reference Example 14

1.18 g of 2- (2-chloroacetate) in 6 ml of an aqueous solution containing 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester and 561 mg of sodium hydrogencarbonate A solution in which tamido-4-thiazolyl) -2-methoxyiminoacetyl chloride (anti isomer) is suspended in 10 ml of tetrahydrofuran is added. The mixture is stirred at room temperature for 2 hours and then the solvent is distilled off in vacuo leaving a solid residue. Water is added to the solid residue and filtered. The filtrate is neutralized with aqueous sodium hydrogen carbonate solution and then extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and the solvent was distilled off in vacuo, resulting in cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-jade Pediazetidine-4-carboxylic acid methyl ester (anti isomer) is obtained. Melting Point 119 ~ 129 ℃

Elemental Analysis: C ₁₃ H ₁₄ ClN ₅ O ₆ S

Calculated Value: C; 38.66%, H; 3.49%, N; 17.34%

Found: C; 38.56%, H; 3.60%, N; 17.05%

Reference Example 15

2.94 g of cis-3-amino-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester in a solution of 40 ml of methylene chloride, ice-cooled and stirred, After adding 2.10 ml of triethylamine, a solution of 2.31 g of phenylacetyl chloride in 15 ml of methylene chloride is added dropwise over 1 hour. Stirring is continued for another hour under ice-cooling, and the reaction mixture is washed successively with dilute hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off in vacuo. Ether was added to the residue and the precipitated crystals were collected by filtration, cis-1- (2, 4-dimethoxybenzyl) -3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester Is obtained. Melting point 124-126 ° C

Elemental Analysis: C ₂₂ H ₂₄ N ₂ O ₆

Calculated Value: C; 64.07%, H; 5.86%, N; 6.79%

Found: C; 63.98%, H; 5.98%, N; 6.70%

Reference Example 16

412 mg cis-1- (2,4-dimethoxybenzyl) -3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester, 810 mg potassium persulfate and 261 mg in 20 ml acetonitrile The mixture of dipotassium phosphate and 20 ml of water is heated under reflux for another hour. The reaction mixture is concentrated in vacuo, the residue is dissolved in ethyl acetate, washed with 5% aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off in vacuo. Ethyl acetate was added to the residue and the precipitated crystals were collected by filtration to give cis-3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester. Melting point 176 to 180 ° C.

Reference Example 17

Ice-cooled in a solution of 2.06 g of cis-1- (2,4-dimethoxybenzyl) -3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester in 24 ml of tetrahydrofuran. And 12 ml of an aqueous solution containing 570 mg of sodium borohydride under stirring. The reaction mixture is stirred for 30 minutes under ice-cooling and then at room temperature for 1.5 hours. Tetrahydrofuran is distilled off in vacuo and an aqueous sodium chloride solution and ethyl acetate are added to the residue. The resulting ethyl acetate layer was separated and washed continuously with an aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent is distilled off in vacuo. Ether was added to the residue and the resulting precipitate was collected by filtration, resulting in 1.75 g (91%) of cis-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-3-phenylacetamido-2 Oxoazetidine is obtained. Melting Point 152-154 ° C

Elemental analysis: C ₂₁ H ₂₄ N ₂ O ₅

Calculated Value: C; 65.61%, H; 6.29%, N; 7.29%

Found: C; 65.37%, H; 6.47%, N; 7.55%

Reference Example 18

1.12 g of cis-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-3-phenylacetine was stirred at 0 ° C in a solution of 1.12 g of P-toluenesulfonyl chloride dissolved in 6 ml of pyridine. Tamido-2-oxoazetidine is added. The reaction mixture is stirred for 2 hours and then left in the refrigerator overnight. 0.68 ml of lactic acid is added to the reaction mixture, and the mixture is stirred for 1 hour. The reaction mixture is washed with 45 ml of ethyl acetate and 15 ml of tetrahydrofuran, followed by dilute hydrochloric acid, aqueous sodium chloride solution, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution. The organic solution is dried over magnesium sulfate and the solvent is distilled off in vacuo. A mixed solvent of ether and ethyl acetate (5: 1) was added to the residue, and the resulting crystals were collected by filtration. 2.21 g (91%) of cis-1- (2,4-dimethoxybenzyl) -3-phenyl Acetamido-4- (P-toluenesulfonyloxymethyl) -2-oxoazetidine is obtained. Melting point 109-110 ° C

Elemental analysis: C ₂₈ H ₃₀ N ₂ O ₇ S

Calculated Value: C; 62.43%, H; 5.63%, N; 5.20%

Found: C; 62.18%, H; 5.72%, N; 5.07%

Reference Example 19

2.27 g of cis-1- (2,4-dimethoxybenzyl) -3-phenylacetamido-4- (P-toluenesulfonyloxymethyl) -2-oxoazetidine and 4.95 g of 70 ml of acetone Sodium iodide is added and the mixture is heated under stirring and reflux for 6 hours and then concentrated in vacuo. To dissolve the residue, methylene chloride and water are added thereto, and the methylene chloride layer is separated and washed with an aqueous sodium thiosulfate solution and an aqueous sodium chloride solution. The methylene chloride layer is then dried over magnesium sulfate and the solvent is distilled off in vacuo. Ethyl acetate was added to the residue and the precipitated crystals were collected by filtration to give cis-1- (2, 4-dimethoxybenzyl) -4-iodinemethyl-3-phenylacetamido-2-oxoazetidine. . Melting point 181 to 182 ° C

Elemental Analysis: C ₂₁ H ₂₃ IN ₂ O ₄

Calculated Value: C; 51.03%, H; 4.69%, N; 5.67%

Found: C; 51.14%, H; 4.64%, N; 5.81%

Reference Example 20

740 mg of cis-1- (2,4-dimethoxybenzyl) -4-iodinemethyl-3-phenylacetamido-2-oxoazetidine and 146 mg of sodium azide in 6 ml of N, N-dimethylformamide Was added and the mixture was stirred for 4 days at room temperature. The solvent is distilled off in vacuo and ethyl acetate and water are added to the residue. The ethyl acetate layer is separated, washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off in vacuo. Ether was added to the residue and the precipitated crystals were collected by filtration to give cis-4-azidomethyl-1- (2,4-dimethoxybenzyl) -3-phenylacetamido-2-oxoazetidine. do. Melting Point 110 ~ 111 ℃

Reference Example 21

449 mg of cis-4-azidomethyl-1- (2,4-dimethoxybenzyl) -3-phenylacetamido-2-oxoazetidine was added to 80 ml of ethanol and 200 mg of 10% palladium-charcoal, The mixture is hydrogenated at room temperature and atmospheric pressure for 1.5 hours. The reaction mixture is filtered to remove the catalyst and the filtrate is concentrated from vacuum to dryness. The residue is taken up in 30 ml of methylene chloride. Under stirring at 0 ° C., 0.20 ml of triethylamine is added to the resulting methylene chloride solution and 0.10 ml of acetylchloride solution in methylene chloride is added dropwise over 10 minutes. The reaction mixture is stirred for 40 minutes, then washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate and aqueous sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off in vacuo. Ethyl acetate was added to the residue and the resulting crystals collected by filtration, cis-4-acetamidomethyl-1- (2,4-dimethoxybenzyl) -3-phenylacetamido-2-oxoazetidine Is obtained. Melting point 205-207 캜.

Reference Example 22

298 mg cis-4-acetamidomethyl-1- (2,4-dimethoxybenzyl) -3-phenylacetamido-2-oxoazetidine, 576 mg potassium persulfate and 183 mg phosphoric acid in 15 ml water 2 The mixture of potassium and 15 ml of acetonitrile is heated under reflux for 1.5 hours. The reaction mixture is concentrated in vacuo. The residue is taken up in ethyl acetate and the solution is washed continuously with aqueous sodium bicarbonate solution and aqueous sodium chloride solution. The ethyl acetate solution is dried over anhydrous magnesium sulfate and the solvent is distilled off in vacuo. Ethyl acetate was added to the residue and the precipitated crystals were collected by filtration to give cis-4-acetamidomethyl-3-phenylacetamido-2-oxoazetidine. Melting Point 200-202 ° C

Reference Example 23

8.5 g cis-1- (2,4-dimethoxybenzyl) -3-phthalimido-2-oxoazetidine-4-carboxylic acid methyl ester and 3.1 g 1,8-dia in 200 ml benzene Xabicyclo [5, 4, 0] -7-undecane is added and the mixture is heated to reflux for 72 hours. After cooling, 100 ml of ethyl acetate was added to the reaction mixture, followed by washing in order of 100 ml and 50 ml of 1N-HCl and 100 ml of water. To the resulting mixture is added 100 ml of chloroform and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. To the residue is added 50 ml of ethyl acetate. The resulting insolubles were collected by filtration and washed with 30 ml of ethyl acetate to give 6.4 g of crude product, which was recrystallized from 220 ml of ethyl acetate to give trans-1- (2,4-dimethoxybenzyl) -3- Phthalimido-2-oxoazetidine-4-carboxylic acid methyl ester is obtained. Melting point 186-188 degreeC.

Elemental Analysis: C ₂₂ H ₂₀ N ₂ O ₇

Calculated Value: C; 62.26%, H; 4.75%, N; 6.60%

Found: C; 62.13%, H; 4.64%, N; 6.43%

Reference Example 24

8.3 g of 2, 4-dimethoxybenzylamine and 6.0 g of anhydrous magnesium sulfate were added to 83 ml of methylene chloride, and a solution of 6.5 g of glyoxylic acid n-butyl ester in 65 ml of methylene chloride was stirred under ice water cooling while stirring. After addition to the mixture, it is further stirred for 2 hours. The reaction mixture is filtered. After adding 5 g of triethylamine to the filtrate, a solution of 11 g of phthalimido-acetylchloride in 110 ml of methylene chloride is added. The mixture was stirred overnight, then washed with dilute hydrochloric acid, aqueous sodium chloride solution, aqueous sodium bicarbonate solution and aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The mixture is filtered and the filtrate is concentrated. Ether is added to the residue and the insolubles are filtered off. The filtrate was concentrated under reduced pressure to give 20.1 g (86%) of cis-1- (2,4-dimethoxybenzyl) -3-phthalimido-2-oxoazetidine-4-carboxylic acid n-butyl ester as an orange oil. ) Is obtained. Part of the product was purified by silica gel chromatography to give a colorless foamy material. However, from this point on, the above products are used in crude form.

Reference Example 25

3.7 g of a solution of 19 g of cis-1- (2,4-dimethoxybenzyl) -3-phthalimido-2-oxoazetidine-4-carboxylic acid n-butylester in 190 ml of methylene chloride Methylhydrazine is added. The mixture is stirred overnight at room temperature. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. Ethyl acetate is added to the residue and the insolubles are filtered off. The filtrate is extracted twice with 100 ml of 1N-HCl. The extract is neutralized with sodium bicarbonate and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The oily cis-3-amino-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4 12 g (87.5%) of carboxylic acid n-butyl ester are obtained.

Reference Example 26

10 g of cis-3-amino-1- (2,4-dimethoxybenzyl-2-oxoazetidine-4-carboxylic acid n-butyl ester was dissolved in 40 ml of methylene chloride, ice-cooled and stirred, 1.8 g of propylene oxide, followed by 5.5 g of carbobenzoxychloride, is allowed to warm to room temperature and stirred for 1 hour The solvent is evaporated under reduced pressure Isopropyl ether is added to the residue and the resulting crystals Collected by filtration, colorless crystalline cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid having a melting point of 97 to 98 ° C. 11.7 g (83.5%) of n-butyl ester are obtained, melting point 97-98 캜.

Elemental analysis: C ₂₅ H ₃₀ N ₂ O ₇

Calculated Value: C; 63.81%, H; 6.42%, N; 5.95%.

Found: C; 63.51%, H; 6.26%, N; 6.09%.

Similarly, trans-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester is prepared.

Since this product is not crystallized by treatment similar to the above, purification by column chromatography (silica gel, eluent: hexane-ethyl acetate, 1: 1) yields a colorless oil. Yield 89%.

Reference Example 27

2.35 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid n-butyl ester in each 60 ml of acetonitrile and a mixture of water 4.05 g potassium persulfate and 1.74 g dipotassium hydrogen phosphate are added and the resulting mixture is heated at reflux for 1 h under argon pressure. Acetonitrile is evaporated under reduced pressure. Ethyl acetate and water are added to the residue and the mixture is shaken. The ethyl acetate layer was separated, washed with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography with a mixture of ethyl acetate-hexane (1: 1) to give a cis-3-benzyloxycarboxamido-2-oxoazetidine having a melting point of 112 to 113 ° C. Crystals of 4-carboxylic acid n-butyl ester are obtained.

Elemental analysis: C ₁₆ H ₂₀ N ₂ O ₅

Calculated Value: C; 59.98%, H; 6.29%, N; 8.74%

Found: C; 60.25%, H; 6.33%, N; 8.53%

Similarly, trans-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester is prepared. Melting point 139 to 140

Reference Example 28

10% palladium-carbon was added to a solution of 640 mg of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid n-butyl ester in 23 ml of ethanol, and the mixture was stirred under atmospheric pressure. Catalytic reduction. After stopping the hydrogen uptake, the reaction mixture is filtered to remove the catalyst. Concentrate the filtrate under reduced pressure and crystallize the residue to give 330 mg (87.1%) of cis-3-amino-2-oxoazetidine-4-carboxylic acid n-butylester. Recrystallization of a portion of the product with a mixture of ethyl acetate and hexane yields orange scale crystals with a melting point of 87 to 89 ° C.

Elemental Analysis: C ₈ H ₁₄ N ₂ O ₃

Calculated Value: C; 51.60%, H; 7.57%, N; 15.04%

Found: C; 51.35%, H; 7.58%, N; 14.80%

Similarly: trans-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester is prepared. Melting point 135-136 degreeC.

Reference Example 29

20.8 g of potassium carbonate is added to a solution of 13.6 g of 2-hydroxyiminoacetoacetic acid methyl ester dissolved in 70 ml of acetone under ice-cooling. 17.0 g of n-propyl iodide is added dropwise to the mixture over 30 minutes. At the end of the dropping the mixture is stirred for 2 hours at room temperature. Acetone is evaporated under reduced pressure. 250 ml of water is added to the residue and the mixture is extracted with methylene chloride. The extract was washed twice with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a pale yellow oily 2- (n-propoxyimino) acetoacetic acid methyl ester.

Similarly, light yellow oily 2- (n-butoxyimino) acetoacetic acid methylester is synthesized. Yield 80%

14 "ALIGN =" JUSTIFIED "> Light yellow oily 2-benzyloxyiminoacetoacetic acid methyl ester. Yield 98%.

Reference Example 30

To a solution of 7.4 g of 2- (n-propoxyimino) acetoacetic acid methyl ester in 7.4 ml of acetic acid is added 5.5 g of sulfaryl chloride, and the mixture is stirred at 40 ° C. for 10 minutes and then at room temperature for 6 hours. Let's do it. The reaction mixture is poured into 100 ml of ice water and extracted twice with chloroform. The extract is washed with an aqueous sodium chloride solution, an aqueous sodium bicarbonate solution and water in this order and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure yields 8.2 g (94%) of light yellow oily 4-chloro-2- (n-propoxyimino) acetoacetic acid methyl ester.

Similarly, light yellow oily 4-chloro-2- (n-butoxyimino) acetoacetic acid methylester is synthesized. Yield 92%.

Light yellow oily 4-chloro-2-benzyloxyiminoacetoacetic acid methyl ester, yield 97%.

Reference Example 31

To a mixture of 20 ml of water and 25 ml of ethanol is added 7.0 g of 4-chloro-2- (n-propoxyimino) acetoacetic acid methylester, 2.4 g of thiourea and 4.3 g of sodium acetate (trihydrate). The mixture is stirred at 40 ° C. for 1 hour. Under ice-cooling, the pH of the reaction mixture was adjusted to 6.5 with saturated aqueous potassium carbonate solution, followed by stirring for 30 minutes. The resulting crystals were collected by filtration, washed with water and isopropyl ether, and dried to give 2- (2-amino-4-thiazolyl)-(z) -2- (n in crystalline phase having a melting point of 115 to 116 ° C. Propoxyimino) acetic acid methyl ester is obtained.

Elemental Analysis: C ₉ H ₁₃ N ₃ O ₃ S

Calculated Value: C; 44.43%, H; 5.39%, N; 17.27%.

Found: C; 44.20%, H; 5.38%, N; 17.11%.

Similarly: 2- (2-amino-4-thiazolyl)-(z) -2- (n-butoxyimino) acetic acid methyl ester, melting point 118 ° C.

2- (2-amino-4-thiazolyl)-(z) -2-benzyloxyimino acetic acid methyl ester and melting | fusing point 148-149 degreeC are synthesize | combined.

Reference Example 32

In a solution of 5.0 g of 2- (2-amino-4-thiazolyl)-(z) -2- (n-propoxyimino) acetic acid methyl ester in 35 ml of N, N-dimethylacetamido, ice-cold and 3.25 g of chloroacetyl chloride was added dropwise for 10 minutes while stirring. The mixture was stirred for 1 hour at room temperature, poured into 200 ml of ice water, and the oily substance was separated and left to crystallize. The crystals were collected by filtration, washed with water and dried to give 6.35 g (96.7%) of 2- (2-chloroacetamido-4-thiazolyl)-(z) -2- (n-pro having a melting point of 100 ° C. Foxymino) -acetic acid methyl ester is obtained.

Elemental Analysis: C ₁₁ H ₁₄ ClN ₃ O ₄ S

Calculated Value: C; 41.31%, H; 4.41%, N; 13.14%.

Found: C; 41.35%, H; 4.34%, N; 13.14%.

Similarly: 2- (2-chloroacetamido-4-thiazolyl)-(z) -2- (n-butoxyimino) -acetic acid methyl ester, melting point 86-87 degreeC. Yield 85%.

2- (2-chloroacetamido-4-thiazolyl)-(z) -2-benzyloxyimino) -acetic acid methyl ester, melting | fusing point 110-115 degreeC, 96% of yield is synthesize | combined.

Reference Example 33

3.2 g of 2- (2-chloroacetamido-4-thiazolyl)-(z) -2- (n-propoxyimino) acetic acid methyl ester in 50 ml of ethanol was dissolved in 50 ml of ethanol, and cooled on ice and stirred. A solution of g potassium hydroxide (85%) in 20 ml of water is added and the mixture is stirred at room temperature for 5 hours and then concentrated under reduced pressure. The concentrate was dissolved in 30 ml of water, washed twice with 30 ml of ethyl acetate, the filtrate was adjusted to pH 2 with 1N-HCl, and the resulting crystals were collected by filtration and washed with water, hexane and ether in that order. 2- (2-chloroacetamido-4-thiazolyl)-(z) -2- (n-propoxyimino) acetic acid, which is 170 to 171 ° C (decomposition), is obtained.

Elemental Analysis: C ₁₀ H ₁₂ ClN ₃ O ₄ S

Calculated Value: C; 39.28%, H; 3.96%, N; 13.74%.

Found: C; 39.34%, H; 3.84%, N; 13.41%.

Similarly: 2- (2-chloroacetamido-4-thiazolyl)-(z) -2- (n-butoxyimino) acetic acid, melting point 167-168 ° C. (decomposition).

2- (2-chloroacetamido-4-thiazolyl)-(z) -2-benzyloxyimino acetic acid and melting | fusing point 160-161 degreeC (decomposition) are synthesize | combined.

