KR830002686B1 - Process for preparing novll cephem and cepham compounds - Google Patents

Abstract

Cephem and cepham compds. I were prepd. Thus, a trimethylcylacetamide mixt., contg. 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid and CH2Cl2, was added to a mixt. contg. 2-(4-chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetate, PCl5, and CH2Cl2. CH2Cl2 was removed by distillation from the mixt. and AcC2H5 was added Resulting mixt. was extd. with AcC2H5, dried with MgSO4, and treated with activated charcoal to give 7-[2-(4-chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl) acetamido -3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid.

Description

Process for preparing new cefem and sefam compounds

The present invention relates to a process for the preparation of 7-substituted 3-cefem and cefam-4-carboxylic acids and their pharmaceutically acceptable salts which exhibit bactericidal properties. It is therefore an object of the present invention to prepare 7-substituted-3-cepem and cefam-4-carboxylic acids and their pharmaceutically acceptable salts which have excellent bactericidal activity against a wide range of pathogen microorganisms, including gram-negative and gram-positive bacteria. To provide a way.

7-Substituted 3-cefem and cefam-4-carboxylic acid can be represented by the following general formula.

In the above formula

R ¹ is amino or protected amino,

R ² is hydrogen, acyl, aryl which may be substituted with a suitable substituent, lower alkyl substituted by a suitable substituent, lower alkenyl, lower alkynyl, cycloalkyl which may be substituted by a suitable substituent, cyclo (lower) alkenyl or S Or a 5-membered heterocyclic group substituted with an O-containing oxo group,

R ³ is hydrogen or a lower alkyl group,

R ⁴ is hydrogen, acyloxy (lower) alkyl, alkylthioalkyl, pyridium (lower alkyl) which may be substituted with a suitable substituent, heterocyclic thio (lower) alkyl which may be substituted by a suitable substituent, lower alkyl, halogen or Hydroxy,

R ⁵ is R ⁴ is pyridinium (lower) alkyl which may be substituted when R ⁵ is substituted with zero suitable COO as carboxy or protected carboxy ^group-is, the thick line refers to a single or double bond.

According to the invention 7-substituted 3-cefem and cefam-4-carboxylic acid (I) can be prepared by the following method.

Method 1

In the above formula

R ¹ , R ² , R ³ , and R ⁴ are as defined above, respectively.

Among the starting materials of the present invention, compound (III) is novel and prepared by the following method.

i) halogenation

ii) MSCN

In the above formula

R ² and R ¹ are each as defined above and R ^2h is aryl which may be substituted with a suitable substituent or cycloalkyl which may be substituted by a suitable molar agent,

Z is carboxy or protected carboxy,

R ¹⁰ is protected amino (C ₃ -C ₆ ) alkyl,

R ¹¹ is amino (C ₃ -C ₆ ) alkyl,

R ⁶ is a protecting group of a carboxyl group,

M is an alkali metal,

X is hydroxy or a reaction derivative,

R ⁹ is amino with a protecting group,

R ^1a is protected amino,

R ⁷ is lower alkyl,

R ^2a is a protecting group of hydroxy,

R ² _f is ar (lower) alkyl or protected amino (lower) alkyl substituted with protected (lower) alkyl,

R ² _g is ar (lower) substituted with amino (lower) alkyl or amino (lower) alkyl.

으로 표시된 부분구조는 하기 두식의 기하구조를 모두 포함하는 것으로 믿어진다.Formula (I) and starting material (III)

It is believed that the substructures indicated by include all of the following two geometries.

In all the compounds having the above partial structure in the present invention, the compound having the geometric structure shown by the formula (A) is the "syn isomer", and the compound of the structure shown by the formula (A ') is the "anti isomer. Is called.

As for the compounds of formula (I) and the starting materials of formula (III), the above-mentioned objects and starting materials include tautomeric isomers in their thiadiazolyl groups. That is, in the formula of the above purpose and starting material,

(상기에서 R'은 아미노나 보호된 아미노)로 나타나는 다음식 R¹

(B)로 나타내는데, 이 식은 토우토머리 구조에 의하

The food appears to R ¹ (R 'is amino or a protected amino in the above)

Represented by (B), which is based on the

(B')(R')는 아미노나 보호된 아미노)로 표시될 수 있다. 즉 상기기(B)와 (B')는 다음식으로 표현될 수 있는 토우토머리 형태로 평형상태에 있을 수 있다.

(B ') (R') may be represented as amino or protected amino). That is, the groups (B) and (B ') may be in an equilibrium state in the form of a toetom head which can be expressed by the following equation.

(Wherein R ¹ and R ^{1 ′} are as defined above)

표현한다.In the present invention, the purpose and starting material having the above two groups

Express.

Pharmaceutically suitable salts of the desired compound (I) are known non-toxic salts and are inorganic salts such as alkali metal salts (e.g., narium salts, potassium salts), alkaline earth metal salts (e.g. calcium salts, magnesium salts), ammonium salts and the like. Metal salts, organic salts such as organic amine salts (e.g. trimethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, NN-dibenzylethylenediamine salt N-methylglucamine salt, diethanolamine Salts, triethanolamine salts, tris (hydroxymethylamino) methane salts, phenylethylbenzylamine salts, dibenzylethyldiamine salts, and the like, organic carboxylic acids and sulfonates (e.g., folate, acetate, maleate, detalate) , Methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), inorganic acid salts (e.g. hydrochloride, hydrobromide, sulfate, phosphate),

Salts with bases and acidic amino acids (e.g., arginine, aspartic acid, glutamic acid, lysine, etc.).

"Lower" means a group of 1-6 carbon atoms unless otherwise specified.

Suitable protected amino groups are known protecting groups other than acyl groups such as ar (lower) alkyl (e.g. benzyl, trityl), ar (lower) alkylidene (e.g. benzylidene), lower alkoxycarbonyl or di Lower alkylidene substituted with (lower) alkyl amino (eg 1-ethoxycarbonyl-2-propylidene, dimethylaminomethylene, etc.).

Suitable protected aminos include acylimino and imino groups substituted with known protecting groups other than acyl groups such as ar (lower) alkyl described above.

Suitable acyls in the terms "acyl amino" "acylimino" "acyloxy (lower) alkyl" and "acylthio (lower) alkyl" are carbamoyl, aliphatic acyl groups, aromatic and heterocyclic acyl groups. .

Suitable examples of acyl include lower alkanoyls (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succiryl, pivalyl, etc.), preferably 1-. Particularly suitable as quaternary carbon atoms are 1-2 carbon atoms, and lower alkoxy carbonyl of 2-7 carbon atoms (e.g., methoxy carbonyl, ethoxy carbonyl, propoxy carbonyl, 1-cyclopropylethoxycarbonyl Isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonylphene, t-tyloxycarbonyl, hexyloxycarbonyl, etc.), 3-6 carbon atoms, Lower alkanesulfonyl (e.g. benzenesulfonyl, tosyl, etc.), aroyl (e.g. benzoyl, toluoyl, naphthoyl, phthaloyl, indacarbonyl, etc.), ar (lower) alkanoyl (e.g. phenylacetyl, phenyl Propionyl and the like) and cyclo (lower) alkyl (lower) alkanoyl (eg, cyclohexylacetyl, cyclopentyl acetyl, etc.); Ar (lower) alkoxy carbonyl (eg benzyloxycarbonyl, phenethyloxy carbonyl) and the like.

Said acyl and acyl moieties include halo gulp (eg chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy), lower Suitable substituents such as alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl etc., lower alkenyl) (e.g. vinyl, allyl, etc.), aryl (e.g. phenyl, tolyl, etc.), amino, protected, amino, etc. It may have 1-3.

Examples of preferred acyls having such substituents include phenyl substituted with di (lower) alkyl carbamoyl (eg, methylcarbamoyl, diethylcarbamoyldipropylcarbamoyl, etc.), amino and lower alkoxycarbonyl amino ( Low) alkanoyl. Suitable examples of R ² acyl are halo (lower) alkanols, more preferably dihalo (lower) alkanoyls (eg, dicroacetyl, dibromoacetyl, etc.).

Suitable acyls may have phenyl, tolyl, xylyl, mesityl, cumenyl and the like and the aforementioned acyl groups are halogen (eg chlorine, bromine, fluorine, iodine), nitro, lower alkoxy (eg methoxy, Ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.) Preferably alkyl of 1-3 carbon atoms, protected carboxy, as described below, preferably lower alkoxycarbonyl, more preferably 2-4 carbon atoms And so on.

"Acyloxy (lower) alkyl", "acylthio (lower) alkyl", "pyridylium (lower) alkyl", protected amino (lower) alkyl ", amino (lower) alkyl", "protected carboxy (lower) Alkyl "," carboxy (lower) alkyl "," heterocyclic thio (lower) alkyl ",: ar (lower) alkyl" lower alkyl means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, Linear or branched alkyl of 1-6 carbon atoms, such as pentyl, tertiary pentyl and pexyl.

Suitable substituents in “lower alkyl substituted with appropriate substituents” include halogen (eg, chlorine, bromine, fluorine or iodine); Cyano; Carboxy; Lower alkyl thio (eg, methylthio, ethylthio, propylthio, butylthio), acetyl (eg, phenyl, tolyl, xylyl, mesityl, cumenyl, etc.); Aryloxy (eg phenoxy, tolyloxy, mesityloxy, etc.); The aforementioned acyl; Lower alkoxy (lower) alkoxy (low, alkoxy, yemethoxymethoxy, methoxy, ethoxyxituxetux, propoxytucci, butuxitux, pentyloxymethux, hexyloxymethux, Hexyloxyethoxy and the like); The above-mentioned protected amino, preferably acylamino, more preferably lower alkoxycarbonylamino or aryl (lower) alkanoylamino or loweralkoxycarbonylamino substituted with amino, cyclo (lower) alkyl substituted with amino, (Lower) alkanoylamino; Amino and the like, wherein the aryl groups described above may be substituted with amino (lower) alkyl (eg, aminomethyl, aminoethyl, aminopropyl, etc.) or protected amino (lower) alkyl. Suitable number of substituents in the lower alkyl group may be 1-3.

Suitable protected carboxyl groups may have the following esterified carboxy. Lower alkyl esters (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester pentyl ester, t-pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.) Wherein the lower alkyl moiety is suitable for 1-4 carbon atoms; Lower alkenyl esters (eg, vinyl esters, aryl esters, etc.); Lower alkynyl esters (eg, ethynyl ester, propynyl ester, etc.); Lower alkynyl esters (eg, ethynyl esters, propynyl esters, etc.); Lower alkynyl esters (eg ethylyl ester, propynyl ester, etc.); Mono (nadi or tri) -halo- (lower) alkyl esters (eg, 2-uridoethyl ester, 2, 2, 2-trichloroethyl ester, etc.); Lower alkanoyloxy (lower) alkyl esters (e.g. acetuxylmethyl ester, propionyl oxymethyl ester, 1-acetoxy propyl ester, valeryloxy methyl ester, 2-propionyl oxy ethyl ester, 1-isobuty Ryl oxyethyl ester); Lower alkanoyloxy (lower) alkyl esters (e.g. acetuxylmethyl ester, propionyl oxymethyl ester, hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-propionyloxyethyl ester, 1-acetux Cipropyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-isobutyryloxyethyl ester); Lower alkalescence; Lower alkaline sulfonyl (lower) alkyl esters (eg, mesylmethyl ester, 2-mesylethyl ester, etc.); Ar (lower) alkyl esters such as phenyl (lower) alkyl esters which may be substituted with one or two suitable substituents (e.g. benzyl esters, 4-metuxibenzyl esters, nitrobenzyl esters, phenethyl esters, trityl esters, diphenimmethyl Esters, bis (methutoxyphenyl) methyl esters, 3,4-methuxibenzyl esters, 4-hydroxy-3-, 5-tert-butylbenzyl esters, etc.);

Lower alkoxy carbonyloxy (lower) alkyl esters which may be substituted with azido (e.g., methoxycarbonyloxy methyl ester, ethoxycarbonyloxymethyl ester, ethoxycarbonyloxyethyl ester, etc.);

Heterocyclic esters, preferably benzo tetra hydrofuryl esters which may be substituted with oxo groups, more preferably phthalidyl esters; Azolyloxy (lower) alkyl esters (eg, benzoyl oxymethyl ester, benzoyloxyethyl ester, toluoyloxyethyl ester, etc.);

Aryl esters that may be substituted with one or two suitable substituents (eg, phenyl esters, tolyl esters, tertiary butylphenyl esters, xylyl esters, mesityl esters, cumenyl esters, etc.).

The protected carboxyl group is a lower alkoxy carbonyl of 2-7 carbon atoms, in particular 2-5 carbon atoms (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, t -Tiloxenoxycarbonyl, hexyloxycarbonyl, etc.), phenyl (lower) alkoxy carbonyl (eg, 4-nitrobenzyloxy carbonyl, benzyloxycarbonyl, 4-nitrophenethyloxy) which may also be substituted by natro Carbonyl, etc.), lower alkanoyloxy (lower) alkoxycarbonyl (eg, acetoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl, hexanoyloxymethoxycarbonyl, 1-acetoxyethoxycarbonyl 1-acetoxypropoxycarbonyl, 1-isototyryloxyethoxycarbonyl and the like), preferably a carbonyl of 3-8 carbon atoms; Lower alkoxycarbonyloxy (lower) alkoxycarbonyl (eg, ethoxycarbonyl oxyethoxycarbonyl, ethoxycarbonyloxypropoxycarbonyl, etc.) which may be substituted with azido, preferably 5-7 carbon atoms ; Phthalidinyloxy carbonyl; And aroyloxy (lower) alkoxycarbonyl (eg, benzoyloxymethylcycarbonyl, benzoyloxyethoxycarbonyl, etc.).

Suitable lower alkenyl are vinyl, aryl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl, preferably 2-4 carbon atoms.

Suitable lower alkynyl are alkynyl of 2-6 carbon atoms such as ethynyl, 2-propynyl, 2-butynyl, 3-pentynyl, 3-hexynyl and preferably alkynyl of 2-4 carbon atoms.

Suitable cycloalkyls are cycloalkyls of 3-8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and are preferably cycloalkyls of 4-7 carbon atoms.

Suitable substituents for cycloalkyl may be referred to as exemplified by substituents of lower alkyl, preferably carboxy or protected carboxy.

Suitable cyclo (lower) alkenyls are 3-6 carbon atoms such as cyclopentenyl, cyclohexenyl, preferably cycloalkenyl of 5-6 carbon atoms.

Suitable five-membered heterocyclic groups containing sulfur and oxygen may be saturated or unsaturated groups of, for example, dihydrofuryl, tetrahydrofuryl, thioranyl, substituted with 1-2 oxo groups.

Suitable heterocyclic groups and heterocyclic moieties in heterocyclic thio (lower) alkyl refer to saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one heteroatom such as oxygen, sulfur and nitrogen atoms.

In particular, good heterocyclic groups are heteromonocyclic groups having 1-4 nitrogen atoms of unsaturated 3-8 elements such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, N-oxides, pyrimidyl, Pyrazinyl, pyridazinyl, triazonyl (e.g., 4H-1, 2-4-triazolyl, 1H-1,2,3-triazolyl, 2-1,2,3-triazolyl, etc.) , 1H-tetrazolyl, 2H-tetrazolyl, etc.) dihydro thiazinyl, etc.);

Saturated 3-8 ring heteromonocyclic groups having 1-4 nitrogen atoms such as pyrrolidinyl, amidazolidinyl, piperidino, piperadinyl and the like;

Unsaturated condensed heterocyclic groups having 1-5 nitrogen atoms such as indoryl, isoindoryl, indolizinyl, benzimidazolyl, quinolyl, isoquinonyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolo Pyridazinyl, dihydro triazolo, pyridazinyl and the like;

Unsaturated 3-8 element small monocyclic groups having 1-2 oxygen atoms and 1-3 nitrogen atoms such as oxozolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4 -Oxadiazolyl, 1,2,5-oxadiazolyl, etc.); Heteromonocyclic groups of saturated 3-8 elements having 1-3 oxygen atoms and 3-8 nitrogen atoms such as morpholinyl;

Unsaturated condensed heterocycles having 1-2 oxygen atoms and 1-3 nitrogen atoms such as benzooxazolyl, benzooxadiazolyl and the like;

Heterocyclic unsaturated monocyclic groups having 1-2 sulfur atoms and 1-3 nitrogen atoms such as thiazolyl, thiazolinyl, thiadiazolyl (eg 1,2,4-thiadiazolyl, 1,3 , 4-thiadiazolyl, 1,2,5-thiadiazolyl and the like); Saturated 3-8 element heteromonocyclic groups having 1-2 sulfur atoms and 1-3 nitrogen atoms such as thiazolidinyl and the like;

Heteromonocyclic groups of unsaturated 3-8 elements having a sulfur atom; Unsaturated condensed heterocyclic groups having 1-2 sulfur atoms and 1-2 nitrogen atoms such as benzothiazolyl, benzothiadiazoli, and the like;

Wherein the heterocyclic group is lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, etc.); Lower alkylthio (eg, methylthio, ethylthio, propylthio); Lower alkenyl (eg, vinyl, allyl butenyl, etc.); Lower alkenylthio (for example, vinylthio, allylthio, butenylthio, etc.); Hydroxy; aryl (e.g., halogen (e.g., chlorine, bromide, fluorine, iodine) such as phenyl, tolyl); amino'di (lower) alkyl (e.g., dimethylamino methyl dimethyl aminoethyl, dimethylaminopropyl, diethylaminopropyl, Diethylaminobutyl, etc.); carboxyl (lower) alkyl (e.g., carboxymethyl, carboxyethyl, carboxypropyl, etc.); esterified carboxyl (lower) alkyl with esterified carboxy moiety as illustrated above Amino (lower) alkyl (e.g. aminomethyl, aminoethyl, aminopropyl, 1-aminomethylethyl, aminobutyl, aminohexyl, etc.); protected amino (lower) as defined above for each protected amino and lower alkyl moiety; ) Alkyl, preferably lower alkoxycarbonyl amino (lower) alkyl, (e.g. methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, t-butoxycarbonyl aminomethyl, t-butoxycarbonyl aminoethyl , t- Oxycarbonylaminopropyl, etc.) or lower alkoyl amino (lower) alkyl (e.g., acetylaminomethyl acetylaminoethyl acetylaminopropyl 1-acetylaminomethylethyl, etc.); carboxy; oxo; Lower alkoxycarbonyl; lower alkoxy (lower) alkyl (e.g., methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, etc.); hydroxy (lower) alkyl (e.g., hydroxymethyl, Hydroxyethyl, hydroxypropyl, hydroxybutyl, etc.) Lower alkyl thio (lower) alkyl (e.g. methylthiomethyl, methylthioethyl, ethylthiomethyl, etc.); sulfo (lower) alkyl (e.g. sulfomethyl, sulfoethyl Acyl and lower alkyl moieties such as acyl (lower) alkyl, preferably lower alkane sulfonyl (lower) alkyl (e.g. mesylmethyl, mesylethyl, ethanesulfonylmethyl) Etc.), Acyl And the lower alkyl moiety is acylamino (lower) alkyl as exemplified above, preferably lower alkane sulfonylamino (lower) alkyl (e.g. mesylaminomethyl, mesylaminoethyl, mesylaminopropyl, ethanesulfonylamino methyl, etc.). ), Carboxy (lower) alkylthio (e.g., carboxymethylthio, carboxyethyl thio, etc.), monopolynopropyl, etc.); Piperidino (lower) alkyl (eg piperidinomethyl, piperidinoethyl, piperidinopropyl); Piperazino (lower) alkyl, (eg, 4-methyl-1-piperazinyl pronyl, and the like).

Suitable substituents on pyridinium (lower) alkyl, pyridine, pyridinium are carbamoyl and the like.

Suitable halogens are as exemplified above.

Suitable lower alkylenes are preferably 1-2 carbon atoms, most preferably as straight or branched divalent aliphatic hydrocarbon residues of 1-6 carbon atoms such as methylene, ethylene, methyl, ethylene, propylene, trimethylene, 2-methyltrimethylene Preferably it may have a hydrocarbon of 1 carbon atom.

Suitable protecting groups for hydroxy can be acyl, ar (lower) alkyl groups.

Suitable protecting groups for the carboxy can be esterified carboxyl groups, as exemplified in the ester component.

An excellent example of a carboxy protecting group may be the lower alkyl mentioned above.

Suitable alkyllimetals are sodium, potassium, lithium and the like.

Suitable reactive derivatives of the hydroxy groups include residues of acids such as the halogens described above.

Suitable aminos having a protecting group of R ⁹ are pralimino, succinimido, ethoxycarbonylamino and the like, preferably pralimido.

Suitable ar (lower) alkyls are preferably phenyl (lower) alkyl (eg benzyl, phenethyl) and the like.

Suitable (C ₃ -C ₆ ) alkyl in “amino (C ₃ -C ₆ ) alkyl” and “protected amino”, “protected amino (C ₃ -C ₆ ) alkyl” are alkyl of 3-6 carbon atoms, eg Propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like. The amino groups protected at appropriate protected amino (lower) alkyl and amino (lower) alkyl and protected amino (C ₃ -C ₆ ) alkyl "at R ^2f and R ^2g are as described above.

Preferred examples of the target compound (I) are as follows.

R ¹ is amino, acylamino (more preferably lower alkanoyl amino) or di (lower amino (lower) alkylidene amino);

R ² is hydrogen; Aryl (preferably phenyl); Lower alkenyl; Lower alkenyl; Cyano (lower) alkyl; Ar (lower) alkyl, more preferably panel (lower) alkyl or triphenyl (lower) alkyl;

Halo (lower) alkyl (preferably thiohalo (lower) alkyl); Lower alkylthio (lower) alkyl; Esterified carboxy (lower) alkyl carbamoyl (lower) alkyl; Lower alkoxy (lower) alkoxy (lower) alkyl; Lower alkanesulfonyl (lower) alkyl; Acylamino (lower) alkyl (preferably lower alkoxy carbonylamino (lower) alkyl); Amino (lower) alkyl; Carboxy (lower) alkyl, cycloalkyl; Cyclo (lower) alkenyl; Aryl (preferably phenyl) substituted with halogen, nitro, lower alkoxy, halo (lower) alkyl or lower alkoxy carbonyl; Thiophenyl substituted with the oxo group; Ar (lower) alkyl substituted with carboxy or lower alkoxycarbonyl; Cycloalkyl substituted with carboxy or lower alkoxy carbonyl; ano (lower) alkyl or lower alkoxy carbonyl amino (lower) alkyl substituted ar (lower) alkyl (preferably phenyl (lower) alkyl); Cycloalkyloxy carbonyl (lower) alkyl; Ar (lower) alkoxy carbonyl (lower) alkyl; Ar (lower) alkanoylamino (lower) alkyl substituted with amino or lower alkoxy carbonyl amino; Cyclo (lower) alkyl (lower) alkanoylamino (lower) alkyl; Tetrahydrofuryl substituted with an oxo group;

R ³ is hydrogen or lower alkyl;

R ⁴ is hydrogen; Acyloxy (lower) alkyl (preferably lower alkanoyloxy (lower) alkyl or carbamoyloxy (lower) alkyl, most preferably lower alkanoyl oxymethyl or carbamoyl oxymethyl); Acylthio (lower) alkyl (preferably lower alkanoylthio ((lower) alkyl, most preferably lower alkanoyloxythiomethyl); lower alkyl, lower alkenyl lower alkoxy (lower) alkyl, lower alkylthio (lower) Alkyl, hydroxy (lower) alkyl, amino (lower) alkyl, lower alkoxycarbonylamino (lower) alkyl, lower alkanoylamino (lower) alkyldi (lower) alkylaminoalkyl, sulfo (lower) alkyl, carboxy ( Lower) alkyl, aryl (preferably phenyl) lower alkoxy carbonyl (lower) alkyl, morpholic (substituted by lower (alkyl, lower alkyl substituted pyreridino (lower) alkyl or piperadinyl (lower) alkyl) Terrazolylthio (lower) alkyl (preferably tetrazolylthiomethyl); lower alkyl, lower alkoxy (lower) alkyl, lower alkylthio (lower) alkyl, lower alkenylthio, carboxy lower alkoxycarbonyl, hydroxy Hydroxy (lower) alkyl, amino (lower) alkyl, loweralkoxycarbo Amino (lower) alkyl, lower alkanesulfonyl (lower) alkyl, thiadiazolylthio, substituted pyridinium (lower) alkyl, which may be substituted with lower alkane sulfonylamino (lower) alkyl or carboxy (lower) alkylthio; Lower alkyl; halogen; hydroxy; dihydrothiazolo pyridazinylthio (lower) alkyl (preferably dihydrothiazolo pyridazinyl chinomethyl) substituted with oxo and carboxy (lower) alkyl; tetrazolo pyridazinyl Thio (lower) alkyl (preferably tetrazolopyridazinylthiomethyl);

R ⁵ is carboxy, phenyl (lower) alkoxycarbonyl, lower alkanoyloxy (lower) alkoxy carbonyl, lower alkoxy carbonyloxy (lower) alkoxycarbonyl, phthalidyloxy carbonyl which may be substituted by azido Aroyl (preferably benzoyl) oxy (lower) alkoxy carbonyl. And if R ⁴ is pyridinium (lower) alkyl substituted with carbamoyl, then R ⁵ is COO ⁻ .

The preparation method of the target compound is detailed below.

Method 1.

The target compound (I) can be produced by reacting a reaction derivative with compound (II) or an amino group thereof and a reaction derivative with compound (III) or a carboxy group thereof.

Suitable reaction derivatives in the amino group of compound (II) include known reaction derivatives used in the amination reaction, for example, Schiff base imino or its tautomeric enamine isomer formed by reacting compound (II) with a carbonyl compound; Silyl derivatives formed by reacting compound (II) with a silin compound such as bis (trimethylsilyl) acetamide and trimethyl silylacetamide; Derivatives formed by reacting compound (II) with phosphorus trichloride or phosgene.

Suitable salts of compound (II) include acid addition salts such as organic acid salts (acetates, maleates, tartarate salts, benzenesulfonate salts, toluenesulfonate salts) or inorganic acid salts (hydrochloride salts, bromate salts, sulfate salts, phosphates); Metal salts (eg, sodium salts, potassium salts, calcium salts, magnesium salts); Ammonium salts; Organic amine salts (eg, trimethylamine salt, disclohexylamine salt).

Suitable reaction derivatives in the carbo group of compound (III) are acid halides, acid anhydrides, activated amides, activated esters and the like.

Suitable examples include acid chlorides; Acid azide; substituted phosphoric acid (e.g. dialkylphosphoric acid, phenyl phosphoric acid, diphenyl phosphate, dibenzyl phosphoric acid, halogenated phosphoric acid) Mixed acid anhydrides with acids such as pivalic acid, pentanoic acid, isopentanoic acid, 2-ethyl butyric acid, acetic acid and trichloroacetic acid) and aromatic carboxylic acids (eg, benzoic acid); Corresponding acid anhydrides; Activated amides with imidazole, dimethylpyrazole, triazole and tetrazole; Activating esters (eg cyanomethyl ester, methoxymethyl ester, dimethyl iminomethyl (CH ₃ ) 2 N + = CH ester, vinyl ester, proparyl ester, P-nitrophenyl ester, 2,4-dinitrophenyl ester, Trichlorophenyl ester, tentachlorophenyl ester, mesylphenyl ester, phenyl azophenyl ester, phenylthioester, P-nitrophenyl thio ester, P-cresylthio ester, carboxymethylthio, ester, pyranyl ester, pyrityl Ester, piperidine ester, 3-quinolylthioester or NN-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinamide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzothiazole).

The present reaction derivative can be selected according to the type of compound (III) used.