Reference Example 34

543 mg of 2- (2-chloroacetamido-4-thiazolyl)-(z) -2-ethoxyimino-acetic acid was added to 243 mg of triethylamine under ice-cooling in a solution suspended in 5 ml of methylene chloride. 416.5 mg of phosphorus pentachloride is added to the mixture and stirred for 30 minutes at room temperature. Methylene chloride is evaporated off under reduced pressure. The residue is washed three times with hexane and suspended in 7 ml of tetrahydrofuran. To the suspension is added dropwise a solution of 216 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester and 3.8 mg of sodium bicarbonate in 4.2 ml of water. The mixture is stirred at room temperature for 2 hours and then the solvent is evaporated. 20 ml of water is added to the residue followed by sodium hydrogen carbonate to slightly alkalinize. Then, the insolubles were collected by filtration, washed with aqueous sodium bicarbonate solution, water, hexane and ether, followed by drying, and the cis-3- [2- (2-chloroacetamido-4) having a melting point of 270 to 280 ° C (decomposition). -Thiazolyl) -2-ethoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn-isomer) is obtained.

Elemental analysis: C ₁₄ H ₁₆ CIN ₅ O ₆ S

Calculated Value: C; 40.24%, H; 3.86%, N; 16.76%

Found: C; 39.98%, H; 3.80%, N; 16.91%

Similarly: -cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2- (n-propoxyimino) acetamido] -2-oxoazetidine-4-carboxyl Acid methyl ester (syn-isomer), melting point 260-270 degreeC (decomposition).

Cis-3- [2- (5-chloroacetamido-4-thiazolyl) -2-isopropoxy imino acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn- Isomer), melting point 215-225 ° C. (decomposition).

Cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2- (n-propoxyimino) acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester ( syn-isomer), melting point 275-280 ° C. (decomposition).

Cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-benzyl oxyimino acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn-isomer) , Melting point 275-285 ° C (decomposition).

Cis-3- [2- (2-chloro-2-chloroacetamido-4-triazolyl) -2-methoxyimino acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester ( syn-isomer), melting point 215-220 ° C. (decomposition).

Cis-3- [2- (2-chloroacetamido-4-triazolyl) -2-methoxyimino acetamido] -2-oxoazetidine-4-carboxylic n-butyl ester (syn-isomer ), Melting point of 235 to 239 ° C (decomposition).

Trans-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyimino acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn-isomer) Melting | fusing point 137-139 degreeC is synthesize | combined.

Elemental analysis: C ₁₃ H ₁₄ CIN ₅ O ₆ S · CH ₃ OH

Calculated Value: C; 38.57%, H; 4.16%, N; 16.07%

Found: C; 38.93%, H; 4.15%, N; 16.04%

Reference Example 35

7.91 g of chloroacetyl is added to a solution of 9.3 g of 2-amino-4-thiazolyl acetic acid ethyl ester in 50 ml of N, N-dimethylacetamido under ice-cooling and stirring. The mixture is stirred at room temperature for 1 hour and 300 ml of water are added. The resulting crystals are then collected by filtration. The crystals were washed with water and then ether and dried over phosphorus pentachloride to give 12.1 g (92%) of 2-chloroacetamido-4-thiazolyl-acetic acid ethyl ester having a melting point of 145 to 146 ° C.

Elemental analysis: C ₉ H ₁₁ CIN ₂ O ₃ S

Calculated Value: C; 41.14%, H; 4.22%, N; 10.66%

Found: C; 41.16%, H; 4.14%, N; 10.86%

Reference Example 36

To a solution of 2.5 g of potassium hydroxide dissolved in a mixture of 10 ml of water and 100 ml of ethanol, 3.0 g of 2-chloroacetamido-4-thiazolyl acetic acid ethyl ester was added, and the mixture was stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure. To the residue is added 10 ml of water. The resulting aqueous solution was washed with ethyl acetate and then adjusted to pH 2 with 10% hydrochloric acid to separate the crystals. The crystals were collected by filtration, washed with water and dried to yield 2.2 g (84%) of 2-chloroacetamido-4-thiazolyl acetic acid having a melting point of 193 to 195 ° C.

Elemental Analysis: C ₇ H ₇ CIN ₂ O ₃ S

Calculated Value: C; 35.83%, H; 3.01%, N; 11.94%

Found: C; 36.00%, H; 3.15%, N; 12.24%

Reference Example 37

To a solution of 1.41 g of 2-chloroacetamido-4-thiazolyl acetic acid suspended in 30 ml of methylene chloride, 1.5 g of phosphorus pentachloride is added under ice cooling and stirring. The mixture is then stirred at room temperature for 40 minutes and then filtered to give 1.7 g (98%) of the corresponding acid chloride hydrochloride as colorless crystals having a melting point of 123 to 125 ° C (decomposition).

840 mg of sodium hydrogen carbonate, followed by ice cooling and stirring in a solution of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester in a mixture of 4 ml of water and 4 ml of tetrahydrofuran. 864 mg of extracted acid chloride hydrochloride is added. The mixture is stirred at room temperature for 2 hours and then concentrated to dryness under reduced pressure. 5 ml of water was added to the residue, and the non-condensate was collected by filtration, washed with an aqueous sodium bicarbonate solution, water, hexane and ether, followed by drying, and the cis-3- [2- (2-chloroacetami) having a melting point of 120 to 122 ° C. Do-4-thiazolyl) acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester is obtained.

Elemental analysis: C ₁₂ H ₁₃ CIN ₄ O ₅ S.1 / 2H ₂ O

Calculated Value: C; 38.97%, H; 3.82%, N; 15.15%

Found: C; 39.01%, H; 4.23%, N; 15.40%

Reference Example 38

0.766 g of trimethyl chlorosilane is added to a solution of 1 g of 1- (n-butyl) -2,3-dioxopiperazine in 10 ml of anhydrous methylene chloride. 0.712 g of triethylamine was added to the mixture under a stream of nitrogen at room temperature, followed by stirring for 1 hour. After cooling the reaction mixture to −30 ° C., 0.39 ml of trichloro methyl chloroformmate is added dropwise. The temperature of the mixture is gradually raised, the mixture is stirred at room temperature for 30 minutes, and then concentrated to dryness under reduced pressure.

Meanwhile, 1.28 g of trimethyl chlorosilane was added to a solution of 0.924 g of D- (2-thienyl) glycine suspended in 200 ml of anhydrous methylene chloride, and then 1.19 g of triethylamine was added at room temperature and stirred for 1 hour. The reaction mixture is cooled to 0 ° C. and the solid obtained by the above concentration is added. The mixture is stirred at room temperature for 2 hours and dissolved in ethyl acetate. The solution was washed with water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then quantitatively solid D-2- [4- (n-butyl) -2,3-dioxo-1-piperazine carboxa. Mido] -2- (2-thienyl) acetic acid is obtained.

Similarly: -D-2- [4- (n-octyl) -2, 3-dioxo-1-piperazine carboxyamide] -2- (2-thienyl) acetic acid.

Reference Example 39

362 mg of D-2- [4- (n-butyl) -2, 3-dioxo-1-piperazine carboxamido] -2-phenylacetic acid and 150 mg of cis-3-amino-2-oxoazetidine 236 mg of dicyclohexyl carbodiimide is added to the solution which melt | dissolved 4-carboxylic acid ethyl ester in 3 ml of anhydrous N and N-dimethylformamide under ice-cooling. The mixture is stirred for 5 hours at room temperature in a nitrogen stream, then tetrahydrofuran is added and the insolubles are filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (200 g of silica gel, eluent: ethyl acetate-chloroform, 1: 1, then ethyl acetate-chloroform-methanol, 15: 15: 1) to give a diastereomer. As a mixture of the desired cis-3- {D-2- [4- (n-butyl) -2,3-dioxo-1-piperazine carboxamido] -2-phenylacetamido} -2-jade A pediatric zetidine-4-carboxylic acid methyl ester is obtained, in which the eluted compound is called experimentally beta form and the eluted compound is called experimental alpha form.

Similarly: -cis-3- {D-2- [4- (n-butyl-2, 3-dioxo-1-piperazine-carboxamido] -2- (2-thienyl) acetamido} 2-oxoazetidine-4-carboxylic acid methyl ester is synthesized.

Cis-3- {D-2- [4- (n-octyl) -2,3-dioxo-1-piperazine-carboxamido] -2- (2-thienyl) acetamido} -2- Oxoazetidine-4-carboxylic acid methyl ester is synthesized.

Trans-3- {D-2- [4- (n-octyl) -2,3-dioxo-1-piperazine-carboxamido] -2- (2-thienyl) acetamido} -2- Oxoazetidine-4-carboxylic acid methyl ester is synthesized.

Reference Example 40

1.18 g of cis-3-amino-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester was dissolved in 5 ml of methylene chloride, ice-cooled and stirred, After adding 2.7 ml of propylene oxide, a solution of 0.83 ml of 2, 2, 2-trichloroethylchloroformate in 1 ml of methylene chloride is added dropwise over 10 minutes. The mixture is stirred for 30 minutes at room temperature. The solvent is evaporated under reduced pressure, and the residue crystallizes. The crystals were washed with ether and dried to give 1.67 g (89%) of cis-1- (2, 4-dimethoxybenzyl) = 3- (2, 2, 2-trichloro ethoxy carboxamido) -2- Oxoazetidine-4-carboxylic acid methyl ester is obtained. Melting point 135-136 ° C.

Elemental Analysis: C ₁₇ H ₁₉ Cl ₃ N ₇ O

Calculated Value: C; 43.51%, H; 4.34%, N; 6.34%

Found: C; 43.64%, H; 4.42%, N; 6.16%

Reference Example 41

10 ml of 939 mg cis-1- (2,4-dimethoxybenzyl) -3- (2,2,2-trichloroethoxy carboxamido) -2-oxoazetidine-4-carboxylic acid methylester To the solution dissolved in tetrahydrofuran, ice-cooled and stirred, a solution in which 228 mg of sodium borohydride was dissolved in 10 ml of water was added. The mixture is stirred for 10 minutes under ice-cooling and then at room temperature for 4.5 hours. The excess sodium borohydride is decomposed with acetic acid under ice cooling and the solvent is evaporated under reduced pressure. A saturated aqueous sodium chloride solution was added to the residue, followed by extraction with ethyl acetate. The extract is subsequently washed with 5% aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dilute hydrochloric acid and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue is purified by column chromatography (30 g of silica gel, eluent: ethyl acetate-chloroform, 2: 1). The eluted solution is evaporated and ether is added to the residue. The resulting crystals were collected by filtration, and the cis-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-3- (2, 2, 2-trichloro ethoxycarb having a melting point of 112 to 114 ° C. Voxamido) -2-oxoazetidine is obtained.

Elemental Analysis: C ₁₆ H ₁₉ Cl ₃ N ₂ O ₆

Calculated Value: C; 43.51%, H; 4.34%, N; 6.34%

Found: C; 43.64%, H; 4.42%, N; 6.16%

Reference Example 42

340 mg of cis-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-3- (2,2,2-trichloroethoxy carboxamido) -2-oxoazetidine 3 ml pyridine To the solution dissolved in, 132 mg of methanesulfonyl chloride was added under ice cooling and stirring. After the mixture was stirred at room temperature for 50 minutes, water and ethyl acetate were added and the pH was adjusted to 2 with dilute hydrochloric acid. The ethyl acetate layer was separated, washed successively with saturated aqueous sodium chloride solution, aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to crystallize the residue. When ether was added to the crystals and the crystals were collected by filtration, colorless crystalline cis-1- (2,4-dimethoxybenzyl) -4-methanesulfonyl oxymethyl-3- (2, 2) having a melting point of 139 to 140 ° C. 375 mg (94%) of 2-trichloro ethoxy carboxamido) -2-oxoazetidine are obtained.

Elemental analysis: C ₁₇ H ₂₁ Cl ₃ N ₂ O ₈ S

Calculated Value: C; 39.28%, H; 4.07%, N; 5.39%

Found: C; 39.21%, H; 4.16%, N; 5.48%

Reference Example 43

8.32 g of cis-1- (2,4-dimethoxybenzyl) -4-methanesulfonyl oxymethyl-3- (2, 2, 2-trichloro ethoxy carboxamido) -2-oxoazetidine To a solution dissolved in 450 ml of acetonitrile, a solution of 7.79 g of potassium persulfate and 4.70 g of dihydrogen phosphate dissolved in 180 ml of water is added dropwise over 20 minutes at 85 to 90 ° C. in a nitrogen stream. The mixture is stirred for 2.5 hours at the same temperature, after cooling to pH 6-7 with dipotassium hydrogen phosphate and then concentrated under reduced pressure. The residue is extracted with ethyl acetate and the extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel 270 g eluent: ethyl acetate-hexane, 2: 1 and ethyl acetate) to give a colorless crystallized cis-4-methanesulfonyl having a melting point of 85 to 86 ° C. Oxymethyl-3- (2, 2, 2-trichloro ethoxy carboxamido) -2-oxoazetidine is obtained.

Elemental Analysis: C ₈ H ₁₁ Cl ₃ N ₂ O ₆ S

Calculated Value: C; 26.00%, H; 3.00%, N; 7.58%

Found: C; 26.15%, H; 3.04%, N; 7.62%

Reference Example 44

To 130 ml of methyl ethyl ketone, 3.7 g of cis-4-methanesulfonyl oxymethyl-3- (2, 2, 2-trichloro ethoxy carboxamido) -2-oxoazetidine and 8.85 g of sodium iodide were added The mixture is heated for 3 hours at reflux in a stream of nitrogen. The solvent is evaporated under reduced pressure. Water and ethyl acetate are added to the residue and the mixture is shaken. The ethyl acetate layer was separated, washed with an aqueous sodium sulfite solution and an aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to crystallize the residue. When ether was added to the crystals and the crystals were collected by filtration, colorless crystal cis-3- (2, 2, 2-trichloroethoxy carboxamido) -4-iodomethyl-2-jade having a melting point of 152 to 154 占 폚. 3.56 g (88.6%) of pediatric zetidine are obtained.

Elemental Analysis: C ₇ H ₈ Cl ₃ IN ₂ O ₃

Calculated Value: C; 20.95%, H; 2.01%, N; 6.98%

Found: C; 21.19%, H; 2.06%, N; 7.21%

Reference Example 45

0.78 in a solution of 3.21 g cis-3- (2, 2, 2-trichloroethoxy carboxamido) -4-iodomethyl-2-oxoazetidine in 40 ml of N, N-dimethylformamide g of sodium azide are added and the mixture is stirred at room temperature for 43 hours before further 260 mg of sodium azide. The mixture is further stirred at 35 ° C. for 12 hours. N, N-dimethylformamide is evaporated under reduced pressure. Water and ethyl acetate are added to the residue and the mixture is shaken. The ethyl acetate layer was separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (150 g of silica gel, eluent: ethyl acetate-hexane 1: 1) to give a colorless crystal cis-4-azidomethyl-3- (93-95 ° C.). 2, 2, 2-trichloroethoxycarboxamido) -2-oxoazetidine is obtained.

Reference Example 46

560 mg of 5% palladium-carbon in a solution of 1.12 g cis-4-azidomethyl-3- (2, 2, 2-trichloroethoxycarboxamido) -2-oxoazetidine in 35 ml ethanol Is added and the mixture is stirred for 2 h at ambient temperature and pressure in a hydrogen stream. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. Residue 10 ml of methylene chloride and 10 ml of N, N-dimethylacetami are also dissolved in the mixture. 2.45 ml of propylene oxide and 0.50 ml of acetyl chloride were added sequentially to the solution under ice cooling and stirring. The mixture is stirred at room temperature for 2 hours and then the solvent is evaporated under reduced pressure. To the residue is added 50 ml of saturated aqueous sodium chloride solution and the mixture is extracted with a mixture of ethyl acetate and tetrahydrofuran (4: 1). The extract was washed with dilute hydrochloric acid, saturated aqueous sodium chloride solution, aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. 40 ml of hexane is added to the residue and the mixture is left to cool overnight. The resulting crystals were collected by filtration and washed with ether, and the melting point was cis-4-acetamidomethyl-3- (2, 2, 2-trichloroethoxy carboxamido) -2-jade with a melting point of 178-180 캜. Sodazetidine is obtained.

Elemental Analysis: C ₉ H ₁₂ Cl ₃ N ₃ O ₄

Calculated Value: C; 32.50%, H; 3.64%, N; 12.63%

Found: C; 32.83%, H; 3.60%, N; 12.79%

Reference Example 47

3.0 g of active zinc in a solution of 372 mg of cis-4-acetamidomethyl-3- (2, 2, 2-trichloroethoxy carboxamido) -2-oxoazetidine in 30 ml of tetrahydrofuran Add. 6 ml of aqueous solution of phosphoric acid-potassium dihydrogen phosphate (1 M concentration) was added to the mixture, followed by stirring at room temperature for 8 hours. 30 ml of tetrahydrofuran is added to the reaction mixture, and zinc is filtered off. The filtrate is concentrated under reduced pressure. To the residue is added 15 ml of water and 20 ml of ethyl acetate and the mixture is shaken. The aqueous layer is separated and concentrated under reduced pressure until its volume is reduced to 11 ml. 11 ml of tetrahydrofuran was added to the concentrate, and ice-cooled and stirred, 282 mg of sodium hydrogencarbonate and 559 mg of 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-methoxyimino Acetyl chloride is added continuously. The mixture was stirred for 1 hour under ice-cooling, then 2 g of sodium bicarbonate and saturated aqueous sodium chloride solution were added and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to crystallize the residue. When a mixture of ethyl acetate and ether was added to the crystals and the crystals were collected by filtration, the crystals were gradually decomposed while being colored in the temperature range of 140 to 165 ° C. Thus, cis-4-acetamidomethyl-3- [colorless crystals did not exhibit a specific melting point. 2- (2-chloroacetamido-4-thiazolyl) -2-methoxyimino acetamido] -2-oxoazetidine (syn-isomer) is obtained.

Reference Example 48

1.0 g cis-3-benzyl oxy carboxamido-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-2-oxoazetidine, 787 mg triphenylphosphine in 20 ml tetrahydrofuran And 441 mg of phthalimide are dissolved. 0.471 ml of azodi carboxylic acid diethyl ether was added to the solution, and the mixture was stirred at room temperature for 1 hour. Evaporation of the solvent under reduced pressure solidifies the residue. 30 ml of ethyl acetate was added to the solid residue, and the insolubles were collected by filtration and washed with ethyl acetate to give the colorless crystals of cis-3-benzyl oxy carboxamido-1- (2,4-dimethoxybenzyl) -4 882 mg of phthalimidomethyl-2-oxoazetidine is obtained. The mother liquor and washing solution were mixed and purified by silica gel column chromatography to yield 280 mg of colorless crystals. The total yield is 1.16 g (87.8%). Melting point 182-184 캜.