Salts of compound (III) are salts of organic bases such as alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts), trimethylamine, triethylamine pyridine and salts (e.g., Hydrochloric acid or bromic acid).

The reaction is usually carried out in water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, NN-dimethylformamide, pyridine or other known solvents that do not harm the reaction. .

When compound (III) is used in the free acid form or in the salt form in the reaction, the reaction is carried out with N, N-dicyclohexyl carbodiimide-N-cyclohexyl N-morphoethylethyl carbodiimide, N-cyclo-hexyl-N- ( 4-diethyl aminocyclohexyl) carbodiimide; N-N-diethylcarbodiimide; N, N-diisopropyl carbodiimide; N-ethyl-N- (3-dimethylaminopropyl) carbodiimide;

N-N-carbonyl-bis (2-methylimidazole); Pentamethylene-ketene-N-cyclohexylimine; Diphenylketene-N-cyclohexylimine; Ethoxyacetylene; Ethyl polyphosphate; Isopropyl polyphosphate; Diethyl phosphochloridite; Phosphorus oxcycloide; Phosphorus chloride; Phosphorus pentachloride; Thionyl chloride; Oxalyl chloride; Triphenylphosphine, N-ethyl-7-hydroxy benzisoxazolium fluoroborate; N-ethyl-5-phenyl-ioxazolium-so-3'-sulfonate: 1- (P-chlorobenzene sulfonyloxy) -6-chloro-1H-benzotriazole: Vilsmeier reagent, eg thionyl chloride or phosgene It is carried out in the presence of a known condensing agent such as a compound produced by reacting (chloromethylene) dimethyl ammonium chloride produced by the reaction of dimethylformamide with dimethylformamide with dimethylformamide. Reactions include alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali metal acetates, tri (lower alkylamine pyridines, N- (lower) alkylphorolines, N, N-di (lower) alkylbenzylamines, N, N It can be carried out in the presence of inorganic and organic salts, such as di (lower) alkaline, etc. If the base or condensing agent is a liquid, it can be used as a solvent The reaction temperature is not critical and the reaction is usually carried out at cooling or at room temperature.

In this reaction, the syn-isomer of target compound (I) is obtained by reacting compound (II) with syn-isomer of starting compound (III).

In the present reaction, the amino group of the R 'group in the compound (III) is converted into a protected amino group to form a compound wherein R ¹ is protected amino, which is converted into hydrogen during the reaction according to the conditions of the present invention, It belongs to a category. The method for preparing starting material (II) is described in detail below.

[Manufacture 1]

Compound (V) can be produced by reacting compound (V) or a salt thereof with a halogenating agent and compound (VI).

Suitable halogenating agents used in this reaction are bromine, chlorine and the like.

The reaction is carried out in the presence of an inorganic or organic base such as alkali metal carbonate, alkali metal alkoxide and trialkylamine. The reaction is carried out in alcohols (eg methanol, ethanol) or other solvents which do not adversely affect the reaction. The reaction temperature is not critical and usually proceeds at cooling or room temperature.

In the present reaction, R ⁶ of compound (V) is converted to other carboxyl protecting groups depending on the reaction conditions and the type of protecting group and belongs to the present invention.

[Manufacture 2]

Compound (VII) can be manufactured by adding and reacting an amino protecting group with compound (VII).

The present invention can be carried out by a known method and when the protecting group of amino introduced into an amino group is known, the reaction can be carried out as in the method (1).

[Manufacture 3]

Compound (VII) can be produced by reacting compound (VII) with compound (VII).

The process proceeds in the presence of bases such as alkali metal hydrates (e.g. sodium hydrate, potassium hydrate), alkaline earth metal hydrates (calcium hydrate) and is carried out in the presence of dimethyl formamide or a solvent that is harmless to the reaction. The reaction temperature is not critical and proceeds at cooling or ambient temperature.

[Manufacture 4]

Compound (XI) can be prepared by reacting compound (X) with an acid such as acetic acid or acetic anhydride or anhydrous acid. The reaction method includes alkali metals and halides (e.g. sodium, perchlorate, sodium poiode, potassium perchlorate), alkaline earth metal perchlorates (e.g. magnesium perchlorate, calcium perchlorate), organic acids (e.g. formic acid) or inorganic acids (e.g. Eg, hydrochloric acid).

The reaction temperature is not critical and is run warm.

Manufacturing (5) and (7)

Manufacturing (5) and (7) can be performed by methods, such as hydrolysis.

According to the reaction conditions in Preparation (5), it is possible to obtain a product of R ^1a (XIa) or a product having amino instead of R ^1a (XI _b ) and continuously react with Compound (XII) To obtain III _a ) or (III _b ).

[Manufacture 6]

Suitable salts of compound (XII) are salts such as inorganic acid salts (eg hydrochloride) and organic acid salts (eg P-toluene sulfonate). When salts of the above compounds (XII) are used in the process, the reaction is carried out in the presence of a base such as an alkali metal, a hydroxide (eg sodium hydroxide). The reaction is usually carried out in the presence of water, alcohols (eg methanol, ethanol) or a solvent suitable for the reaction.

The reaction temperature is not critical and is carried out at room temperature.

[Manufacture 8]

Compound (III _d ) can be prepared by adding a hydroxyl group protecting group to compound (III _c ).

The method is carried out by a known method, and when the protecting group introduced into the hydroxyl group is known, the reaction is carried out by the method; It can proceed in the same way as in.

When the protecting group added is ar (lower) alkyl, this reaction is prepared by reacting compound (III _c ) with a R ^2f -Y (VII) compound. (Wherein Y is ar (lower) alkyl and Y is an acid residue)

Suitable acid residues include residues of acids such as inorganic or organic acids.) The present invention is carried out in the presence of a base as described above and in a solvent such as dimethylformamide. The reaction temperature is not critical and the reaction can be carried out under cooling, room temperature or warming.

[Manufacture 9]

Compound (XV) can be prepared by reacting compound (XIII) with compound (XIV).

The reaction is carried out in the presence of the bases exemplified in Method 1 in case of (X) is the acid residue and in the presence of a condensing agent with triphenylphosphine and diethyl azoformate when (X) is a hydroxy group.

The reaction is carried out in acetonitrile dimethylformamide tetrahydrofuran or other solvents which are harmless to the present reaction. The reaction temperature is not critical and is usually carried out between the solvent boiling points in cooling.

[Manufacture 10]

Compound (XVI) can be prepared by removing the amino protecting group as compound (XV).

Removal of the amino protecting group of compound (XV) can be carried out similarly as in method 4.

Suitable solvents include water, ethanol, chloroform, diethyl ether and the like. The reaction temperature is not critical and is usually carried out under warming.

This reaction includes the case where the amino group protected at R ² is converted to a free amino group.

[Manufacture 11]

Compound (XX) can be prepared by adding an amino protecting group as compound (XIX).

This reaction is carried out in the same manner as in Method 1.

When the added protecting group is a lower alkoxy carbonyl group, this reaction is carried out by reacting compound (XIX) with a compound of formula (XXIX).

Wherein R ¹² is lower alkoxycarbonyl R ¹³ is aryl.

[Manufacture 12]

Compound (XXII) can be prepared by adding a substituent to the hydroxy group of compound (XXI).

When the introduced substituent is aryl, it is carried out by reacting compound (XXI) or a salt thereof with a compound of formula (XXX).

R ²ⁱ -X ² (-R ²ⁱ Y (XXX)

Wherein R ⁱ is aryl substituted with a suitable substituent, X ² is halogen and Y is an acid residue.

Suitable acid residues are halogen, toluene and sulfonyloxy sulfate residues.

The reaction is usually carried out in alcohol (eg methanol, ethanol), water or other solvents that are harmless to the reaction and preferably in the presence of a base.

When the added substituent is cycloalkyl which may be substituted with a suitable substituent, it is carried out by reacting compound () with compound (XXXI).

R ^2J -Y (XXXI)

^Wherein R ^2J is cyclo alkyl which may be substituted with suitable substituents and Y is as defined above. This reaction is carried out in the same manner as in Preparation 8.

[Manufacture 13]

Compound (XXIV) can be prepared by cyclizing compound (XXIII).

The reaction is carried out in a solvent such as alcohol.

The reaction is carried out in the presence of dehydrogenating agents such as magnesium sulfate, acid anhydride (acetic anhydride).

The reaction temperature is not critical and is carried out at warm or room temperature.

[Manufacture 14]

Compound (XXVI) can be prepared by reacting compound (XXV) with NH ₃ or a salt thereof.

Suitable salts of NH ₃ may be alkali metal salts.

The reaction is carried out in water, dioxane, mixed solvents or other solvents which are harmless to the present reaction.

The reaction temperature is not critical and the reaction is usually carried out under warming.

[Manufacture 15]

Compound (XXVII) can be prepared by removing the protecting group of amino from compound (XXVI).

[Manufacture 16]

Compound (XXVIII) can be prepared by adding a protecting group of amino to compound (XXVII).

In the above-described reaction and post-reaction treatment of the present invention, the above-mentioned tautomer isomers can be converted into various isomers, which are within the scope of the present invention.

When the desired compound (I) is obtained in free acid form in the 4 position or has a free amino group, it is possible to convert the salt into a pharmaceutically suitable salt thereof by known methods.

Pharmaceutically suitable salts with the objective compound (I) of the present invention are novel compounds useful as high antibacterial activity, gram positive and gram negative bacteria-containing microorganisms and growth inhibitors and fungicides.

In order to determine the usefulness of the target compound (I), the antimicrobial activity of the representative compounds of the present invention was tested and reported below.

Experimental Compound

(1) 7- [2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cepem-4-carboxylic acid (syn Isomers)

(2) 7- [2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadia Zol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer)

(3) 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cef 4-carboxylic acid (syn isomer)

(4) 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- ( 1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer)

(5) 7- [2- (2-cyclohexen-1-yl) oxyiminoamino-2- (5-amino-1,2,4-adi, azol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer)

(6) 7- [2- (4-chlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3, 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer)

(7) 7- [2-allyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1-allyl-1H-tetrazol- 5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer)

(8) 7- [2-carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1- (2-aminoethyl) -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer)

(9) 7- [2-carboxyethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1- (2-aminopropyl) -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer)

(10) 7- [2-cyclopentyloxyiminoamino-2- (5-adi, -1,2,4-thiadiazol-3yl) acetamido] -3- (tetrarazoro [1,5 -b] pyridinzin-6-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer)

(11) N- [7- {2-cyclopentyloxyimino-2- (5-amino, -1,2,4-thiadiazol-3) acetamido] -3-cephem-3-yl methyl] -4'-carbamoylpyridinium-4-carboxylate (syn isomer)

Experimental Method

)를 실험화합물을 용해한 HI-한천배지에 접종시키고 37℃, 20시간 배양한후 최소 억제농도를 (MIC)μg/m

로 결정하였다.The bactericidal properties were determined by the dilution method of bilayer agar plate medium as described below. Tryticase-culture in broth (10 ⁸ / m)

) Was inoculated into HI-agar medium containing the experimental compound and incubated for 20 hours at 37 ℃, and the minimum inhibitory concentration was (MIC) μg / m.

Determined.

[Experiment result]

[Manufacturing Method 1]

)와 1-브로모-2-시클로헥센(8.05g)의 혼합물을 상온에서 3.5시간 교반한다.(1) N-hydroxyphthalimide (8.15 g), triethylamine (5.05 g), NN-dimethylformamide (60 m

) And 1-bromo-2-cyclohexene (8.05 g) are stirred at room temperature for 3.5 hours.

)을 부으며 침전된 결정물을 여과에 의행 수집, 연속적으로 물과 n-헥산으로 세척한후 건조시켜 N-(2-사이클로헥센-1-일옥시)프탈아미드(9.8g)을 얻는다. 융점 87℃ I.R.( 뉴졸) : 1770, 1720, 1610 cm^-1 Water (300m) in reaction mixture

The precipitated crystals were collected by filtration, washed successively with water and n-hexane, and dried to obtain N- (2-cyclohexen-1-yloxy) phthalamide (9.8 g). Melting Point 87 ℃ IR (New Sol): 1770, 1720, 1610 cm ^-1

NMR (d ₆ -DMSO, S): 1.50-2.17 (6H, m), 4.60-4.77 (1H, m), 5.73-6.27 (2H, m), 7.90 (4H, S)

)와 탄산칼륨(44.16g)의 혼합물을 70℃에서 74시간 동안 교반한다.(2) N-hydroxyphthalimide (52.16 g), bromocycloheptane (62.41 g) dimethyl sulfoxide (385 m

) And potassium carbonate (44.16 g) are stirred at 70 ° C. for 74 hours.

)을 첨가한다. 침전물을 여과에 의해 수집, 얼음-물(2배)로 세척한 후 건조시켜 N-시클로헵틸옥시)프탈이미드(63g)을 얻는다. 융점 110 내지 112℃, N.M.R.(d₆-DMSO,δ) : 1.57 (8H, m), 1.90(4H, m), 4.20(1H, m), 7.93(4H, S)The reaction mixture is cooled under ice-cooling and ice-water (1.5

Add). The precipitate is collected by filtration, washed with ice-water (twice) and dried to give N-cycloheptyloxy) phthalimide (63 g). Melting point 110-112 ° C., NMR (d ₆ -DMSO, δ): 1.57 (8H, m), 1.90 (4H, m), 4.20 (1H, m), 7.93 (4H, S)

)에 용해시킨 N-하이드록시프탈이미드(58.2g), 1-클로로-2-사이클로 펜텐(36.9), 트리에틸아민(53.9g)의 혼합물을 제조방법 1-(1)과 1-(2)와 같은 방법으로 처리하여 N-(2-시클로펜텐-1-일옥시)프탈이미드(56.5g)를 얻는다.(3) acetonitrile (370m

A mixture of N-hydroxyphthalimide (58.2 g), 1-chloro-2-cyclopentene (36.9), and triethylamine (53.9 g) dissolved in 1) was prepared in 1- (1) and 1- (2). N- (2-cyclopenten-l-yloxy) phthalimide (56.5 g) is obtained by the same method as above.

IR (NujoI): 1780,1730,1610cm ^-1

NMR (d ₆ -DMSO, δ): 7.92 (4H, S), 6.28 (1H, m), 6.00 (1H, m), 5.42 (1H, m), 2.9-1.98 (4H, m)

[Manufacturing Method 2]

)에 용해시킨N-(시클로헵틸옥시)프탈이미드(2.59g), 하이드라진 하이드레이트(0.45g)의 혼합물을 3분간 환류시킨다.Ethanol (12 m

A mixture of N- (cycloheptyloxy) phthalimide (2.59 g) and hydrazine hydrate (0.45 g) dissolved in) was refluxed for 3 minutes.

The reaction mixture is cooled and filtered to give a filtrate comprising cycloheptyloxy amine.

[Manufacturing Method 3]

)에 용해시킨 N-(2-시클로펜텐-1-일옥시)-프탈이미드(22.9g)과 하이드라진 하이드레이트(4.75g)의 혼합물을 5분간 환류시킨다. 반응 혼합물을 여과하며(2-시클로펜텐-1-일) 옥시아민을 포함하는 여과물을 물에 용해시킨 소디움 2-(5-포름아미도-1, 2,4-티아디아졸-3-일)글리옥시레이트(22.4g)의 용액에 첨가한다. 혼합물을 10%염산으로 pH2로 맞추며 2시간 교반한 후 농축시킨다. 농축물을 10%염산으로 pH1로 맞추며 침전물을 여과에 의해 수집하고 건조시켜 2-(2-시클로펜텐-1-일) 옥시이미노-20-(5-포름아미도-1,2,4-티아디아졸-3-일) 아세트산(syn 이성체)(20.0g)을 얻는다. 융점 150℃(1) ethanol (115 m

A mixture of N- (2-cyclopenten-1-yloxy) -phthalimide (22.9 g) and hydrazine hydrate (4.75 g) dissolved in) is refluxed for 5 minutes. Sodium 2- (5-formamido-1, 2,4-thiadiazol-3-yl) in which the reaction mixture was filtered (2-cyclopenten-1-yl) and the filtrate comprising oxyamine was dissolved in water. ) To a solution of glyoxylate (22.4 g). The mixture was adjusted to pH 2 with 10% hydrochloric acid, stirred for 2 hours, and then concentrated. The concentrate was adjusted to pH 1 with 10% hydrochloric acid and the precipitate collected by filtration and dried to give 2- (2-cyclopenten-1-yl) oxyimino-20- (5-formamido-1,2,4-thia Diazol-3-yl) acetic acid (syn isomer) (20.0 g) is obtained. Melting point 150 ℃

(decomposition)

IR (New sol): 3400, 3100, 1720, 1690, 1540cm ^-1

NMR (d ₆ -DMSO, δ): 1.80-2.50 (4H, m), 5.30-5.50 (1H, m), 5.83-6.30 (2H, m), 8.90 (1H, S)

)에 용해시킨 N-(2-시클로헥센-1-일옥시)-프탈이미드(7.29g), 하이드라진 하이드레이트(1.5g)의 혼합물을 5분간 환류시킨다. 반응 혼합물을 냉각하고 여과시켜(2-시클로헥센-1-일)-옥시아민(여과물 A)을 포함하는 여과물을 얻는다.(2) ethanol (40m

A mixture of N- (2-cyclohexen-1-yloxy) -phthalimide (7.29 g) and hydrazine hydrate (1.5 g) dissolved in) is refluxed for 5 minutes. The reaction mixture is cooled and filtered to afford a filtrate comprising (2-cyclohexen-1-yl) -oxyamine (filtrate A).

On the other hand,

)의 1N-수용액에 용해시킨 S-메틸-2-(5-포름아미도-1,2,4-티아디아졸-3-일)티오글리옥시레이트(6.93g)의 혼합물을 상온에서 30분간 교반한다. 소디움 2-(5-포름아미도-1,2,4-티아디아졸-3-일)글리옥시레이트를 포함하는 반응혼합물을 10%염산으로 pH7로 맞추고 여기에 여과물을 첨가한 후 pH를 10%염산으로 pH3으로 맞춘다.Sodium hydroxide (90 m

A mixture of S-methyl-2- (5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxylate (6.93 g) dissolved in 1N-aqueous solution of Stir. The reaction mixture containing sodium 2- (5-formamido-1,2,4-thiadiazol-3-yl) glyoxylate was adjusted to pH 7 with 10% hydrochloric acid, and the filtrate was added thereto to adjust the pH. Adjust to pH 3 with 10% hydrochloric acid.

The mixture is stirred at room temperature for 3 hours to concentrate the reaction mixture and ethyl acetate is added to the concentrate.

The mixture was adjusted to pH 1 with 10% hydrochloric acid and the precipitate collected by filtration to collect 2- (2-cyclohexen-1-yl) oxyamino-2- (5-formamido-1,2,4-thiadiazole- 3-yl) acetic acid (syn isomer) (2.5 g) is obtained. On the other hand, the ethyl acetate layer is separated from the filtrate and evaporated. The residue is treated with diethyl ether to give the same title compound (1.5 g).

Total yield: 4.0g Melting point 190 ~ 192 ℃ (decomposition)

IR (NujoI): 3500, 3400, 3200, 2500, 1690, 1590 1540cm ^-1

NMR (d ₆ -DMSO, δ): 1.5-2.3 (6H, m), 4.73-5.0 (1H, m), 5.76-6.23 (2H, m), 8.97 (1H, S), 13.60 (1H, br. s)

)에 용해시킨 수산화나트륨(11.2g)의 용액에 10℃에서 S-메틸-2-(5-포름아미도-1,2,4-티아디아졸-3-일) 티오글리옥실레이트(27g)을 첨가하고 혼합물을 20℃에서 30분간 교반한다.(3) water (140m)

In a solution of sodium hydroxide (11.2 g) dissolved at 10 ° C. at 10 ° C. S-methyl-2- (5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxylate (27 g) Is added and the mixture is stirred at 20 ° C. for 30 minutes.

)에 용해시킨 사이클로펜틸옥시아민(15.3g)의 용액을 첨가한다. 혼합물을 10%염산으로 pH3으로 맞추고 1.5시간 교반한다. 반응혼합물을 이탄산나트륨의 수용액으로 pH7로 맞춘후 증발시켜 에탄올을 제거한다.Cool the reaction mixture containing sodium 2- (5-formamido-1,2,4-thiadiazol-3-yl) glyoxylate to pH 7 with 10% hydrochloric acid and add ethanol (150 m).

A solution of cyclopentyloxyamine (15.3 g) dissolved in) is added. The mixture is adjusted to pH 3 with 10% hydrochloric acid and stirred for 1.5 hours. The reaction mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and then evaporated to remove ethanol.

The residue is washed with ethyl acetate and ethyl acetate is added to the aqueous layer and the mixture is adjusted to pH 1 with 10% hydrochloric acid. The precipitate is collected by filtration to give 2-cyclopentyloxy imino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (3.99 g). The filtrate is extracted with ethyl acetate and the extract is dried over magnesium sulfate and concentrated.

The precipitate is collected by filtration and washed with diethyl ether to give the same title compound (8.1 g). Total yield: 12.09g Melting point 180 ~ 185 ℃ (decomposition)

IR (NujoI): 3130, 3040, 2680, 2610, 2520, 1720, 1690, 1660, 1600, 155cm ^-1

NMR (d ₆ -DMSO, δ): 1.33-2.10 (8H, m), 4.67-5.0 (1H, m), 8.88 (1H, S), 13.50 (1H, S)

(4) The following compound is obtained according to the same method as Preparation Method 3 (1) to 3 (3).

2-cycloheptyloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

NMR (d ₆ -DMSO, δ): 1.50 (8H, m), 1.80 (4H, m), 4.37 (1H, m), 8.81 (1H, s), 9.88 (1H, s)

[Manufacturing Method 4]

)혼합물을 50내지 55℃에서 1시간 동안 교반한다.2- (2-cyclopenten-1-yl) oxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (20.0 g) and sodium hydroxide 1N aqueous solution (200m

The mixture is stirred at 50-55 ° C. for 1 hour.

The reaction mixture is cooled, adjusted to pH 7 with 10% hydrochloric acid, and ethyl acetate is added thereto.

The mixture is adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated. The residue was triturated with diisopropyl ether to give 2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer Get)

Melting Point 150 ° C (decomposition)

IR (NujoI): 3300, 3150, 1710, 1620, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.80-2.50 (4H, m), 5.30-5.50 (1H, m), 5.83-6.30 (2H, m), 8.20 (2H, s)

[Manufacturing Method 5]

The following compounds are obtained according to the same method as Preparation Method 5.

(1) 2- (2-cyclohexen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) Melting point 173 DEG C IR (New sol) ): 3400, 3300, 3200, 1720, 1620, 1600, 1520, cm ^-1

NMR (d ₆ -DMSO, s): 1.50-2.17 (6H, m), 4.53-4.83 (1H, m), 5.57-6.13 (2H, m), 8.18 (2H, s)

(2) 2-cyclopentyloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 160 to 165 캜 (decomposition)

I.R (New sol): 3470, 3290, 3200, 2400, 1715, 1615, 1600, 1520

NMR (d ₆ -DMSO, δ): 1.17-2.10 (8H, m), 4.60-4.97 (1H, m), 8.22 (2H, s)

(3) 2-cycloheptyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point 116 to 119 캜 (decomposition)

IR (New sol): 3250, 3200, 1650, 1600, 1520, 1400, 1260, 1150, 1000, 820, 720cm ^-1

[Manufacturing Method 6]

)에 용해시킨 4-(3-아미노프로필)모트프틴(122.6g) 용액을 0℃이하에서 물(420m

)에 용해시킨 97%수산화나트륨(35.1g)의 용액에 첨가하고 0 내지 5℃에서 0.5시간 동안 카본디설피드(64.71g)을 방울방울 첨가한다. 혼합물을 같은 온도에서 1시간 동안 교반하고 여기에 0내지 5℃에서 0.5시간 동안 요오드화 메틸(120.65g)를 첨가한다. 생성혼합물을 같은 온도에서 2시간 동안 교반하며 참조물을 여과에 의해수집 물로 세척(X2)하고 건조시켜 4-〔3-{N-메틸티오(티오카보닐)아미노 프로필〕모르포린(174.55g)의 인한노란색분말을 얻는다.(1) Dioxan (520m)

Solution of 4- (3-aminopropyl) morphtine (122.6 g) dissolved in water)

) Was added to a solution of 97% sodium hydroxide (35.1 g) and dropwise carbon disulfide (64.71 g) was added at 0-5 ° C. for 0.5 h. The mixture is stirred at the same temperature for 1 hour and thereto is added methyl iodide (120.65 g) at 0-5 ° C. for 0.5 hours. The resulting mixture was stirred for 2 hours at the same temperature and the reference was washed (X2) with water by filtration and dried to collect 4- [3- {N-methylthio (thiocarbonyl) amino propyl] morpholine (174.55 g). Yellow powder is obtained.

NMR (d ₆ -DMSO, δ): 1.73 (2H, m), 2.3 (6H, m), 2.48 (3H, s), 3.2-3.9 (6H, m), 9.91 (1H, brs)

)에 용해시킨 4-〔3-{N-메틸티오(티오카보닐)아미노 프로필〕모르포린(152g)의 용액에 물(290m)에 용해시킨 소디움아자이드(42.25g)의 용액을 첨가한다.(2) Dioxan (430m)

Water (290 m) in a solution of 4- [3- {N-methylthio (thiocarbonyl) amino propyl] morpholine (152 g) dissolved in A solution of sodium azide (42.25 g) dissolved in) is added.

The resulting mixture is refluxed for 2 hours and the reaction mixture is evaporated, adjusted to pH 8 and washed with diethyl ether. The aqueous layer is adjusted to pH5 and cooled. The precipitate is collected by filtration, washed with ice-water (X2) and dried to give white crystals of 1- (3-morpholinopropyl) -1 H-tetrazol-5-thiol (116 g). Melting Point 210 ~ 212 ℃

IR (New sol): 3550, 3500, 2350, 1610, 1410, 1360, 1280, 1190, 1130, 1090, 1050, 990, 880, 825, 785cm ^-1

NMR (d ₆ -DMSO, δ): 2.14- (2H, m), 2.99 (2Ht, = 7Hz), 3.09 (4H, m), 3.79 (4H), 4.24 (2H, t J = 7Hz)

[Manufacturing Method 7]

(1) The following compound is obtained in the same manner as in Production Process (1). 1- [3- {N-methylthio (thiocarbonyl) amino) propyl] -piperidine white powder melting point 74 to 76 ° C

IR (New sol): 3450, 3150, 1670, 1560, 1410, 1340, 1315, 1255, 1030, 1000, 950, 880, 800, 750cm ^-1

(2) The following compound is obtained in the same manner as in Production Method 6 (2). 1- (3-piperidinopropyl) -1H-tetrazol-5-thiol melting point 142-144 ° C. (decomposition)

IR (New sol): 3500, 3350, 2450, 1635, 1360, 1280, 1200, 1185, 1120, 1100, 1085, 1070, 1000, 965, 950, 810cm ^-1

NMR (d ₆ -DMSO, δ): 1.3-1.9 (6H, m), 2.20 (2H, m), 3.07 (2H, t, J = 7H z), 3.07 (4H, m), 4.24 (2H, t J = 7 Hz)

[Manufacturing Method 8]

)에 용해시킨 테트라부틸암모늄 브로마이드(3.22g)의 혼합물에 -20℃에서 에틸 클로로포름에이트(108.5g)를 첨가한다. 혼합물에 물(200m

)에 용해시킨 시안산나트륨(49g)의 용액을 -10 내지 -13℃에서 15분간 걸쳐 첨가하고 생성 혼합물을 -13℃에서 1분간 교반한다.(1) methylene chloride (300m

To a mixture of tetrabutylammonium bromide (3.22 g) dissolved in) is added ethyl chloroformate (108.5 g) at -20 ° C. Water in the mixture (200 m

A solution of sodium cyanate (49 g) dissolved in) is added over 15 minutes at -10 to -13 占 폚 and the resulting mixture is stirred at -13 占 폚 for 1 minute.