Elemental analysis: C ₂₉ H ₂₇ N ₃ O ₇

Calculated Value: C; 65.11%, H; 5.20%, N; 7.85%

Found: C; 65.05%, H; 5.17%, N; 7.80%

Reference Example 49

0.39 ml of hydrazine in a solution of 1.059 g of cis-3-benzyloxy carboxamido-1- (2,4-dimethoxybenzo) -4-phthalimidomethyl-2-oxoazetidine suspended in 80 ml of ethanol After adding anhydride, it is heated under reflux for 3.5 hours. The reaction mixture is cooled and the resulting crystals are filtered off. The filtrate is concentrated under reduced pressure, 30 ml of methylene chloride is added thereto, and the insolubles are filtered off. The filtrate is washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue is dissolved in a mixture of 10 ml of methylene chloride and 5 ml of N, N-dimethylacetamide. 1.4 ml of propylene oxide and 0.28 ml of acetyl chloride are continuously added to the solution under ice-cooling. The mixture is stirred at room temperature for 1 hour. To the mixture is added 10 ml of methylene chloride and 50 ml of sodium bicarbonate aqueous solution. The mixture was shaken and the methylene chloride layer was separated, washed with water, dilute hydrochloric acid and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the residue is purified by column chromatography (100 g of silica gel, eluent: chloroform-acetonitrile, 4: 1 and 3: 2). The elution solvent was evaporated under reduced pressure, and a mixture of ethyl acetate and ether (1: 3) was added to the residue, and the resulting crystals were collected by filtration. Cis-4-acetamidomethyl-3 having a melting point of 195 to 196 캜. -Benzyl oxy carboxamido-1- (2, 4-dimethoxybenzyl) -2-oxoazetidine is obtained.

Elemental Analysis: C ₂₃ H ₂₇ N ₃ O ₆

Calculated Value: C; 62.57%, H; 6.16%, H; 9.52%

Found: C; 62.20%, H; 6.08%, N; 9.41%

Similarly: -cis-3-benzyloxycarboxamido-4-benzamidomethyl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine is synthesized. Melting point 112-115 ° C.

Reference Example 50

1.081 g of cis-4-acetamidomethyl-3-benzyl oxy carboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine suspended in 65 ml of acetonitrile, 1.081 A solution of 25 g of potassium persulfate and 653 mg of dihydrogen phosphate dissolved in 25 ml of water is added dropwise over 15 minutes under heating reflux in a stream of nitrogen. After heating at reflux for 1.5 hours, the reaction mixture is neutralized with aqueous sodium bicarbonate solution and then concentrated under reduced pressure. The residue is extracted with a mixed solution of ethyl acetate and tetrahydrofuran (1: 1) and the extract is dried over an aqueous sodium bicarbonate solution and sodium chloride. The solvent was evaporated, ethyl acetate was added to the residue, and the crystals thus formed were collected after filtration. The resulting crystals were collected after filtration at a concentration of 226 to 228 ° C. Is obtained.

Similarly, cis-3-benzyl oxy carboxamido-4-benzamidomethyl-2-oxoazetidine is obtained. Melting point 209 to 211 ° C.

Reference Example 51

364 mg of 5% palladium-carbon is added to a solution in which 364 mg of cis-4-acetamidomethyl-3-benzyl oxycarboxamido-2-oxoazetidine is suspended in a mixture of 80 ml of ethanol and 20 ml of methanol. . The mixture undergoes catalytic reduction while stirring at ambient temperature and atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is dissolved in a mixture of 12 ml tetrahydrofuran and 12 ml water. 315 mg of sodium hydrogencarbonate was added to the mixed solution under ice-cooling and stirring, followed by 624 mg of 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-methoxyimino acetyl chlorochloride hydro, Chloride is added. After the mixture was stirred for 1 hour under ice cooling, a mixture of sodium bicarbonate, a saturated aqueous sodium chloride solution, ethyl acetate, and tetrahydrofuran (2: 1) was added thereto, followed by shaking. The organic layer was separated. The aqueous layer is extracted four times with a mixture of ethyl acetate and tetrahydrofuran (2: 1). The organic layers are combined, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the residue crystallizes. A mixture of ethyl acetate and ether (1: 2) is added thereto. When the crystals are collected by filtration, cis-4-acetamidomethyl-3- [2- (2-chloroacetamido as colorless crystals which do not show a distinct melting point by being gradually degraded while being colored within the range of 140 ° C to 165 ° C. 4-thiazolyl) -2-methoxy imino acetamido] -2-oxoazetidine (syn-isomer) is obtained. The IR and NMR spectra of this product are exactly the same as those of the product obtained in Reference Example 47.

Similarly cis-4-benzamidomethyl-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxy amino acetamido] -2-oxoazetidine (syn-isomer ) Is synthesized. This product does not exhibit a particular melting point but degrades slowly with coloration within the temperature range of 130 ° C to 150 ° C.

Reference Example 52

557 mg of cis-3-benzyl oxy carboxamido-2-oxoazetidine-4-carboxylic acid methyl ester was dissolved in 2.6 ml of tetrahydrofuran, and ice-cooled and stirred. Add 1.3 ml. The mixture is stirred under ice cooling for 80 minutes and then excess sodium borohydride is decomposed with acetic acid. Tetrahydrofuran is evaporated under reduced pressure. A saturated aqueous sodium chloride solution was added to the residue, followed by extraction with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The residue was purified by column chromatography (30 g of silica gel, eluent: ethyl acetate-acetonitrile 4: 1) to give a colorless crystal cis-3-benzyl oxy carboxamido-4-hydroxymethyl having a melting point of 103 to 104 캜. 2-oxoazetidine is obtained.

Elemental Analysis: C ₁₂ H ₁₄ N ₂ O ₄

Calculated Value: C; 57.59%, H; 5.64%, N; 11.19%

Found: C; 57.32%, H; 5.41%, N; 11.12%

Reference Example 53

To 250 ml of cis-3-benzyloxy carboxamido-4-hydroxymethyl-2-oxoazetidine in 5 ml of ethanol was added 250 ml of 5% palladium-carbon and the mixture was stirred at ambient temperature and atmospheric pressure. Catalytic reduction. The catalyst is filtered off and the filtrate is concentrated under reduced pressure and left to cool to crystallize the residue. The crystals were recovered by filtration to give 108 mg (93%) of cis-3-amino-4-hydroxymethyl-2-oxoazetidine having a melting point of 105 to 107 캜.

Elemental Analysis: C ₄ H ₈ N ₂ O ₂

Calculated Value: C; 41.37%, H; 6.94%, N; 24.12%

Found: C; 41.40%, H; 6.84%, N; 23.85%

Reference Example 54

0.4 ml of a solution of 58 mg of cis-3-amino-4-hydroxymethyl-2-oxoazetidine in a mixture of 5 ml of methylene chloride and 1 ml of N, N-dimethylacetamide, ice-cooled and stirred, 0.4 ml After triethylamine was added, 498 mg of 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-methoxyimino acetylchloride hydrochloride were added. The mixture is stirred under ice-cooling for 1 hour, and 200 ml of water is added thereto, and the pH is adjusted to 7-8 with sodium hydrogen carbonate. The reaction mixture is concentrated under reduced pressure and the residue is extracted with a mixture of ethyl acetate and tetrahydrofuran (2: 1). The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. When the solvent is evaporated under reduced pressure, the residue crystallizes. A mixture of ethyl acetate and ether (1: 2) is added thereto, and the crystals are recovered by filtration. -(2-Chloroacetamido-4-thiazolyl)-(Z) -2-methoxyimino acetamido] -4- [2- (2-chloroacetamido-4-thiazolyl)-(Z ) -2-methoxyimino acetoxymethyl] -2-oxoazetidine is obtained.

Elemental analysis: C ₂₀ H ₂₀ Cl ₂ N ₈ O ₈ S ₂

Calculated Value: C; 37.80%, H; 3.17%, N; 17.63%

Found: C; 37.85%, H; 3.27%, N; 17.22%

Reference Example 55

Cis-1- (2,4-dimethoxybenzyl) -3- (2,2,2-trichloro ethoxy carboxamido) -2-oxoazetidine-4-carboxylic acid methyl in 20 ml acetonitrile To the ester solution was added dropwise a solution of 1.08 g of potassium persulfate and 716 mg of crystalline dihydrogen phosphate in 20 ml of water over 10 minutes while heating to reflux. Continue to reflux while heating for 30 minutes. After cooling the reaction mixture, acetonitrile is evaporated under reduced pressure. The residue is extracted with ethyl acetate, washed with 5% aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (20 g of silica gel, eluent; chloroform-ethyl acetate, 1: 2) to give a colorless crystal cis-3- (2, 2 having a melting point of 140 to 141 ° C. , 2-trichloro ethoxy carboxamido) -2-oxoazetidine-4-carboxylic acid methyl ester is obtained.

Elemental analysis; C ₈ H ₉ Cl ₃ N ₂ O ₅

Calculated Value: C; 30.07%, H; 2.84%, N; 8.77%

Found: C; 30.30%, H; 2.82%, N; 8.87%

Reference Example 56

1.41 g of cis-3- (2,2,2-trichloroethoxy carboxamido) -2-oxoazetidine-4-carboxylic acid methyl ester in a solution of 40 ml of tetrahydrofuran, ice-cooled and Under stirring, a solution of 417 mg of sodium borohydride dissolved in 20 ml of water is added. The mixture is stirred for 30 minutes under ice-cooling, 1 hour at room temperature, and then tetrahydrofuran is evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed twice with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. When concentrated under reduced pressure, the residue is crystallized, ether is added, and the crystals are collected by filtration, and the cis-4-hydroxymethyl-3- (2, 2, 2-trichloroethoxycarb having a melting point of 162 to 164 캜 is obtained. Copyomido) -2-oxoazetidine is obtained.

Reference Example 57

424 mg of thionyl chloride is added to a solution of 468 mg of 2-thienyl acetic acid in 7 ml of anhydrous methylene chloride, and the mixture is heated to reflux for 2 hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in 5 ml of anhydrous methylene chloride.

Meanwhile, 416 mg of triethylamine was dissolved in a solution of cis-4-hydroxymethyl-3- (2, 2, 2-trichloro methoxy carboxamido) -2-oxoazetidine in 300 ml of anhydrous methylene chloride. Add. To this mixture is added dropwise a methylene chloride solution of 2-thienyl acetylchloride prepared above under ice cooling and stirring. The resulting mixture is stirred overnight at room temperature under ice cooling for 20 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 3N-HCl, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. Finally, the residue was purified by column chromatography (60 g of silica gel, eluent; hexane-ethyl acetate, 1: 1 and 2: 3) to give cis-4- (2-thienylacetoxymethyl) -3- (2 , 2, 2-trichloro ethoxy carboxamido) -2-oxoazetidine is obtained.

Reference Example 58

600 mg of cis-4- (2-thiethyl acetoxymethyl) -3- (2, 2, 2-trichloro ethoxy carboxamido) -2-oxoazetidine in 25 ml of tetrahydrofuran and 5 ml of 1N 2.16 g of activated zinc is added to the solution dissolved in the mixture of aqueous ammonium acetate solution, and the mixture is stirred at room temperature for 5 hours. The mixture is filtered through celite. Methylene chloride is added to the filtrate and then dried over anhydrous magnesium sulfate. The filtrate is concentrated under reduced pressure, and the residue is dissolved in a mixture of 2 ml of tetrahydrofuran and 2 ml of water, followed by addition of 850 mg of sodium hydrogencarbonate under ice cooling. 720 mg of 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-methoxyiminoacetylchloride hydrochloride was added to the mixture, followed by vigorous stirring for 15 minutes under ice-cooling. The reaction mixture is stirred for an additional hour at room temperature and then the solvent is evaporated under reduced pressure. Water was added to the residue, and the resulting crystals were collected by filtration and washed in the order of water, aqueous sodium bicarbonate solution, ether and nucleic acid. Acetamido-4-thiazolyl) -2-methoxyimino acetamido] -4- (2-thienylacetoxymethyl) -2-oxoazetidine (syn-isomer) is obtained.

Reference Example 59

To a solution of 314 mg of 1-methyl-1H-tetrazol-5-ylmercaptan dissolved in 2 ml of anhydrous N, N-dimethylformamide, 65 mg of sodium hydride under ice-cooling was added. The mixture was stirred for 10 minutes at room temperature under ice-cooling, and 3 ml of 724 mg of cis-3- (2, 2, 2-trichloroethoxy carboxamido) -4-iodomethyl-2-oxoazetidine The solution dissolved in N, N-dimethylformamide was added, followed by stirring at room temperature for 2 days. The reaction mixture was dissolved in ethyl acetate, washed five times with water, further washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (60 g of silica gel, eluent: nucleic acid-ethyl acetate, 1). : 2 then 1: 4) purified to 610 mg (86.8%) cis-4- (1-methyl-1H-tetrazol-5-yl-thiomethyl) -3- with a melting point of 67 to 69 ° C. (2, 2, 2-trichloro ethoxy carboxamido) -2-oxoazetidine is obtained.

Reference Example 60

After adding 1.49 ml of methyl mercaptan solution in 4N-tetrahydrofuran to 10 ml of tetrahydrofuran, 1.37 ml of n-butyllithium solution in 1.6N-nucleic acid is added dropwise under ice-cooling. The mixture was stirred for 10 minutes under ice-cooling in a nitrogen stream, then cooled to -45 ° C and 800 mg of cis-3- (2, 2, 2-trichloroethoxy carboxamido) -4-iodomethyl-2-jade A solution of pediatric zetidine dissolved in 5 ml tetrahydrofuran is added dropwise. The temperature of the reaction mixture is raised in the range of -20 ° C to -30 ° C and the reaction mixture is stirred for 4 hours. After the reaction mixture is dissolved in ethyl acetate, saturated aqueous ammonium chloride solution is added and the mixture is stirred. The organic layer is separated, washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (100 g of silica gel, eluent: nucleic acid-ethyl acetate, 2: 1 and 1: 1) to give the crystal phase cis-4-methylthiomethyl-3- (2). , 2, 2-trichloroethoxycarboxamido) -2-oxoazetidine is obtained.

Reference Example 61

10 ml of 674 mg cis-4- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3- (2, 2, 2-trichloroethoxy carboxamido) -2-oxoazetidine 2 ml of 1N-ammonium acetate solution is added to the solution dissolved in tetrahydrofuran. 1 g of activated zinc was added to the mixture, followed by stirring at room temperature for 3 hours. The reaction mixture is filtered. Methylene chloride is added to the filtrate and the mixture is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in a mixture of 3 ml of tetrahydrofuran and 3 ml of water and then 1.02 g of sodium hydrogen carbonate is added under ice cooling. 863 mg of 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-methoxyimino acetylchloride hydrochloride was added to the mixture, followed by stirring for 15 minutes under ice-cooling, followed by further stirring at room temperature for 1 hour. Let's do it. The solvent is evaporated under reduced pressure. Water was added to the residue, and the resulting crystals were collected by filtration, washed with water, aqueous sodium bicarbonate solution, ether and hexane, and then crystallized cis-3- [2- (2-chloroacetamido-4-thiazolyl in crystalline phase. ) -2-methoxyimino acetamido] -4- (1-methyl-1H-tetrazol-5-ylthiomethyl) -2-oxoazetidine (syn-isomer) is obtained. Melting Point 195-198 ° C (Decomposition)

Similarly, cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyimino acetamido] -4-methylthiomethyl-2-oxoazetidine (syn-isomer ) Is synthesized. Melting point 172-176 DEG C (decomposition).

Reference Example 62

To a solution in which 1.0 g of cis-3-benzyl oxy carboxamido-1- (2,4-dimethoxybenzyl) -4-methanesulfonyl oxymethyl-2-oxoazetidine is suspended in 50 ml of methyl ethyl ketone 1.88 g of sodium iodide is added. The mixture is stirred under heating at 90 ° C. for 6 hours and the solvent is evaporated under reduced pressure. To the residue is added 150 ml of ethyl acetate and 100 ml of water and the mixture is shaken. The ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting solid residue was recrystallized from 50 ml of a mixture of nucleic acid and ethyl acetate (1: 1) to give a colorless acetic cis-3-benzyl oxycarboxamido-1- (2,4-dimethy). 850 mg (80%) of oxybenzyl) -4-iodomethyl-2-oxoazetidine is obtained. Melting point 165 to 166 ° C.

Elemental analysis; C ₂₁ H ₂₃ IN ₂ O ₅

Calculated Value: C; 49.43%, H; 4.54%, N; 5.49%

Found: C; 49.55%, H; 4.56%, N; 5.67%

Reference Example 63

3.29 g of cis-3-benzyl oxy carboxamido-1- (2,4-dimethoxybenzyl) -4-iodomethyl-2-oxoazetidine in a solution dissolved in 10 ml of hexamethyl phosphoric triamide 1.62 g sodium cyano borohydride is added. The mixture is stirred at 90-110 ° C. for 5 hours in a stream of nitrogen. The reaction mixture is added to 250 ml of ether, washed 6 times with 20 ml of water and once with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After addition of ether and nucleic acid to the resulting solid residue and filtration, 2.15 g (86.7%) of cis-3-benzyl oxy carboxamido-1- (2,4-dimethoxybenzyl) -4-methyl-2 Oxoazetidine is obtained. Melting point 130 to 132 ° C.

Elemental analysis: C ₂₁ H ₂₄ N ₂ O ₅

Calculated Value: C; 65.61%, H; 6.29%, N; 7.29%

Found: C; 65.23%, H; 6.49%, N; 7.53%

Reference Example 64

5.10 g of 2,4-dimethoxybenzylamine hydrochloride is added to an aqueous calcium carbonate solution, and the resulting oily portion is extracted with 120 ml of benzene. The extract is washed with water, dried over anhydrous sodium sulfate and then 3.50 g of p-chlorobenzaldehyde is added. The mixture is heated to reflux for 1 hour with a water-separator. Evaporation of the solvent crystallizes the residue, which dissolves in 68 ml of methylene chloride. To the resulting solution was added 3.8 ml of a solution of triethylamine in 20 ml of methylene chloride under stirring at −5 ° C. to −10 ° C., followed by dropwise addition of a solution of 6.15 g of phthalimido acetyl chloride in 25 ml of methylene chloride. do. After 20 minutes, the mixture was continuously added with 1.9 ml of triethylamine solution in 10 ml methylene chloride and 3.1 ml of phthalimide acetyl chloride in 13 ml of methylene chloride. The resulting mixture is stirred for 7 hours under ice-cooling, left overnight under ice-cooling, washed with water, aqueous sodium bicarbonate solution, 5% hydrochloric acid and water, dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure. The residue was purified by column chromatography (60 g of silica gel, eluent: chloroform-methanol, 20: 1) to give a colorless crystalline cis-4- (4-chlorophenyl) -1- (2,4-dimethoxybenzyl) -3. 9.4 g (84%) of phthalimido-2-oxoazetidine is obtained. Recrystallization with acetone-hexane yields a colorless prism material having a melting point of 178-180 ° C.

Elemental Analysis Value: C ₂₆ H ₂₁ CIN ₂ O ₅

Calculated Value: C; 65.46%, H; 4.44%, N; 5.87%

Found: C; 65.42%, H; 4.42%, C; 5.90%

Reference Example 65

0.89 ml of methyl in a solution of 4 g of cis-4- (4-chlorophenyl) -1- (2,4-dimethoxybenzyl) -3-phthalimido-2-oxoazetidine in 50 ml of methylene chloride Add hydrazine. The mixture is stirred at 35-40 ° C. for 17 hours and then filtered, and the filtrate is concentrated under reduced pressure. Ethyl acetate is added to the residue and the resulting insolubles are filtered off. The filtrate (about 100 ml) is extracted with a mixture of 30 ml of water and 10 ml of 10% hydrochloric acid. The extract was neutralized with aqueous sodium bicarbonate solution, extracted twice with methylene chloride, and extracted with saturated aqueous sodium chloride solution. The extract is dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure. The residue (2.6 g) was dissolved in 30 ml of methylene chloride, then 5.5 ml of propylene oxide was added dropwise with ice cooling and stirring, and 2.3 g of carbobene cichloride was added dropwise. The mixture is stirred at room temperature for 2 hours and the solvent is evaporated under reduced pressure. Crystals formed by adding nucleic acid to the residue are collected by filtration. 3.31 g (81%) of cis-3-benzyloxycarboxamido-4- (4-chlorophenyl) -1- (2,4-dimethoxybenzyl) -2-jade Sodazetidine is obtained.

Reference Example 66

2.42 g of potassium persulfate in a solution of 2.15 g cis-3-benzyloxycarboxamido 1- (2,4-dimethoxybenzyl) -4-methyl-2-oxoazetidine in 150 ml of acetonitrile and A solution of 1.46 g of potassium dihydrogen phosphate dissolved in 75 ml of water at 90 to 100 ° C. is added dropwise. The mixture is heated to reflux for 1.5 hours at reflux and the acetonitrile is evaporated under reduced pressure. Ethyl acetate and water were added to the residue, followed by shaking. The ethyl acetate layer was separated, washed with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (200 g of silica gel, eluent: nucleic acid-ethyl acetate, 1: 2) to give a crystallized cis-3-benzyloxycarbox having a melting point of 168 to 169 ° C. Mido-4-methyl-2-oxoazetidine is obtained.

Elemental Analysis Value: C ₁₂ H ₁₄ N ₂ O ₃

Calculated Value: C; 61.53%, H; 6.20%, N; 11.96%

Found: C; 61.36%, H; 6.05%, N; 11.65%

Similarly: -cis-3-benzyloxycarboxamido-4- (4-chlorophenyl) -2-oxoazetidine is synthesized.

Reference Example 67

210 mg of 5% palladium-carbon was added to a solution of 210 mg of cis-3-benzyloxycarboxamido-4-methyl-2-oxoazetidine suspended in 10 ml of ethanol, followed by stirring for 1 hour under water flow. The mixture is filtered and the filtrate is concentrated. The residue is crystallized (melting point 111-112 ° C.). 1 ml of water and 1 ml of detrahydrofuran are added to the crystals, followed by 382 mg of sodium carbonate under ice-cooling. To the mixture is added 453 mg of 2- (2-chloroaceramido-4-thiazolyl)-(z) -2-methoxyiminoacetyl chloride with vigorous stirring. The resulting mixture was stirred for 15 minutes under ice-cooling and then concentrated under reduced pressure. Water was added to the residue, and the resultant insolubles were collected by filtration, washed with water, aqueous sodium bicarbonate solution, ether and hexane in this order, and crystallized cis-3- [2- (2-chloroacetamido-4- 276 mg (84%) of thiazolyl) -2-methoxyiminoacetamido] -4-methyl-2-oxoazetidine (syn-isomer) are obtained. Melting point 212-215 캜 (decomposition).

Similarly: -cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxy-iminoacetamido] -4- (4-chlorophenyl) -2-oxoazeti Dines (syn-isomers) are synthesized.

Reference Example 68

1.4 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester was dissolved in 14 ml of methanol, and ice-cold and 0.9 g of potassium carbonate was dissolved in 9 ml of water. The solution is added dropwise. The mixture is stirred at rt for 1 h and the methanol is evaporated. The remaining aqueous solution is washed with ethyl acetate and neutralized with dilute hydrochloric acid. The neutralized solution is extracted with ethyl acetate and the extract is washed with an aqueous sodium softening solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue crystallizes. Filtration of ethyl acetate to the crystals gave 1.1 g (84.6%) of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid, which was recrystallized from acetonitrile to give a melting point. This 156 to 157 ° C. crystal is obtained.

Elemental Analysis Value: C ₁₂ H ₁₂ N ₂ O ₅

Calculated Value: C; 54.54%, H; 4.57%, N; 10.60%

Found: C; 54.55%, H; 4.45%, N; 10.77%

Reference Example 69

4 g of dicycloexyl carbodiimide is added to a solution of 1.32 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid in anhydrous tetrahydrofuran. After 10 minutes, 0.5 ml of 40% aqueous dimethylamine solution is added to the mixture and stirred at room temperature for 2 hours. The insolubles are filtered off and the filtrate is concentrated under reduced pressure. Ethyl acetate and sodium bicarbonate aqueous solution were added to the residue, followed by shaking. The ethyl acetate layer was separated, washed with an aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification of the residue by column chromatography (silica gel) affords crystalline cis-3-benzyloxycarboxamido-4- (N, N-dimethylcarbamoyl) -2-oxoazetidine.

Reference Example 70

291 mg of 5% palladium-carbon was added to a solution of 291 mg of cis-3-benzyloxycarboxamido-4- (N, N-dimethylcarbamoyl) -2-oxoazetidine in 10 ml of methanol, Catalytic reduction is performed at ambient temperature and atmospheric pressure. After 2 hours the reaction mixture was filtered and the filtrate was concentrated to give 141 mg (90%) of colorless crystals of cis-3-amino-4- (N, N-dimethylcarbamoyl) -2-oxoazetidine. When this product is reacted with 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-methoxyiminoacetyl chloride in the same manner as in Reference Example 34, the crystal phase has a melting point of 160 to 165 캜. Cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (N, N-dimethylcarbamoyl) -2-oxo azetidine Obtained.

Reference Example 71

, 10ml의 테트라히드로푸란 및 5ml의 1N-탄산수소나트륨의 빙냉하 미리 교반시킨 혼합물에, 0.32ml의 2-티에틸아세틸 클로라이드를 10ml의 테드라히드로푸란에 녹인 용액을 적가한다. 10분간 교반시킨 후, 혼합물에 100ml의 에틸아세테이트 및 20ml의 염화나트륨 포화수용액을 가한 후 교반시키고 유기층을 분리한다. 수층을 30ml의 에틸아세테이트로 추출하고, 추출물을 유기층과 배합한다. 전체 유기층을 염화나트륨 포화수용액(20ml×3)으로 세척하여 건조시키고 감압하 농축시킨다. 잔류물에 4ml의 혼합용액(에틸 아세테이트 : 핵산 = 1 : 2)을 가하고 생성된 결정을 여과로 수집하여 건조시키면, 융점이 133내지 136℃인 430mg(80%)의 시스-3-(2-티에닐아세타미도)-2-옥소아제티딘-4-카르복실산 메틸에스테르가 수득된다.288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid

To a mixture of 10 ml of tetrahydrofuran and 5 ml of 1N-sodium hydrogen carbonate precooled under ice-cooling, a solution of 0.32 ml of 2-thiethylacetyl chloride dissolved in 10 ml of tetrahydrofuran was added dropwise. After stirring for 10 minutes, 100 ml of ethyl acetate and 20 ml of saturated aqueous sodium chloride solution were added to the mixture, followed by stirring and the organic layer was separated. The aqueous layer is extracted with 30 ml of ethyl acetate and the extract is combined with the organic layer. The whole organic layer is washed with saturated aqueous sodium chloride solution (20 ml x 3), dried and concentrated under reduced pressure. 4 ml of a mixed solution (ethyl acetate: nucleic acid = 1: 2) was added to the residue, and the resulting crystals were collected by filtration and dried, and 430 mg (80%) of cis-3- (2- having a melting point of 133 to 136 ° C. Thienylacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester is obtained.

Elemental Analysis Value: C ₁₁ H ₁₂ N ₂ O ₄ S

Calculated Value: C; 49.43%, H; 4.15%, N; 10.48%

Found: C; 49.00%, H; 4.37%, N; 10.20%

Reference Example 72

288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 4 ml of propylene oxide, and 3 ml of N, N-dimethylacetamide in a pre-stirred mixture under ice-cooling, 400 ml of 1H Tetrazol-1-yl acetylchloride is added dropwise and stirred for 30 minutes. 50 ml of ethyl ether was added to the mixture, and the mixture was cooled to -30 ° C, stirred, and then the upper layer was removed at an angle. The bottom layer is subjected to the same procedure twice before adding 10 ml of acetone. The resulting solvent was developed and purified by silica gel (40 g, 3 × 10 cm) column chromatography using acetone: methylene chloride (1: 1) mixture as the eluent, to obtain 403 mg (84%) of cis-3- (1H- Tetrazol-1-ylacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester is obtained.

Elemental _{analysis: C 8 H 10 N 6 O} 4 .2 / 3CH 3 COCH 3

Calculated Value: C; 41.00%, H; 4.82%, N; 28.69%

Found: C; 41.16%, H; 5.08%, N; 28.65%

Reference Example 73

A mixture of 696.7 mg of nalidixic acid and 10 ml of methylene chloride is pre-stirred at room temperature, to which 2 ml of thionyl chloride is added and stirred for 1 hour. The reaction mixture is concentrated to dryness under reduced pressure, and the residue is dissolved in N, N-dimethylacetamide. Meanwhile, a mixture of 288 mg of cis-3-amino-2-oxoazetin-4-carboxylic acid methyl ester, 6 ml of propylene oxide and 3 ml of N, N-dimethylacetamide was previously stirred under ice-cooling and 5 ml of N, N-dimethylacetamide solution obtained above was added thereto, followed by stirring at room temperature for 2 hours. Insolubles are removed by suction filtration and the filtrate is shaken with a mixture of 100 ml of ethyl acetate and 200 ml of water. The organic layer was separated, washed with saturated aqueous sodium chloride solution (50ml × 3), dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give cis-3- (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-yl-carbonylamino) 2-oxoazetidine-4-carboxylic acid methyl ester is obtained. Melting Point 223 ~ 224 ℃

Reference Example 74

A solution of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester in 2 ml of N, N-dimethylacetamide was previously stirred under ice-cooling, and 534 mg of mandelic acid- After adding carboxylic anhydride, it is stirred for 30 minutes at room temperature. The mixture is stirred in advance under ice-cooling, and 1.05 ml of chloroacetyl chloride is added dropwise thereto, followed by stirring at room temperature for 3 hours. The reaction mixture is shaken with 100 ml of ethyl acetate and 20 ml of 1N-HCl, and then the organic layer is separated. The organic layer was washed successively with saturated sodium chloride solution (30ml × 3), 20ml of 1N-NaHCO ₃ aqueous solution and saturated sodium chloride solution (30ml × 3), 20ml of 1N-NaHCO ₃ aqueous solution and saturated sodium chloride solution (30ml × 3). Dry and evaporate the solvent under reduced pressure. Purification of the residue by silica gel column chromatography yields cis-3- (2-chloroacetyloxy-2-phenylacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester.

Reference Example 75

A mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 1 ml of tetrahydrofuran 2 ml of water and 15 ml of 1N-NaHCO ₃ aqueous solution was pre-cooled under ice-cooling, 469 mg D-α-sulfophenylacetyl chloride was added thereto, followed by stirring for 10 minutes under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in 5 ml of water. The aqueous solution was chromatographed with Amberlite XAD-II column, purified by Sephadex LH-20 column chromatography, and lyophilized to obtain cis-3- (D-2-sulfo-2-phenylacetamido) -2-jade. Sodium zetidine-4-carboxylic acid methyl ester sodium salt is obtained.

Elemental Analysis Value: C ₁₃ H ₁₃ N ₂ NaO ₇ S.3 / 2H ₂ O

Calculated Value: C; 39.90%, H; 4.12%, N; 7.16%

Found: C; 39.78%, H; 4.48%, N; 7.29%

Reference Example 76

2.7 g of phenylmalonic acid monobenzyl ester and 5 ml of thionyl chloride are stirred at room temperature for 16 hours and then concentrated under reduced pressure. Methylene chloride is added to the residue to a total volume of 10 ml. Meanwhile, a mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 0.42 ml of triethylamine and 10 ml of methylene chloride was stirred under ice-cooling, and the 3 ml of chloride obtained above was The methylene mixture is evaporated under reduced pressure. 200 ml of ethyl acetate and 30 ml of water were added to the residue, followed by shaking. The organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride solution (30 ml × 3), 20 ml of 1N-HCl and saturated aqueous sodium chloride solution (20 ml × 2), dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of ethyl acetate: methylene chloride (1: 1) as eluent, to obtain cis-3- (2-benzyloxycarbonyl-2-denylacetamido) -2-. Oxoazetidine-4-carboxylic acid methyl ester is obtained.

Reference Example 77

From 400 mg of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester, the 3-amino compound prepared in the same manner as in Reference Example 3 is dissolved in 15 ml of tetrahydrofuran. . 120 mg of cyanoacetic acid is added to the solution, followed by stirring under ice cooling. 290 mg of diclohexyl carbodiimide was added to the mixture, followed by stirring at room temperature for 2 hours. The reaction mixture is filtered and the filtrate is concentrated. 30 ml of ethyl acetate is added to the residue, filtered again and the filtrate is concentrated. Purification of the concentrate by column chromatography (20 g of silica gel, eluent: ethyl acetate) affords cis-3- (2-cyanoacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester.

Reference Example 78

40 ml of 808 mg cis-3- [2-chloroacetamido-4-thiazolyl) -2-methoximinoacetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer) To a solution suspended in methanol, a solution of 552 mg of potassium carbonate dissolved in 12 ml of water was added dropwise under ice-cooling. The mixture is stirred at room temperature for 1 hour. 6 ml of 1N-HCl is added to the reaction mixture, followed by evaporation of ethanol. The remaining aqueous mixture was washed with ethyl acetate, adjusted to pH 2 with dilute hydrochloric acid, and extracted with a mixture of ethyl acetate and tetrahydrofuran (1: 2). The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue is suspended in a mixture of 40 ml methylene chloride and 10 ml tetrahydrofuran. To the suspension was added 1.0 ml of pyridine under stirring at room temperature, followed by dropwise addition of a solution of 864 mg of p-nitrobenzyl chloroformate dissolved in 4 ml of methylene chloride over 30 minutes. The mixture is stirred for 30 minutes at room temperature, washed with water, diluted hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was purified by column chromatography (100 g of silica gel, eluent: ethyl acetate) to give the crystal form cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido. ] -2-oxoazetidine-4-carboxylic acid p-nitrobenzyl ester (syn isomer) is obtained. Melting point 231-236 ° C (decomposition)

Reference Example 79

Dissolve 53.2 g of ethyl 2-chloroacetamido-4-thiazolyl acetate in a mixture of 510 ml of dioxane and 42.6 ml of acetic acid, add 28.3 g of selenium dioxide, and add the mixture at 110 to 115 ° C. for 4 hours. Stir under heating. After cooling, the resulting black precipitate is discarded and the solution thus obtained is concentrated under reduced pressure. The residue is dissolved in 3 l of ethyl acetate, washed twice with aqueous sodium hydrogen carbonate solution and then twice with water. The solution is dried over anhydrous magnesium sulfate and concentrated to 1 l. The concentrate was heated to reflux to dissolve the precipitate, 800 ml of hexane was heated to cool the solution and recrystallized from ethyl acetate-hexane to give a yellow needle of ethyl 2-chloroacetamido-4-thiazolyl glyoxylate. do. Melting point 178-180 ° C.

Reference Example 80

Suspend 35 g of ethyl 2-chloroacetamido-4-thiazolylglyoxylate in 646 ml of ethanol and add 250 ml of 1N aqueous sodium hydroxide solution dropwise with ice cooling and stirring. The mixture is stirred at room temperature for 1 hour and then concentrated to 200 ml under reduced pressure. After 200 ml of water was added, the concentrate was washed with 400 ml of ethyl acetate. After decolorizing with activated charcoal, the pH of the concentrate is adjusted to 1.5 with 10% hydrochloric acid to separate light yellow crystals. The crystals were recovered by filtration, washed with water and hexane in that order and dried to afford 2-chloroacetamido-4-thiazolylglyoxylic acid. Recrystallization from ethyl acetate-hexane gives a light yellow prism-like material. Melting point 205 to 210 ° C (decomposition)

Reference Example 81

To 50 ml of anhydrous N, N-dimethylformamide, 10 g of N-hydroxyphthalimide and 9.38 g of methyl bromoacetate are added followed by 8.5 g of calcium carbonate. The mixture is stirred for 2 days at room temperature and then poured into 400 ml of water. The resulting crystalline precipitate was recovered by filtration and washed with water, hexane and ether in order to give a colorless needle-like N-methoxycarbonylethyloxyphthalimide. Melting point 137-142 ° C.

In the same manner as above, the following compounds are synthesized: N- (p-nitrobenzyl oxycarbonylmethyloxy) pralimide, melting point. 158-160 degreeC.

Reference Example 82

3.5 g of N-methoxycarbonyl methyloxyphthalimide is dissolved in 600 ml of methylene chloride, and 745 mg of hydrazine hydrate is added with ice cooling and stirring. The mixture is stirred at room temperature for 2 hours before further 149 mg hydrazine hydrate is added. The mixture is stirred for 2 hours and the resulting hard precipitates are filtered off. The filtrate is washed with 15 ml of diluted ammonia water and then with 15 ml of water. The solution is dried over anhydrous sodium sulfate and the solvent is distilled off. To the residue is added 10 ml of ether and the insolubles are filtered off. Concentration of the filtrate affords a light yellow oily 0-methoxycarbonyl methylhydroxylamine.

Reference Example 83

In a mixture of 20 ml of water and 12 ml of tetrahydrofuran, 1.0 g of 2-chloroacetamido-4-thiazolylglyoxylic acid obtained in Example 80 was dissolved and ice-cooled to 465 mg of O-methoxycarbonyl methyl. Add hydroxylamine. Aqueous 1N sodium hydroxide solution was added to adjust the pH of the mixture to 5 and stirred at room temperature for 20 minutes. The pH of the mixture was adjusted to 7 with aqueous sodium hydrogen carbonate solution and washed twice with 15 ml of ethyl acetate. The aqueous layer was separated and the pH was adjusted to 2 with 2N-HCL, and the resulting crystalline precipitate was recovered by filtration and washed with water, hexane and ether. 2- (2-chloroacetamido-4-thiazolyl)-(z) -2-methoxycarbonyl methyloxyiminoacetic acid is obtained as colorless crystals. Melting point 177 to 179 ° C (decomposition).

Reference Example 84

810 mg of 2- (2-chloroacetamido-4-thiazolyl)-(z) -2-methoxycarbonyl methyloxyiminoacetic acid is suspended in 20 ml of methylene chloride and 602 m of phosphorus pentachloride under ice cooling and stirring Add. The mixture was stirred for 1 hour at room temperature under ice-cooling, and then 30 ml of hexane was added under ice-cooling. The resulting crystals were collected by filtration and washed with hexane to give 910 mg of 2- (2-chloroacetamido-4-thiazolyl)-(z) -2-methoxycarbonyl methyloxyiminoacetyl chloride hydrochloride. do. Melting point 77-80 ° C.

In the same manner as above, the following compounds are synthesized. 2- (2-Chloroacetamido-4-thiazolyl)-(Z) -2- (P-nitrobenzyl oxycarbonylmethyloxyimino) acetyl chloride hydrochloride, melting | fusing point 158-161 degreeC.

Reference Example 85

280 mg of methyl cis-3-amino-2-oxoazetidine-4-carboxylate is dissolved in a mixture of 5 ml of tetrahydrofuran and 5 ml of water and 773 mg of sodium hydrocarbon is added.

Under ice-cooling and stirring, 910 mg of 2- (2-chloroacetamido-4-thiazolyl- (Z) -2-methoxycarbonyl methyloxyimino acetylchloride hydrochloride are added.The mixture is stirred at room temperature for 2 hours. Water is added to the reaction mixture, and the resulting crystals are collected by filtration, washed with water, hexane and ether in order, and methylcis-3- [2- (2-chloroacetamido-4-thiazolyl). 2-methoxycarbonyl methyloxyimino acetamido] -2-oxoazetidine-4-carboxylate (syn-isomer) is obtained Melting point 260-265 ° C. (decomposition)

In the same manner as above, the following compounds are synthesized. Cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-p-nitrobenzyl oxycarbonyl methyloxyimino) acetamido] -4-methoxycarbonyl-2-oxoa Zetidine (syn) isomer, melting point. 270-275 degreeC (decomposition).