The organic layer is separated from the reaction mixture, dried over magnesium sulfate and raised to room temperature.

)을 대기압에서 증류시켜 에틸시아노포름에이트(335m

)를포함하는 용액을 얻는다. 비점 42 내지 117℃The methylene chloride layer is decanted and the insoluble material is washed with methylene chloride. Mixed methylene chloride layer (370 m)

) Was distilled at atmospheric pressure to give ethyl cyanoformate (335 m).

Obtain a solution containing Boiling Point 42-117 ° C

)에서 얻어진 용액에 첨가한다. 생성용액을 -5내지 5℃에서 6시간 교반, -10℃로 냉각하고 여기에 염화 메틸렌(400m

)을 첨가한다.(2) Method 8 (1) (335 m) comprising ethyl cyanoformate, cooled at -10 ° C, and hydrochloric acid (32.5 g) solution dissolved in ethanol (34.5 g).

To the solution obtained). The resulting solution was stirred at -5 to 5 DEG C for 6 hours, cooled to -10 DEG C and methylene chloride (400 m

Add).

)와 물(200m

)에 용해시킨 트리에틸 아민(85.8g)의 용액을 -5내지 0℃에서 방울방울 첨가한다. 염화메틸렌층을 분리, 물(200m

×2)로 세척, 마그네슘 설펄이트로 건조하고 증발시켜 78.8% 에틸 2-아미노-2-에톡시아세테이트를 포함하는 생성물(112g)을 얻는다. 본 생성물을 증류(비점 80 내지 88℃/40mmHg)에 의해 정제시켜 순수 생성물을 얻는다.Methylene chloride (80 m) in the mixture

) And water (200 m

A solution of triethyl amine (85.8 g) dissolved in) is added dropwise at -5 to 0 ° C. Separate methylene chloride layer, water (200 m

X2), dried over magnesium sulphite and evaporated to afford the product (112 g) comprising 78.8% ethyl 2-amino-2-ethoxyacetate. The product is purified by distillation (boiling point 80-88 ° C./40 mmHg) to give pure product.

)에 용해시킨 포타슘 티오시안에이트(31.0g)을 30분간에 걸쳐 방울방울 첨가한다. 생성 혼합물을 -10 내지 -5°에서 15분간 교반하고 0내지 5℃에서 부가적으로 1.5시간 교반한다.(3) A mixture of ethyl 2-amino-2-ethoxyacetate (60 g) (purity 78.8%) and ammonium chloride (17.4 g) dissolved in methanol (180 ()) was stirred at room temperature for 3 hours and then -15 to -10. Cool down to C. In a resulting mixture containing 1-methoxycarbonylformamidine hydrochloric acid, bromine (51.2 g) for 10 minutes and triethylamine (71.7 g) for 30 minutes in methanol (150 m)

Potassium thiocyanate (31.0 g) dissolved in) was added dropwise over 30 minutes. The resulting mixture is stirred for 15 minutes at -10 to -5 ° and for an additional 1.5 hours at 0-5 ° C.

)을 첨가한다. 혼합물을 교반하고 침전물을 여과에 의해 수집, 얼음물로 세척하고 건조시켜 5-아미노-1,2,4-티아디아졸-3-카복실레이트(32.54g)을 얻는다.The precipitate was collected by filtration, washed with methanol and iced water (200 m

Add). The mixture is stirred and the precipitate collected by filtration, washed with ice water and dried to give 5-amino-1,2,4-thiadiazole-3-carboxylate (32.54 g).

)에 용해시킨 에틸시아노포름 에이트(25.0g)의 용액에 염산(16.8g)의 43.5% 에탄올성용액을 첨가하며 3℃에서 교반한다. 혼합물을 3내지 5℃에서 5시간 교반하고 -5내지 -3℃에서 철야 방치한다. 생성혼합물을 6℃이하에서 염화메틸렌(120m

)를 첨가하고 염화메틸렌(20m

)에 용해시킨 트리에틸아민의 용액을 6℃이하에서 30분간 첨가한다. 혼합물을 40분간 교반하고 여기에 6℃이하에서 물(40m

)을 첨가한다. 생성혼합물을 3분간 교반하고 염화 메틸렌층을 분리, 마그네슘 설페이트로 건조시킨 후 증발시킨다. 잔류물에 디이소프로필 에테르(40m

)를 첨가한 후, 불용성물질을 여과에 의해서 분리하고 디이소프로필 에테르(10m

)로 세척한다. 여과물과 세척물을 혼합하고 증발시켜 연한 노란색오일인 에틸 2-이미노-2-에톡시아세테이트(26.2g)을 얻는다.(4) methylene chloride (55 m

43.5% ethanol solution of hydrochloric acid (16.8 g) was added to a solution of ethyl cyanoformate (25.0 g) dissolved in the solution) and stirred at 3 ° C. The mixture is stirred for 5 h at 3-5 ° C. and left overnight at −5 to −3 ° C. The resulting mixture was methylene chloride (120 m) below 6 ° C.

) And methylene chloride (20 m

The solution of triethylamine dissolved in) is added at 6 ° C. or lower for 30 minutes. Stir the mixture for 40 minutes and add water (40 m or less)

Add). The resulting mixture is stirred for 3 minutes, the methylene chloride layer is separated, dried over magnesium sulfate and evaporated. Diisopropyl ether (40m on residue)

) Was added, the insoluble matter was separated by filtration and diisopropyl ether (10m

). The filtrate and washings are mixed and evaporated to afford ethyl 2-imino-2-ethoxyacetate (26.2 g) as a pale yellow oil.

Obtain ethoxy acetate (26.2 g).

)에 용해시킨 염화암모늄(6.42g)의 혼합물을 상온에서 2시간 교반하고 여기에 디이소프로필 에테르(450m

)를 첨가한다. 혼합물을 빙-냉각시키고 30분간 교반한다. 침전물을 여과에 의해 수집하여 백색분말인 1-메톡시카보닐 포름아미딘 염산(13.8g)을 얻는다.The obtained oil (26.2 g), methanol (90 m

), A mixture of ammonium chloride (6.42 g) was stirred at room temperature for 2 hours, and diisopropyl ether (450 m) was added thereto.

Add). The mixture is ice-cooled and stirred for 30 minutes. The precipitate is collected by filtration to give 1-methoxycarbonyl formamidine hydrochloric acid (13.8 g) as a white powder.

Melting Point 150-155 ° C (Decomposition)

IR (New sol): 330-3050, 1780, 1710, 1695, 1290, 1270, 1070, 980, 800cm ^-1

NMR (d ₆ -DMSO, δ): 3.97 (3H, s, 9.8 (4H, br.s)

)에 용해시킨 1-메톡시카보닐포름 아미딘 염산(7.6g)의 용액에 브로민(8.8g)을 -5내지 0에서 5분간에 걸쳐 방울방울 첨가한다. 혼합물에 트리에틸아민(11.1g)을 10분간 첨가하고, 메탄올(30m

)에 용해시킨 포타슘티오시안에이트(5.3g)의 용액에 -5 내지 0℃에서 20분간에 걸쳐 첨가한다. 혼합물을 0내지 5(℃)에서 1.5시간 교반시키며 침전물을 여과에 의해 수집 메탄올(11m

)로 세척, 건조시키고 여기에 물(15.5m

)을 첨가한다. 혼합물을 30분간 교반하고 침전물을 여과에 의해 수집, 물(5m

×3)로 세척하고 건조시켜 백색분말인 메틸-5-아미노-2-1,2,4-티아디아졸-3-카복실에이트(6.3g)을 얻는다.(5) methanol (55 m

To a solution of 1-methoxycarbonylform amidine hydrochloric acid (7.6 g) dissolved in), bromine (8.8 g) is added dropwise over -5 to 0 to 5 minutes. Triethylamine (11.1 g) was added to the mixture for 10 minutes, and methanol (30 m)

To a solution of potassium thiocyanate (5.3 g) dissolved in) over 20 minutes at -5 to 0 ° C. The mixture was stirred for 1.5 h at 0-5 (° C.) and the precipitate was collected by filtration.

), Dry and add water (15.5m)

Add). The mixture was stirred for 30 minutes and the precipitate was collected by filtration, water (5 m

X3) and dried to obtain white powder of methyl-5-amino-2-1,2,4-thiadiazole-3-carboxylate (6.3 g).

)에 용해시킨 암모늄 브로마이드(21.2g)의 혼합물을 상온에서 4시간 동안 교반하고 여기에 디이소프로필에테르(400m

)를 교반하면서 첨가한다. 혼합물을 30분간 방치시키며 침전물을 여과에 의해 제거한다. 여과물에 디이소프로필에테르(200m

)를 첨가하고 혼합물을 10분간 방치시킨다. 침전물을 여과에 의해 수집하여 백색분말인 메톡시카보닐포름 아미드하이드로브로마이드(16.1g)의 백색분말을 얻으며, 여과물을 150m

체적으로 농축시킨다.(6) ethyl-5-amino-2-ethoxyacetate (36.2 g), methanol (180 m)

), A mixture of ammonium bromide (21.2 g) was stirred at room temperature for 4 hours, and diisopropyl ether (400 m) was added thereto.

) Is added with stirring. The mixture is left for 30 minutes and the precipitate is removed by filtration. Diisopropyl ether (200 m) in the filtrate

) Is added and the mixture is left for 10 minutes. The precipitate was collected by filtration to obtain a white powder of methoxycarbonylform amide hydrobromide (16.1 g) as a white powder. The filtrate was 150 m.

Concentrate by volume.

Diisopropyl ether (200m) in concentrate ) Is added and the mixture is left for 30 minutes.

The precipitate is collected by filtration to give the same compound (11.6 g) as a white powder.

Total yield: 27.7g

IR (New sol): 3350-3150, 1780, 1750, 1690, 1290, 1270, 1060, 980, 850, 800, 730cm ^-1

NMR (d ₆ -DMSO, δ): 3.91 (3H, s), 11.0 (4H, br.s)

)에 용해시킨 염화암모늄(5.8g)의 혼합물을 상온에서 6시간 동안 교반하며, 불용성 물질을 여과에 의해 분리하고 에탄올로 세척한다.여과물과 세척물을 혼합하고 증발시키며 잔류오일에 아세톤(50m

)을 첨가한다.침전물을 여과에 의해 수집하고 아세톤(10m

×2)로 세척하고 백색분말인 1-에톡시카보닐포름아마이드 염산(1.2g)을 얻는다. 여과물과 세척물을 혼합하고 증발시키며 잔류물을 아세톤(30m

)로 분쇄, 여과에 의해 수집, 아세톤, 염화메틸렌와 디이소프로필에테르로 연속적으로 세척하여 백색분말인 같은 화합물(7.3g)을 얻는다.(7) ethyl-2-amino-2-ethoxy acetate (18.1 g), ethanol (90 m

The mixture of ammonium chloride (5.8 g) dissolved in) was stirred at room temperature for 6 hours, the insoluble materials were separated by filtration and washed with ethanol. The filtrate and the washings were mixed, evaporated and acetone (50 m) in residual oil.

The precipitate is collected by filtration and acetone (10 m)

X2) and white powder of 1-ethoxycarbonylformamide hydrochloric acid (1.2 g) is obtained. The filtrate and washings are mixed and evaporated and the residue is washed with acetone (30 m).

), Collected by filtration, washed successively with acetone, methylene chloride and diisopropyl ether to obtain the same compound (7.3 g) as a white powder.

Total yield: 8.5g

IR (New sol): 3400-3100, 1770, 1730, -1680, 1650, 1300-1260, 1120, 1010, 860, 760cm ^-1

[Manufacturing Method 9]

Method for preparing methyl-5-amino-1,2,4-thiadiazole-3-carbolate

)에 용해시킨 1-에톡시카보닐포름아마이드 브롬산(16.6g)의 용액에 무수메탄올(42m

)에 용해시킨 염수(1.93g)용액을 0℃에서 첨가한다. 혼합물에 브로민(12.8 g)과 무수메탄올(42m

)에 용해시킨 소디움(1.93g)용액을 (0℃)에서 차례대로 첨가한 후 현탁액에 무수메탄올(100m

)에 용해시킨 포타슘 티오시안에이트(8.1g)을 첨가한다. 반응 혼합물을 0℃에서 1시간 교반하고 부가적으로 주위 온도에서 6시간 교반한다. 혼합물을 셀룰로오스 분말을 통하여 여과시키고 여과물을 증발하여 건조시킨다. 잔류물을 에틸아세테이트와 물의혼합물에 용해시킨 후 에틸아세테이트층을 분리하고 무수 마그네슘 설페이트로 건조시킨다.Anhydrous methanol (84m

Methanol (42 m) in a solution of 1-ethoxycarbonylformamide bromic acid (16.6 g) dissolved in

A solution of brine (1.93 g) dissolved in) is added at 0 ° C. Bromine (12.8 g) and anhydrous methanol (42 m)

Sodium (1.93 g) solution dissolved in) was added sequentially at (0 ° C) and anhydrous methanol (100 m) was added to the suspension.

Potassium thiocyanate (8.1 g) dissolved in) is added. The reaction mixture is stirred at 0 ° C. for 1 hour and additionally at ambient temperature for 6 hours. The mixture is filtered through cellulose powder and the filtrate is evaporated to dryness. The residue is dissolved in a mixture of ethyl acetate and water, the ethyl acetate layer is separated and dried over anhydrous magnesium sulfate.

The solvent is evaporated and the residue is treated with diethyl ether to give the title compound (9.0 g).

Melting Point 202-205 ℃

IR (New sol): 3400, 3250, 3100, 1710, 1610, 1540cm ^-1

NMR (d ₆ -DMSO, δ): 3.85 (3H, s), 8.25 (2H, s)

[Manufacturing Method 10]

Method for preparing methyl-5-formamido-1,2,4-thiadiazole-3-carbosylate

To the mixture of formic acid (33 g) and acetyl anhydride (22 g) is added methyl-5-formamido-1,2,4-thiadiazole-3-carbosylate (6.2 g), and the mixture is then cooled at ambient temperature. Stir for hours. The reaction mixture is concentrated under reduced pressure and the residue is treated with a mixture of diethyl ether and n-hexane to give the title compound (7.2 g).

Melting Point 210-215 ° C

IR (New sol): 3100, 1720, 1680cm ^-1

NMR (d ₆ -DMSO) δ: 3.90 (3H, s), 8.85 (1H, s)

[Manufacturing Method 11]

Method for preparing methyl-5-formamido-3- (2-methylthio-2-methylsulfacetyl) -1,2,4-thiadiazole

)에 용해시킨 메틸메틸오메틸 설폭사이드(6.1g)의 혼합물에 50% 소디움 하이드라이드(7.1g)를 얼음욕으로 냉각하면서 혼합물을 주위온도에서 1시간 동안 교반하고 부가적으로 40℃에서 1시간 동안 교반한다. 주위온도로 냉각한후, 염화메틸렌(300m

)를 반응 혼합물에 첨가하고 생성 침전물을 여과에 의해 수집하고 염화메틸렌으로 세척한다. 침점물을 염산(14.7m

),얼음-물(200m

)와 염화 메틸렌(200m

)의 교반된 혼합물에 첨가하며 불용성물질을 여과 제거하고 염화 메틸렌층을 여과물로 분리시킨다. 용액을 무수 마그네슘 설페이트로 건조, 증발시키고 잔류물을 디에틸에테르로 처리하여 표제화합물(4.5g)을 얻는다. 융점 130내지 132℃Methyl-5-formamido-1,2,4-thiamiazole-3-cacarboxylate (9.2 g) and NN-dimethylformamido (100 m)

In a mixture of methylmethylomethyl sulfoxide (6.1 g) dissolved in a), 50% sodium hydride (7.1 g) was cooled in an ice bath, and the mixture was stirred at ambient temperature for 1 hour and additionally at 40 ° C for 1 hour. Stir while. After cooling to ambient temperature, methylene chloride (300 m)

) Is added to the reaction mixture and the resulting precipitate is collected by filtration and washed with methylene chloride. Hydrochloric acid (14.7m)

), Ice-water (200 m

) And methylene chloride (200 m)

), The insolubles are filtered off and the methylene chloride layer is separated by filtrate. The solution is dried over anhydrous magnesium sulfate, evaporated and the residue is treated with diethyl ether to give the title compound (4.5 g). Melting Point 130 ~ 132 ℃

IR (New sol): 3100, 1680, 1670cm ^-1

NMR (d ₆ -DMSO)

[Manufacturing Method 12]

Method for preparing s-methyl (5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxylate

)에 용해시킨 과요오드화 나트륨(0.2g)의 혼합물을 70℃에서 45분간 교반한다.5-formamido-3- (2-methylthio-2-methylsulfacetyl) -1,2,4-thiadiazole (0.85 g) and glacial acetic acid 10 m

The mixture of sodium periodate (0.2 g) dissolved in) is stirred at 70 ° C. for 45 minutes.

)을 얻는다.The reaction mixture is evaporated and the residue is dissolved in a mixture of ethyl acetate and water. The mixture is adjusted to pH 7 with aqueous sodium bicarbonate solution and treated with an aqueous solution of sodium thiosulfate. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was treated with a mixture of diethyl ether and petroleum ether to give the title compound (280m

Get)

Melting point 186 to 187 ° C

IR (New sol): 3100, 1680, 1660cm ^-1

NMR (d ₆ -DMSO) δ: 2.55 (3H, s), 8.95 (1H, s)

[Manufacturing Method 13]

)에 용해시킨 과요오드화 나트륨(2.0g)의 혼합물을 70에서 50분간 교반한다. 용매를 증발시키고 잔류물을 n-헥산으로 세척한다. 잔류물에 수산화나트륨(16m

)의 /N수성용액을 첨가하고 혼합물을 주의온도에서 1시간 교반한다. 반응혼합물에 0-알릴하이드록실아민 염산(4.31g)를 첨가하고 용액을 10%염산으로 pH3 내지 4로 맞춘후에 주위온도에서 1시간동안 교반한다.5-formamido-3- (2-methylthio-2-methylsulfacetyl) -1,2,4-thiadiazole (10 g) and glacial acetic acid (50 m

The mixture of sodium periodate (2.0 g) dissolved in) is stirred for 70-50 minutes. The solvent is evaporated and the residue is washed with n-hexane. Sodium hydroxide (16m

/ N aqueous solution is added and the mixture is stirred at ambient temperature for 1 hour. 0-allyl hydroxylamine hydrochloric acid (4.31 g) is added to the reaction mixture, the solution is adjusted to pH 3-4 with 10% hydrochloric acid, and then stirred at ambient temperature for 1 hour.

After filtering off the insoluble material, the filtrate was washed with ethyl acetate, adjusted to pH with 10% hydrochloric acid and extracted with ethyl acetate. The extract is dried over magnesium sulfate and evaporated to dryness. The residue was treated with a mixture of diethyl ether and diisopropyl ether to give 2-allyloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer). (5.6 g) is obtained.

Melting Point 169-172 ° C (Decomposition)

IR (New sol): 3130, 2500, 1720, 1690, 1590, 1550cm ^-1

NMR (d ₆ -DMSO): 4.79 (2H, d, J = 6 Hz) 5.1-5.6 (2H, m), 5.8-6.4 (11H, m), 8.88 (1H, s)

(1) 2-benzyloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 90 to 95 DEG C (decomposition)

IR (New sol): 1720, 1680, 1590, 1550, 1530cm ^-1

NMR (d ₆ -DMSO) δ: 5.28 (2H, s), 7.37 (5H, s), 8.83 (1H, s)

(2) 2- (2-propynoxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 150 to 155 占 폚 (decomposition) )

IR (New sol): 3570, 3360, 326, 03120, 1720, 1760, 1550, 1530 cm ^-1

NMR (d ₆ -DMSO) δ: 3.55 (1H, t, J = 2 Hz), 4.88 (2H, d, J = 2 Hz), (8.85 (1 H, s)

(3) 2- (2-phenoxyethoxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point 147 to 150 캜 (decomposition) )

IR (New sol): 3200, 1740, 1720, 1640, 1590, 1530cm ^-1

NMR (d ₆ -DMSO) δ: 4.0-4.7 (4H, m), 6.7-7.5 (5H, m), 8.3 (1H, s)

(4) 2-hydroxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 240 to 241 ° C (decomposition)

IR (New sol): 3350, 3460, 1655, 1635, 1560cm ^-1

[Manufacturing Method 15]

)의 1N수용액에 용해시킨 s- 메틸(5-포름아미도-1,2,4-티아디아졸-3-일) 티오글리옥실 레이트(6.64g)의 용액을 10%염산으로 pH8.5 맞추고 주위온도에서 30분간 교반한다. 다른한편, N-(2,2,2-트리플우오토에톡시)프탈이미드(8.178g)과 에탄올(40m

)에 용해시킨 하이드라진 하드레이트(1.7g)의 혼합물을 5분간 환류시킨 후 얼음욕에서 냉각한다. 생성 침전물을 여과 제거하고 에탈올로 세척한다.Sodium hydroxide (80 m

A solution of s-methyl (5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxylate (6.64 g) dissolved in 1N aqueous solution) was adjusted to pH8.5 with 10% hydrochloric acid. Stir for 30 minutes at ambient temperature. On the other hand, N- (2,2,2-triple autoethoxy) phthalimide (8.178g) and ethanol (40m

The mixture of hydrazine hydrate (1.7 g) dissolved in) is refluxed for 5 minutes and then cooled in an ice bath. The resulting precipitate is filtered off and washed with ethanol.

The filtrate and washes are mixed and a mixed solution comprising 0- (2,2,2-trifluorotoethyl) hydroxyl amine is added to the aqueous solution.

The mixture is adjusted to pH 3-4 with 10% hydrochloric acid and stirred at cold temperature for 1.5 hours. The solution is neutralized with aqueous sodium bicarbonate solution, the volume is concentrated in half in vacuo and washed with ethyl acetate. The aqueous solution is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate, evaporated to dryness, and the residue was treated with diisopropyl ether to give 2- (2,2,2-trifluorooethoxyimino) -2- (5-formamido- 1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (2.46 g) is obtained.

Melting point 180 to 185 ° C (decomposition)

NMR (d ₆ -DMSO) δ: 4.80 and 5.07 (2H, ABq, J = 9Hz), 8.85 (1H, s)

[Manufacturing Method 16]

The following mixture is obtained according to the same method as Preparation Method 15.

(1) 2-methylthiomethoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point 146 to 148 ° C (decomposition)

IR (New sol): 3300, 2600, 2550, 1730, 1705, 1680, 1600, 1530cm ^-1

NMR (d ₆ -DMSO) δ: 2.23 (3H, s), 5.40 (2H, s), 8.87 (1H, s)

(2) 2- (2-methylthioethoxyimino) -2-((5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

IR (New sol): 3230, 1720, 1690, 1590, 1520cm ^-1

NMR (d ₆ -DMSO) δ: 2.17 (3H, s), 2.82 (H, t, J = 7 Hz), 4.42 (2H, t, J = 7 Hz), 8.87 (1H, s)

(3) 2--phenoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point 145 to 147 ° C (decomposition)

IR (New sol): 3130, 1720, 1690, 1595, 1550cm ^-1

NMR (d ₆ -DMSO) δ: 7.0-7.6 (5H, m), 8.88 (1H, s)

(4) 2- [2- (2-hexyloxyethoxy) ethoxyimino] -2-((5-formamido-1,2,4-thiazol-3-yl) acetic acid (syn isomer)

IR (New sol): 3420, 3180, 1740, 1700, 1600, 1530, 1460 cm ^-1

NMR (d ₆ -DMSO) δ: 0.87 (H, t, J = 5 Hz), 0.87-1.73 (8H, m), 3.20-3.90 (8H, m), 4.23-4.53 (2H, m), 8.84 (1H) , s) 13.55 (1H, br.s)

(5) 2-trityloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 188 to 190 deg.

IR (New sol): 3150, 1620, 1600, 1540cm ^-1

NMR (d ₆ -DMSO) δ: 7.00 (15H, s) 8.92 (1H, s)

[Manufacturing Method 17]

)의 혼합물을 50내지 55에서 1시간동안 교반한다. 혼합물을 주위온도로 냉각하고 10%염산으로 pH7로 맞춘다. 다른 한편, N-(에톡시카보닐메톡시)프탈이미드(12.9g)와 에탄올(60m

)에 용해시킨 하아드진하이드레이트(2.08g)의 혼합물을 분간환류시키고 얼음욕에서 냉각한다.생성침전물을 여과제거하고 에탄올로 세척한다. 여과물과세척물을 혼합하고 50O-(에톡시카보닐메틸)-하이드록실아민을 포함하는 혼합된 용액을 상기수성액에 첨가한다.S-methyl (5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxy oxylate (6 g) and sodium hydroxide (4.2 g) aqueous solution (50 m

A) is stirred at 50-55 for 1 h. The mixture is cooled to ambient temperature and adjusted to pH 7 with 10% hydrochloric acid. On the other hand, N- (ethoxycarbonylmethoxy) phthalimide (12.9 g) and ethanol (60 m

The mixture of hardazine hydrate (2.08 g) dissolved in) is refluxed for a minute and cooled in an ice bath. The resulting precipitate is filtered off and washed with ethanol. The filtrate and the wash are mixed and a mixed solution comprising 50O- (ethoxycarbonylmethyl) -hydroxylamine is added to the aqueous solution.

The mixture is adjusted to pH 3-4 with 10% hydrochloric acid and stirred at ambient temperature for 1.5 hours. The solution is neutralized with aqueous sodium bicarbonate solution and the volume is concentrated in half in vacuo and washed with ethyl acetate. The aqueous solution is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate, evaporated to dryness and the residue was treated with diisopropyl ether.

2-Ethoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (1.8 g) is obtained. Melting Point 135-140 ° C (decomposition)

IR (New sol): 3500, 3350, 3210, 2670, 2550, 1740, 1610, 1540cm ^-1

NMR (d ₆ -DMSO)

δ: 1.24 (3H, t, J = 7 Hz), 4.14 (2H, q, J7 Hz), 4.80 (2H, s) 8.15 (2H, br.s)

[Manufacturing Method 18]

The following compounds are obtained according to the same method as in Preparation 17.

(1) 2-cyanomethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point 130 to 135 DEG C (decomposition)

IR (New sol): 3350, 3150, 1730, 1630, 1540cm ^-1

NMR (d ₆ -DMSO) δ: 5.17 (2H, s), 8.28 (2H, br.s)

(2) 2- (1-ethoxycarbonyl-1-methylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting point 165 to 168 ° C (decomposition)

IR (New sol): 3450, 3350, 3240, 1750, 1730, 1630, 1530cm ^-1

NMR (d ₆ -DMSO)

δ: 1.18 (3H, t, J = 7th), 1.50 (6H, s), 4.15 (2H, q, J = 7 Hz), 8.23 (2H, br.s)

(3) 2- (NN-diethylcarbamoylmethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) Melting point 150 to 155 캜 (decomposition) )

IR (New sol): 3400, 3150, 1745, 1635, 1610, 1595 cm ^-1

NMR (d ₆ -DMSO)

δ: 1.05 (3H, t, J = 7 Hz), 1.10 (3H, t, J, 7 Hz 3.28 (4H, q, J = 7 Hz), 4.90 (2H, s), 8.23 (2H, br.s)

(4) 2-methylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

IR (New sol): 3450, 3400, 3270, 2600, 2460, 1735, 1640, 1620, 1530cm ^-1

NMR (d ₆ -DMSO) δ: 3.00 (3H, s), 5.38 (2H, s), 8.22 (2H, br.s)

[Manufacturing Method 19]

The following compounds are obtained following methods analogous to preparation method 4.