Reference Example 86

After dissolving 15.3 g of p-nitrobenzyl alcohol in 250 ml of anhydrous ether, 8.90 ml of pyridine is added under ice cooling and stirring. 25.3 g of α-bromo isobutyl bromide is then added dropwise over 50 minutes. The mixture is stirred for 5 hours at room temperature and the resulting crystalline precipitate is separated by filtration and washed with ether. The filtrate and washings are synthesized and 150 ml of ethyl acetate are added. The mixture is washed with dilute hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was chromatographed with a silica gel column [silica gel: 600 g, eluent: chloroform-hexane (1: 1)] to give yellow oily P-nitrobenzyl α-bromoisobutylate 29.6. g is obtained. This product solidifies on standing under ice-cooling.

Reference Example 87

Dissolve 14.7 g of N-hydroxyphthalimide and 27.2 g of P-nitrobenzyl α-bromoisobutyrate in 75 ml of anhydrous N, N-dimethylformamide and then add 12.4 g of potassium carbonate. The mixture is stirred at room temperature for 1 hour. 75 ml of anhydrous N, N-dimethylformamide is added because orange solid precipitates, making stirring difficult. After stirring for 24 hours at room temperature, the reaction mixture is concentrated under reduced pressure to half its original volume and the concentrate is poured into 700 ml of water under ice-cooling and stirring. The mixture is further stirred for 30 minutes, and the crystalline precipitate obtained is filtered off and washed with water. The crystals are dissolved in 500 ml of methylene chloride, washed with water and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure. The residue in the solid phase was washed with ether-petroleum ether (1: 1) followed by a small amount of ether, and the colorless crystalline N- (1-methyl-1- (P-nitrobenzyloxycarbonyl) having a melting point of 145 to 146 占 폚. 27.0 g of) -ethyloxy] phthalimide are obtained.

Elemental Analysis Value: C ₁₉ H ₁₆ N ₂ O ₇

Calculated Value: C; 59.38%, H; 4.20%, N; 7.29

Found: C; 59.14%, H; 4.27%, N: 7.26

Reference Example 88

7.68 g of N- [1-methyl-1- (P-nitrobenzyl oxycarbonyl) ethyloxy] phthalimide is dissolved in 80 ml of methylene chloride, and 0.97 ml of hydrazine hydrate is added under ice cooling and stirring. The mixture is stirred at room temperature for 2 hours before further 0.97 ml of hydrazine hydrate is added. The mixture is stirred for 3 hours, and the resulting crystalline precipitate is separated by filtration and washed with methylene chloride. The combined filtrate and washings are further washed with dilute ammonia water and water and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was chromatographed with a silica gel column [silica gel: 300 g, eluent: ethyl acetate-hexane (1: 1)] to give O- [1-methyl-1- (P) as a yellow oil. 4.58 g of nitrobenzyl oxycarbonyl) ethyl] hydroxylamine are obtained. This product solidifies upon cooling.

Reference Example 89

Dissolve 1.49 g of 2-chloroacetamido-4-thiazolylglyoxylic acid in a mixture of 30 ml of water and 18 ml of tetrahydrofuran, and 1.83 g of 0- [1-methyl-1- under ice-cooling and stirring. (P-nitrobenzyl oxycarbonyl) ethylhydroxylamine is added. The mixture is adjusted to pH 5 with 1N aqueous sodium hydroxide solution and stirred for 12 hours at room temperature. The reaction mixture is adjusted to pH 7.0 with sodium hydrogen carbonate, and then tetrahydrofuran is distilled off under reduced pressure. The remaining aqueous solution is washed with ether, adjusted to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate. The extract is washed with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is dissolved in ether and poured into 2 volumes of petroleum ether. The resulting powdery precipitate was collected by filtration, then 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2- [1-methyl-1- (P-nitrobenzyl oxycarbonyl) ethyl Oxyimino] acetic acid is obtained.

Reference Example 90

1.445 g of 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2- [1-methyl-1- (P-nitrobenzyl oxycarbonyl) ethyloxyimino] in 15 ml of methylene chloride Acetic acid is dissolved, and ice-cooled and stirred, 686 mg of phosphorus pentachloride is added. The mixture was stirred for 30 minutes under ice-cooling, and then 4.5 ml of hexane was added. The resulting crystalline precipitates were collected by filtration and washed with hexane, then 2- (2-chloroacetamido-4-thiazolyl)-(Z)-[1-methyl-1- (P) having a melting point of 79 to 82 ° C. Nitrobenzyl oxycarbonyl) -ethyloxyimino] acetylchloride hydrochloride is obtained.

Reference Example 91

417 mg of methylcis-3-benzyloxy carboxamido-2-oxoazetidine-4-carboxylate obtained in Reference Example 2 is suspended in 20 ml of ethanol, and 200 mg of 5% palladium-carbon is added. The mixture is stirred for 30 minutes at room temperature in a hydrogen stream and then the catalyst is filtered off. The filtrate is concentrated under reduced pressure and the residue is dissolved in a mixture of 15 ml of water and 15 ml of tetrahydrofuran. Under ice cooling and stirring, 366 mg sodium bicarbonate and 972 mg 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2- [1-methyl-1- (P-nitrobenzyl oxycarbonyl ) -Ethyloxyimino] acetylchloride hydrochloride is added. After stirring for 30 minutes, the reaction mixture is extracted with ethyl acetate-tetrahydrofuran. The extract is washed sequentially with an aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the solid residue was washed with ether-ethyl acetate (5: 1) and then ether to give cis-3- {2- (2-chloroacetamido-4-thiazolyl) as colorless crystals. 2- [1-methyl-1- (P-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido} -4-methoxy carbonyl-2-oxoazetidine (syn-isomer) is obtained. Melting point 198-202 캜 (decomposition).

Reference Example 92

19 g of methyl 2-hydroxyiminoacet acetate is dissolved in 50 ml of methylene chloride, and 19.6 g of sulfylyl chloride are added dropwise under ice-cooling and stirring. The mixture is stirred at room temperature for 3 days and then methylene chloride is distilled off under reduced pressure. The residue is dissolved in 200 ml of ether and washed 7 times with 100 ml of water. The ether layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 20.2 g of light yellow oily methyl 4-chloro-2-hydroxyiminoaceto acetate.

NMR (CDC1 ₃ , ppm): 2.65 (1H, br.s, N-OH), 3.90 (3H, s, COCH ₃ ), 4.57 (2H, s, C1CH ₂ ).

This product is dissolved in 200 ml of a mixture of water and tetrahydrofuran (1: 1), and under ice-cooling, 16.96 g of thiourea and 49.27 g of sodium acetate are added. The mixture is stirred overnight at room temperature. The reaction mixture was adjusted to pH 7.0 with sodium hydrogen carbonate and saturated with sodium chloride, whereupon the organic layer was separated. The aqueous layer is extracted with tetrahydrofuran, and the tetrahydrofuran extract mole and the organic layer are combined, washed twice with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off and the oily residue is crystallized with 100 ml of ether. After standing overnight, the crystals are collected by filtration and washed well with water. The resulting crystals are dissolved in a mixture of ethyl acetate and ethanol (5; 1) and concentrated until a crystalline precipitate is produced. The concentrate was left overnight and the resulting crystalline precipitate was recovered by filtration and dried to give methyl 2- (2-amino-4-thiazolyl)-(Z) -2-hydroxyimino acetate as light yellow granules. Melting point 191-192 캜 (decomposition).

Reference Example 93

Dissolve 4.62 g of methyl 2- (2-amino-4-thiazolyl)-(Z) -2-hydroxyimino acetate in 10 ml N, N-dimethylformamide, then add 3 ml of triethylamine. Then, stirring at −30 ° C., 6.42 g of trityl chloride was added for 1 hour. The mixture is stirred at the same temperature for 1 hour and then further stirred at 15 ° C. for 2 hours. 200 ml of water was added to the reaction mixture, followed by extraction with 200 ml of ethyl acetate. The ethyl acetate extract is washed twice with 200 ml of water and dried over anhydrous sodium sulfate. The solvent is evaporated off. The residue was purified by column chromatography [silica gel: 100 g, eluent: hexane-ethyl acetate (1: 1)] to recrystallize the crystals with ethyl acetate, thereby obtaining a colorless granular methyl 2- (2-tritylamino-4). -Thiazolyl)-(Z) -2-hydroxyiminoacetate is obtained. Melting point 204-205 degreeC

Reference Example 94

To 70.5 ml of N, N-dimethylformamide is added 7.05 g of methyl 2- (2-tritylamino-4-thiazolyl)-(Z) -2-hydroxyimino acetate and 3.3 g of potassium carbonate. Under ice cooling and stirring, 2.12 g of allylbromide is added dropwise for 5 minutes. The mixture is stirred for 4 hours under ice-cooling. 1.65 g of potassium carbonate and 1.06 g of allyl bromide are added to the reaction mixture, and the mixture is further stirred for 4 hours. The reaction mixture is diluted with 150 ml of water and extracted three times with 100 ml of ether. The ether extract is washed twice with 100 ml aqueous sodium chloride solution and dried over anhydrous sodium sulfate.

The solvent was distilled off and the residue was purified by column chromatography [300 g of silica gel, eluent; Hexane-ethyl acetate (1: 1)] and recrystallized with ether-hexane, 7.0 g of methyl 2- (2-tritylamino-4-thiazolyl)-(Z) -2-allyloxyiminoacetate Obtained. Melting point 115 to 116 ° C.

Reference Example 95

Dissolve 6.45 g of methyl2- (2-tritylamino-4-thiazolyl)-(Z) -allyloxyimino acetate in 32 ml of tetrahydrofuran and add 32 ml of 50% formic acid. The mixture is stirred at 60 ° C. for 40 minutes. The reaction mixture is concentrated under reduced pressure, and the solid residue is dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by column chromatography [silica gel: 150 g: eluent: nucleic acid-ethyl acetate (1: 1)]. The solvent was distilled off, and the residue was washed with hexane and a small amount of ether and dried to give methyl 2- (2-amino-4-thiazolyl)-(Z) -2-allyloxy having a melting point of 133 to 134 캜. Mino acetate is obtained.

Reference Example 96

In the same manner as in Reference Example 32, methyl 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-allyloxyimino acetate having a melting point of 114 to 115 ° C is obtained.

Reference Example 97

In the same manner as in Reference Example 33, 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-allyloxyiminoacetic acid having a melting point of 162 ° C (decomposition) is obtained.

Reference Example 98

610 ml of 2- (2-chloroacetamido-4-thiazolyl)-(Z) -allyloxyiminoacetic acid are suspended in 13 ml of methylene chloride, and 502.4 mg of phosphorus pentachloride is added under ice-cooling and stirring. After the mixture is stirred at room temperature for 30 minutes, 100 ml of hexane is added to the reaction mixture. The resulting crystals were collected by filtration and washed with hexane to give 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-allyloxyimino acetylchloride hydrochloride having a melting point of 67 to 70 캜. Obtained.

Elemental analysis: C ₁₀ H ₉ Cl ₂ N ₃ O ₃ S.HCl

Calculated Value: C; 33.81%, H; 2.76%, N; 11.72%

Found: C; 33.87% H; 2.76%, N: 11.79%

Reference Example 99

2 ml of tetrahydrofuran and 2 ml of water dissolve 185.5 ml of methylcis-3-amino-2-oxoazetidine-4-carboxylate in a mixture and, upon ice-cooling and stirring, add 469.9 mg of sodium hydrogencarbonate. Then 600 mg of 2- (2-chloroacetamido-4-thiazolyl)-(Z) -allyloxyiminoacetylchloride hydrochloride are added. The mixture is stirred for 2 hours at room temperature and concentrated under reduced pressure. 20 ml of water was added to the residue, and the insolubles were collected by filtration, washed with aqueous sodium bicarbonate solution, water, hexane, and ether, followed by drying, and then light yellow granular methylcis-3- [2- (2-chloroacetami). Do-4-thiazolyl) -2-allyloxyimino acetamido] -2-oxoazetidine-4-carboxylate (syn-isomer) is obtained. Melting point 270-280 degreeC (decomposition).

Reference Example 100

675 mg cis-3-benzyloxycarboxamido-4-methylsulfonyloxymethyl-2-oxoazetidine obtained in Reference Example 11 was dissolved in 7.8 ml of N, N-dimethylformamide, and 861 mg of lithium chloride was dissolved. The solution is poured into a solution dissolved in 7.8 ml of N, N-dimethylformamide.

The mixture is stirred at 73 ° C. in argon atmosphere for 3 hours. The reaction mixture is cooled, poured into 60 ml of sodium chloride aqueous solution and extracted with ethyl acetate. The extract is washed with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography [silica gel: 50 g: eluent: hexane-ethyl acetate (1: 2)]. The resulting crystals were washed with ether to give cis-3-benzyloxycarboxamido-4-clomethyl-2-oxoazetidine having a melting point of 147 to 149 ° C.

Elemental Analysis: C ₁₂ H ₁₃ ClN ₂ O ₃

Calculated Value: C; 53.64%, H; 4.88%, N; 10.43%

Found: C; 53.49%, H; 4.81%, N; 10.35%

Reference Example 101

376 mg of cis-3-benzyloxycarboxamido-4-chloromethyl-2-oxoazetidine is suspended in 20 ml of methanol and 376 mg of 5% palladium-carbon is added.

The mixture is stirred for 20 minutes at room temperature in a hydrogen atmosphere. Filter off the catalyst and concentrate the filtrate. The solid residue was dissolved in 28 ml of a mixture of tetrahydrofuran and water (1: 1), quenched and stirred, 470 mg of sodium bicarbonate was added, followed by 698 mg of 2- (2-chloroacetamido-4-thia Zolyl) -2-methoxyiminoacetyl chloride hydrochloride (syn isomer) is added. Under ice-cooling, the mixture is stirred for 30 minutes and ethyl acetate is extracted. The aqueous layer is extracted again with a mixture of ethyl acetate and tetrahydrofuran. The extracts are mixed, washed with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The solid residue was washed with ethyl acetate-ether (1: 3) and the colorless crystalline cis-3-2- (2-chloroacetamido-4-thiazolyl) having a melting point of 212 to 217 占 폚 (decomposition). 2-methoxyimino acetamido-4-chloromethyl-2-oxoazetidine (syn isomer) is obtained.

Reference Example 102

When cis-3-benzyloxycarboxamido-4-methylsulfonyloxymethyl-2-oxoazetidine obtained in Reference Example 11 is reacted in the same manner as Reference Example 88, the melting point is 186 to 189 ° C (decomposition). Cis- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methylsulfonyloxymethyl-2-oxoazetidine (syn-isomer) is synthesized do.

Elemental Analysis: C ₁₃ H ₁₅ ClN ₅ O ₇ S ₂

Calculated Value: C; 34.40%, H; 3.55%, N; 15.43%

Found: C; 34.72%, H; 3.63%, N; 15.28%

Reference Example 103

3.28 g of cis-3-benzyloxycarboxamido-4-methylsulfonyloxymethyl-2-oxoazetidine obtained in Reference Example 11 was suspended in 100 ml of ethanol, and 3.28 g of 5% palladium-carbon was suspended. Add. The mixture is stirred for 50 minutes at room temperature in a hydrogen atmosphere. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is dissolved in a mixture of 100 ml of methylene chloride and 15 ml of N, N-dimethyl acetamide, and 6.99 ml of propylene oxide is added with ice cooling and stirring, followed by 2.79 g of 2-methylsulfonyl ethylchloro formate. A solution dissolved in 25 ml of methylene chloride is added. The mixture is stirred at room temperature for 2 hours and methylene chloride is distilled off. To the residue is added a mixture of water and ethyl acetate and tetrahydrofuran (1: 1) and shake the mixture. The organic layer is separated, and the aqueous layer is concentrated and concentrated to dryness. The residue is dissolved in tetrahydrofuran, dried over anhydrous magnesium sulfate and combined with the organic layer described above. The combined mixture is again dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel: 150 g: eluent: ethyl acetate and then ethyl acetate-ethanol (9: 1)] to wash the resulting crystals with ethyl acetate-ether (1: 1). Colorless crystalline cis-3- (2-methylsulfonylethoxy carboxamido) -4-methylsulfonyloxymethyl-2-oxoazetidine at 141 to 142 ° C is obtained.

Elemental analysis: C ₉ H ₁₅ N ₂ O ₈ S ₂

Calculated Value: C; 31.39%, H; 4.68%, N; 8.14%

Found: C; 31.34%, H; 4.76%, N; 8.34%

Reference Example 104

Suspend 1.894 g of cis-3- (2-methylsulfonylethoxy carboxamido) -4-methylsulfonyloxymethyl-2-oxoazetidine and 4.864 g of sodium iodide in 75 ml of methyl ethyl ketone, The suspension is heated under reflux for 3 hours in a nitrogen atmosphere. The reaction mixture is concentrated under reduced pressure, and water, ethyl acetate and aqueous sodium thiosulfate solution are added to the residue. The resulting crystalline precipitates were collected by filtration, washed with water, ethyl acetate and ether in order to give a colorless crystalline cis-3- (2-ethylsulfonylethoxy carboxamido) -4-iodomethyl-2-oxoa. 382 mg of zetidine are obtained. The filtrate and washings are mixed and the organic layer is separated. The aqueous layer is saturated with sodium chloride and extracted with tetrahydrofuran-ethyl acetate (4: 1). When the extract and the organic layer were mixed, distilled off under reduced pressure, and the crystalline residue was washed with ethyl acetate, 1.367 g of the aforementioned 4-iodomethyl-compound having a melting point of 186 to 190 DEG C (decomposition) was obtained.

Elemental Analysis: C ₈ H ₁₃ IN ₂ O ₅ S

Calculated Value: C; 25.54%, H; 3.48%, N; 7.45%

Found: C; 25.64%, H; 3.53%, N; 7.34%

Reference Example 105

To 20 ml of N, N-dimethylformamide was added 1.504 g of cis-3- (2-methylsulfonylethoxycarboxamido) -4-iodinemethyl-2-oxoazetidine and 390 mg of sodium azide and the mixture The mixture is stirred at room temperature for 66 hours and then at 40 ° C. for 24 hours. The reaction mixture is concentrated under reduced pressure, and the residue is purified by column chromatography [silica gel: 100 g, eluent: ethyl acetate: then ethyl acetate-ethanol (9: 1)]. The solvent was then distilled off, and the residue was crystallized with ethyl acetate and filtered. Colorless crystalline cis-3- (2-methylsulfonylethoxy carboxamido) -4-azidomethyl- having a melting point of 158 to 160 ° C. 2-oxoazetidine is obtained.

Reference Example 106

60 ml of ethanol and 6 ml of N, N-dimethylformamide were added 757 mg of cis-3- (2-methylsulfonylethoxy carboxamido) -4-azidomethyl-2-oxoazetidine to the mixture and ice-cooled. And 11.4 ml of 0.5N ethanol sodium hydroxide was added under stirring. After 40 minutes, 5.7 ml of 1N HCl is added and the mixture is concentrated under reduced pressure. 15 ml of water and 15 ml of tetrahydrofuran are added to the residue, followed by ice cooling and stirring, and 874 mg of sodium hydrogen carbonate is added. After adding 1.297 g of 2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetyl chloride hydrochloride (syn-isomer), the mixture is stirred for 40 minutes. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water and aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the crystalline residue was washed with ethyl acetate and ether in order to give a colorless crystal cis-3- [2- (2-chloroacetamido-) having a melting point of 223 to 230 캜 (decomposition). 4-thiazolyl) -2-methoxyiminoacetamido] -4-azidomethyl-2-oxoazetidine (syn isomer) is obtained.

Reference Example 107

Dissolve 5.0 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-2-oxoazetidine obtained in Reference Example 5 in 50 ml of methylene chloride. Then, 3.75 ml of pyridine is added at 0 degreeC under stirring. After dropwise addition of 3.94 g of benzyl chloride, the mixture is stirred at room temperature for 1.5 hours. 100 ml of ice water is added to the reaction mixture, the organic layer is separated, washed with sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography [silica gel: 325 g; Eluent: hexane-ethyl acetate (1: 2)]. The solvent was distilled off, hexane was added, and the crystalline residue was recovered by filtration. Colorless crystal cis-3-benzyloxy carboxamido-4-benzoyloxymethyl-1- (2 having a melting point of 133 to 134 占 폚. , 4-dimethoxybenzyl) -2-oxoazetidine is obtained.

Elemental Analysis: C ₂₈ H ₂₈ N ₂ O ₇

Calculated Value: C; 66.65%, H; 5.59%, N; 5.55%

Found: C; 66.48%, H; 5.49%, N; 5.36%

Reference Example 108

In the same manner as in Reference Example 7, cis-3-benzyloxycarboxamido-4-benzoyloxymethyl-2-oxoazetidine having a melting point of 188 to 189 ° C is synthesized.

Reference Example 109

550 mg of cis-3-benzyloxy carboxamido-3-benzoyloxymethyl-2-oxoazetidine is suspended in 20 ml of ethanol and 550 mg of 5% palladium-carbon is added. The suspension is stirred for 2.5 hours in a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give a colorless crystalline cis-3-amino-4-benzoyloxymethyl-2-oxoazetidine having a melting point of 150 to 151 占 폚.

Reference Example 110

In the same manner as in Reference Example 9, cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyimino acetamido] -4 having a melting point of 210 to 220 ° C. (decomposition) -Benzoyloxymethyl-2-oxoazetidine (syn isomer) is obtained.

Reference Example 111

의 염화메틸렌에 용해 시킨다. 빙냉 및 교반하, 29g의 트리에틸아민을 가한후, 53.5g의 프탈이미도 아세틸클로라이드를 250ml의 염화메틸렌에 녹인 용액을 45분에 걸쳐 적가한다. 혼합물을 실온에서 24시간 동안 교반 시킨후, 물로 세척하고 무수황산마그네슘 상에서 건조시키고 농축시킨다. 고상의 잔류물을 에틸아세테이트-헥산으로 재결정하면, 융점이 105 내지 107℃의 시스-3-프탈이미도-4-(α-메틸스티릴)-1-(4-메톡시페닐)-2-옥소아제티딘이 수득된다.To 250 ml of benzene, 35 g of α-methylcinnamaldehyde and 29.5 g of P-anisidine are added, and the mixture is heated at reflux for 1 hour while the water is removed by boiling distillation together. The solvent is distilled off under reduced pressure and the residue is 1

Is dissolved in methylene chloride. 29 g of triethylamine was added under ice-cooling and stirring, and a solution of 53.5 g of phthalimido acetylchloride in 250 ml of methylene chloride was added dropwise over 45 minutes. The mixture is stirred at rt for 24 h, then washed with water, dried over anhydrous magnesium sulfate and concentrated. When the solid residue is recrystallized from ethyl acetate-hexane, the melting point is cis-3-phthalimido-4- (α-methylstyryl) -1- (4-methoxyphenyl) -2- at 105 to 107 캜. Oxoazetidine is obtained.

Reference Example 112

After dissolving 28 g of cis-3-phthalimido-4- (α-methylstyryl) -1- (4-methoxyphenyl) -2-oxoazetidine in 200 ml of dimethoxyethane, 10.2 g of Methylhydrazine is added. The mixture is stirred at rt for 12 h. The resulting crystalline precipitate is filtered off and the filtrate is concentrated. The residue is dissolved in 200 ml of methylene chloride and then 14.8 g of propylene oxide and 10.62 g of carbobenzoic chloride are added continuously. The mixture is stirred for 1 hour and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel: 300 g, eluent: hexane-ethyl acetate (1: 1 and then 1: 2)] to give cis-3-benzyloxycarboxamido-4- (α-methylsty Reel) -1- (4-methoxyphenyl) -2-oxoazetidine is obtained.

Reference Example 113

Dissolve 75 g of cis-3-benzyloxycarboxamido-4- (α-methylstyryl) -1- (4-methoxyphenyl) -2-oxoazetidine in 750 ml of methylene chloride and remove excess ozone Pass the solution at -78 ° C. Nitrogen gas is passed through to remove excess ozone, and then 11.6 g of dimethyl sulfide is added. The mixture is then stirred for 30 minutes at room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography [silica gel: 400 g: eluent: hexane-ethyl acetate (1: 2 and then 1: 4)] to give a cis-3-benzyloxycarboxamido- having a melting point of 188 to 191 ° C. 4-acetyl-1- (4-methoxyfinyl) -2-oxoazetidine is obtained.

Reference Example 114

1 g of cis-3-benzyloxycarboxamido-4-acetyl-1- (4-methoxytenyl) -2-oxoazetidine is dissolved in a mixture of 50 ml of acetonitrile and 25 ml of water. Cool to −15 ° C., 3 g ammonium cerium (IV) nitrate is added and the mixture is stirred for 10 minutes. In order to terminate the reaction, a saturated aqueous solution of sodium sulfite is dried, and the pH is adjusted to 5-6 with sodium hydrogen carbonate. The acetonitrile is then distilled off under reduced pressure, and the residue is acidified with 3N hydrochloric acid and extracted with chloroform. The aqueous layer is extracted twice with chloroform-ethanol (4: 1). The extracts are mixed, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography [silica gel: 80 g: eluent: hexane-ethyl acetate (1: 2), ethyl acetate and then ethyl acetate-methanol (9: 1)] to give cis-3-benzyloxycarboxamido- 4-acetyl-2-oxoazetidine is obtained.

Reference Example 115

In the same manner as in Reference Example 67, cis-3-2- (2-chloroacetamido-4-thiazolyl) -2-methoxyimino acetamido 4-acetyl-2-oxoazetidine (syn isomer) Are synthesized.

Reference Example 116

In a mixture of 2 ml of tetrahydrofuran and 2 ml of water, 75 mg of cis-3-amino-4-hydroxymethyl-2-oxoazetidine obtained in Reference Example 53 was dissolved, and 168 mg of sodium hydrogen carbonate under ice cooling and stirring. Then, 332 mg of 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-methoxyiminoacetylchloride hydrochloride are added. The mixture is stirred under ice-cooling for 1 hour, and the reaction mixture is neutralized with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate-tetrahydrofuran (2: 1). The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, ethyl acetate-ether (1: 2) was added thereto, and the crystalline residue was recovered by filtration. Colorless crystalline cis-3- [2- (2-chloroacetamido-4 -Thiazolyl) -2-methoxyiminoacetamido] -4-hydroxymethyl-2-oxoazetidine (syn isomer) is obtained. Melting point 238 to 241 ° C (decomposition)

Reference Example 117

172 mg of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyimino acetamido]-in a mixture of 17 ml methylene chloride and 6 ml N, N-dimethylformamide After dissolving 4-hydroxymethyl-2-oxoazetidine (syn isomer), 0.2 ml of pyridine is added. While the mixture is cooled and stirred with a mixture of ice-sodium chloride, 0.12 ml of chloroacetyl chloride is added dropwise. The mixture is stirred for 30 minutes under cooling and the solvent is distilled off. To the residue is added aqueous sodium chloride solution and ethyl acetate and the mixture is shaken well. The organic layer is separated, washed with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is crystallized with ether. When recrystallized from chloroform-methanol, colorless crystal cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] having a melting point of 225 to 227 ° C. (decomposition). 4-chloroacetoxymethyl-2-oxoazetidine (syn isomer) is obtained.

Elemental Analysis: C ₁₄ H ₁₅ Cl ₂ N ₅ O ₆ S

Calculated Value: C; 37.17%, H; 3.34%, N; 15.48%

Found: C; 36.79%, H; 3.37%, N; 15.44%

Reference Example 118

4.45 g cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-phthalimido methyl-2-oxoazetidine obtained in Reference Example 48 was suspended in 320 ml of ethanol. 2.03 ml of hydrazine hydrate is added. The mixture is heated to reflux for 2 hours and cooled. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. 200 ml of methylene chloride is added to the residue and the insolubles are filtered off. The filtrate is handmade, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 84 ml of methylene chloride and 11 ml of a mixture of N, N-dimethylacetamide and, on ice cooling and stirring, 5.88 ml of propylene oxide, followed by 2.35 g of β-methylsulfonylethyl chloroformmate. A solution dissolved in 20 ml of methylene chloride is added dropwise. The mixture is stirred at room temperature for 1 hour, washed with water, aqueous sodium bicarbonate solution, water, diluted hydrochloric acid and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the crystalline residue was washed with ethyl acetate and 2.94 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4- (2-methylsulphate Phenylethoxy carbonylaminomethyl) -2-oxoazetidine is obtained. Melting point 172 to 174 ° C.

Reference Example 119

In the same manner as in Reference Example 50, cis-3-benzyloxycarboxamido-4- (2-methylsulfonylethoxy carbonylaminomethyl) -2-oxoazetidine having a melting point of 149 to 150 ° C is synthesized. .

Elemental analysis: C ₁₆ H ₂₁ N ₃ O ₇ S

Calculated Value: C; 48.11%, H; 5.30%, N; 10.52%

Found: C; 47.99%, H; 5.22%, N; 10.37%

Reference Example 120

In the same manner as in Reference Example 51, cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (2-methylsulfonyl ethoxy Carbonylaminomethyl) -2-oxoazetidine (syn isomer) is obtained. The product decolorizes gradually at 150-170 ° C. and decomposes at 195-199 ° C.

Reference Example 121

1.197 g of cis-3-benzyloxycarboxamido-4- (2-methylsulfonyl ethoxy carbonylaminomethyl) -2-oxoazetidine obtained in Reference Example 119 in 3 ml of N, N-dimethylformamide And 475 mg of dimethyl-t-butylsilyl chloride were dissolved, cooled to 0 ° C., and 0.46 ml of triethylamine was added dropwise. The mixture was stirred for 30 minutes under ice-cooling, followed by addition of water and ethyl acetate. The ethyl acetate layer is taken, washed with dilute hydrochloric acid, aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography [cipica gel: 100 g; Eluent: Hexane-ethyl acetate (1: 2 and then 1: 3)], cis-3-benzyloxycarboxamido-4- (2-methylsulfonyl ethoxy carbonylaminomethyl) -1-dimethyl on foam -t-butylsilyl-2-oxoazetidine is synthesized.

Reference Example 122

Dissolve 514 mg of cis-3-benzyloxycarboxamido-4- (2-methylsulfonyl ethoxy carbonylaminomethyl) -1-dimethyl-t-butylsilyl-2-oxoazetidine in 20 ml of ethanol and Under ice-cooling and stirring, 4.4 ml of ethanol sodium hydroxide (0.5N) is added. The mixture is stirred for 15 minutes under ice-cooling, and 2.2 ml of 1N hydrochloric acid is added to the reaction mixture. The solvent is distilled off under reduced pressure and the residue is distilled off with methylene chloride-tetrahydrofuran. The extract is washed with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and 4 ml of trifluoro acetic anhydride and 2 ml of trifluoro acetic acid are added under ice cooling. The mixture is stirred for 30 minutes and concentrated under reduced pressure. The residue was subjected to column chromatography [silica gel: 40 g; Eluent: Hexane Ethyl Acetate (1: 1 and then 1: 2)], the cis-3-benzyloxycarboxamido-4-trifluoro acetylaminomethyl-2-oxoa having a melting point of 197 to 201 캜. Zetidine is obtained.

By the above reaction, as a by-product, cis-3-benzyloxycarboxamido-4-trifluoro acetylaminomethyl-1-dimethyl-t-butylsilyl-2-oxoa in a yellow crystalline phase (melting point 130 to 135 ° C) Zetidine is obtained.

Reference Example 123

Cis-3-[-2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] having a melting point of 220 to 225 ° C. (decomposition) in the same manner as in Reference Example 67; 4-trifluoro acetylaminomethyl-2-oxoazetidine (syn isomer) is synthesized.

Reference Example 124

525 mg of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoa obtained in Reference Example 119 in a mixture of 25 ml of ethanol and 5 ml of N, N-dimethylformamide Setamido] -4- (2-methylsulfonyl ethoxy carbonylaminomethyl) -2-oxoazetidine (syn isomer) is added followed by 5 ml of ethanol sodium hydroxide (0.5N). The mixture is stirred at room temperature for 20 minutes before 2.5 ml of 1N HCl is added. Ethanol is distilled off under reduced pressure and the residue is dissolved in a mixture of 8 ml of water and 10 ml of tetrahydrofuran. Under ice cooling and stirring, 185 mg of sodium hydrogen carbonate was added, followed by dropwise addition of a solution of 432 mg of P-nitrobenzyl chloropotmate dissolved in 10 ml of tetrahydrofuran over 50 minutes. The mixture is stirred for 20 minutes under ice-cooling, and 10 ml of water and 20 ml of ethyl acetate are added to the reaction mixture. Shaking the mixture well separates the organic layer. The aqueous layer is extracted with ethyl acetate, the ethyl acetate extract and the organic layer are combined, washed with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was crystallized with ethyl acetate and collected by filtration, and cis-3- [2- (2-chloroacetamido-4- thiazolyl) -2-methoxy imino Acetamido] -4- (P-nitrobenzyl oxycarbonylaminomethyl) -2-oxoazetidine (syn isomer) is obtained. Melting point 235-245 캜 (decomposition).

Reference Example 125

In the same manner as in Reference Example 39, the following compound was synthesized.

Methyl cis-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazine carboxamido) -2-phenylacetamido] -2-oxoazetidine-4-carboxyl Rate.

Reference Example 126

In the same manner as in Reference Example 39, 300 mg of D-2- [3- (furan-2- aldimino) -2-oxo-1-imidazolidine carboxamido] -2-phenylacetic acid was 110 mg of methyl cis When reacted with 3-amino-2-oxoazetidine-4-carboxylate, methylcis-3- {D-2- [3- (furan-2- aldimino) -2-oxo-1-imide Dazolidine carboxamido] -2-phenylacetamido} -2-oxoazetidine-4-carboxylate is synthesized.

In the same manner as described above, the following compound is synthesized: methyl cis-3- [D-2- [3- (thiophene-2-aldimino-2-oxo-1-imidazolidine carboxamido]- 2-phenylacetamido] -2-oxoazetidine-4-carboxylate.

Reference Example 127

3-amino compound (prepared from 0.8 g of methylcis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylate in the same manner as in Reference Example 3) was dissolved in 10 ml of tetrahydrofuran 1.2 ml of triethylamine were added under ice-cooling and stirring, and then 1.2 g of 2- (2-chloroacetamido-4-thiazolyl) -2-diethyl phosphonoacetyl chloride was added to 10 ml of tetrahydrofuran. Add the dissolved solution to the solution. The mixture is stirred at room temperature for 2.5 hours and the tetrahydrofuran is distilled off. To the residue, ethyl acetate and water are added and the mixture is shaken well. The organic layer is taken, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography [eluent: chloroform-methanol (95: 5)] to give methylsis-3- [2- (2-chloroacetamido-4-thia). Zolyl) -2-diethyl phosphonoacetamido] -2-oxoazetidine-4-carboxylate is obtained.

Reference Example 128

3-amino compound (prepared from 0.8 g of methyl cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylate in the same manner as Reference Example 3) was dissolved in 20 ml of tetrahydrofuran After cooling, 0.42 ml of triethylamine and 0.56 g of 3-triethylsilyl propionyl chloride are added in sequence under ice-cooling and stirring. The mixture is stirred for 3 hours at room temperature and tetrahydrofuran is distilled off. To the residue is added water and ethyl acetate. After phase separation, the organic layer is washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from chloroform-ether and collected by filtration, and methyl cis-3- (2-triethylsilylethylcarboxamido) -2-oxoazetidine-4-carboxylate having a melting point of 143 to 145 캜. Is obtained.

Reference Example 129

5.01 g of 2,4-dimethoxybenzylamine is dissolved in 100 ml of methylene chloride, followed by addition of 4.2 g of trans-cinnamaldehyde and 30 g of anhydrous magnesium sulfate. The mixture is stirred for 3.5 hours at room temperature and filtered. To the filtrate, 8.4 ml of triethylamine are added under ice cooling and stirring, and a solution of 7.0 g of phthalimidoacetyl chloride in 50 ml of methylene chloride is added dropwise over 30 minutes. The mixture is stirred for 2.5 hours at room temperature, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. 50 ml of chloroform is added to the concentrate and the precipitate is filtered off. The filtrate is concentrated and the residue is passed through a silica gel column (30 g). Concentrate the eluate and recrystallize the solid residue with ethyl acetate to give cis-3-phthalimido-4- (E) -styryl-1- (2,4-dimethoxybenzyl) with a melting point of 173 to 177 ° C. 2-oxoazetidine is obtained.

Reference Example 130

5 g of cis-3-phthalimido-4- (E) -styryl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine was dissolved in 150 ml of tetrahydrofuran, followed by 2.5 g. 10% palladium-carbon is added. The mixture is stirred for 30 minutes in a hydrogen atmosphere. The catalyst is considered and the filtrate is concentrated under reduced pressure. The residue was crystallized with ether and recovered by filtration, and the cis-3-phthalimido-4- (2-phenylethyl) -1- (2,4-dimethoxybenzyl) -2- having a melting point of 148 to 150 ° C. 4.8 g of oxoazetidine is obtained.

Reference Example 131

4.1 g of cis-3-phthalimido-4- (2-phenylethyl) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine was suspended in 35 ml of dimethoxyethane, followed by 1.4 ml of methylhydrazine are added. The mixture is left for 3 days at room temperature. The resulting precipitate is filtered off and the filtrate is concentrated. The residue is dissolved in ethyl acetate and extracted three times with dilute hydrochloric acid. The extract is adjusted to pH 7-8 with sodium bicarbonate and extracted three times with chloroform. The extract is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is dissolved in 50 ml of methylene chloride, then 20 ml of propylene oxide is added and 3 ml of carbobenzoic chloride is added dropwise. The mixture is stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography, eluting with chloroform-ethyl acetate (1: 1). The solvent was distilled off, the residue was crystallized with ether and collected by filtration, with a melting point of cis-3-benzyloxycarboxamido-4- (2-phenylethyl) -1- (2,4- Dimethoxybenzyl) -2-oxoazetidine is obtained.

Reference Example 132

In the same manner as in Reference Example 2, cis-3-benzyloxycarcopymido-4- (2-phenylethyl) -2-oxoazetidine having a melting point of 173 to 175 캜 is synthesized.

Reference Example 133

In the same manner as in Reference Example 67, cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyimino acetamido] -4- (2-phenylethyl) -2- Oxoazetidine (syn isomer) is obtained.