(1) 2-allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (neomer) melting point 93 to 95 ° C

(decomposition)

IR (New sol): 3430, 3100, 1710, 1525cm ^-1

NMR (d ₆ -DMSO) δ: 4.27 (2H, d, J = 6Hz), 5.1-5.5 (2H, m), 5.7-6.3 (1H, m), 8.17 (1H, br.s)

(2) 2-benzyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point 158 to 160 ° C (decomposition)

IR (New sol): 3430, 3380, 3260, 1730, 1640, 1610, 1535cm ^-1

NMR (d ₆ -DMSO) δ: 5.22 (2H, s), 7.33 (5H, s), 8.17 (2H, br.s)

(3) 2- (2-propynyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 155 to 157 ° C (decomposition)

IR (New sol): 3500, 3310, 3160, 2600, 2480, 1745, 1610, 1535cm ^-1

NMR (d ₆ -DMSO) δ: 3.53 (1H, t, J = 2 Hz), 4.87 (2H, d) J = 2 Hz) 8.23 (2H, br.s)

(4) 2- (2-phenoxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) Melting point 150-153 DEG C (decomposition)

IR (New sol): 3470, 3300, 3150, 2550, 1750, 1620, 1600, 1540, 1500cm ^-1

NMR (d ₆ -DMSO) δ: 4.0-4.7 (4H, m), 6.7-7.5 (5H, m), (8.20 (2H, br.s)

(5) 2- (2,2,2-trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point (140 to 140) 143 ° C (decomposition)

IR (New sol): 3450, 3350, 3260,1745, 1670, 1645, 1615cm ^-1

NMR (d ₆ -DMSO) δ: 4.72 and 4.95 (2H, ABq, J = 9 Hz) 8.25 (2H, br.s)

(6) 2-methylthiomethoxyimino-2-15-amino-1,2,4-thiadiazol-3-yl) acetic acid (new isomer) melting point 140 to 143 deg.

IR (New sol): 3500, 3300, 3510, 2670, 2580, 1740, 1615, 1605, 1530cm ^-1

NMR (d ₆ -DMSO) δ: 2.22 (3H, s), 5.33 (2H, s), 8.20 (2H, br.s)

(7) 2- (2-methylthioethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) Melting point 140 to 143 캜 (decomposition)

IR (New sol): 3430, 3340, 3230, 2650, 2450,1720, 1610, 1520cm ^-1

NMR (d ₆ -DMSO) δ: 2.08 (3H, s), 2.72 (2H, t, J = 7 Hz), 4.28 (2H, t, J = 7 Hz), 8.17 (2H, br.s)

(8) 2-phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 143-147 캜 (decomposition)

IR (New sol): 3350, 3170, 2500, 1730, 1710, 1645, 1630, 1595, 1535cm ^-1

NMR (d ₆ -DMSO) δ: 7.0-7.5 (5H, m), 8.30 (2H, br.s)

(9) 2- (2-hexyloxyethoxy) ethoxyimino] -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

IR (CHCl ₃ ): 3350, 3230, 2600, 2500, 1730, 1620, 1520, 1460 cm ^-1

NMR (d ₆ -DMSO)

δ: 0.87 (3H, t, J = 5 Hz), 0.87-1.78 (8H, m), 3.20-3.90 (8H, m), 4.13-4.47 (2H, m), 8.17 (2H, br.s)

(10) 2-trityloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point 173 to 174 ° C

IR (New sol): 3450, 1735, 1620,1540cm ^-1

NMR (d ₆ -DMSO) δ: 7.33 (15H, s), 8.22 (2H, s)

(11) 2-trityl oxoimino-2- (5-amino-1,2,4-thiadiazol-30yl) acetic acid (syn isomer) melting point 170 to 171 ° C

IR (New sol): 3300, 3150, 1680, 1635, 1520cm ^-1

NMR (d ₆ -DMSO) δ: 7.33 (15H, s), 8.13 (2H, s)

[Manufacturing Method 20]

)에 용해시킨 디클로로이세틸클로라이드(9.0g)의 혼합물을 주위온도에서 6.5시간 교반한다. 생성침전물을 여과하고 에틸아세테이트에 용해시킨다.3.3 g of 2-hydroxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) and methylene chloride (50 m)

A mixture of dichloroacetyl chloride (9.0 g) dissolved in) is stirred at ambient temperature for 6.5 hours. The resulting precipitate is filtered and dissolved in ethyl acetate.

After the insoluble matter is removed by filtration, the filtrate is evaporated to dryness. The residue was treated with diisopropyl ether to give 2-dichloroacetoxy-imino-2- (5-formamido-2-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) ( 2.3 g). Melting point 123 ℃

IR (new sol) 7 3150, 1790, 1690, 1550 cm ^-1

[Manufacturing Method 21]

)의 혼합물에 주위온도에서 교반되면서 트리틸클로라이드(22.8g)를 첨가하고 트리에틸아민(4.1g)을 3분후에 교반하면서 첨가한다. 생성혼합물을 10분간 교반하고 에틸아세테이트로(250m

)를 여기에첨가한다. 혼합물을 물과 포화염 수용액으로 3번세척 ,마그네슘 설페이트로 건조시키고 농축시킨다. 잔류물에 소디움비 카본에이트(50m

)의 수성용액과 디이소프로필에테르(100m

)를 첨가한다.2-hydroxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) and dimethylformamido (9.5 g) (80 m

Trityl chloride (22.8 g) is added to the mixture of N 2 while stirring at ambient temperature and triethylamine (4.1 g) is added with stirring after 3 minutes. The resulting mixture was stirred for 10 minutes and ethylacetate (250 m

) Is added here. The mixture is washed three times with water and an aqueous saturated salt solution, dried over magnesium sulfate and concentrated. Sodium bicarbonate (50m)

) Aqueous solution and diisopropyl ether (100m)

Add).

The precipitate is collected by filtration and the aqueous layer is separated from the filtrate. The collected precipitate is suspended in saturated aqueous layer and ethyl acetate is added thereto. The mixture is adjusted to pH 2 2- with 10% hydrochloric acid and extracted with ethyl acetate.

The extract is dried over magnesium sulfate and concentrated in vacuo. The residue is treated with hexane to give 2-trityloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid. (syn isomer) (17.1 g) is obtained. Melting Point 175-196 ℃ (Decomposition)

IR (New sol): 3180, 3070, 1700, 1500, 1540cm ^-1

NMR (d ₆ -DMSO) δ: 7.35 (15H, s), 8.83 (1H, s), 13.52 (1H, br.s)

[Manufacturing Method 22]

)에 용해시킨 N-(3-아미노프로필)아세트 아미드(146g)의 용액을 물(620m

)에 용해시킨 97%소디움 하이드록사이드(52g)의 용액에 첨가한 후 카본디설피드(96g)을 -1내지 3℃에서 35분간에 걸쳐 방울방울 첨가한다. 혼합물을 0내지 2℃에서 1시간 동안 교반하며, 소디움N-(3-아세트아미도프로필)디옥오카바메이트를 포함하는 혼합물에 요요드화메틸(179g)를 0내지 5℃에서 35분간 걸쳐 방울방울 첨가한 후 생성혼합물을 같은 온도에서 3시간 동안 교반한다. 디옥산을 반응 혼합물로부터 진공에서 증류 제거하고 잔류물을 에틸아세테이트(300m

,200m

×4)로 추출한다. 마그네슘 설페이트로 건조시키고 진공에서 농축하여 오입인 메틸 N-(3-아세트아미도프로필)디옥오 카바메이트(193.18g)를 얻는다.(1) Dioxane (710m

Solution of N- (3-aminopropyl) acetamide (146 g) dissolved in water)

) Was added to a solution of 97% sodium hydroxide (52 g), followed by dropwise addition of carbon disulfide (96 g) at −1 to 3 ° C. over 35 minutes. The mixture was stirred for 1 hour at 0-2 ° C., and methyl iodide (179 g) was dropped over 35 minutes at 0-5 ° C. in a mixture containing sodium N- (3-acetamidopropyl) dioxocarbamate. After addition the resulting mixture is stirred at the same temperature for 3 hours. Dioxane was distilled off from the reaction mixture in vacuo and the residue was purified by ethyl acetate (300m).

, 200 m

4 ×). Dry over magnesium sulfate and concentrate in vacuo to afford the methyl N- (3-acetamidopropyl) dioxo carbamate (193.18 g) as an integrant.

)에 용해시킨 메틸 N-(3-아세트아미도프로필)디옥오 카바메이트(193g)용액과 물(500m

)에 용해시킨 소디움아자이드(79.42g) 용액의 혼합물을 교반하면서 4시간동안 환류시킨다.(2) Dioxane (610m

Solution of methyl N- (3-acetamidopropyl) dioxocarbamate (193g) and water (500m)

The mixture of sodium azide (79.42 g) solution dissolved in) is refluxed for 4 hours with stirring.

×2)로 세척하여 17.5%염산으 pH로 맞추고 얼음옥에서 냉각한다. 침전물을 여과에의해 수집하고 얼음-물로 세척하여 백색분말인 1-(3-아세트아미도프로필)-1H-5-테트라졸-9-티올(91.75g)을 얻는다. 융점 152 내지 154℃Dioxane was distilled off and the remaining aqueous layer was diluted with diethyl ether (150m).

× 2), adjust the pH to 17.5% hydrochloric acid and cool in ice jade. The precipitate is collected by filtration and washed with ice-water to give the white powder 1- (3-acetamidopropyl) -1H-5-tetrazol-9-thiol (91.75 g). Melting Point 152-154 ° C

NMR (d ₆ -DMSO)

δ: 1.87 (3H, s), 1.97 (2H, m), 3.17 (2H, m), 4.28 (H, t, J = 7 Hz), 7.9 (1H, br.s), 15.0 (1H, br.s )

)의 혼합물을 교반하에서 75분간 환류시킨다. 반응 혼합물은 진공에서 농축시키고 침전물을 여과에 의해 수집하고 헥산과 디에틸 에테르로 세척하여 1-(3-아미노프로필)-1H-5-테트라졸-9-티올염산(67.15g)을 얻는다.(3) 1- (3-acetamidopropyl) -1H-5-tetrazol-9-thiol (85 g) with 6N hydrochloric acid (1

) Is refluxed for 75 minutes under stirring. The reaction mixture is concentrated in vacuo and the precipitate is collected by filtration and washed with hexane and diethyl ether to give 1- (3-aminopropyl) -1H-5-tetrazol-9-thiol hydrochloric acid (67.15 g).

NMR (D ₂ O) δ: 2.45 (2.45 (2H, m), 3.23 (2H, t, J = 7 Hz), 4.50 (2H, t, J = 7 Hz),

)에 용해시킨 2-t-부톡시카보닐옥시아미노-2-페닐아세토니트릴(12.3g)의 용액을 1-(3-아미노프로필)-1H-테트라졸-5-티올염산(9.78g)의 교반된 용액과 디옥산(25m

)와 물(25m

)의 혼합물에 용해시킨 트리에틸 아민(11.1g)에 빙냉하에서 첨가한후 생성 혼하물은 주위온도에서 1.75시간 교반한다. 디옥산을 증류제거시키고 잔류물에 디에틸에테르의 소량의 물을 첨가한다. 진탕시킨 후, 수성층을 분리하고 유기층을 10%탄산 칼륨으로 두번 추출한다.(4) Dioxane (30m

Solution of 2-t-butoxycarbonyloxyamino-2-phenylacetonitrile (12.3 g) was dissolved in 1- (3-aminopropyl) -1H-tetrazol-5-thiol hydrochloride (9.78 g). Stirred solution and dioxane (25m

) And water (25m

After triethyl amine (11.1 g) dissolved in the mixture of the mixture under ice-cooling, the resulting mixture was stirred at ambient temperature for 1.75 hours. Dioxane is distilled off and a small amount of diethyl ether is added to the residue. After shaking, the aqueous layer is separated and the organic layer is extracted twice with 10% potassium carbonate.

The extract combined with the separated aqueous layer was washed three times with diethyl ether, adjusted to pH 1 with hydrochloric acid and extracted with diethyl ether. The extract is washed with water, dried and evaporated in vacuo.

The residual oil (10.92 g) is triturated with diisopropyl ether to give 1- [3- (N-t-butoxycarbonylamino) propyl] -1H-tetrazol-5-thiol (9.6 g). Melting Point 75 ~ 77 ℃

IR (New sol): 3380, 3260, 1650, 1530, 1170, 1050cm ^-1

NMR (CDCl ₃ )

δ: 1.50 (9H, s), 2.14 (2H, m), 3.25 (2H, m), 4.39 (H, t, J = 7 Hz), 4.9-6.7 (1H, br.s)

[Manufacturing Method 23]

)에서 용해시킨 요드(7.7g)의 교반된 용액에 첨가하고 혼합물을 35내지 40℃온도에서 1.5시간 동안 교반시킨다. 아세트무수물(30m

)를 10℃에서 0.5시간 동안 여기에 첨가한 후 1,2-디클로로벤젠(44.69g)을 10℃하에서 0.5시간 첨가한다.Sulfuric acid (70 m) with potassium iodide (20.0 g) at ambient temperature

Is added to a stirred solution of iodine (7.7 g) dissolved in) and the mixture is stirred for 1.5 h at 35-40 ° C. Acetic anhydride (30m

) Is added thereto at 10 ° C. for 0.5 hours and then 1,2-dichlorobenzene (44.69 g) is added at 10 ° C. for 0.5 hours.

)에 붓고 디에틸에테르로 세척한다. 수성층에 염(8.9g)을 수용액(50m

)에 첨가하고 침전물을 여과에 의해 수집하고 얼음-물로 세척하여 3,4,3',4-테트라클로로디페닐 요도늄 클로라이드(58g)을 얻는다. 융점 183 내지 186℃(분해)The mixture is stirred at the same temperature for 1 hour and then stirred for 19 hours at ambient temperature. The reaction mixture is ice-water (500 m

) And washed with diethyl ether. Aqueous salt (8.9 g) was added to the aqueous layer (50 m

) And the precipitate is collected by filtration and washed with ice-water to give 3,4,3 ', 4-tetrachlorodiphenyl iodonium chloride (58 g). Melting point 183 to 186 ° C (decomposition)

IR (New sol): 1555, 1450, 1250, 1210, 1170, 1125, 1030cm ^-1

[Manufacturing Method 24]

The following compounds are obtained according to methods analogous to preparation 23.

(1) 3.3'-di (trifluoromethyl) diphenyl iodonium chloride

IR (New sol): 3600-3200, 1600, 1420, 1320, 1310, 1190, 1170, 1120, 1095, 1085, 1055, 800, 700, 685cm ^-1

(2) 3.3'-dicarboxydiphenyl iodonium broide

(New sol): 3400, 1700, 1290, 1210, 1170, 1050, 750cm ^-1

(3) 3.3 '-(3) 3,3'-di (ethoxycarbonyl) diphenyl iodonium bromide, melting point 154-157 (캜)

IR (New sol): 1730, 1295, 1280, 1255, 1110, 1020, 750cm ^-1

[Manufacturing Method 25]

The following compounds are obtained according to methods analogous to preparation methods 1- (2) and 1- (2). (1) N- (2-phthalimido propoxy) phthalamide, melting point 168-170 degreeC

IR (New sol): 1790, 1770, 1730, 1710, 1390, 1060, 725, 705cm ^-1

(2) N- (1-cyclohexyloxycarbonylethoxy) phthalamide melting point 50 to 54

C (d ₆ -DMSO, δ): 1.51 (3H, d, J = 7 Hz), 0.6-2.1 (10H, m), 4.7 (1H, m), 4.82 (1H, q, J = 7 Hz), 7.87 ( 4H, s)

(3) N- (α-t-butoxycarbonylbenzyloxy) phthalimide

(4) N- (1-t-butoxycarbonyl-2-methylpropoxy) phthalimide, melting | fusing point 84-87 degreeC

IR (New sol): 1790, 1730, 1360, 1140, 1000, 800, 780, 700cm ^-1

(5) N- (1-t-butoxycarbonylpropoxy) phthalimide, melting point 49-52

C (d ₆ -DMSO, δ): 1.02 (3H, t, J = 7 Hz), 1.40 (9H, s), 1.9 (2H, m), 4.55 (1H, t, J = 6 Hz), 7.82 (4Hs)

(6) N- (1-t-butoxycarbonylethoxy) phthalimide, melting | fusing point 80-82 degreeC

NMR (d ₆ -DMSOδ): 1.42 (9H, s), 1.48 (3H, d, J = 7 Hz), 4.72 (1H, f, J = 7 Hz), 7.86 (4H, s)

(7) N- (1-t-butoxycarbonyl-1-methoxyethoxy) phthalimide, melting point 96-100 degreeC

NMR (d ₆ -DMSOδ): 1.42 (9H, s), 1.48 (6H, s), 7.87 (4H, s)

(8) N- (1-butoxycarbonylethoxy) phthalimide, melting | fusing point 48-53 degreeC

IR (New sol): 1755, 1720, 1210, 1140, 1110, 1080, 875, 695 cm ^-1

(9) N- (1-benzyloxycarbonylethoxy) phthalimide, melting point 65-68 degreeC

IR (New sol): 1790, 1740, 1450, 1210, 1190, 1110, 1080, 980, 880, 735, 700cm ^-1

(10) N- (2-oxo-3-tetrahydropyryloxy) phthalimide, melting point 140-142 degreeC

IR (New sol): 1785, 1760, 1720, 1605, 1215, 1185, 870, 695 cm ^-1

[Manufacturing Method 26]

The following compounds are obtained following methods analogous to preparation method 2.

(1) 3-aminopropoxyamine dihydrochloride

NMR (D ₂ O, δ): 2.20 (2H, m), 3.27 (2H, t), J = 7H), 4.33 (2H, t, J = 6 Hz)

(2) 1-phenylethoxyamine

(3) 1-t-butoxycarbonyl-2-methylpropoxyamine

(4) α-t-butoxycarbonyl benzyloxamine

(5) 1-butoxycarbonylethoxyamine

[Manufacturing Method 27]

The following compounds are obtained following methods analogous to preparation 17.

(1) 2- (t-butoxycarbonyl methoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point 150 to 155 ° C (decomposition) )

IR (New sol): 3420, 3230, 3100, 1725, 1610, 1530cm ^-1

NMR DMSO-d ₆ , s): 1.45 (9H, s), 4.70 (2H, s), 8.12 (2H, br.s)

(2) 2- (1-cyclohexyl oxycarbonyl ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point 175 to 180 占 폚 ( decomposition)

IR (New sol): 3380, 3260, 3170, 1720, 1610, 1520, 1220, 990, 710cm ^-1

NMR (d ₆ -DMSO, δ): 0.9-2.1 (13H, m), 4.7 (1H, m), 4.85 (1H, f, J = 6Hz), 8.13 (2H, s)

(3) 2- (thiorin-1,1-dioxide-3-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point 200 To 205 ° C (decomposition)

IR (New sol): 3300, 1720, 1620, 1530cm ^-1

NMR (d ₆ -DMSO, δ): 2.20-2.50 (2H, m), 3.00-3.50 (4H, m), 5.00-5.27 (1H, m), 8.20 (2H, s)

(4) 2- (α-t-butoxycarbonyl benzyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point 155 to 160 ° C (decomposition)

IR (New sol): 3440, 3350, 3250, 1750, 1730, 1640, 1535cm ^-1

NMR (d ₆ -DMSO, δ): 1.37 (9H, s), 5.67 (1H, s), 7.45 (5H, s), 8.25 (2H, br.s)

(5) 2- (1-t-butoxycarbonyl-2-methylpropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point 158-162 degreeC (decomposition)

IR (New sol): 3600, 3400, 1740, 1720, 1630cm ^-1

NMR (d ₆ -DMSO, δ): 0.95 (6H, d, J = 7 Hz), 1.8-2.4 (1H, m), 4.33 (1H, d, J = 6 Hz), 8.B, br.s)

(6) 2- (1-t-butoxycarbonylpropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point 152 to 155 ° C (decomposition)

NMR (d ₆ -DMSO, δ): 0.94 (3H, t, J = 7 Hz), 1.42 (9H, s), 1.80 (2H, m), 4.51 (1H, t, J = 6 Hz), 8.16 (2H, br.s)

(7) 2- (1-t-butoxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) Melting point 155-156 degreeC (decomposition)

IR (New sol): 3400, 3300, 3200, 1720, 1710, 1620, 1520cm ^-1

NMR (d ₆ -DMSOδ): 1.2-1.7 (12H, m), 4.72 (1H, q, J = 7 Hz), 8.2 (2, br.s)

(8) 2- (1-t-butoxycarbonyl-1-methylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point 180 to 181 ° C (decomposition)

IR (New sol): 3400, 3300, 3200, 1745, 1515, 1630, 1530, 1530cm ^-1

NMR (d ₆ -DMSO, δ): 1.38 (9H, s), 1.43 (6H, s), 8.15 (2H, br.s)

(9) 2- (1-butoxycarbonyl-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) Melting point 120 to 123 ° C ( decomposition)

IR (New sol): 3400, 3300, 3200, 1725, 1615, 1510, 1410, 1210, 1170, 1135, 1100, 1040, 990, 870, 720cm ^-1

IMR (d ₆ -DMSO, δ): (0.85 (3H, t, J = 6Hz), 1.43 (3H, d, J = 7Hz), 1.0 = 1.7 (4H, m), 4.12 (3H, t, J = 6Hz), 4.85 (1H, f, J = 7Hz (, 8.04 (2H, br.s) 7.45 (5H, s), 8.25 (2H, br.s)

(10) 2- (1-benzyloxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) Melting point 129 to 133 ° C (decomposition) )

IR (New sol): 3300, 3200, 1720, 1620, 1530cm ^-1

NMR (DMSO-d ₆ , δ): 1.45 (3H, d, J = 6 Hz), 4.97 (H, q, J = 6 Hz), 5.18 (2H, s), 7.31 (5H, s), 8.17 (2H, br.s)

[Manufacturing Method 28]

The following compounds are obtained according to the method of Preparation 15.

(1) 2- (thiolin-1,1-dioxide-3-yloxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) Melting Point 214 ° C (Decomposition)

IR (New sol): 3200, 1720, 1680, 1600, 1530cm ^-1

NMR (DMSO-d _6, δ): 2.30-2.50 (2H-, m), 2.90-3.83 (4H, m), 5.10-5.50 (1H, m), 8.92 (1H, 8.92 (1H, s)

(2) 2- (1-phenylethoxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) Melting point 174 to 175 캜 (decomposition)

IR (New sol): 3100, 1720, 1690, 1550cm ^-1

NMR (d ₆ -DMSO, δ): 1.58 (3H, d, J = 6 Hz), 5.44 (1H, q, J = 6 Hz), 7.32 (5H, m), 8.78 (1H, m), 13.34 (1H, br.s)

[Manufacturing Method 29]

)에 용해시킨 2-t-부톡시카보닐옥시이미노-2-페닐아세트니트릴(27g)의 용액을 첨가하고 혼합물을 주위온도에서 2시간동안 디옥산을 증발시킨후, 수성용액을 10%염산으로 pH6맞추고 에틸아세테이트로 세척한다. 수성층에 에틸아세테이트를 첨가하고 혼합물을 10%염산으로 pH3으로 맞춘다. 유기층을 소금물로 세척마그네슘 설페이트로 건조하고 증발하여 건조시킨다.Sodium 2- (3-aminopropoxy imino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetate (syn isomer) prepared in a similar manner to preparation method 15 Triethylamine (20g) and dioxane (270m) in an aqueous solution containing

A solution of 2-t-butoxycarbonyloxyimino-2-phenylacetnitrile (27 g) dissolved in) was added and the mixture was evaporated at dioxane for 2 hours at ambient temperature, and then the aqueous solution was diluted with 10% hydrochloric acid. Adjust to pH 6 and wash with ethyl acetate. Ethyl acetate is added to the aqueous layer and the mixture is adjusted to pH 3 with 10% hydrochloric acid. The organic layer is dried over brine magnesium sulfate and evaporated to dryness.

The residue was treated with diisopropyl ether to give 2- [3- (Nt-butoxycarbonylamino) propoxyimino] -2 (5-formamido-1,2,4-thiadiazol-3-yl ) Acetic acid (syn isomer) (14.2 g) is obtained. Melting Point 115-117 ° C (Decomposition)

IR (New sol): 3320, 3150, 1740, 1680, 1560-1530, 1400, 1230, 1140, 1440, 1030, 860cm ^-1

NMR (DMSO-d ₆ , δ): 1.47 (9H, s), 1.97 (2H, m), 3.10 (2H, t, J = 7Hz), 4.30 (2H, t, J = 7Hz), 8.80 (1H, s)

[Manufacturing Method 30]

The following compounds are obtained following methods analogous to preparations 13 and 29.

(1) 2- (Nt-butoxycarbonylamino) ethoxyimino] -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 139 To 154 ° C (decomposition)

IR (New sol): 3400, 3150, 1748, 1700, 1690, 1540cm ^-1

NMR (DMSO-d ₆ + D ₂ O, δ), 3.40 (2H, t, J = 6 Hz), 4.32 (2H, t, J = 6 Hz), 8.07 (1H, s)

(2) 2- [4- (N-t-butoxycarbonylaminomethyl) benzyloxyidino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

IR (New sol): 3300, 3150, 1700cm ^-1

NMR (DMSO-d ₆ , δ): 1.65 (9H, s), 4.12 (2H, d, J = 5.5), 5.19 (2H, s), 7.21 (4H, s)

[Manufacturing Method 31]

The following compounds are obtained following methods analogous to preparation method 4.

(1) 2- [2- (Nt-butoxycarbonylamino) ethoxyimino] -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 172-177 ° C (decomposition)

IR (New sol): 3300, 3140, 1738, 1680, 1628, 1595, 1550, 1527, 1285, 1245, 1165, 1120cm ^-1

NMR (DMSO-d ₆ + D ₂ O, δ): 1.42 (9H, s), 3.35 (2H, t, J = 6Hz), 4.22 (2H, t, J = 6Hz)

(2) 2- [3- (N-t-butoxycarbonylamino) propoxyimino] -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

IR (New sol): 3300, 3150, 2600-2400, 1720-1660, 1620, 1530, 1250, 1160, 1030, 720cm ^-1

NMR (DMSO-d ₆ , δ): 1.33 (9H, s), 1.82 (2H, s), 3.03 (2H, s), 4.17 (2H, t, J = 6Hz), 6.73 (1H, br.s)

(3) 2 (4-chlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 150-155 占 폚 (decomposition)

IR (New sol): 3300, 3200, 1710, 1640,1580, 1530cm ^-1

,J=9Hz), 7.67(2H,d,J=9Hz), 8.50(2H, br.s)NMR (DMSO-d ₆ , δ): 7.37 (2H,

, J = 9 Hz, 7.67 (2H, d, J = 9 Hz), 8.50 (2 H, br.s)

(4) 2- (4-fluorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 140-145 ° C. (decomposition)

IR (New sol): 3450, 3300, 3200, 1730, 1630, 1530, 1500cm ^-1

NMR (DMSO-d ₆ , δ): 7.17 (2H, s), 7.27 (2H, s), 8.27 (2H, s)

(5) 2- [1-t-butoxycarbonyl-1-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 174-175 ° C (decomposition)

IR (New sol): 3400, 3300, 3200, 1745, 1751, 1630, 1530cm ^-1

NMR (d _6- DMSO, δ): 1.37 (9H, s), 1.65 (4H, m), 1.97 (4H, m) 8.17 (2H, (b rs)

(6) 2- (1-phenoxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 103-107 ° C. (decomposition)

IR (New sol): 3250, 3150, 1710, 1610, 1520cm ^-1

NMR (d _6- DMSO, δ): 1.57 (3H, d, J = 6 Hz), 5.42 (1H, q, J = 6H) 7.40 (5H, m), 8.20 (2H, m)

[Manufacturing Method 32]

)와 수산화나트륨의 1N수용액(83.7m

)로 부터 제조된 메탄올성 수산화나트륨 수용액에 용해시킨 2-하이드록시아미노-2-(5-포름아미도-1,2,4-티아디아졸-3-일)아세트산(syn 이성체)(7.2g)에 4,4'-디플루오로디페닐 요도늄 클로라이드(11.8g)을 첨가하고 혼합물을 주위온도에서 1시간동안 교반한다.Methanol (83.7 m

) And 1N aqueous solution of sodium hydroxide (83.7m

2-hydroxyamino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (7.2 g) dissolved in an aqueous methanolic sodium hydroxide solution prepared from ), 4,4'-difluorodiphenyl iodonium chloride (11.8 g) is added and the mixture is stirred at ambient temperature for 1 hour.