Reference Example 134

9.6 g of methyl 2-methoxyimino aceto acetate is dissolved in 40 ml of chloroform, and a solution of 9.1 g of bromine in 10 ml of chloroform is added dropwise while stirring at 40 ° C. The mixture is stirred for 20 minutes and poured into ice water. The organic layer is taken, washed with saturated aqueous sodium hydrogen carbonate solution and water and dried over anhydrous sodium sulfate. When the solvent is distilled off under reduced pressure, 13.12 g of oily methyl 4-bromo-2-methoxyimino aceto acetate is obtained. 10.74 g of this oil and 4.4 g of methylthio carbamate are added to 40 ml of ethanol and the mixture is heated at reflux for 1.5 h. Ethanol is distilled off and the residue is dissolved in chloroform, washed with water and dried over anhydrous sodium sulfate. When the solvent is distilled off under reduced pressure, crystalline methyl 2- (2-hydroxy-4-thiazolyl)-(Z) -2-methoxyimino acetate is obtained. Melting Point 97 ~ 98 ℃

Reference Example 135

1.0 g of methyl 2- (2-hydroxy-4-thiazolyl)-(Z) -2-methoxyiminoacetate is dissolved in 3 ml of ethanol, and an aqueous solution of potassium hydroxide (1.3 g) is added dropwise under ice-cooling. The mixture is left for 4 hours, adjusted to pH 2-3 with 1N hydrochloric acid and extracted three times with n-butanol. The extracts are mixed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. A light brown powdery 2- (2-hydroxy-4-thiazolyl)-(Z) -2-methoxyimino acetic acid having a melting point of 143 to 144 DEG C (decomposition) is obtained.

Reference Example 136

In the same manner as in Reference Example 34, cis-3- [2- (2-hydroxy-4-thiazolyl) -2-methoxyimino acetamido] -4-meth having a melting point of 202 to 204 캜 (decomposition). Oxycarbonyl-2-oxoazetidine (syn isomer) is synthesized.

Reference Example 137

Dissolve 2.14 g of methyl cis-3-benzyloxycarcopymido-1- (2.4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylate obtained in Reference Example 1 in 150 ml of methanol, Under ice-cooling and stirring, 25 ml of potassium hydrogen carbonate (0.83 g) solution is added. The mixture is stirred at room temperature for 6.5 hours, and methanol is distilled off under reduced pressure. Water is added to the residue, the mixture is washed with ethyl acetate-ether and acidified with 1N hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried to give 1.95 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid. Obtained. Melting point 189-191 ° C.

Reference Example 138

After dissolving 4.1 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid in 80 ml of anhydrous tetrahydrofuran, 4 ml of Oxalyl chloride is added. The mixture is heated to reflux for 30 minutes and the solvent is distilled off. The residue is washed with hexane and dissolved in 80 ml of methylene chloride. Under ice-cooling, 4 ml of ethanol are added, and the mixture is stirred for 20 minutes. The solvent is distilled off. The residue was crystallized with ether, filtered and recrystallized with ethanol to give ethyl cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxyl as colorless crystals. The rate is obtained. Melting point 117 to 118 ° C.

Reference Example 139

In the same manner as in Reference Example 2, ethyl cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylate having a melting point of 134 to 135 ° C is synthesized.

Reference Example 140

In the same manner as in Reference Example 3, ethyl cis-3-amino-2-oxoazetidine-4-carboxylate having a melting point of 105 to 106 ° C (decomposition) is synthesized.

Reference Example 141

In the same manner as in Reference Example 4, the following compound was synthesized: ethyl cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyimino acetamido] -2-jade Pediazezetidine-4-carboxylate.

Reference Example 142

2 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl-2-oxoazetidine-4-carboxylic acid obtained in Reference Example 137 was dissolved in 60 ml of anhydrous tetrahydroputane. 2 ml of oxalyl chloride are then added, the mixture is heated to reflux for 30 minutes, the solvent is distilled off, the residue is washed with hexane and dissolved in 40 ml of anhydrous tetrahydrofuran. ), And the mixture is stirred for 30 minutes The resulting crystalline precipitate is recovered by filtration, washed with ether and methanol in turn, recrystallized with chloroform-methanol and cis-3-benzyloxycar having a melting point of 255 to 257 ° C. Copyomido-1- (2,4-dimethoxybenzyl) -4-phenylcarbamoyl-2-oxoazetidine is obtained.

Reference Example 143

In the same manner as in Reference Example 2, cis-3-benzyloxycarboxamido-4-phenylcarbamoyl-2-oxoazetidine having a melting point of 235 to 238 ° C (decomposition) is obtained.

Reference Example 144

In the same manner as in Reference Example 3, cis-3-amino-4-phenylcarbamoyl-2-oxoazetidine having a melting point of 152 to 154 占 폚 (decomposition) is synthesized.

Reference Example 145

In the same manner as in Reference Example 4, cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyimino acetamido] -4-phenylcarbamoyl-2-oxoa Zetidine (syn isomer) is obtained.

NMR (d ₆ -DMSO, ppm): 3.53 (3H, s, NOCH ₃ ), 4.3 (2H, s, ClCH ₂ ), 4.48 (1H, d, J = 5Hz, C ₄ -H), 5.57 (1H, D, D, J = 5, 9 Hz, C ₄ -H), 5. 57 (1H, d, d, J = 5, 9 Hz, C ₃ -H).

Reference Example 146

Dissolve 2.502 g of methyl cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylate obtained in Reference Example 2 in 160 ml of methanol, and 50 ml of potassium carbonate (1.242) under ice cooling and stirring. g) Aqueous solution is added. The mixture is stirred at room temperature for 70 minutes, then, ice-cooled and stirred, 9 ml of 1N hydrochloric acid is added. Methanol is distilled off under reduced pressure, chromatographed and freeze-dried to give a colorless powder of cis-3-benzyloxycarcopymido-2-oxoazetidine-4-carboxylic acid potassium.

Reference Example 147

Dissolve 717 mg of cis-3-benzyloxy carboxamido-2-oxoazetidine-4-carboxylic acid potassium in 5 ml of N, N-dimethyl formamide, and 0.25 ml of ethyl bromoacetate under ice-cooling and stirring. Add. The mixture was stirred at room temperature for 1 hour, and then 50 ml of water was added and extracted with ethyl acetate. The extract is washed with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and then ether was added and the solid residue collected by filtration. Colorless crystalline cis-3-benzyloxycarcopymido-4-ethoxycarbonyl methyl having a melting point of 109 to 111 占 폚. Oxycarbonyl-2-oxoazetidine is obtained.

Reference Example 148

In the same manner as in Reference Example 67, cis-3- [2- (2-chloroacetamado-4-thiazolyl) -2-methoxyimino acetamido] -4-ethoxycarbonyl methyloxycarbonyl- 2-oxoazetidine (syn isomer) is obtained. Melting point 226 to 231 ° C. (decomposition).

Reference Example 149

Methyl trans-3-benzyloxycarcopymido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylate obtained in Reference Example 26 is added to the ether and the mixture is cooled. If left to stand, the crystals will gradually precipitate. The crystals are collected by filtration and washed with ether to give colorless crystals having a melting point of 65 to 68 ° C.

Elemental analysis: C ₂₂ H ₂₄ N ₂ O ₇

Calculated Value: C; 61.67%, H; 5.65%, N; 6.54%

Found: C; 61.84%, H; 5.48%, N; 6.36%

The above product was reduced by sodium borohydride in the same manner as in Reference Example 5, and then purified by silica gel column chromatography [eluent: hexane-ethyl acetate (1: 4)] to give a colorless oily trans-3-benzyloxycarb. Copyomido-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-2-oxoazetidine is obtained.

Reference Example 150

Dissolve 5.8 g of trans-3-benzyloxycarcopymido-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-2-oxoazetidine in 50 ml of methylene chloride, and ice-cool and stir 2.29 g of pyridine and then 1.54 ml of acetylchloride are added. The mixture is stirred at room temperature for 1 hour, and the solvent is distilled off under reduced pressure. The residue is dissolved in ethyl acetate, washed with 3N hydrochloric acid, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in 300 ml of acetonitrile and added dropwise with an aqueous solution containing 5.87 g of potassium persulfate and 3.7 g of dipotassium hydrogen phosphate under reflux while heating. After completion of the dropwise addition, the mixture is heated at reflux for 1 hour. Acetonitrile is distilled off under reduced pressure, and the remaining aqueous solution is extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel: 140 g, eluent: hexane-ethyl acetate (1: 2)] to give trans-3-benzyloxycarboxamido-4-acetoxymethyl-2-oxoazetidine. Obtained. Melting point 119-121 ° C

Reference Example 151

In the same manner as in Reference Example 67, trans-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-acetoxymethyl-2-oxoazeti Dean (syn isomer) is obtained. Melting point 177 to 190 ° C (decomposition)

Reference Example 152

In 50 ml of pyridine, 18.3 g of trans-3-benzyloxycarcopymido-1- (2,4-dimethoxybenzyl) -4-higeshimethyl-2-oxoazetidine is dissolved and under ice cooling, 5.76 g of methinesulfonylchloride are added. The mixture is stirred at room temperature for 1 hour. The reaction mixture was added to ethyl acetate, and the mixture was washed with 6N hydrochloric acid, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue is dissolved in 400 ml of methylethylcatone and then 34.25 g of sodium iodide is added. The mixture is heated to reflux for 2.5 hours and concentrated under reduced pressure. The residue is dissolved in ether acetate and the solution is washed with saturated aqueous sodium bisulfate solution and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. An oily trans-3-benzyloxycarboxamido-4-iodomethyl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine is obtained.

Reference Example 153

In the same manner as in Reference Example 63, trans-3-benzyloxycarcopymido-1- (2,4-dimethoxybenzyl) -4-methyl-2-oxoazetidine is synthesized. Since this compound is not crystallized, column chromatography [silica gel: 350 g; Eluent: hexane-ethyl acetate (2: 1 and then 1: 2)].

Reference Example 154

In the same manner as in Reference Example 66, trans-3-benzyloxycarcopymido-4-methyl-2-oxoazetidine is synthesized. Melting point 109-111 ° C

Reference Example 155

In the same manner as in Reference Example 67, trans-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyimino acetamido] -4-methyl-2-oxoazetidine ( syn isomers) are synthesized. Melting Point 240 ~ 248 ℃ (Decomposition)

Reference Example 156

After dissolving 140 mg of cis-3-benzyloxycarcopymido-4-methoxycarbonyl-2-oxoazetidine in 1.4 ml of anhydrous tetrahydrofuran, 0.1 ml of 40% methylamine solution and 1 drop of acetic acid Add. The mixture was allowed to stand for 4 hours under cooling (5 ° C.), and the resulting crystalline precipitate was recovered by filtration and washed with ether to give cis-3-benzyloxycarboxomido-4-methylcarbamoyl-2-oxoazetidine. It is obtained, which is recrystallized from ethyl acetate-methanol. Melting point 207-208 ° C

Reference Example 157

After dissolving 831 mg of cis-3-benzyloxycarboxamido-4-methylcarbamoyl-2-oxoazetidine in a mixture of 50 ml of tetrahydrofuran and 50 ml of methanol, 830 mg of 5% palladium-carbon was dissolved. Add. The mixture is stirred for 1 hour in a hydrogen atmosphere. The catalyst is then filtered off and the filtrate is concentrated under reduced pressure to give 410 mg of a colorless powder of cis-3-amino-4-methylcarbamoyl-2-oxoazetidine.

This product (320 mg) is dissolved in a mixture of 6 ml of water and 6 ml of tetrahydrofuran, and then 500 mg of sodium carbohydrate is added. Under ice-cooling and stirring, 960 mg of 2- (2-chloroacetamido-4-thiazolyl) -2- (Z) -methoxyiminoacetyl chloride hydrochloride are added and the mixture is stirred for 1 hour. Tetrahydrofuran is distilled off and the remaining mixture is filtered. The resulting powder was washed with sodium hydrogen carbonate, water, ethanol and ether in order, cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyimino acetamido] -4 -Methylcarbamoyl-2-oxoazetidine (syn isomer) is obtained.

Reference Example 158

Repeating the same procedure as in Reference Example 91 using methyltrans-3-benzyloxycarcopymido-2-oxoazetidine-4-carboxylate in place of the corresponding cis compound, the trans-3- {2- (2-chloro acetamido-4-thiazolyl) -2- [1-methyl-1- (P-nitrobenzyloxy carbonyl) ethyloxyimino] acetamido} -4-methoxycarbonyl-2- Oxoazetidine (syn isomer) is obtained. Melting Point 110-120 ℃ (Decomposition)

Reference Example 159

In the same manner as in Reference Example 81, the following compound was synthesized: N- (1-methoxycarbonyl-1-methylethoxy) phthalimide. Melting point 106-107 ° C

Reference Example 160

In the same manner as in Reference Example 82, the following compound was synthesized: 0- (1-methoxycarbonyl-1-methylethyl) hydroxylamine.

Reference Example 161

In the same manner as in Reference Example 83, the following compound was synthesized: 2- (2-chloroacetamido-4-thiazolyl) -2- (1-methoxycarbonyl-1-methylethoxyimino) acetic acid.

Reference Example 162

In the same manner as in Reference Example 84, 2- (2-chloroacetamido-4-thiazolyl) -2- (1-methoxycarbonyl-1-methylethoxyimino) acetylchloride hydrochloride is synthesized. Melting point 105-115 ° C

Reference Example 163

In the same manner as in Reference Example 85, cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2- (1-methoxycarbonyl-1-methylethoxyimino) acetamido] 4-methoxycarbonyl-2-oxoazetidine (syn isomer) is synthesized. Melting Point 212-214 ° C (Decomposition)

Reference Example 164

820 mg of 2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (2-trimethylsilylethoxycarbonyl) ethoxyimino] acetic acid was dissolved in 25 ml of methylene chloride. 221 mg of triethylamine, and then 380 mg of phosphorus pentachloride are added under ice-cooling. The mixture is stirred on ice for 15 minutes, then at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in 5 ml of tetrahydrofuran to prepare a solution containing an acid chloride.

On the other hand, 219 mg of cis-3-amino-4-methoxycarbonyl-2-oxoasedidine is dissolved in a mixture of 5 ml of tetrahydrofuran and 10 ml of water, and then 638 mg of sodium hydrogencarbonate is added under ice cooling. To this solution is added dropwise the above acid chloride solution with stirring. The mixture is stirred for 15 minutes under ice-cooling, then stirred at room temperature for 1 hour, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off, and the mixture was diluted with cis-3- {2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (2-trimethylsilyl Oxycarbonyl) -ethoxyimino] acetamido} -4-methoxycarbonyl-2-oxoazetidine (syn isomer) is obtained.

Reference Example 165

After dissolving 1.5 g of methyl cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylate obtained in Reference Example 2 in 20 ml of tetrahydrofuran, 10 ml of 1M aqueous ammonium chloride solution was added thereto. do. Under stirring at room temperature, 0.5 ml of ammonia water (25-28%) is added, and the mixture is stirred for 3 hours, followed by further 2 ml of ammonia water. The mixture is stirred for 16 hours. Tetrahydrofuran is distilled off under reduced pressure, and the resulting crystalline precipitates are collected by filtration, washed with water and ether in order and dried, and cis-3-benzyloxycarboxamido-4-carbamoyl-2-oxoazeti Dean is obtained. Melting Point 236-237 ° C (Decomposition)

In the same manner as above, the corresponding trans-compound is obtained.

Reference Example 166

304 mg of cis-3-benzyloxycarboxamido-4-carbamoyl-2-oxoazetidine is suspended in 15 ml of ethanol, followed by addition of 304 mg of 5% palladium-carbon. The mixture is stirred for 1.5 hours at room temperature in a hydrogen atmosphere. After filtering off the catalyst, the filtrate is concentrated by concentration. The residue is dissolved in a mixture of 6 ml of tetrahydrofuran and 6 ml of water and under ice cooling, 534 mg of sodium hydrogen carbonate is added. To this solution 686 mg of 2- (2-chloroacetamido-4-thiazolyl)-(z) -2- [1-methyl-1- (P-nitrobenzyloxycarbonyl) ethyloxy was obtained in Reference Example 90. Mino] acetylchloride hydrochloride is added. The mixture is stirred for 15 minutes under ice-cooling at room temperature. Then, 200 ml of ethyl acetate is added and extracted. The organic layer was washed twice with 0.1 N aqueous sodium hydroxide solution and then with aqueous sodium chloride solution once, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then foamed cis-3- {2- (2-chloroacetamido-4 -Thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido} -4-carbamoyl-2-oxoazetidine (syn isomer) is obtained do. Melting point 144-147 캜

In the same manner as above, the corresponding trans-compound is obtained.

Reference Example 167

4 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-2-oxoazetidine obtained in Reference Example 5 was dissolved in 80 ml of methylene chloride, Under ice-cooling, 0.9 ml of chlorosulfonyl isocyanate is added, and then the mixture is stirred for 30 minutes. An equivalent amount of the above chlorosulfonyl isocyanate is added and the mixture is further stirred for 10 minutes. The reaction mixture is added dropwise to 60 ml of sodium sulfite (2.8 g) solution with ice cooling and stirring. The mixture is stirred at room temperature for 1 hour to precipitate crystals. The crystals are dissolved in an additional methylene chloride, then the methylene chloride layer is taken, washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is distilled off and ether is added to the residue. The resulting crystals were collected by filtration to give 3.3 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-carbamoyloxymethyl-2-oxoazetidine .

The above product is added to a mixture of 75 ml of acetonitrile and 37.5 ml of water, followed by 6.5 g of potassium persulfate and 3.9 g of potassium dihydrogen phosphate. The mixture is stirred for 1 hour under heating to 95 ° C. in argon stream. After cooling, ethyl acetate is added and the organic layer is taken, washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is distilled off and ether is added to the residue. Insoluble matters were collected by filtration and subjected to silica gel column chromatography [silica gel: 90 g; Eluent: chloroform-methanol-ethyl acetate (85: 10: 5)] to give cis-3-benzyloxycarboxamido-4-carbamoyloxymethyl-2-oxoazetidine as colorless crystals. . Melting point 205-207 캜.

Reference Example 168

In a mixture of 30 ml of tetrahydrofuran and 30 ml of water, 3 g of methyltrans-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylate obtained in Reference Example 27 was dissolved, and cooled on ice, 6 ml ( 1M) aqueous ammonium chloride solution, then 4 ml of 25-28% aqueous ammonia. The mixture is stirred for 3 hours at room temperature. Tetrahydrofuran is distilled off under reduced pressure, and sodium chloride is added to the remaining aqueous solution, followed by extraction twice with chloroform-ethanol (3: 1). The extracts are mixed, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [silica gel: 180 g: eluent: ethyl acetate, then ethyl acetate-methanol (8: 1)] to obtain trans-3-benzyloxycarboxamido-4 at 179 to 184 DEG C. -Carbamoyl-2-oxoazetidine is obtained.

Reference Example 169

After dissolving 31.0 g of freshly distilled methacrolein to 300 ml of methylene chloride, 36.9 g of 2,4-dimethoxybenzylamine is added. 100 g of anhydrous sodium sulfate and 440 mg of p-toluenesulfonic acid monohydrate are added to this solution, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in 300 ml of methylene chloride and, on ice cooling and stirring, a solution of 24.5 g of triethylamine in 100 ml of methylene chloride is added dropwise. Then, a solution of 49.4 g of phthalimido acetyl chloride in 300 ml of methylene chloride was added dropwise over 1 hour. The mixture is stirred overnight at room temperature. The reaction mixture is filtered and the insolubles are washed with methylene chloride. The filtrate and washings are combined and concentrated to 0.5 l under reduced pressure. The concentrate was washed with 200 ml of 1N hydrochloric acid, 200 ml of water, 300 ml of 2% sodium hydrogen carbonate solution (twice) and 200 ml of water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column [silica gel: 400 g; Eluent: hexane-ethyl acetate (1: 1)], 55.8 g of cis-3-phthalimido-4-isopropenyl-1- (2,4-dimethoxybenzyl) -2 as a crude product Oxoazetidine is obtained.