The resulting oily substance is removed by decantation and the solution is concentrated under reduced pressure to remove methanol. The aqueous solution is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and evaporated to dryness. The residue was treated with diisopropyl ether to give 2- (4-fluorophenoxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (6.0 g) is obtained. Melting Point 130-135 ° C (Decomposition)

IR (New sol): 3100, 3050, 1730, 1690, 1530, 1500cm ^-1

NMR (DMSO-d ₆ , δ): 7.17 (2H, s), 7.27 (2H, s), 8.83 (1H, s), 13.42 (1H, s)

[Manufacturing Method 33]

The following compounds are obtained by methods analogous to preparation 32.

(1) 2- (4-chlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (6.0 g) is obtained. Melting point 155 to 160 ° C (decomposition)

IR (New sol): 3180, 1725, 1690, 1580, 1530cm ^-1

NMR (DMSO-d ₆ , δ): 7.30 (2H, d, J = 9 Hz), 7.57 (2H, d, J = 9 Hz), 9.0 (1H, s)

(2) obtaining 2- (2-methoxy-5-nitrophenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (6.0 g) Melting point 125 to 128 ° C. (decomposition)

IR (New sol): 3400, 3280, 1740, 1690, 1630, 1590, 1510, 1340, 1275, 970, 720cm ^-1

NMR (DMSO-d ₆ , δ): 3.93 (3H, s), 7.27 (1H, d, J = 8Hz), 8.01 (1H, d, J = 8H z), 8.07 (1H, s), 8.30 (2H , br.s)

[Manufacturing Method 34]

The following compounds are obtained by methods analogous to preparation 21. 2- (1-t-butoxycarbonyl-1-cyclopentyloxyimino) -2- (5-formamido-1,22,4-thiadiazol-3-yl) acetic acid (syn isomer) melting point 140 To 141 ° C (decomposition)

IR (New sol): 3550, 1730, 1550, 1540, 1280, 1255, 1150, 980, 720cm ^-1

NMR (DMSO-d ₆ , δ): 1.48 (9H, s), 1.83 (4H, m), 2.03 (4H, m), 8.87 (1H, s), 13.6 (1H, br.s)

[Manufacturing Method 35]

2-hydroxy imino-2-hydroxy imino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn Isomers) are obtained in a similar manner to Preparation 32 using the starting material.

(1) 2- [0- and p-tolyloxoimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

NMR (DMSO-d ₆ , δ): 2.20 (1H, s), 2.27 (2H, s), 6.97-7.43 (4H, m), 8.33 (2H, bs.s)

(2) 2- (3,4-dichlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 177 to 178 ° C

IR (New sol): 3300, 1710, 1625, 1585, 1530, 1300, 1210, 1120, 980cm ^-1

NMR (DMSO-d ₆ , δ): 6.83-7.73 (1H, m) 8.38 (2H, br.s)

(3) 2- (3-trifluoromethylphenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 167-168 degreeC

IR (New sol): 3250, 1645, 1620, 1570, 1450, 1320, 1170, 1140, 101, 995, 845, 730 cm ^-1

NMR (DMSO-d ₆ , δ): 7.63 (4H, m), 8.44 (2H, br.s)

(4) 2- (3-ethoxycarbonylphenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 161 to 164 ° C ( decomposition)

IR (New sol): 3400, 3300, 3180, 1755, 1720, 1690, 1630, 1590, 1545, 1410, 1290, 1275, 970, 900, 755cm ^-1

NMR (DMSO-d ₆ , δ): 1.36 (3H, t, J = 7 Hz), 4.40 (12H, q, J = 7 Hz), 7.4-8.0 (3H, m), 8.5 (2H, br.s)

(5) 2- (3-carboxyphenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 186 to 188 ° C

IR (New sol): 3420, 3150, 1735, 1690, 1620, 1580, 1265, 1200, 1000, 980, 760cm ^-1

NMR (DMSO-d ₆ , δ): 7.3-8.0 (4H, m), 8.30 (2H, br.s)

(6) 2-phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 145 to 147 ° C (decomposition)

IR (New sol): 3350, 3170, 2500, 1730, 1710, 1645, 1630, 1595, 1535cm ^-1

NMR (DMSO-d ₆ , δ): 7.0-7.5 (5H, m), 8.30 (2H, br.s)

[Manufacturing Method 36]

)와 물(200m

)의 혼합물을 1시간 환류시켜 제조한 1-카복시-3-하이드록시프로폭시아민을 제조방법 17과 유사한 방법으로 처리하여s-methyl (5-formamido-1,2,4-thiadiazol-3-yl) -thioglyoxylate (64,8 g) and N- (2-oxo-3-tetrahydropyryloxy) pral Imide (65.0g), concentrated hydrochloric acid (50m

) And water (200 m

1-carboxy-3-hydroxypropoxyamine prepared by refluxing the mixture for 1 hour was treated in a similar manner to Preparation 17.

Obtain 2- (1-carboxy-3-hydroxypropoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (33.2 g) Melting point 186 To 188 ° C (decomposition)

IR (New sol): 3400, 3250, 3100, 1710, 1620, 1540cm ^-1

NMR (DMSO-d ₆ , δ): 1.73-2.10 (2H, m), 3.50 (2H, t, J = 6Hz),, 4.73 (1H, t, J = 6Hz), 8.13 (2H, s)

[Manufacturing Method 37]

)에 용해시킨 2-(1-카복시-3-하이드록시프로폭시이미노-2-(5-아미노-1,2,4-티아디아졸-3-일)아세트산(syn 이성체)의 용액에 무수마그네슘 설페이트(120g)와 아세트 무수물(60g)을 첨가한다. 혼합물을 주위온도에서 30분간 교반, 여과하고 여과물을 증방하여 증가시킨다. 잔류물을 아세톤(200m

)에서 처리하고 에틸 아세테이트(1

)를 첨가한다. 혼합물을 주위온도에서 1시간 교반하고 침전물을 여과에수집하고 에틸 아세테이트로 세척한다.Methanol (2.8

Magnesium anhydride in a solution of 2- (1-carboxy-3-hydroxypropoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) dissolved in Sulfate (120 g) and acetic anhydride (60 g) are added The mixture is stirred at ambient temperature for 30 minutes, filtered and the filtrate is increased to increase the residue to acetone (200 m).

) And ethyl acetate (1

Add). The mixture is stirred at ambient temperature for 1 hour and the precipitate is collected by filtration and washed with ethyl acetate.

)에서 용해하고 에틸 아세테이트(500m

)아세톤(200m

)와 6N염산)40m

)을 여기에 첨가한다. 유기층을 분리제거하고 수성층을 에틸아세테이트로 세척한다. 잔류물을 디에틸 에테르로 세척, 여과하고 디이소프로필 에테르로 세척하여 2-(2-옥소-3-테트라하이드로푸릴옥시이미노-2-(5-아미노-1,2,4-티아디아졸-3-일)아세트산(syn 이성체)(26.5g)을 얻는다.Sediment into water (200m)

) In ethyl acetate (500 m

Acetone (200 m

) And 6N hydrochloric acid) 40m

) Is added here. The organic layer is separated off and the aqueous layer is washed with ethyl acetate. The residue was washed with diethyl ether, filtered and washed with diisopropyl ether to give 2- (2-oxo-3-tetrahydrofuryloxyimino-2- (5-amino-1,2,4-thiadiazole- 3-yl) acetic acid (syn isomer) (26.5 g) is obtained.

Melting Point 185-187 ° C (Decomposition)

IR (New sol): 3400, 3300, 3200, 1775, 1730, 1640, 1605, 1535cm ^-1

NMR (DMSO-d ₆ , δ): 2.27-2.70 (2H, m), 4.17-4.50 (2H, m,, 5.27 (1H, t, J = 8Hz), 8.22 (2H, s)

[Manufacturing Method 38]

(1) The following compound is obtained by a method similar to the preparation method 22- (1). Methyl-N- (6-acetamidohexyl) dithiocarbamate

NMR (DMSO-d ₆ , δ): 1.33 (3H, br.s), 1.80 (3H), 2.50 (3H, s), 3.07 (2H, m), 3.53 (2H, m), 7.77 (1H, m ), 9.80 (1 H, m)

(2) The following compound is obtained by a method similar to Preparation 22- (2). (a) 1- (4-acetamidobutyl) -1H-tetrazolo-5-thiol

IR (New sol): 3300, 1620, 1560, 1520cm ^-1

NMR (DMSO-d ₆ , δ): 1.23-1.93 (4H, m), 1.77 (3H, s), 3.10 (2H, m), 4.23 (2H, m), 7.80 (1H, br.s)

(b) 2- (6-acetamidohexyl) -1H-tetrazolo-5-thiol, oil.

(3) The following compound is obtained by a method similar to Preparation 22- (3).

(a) 1- (4-aminobutyl) -1H-tetrazol-5-thiol hydrochloride, white powder.

(b) 2- (6-aminohexyl) -1H-tetrazol-5-thiol hydrochloride red oil

(4) The following compound is obtained by a method similar to Preparation 22- (4).

(a) 1-4- (N-t-butoxycarbonylamino) butyl-1H-tetrazole-5-thiol, melting point 107-108.5 ° C.

IR (New sol): 3200, 1640, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.37 (9H, s), 1.38-2.1 (4H, m), 2.97 (2H, m), 4.23 (2H, m), 6.73 (1H, br.s)

(b) 1- (6- (N-t-butoxycarbonylamino) hexyl) -1H-tetrazole-5-thiol

oil

NMR (d ₆ -DMSO, δ): 1.40 (15H, m), 1.77 (2H, m), 2.93 (2H, m), 4.20 (2H, m), 6.70 (1H, br.s)

[Manufacturing Method 39]

)에 용해시킨 N-(3-브로모프로필)프탈이미드(402g)의 용액에 1-메틸피페라진(225g)과 탄산칼륨(415g)을 첨가한다. 생성혼합물을 3.5시간 교반하며 반응 혼합물을 냉각하고 여과시킨다. 필터케이크를 아세톤(500m

)로 세척하며 여과물과 세척물을 혼합하고 감압하에서 증발시킨다. 잔류성 오일에 용해시킨 잔류출발물질을 벤젠으로 공비적으로 제거하여 N-〔2-(4-메틸-1-피페라지닐)-프로필프탈이미드(502g)을 얻는다.(1) acetone (2.5

1-methylpiperazine (225 g) and potassium carbonate (415 g) are added to a solution of N- (3-bromopropyl) phthalimide (402 g) dissolved in. The resulting mixture is stirred for 3.5 hours while the reaction mixture is cooled and filtered. Filter cake with acetone (500 m

), The filtrate and washings are mixed and evaporated under reduced pressure. The residual starting material dissolved in the residual oil was azeotropically removed with benzene to obtain N- [2- (4-methyl-1-piperazinyl) -propylphthalimide (502 g).

IR (Film): 1770, 1700cm ^-1

)에 용해시킨 N-〔3-(4-메틸-1-피페라지닐)-프로필프탈이미드(502g)에 100% 하이드라진하이드레이트(187.6g)을 환류시킨다. 생성혼합물을 1.5시간 환류시키며 반응혼합물을 냉각한 후 여과한다. 필터케이크를 에탄올(1

)로 세척, 여과물과 세척물을 혼합하고 감압하에서 증발시킨다. 잔류오일을 감압하에서 증류시켜 3-(4-메틸-1-피페라지닐)-프로필아민(146.6g)을 얻는다. 비점 34mmHg 127 내지 128℃(2) ethanol (3.0

100% hydrazine hydrate (187.6 g) was refluxed in N- [3- (4-methyl-1-piperazinyl) -propylphthalimide (502 g) dissolved in. The resulting mixture is refluxed for 1.5 hours and the reaction mixture is cooled and filtered. Filter cake is ethanol (1

), The filtrate and washings are mixed and evaporated under reduced pressure. The residual oil is distilled off under reduced pressure to afford 3- (4-methyl-1-piperazinyl) -propylamine (146.6 g). Boiling point 34mmHg 127-128 degreeC

)에 용해시킨 수산화칼륨(57.3g)의 용액에 3-(4-메틸-1-피페라지닐)-프로필프탈이미드(146g)을 첨가하고 카본디설피이드(70.6g)을 얼음냉각하에서 40분간 교반하면서 첨가한다. 생성혼합물을 얼음냉각하에서 3.5시간 교반한다. 반응혼합물을 감압하에서 증발시키며 잔류오일을 물(400m

)에 용해하고 디에틸 에테르로 두번 세척한다. 세척된 수성층을 얼음 냉각하고 여기에 요오드화 메틸(132.1g)을 교반하면서 첨가한다. 생성 혼합물을 얼음 냉각하에서 2번 냉각하고 여기에 요오드화 메틸(132.1g)을 교반하면서 첨가한다. 생성 혼합물을 얼음 냉각하에서 2번 교반하고 에틸 아세테이트(400m

×3)와 클로로포름(400m

×2)으로 추출시킨다.(3) methanol (250 m

To the solution of potassium hydroxide (57.3 g) dissolved in (), 3- (4-methyl-1-piperazinyl) -propylphthalimide (146 g) was added and carbon disulfide (70.6 g) was added for 40 minutes under ice cooling. Add while stirring. The resulting mixture is stirred for 3.5 hours under ice cooling. The reaction mixture is evaporated under reduced pressure and residual oil is evaporated in water (400m).

) And wash twice with diethyl ether. The washed aqueous layer is ice cooled and to this is added methyl iodide (132.1 g) with stirring. The resulting mixture is cooled twice under ice cooling and thereto is added methyl iodide (132.1 g) with stirring. The resulting mixture was stirred twice under ice cooling and ethyl acetate (400 m

× 3) and chloroform (400 m

X 2).

The extract is mixed, dried over magnesium sulfate and evaporated under reduced pressure to afford methyl N- [3- (4-methyl-1-piperazinyl) propyl] dithiocarbaate (139.3 g). The product obtained is used directly in the next reaction without further purification.

)와 에탄올(280m

)의 혼합물에 용해시킨 제조방법 39(3)에서 얻어진 메틸 3-〔4-메틸-1-피페라지닐)프로필〕디티오카바메이트(139.3g)의 용액에 소디움 아가이드(47.6g)를 첨가한다. 생성혼합물을 교반하면서 3시간동안 환류시키며 반응혼합물을 감압하에서 농축시킨다. 농축물을 에틸아세테이트와 디에틸에테르로 차례로 세척하고 증발시킨다. 잔류물에 에탄올을 첨가하고 혼합물을 여과한다. 여과물을 감압하에서 증발시키고 잔류오일에 6N염산을 첨가한다. 혼합물을 감압하에서 증발시키며 잔류물을 물을 포함하는 이소프로필 알콜로 재결정화시켜 1-〔3-(4-메틸-1-피페라지닐)프로필〕-1H-테트라졸-5-티올-디하드로클로라이드(48.1g)을 얻는다. 융점 239 내지 243℃(4) water (420m)

) And ethanol (280 m

Sodium amide (47.6 g) was added to a solution of methyl 3- [4-methyl-1-piperazinyl) propyl] dithiocarbamate (139.3 g) obtained in the preparation method 39 (3) dissolved in a mixture of do. The resulting mixture is refluxed for 3 hours with stirring and the reaction mixture is concentrated under reduced pressure. The concentrate is washed sequentially with ethyl acetate and diethyl ether and evaporated. Ethanol is added to the residue and the mixture is filtered. The filtrate is evaporated under reduced pressure and 6N hydrochloric acid is added to the residual oil. The mixture was evaporated under reduced pressure and the residue was recrystallized from isopropyl alcohol with water to give 1- [3- (4-methyl-1-piperazinyl) propyl] -1H-tetrazol-5-thiol-dihard Obtain low chloride (48.1 g). Melting Point 239-243 ° C

NMR (D ₂ O, δ): 2.3-2.8 (2H, m), 3.07 (2H, s) 3.3-3.7 (2H, s), 3.75 (8H, s), 4.42 (2H, t, J = 6Hz) .

Example 1

)에 용해시킨 포스포러스 펜타클로라이드의 냉각용액에 -15℃에서 2-(4-클로로페녹시이미노)-2-(5-아미노-1,2,4-티아디아졸-3-일)아세트산(syn 이성체)(650mg)을 첨가하고 혼합물을 같은온도에서 30분간 교반한다.Methylene chloride (10 m)

) Was dissolved in a cooling solution of phosphorus pentachloride at -15 ° C to 2- (4-chlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid ( syn isomer) (650 mg) and the mixture is stirred at the same temperature for 30 minutes.

)에 용해시킨 트리메틸실아세트아미드(2.1g)의 혼합물을 따뜻하게하여 용액을 투명하게한후 -20℃로 냉각한다. 용액을 -20℃에서 상기 활성화시킨 혼합물에 첨가하고 혼합물을 -15℃에서 40분간 교반한다.On the other hand, 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (785 mg) with methylene chloride (10 m)

The mixture of trimethylsilacetamide (2.1 g) dissolved in) is warmed to make the solution transparent and then cooled to -20 ° C. The solution is added to the activated mixture at −20 ° C. and the mixture is stirred at −15 ° C. for 40 minutes.

)의 냉각수용액에 붓고 주위온도에서 30분간 교반한다.The reaction mixture was added to sodium bicarbonate (20 m

Pour into the cooling water solution of) and stir for 30 minutes at ambient temperature.

Methylene chloride is distilled off and ethyl acetate is added to the residual aqueous solution. The mixture is adjusted to pH 3 or 4 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is dried over magnesium sulfate, treated with activated charcoal and evaporated to dryness. The residue is treated with diethyl ether and reprecipitated from a mixed solvent of acetone and diethyl ether.

The precipitate is dissolved in an aqueous sodium bicarbonate solution and the solution is adjusted to pH 1 or 2 with 10% hydrochloric acid to obtain a precipitate. The precipitate was collected by filtration and washed with water to give 7- [2- (4-chlorophenoxyimino) -2- (5-amino-1, 24-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) (0.35 g) Melting point 150-155 ° C. (decomposition)

IR (New sol): 3300, 3200, 1770, 1670, 1620, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 7.00-7.50 (4H, m), 3.67 (H, br.s), 8.22 (2H, s), 4.27 and 4.50 (2H, ABq, J = 14 Hz), 9.50 (1H, s), 5.17 (1H, d, J = 4 Hz), 9.80 (1H, d, J = 8 Hz). 5.80 (1H, doublet of doublets, J = 48 Hz),

Example 2

To a cooling solution of phosphorus pentachloride (1.04 g) dissolved in methylene chloride (25 ml), 2- (4-fluorophenoxyimino) -2- (5-amino-1, 2, 4-thia at -15 ° C Diazol-3-yl) acetic acid (syn isomer) (1.4 g) is added and the mixture is stirred at the same temperature for 30 minutes. On the other hand, trimethylsilylacetate dissolved in 7-amino-3- (1, 3, 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (1.65 g) and methylene chloride (25 ml) The mixture of amides (5 g) is warmed to make the solution clear and then cooled to -15 ° C. The solution is added to the activated mixture and the mixture is stirred at 0-5 ° C. for 1 hour.

The reaction mixture is concentrated and ethyl acetate and water are added to the residue. After the insoluble matters were filtered off, the ethyl acetate layer was poured into an aqueous solution of sodium bicarbonate. The aqueous layer was separated and added to ethyl acetate, adjusted to pH 4 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is dried over magnesium sulfate and evaporated to a volume of 10 ml. The precipitate was collected by filtration, washed with ethyl acetate and diethyl ether to give 7- [2- (4-fluorophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazole-3- Yl) -3-acetamido] -4- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-carboxylic acid (syn isomer) (1.2 g). Melting point 140 to 145 ° C (decomposition)

IR (New sol): 3300, 3200, 1770, 1680, 1620, 1520cm ^-1

NMR (d ₆ -DMSO, δ):

3.57 and 3.80 (2H, ABq, J = 18 Hz), 7.17-7.3 (4H, m),

4.27 and 4.57 (2H, ABq, J = 13 Hz), 8.20 (2H, s),

5.20 (1H, d, J = 4 Hz), 9.50 (1H, s)

5.87 (1H, dd, J = 4 and 8 Hz), 9.83 (1H, d, J = 8 Hz).

Example 3

In a cooling solution of phosphorus pentachloride (2.08 g) dissolved in methylene chloride (50 ml), 2-phenoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl at −15 ° C. ) Acetic acid (syn isomer) (2.64 g) is added and the mixture is stirred at the same temperature for 30 minutes. On the other hand, warm the mixture of 4-nitrobenzyl-7-amino-3-cepem-4-carboxylate (3.35g) and trimethylsilylacetamide (10g) dissolved in methylene chloride (50ml) to make the solution transparent. Cool to -15 ° C.

The solution is added to the activated mixture and the mixture is stirred at 0-5 ° C. for 0.5 hours. The reaction mixture is poured into a cooling solution of sodium bicarbonate (5.9 g) (100 ml). The methylene chloride layer is dried over magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether and the resulting powder was collected by filtration and dried to give 4-nitrobenzyl 7- [2-phenoxyimino-2- [5-amino-1, 2, 4-thiadiazole-3 -Yl) acetamido] -3-cepem-4-carboxylate (syn isomer) (5.1 g). Melting point 140 to 140 ° C (decomposition)

IR (New sol): 3300, 1775, 1720, 1680, 1625, 16001590, 1520cm ^-1

NMR (d ₆ -DMSO, δ):

3.60 (2H, broad singlet) 7.0-7.50 (5H, multimeter),

5.23 (1H, d, J = 4 Hz), 7.73 (2H, d, J = 8 Hz),

5.42 (2H, s), 8.27 (2H, d, J = 8 Hz),

6.00 (1H, dd, J = 4 and 8 Hz), 8.30 (2H, s)

6.67 (1H, t, J = 4 Hz), 9.97 (1H, d, J = 8 Hz).

Example 4

The following compounds are obtained according to methods analogous to Examples 1 to 3, 5 and 7 to 12.

(1) 7- [phenoxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) aceteamido] -3- (1-carboxymethylte-1H-triazole- 5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 175-180 ° C. (decomposition)

IR (New sol): 3400, 3200, 1770, 1700, 16601620, 1580, 1510cm ^-1

NMR (d ₆ -DMSO, δ):

3.70 (2H, b.rs) 5.89 (1H, dd, J = 4 and 8 Hz),

4.23 and 4.50 (2H, ABq, J = 14 Hz), 7.0-7.5 (5H, m),

5.17 (1H, d, J = 4 Hz), 8.22 (1H, s),

5.30 (2H, s), 9.83 (1H, d, J = 8 Hz)

(2) 7- [2-phenoxyimino-2- (5-amino-1, 2,4-thiadiazol-30yl) acetamido] -3- (1-allyl-1H tetrazol-5- Yl) -thiomethyl-3- (1-cepem-1H-carboxylic acid (syn isomer).

Melting Point 145 ° -150 ° C (Decomposition)

IR (New sol): 3450, 3350, 3180, 1710, 1680, 1610, 1590, 1510 cm ^-1

NMR (d ₆ -DMSO, δ):

3.70 (2H, broad), 5.93 (1H, doublet of doublets, J = 4 and 8 Hz),

4.28 and 4.45 (2H, ABq, J = 13 Hz), 5.67-6.30 (1H, m),

4.83-5.10 (2H, d), 7.0-7.57 (5H, m),

5.18 (1H, dd, J = 4 Hz), 8.30 (2H, s),

5.20-5.43 (2H, m), 9.92 (1H, d, J = 8 Hz)

(3) 7- [2-phenoxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1-methyl-1H-tetrazol- 5-yl) -thiomethyl-3-cepem-4-carboxylic acid (syn isomer), Melting point 155-158 ° C. (decomposition)

IR (New sol): 3400, 3300, 3200, 1770, 1720, 1680, 1620, 1590, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 3.77 (2H, br.s)

5.93 (1H, dd, J = 4 and 8 Hz), 7.0-7.67 (5H, m),

3.95 (3H, s), 8.37 (2H, s),

4.33 (2H, br.s) 10.0 (1H, d, J = 8 Hz)

5.27 (1H, doublet, J = 4 Hz),

(4) 7- [2-phenoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] cephalospotanic acid (syn isomer).

Melting Point 150-155 ° C (Decomposition)

IR (New sol): 3450, 3350, 3180, 1775, 1710, 1680, 1610, 1580, 1515 cm ^-1

NMR (d ₆ -DMSO, δ): 5.97 (1H, dd, J = 4 and 8 Hz),

2.03 (3H, s), 7.0-7.67 (5H, m),

3.62 (2H, broad singlet), 8.37 (2H, singlet),

4.77-5.03 (2H, ABq, J = 14 Hz) 9.97 (1H, d, J = 8 Hz

5.28 (1H, doublet, J = 4 Hz),

(5) 7- [2- (2-methoxy-5nitrophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- ( 1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 160-169 ° C. (decomposition)

IR (New sol): 3380, 3220, 3100, 1780, 1690, 1620, 1600, 1520, 1340, 1280, 1085, 1065, 820, 850cm ^-1

NMR (d ₆ -DMSO, δ): 7.33 (1H, d, J = 8 Hz),

3.71 (2H, m), 8.10 (1H, d, J = 8 Hz),

3.98 (3H, s) 8.19 (1H, s)

4.25-4.66 (2H, ABq, J = 14 Hz) 8.34 (2H, br.s),

5.23 (1H, d, J = 5 Hz), 9.58 (1H, s),

5.94 (1H, doublet of doublets, J = 5-9 Hz), 9.87 (1H, doublet, J = 9 Hz).

(6) 7- [2- (4-fluorophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3-tetrazolo [1 , 5-b] -pyridazin-6-yl) thiomethyl-3-cepem-carboxylic acid (syn isomer), melting point 125-130 ° C. (decomposition)

IR (New sol): 3300, 3190, 1770, 1670, 1615, 1520, 1495 cm ^-1

NMR (d ₆ -DMSO, δ): 7.35 (2H, s),

3.80 (2H, br.s) 7.80 (1H, d, J = 10 Hz)

4.30, 4.65 (2H, ABq, J = 13 Hz), 8.37 (2H, br.s),

5.27 (1H, d, J = 5 Hz), 8.62 (1H, d, J = 10 Hz)

5.95 (1H, dd, J = 5.8 Hz), 9.92 (1H, d, J = 8 Hz)

7.25 (2H, s),

(7) 4-nitrobenzyl 7- [2- (4-fluorophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- Cefem-4-carboxylate (syn isomer). Melting point 135-140 ° C. (decomposition).

IR (New sol): 3300, 3200, 1770, 1720, 1680, 1625, 1605, 1500, 1495 cm ^-1

NMR (d ₆ -DMS, δ): 7.08 (2H, s),

3.45-3.75 (2H, m), 7.18 (2H, s),

5.15 (1H, d, J = 5 Hz), 7.60 (2H, d, J = 8 Hz),

5.35 (2H, s) 8.13 (2H, d, J = 8 Hz),

5.92 (1H, doublet of doublets, J = 5.8 Hz), 8.17 (2H of broad s,),

6.58 (1H, t, J = 4 Hz) 9.75 (1H, d, J = 8 Hz)

(8) 7- [2- (4-chlorophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (5-hydroxy Methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (yn isomer)

Melting Point 135-140 ° C (Decomposition)

IR (New sol): 3450, 3280, 3180, 1760, 1720, 1660, 1620, 1580, 1520, 1480cm ^-1

NMR (d ₆ -DMSO, δ): 5.88 (1H, doublet of doublets, J = 5, 8 Hz),

3.72 (2H, broad singlet), 7.25 (2H, doublet, J = 9 Hz),

4.27, 4.55 (2H, ABq, J = 13 Hz), 7.42 (2H, d, J = 9 Hz),

4.80 (2H, s), 8.23 (2H, br.s),

5.22 (1H, d, J = 5 Hz), 9.85 (1H, d, J = 8 Hz)

(9) 7- [2- (4-chlorophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1-carboxymethyl -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 135-140 DEG C

IR (New sol): 3400, 3250, 3170, 1765, 1700, 1680, 1650, 1615, 1580, 1510, 1480cm ^-1

NMR (d ₆ -DMSO, δ): 5.93 (1H, dd, J = 5-8 Hz),

3.70 (2H, br s), 7.35 (2H, d, J = 9 Hz),

4.27-4.48 (2H, ABq, J = 13 Hz), 7.48 (2H, d, J = 9 Hz),

5.22 (1H, doublet, J, J = 5 Hz), 8.37, br.s),

5.30 (2H, s), 9.97 (1H, d, J = 8 Hz)

(10) 7- [2- (4-chlorophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -2-methyl-3-cepem 4-carboxylic acid (syn isomer), melting point 150-155 ° C. (decomposition).

IR (New sol): 3400, 3270, 3180, 1770, 1620, 1580, 1520, 1480cm ^-1

NMR (d ₆ -DMSO, δ): 7.35 (2H, d, J = 9 Hz),

1.45 (3H, d, J = 7 Hz), 7.48 (2H, d, J = 99 Hz),

3.60-4.10 (1H, m,), 8.03-8.73 (2H, m),

5.20 (1H, d, J = 5 Hz), 9.97 (1H, d, J = 8 Hz),

5.80 (1H, dd, J = 5-8 Hz), 6.62 (1H, d, J6 Hz),

(11) 4-nitrobenzyl-7- [2- (4-chlorophenoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- Cefem-4-carboxylate (syn isomer), melting point 155 to 160 ° C. (decomposition)

IR (New sol): 3300, 3180, 1770, 1720, 1680, 1625, 1600, 1580, 1520, 1480cm ^-1

NMR (d ₆ -DMSO, δ): 7.25 (2H, d, J = 9 Hz),

3.62 (2H, broad doublet), 7.38 (2H, doubled, J = 9 Hz)

5.18 (1.H, d, J = 5 Hz), 7.65 (2H, d, J = 8 Hz),

5.38 (2H, s), 8.20 (2H, d, J = 8 Hz)

5.95 (1H, doublet of doublets, J = 5-8 Hz), 8.23 (2H, broadenings)

6.63 (1H, t, J = 4 Hz), 9.85 (1H, d, J = 8 Hz)

(12) 7- [2- (4-chlorophenoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3-1 (2-hydr Oxyethyl) -1-tetrazol-5-yl thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 120-120 ° C. (decomposition)

IR (New sol): 3400, 3300, 3180, 1765, 1670, 1615, 1580, 1520, 1480cm ^-1

NMR (J ₆ -DMSO, δ): 7.28 (2H, d, J = 9 Hz),

3.50-3.93 (4H, m), 7.45 (2H, d, J-9 Hz),

4.12-4.48 (4H, m), 8.30 (2H, broad),

5.18 (1H, d, J = 5 Hz), 9.94 (1H, d, J = 8 Hz)

5.88 (1H, doublet of doublets, J = 5-8 Hz),

(13) 7- [2- (3,4-dichlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] cephalosporonic acid ( syn isomer), decomposition 200 ℃

IR (New sol): 3600, 3400, 1770, 1720, 1680, 1530, 1250, 1120, 970cm ^-1

NMR (d ₆ -DMSO, δ): 5.97 (1H, dd, J = 5-8 Hz),

2.03 (3H, s), 7.13-7.77 (3H, m),

3.60 (2H, m), 8.35 (2H, m),

4.65, 5.05 (2H, ABq, J = 15 Hz), 9.90 (1H, d, J = 8 Hz).

5.27 (1H, doublet, J = 5 Hz),

(14) 7- [2- (3, 4-dichlorophenoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1, 3 , 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), decomposition 160 ° C

IR (New sol): 3300, 3200, 1770, 1680, 1520, 1250, 1205, 1060cm ^-1

NMR (d ₆ -DMSO, δ): 7.16-7.80 (3H, m),

3.77 (2H, m), 8.36 (2H, s),

4.28-4.68 (2H, ABq, J = 14 Hz), 9.60 (1H, s),

5.37 (1H, d, J = 5 Hz), 9.93 (1H, d, J = 8 Hz)

5.97 (1H, doublet of doublets, J = 5-8 Hz),

(15) 4-nitrobenzyl 7- [2- (3-trifluoromethyl-acetamido] 3-cefe-4-carboxylate (syn isomer) melting point 136 to 140 ° C. (decomposition)

IR (New sol): 3370, 3200, 1780, 1730, 1690, 1680, 1630, 1610, 1520, 1450, 1325, 1160, 1125, 975, 850, 740cm ^-1

NMR (d ₆ -DMSO, δ): 6.63 (1H, m),

3.7 (2H, m), 7.50 (4H, broad singlet),

5.22 (1H, d, J = 5 Hz), 7.66 (2H (d, J = 9 Hz),

5.37 (2H, s), 8.20 (2H, d, J = 9 Hz),

5.99 (1H, dd, J-5-8 Hz), 9.89 (1H, d, J-8 Hz),

(16) 7- [2- (3-trifluoromethylphenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1 , 3, 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), decomposition (164 ° C.).

IR (New sol): 3300, 3180, 1765, 1670, 1610, 1520, 1320, 1165, 1120, 1060, 930, 790, 700cm ^-1

NMR (d ₆ -DMSO, δ): 7.55 (4H, br.s),

3.73 (2H, m), 8.34 (2H, broad singlet),

4.23-5.63 (2H, ABq, J = 14 Hz), 9.60 (1H, s),

5.27 (1H, d, J = 5 Hz), 9.99 (1H, d, J = 8 Hz).

5.93 (1H, doublet of doublets, J = 5-8 Hz),

(17) 7- [2- (3-ethoxycarbonylphenoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1 , 3, 4-tididiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), decomposition 162 ° C

IR (New sol): 3350-3150, 1770, 1720-1660, 1620, 1520, 1290, 1270, 1100, 1060, 900, 760cm ^-1

NMR (d ₆ -DMSO, δ): 5.73 (1H, dd, J = 5-8 Hz),

1.32, t, J = 7 Hz) 7.40-7.95 (4H, m),

3.71 (2H, m), 8.67 (2H, broad singlet),

4.25-4.60 (2H, ABq, J = 14 Hz), 9.59 (1H, s),

4.32 (2H, q, J = 7 Hz), 9.98 (1H, d, J = 8 Hz).

5.23 (1H, doublet, J = 5 Hz),

(18) 7- [2- (4-fluorophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- ( 2-hydroxyethyl-1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 145 to 150 ° C (decomposition)

IR (New sol): 3300, 3200, 1770, 1670, 1610, 1520cm ^-1

NMR (d ₆ -DMSOδ): 5.83 (1H, doublet of doublets, J = 4-8 Hz),

3.50-3.83 (4H, m) 7.12 (2H, s),

4.0-4.53 (4H, m), 7.23 (2H, s),

5.13 (1H, d, J = 4 Hz), 9.77 (1H, d, J = 8 Hz).

(19) 7-2 (4-fluorophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- (1-carboxymethyl-1 Tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 150-155 ° C. (decomposition)

IR (New sol): 3300, 3200, 1770, 1720, 1670, 1620, 1520, 1500cm ^-1

NMR (d ₆ -DMSO, δ): 5.93 (1H, dd, J = 4-8 Hz),

3.57 (2H, broad singlet), 7.25 (2H, singlet),

4.27-4.53 (2H, ABq, J = 14 Hz), 7.37 (2H, s),

5.23 (1H, d, J = 8 Hz), 8.32 (2H, s),

5.37 (2H, s), 9.92 (1H, d, J = 8 Hz),

(20) 7- [2- (4-fluorophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (2-carboxy Methyl-3-oxo-2, 3-dihydro-1, 2, 4-triazolo [4, 3-b] pyridazin-6-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), Melting Point 165 ° C to 170 ° C (Decomposition)

IR (New sol): 3300, 3200, 1770, 1710, 1620, 1540, 1520, 1500cm ^-1

NMR (d ₆ -DMSO, δ): 7.08 (1H, d, J = 10 Hz),

3.67-3.90 (2H, ABq, J = 18 Hz) 7.17 (2H, s),

4.13-4.37 (2H, ABq, J = 13 Hz), 7.28 (2H, s),

4.73 (2H, s), 7.72 (1H, d, J = 10 Hz),

5.23 (1H, d, J = 4 Hz), 8.23 (2H, s)

5.90 (1H, dd, J = 4-8 Hz), 9.83 (1H, d, J = 8 Hz),

(21) 7- [2- (4-fluorophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1-2 -(Carboxyethyl-1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 140-145 ° C. (decomposition).

IR (New sol): 3300, 3200, 1770, 1700, 1620, 1520, 1500cm ^-1

NMR (d ₆ -DMSO, δ): 5.87 (1H, dd, J = 4-8 Hz),

2.90 (2H, t, J = 6 Hz), 7.15 (2H, s),

3.70 (2H, brs), 7.25 (2H, s),

4.40 (2H, t, J = 6 Hz), 8.22 (2H, s),

4.27-4.47 (2H, ABq, J = 13 Hz), 9.83 (1H, d, J = 8 Hz)

5.17 (1H, doublet, J = 4 Hz),

(22) 7- [2- (4-fluorophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1-allyl -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 145-150 ° C. (decomposition)

IR (New sol): 3450, 3350, 3150, 1780, 1705, 1670, 1610, 1510 cm ^-1

NMR (d ₆ -DMSO, δ): 5.96 (1H, dd, J = 4-8 Hz)

3.66-3.84 (2H, ABq, J = 18 Hz), 5.80-6.20 (1H, m),

4.30-4.50 (2H, ABq, J = 14 Hz), 7.28 (2H, s),

5.00 (2H, d, J = 5 Hz), 7.34 (2H, s),

5.24 (1H, d, J = 4 Hz), 8.32 (2H, s),

5.20-5.40 (2H, m), 9.96 (1H, d, J = 8 Hz).

(23) 7- [2- (4-fluorophenoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido cephalosporonic acid (syn isomer Melting point 156-161 ° C (decomposition)

IR (New sol): 3450, 3300, 3200, 1770, 1730, 1680, 1610, 1510, 1500cm ^-1

NMR (d ₆ -DMSO, δ): 5.94 (1H, dd, J = 4-8 Hz),

2.04 (3H, s), 7.26 (2H, s),

3.52-3.68 (2H, ABq, J = 18 Hz), 7.34 (2H, s),

4.74-5.02 (2H, ABq, J = 14 Hz), 8.30 (2H, s),

5.26 (1H, d, J = 4 Hz), 9.94 (1H, d, J = 8 Hz),

(24) 7- [2-phenoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- (tetrazolo [1, 5-b] pyrid Chopped-6-yl) -melting point 175 to 180 ° C. (decomposition)

IR (New sol): 3300, 3200, 1775, 1680, 1615, 1585, 1520cm ^-1

(25) 7- [2-phenoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- [2- (Nt-appendix Cycarbonylamino] -ethyl] -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 150-155 ° C. (decomposition)

IR (New sol): 3300, 3200, 1770, 1680, 1620, 1590, 1520cm ^-1

(26) 7- [2- (3-trifluoromethylphenoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3-cepem- 4-carboxylic acid (syn isomer). Decomposition 193 ℃

IR (New sol): 3450, 3320, 3200, 1770, 1710, 1665, 1630, 1560, 1515, 1325, 1170, 1110, 940 cm ^-1

(27) 7- [2-phenoxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3-cepem-4-carboxylic acid (syn isomer), Melting Point (168-170 ° C (Decomposition)

IR (New sol): 3400, 3200, 1780, 1660, 1620, 1600, 1590, 1540cm ^-1

(28) 7- [2- (4-chlorophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl] acetamido] -3-cepem-4-carboxylic acid (syn isomer) Melting point 145-150 ° C. (decomposition)

IR (New sol): 3400, 3260, 3180, 1775, 1675, 1625, 1600, 1520, 1480cm ^-1

(29) 7- [2- (4-fluorophenoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3-cepem-4- Carboxylic acid (syn isomer). Melting Point 130-135 ° C (Decomposition)

IR (New sol): 3400, 3270, 3180, 1765, 1675, 1500cm ^-1

(30) 7- [2-phenoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (2-aminoethyl]- 1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 180-185 ° C. (decomposition)

IR (New sol): 3300, 3250, 1760, 1670, 1620, 1590, 1520cm ^-1

Example 5

To a cooling solution of phosphorus pentachloride dissolved in methylene chloride (45 ml) at -17 ° C, 2- (t-butoxycarbonylmethoxyimino) -2- (5-amino-1, 2, 4-thiadiazole- 3-yl) acetic acid (syn isomer) (2.51 g) is added and the mixture is stirred at the same temperature for 50 minutes. On the other hand, trimethyl dissolved in 7-amino-3- (tetrazolo [1,5-b] pyridazin-6-yl) thiomethyl-3-cepem-4-carboxylic acid (3.34 g) and methylene chloride (45 ml) The mixture of silylacetamide (12 g) is warmed to a clear solution and then cooled to -20 ° C.

The solution is added to the activated mixture and the mixture is stirred at −10 to −15 ° C. for 1 hour. The reaction mixture is evaporated and ethyl acetate and aqueous sodium bicarbonate solution are added to the residue. The aqueous layer is separated off and adjusted to pH 3-4 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is dried over magnesium sulfate and evaporated under reduced pressure. The residue was treated with diethyl ether to give 7- [2- (t-butoxycarbonylmethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] 2.4 g of 3- (tetrazolo [1,5-b] -pyridazin-6-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) is obtained. Melting point 125 to 130 ° C (decomposition)

IR (New sol): 3400, 3300, 3180, 1770, 1720, 1680, 1620, 1525cm ^-1

NMR (d ₆ -DMSO, δ): 5.87 (1H, dd, J = 5

1.47 (9H, s), 7.78 (1H, d, J = 10 Hz),

3.73 (2H, broad singlet), 8.17 (2H broad, singlet),

4.28 and 4.60 (2H, ABq, J = 13 Hz), 8.62 (1H, d, J = 10 Hz),

4.65 (2H, s), 9.55 (1H, d, J = 8 Hz)

5.18 (1H, doublet, J = 5 Hz),

Example 6

The following compounds are obtained in a similar manner to Examples 1-3, 5 and 7-12.

(1) 7- [2- {3- (Nt-butoxycarbonylamino) propoxyimino] -2- (5-amino-1, 2, 4-thiadiazol-3-ylacetamido]- 3-Methyl-3-cepem-4-carboxylic acid (syn isomer), melting point 114-119 占 폚 (decomposition)

NMR (d ₆ -DMSO, δ): 5.10 (1H, d, J = 5 Hz),

1.40 (9H, s), 5.72 (1H, dd, J = 5-8 Hz)

1.74 (3H, s), 6.70 (1H, br.s),

1.80 (2 H, m), 8.10 (2 H, br.s),

3.00 (4H, m), 9.44 (1H, doublet, J = 8 Hz).

4.14 (2H, m),

(2) 4-nitrobenzyl-7- [2- {3- (Nt-butoxycarbonylamino) -propoxyimino] -2- (5-amino-1, 2, 4-thiadiazole-3- Ilacetamido] -3-chloro-3-cepem-4-carboxylate (syn isomer) Melting point 91-100 ° C. (decomposition)

NMR (d ₆ -DMSO, δ): 5.33 (1H, d, J = 5 Hz),

1.38 (9H, s), 5.49 (2H, s),

1.80 (2H, m), 5.95 (1H, d, J = 5 Hz),

3.06 (2H, m), 7.74 (2H, d, J = 9 Hz),

3.7-4.3 (4H, m), 8.92 (2H, d, J = 9 Hz)

(3) 7- [2- {3- (Nt-butoxycarbonylamino) propoxyimino] 2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido]- 3- [3- {2- (Nt-butoxycarbonylamino) ethyl] -1-tetrazol-5-yl-thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting point 107-112 ° C. (decomposition)

NMR (d ₆ -DMSO + DOδ): 3.30 (2H, m),

1.32 (9H, s), 3.70 (2H, m),

1.34 (9H, s), 4.0-4.5 (6H, m),

1.80 (2H, m), 5.13 (1H, d, J = 5 Hz),

3.10 (2H, m), 5.83 (1H, d, J = 5 Hz),

(4) 4-nitrobenzyl 7- [2-allyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3-cepem-4-carboxylate (syn isomer) Melting point 125 to 130 ° C (decomposition)

IR (New sol): 3300, 1770, 1720, 1680, 1630, 1610, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 5.87-6.17 (1H, m),

3.60 (2H, broad), 6.63 (1H, t, J = 3 Hz)

4.57-4.83 (2H, m), 7.70 (2H, d, J = 9 Hz),

5.17 (1H, d, J = 4 Hz), 8.10 (2H, s),

5.0-5.35 (2H, m), 8.23 (2H, d, J = 9 Hz),

5.40 (2H, s), 9.57 (1H, d, J = 8 Hz).

5.93 (1H, doublet of doublets, J = 4 Hz),

(5) 7- [2- (2, 2, 2-trifluoroethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamidocephalosporinic acid (syn isomers). Melting point 185-195 ° C (decomposition)

IR (New sol): 3470, 33303210, 3060, 1770, 1735, 1700, 1670, 1620, 1555, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 5.12 (1H, d, J = 5 Hz),

2.00 (3H, s), 5.78 (1H, doublet of doublets, J = 5-8 Hz),

3.53 (2H, broad singlet) 8.12 (2H, broad singlet),

4.65-4.87 (2H, ABq, J = 9 Hz), 9.62 (1H, d, J = 8 Hz).

4.70-4.93 (2H, ABq, J = 13 Hz),

(6) 7- [2- (2, 2, 2-trifluoroethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 125-130 ° C. (decomposition)

IR (New sol): 3300, 3200, 1770, 1680, 1620, 1520cm ^-1

NMR (d ₆ -DMSO, s): 5.17-5.47 (2H, m),

3.68 (2H, broad singlet), 5.83 (1H, doublet of doublets, J = 5-8 Hz),

4.30-4.40 (2H, ABq, J = 13 Hz), 5.67-6.27 (1H, m),

4.68-4.92 (2H, ABq, J = 9 Hz), 8.25 (2H, br.s),

4.87-5.10 (2H, m), 9.77 (1H, d, J = 8 Hz).

(7) 7- [2- (2, 2, 2-trifluoroethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 145 to 150 ° C. (decomposition)

IR (new sol) 3300, 3200, 1770, 1680, 1620, 1525cm ^-1

NMR (d ₆ -DMSO, δ): 3.70 (2H, br.s), 3.95 (3H, s), 4.32 (2H, br.s), 4.68-4.92 (2H, ABq, J = 9H), 5.15 ( 1H, d, = 5). 5.85 (1H, dd, J = 5-8 Hz), 8.25 (2H, br.s) 9.75 (1H, d, J = 8 Hz)

(8) 7- [2- {2- (Nt-butoxycarbonylamino) ethoxyimino] -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] 2-Methyl-3-cepem-4-carboxylic acid (syn isomer, melting point 215-220 ° C. (decomposition)

IR (New sol): 3230, 3150, 1775, 1680, 1620, 1525cm ^-1

NMR (d ₆ -DMSO, δ): 1.37 (9H, s), 1.43 (3H, d, J = 7 Hz), 3.0-3.5 (2H, m), 4.0-4.4 (2H, m), 5.10 (1H, d, J = 4.5 Hz), 5.8-6.1 (1H, m, 6.53 (H, J = 6.9 Hz)

(9) 7- [2- {2- (Nt-butoxycarbonylamino) ethoxyimino] -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- {2- (Nt-butoxycarbonylamino) ethyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 181 to 186 ° C ( decomposition)

IR (New sol): 3320, 1780, 1680, 1620, 1520, 1165cm ^-1

NMR (d ₆ -DMSO, δ): 1.32 (18, s) 3.07-3.52 (4, m), 3.7 (2, br.s), 4.0-4.5 (6, m), 5.15 (1, d, = 4.5), 5.85 (1, d, = 4.5), 8.23 (2, br.s)

(10) 7- [2-trityloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (5-methyl-1, 3, 4-thiadiazol-2yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 147-161 캜 (decomposition)

IR (New sol): 3420, 1780, 1680, 1615, 1525cm ^-1

NMR (d ₆ -DMSO + D, O, s): 2.72 (3H, s) 3.73 (2H, br.s), 4.30-4.67 (2H, ABq, J = 14 Hz), 5.35 (1H, d, J = 5.0 Hz), 6.15 (1H, d, J = 5.0 Hz) 7.50 (15H, s)

(11) 7- [2- (2- (Nt-butoxycarboamino) epoxyimino] -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3 -(1-carboxymethyl-1-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 105 DEG C (decomposition)

IR (New sol): 3305, 3160, 1770, 1670, 1520, 1245cm ^-1

NMR (d ₆ -DMSO + D ₂ O, δ): 1.37 (9H, s), 3.0-3.5 (2H, m), 3.72 (2H, br.s), 3.9-4.3 (H, m), 4.1- 4.6 (2H, m), 5.13 (H, d, J = 4.5 Hz), 5.33 (2H, s), 5.7-6.0 (1H, m)

(12) 7- [2- (t-butoxycarbonylmethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1, 3,4-thiadiazol-2-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 140-145 ° C. (decomposition)

IR (New sol): 3300, 3175, 1770, 1720, 1680, 1620, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.50 (9H, s), 3.73 (2H, br.s), 4.33-4.58 (2H, ABq, J = 13 Hz), 4.65 (2H, s), 5.17 (1H, d, J = 4 Hz), 5.85 (1H, dd, J = 4-8 Hz) 8.18 (2H, s), 9.50 (1H, dJ = 8 Hz), 9.53 (1H, s)

(13) 7- [2- (t-butoxycarbonylmethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] cephalospotanoic acid (syn Isomer) Melting Point 125-130 ℃ (Decomposition)

IR (New sol): 3300, 3200, 1770, 1720, 1680, 1620, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.50 (9H, s), 2.10 (3H, s), 3.62 (2H, br.s), 4.68 (2H, s) 4.77-5.03 (2H, ABq, J = 13Hz ) 5.20 (1H, d, J = 4 Hz), 5.88 (1H, dd, J = 4-8 Hz), 8.18 (2H, s), 9.55 (1H, d, J = 8 Hz)

(14) 7- [2- (t-butoxycarbonylmethoxyimino] -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1- Alyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (isomer) Melting point 130 to 135 ° C (decomposition)

IR (New sol): 3400, 3280, 3180, 1770, 1720, 1680, 1620, 1520 cm ^-1

NMR (d ₆ -DMSO, δ): 1.42 (9H, s), 3.67 (2H, br.s) 4.27-4.43 (2H, ABq, J = 13 Hz), 4.62 (2H, s), 4.87-5.07 (2H , m), 5.10 (1H, d, J = 5 Hz), 5.13-5.43 (2H, m), 5.82 (1H, d, J = 5-8 Hz), (1H, m) 8.10 (2H, br.s) , 9.47 (1H, d, J = 8 Hz)

(15) 7- [2- (t-butoxycarbonylmethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- (1- ( 2- (Nt-butoxycarbonylamino) ethyl] -1H-tetrazol-5-yl] -thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 110-115 ° C. (decomposition)

IR: 3300, 3200, 1775, 1680, 1620, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.32 (9H, s), 1.42 (9, s), 3.33 (2H, br.s), 3.53-3.80 (2H, m) 4.13-4.47 (4H, m), 4.58 (2H, s), 5.08 (1H, d, J = 5 Hz), 5.78 (1H, dd, J = 5-8 Hz), 8.07 (2H, br.s), 9.45 (1H, d, J = 8 Hz)

(16) 7- [2- (t-Newzolbutoxycarbonylmethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1 -Phenyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 135-140 ° C. (decomposition)

IR (New sol): 3400, 3300, 3200, 1775, 1720, 1685, 1620, 1525, 1500cm ^-1

NMR (d ₆ -DMSO, δ): 1.43 (9H, s), 3.70 (2H, br s) 4.32-4.57 (2H, ABq, J = 13 Hz), 4.65 (2H, s) 5.12 (1H, d, J = 5 Hz), 5.85 (1H, dd, J = 5-8H), 7.67 (5, s), 8.17 (2H, br.s), 9.50 (1H, d, J = 8 Hz)

(17) 7- [2- (3- (Nt-butoxycarbonylamino) propoxyimino] -2 (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido]- 2-Methyl-3-cepem-4-carboxylic acid (syn isomer), melting point 133-146 ° C. (decomposition)

IR (New sol): 3280, 3170, 1775, 1685, 1670, 1520, 1625cm ^-1

NMR (d ₆ -DMSO, s): 1.40 (9H, s), 1.46 (3H, d, J = 7 Hz), 1.56-2.06 (2H, m) 3.03 (2H, t, J = 7 Hz), 3.1-4.1 (1H, m, 4.23 (2H, t, J = 7 Hz), 5.13 (1H, d, J = 5 Hz) 5.97 (1H, d, J = 5 Hz), 6.65 (1H, d, J = 6.5 Hz)

(18) 7- [2-allyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1-allyl-m-tetrazol- 5-yl) -thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 150-155 ° C. (decomposition)

IR (New sol): 3300, 3200, 1775, 1670, 1620, 1520cm ^-1

(19) 7- [2-allyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamino] -3- (tetrazol- [1, 5, -6 Pyridazyl-6-ylthiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 180-185 ° C. (decomposition)

IR (New sol): 3300, 3200, 1770, 1670, 1620, 1525cm ^-1

(20) 7- [2- (2, 2, 2-trifluoroethoxyimino) -2- (5- [amino-1, 2, 4-thiadiazol-3-yl) acetamido]- 3- [1- (2- (Nt-butoxycarbonylamino) ethyl] -1 H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), powder.

(21) 7- [2- (2, 2, 2-trifluoroethoxyamino) -2- (5-imino-1, 2, 4-thiadiazol-3-yl) acetamido]- 3- (5-Aminomethyl-1, 3, 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 150 to 155 캜 (decomposition)

IR (New sol): 3300, 3180, 1760, 1610, 1520cm ^-1

(22) 7- [2- (2, 2, 2-trifluoroethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3 -(Tetrazonero [1,5-b] pyridazin-6-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 165 to 170 ° C (decomposition)

IR (New sol): 3420, 3300, 3190, 1770, 1705, 1670, 1620, 1525cm ^-1

(23) 7- [2- (3- (N-butoxycarbonylamino) propoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3-chloro-3-cefe-4-carboxylic acid (syn isomer). Melting point 111-1155 ° C. (decomposition).

IR (New sol): 3300-3100, 1780, 1690, 1660, 1520, 1270, cm ^-1

(24) 7- [2-allyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3-cepem-4-carboxylic acid (syn isomer) melting point 160 to 165 ° C. (decomposition).