This product is dissolved in 500 ml of methanol and then 25 g of 5% palladium-carbon is added. 870 cc of hydrogen are absorbed by stirring the solution for 7 hours in a hydrogen atmosphere. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed three times with 100 ml of 1N hydrochloric acid and once with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to give 47 g of residue. This residue is dissolved in 700 ml of ethanol and then 47 g of 5% palladium-carbon is added. 1900 cc of hydrogen is absorbed by stirring the mixture in a hydrogen atmosphere for 24 hours. The reaction mixture is filtered and the filtrate is concentrated. The residue was subjected to column chromatography [silica gel: 400 g; Eluent: hexane-ethyl acetate (1: 1)], the solvent was distilled off, and ethanol was added thereto. The resulting crystalline precipitates were collected by filtration to yield 8.6 g of cis-3-phthalimido-4-isopropyl-1- (2, 4-dimethoxybenzyl) -2-oxoazetidine. The mother liquor is concentrated to dissolve the residue in 450 ml of ethanol.

Reference Example 170

Dissolve 8.5 g of cis-3-pralimido-4-isopropyl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine in 170 ml of dimethoxyethane and 2.1 ml under ice-cooling and stirring Methyl hydrazine is added dropwise. The mixture is stirred at room temperature for 4 hours and then at 35-40 ° C. for 2 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The crystals previously collected by filtration are added to the residue, then 120 ml of dichloroethanol are added and the mixture is stirred at 60 to 70 ° C. for 3 hours. After cooling, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and extracted with 50 ml and 20 ml each of 1N hydrochloric acid and the extract is washed with ether. Adding 8.4 g of sodium bicarbonate causes the oil to precipitate out. The oil is extracted with chloroform, washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, the residue is dissolved in 10 ml of methylene chloride and 30 ml of propylene oxide is added. Under ice-cooling and stirring, a solution of 3.55 g of carbobenzoxychloride dissolved in 10 ml of methylene chloride was added dropwise to separate the crystals. After adding 70 ml of propylene oxide and 30 ml of methylene chloride, the mixture is stirred at room temperature, and the crystals described above are gradually dissolved for 4 hours to obtain a clear solution. Then the solvent was distilled off and the residue was subjected to column chromatography [silica gel: 250 g;

Eluent: hexane-ethyl acetate (1: 1)] and crystallized with ether, 4.7 g of cis-3-benzyloxycarboxamido-4-isopropyl-1- (2, 4-dimethoxybenzyl) -2-oxoazetidine is obtained.

Reference Example 171

2.06 g cis-3-benzyloxycarboxamido-4-isopropyl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine, 1.89 g in a mixture of 50 ml acetonitrile and 25 ml water Potassium persulfate and 1.13 g of potassium dihydrogen phosphate are added and the mixture is refluxed at 95 ° C. for 2 hours with stirring. After cooling, acetonitrile was distilled off under reduced pressure, 50 ml of water was added, and the remaining aqueous solution was extracted with 200 ml of ethyl acetate. The extract was washed once with 100 ml of 20% sodium hydrogen carbonate twice with an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the residue is warmed a little with 50 ml of benzene and then cooled. The insolubles were collected by filtration and washed with benzene and a small amount of ether in order to obtain 1.1 g of cis-3-benzyloxycarboxamido-4-isopropyl-2-oxoazetidine with a melting point of 184 to 185 ° C. do.

Reference Example 172

1.0 g of cis-3-benzyloxycarboxamido-4-isopropyl-2-oxoazetidine is suspended in 30 ml of ethanol, and then 1.0 g of 5% palladium-carbon is added and the suspension is stirred for 30 minutes in a hydrogen atmosphere. Stir. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 430 mg of cis-3-amino-4-isopropyl-2-oxoazetidine in crystalline form having a melting point of 91 to 93 占 폚.

Reference Example 173

After dissolving 3.7 g of p-anisidine in 100 ml of methylene chloride, 4.2 g of trans-cinnaaldehyde and 300 mg of anhydrous magnesium sulfate are added and the mixture is stirred at room temperature for 2 hours. The reaction mixture is filtered and washed with 60 ml of dichloromethane. The filtrate and washings were combined, 8.4 ml of triethylamine was added under ice cooling and stirring, and a solution of 7 g of phthalimidoacetylchloride in 50 ml of methylene chloride was added dropwise. The mixture is stirred at room temperature for 1.5 hours and the reaction mixture is washed with water and aqueous sodium chloride solution in that order. After methylene chloride was distilled off under reduced pressure, 50 ml of chloroform was added to the residue. The insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue was recrystallized from ethyl acetate in 25 ml and filtered, and the cis-3-phthalimido-4- (E) -styryl-1- (p-methoxyphenyl) -2-jade having a melting point of 202 to 203 캜. Sodazetidine is obtained.

Reference Example 174

Dissolve 1 g of cis-3-pralimido-4- (E) -spiryl-1- (p-methoxyphenyl) -2-oxoazetidine in 25 ml of tetrahydrofuran, -5 ° C to- While stirring at 10 DEG C, a solution of ammonium cerium (IV) nitrate (3 g) in 10 ml water is added dropwise over 5 minutes. The mixture is then stirred for 20 minutes at -5 ° C to 0 ° C. Tetrahydrofuran is distilled off under reduced pressure and the residue is shaken with ethyl acetate and water. The ethyl acetate layer is taken, washed with an aqueous sodium sulfite solution and an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography [eluent: chloroform-ethyl acetate (7: 3)] and crystallized with ethyl acetate-ether to obtain a cis-3-phthalimido having a melting point of 168 to 170 ° C. 4- (E) -thryl-2-oxoazetidine is obtained.

Reference Example 175

Dissolve 546 mg of cis-3-phthalimido-4- (E) -stryl-2-oxoazetidine in 6 ml of NN-dimethylformamide and, under ice-cooling and stirring, add 0.36 ml of triethylamine and 323 mg. t-butyldimethylsilyl chloride is added. The mixture is stirred for 30 minutes, then 4 hours at room temperature, then the reaction mixture is shaken with ethyl acetate and water. The ethyl acetate layer is taken, washed twice with water and once with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentration under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform) to crystallize with ether, cis-3-phthalimido-4- (E) -stri-1- having a melting point of 167 to 168 ℃ (t-butyldimethylsilyl) -2-oxoazetidine is obtained.

Reference Example 176

440 mg of cis-3-phthalimido-4- (E) -styryl-1- (t-butyldimethylsilyl) -2-oxoazetidine is suspended in 5 ml of dimethoxyethane and 0.26 ml of methylhydrazine After the addition of the mixture, the mixture was stirred at room temperature for 30 minutes. The solvent is distilled off under reduced pressure, and 5 ml of methylene chloride is added to the residue to dissolve and left overnight. The precipitate is filtered off and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: chloroformethyl acetate (6: 4)] to give cis-3-amino-4- (E) -styryl-1- (t-butyldimethylsilyl)-in oil phase. 2-oxoazetidine is obtained. This oil was dissolved in 10 ml of tetrahydrofuran, 0.2 ml of 2- (chloroacetamido-4-thiazolyl) -2-methoxyiminoacetyl chloride hydrochloride after 0.2 ml of triethylamine was added with ice cooling and stirring. Add. The mixture is stirred for 10 minutes under ice cooling and then for 30 minutes at room temperature, then the reaction mixture is shaken with ethyl acetate and water. The ethyl acetate layer is taken, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: chloroform-ethyl acetate (7: 3)] to crystallize with ether, and then was dissolved (decomposed) at 228 to 231 DEG C. 2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido-4- (E) styryl-1- (t-butyldimethylsilyl) -2-oxoazetidine (syn isomer) Is obtained.

Reference Example 177

Cool 50 ml of anhydrous tetrahydrofuran to −78 ° C. in a nitrogen stream under stirring, and then add 20 ml of a 15% n-butyliridium solution in n-hexane. After 3.66 ml of diisopropylamine is added dropwise, the mixture is stirred at -78 ° C for 15 minutes. A solution of 3.1 g of 2, 2-dimethyl-1-aza-3-oxabicyclo [4, 2, 0] octan-8-one in 15 ml of anhydrous terrahydrfuran was added dropwise and the mixture was stirred at 78 deg. Stir for time. Then a solution dissolved in 15 ml of anhydrous tetrahydrofuran of 4.34 g of toluenesulfomilamimerol is added dropwise and the mixture is stirred at -50 ° C to -60 ° C for 1.5 hours. To this mixture is added dropwise 5.1 ml of tremethylsilyl chloride and the reaction mixture is heated at reflux for 5 hours. After cooling, the insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue is shaken with water and ethyl acetate and the ethyl acetate layer is separated, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then, the solvent was distilled off and the residue was purified by silica gel column chromatography, and the mixing ratio of cis- and trans-isomer 1: 4, 2, 2-dimethyl-7-azido-1-aza-3-oxabi Cyclo [4, 2, 0] -octane-8-one is obtained.

Selective crystallization of the mixture from diisopropyl ether yields a crystalline trans-compound having a melting point of 78 to 80 ° C.

Reference Example 178

Dissolve 330 mg of trans-2, 2-dimethyl-7-azido-1-aza-3-oxabicyclo [4, 2, 0] octan-8-one in 30 ml of acetone, and ice-cool and stir to 3.3. Add Jones (8N solution) Jones reagent. After the mixture was stirred for 2.5 hours, 5 ml of isopropyl alcohol was added and the mixture was stirred for another 10 minutes. Insolubles are filtered off with celite and the filtrate is concentrated under reduced pressure. The residue is shaken with tetrahydrofuran and a small amount of saturated aqueous sodium chloride solution. The tetrahydrofuran layers are combined and dried over anhydrous sodium sulfate, and then the mixture is left by adding a solution of diazomethane in ether. The solvent is then distilled off and the residue is shaken with water and ethyl acetate. The ethyl acetate layer is taken, washed with aqueous sodium hydrogen carbonate solution and water and dried over anhydrous sodium sulfate. Concentration under reduced pressure to purify the residue by silica gel column chromatography yields trans-3-azido-4-methoxycarbonylmethyl-2-oxoazetidine.

NMR (CDCl ₃ , ppm): 2.76 (2H. D. J = 6 Hz. C ₄ -CH ₂ ). 3.70 (3H. S, CO ₂ CH ₃ ). 3.83 (1 H, m. C ₄ -H). 4.36 (1 H, C ₃ -H). 6.75 (1H. S. N ₁ -H).

In the same way, starting with a 1: 4 cis-trans mixture, a 2-oxoazetidine compound is obtained in the form of a 1: 4 cis-trans mixture.

NMR (CDCl ₃ , ppm): 4.83 (cis-C ₃ -H)

Reference Example 179

In a mixture of 20 ml of tetrahydrofuran and 10 ml of water, 800 mg of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid obtained in Reference Example 68 was dissolved. Under ice-cooling, 280 mg of sodium bicarbonate was added, 303 mg of 0-methylhydroxylamine hydrochloride and 638 mg of 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride were added, and then the mixture was stirred at room temperature. Let's do it. After 3 hours, sodium chloride is added and the reaction mixture is extracted with ethyl acetate-ethanol (10: 1). The extract is washed with 3N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and dried over anhydrous sodium sulfate. When the solvent is distilled off under reduced pressure, cis-3-benzyloxycarboxamido-4-methoxyaminocarbonyl-2-oxoazetidine is obtained. Melting Point 212-216 ° C (Decomposition)

Reference Example 180

5.1 g cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-iodinemethine-2-oxoazetidine, 2.6, obtained in Reference Example 62 in 8 ml of anhydrous dimethyl sulfoxide, 2.6 g potassium cyanide and 50 mg 18-crown-6 are added. The mixture is stirred for 2 days at room temperature and then stirred for 3 hours at 50 ° C. and then poured into 250 ml of ethyl acetate. The reaction mixture is washed three times with water and once with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography [silica gel: 400 g, eluent: ethyl acetate-hexane (1: 2 and then 2: 1)] to give cis-3-benzyloxycarboxamido-4-cyanomethyl-1- (2, 4-dimethoxybenzyl) -2-oxoazetidine is obtained.

Reference Example 181

Dissolve 1.7 g cis-3-benzyloxycarboxamido-4-cyanomethyl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine in a mixture of 210 ml acetonitrile and 70 ml water. After adding 1.68 g of potassium persulfate and 1.085 g of potassium dihydrogen phosphate, the mixture was refluxed at 85 to 90 ° C. for 2.5 hours. Acetonitrile is distilled off under reduced pressure and the residue is extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [silica gel: 140 g; Eluent: ethyl acetate-hexane (1: 2 and then 3: 1)], cis-3-benzyloxycarboxamido-4-cyanomethyl-2-oxoazetidine with a melting point of 113-115 ° C. Is obtained.

Reference Example 182

In the same manner as in Reference Example 166, cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino ] Acetamido] -4-cyanomethyl-2-oxoazetidine (syn-isomer) is obtained.

Reference Example 183

In a mixture of 100 ml of tetrahydrofuran and 100 ml of water, 4 g of methyl cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylate obtained in Reference Example 2 was dissolved, and ice-cooled, 1.359 g. Sodium borohydride is added. The mixture is stirred for 1 hour under ice-cooling, followed by 2 hours at room temperature. Next, tetrahydrofuran is distilled off under reduced pressure. The residue is extracted three times with chloroform and the extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in 30 ml of ethanol and 1 g of 5% palladium-carbon is added and then the mixture is stirred in a hydrogen atmosphere for 4 hours. Next, the catalyst is filtered off and the filtrate is concentrated. The residue is dissolved in a mixture of 20 ml of water and 20 ml of tetrahydrofuran and under ice cooling, 3.62 g of sodium bicarbonate is added. After adding 3.41 g of p-nitrobenzyloxycarbonyl chloride, the mixture is stirred at room temperature for 2 hours. The reaction mixture is extracted three times with chloroform and the extract is dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel column chromatography [silica gel: 160 g; Eluent: ethyl acetate and then ethyl acetate-methanol (4: 1)], and the cis-3- (p-nitrobenzyloxycarboxamido-4-hydroxymethyl-2-jade having a melting point of 166 to 167 ° C. Pediatric zetidine is obtained.)

Reference Example 184

2.28 g of sodium hydride is suspended in 40 ml of anhydrous tetrahydrofuran, and a solution of 3 g of 1-methyl-1H-terazole-5-ylthiol dissolved in 40 ml of tetrahydrofuran is added under ice cooling. Next, a solution obtained by dissolving 3.59 g of bromoacetic acid in 80 ml of absolute ethanol was added, and the mixture was stirred for 30 minutes under ice cooling, and then stirred at room temperature for 1 hour. Concentrate under reduced pressure and shake the residue with 100 ml of water and 100 ml of ether. The aqueous layer is taken, acidified with 3N hydrochloric acid and extracted with chloroform-ethanol (3: 1). The extract is dried over anhydrous magnesium sulfate and the solvent is distilled off to give 1-methyl-1H-tetrazol-5-ylthioacetic acid.

Claims (4)

A process for producing a compound of formula (I) or a salt or ester thereof, characterized by sulfonating a compound of formula (II) or a salt or ester thereof.

In the formula (I), R ¹ is (1) a group of the formula

Wherein R ⁶ and R ^b are the same or different and are C _1-6 alkyl, (2) a group of the formula:

Wherein R ⁶ is hydrogen, carbamoyl, formyl, acetyl, C _1-6 alkylsulfonyl, benzoyl, p-toluenesulfonyl, methoxyacetyl, C _1-6 alkoxycarbonyl, 1-methyl-1- Carboxyethylcarbonyl, carboxyethylcarbonyl, carboxyethenylcarbonyl or a formula R ⁸ -CO- group, wherein R ⁸ is formula (i)

A group wherein R ^C is C _1-6 alkyl or (ii) a formula

Group, wherein R ^d is furyl or thienyl.], And R ⁷ is phenyl, thienyl or a formula

Group, wherein R ^e is amino, (3) the group of the following formula:

Wherein R ^f is amino, halogenoacetylamino, C _1-6 alkyl or hydroxyl, R ^g is hydrogen or halogen, R ¹² is C _1-5 alkyl, C _2-6 alkenyl or formula-R ¹³ A R ¹⁴ group wherein R ¹³ is C _1-3 alkylene and R ¹⁴ is phenyl, carboxyl or C _1-6 alkoxycarbonyl; (4) the group of the following formula:

Wherein R ¹⁶ is hydroxyl, sulfo, carboxyl or carboxyl, and (5) a group of the formula: R ¹⁸ -CH ₂ CONH- where R ¹⁸ is cyano, triethyl silylmethyl, thienyl, tetrazolyl Or expression

Wherein R ^e is as defined above. ], Or (6) a group of the formula

Wherein R ^e is as described above and (7) amino, (8) benzyloxycarbonylamino, or (9) azido, and R is (1) 'a group of the formula: -COQ ⁵ where Q ⁵ is C _1-6 alkoxy, P-nitro benzyloxy, hydroxyl or C _1-6 alkoxycarbonyl-C _1-6 alkyloxy, and (2) the group of the formula:

Wherein n is an integer from 0 to 3, R ^{2 "} and R ^3" are the same or different and are hydrogen or C _1-6 alkyl, R ^{4 "} is hydrogen, C _1-6 alkyl, phenyl, halogen, cyan Furnace, hydroxyl, carbamoyloxy, C _1-6 alkyl sulfonyloxy, hydroxysulfonyloxy, amino, azido, C _1-6 alkoxycarbonyl, C _1-6 alkylthio, pyridinio, C _1-6 alkylcarbonyloxy, halo -C _1-6 alkylcarbonyloxy, C _1-6 alkyl, 1-tetrazolyl thio, benzoyloxy, C _1-6 alkylcarbonylamino, benzoylamino, trifluoroacetyl amino , C _1-6 alkylsulfonyl-C _1-6 alkoxycarbonyl amino, P-nitro benzyl oxycarbonylamino or a group of the formula -OCO-X'-Q ¹ wherein X 'is CH ₂ -,-CH ₂ S- or

Q ¹ is thienyl, 1-C _1-6 alkidetrazolyl or 2-amino or halogeno acetyl amino thiazolyl, Q ² is C _1-6 alkoxy. (3) '

Wherein Q ³ and Q ⁴ are the same or different and are hydrogen, C _1-6 alkyl, C _1-6 alkoxy, phenyl, benzyloxycarbonyl-C _1-6 alkyl, carboxy-C _1-6 alkyl or sulfo , (4) 'C _1-6 alkylcarbonyl group, (5)' phenyl-C _1-6 alkenyl group, or (6) 'P-halogenophenyl, With the proviso that R is not an unsubstituted straight or branched alkyl group, X is hydrogen, and wherein in formula (II), the symbols amino, hydroxyl and carboxyl are protected with protecting groups commonly used in the field of β-lactam or peptide synthesis. Each is the same as defined above except that it may be. The method of claim 1 wherein R ^{4 ″} is a carbamoyloxy group (OCONH ₂ ). 10. The method of claim 1 or 9, wherein R ₂ "and R ₃ " are hydrogen. 10. The method of claim 1 or 9, wherein n is zero.