(25) 7- [2- (3-aminopropoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3-1- (2-amino Ethyl) -1-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 184-196 ° C. (decomposition).

IR (New sol): 3400-3100, 1760, 1660, 1610, 1520, 1170, 1060, 1010cm ^-1

(26) 7- [2- (2-aminoethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1-carboxymethyl -1H-thiadiazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 190-198 ° C (decomposition).

IR (New sol): 3250, 3160, 1760, 1650, 1615, 1522, 1020cm ^-1

(27) 7- [2-carboxyethoxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamino] -3- (1,3,4-allyltetrazole -2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting point 170-175 ° C. (decomposition).

IR (New sol): 3250, 3150, 1770, 1710, 1680, 1610, 1520 cm ^-1

(28) 7- [2-carboxymethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetoamido] -3- (1-allyl-1-tetrazole -5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 145-150 ° C. (decomposition).

IR (New sol): 3400, 3300, 32000, 1765, 1720, 1680, 1620, 1520cm ^-1

(29) 7- [2-aminoethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] sephalosporonic acid (syn isomer), melting point 160 to 165 ° C. (decomposition).

IR (New sol): 3300, 3200, 1770, 1720, 1680, 1520cm ^-1

(30) 7- [2-aminoethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -2-methyl-3-cepem-4- Carboxylic acid (syn isomer), melting point 190-195 ° C. (decomposition).

IR (new sol): 3300, 3150, 1760, 1660, 1575, 1520, 1400cm ^-1

(31) 7- [2- (3-aminopropoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -2-methyl-3-cepem 4-carboxylic acid (syn isomer), melting point 182-187 캜 (decomposition).

IR (New sol): 3260, 3150, 1758, 1660, 1616, 1575, 1520, 1400cm ^-1

(32) 7- [2-carboxymethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (tetrazolo- [1, 5- b] -pyridazin-6-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting point 170 ~ 175 ℃

IR (New sol): 3400, 3300, 3180, 1765, 1720, 1680, 1615, 1520cm ^-1

(33) 7- [2- (3-aminopropoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3-methyl-3-cepem 4-carboxylic acid (syn isomer), melting point 175-195 ° C. (decomposition)

IR (New sol): 3300-3100, 1770-1740, 16600, 1620, 1570, 1520, 1280, 1170, 1060, 1020cm ^-1

(34) 7- [2- (3-aminopropoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3-chloro-3-cepem 4-carboxylic acid (syn isomer), melting point 190-205 ° C. (decomposition).

IR (New sol): 3400-3150, 1760, 1660, 1630-1590, 1520, 1340, 1170, 1030cm ^-1

(35) 7- [2- (2-aminoethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (2 -Aminoethyl) -1-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer) melting point 182 to 187 ° C (decomposition).

IR (New sol): 3350, 3150, 1760, 1660, 1625, 1565, 1520cm ^-1

(36) 7-2-carboxymethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (2-aminoethyl)- 1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 185 to 190 ° C. (decomposition)

IR (New sol): 3250, 1775, 1660, 1570, 1520cm ^-1

(37) 7- [2- (2, 2, 2-trifluoroethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- [ 1-2-aminoethyl-1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 185 to 190 ° C. (decomposition)

IR (New sol): 3300, 3170, 1760, 1670, 1615, 1500cm ^-1

(38) 7- [2-carboxymethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1-phenyl-1H-tetrazole -5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 155-160 ° C (decomposition)

IR (New sol): 3400, 3300, 3180, 1765, 1720, 1680, 1615, 1520, 1495 cm ^-1

(39) 7- [2-hydroxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (5-methyl-1, 3, 4 -Thiadiazol-2-yl) -thidomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 153-162 캜 (decomposition)

IR (New sol): 3260, 3160, 1763, 1665, 1608, 1520 cm ^-1

(40) pivaloyloxymethyl 7- [2-hydroxyimino2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetoamido] -3- (5-methyl-1 , 3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylate (syn isomer) melting point 132-135 ° C. (decomposition).

IR (New sol): 3270, 3160, 1775, 1745, 1675, 1610, 1520, 1115 cm ^-1

Example 7

To a cooling solution of phosphorus pentachloride (2.5 g) dissolved in methylene chloride (60 ml), 2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadia Zol-3-yl) acetic acid (syn isomer) (2.54 g) is added at −15 ° C. and the mixture is stirred at the same temperature for 45 minutes.

On the other hand, trimethylsilylacetate dissolved in 7-amino-3- (1, 3, 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (4.0 g) and methylene chloride (60 ml) The mixture of amides (12 g) is warmed to a clear solution and then cooled to -15 ° C. The solution is added to the activated mixture and the mixture is stirred for 0.5 h at 0-5 C. The reaction mixture is poured into a cooling aqueous solution (150 ml) of sodium bicarbonate (7.1 g) and stirred at ambient temperature for 15 minutes. The aqueous layer is separated off and added to ethyl acetate, the mixture is adjusted to pH 3 with 10% hydrochloric acid and filtered. The ethyl acetate layer was separated from the filtrate, washed with saturated brine solution, dried over magnesium sulfate and evaporated to dryness. The residue is treated with diethyl ether and the precipitate is collected by filtration to give a debris product (1.8 g). The product is dissolved in an aqueous solution of sodium bicarbonate and the solution is adjusted to pH 3 with 10% hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl ) Acetamido] -3--1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) (1.4 g) is obtained. Melting Point 155-160 ℃

IR (New sol): 3300, 3200, 1770, 1670, 1620, 1520cm ^-1

NMR (d ₆ -DMSO, δ), 2.0-2.50 (4H, m), 3.70 (2H, br.s), 4.30 and 4.57 (2H, ABq, J = 13 Hz) 5.13 (1H, d, J = 4 Hz) , 5.27-4.43 (1H, m), 5.80 (1H, dd, J = 4 and 8 Hz), 5.83-6.20 (2H, m), 8.08 (2H, s), 9.45 (1H, d, J = 8 Hz) 9.50 , s)

Example 8

In a cooling solution of phosphorus pentachloride (2.5 g) dissolved in methylene chloride (60 ml), 2- (2-cyclopenten-1-yl oxyimino-2- (5-amino-1, 2, 4) at -15 ° C. -Thiadiazol-3-yl) acetic acid (syn isomer) (2.54 g) is added and the mixture is stirred at the same temperature for 30 minutes.

On the other hand, triethylsilyl acetamide (11 g) dissolved in 7-amino-3-cepem-4-carboxylic acid (2.2 g) and methylene chloride (60 ml) was warmed to clear the solution, and then cooled to -15 ° C. The activated mixture is added to the solution and the mixture is stirred at −5 ° C. for 20 minutes. The reaction mixture is poured into a cooling solution (150 ml) of sodium bicarbonate (7 g) and stirred at ambient temperature for 1 hour. The aqueous layer is separated off and added to ethyl acetate. The mixture is adjusted to pH 3 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness. The precipitated crystals are collected by filtration and washed successively with ethyl acetate and diethyl ether to give a debris product (1.5 g). The product is dissolved in an aqueous solution of sodium bicarbonate and the pH is adjusted to 2 with dilute hydrochloric acid.

The precipitate is collected by filtration, washed with water and dried. The resulting product (1.2 g) is dissolved in aqueous acetone, treated with activated carbon and evaporated. The precipitate was collected by filtration, washed with water and dried to give 7- [2- (2-cyclopenten-1-yl (oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl). ) Acetamido] -3-cepem-4-carboxylic acid (syn isomer (0.93 g) is obtained. Melting point 155-160 degreeC (decomposition).

IR (New sol): 3300, 3150, 1770, 1675, 1610, 1560, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.87-2.50 (4H, m) 3.60 (2H, br.s), 5.07 (H, d, J = 8 Hz), 5.27-5.50 (1H, m), 5.80 (1H , dd, J = 4 and 8 Hz), 5.87-6.23 (2H, m), 6.47 (1H, br.s), 8.10 (2H, s), 9.47 (1d, J = 8 Hz)

Example 9

Cooling solution of phosphorus pentachloride (1.25 g) dissolved in methylene chloride (30 ml) 2- (2-cyclohexen-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadia Zol-3-yl) acetic acid (syn isomer) (1.34 g) is added at −15 ° C. and the mixture is stirred at the same temperature for 30 minutes.

On the other hand, trimethylsilylacetate dissolved in 7-amino-3- (1, 3, 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (1.98 g) and methylene chloride (30 ml) The mixture of amides (6 g) is warmed to clear the solution and then cooled to -15 ° C. The solution is added to the activated mixture and the mixture is stirred at 0-5 ° C. for 0.5 hours. The reaction mixture is poured into a cooling water solution (100 ml) of sodium bicarbonate (4.03 g) and stirred at ambient temperature for 30 minutes. The aqueous layer is separated, added to ethyl acetate, adjusted to pH 4 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is dried over magnesium sulfate and evaporated to dryness. The residue is treated with diethyl ether, collected by filtration and dried to give the product (400 mg).

The product is dissolved in aqueous sodium bicarbonate solution and the pH is adjusted to 2 with hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to give 7-2- (2-cyclohexen-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl). Acetamido-3- (1, 3, 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) (250 mg) is obtained. Melting point 180-185 ° C. (decomposition).

IR (New sol): 3300, 1770, 1680, 1620, 1560, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.50-2.17 (6H, m), 3.70 (2H, br.s), 4.33 and 4.58 (2H, ABq, J = 14 Hz), 4.67 (-4.83 (1H, m) 5.17 (1H, d, J = 4 Hz), 5.83 (1H, dd, J = 4 and 8 Hz), 5.60-6.12 (2H, m), 8.15 (2H, s), 9.53 (1H, d) J = 8 Hz) , 9.93 (1 H, s)

Example 10

In a cooling solution of phosphorus pentachloride (1.50 g) dissolved in methylene chloride (30 ml), 2- (2-cyclohexen-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadia Zol-3-yl) acetic acid (syn isomer) (1.61 g) is added at -15 ° C and the mixture is stirred at -13 to -10 ° C for 30 minutes, evaporated and tetrahydro fuman (20 ml) is added to the residue. . On the other hand, 7-amino-3- (tetrazolo [1,5-b] pyridazin-6-yl) thiomethyl-3-cepem-4-carboxylic acid (2.86 g), sodium bicarbonate (2.52 g), water ( 80 ml) and acetone (45 ml) are cooled to 5-10 ° C. The solution is added to the activated mixture and the mixture is stirred at 5-10 ° C. for 20 minutes, warmed to room temperature and evaporated. Ethyl acetate was added to the residue, the mixture was adjusted to pH 2 with 10% hydrochloric acid, and extracted with ethyl acetate. The extract was treated with activated charcoal (0.5 g), dried over magnesium sulfate and evaporated. The residue is treated with diethyl ether and collected by a filter to give a debris product (2.37 g). The product is dissolved in aqueous sodium bicarbonate solution and the pH is adjusted to 2 with hydrochloric acid. The precipitate was collected by filtration to give 7- [2- (2-cyclohexen-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] 3- (Tetrazolo [1,5-b] pyridazin-6-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) (2.28 g) is obtained. Melting point 170 ~ 175 ℃

IR (New sol): 3400, 3300, 3180, 1670, 1620, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.40-2.20 (6H, m), 3.73 (2H, br.s), 4.27 and 4.65 (2H, ABq, J = 13 Hz), 4.65 (-4.88 (1H, m) , 5.18 (1H, d, J = 5 Hz), 5.80 (1H, dd, J = 5 and 8 Hz), 5.78-6.02 (2H, m), 7.80 (1H, d, J = 10 Hz), 8.17 (2H, br .s), 8.60 (1H, d, J = 10 Hz), 9.55 (1H, d, J = 8 Hz)

Example 11

In a cooling solution of phosphorus pentachloride (1.5 g) dissolved in methylene chloride (30 ml), 2-cyclopentyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetic acid ( syn isomer) (1.37 g) is added at −15 ° C. and the mixture is stirred at −13 to −10 ° C. for 30 minutes.

On the other hand, trimethylsilylacetate dissolved in 7-amino-3- (1, 3, 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (2.18 g) and methylene chloride (30 ml) The mixture of amides (6 g) is warmed to clear the solution and then cooled to -20 ° C. The solution is added to the activated mixture and the mixture is stirred at −10 ° C. for 0.5 h. The reaction mixture is poured into saturated aqueous sodium bicarbonate solution (60 ml) and stirred at ambient temperature for 30 minutes. The aqueous layer is separated off and added to ethyl acetate, adjusted to pH 2-3 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is dried over magnesium sulfate and evaporated to dryness. The residue is washed with diethyl ether to give the product (2.62 g). The product is dissolved in aqueous sodium bicarbonate solution and the pH is adjusted to 2 with hydrochloric acid.

The precipitate was collected by filtration to give 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-ylacetamido] -3- (1, 3, 4 -Thiadiazol-2-yl) thiomethyl-3-cepem-carboxylic acid (isomer) (2.22 g) is obtained, melting point 140 to 145 DEG C (decomposition).

IR (New sol): 3400, 3300, 3200, 1770, 1670, 1620, 1520, 1525cm ^-1

NMR (d ₆ , δ): 1.33-2.10 (8H, m), 3.72 (2H, br.s), 4.33 and 4.58 (2H, ABq, = 13 Hz) 4.60-4.90 (1H, m), 5.17 (1H, d, J = 5 Hz), 5.82 (1H, dd, J = 5 and 8 Hz), 8.15 (2H, S), 9.52 (1H, d, J = 8 Hz), 9.58 (1H, s)

Example 12

2-cyclopentyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetic acid in a cooling solution of phosphorus pentachloride (1.5 g) dissolved in methylene chloride (25 ml) ( syn isomer) (1.28 g) is added at -15 ° C. The mixture was stirred at -13 to -10 [deg.] C. for 30 minutes, on the other hand, a mixture of 7-amino-3-cepem-4-carboxylic acid (1.1 g) and trimethylsilyl acetamide (5.5 g) dissolved in methylene chloride (25 ml). Warm the solution to clear the solution and cool it at -15 ℃.

The solution is added to the activated mixture and the mixture is stirred at −10 ° C. for 0.5 hour. The reaction mixture is poured into a saturated aqueous solution of sodium bicarbonate (55 ml), stirred at ambient temperature for 30 minutes and evaporated to remove methylene chloride. The residue is washed with ethyl acetate and ethyl acetate is added to the aqueous layer. The mixture is adjusted to pH 3 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is dried over magnesium sulfate, treated with activated carbon (1.0 g) and evaporated. The residue is washed with diethyl ether to give a debris product (1.03 g).

The product is dissolved in aqueous sodium bicarbonate solution and the solution is adjusted to pH 3 with 10% hydrochloric acid. The precipitate was collected by filtration to give 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3-cefe-4-carboxylic acid (syn isomer) (860 mg). Melting Point 170 ~ 175 ℃

IR (New sol): 3520, 3420, 3320, 3200, 3160, 1770, 1685, 1655, 1635, 1625, 1570, 1505cm ^-1

N.M.R. (d₆-DMSO, δ) : 1.33-2.07- (8H, m), 3.43-3.77- (2H, m), 4.60-4.93 (1H, m), 5.15 (1H, d, J = 5Hz), 5.90 (1H, dd, J = 58Hz ) 6.43-6.67 (1 H, m), 8.23 (2 H, br.s), 9.63 (1 H, d, J = 8 Hz)

Example 13

The following compounds are obtained according to methods analogous to Examples 1 to 3, 5 and 7 to 12.

(1) 7- [2 (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] cephalosporonic acid (syn isomer), melting point 154 to 159 ° C (decomposition)

IR (New sol): 3300, 1770, 1720, 1620, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 2.0 (3H, s), 2.0 (3H, s), 2.0-2.40 (4H, m), 3.52 (2H, br.s), 4.70 and 4.97 (2H, ABq, J = 14 Hz), 5.12 (1H, d, J = 4 Hz) 5.27-5.40 (1H, m), 5.82 (1H, dd, J = 4 and 8 Hz), 5.83-6.17 (2H, m), 8.13 (2H, s), 9.50 (1H, d, J = 8 Hz)

(2) 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- ( 1-ethyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 155-160 ° C. (decomposition)

IR (New sol): 3300, 1770, 1670, 1620, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.90-2.30 (4H, m), 3.62 (2H, br.s), 3.88 (3, s), 4.25 (2H, br.s), 5.07 (1H, d, J = 4 Hz), 5.20-5.40 (1H, m) 5.80 (1H, dd, J = 4 and 8 Hz), 5.83-6.17 (2H, m), 8.08 (2H, s), 9.47 (1H, d, J = 8 Hz)

(3) 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl (acetamido) -3- ( 1-carboxymethyl-1-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 155-160 ° C. (decomposition)

IR (New sol): 3300, 3200, 1770, 1720, 1670, 1620, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.83-2.50 (4H, m), 3.67 (2H, br.s), 4.27 and 4.48 (2H, ABq, J = 14 Hz), 5.17 (1H, d, J = 4 Hz ), 5.30 (2H, s), 5.27-5.50 (1H, m), 5.82 (2H, dd, J = 4 and 8 Hz), 5.83-6.20 (2H, m), 8.17 (2H, s), 9.50 (1H) , d, J = 8 Hz)

(4) 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino 1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1 -(2-carboxyethyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 150-155 ° C. (decomposition).

IR (New sol): 3300, 3200, 1770, 1720, 1670, 1620, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.90-2.50 (4H, m), 2.97 (2H, t, J = 6 Hz), 3.73 (2H, br.s), 4.30 and 4.50 (2H, ABq, J = 14 Hz ),

(6) 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- ( Tetrazolo [1,5-b] pyridazin-6-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 170 to 175 캜 (decomposition)

IR (New sol): 3400, 3300, 3190, 1770, 1670, 1615, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.90-2.43 (4H, m), 3.68 (2H, br.s), 4.22 and 4.58 (2H, ABq, J = 13 Hz) 5.10 (1H, d, J = 5 Hz) , 5.20-5.47 (1H, m), 5.78 (1H, dd, J = 5 and 8 Hz) 5.80-6.20 (2H, m), 7.75 (1H, d, J = 10 Hz) 8.13 (2H, br.s), 8.55 (1H, d, J = 10 Hz) 9.52 (1H, J = 8 Hz)

(7) 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino 1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1 -(2- (N = t-4.52 (2H, t, J = 6Hz), 5.20 (1H, d, J = 4Hz), 5.30 (-5.57 (1H, m), 5.90 (1H, dd, J = 4 And 8 Hz) 5.93-6.33 (2H, m), 8.33 (2H, s) 9.77 (1H, d, J = 8 Hz)

(5) 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- ( 1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid- (syn isomer) Melting point 160-165 ° C. (decomposition)

IR: 3300, 1770, 1670, 1620, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.93-2.33 (4H, m), 3.60 (2H, br.s), 4.22 and 4.37 (2H, ABq, J = 13 Hz) 4.83-5.0 (2H, m), 5.0 -5.40 (4H, m), 5.60-6.17 (4H, m), 8.07 (2H, s), 9.47 (1H, d, J = 8 Hz)

(6) 7-2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- (tetrazolo 1,5-pyridazin-6-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 170-175 ° C. (decomposition)

IR (New sol): 3400, 3300, 3190, 1770, 1670, 1615, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.90-2.43 (4H, m), 3.68 (2H, br.s), 4.22 and 4.58 (2H, ABq, J = 13 Hz) 5.10 (1H, d, J = 5 Hz) , 5.20-5.47 (1H, m), 5.78 (1H, dd, J = 5 and 8 Hz) 5.80-6.20 (2H, m), 7.75 (1H, d, J = 10 Hz) 8.13 (22H, brs), 8.55 ( 1H, d, J = 10 Hz) 9.52 (1H, d, J = 8 Hz)

(7) 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino 1, 2, 4-thiadiazol-3-yl) acetamido] -3-1- (2- (Nt-butoxycarbonylamino) ethyl] -1H-tetrazol-5-yl] -thiomethyl-3-cepem 4 carboxylic acid (syn isomer), melting point 95-100 ° C. (decomposition)

IR (New sol): 3300, 3190, 1770, 1680, 1620, 1520cm ^-1

NMR (d6-DMSO, δ): 1.40 (9H, s), 2.07-2.50 (4H, m), 3.30-3.57 (2H, m), 3.67-3.87 (2H, m), 4.27-4.57 (4H, m ), 5.17 (1H, d, J = 5 Hz) 5.23-5.57 (1H, m), 5.70-6.30 (3H, m), 8.17 (2H, brs), 9.53 (1H, d, J = 8 Hz)

(3) 7- [2- (2-cyclohexen-1-yl) oxyimino] -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3-cefem 4-carboxylic acid (syn isomer), melting point 175 to 180 캜 (decomposition)

IR (New sol): 3300, 3200, 1770, 1670, 1630, 1520, cm ^-1

NMR (d6-DMSO ₂ δ): 1.50-2.12 (6H, m), 3.63 (2H, br.s), 4.60-4083 (1H, m), 5.12 (1H, d, J = 4 Hz), 5.77-6.0 (3H, m), 6.50 (1H, t, J = 3 Hz), 8.15 (2H, s), 9.55 (1H, d, J = 8 Hz)

(9) 7- [2- (2-wacyclohexen-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] cephalospo Lanic acid (syn isomer), Melting point 160 to 165 ° C (decomposition)

IR (New sol): 3300, 3200, 1775, 1720, 16701620, 1520cm ^-1

NMR (d6-DMSO, δ): 1, 50-2, 10 (6, m), 2.07 (3H, s), 3.60 (2H, br.s), 4.67-4.83 (1H, m), 4.77 and 5.03 (2H, ABq, J = 14 Hz), 5.17 (1H, d, J = 4 Hz), 5.77-6.10 (3H, m), 8.17 (2H, s), 9.60 (1H, d, J = 8 Hz)

(10) 7- [2- (2-cyclohexen-1-yl) oxyimino-2- (5-amino 1, 2, 4-thiadiazol-3-yl) acetamido-3- (1- Methyl-1H-tetrazol-3-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 170-173 ° C. (decomposition)

IR (New sol): 3350, 3250, 1780, 1680, 1620, 1520cm ^-1

NMR (d6-DMSO, δ): 1.50-2.17 (6H, m), 3.16 (2H, br.s), 3.93 (3H, s), 4.30 (2H, br.s), 4.55-4.80 (1H, m ), 5.10 (1H, d, J = 4 Hz), 5.80 (1H, dd, J = 48 Hz), 8.08 (2H, m), 9.50 (1H, d, J = 8 Hz), 5.80-5.93 (2H, m)

(11) 7- [2- (2-wacyclohexen-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido]]-2 -(5-Amino-carboxymethyl-H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 170-175 ° C. (decomposition)

IR (New sol): 3300, 3200, 1770, 1720, 1650, 1620, 1520cm ^-1

NMK (d6-DMSO, δ): 1.50-2.27 (6H, m), 3.75 (2H, br.s), 4.30-4.55 (2H, ABq, J = 14 Hz), 4.67-4.83 (1H, m), 5.17 (1H, d, J = Hz), 5.37 (2H, S), 6.17-5.77 (3H, m), 8.18 (2H, s), 9.57 (1H, d, J = 8 Hz)

(12) 7- [2- (2-cyclohexen-1-yl) oxyimino-2- (5-amino 1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1 -(2-carboxyethyl-1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer, melting point 165-170 ° C.

IR (New sol): 3300, 3200, 1770, 1720, 16701620, 1520m ^-1

NMR (d6-DMSO, δ): 1.50-2.17 (6H, m), 3.77 (2H, br.s), 4.37 4.50 (2H, ABq, J = 14 Hz), 4.53 (2H, t, J = 6 Hz), 4.67-4.93 (1H, m), 5.23 (1H, d, J = 4 Hz), 5.93 (1H, dl, J = 4 and 8 Hz), 5.97-6.17 (2H, m), 8.70 (2H, S), 9.80 (1H, d, J = 8)

(13) 7- [2- (2-cyclohexen-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- (1 -Allyl-1H-tetrazol-5-yl) thiomethyl-3cepem-4-carboxylic acid (syn isomer) Melting point 160 to 165 캜 (decomposition)

IR (New sol): 3300, 3200, 1780, 1680, 1620, 1520cm ^-1

NMR (d6-DMSO ₂ δ): 1.50-2.16 (6H, m), 3.66 (2H, br.s), 4.25 and 4.43 (2H, ABq, J = 14 Hz), 4.55-4.80 (1H, m), 4.93 -5.0 (2H, m), 5.10 (1H, d, J = 4Hz), 5.20-5.37- (2H, m), 5.67-6.20 (4H, m), 8.08 (2H, s), 9.50 (1H, d , J = 8 Hz)

(14) 7-] 2- (2-cyclohexen-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- [1 -3- (Nt-butoxycarbonylamino) propyl] -H-tetrazol-5-ylthiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 100-105 DEG C (decomposition)

IR (New sol): 3300, 3170, 1770, 1670, 1620, 1520cm ^-1

NMR (d6-DMSO, δ): 1.37 (9H, S), 1.50-2.0 (3H, m), 2.92 (2H, t, J = 6 Hz), 3.68 (2H, t, J = 6 Hz), 3.68 (2H , br.s), 4.07-4.47 (4H, m), 4.53-4.83 (1H, m), 5.10 (1H, d, J = 5 Hz), 5.80 (1H, dd, J = 5 and 8 Hz), 5.70- 5.93 (2H, m), 8.10- (2H, br.s), 9.47 (1H, d, J = 8 Hz)

(15) 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] cephalospanoic acid (syn isomer), melting point 140 to 140 145 ° C (decomposition)

IR (New sol): 3480, 3370, 3250, 1785, 1730, 1680, 1630, 1530 cm ^-1

NMR (d6-DMSO, δ): 1.33-2.17 (8H, m), 2.30 (3H, s), 3.57 (2H, br.s), 4.60-4.90 (1H, m), 4.79-4.97 (2H, ABq , J = 13 Hz, 5.15 (1, d, J = 5 Hz), 5.80 (1H, dd, J = 5 and 8 Hz), 8.10 (2H, br.s), 3.47 (1H, d, J = 8 Hz)

(16) 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1-methyl-1H-tetrazole -5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) melting point 145-150 ° C. (decomposition).

IR (New sol): 3400, 3290, 3180, 1770, 1670, 1620, 1520cm ^-1

NMR (d6-DMSO, δ): 1.33-2.07 (8H, m), 3.70 (2H, br.s), 3.93 (3H, s), 4.32 (2H, br.s), 4.10-4.90 (1H, m ), 5.12 (1H, d, J = 5 Hz), 5.78 (1H, dd, J = 5 and 8 Hz), 8.10 (2H, br.s), 9.47 (H, d, J = 8 Hz)

(17) 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1-carboxymethyl-1-tetra Sol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (isomer) Melting point 155-160 ° C. (decomposition).

IR (New sol): 3400, 3290, 3180, 1765, 1720, 1670, 1620, 1520cm ^-1

NMR (d6-DMSO, δ): 1.27-2.07, (8Hm), 3.70 (2H, br.s), 4.28 and 4.53 (2H, ABq, J = 13 Hz), 4.70-4.99 (1H, m), 5.17 ( 1H.d.J = 3Hz), 5.33 (2H, s), 5.85 (1H, dd, J = 5Hz 8Hz), 8.23 (2H, br.s), 9.60 (1H, d, J = 8Hz)

(18) 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1-allyl-1H-tetrazole -5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 135-140 ° C. (decomposition).

IR (New sol): 3400, 3300, 3190, 1770, 1670, 1620, 1520cm ^-1

NMR (d6-DMSO, δ): 1.30-2.10 (8H, m), 3.73 (2H, br.s), 4.32 and 4.50 (2H, ABq, J = 13 Hz), 4.60-4.90 (1H, m), 4.83 -5.17 (2H, m), 5.17 (1H, d, J = 5 Hz), 5.17-5.50 (2H, m), 5.87 (1H, dd, J = 5 and 8 Hz), 5.67-6.33 (1H, m), 8.20 (2H, br.s), 9.60 (1H, d, J = 8 Hz)

(19) 7- [2-cyclopentylioxiimino-2- (5-amino-1, 2,4-thiadiazol-3yl) acetamido] -3- (tetrazolo 1,5-pyridazine -6-yl) thiomethyl-3 cefem 4-carboxylic acid (syn isomer), melting point 160-165 ° C. (decomposition)

IR (New sol): 3570, 3440, 3320, 3180, 1775, 710, 1660, 1620, 1580, 1540, 1520cm ^-1

NMR (d6-DMSO, δ): 1.40-2.03 (8H, m), 3.78 (2H, br.s), 4.27 and 4.65 (2H, ABq, J = 13 Hz), 4.67-4.99 (1H, m), 5.20 (1H, d, J = 5 Hz), 5.87 (1H, dd, J = 5 and 8 Hz), 7.78 (1H, d, J = 10 Hz), 8.15 (2H, br.s), 8.58 (1H, d , J = 10 Hz), 9.53 (1H, d, J = Hz)

(20) 7- [2-cyclopentyloxyimino-2--2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (2- Methoxycarbonylethyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 125-130 ° C. (decomposition).

IR (New sol): 3480, 3370, 3250, 1780, 1740, 1685, 1625, 1530 cm ^-1

NMR (d6-DMSO, δ): 1.30-2.07 (8H, m), 2.80-3.20 (2H, m), 3.58 (3H, s), 3.67 (2H, br.s), 4.20-4.70 (4H, m ), 4.60-4.90 (1H, m), 5.12 (1H, d, J = 5 Hz), 5.78 (1H, dd, J = 5 and 8 Hz), 8.07 (2H, br.s), 9.43 (1H, d, J = 8Hz)

(21) 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (4-methyl-5oxo-6 -Hydroxy 4, 5-dihydro-1, 2, 4-triazin-3-yl) -thiomethyl-3-cepem-carboxylic acid (syn isomer), pale yellow powder, melting point 195-199 ° C (decomposition)

IR (New sol): 3300, 3200, 1770, 1710, 1670, 1590, 1520, 1240, 1170, 1090, 1000, 720cm ^-1

(22) 7- [2-cyclohexyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1, 3, 4-thiadia Zol-2-yl) thiomethyl-3 cefe-4-carboxylic acid (syn isomer). White powder, melting point 150-154 ° C. (decomposition).

IR (New sol): 3300, 3200, 1770, 1710, 1670, 1590, 1520, 1240, 1170, 1090, 1000, 720cm ^-1

NMR (d6-DMSO, δ): 1.50 (8H, m), 1.82 (4H, m), 3.54 and 3.76 (2H, ABq, J = 20 Hz), 4.32 (1, m), 4.24 and 4.60 (2H, ABq , J = 14 Hz, 5.10 (1H, d, J = 5 Hz), 5.74 (1H, dd, J = 5 and 8 Hz, 5.74 (1H, dd, J = 5 and 8 Hz), 8.02 (2H, m), 9.48 (1H, s), 9.38 (1H, d, J = 8 Hz)

(23) 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3-cepem-4-carboxylic acid (syn isomer) , White powder, melting point 170-175 ° C (decomposition)

IR (New sol): 3400, 3300, 3200, 1770, 1670, 1620, 1520, 1280, 1240, 1160, 1000, 9801, 730cm ^-1

NMR (d6-DMSO, δ), 1.85 (4H, m), 3.60 (2H, m), 4.0-4.50 (1H, m), 5.13 (1H, d, J = 5 Hz), 5.87 (1H, dd, J = 5 and 8 Hz), 6.50 (1H, m), 8.13 (2H, m), 9.37 (1H, d, J = 8 Hz)

(24) N- [7- [2-cyclopentyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3-cepem-3-ylmethyl -4'-carbadoylpyridinium-4-carboxylate (syn isomer). Melting point 230-235 ° C. (decomposition).

IR (New sol): 3300, 3200, 1770, 1680, 1610, 1560, 1520, 1510 cm ^-1

(25) 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1-3- (Nt-part Oxycarbonylamino] propyl-1H-tetrazol-5-yl] -thiomethyl-3-cepem 4-carboxylic acid (syn isomer) pale navy blue powder.

IR (New sol): 3300, 1770, 1670, 1520, 1240, 1160, 1000cm ^-1

(26) 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3-) (1, 2, 4-thia Diazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 175-178 ° C. (decomposition).

IR (New sol): 3300, 3200, 1775, 1680, 1620, 1525cm ^-1

(27) 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acamido-3- [1- (3-morpholinopropyl ] -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 183-188 ° C. (decomposition)

IR (New sol): 3300, 3150, 1770, 1670, 1610, 1530cm ^-1

(28) 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [ 1 (2-aminoethyl-1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer melting point 175-180 ° C. (decomposition).

IR (New sol): 3400, 3300, 3178, 1760, 1665, 1610, 1520cm ^-1

(29) 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (3-aminopropyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), white powder, melting point 195-199 ° C. (decomposition).

IR (New sol): 3300, 3150, 1760, 1660, 1620, 1520, 1280, 1180, 1000cm ^-1

(30) 7- [2- (2-cyclohexen-1-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- [1 -(3-aminopropyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4 carboxylic acid (syn isomer), melting point 185-190 ° C. (decomposition).

IR (New sol): 3280, 3150, 1760, 1665, 1620, 1520cm ^-1

(31) 7- [2-cyclopentyloxyimino-2-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1-pipelinopropyl) -1H-tetrazole -5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 230 deg. C (decomposition).

IR (New sol): 3300, 3200, 3170, 1600, 1520cm ^-1

Example 14

2-alkoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (1.37 g) and phosphorus oxychloride (3.67 g) in methylene chloride (30 ml) The mixture is stirred at room temperature for 2 hours and then cooled to -12--15 ° C. To the cooled mixture is added amide amide (2.4 ml) and the mixture is stirred at -8 ° -40 ° C for 45 minutes. While 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (2.9 g) and trimethylsilylacetamide (8 g) in methylene chloride (40 ml) The mixture is heated to a solution. The solution is cooled to -25 ° C and added to the active mixture. The reaction mixture is stirred at -8-10 ° C for 30 minutes and poured into aqueous sodium bicarbonate solution. The mixture is stirred at ambient temperature for 30 minutes and the aqueous layer is separated. The aqueous solution was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is dried over magnesium sulfate and then distilled to dryness. The residue was triturated with diethyl ether to give 7- [2-allyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1, 3 , 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) (2.1 g) is obtained. The product was dissolved in an aqueous sodium bicarbonate solution to obtain the pure target compound (1.15 g) melting point 138-140 ° C. (decomposition) which was precipitated by addition of 10% hydrochloric acid.

IR (New sol): 3350, 3230, 1780, 1680, 1620, 1530cm ^-1

NMR (d6-DMSO, δ): 3.633 (2H, br.s), 4.27 and 4.52 (2H.ABq, J = 14 Hz), 4.5-4.8 (2H, m), 5.10 (1H, d, J = 5 Hz) , 5.0-5.5 (2H, m), 5.78 (1H, dd, J = 5 and 9 Hz), 5.7-6.3 (1H, m), 8.90 (2H, br.s), 9.48 (1H, s), 9.53 ( 1H, d, J = 9 Hz)

Example 15

2- (2,2,2-trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) in methylene chloride (30 ml) ( 1.62 g) and phosphorus oxychloride (3.67 g) are stirred at ambient temperature for 1.5 hours and then cooled to -12--15 ° C. Pour into cold aqueous sodium bicarbonate solution. The mixture is stirred at ambient temperature for 30 minutes and the aqueous layer is separated. The aqueous solution is adjusted to pH 2 with 10% hydrochloric acid and guessed with ethyl acetate. The extract is dried over magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give 7- [2-2- (2, 2, 2-trifluoroethoxyimino) -2- (5-amino-1, 2, 4-thiadiazole-3 -Yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) (2.45 g) When dissolved and precipitated by addition of 10% hydrochloric acid, a pure target compound (1.42 g) has a melting point of 153-158 ° C. (decomposition).

IR (New sol): 3350, 3250, 1780, 1680, 1625cm ^-1

NMR (d6-DMSO, δ): 3.70 (2, br.s), 4.33 4.58 (2H, ABq, J = 13 Hz), 4.70 and 4.92 (2H, ABq, J = 9 Hz), 5.17 (1H, d, J = 5 Hz), 5.82 (1H, dd, J = 5 and 8 Hz, 8.18 (2H, br.s), 9.55 ((H, s), 9.70 (1H, d, J = 8 Hz)

Example 16

The mixture of dimethylformamide (6 ml) and phosphorus oxychloride (918 mg) is stirred at ambient temperature for 30 minutes. Methylene chloride (6 ml) was added again followed by 2-dichloroacetoxyimino-2- (5-polamido-1, 2,4-thiadiazol-3-yl) acetic acid (syn isomer) (1.6 g). Add again at -20-25 ° C. The mixture is stirred at -10-15 ° C for 30 minutes. To the resultant mixture, 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (2.0 g) and trimethyl silyacetamide in methylene chloride (30 ml) were added. (6 g) solution is added at -10--15 ° C and the mixture is stirred at -5--15 ° C for 30 minutes. Methylene chloride is evaporated from the reaction mixture and ice water and ethyl acetate are added to the residue. 7- [2-Dichloroacetoxyimino-2- (5-formamido-1, 2, 4-thiadiazol-3-yl) -acetamido] -3- (1, 3, 4-thiadia The resulting mixture containing sol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) is adjusted to pH 5 with aqueous sodium bicarbonate solution.

The aqueous layer is separated and ethyl acetate is added again. The mixture is adjusted to pH 2 with 10% hydrochloric acid and the refractory is filtered off. The filtrate is extracted three times with ethyl acetate. The extract was dried over magnesium sulfate and distilled. The residue was triturated with diethyl ether, and the precipitate was collected by filtration, washed with diethyl ether, and then washed with 7- [2-hydroxyimino-2- (5-formamido-1, 2). , 4-thiadiazol-3-yl) acetamido] -3- (1, 3, 4-thiadiazol-2-yl) -thiomethyl-3-cepem-4-carboxylic acid (syn isomer) (0.9 g) melting point 155-160 ° C. (decomposition) is obtained.

IR (New sol): 3200, 1780, 1680, 1620cm ^-1

NMR (d6-DMSO, δ): 3.67 (8H, br.s), 4.27 and 4.73 (2H, ABq, J = 13 Hz), 5.13 (1H, d, J = 4 Hz), 5.83 (1H, dd, J = 4 and 8 Hz), 8.80 (1H, s), 9.50 (1H, d, J = 9 Hz), 9.53 (1H, s), 12.22 (1H, s)

Example 17

The following compounds are obtained in the same manner as in the examples.

(1) 7- [2- (2-propynyloxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1, 3, 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting point 140-145 ° C. (decomposition).

IR (New sol): 3330, 3250, 1780, 1680, 1620, 1530cm ^-1

NMR (d6-DMSO, δ): 3.47 (1H, t, J = 2 Hz), 3.67 (2H, br.s), 4.28 and 4.53 (2H, ABq, J = 13 Hz), 4.77 (2H, d, J = 2 Hz), 5, 12 (1H, d, J = 5 Hz), 5.78 (1H, dd, J = 5 and 8 Hz), 8.13 (2H, br.s), 9, 55 (1H, s), 9.67 (1H , d, J = 8 Hz)

(2) 7- [2-benzyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1, 3, 4-thiadiazole -2-yl) -thiomethyl-3-cepem-4-carboxylic acid (syn isomer), dew point 130-135 占 폚 (decomposition)

IR (New sol): 3360, 3250, 1780, 1680, 1625, 1530cm ^-1

NMR (d 6 -DMSO, δ): 3.63 (2H, br.s), (4.35 and 4.58 (2H, ABq, J = 13 Hz), 5.13 (1H, d, J = 5 Hz), 5.23 (2H, s), 5.80 (1H, dd, J = 5 Hz and Hz), 7.38 (5H, s), 8.13 (2H, br.s), 9.57 (1H, s) 9.63 (1H, d, J = 8 Hz)

(3) 7- [2- (2-phenoxyethoxyamino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1, 3 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting point 163-167 ° C. (decomposition).

IR (New sol): 3350, 325001780, 1680, 1600, 1600, 1530, 1500cm ^-1

NMR (d6-DMSO, δ): 3.30 and 3.60 (2H, ABq, J = 18 Hz), 4.0-4.70 (6H, m), 6.10 (1H, d, J = 4 Hz), 5, 93 (1H, dd, J = 4 8 Hz), 6.7-7.5 (5H, m), 8.13 (2H, s), 9.50 (1H, s), 9.57 (1H, d, J = 8 Hz)

(4) 7- [2-methylthiomethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1, 3, 4-thia Diazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting point 168-170 ° C. (decomposition).

IR (New sol): 3350, 3250, 1780, 1680, 1620, 1530cm ^-1

NMR (d6-DMSO, δ): 2.17 (3H, s), 3.65 (2H, br.s), 4.30 and 4.57 (2H, ABq, J = 14 Hz), 5.12 (1H, d, J = 4 Hz), 5.20 (2H, s), 5.380 (1H, dd, J = 4 and 8 Hz), 8.17 (2H, s), 9.62 (1H, d, J = 8 Hz)

(5) 7- [2- (2-methylthiomethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1 3, 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 125-130 ° C. (decomposition).

IR (New sol): 3350, 3250, 1780, 1680, 1625, 1530cm ^-1

NMR (d6-DMSO, δ), 2.08 (3H, s), 2.72 (2H, t, J = 7Hz), 3.68 (2H, br.s), 4.28 (2H, t, J = 7Hz), 4.30 4.55 (2H, ABq, J = 13 Hz), 5.13 (1H, d, J = 5 Hz), 5.82 (1H, dd, J = 58 Hz), 8.15 (2H, br.s), 9.52 (1H, d, J = 8 Hz ), 9.53 (1 H, s)

(6) 7-phenoxyimino- [2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido]]-3- (1,3,4-thiadiazole- 2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting Point 145-150 ° C (Decomposition)

IR (New sol): 3350, 3230, 1780, 1680, 1620, 1590, 1530cm ^-1

NMR (d6-DMSO, δ): 3.70 (2H, br.s), 4.30 and 4.60 (2H, ABq, J = 14 Hz), 5.23 (1H, d, J = 5 Hz), 5.92 (1H, dd, J = 5 and 8 Hz), 7.0-7.6 (5H, m), 8.30 (2H, br.s), 9.52 (1H, s), 9.83 (1H, d, J = 8 Hz)

(7) 7- [2-cyanomethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1, 3, 4-thiadia Zol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting Point 105-110 ° C (Decomposition)

IR (New sol): 3350, 3250, 1780, 1680, 1620, 1530cm ^-1

NMR (d6-DMSO, δ): 3, 6 and 3.76 (2H, ABq, J = 18 Hz), 4.3 and 4.56 (2, ABq, J = 13 Hz), 5.12 (2H, s), 5.14 (1, d, J = 5 Hz), 5.80 (1H, dd, J = 5 and 8 Hz), (8.20 (2H, br.s), 9.52 (1H, s), 9.78 (1H, d, J = 8 Hz)

(8) 7- [2- (N, N-diethylcarbaoyl) methoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting Point 175-180 ℃ (Decomposition)

IR (New sol): 3480, 3310, 3200, 1775, 740, 1680, 1630, 1610, 1515 cm ^-1

NMK (d6-DMSO, δ): 1.00 (3H, t, = 7 Hz), 3.62 and 3.72 (2H, ABq, J = 18 Hz), 4.33 and 4.55 (2H, ABq, J = 14 Hz), 4.88 (2H, s ), 5.15 (1H, d, J = 5 Hz), 5.83 (1H, dd J = 5 and 9 Hz), 8.13 (2H, br.s), 6.55 (1H, s), 9.62 (1H, d, J = 9 Hz )

(9) 7- [2- (1-ethoxycarbonyl-1-methylethoxyimino))-2- (5-amino-1, 2, 4 thiadiazol-3-yl) acetamido]- 3- (1, 3, 4-thiadiazol-2-yl) thiadiazol-3-yl) acetamido-3- (1, 3, 4-thiadiazol-2-yl) thiomethyl-3 -Cefem-4 carboxylic acid (syn isomer). Melting Point 130-135 ° C (Decomposition)

IR (New sol): 3360, 3240, 1780, 1730, 1690, 1630, 1530cm ^-1

NMR (d6-DMSO, δ): 1.18 (3H, 5, J = 7 Hz), 1.50 ((6H, s), 3.72 (2H, br.s), 4.13 (2H, q, J = 7 Hz), 4.33 and 4.58 (2H, ABq, J = 13 Hz), 5.18 (1H, d, J = 5 Hz), 5.85 (1H, dd, J = 58 Hz), 8.18 (2H, br.s), 9.48 (1H, d, J = 8 Hz), 9.57 (1 H, s)

(10) 7- [2-ethoxycarbonylmethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3-ylacetamido-3- (1,3,4-thiadiazol-2-yl) thimethyl-3-cepem-4-carboxylic acid (syn isomer). Melting Point 120-125 ° C (Decomposition)

IR (New sol): 3370, 3250, 1780, 1690, 1625, 1530cm ^-1

NMK (d6-DMSO, δ): 1.23 (3H, t, J = 7 Hz), 3.722 (H, br.s), 4.20 (2H, q, J = 7 Hz), 4.35 and 4.58 (2H, ABq, J = 13 Hz), 4.78 (2H, s), 5.17 (1H, d, J = 5 Hz), 5.83 (1H, dd, J = 5 and 8 Hz), 8.20 (2H, br.s), 9.58 (1H, d, J = 8 Hz), 9.60 (1 H,)

(11) 7- [2-hydroxyimino-2- (5-formamido-1, 2, 4-thiadiazol-3-yl) aceteamido] -3- (1, 3, 4-thia Diazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting Point 155-160 ° C (Decomposition)

IR (New sol): 3200, 1780, 1680, 1620cm ^-1

(12) 7- [2- [2 (2-hexyloxyethoxy) ethoxyimino] -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetoamido]- 3-) (1, 3, 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting point 100-105 ℃

IR (New sol): 3340, 3210, 1785, 1685, 1620, 1525cm ^-1

NMK (d6-DMSO, δ): 0.8 (3H, t, J = 5 Hz), 0.87-1,73 (8H, m), 3.10-3.93 (10H, m), 4.10-4.472H, m), 4.30 and 4.58 (2H, ABq, J = 13 Hz), 5.17 (1H, d, J = 5 Hz), 5.83 (1H, dd, J = 5 and 8 Hz), 8.12 (2H, br.s), 9.55 (1H, d, J = 8 Hz), 9.57 (1 H, s)

(13) 7- [2-mesylmethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1, 3, 4-thiadia Zol-2-yl) -thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting Point 164-197 ° C (Decomposition)

IR (New sol): 3360, 3230, 1780, 1690, 1620, 1530cm ^-1

NMR (d6-DMSO, δ): 3.02 (3H, s), 3.72 (2H, br.s), 4.33 and 4.57 (2H, ABq, J = 13), 5.15 (1H, d, J = 5 Hz), 5.30 (2H, s), 5.83 (1H, dd, J = 5 and 8 Hz), 8.20 (2H, br.s), 9.55 (1H, s), 9.78 (1H, d, J = 8 Hz)

(14) 7 [2-trityloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1-methyl-1H-tetrazol- 5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting Point 163-167 ° C (Decomposition)

IR (New sol): 3480, 3350, 3250, 1785, 1690, 1620, 1530cm ^-1

NMK (d6-DMSO, δ): 3.64 and 3.72 (2H, ABq, J = 18 Hz), 3.90 (3H, s), 4.24 and 4.38 (2H, dd, J = 14 Hz), 5.18 (1H, d, J = 4 Hz), 5.98 (1H, dd, J = 4 and 8 Hz), 7.30 (15H, s), 8.08 (2H, s), 9.84 (1H, d, J = 8 Hz)

(15) 7- [2-trityloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1,34-thiadiazole- 2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting Point 175-178 ° C (Decomposition)

IR (New sol): 3450, 3350, 3200, 1790, 1690, 1620, 1530cm ^-1

NMR (d6-DMSO, δ): 3.73 (2H, br.s), 4.33 and 4.63 (2H, ABq, J = 13 Hz), 5.10 (1H, d, J = 4 and 8 Hz), 6.03 (1H, dd, J = 4 and 8 Hz), 7.37 (15H, s), 8.13 (2H, s), 9.60 (1H, s), 9.87 (1H, d, J = 8 Hz)

(16) 7- [2-Altyloxyimino-2- (5-amino-1, 2, 4-thiadiazole-3-acetamido] -cephalosporanic acid (syn isomer). ℃ (decomposition)

IR (New sol): 3350, 3240, 1780, 1730, 1680, 1530, 1240cm ^-1

NMR (d6-DMSO, δ): 2.07 (3H, s), 3.57 (2H, br.s), 4.5 (-5.1 (2H, m), 4.7- (2H, br.s), 5.1-5.6 (2H , m), 5.15 (1H, d, J = 4 Hz), 5.5-6.4 (1H, m), 5.84 (1H, dd, J = 4.59 Hz),

(17) 7- [2-allyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1-methyl-1tetrazole-5 -Yl) thiomethyl-3-cepem-4 carboxylic acid (syn isomer). Melting Point 154-156 ° C (Decomposition)

IR (New sol): 3380, 3245, 1780, 1680, 1625, 1527cm ^-1

NMR (d6-DMSO, δ): 3.53 and 3.77 (2H, ABq, J = 14 Hz), 3.90 (3H, s) 4.27 (2H, br.s), 4.5-4.8 (2H, m), 5.0-5.6 ( 2H, m), 5.15 (1H, d, J = 4.5 Hz), 5.6-6.3 (1H, m), 5.85 (1H, dd, J = 4.59 Hz), 7.23 (2H, br.s), 9.77 (1H , d, J = 9 Hz)

(18) 7- [2-trityloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- (1, 3, 4-thiadiazole -2-yl) thiomethyl-3-cepem-4 carboxylic acid (syn isomer). Melting Point 165-170 ° C (Decomposition)

I.R. (New sol): 3350, 3200, 1785, 1690, 1620, 1515

NMR (d6-DMSO, δ): 3.70 (2H, br.s), 4.33 and 4.60 (2H, ABq, J = 13 Hz), 5.10 (1H, d, J = 4 Hz), 5, 73 (1H, dd, J = 8 Hz), 8.23 (2H, s), 9.60 (1H, s)

(19) 7- [2- and allyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3-yl) acetamido] -3- ( 5-aminomethyl-1, 3, 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Powder melting point 161-164 占 폚 (decomposition).

IR (New sol): 3350, 3220, 1770, 1670, 1620, 1525cm ^-1

(20) 7- [2-allyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- [2-) Nt-part Oxycarbonylimino) ethyl] -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer) powder.

(21) 7- [2-allyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (2-aminoethyl)- 1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting Point 165-169 ° C (Decomposition)

IR (New sol): 3350, 3200, 1768, 1670, 1610, 1522cm ^-1

(22) 7- [2-hydroxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1-methyl-1-H-tetra Sol-5-yl) thiomethyl-3-cepem-4-carboxyl (syn isomer). Melting Point 165-170 ° C (Decomposition)

I.R. (New sol): 3350, 3250, 1780, 1680, 1620, 1530

(23) 7- [2-hydroxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- (1, 3, 4-thiadiazole- 2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting Point 170-175 ° C (Decomposition)

IR (New sol): 3480, 3350, 1770, 1690, 1620, 1530cm ^-1

(24) 7- [2-hydroxyimino-2-1, 2, 4-thiadiazol-3-yl) acetimido-3- (1, 3, 4-thiadiazol-2-yl) thio Methyl-3-cepem-4-carboxylic acid (Anti isomer). Melting Point 155-160 ° C (Decomposition)

IR (New sol): 3350, 3250, 1780, 1680, 1620, 1520cm ^-1

Example 18

A mixture of 1.89 g of phosphorus pentachloride and 20 ml of methylene chloride was stirred at room temperature for 15 minutes, followed by 2- (1-t-butoxycarbonylethoxyimino) -2- (5-amino-1, 2, 2.2 g of 4-thiadiazol-3-yl) acetic acid (syn isomer) was added and the mixture was stirred at -10 -15 ° C for 30 minutes. A solution containing 1.4 g of 7-amino-3-cepem-4 carboxylic acid and 8.4 g of trimethylsilylacetamide in 20 ml of methylene chloride was added thereto at -20 ° C, for 30 minutes at -10 to -15 ° C for 30 minutes at 0 to 5 ° C. Stirred.

Methylene chloride was distilled off from the reaction mixture, ethyl acetate and a small amount of water were added to the residue, and the resulting solution was poured into a sodium bicarbonate solution and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer, acidified with hydrochloric acid at 0∼5 ° C., extracted twice with ethyl acetate, the extract was washed with water, dried over magnesium sulfate, treated with activated carbon and concentrated.

The residue is suspended with diisopropyl ether and the precipitate is filtered off to dissolve at 250 ° C. 7- [2- (1-t-butoxycarbonylethoxyimino) -2- (5-amino-1, 2, 4- Thiadiazol-3-yl) acetamido] -3-cepem-4-carboxylic acid (syn isomer) 2.5 g was obtained.

IR (New sol): 3400, 3250, 177, 1720, 1680, 1610, 1520, 1290, 1240, 1150, 980, 740cm ^- 1

NMR (DMSO-d6, δ): 1.50 (12 wide s), 3.63 (2H, m), 4.73 (1H, q, J = 5 Hz), 5.17 (1H, d, J = 5 Hz), 5.92 (1H, dd , J = 5 and 8 Hz), 6.53 (1H, m, 8.17 and (2H, m), 9.4 and 9.6 (1H, d, J = 8 Hz)

Example 19

The following compounds were obtained in a similar manner to Examples 1-3 and 5.-12.

(1) 7-2- (4-chlorophenoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- (3- (1-allyl- 1-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 120-125 ° C. (decomposition)

IR (New sol): 3290, 3180, 1770, 1680, 1615, 1580, 1520, 1480cm ^-1

NMR (DMSO-d6, δ): 3.73 (2H, wide s), 4.40 (2H, wide s), 5.17 (1H, d, J = 5 Hz), 4.87-5.20 (2H, m) 5.20-5.60 (2H, m), 5.90 (1H, dd, J = 5 and 8 Hz), 5.60-6.30 (1H, m), 7.32 (2H, d, J = 9 Hz), 7.48 (2H, d, J = 9 Hz), 8.32 (2H , Wide s), 9.90 (1H, d, J = 8 Hz).

(2) 7- [2- (4-chlorophenoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1-methyl- 1-tetrazol-5-yl) thiomethyl-30-cefe-4-carboxylic acid (syn isomer). Melting Point 13 ° -135 ° C (Decomposition)

IR (New sol): 3400, 3300, 380, 1770, 1670, 1615, 1580, 1520, 1480cm ^-1

NMR (DMSO-d9, δ): 3.72 (2H, wide S), 3.92 (3H, s), 4.32 (2H, wide s), 5.18 (1H, d, J = 5 Hz), 5.87 (1H, dd, J = 5 and 8 Hz), 7.25 (2H, d, J = 9 Hz), 7.42 (2H, d, J = 9 Hz), 8.25 (2H, wide s), 9.85 (1H, d, J = 8 Hz)

(3) 7- [2- (4-chlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] cephalosporanic acid (syn isomer ). Melting Point 120-125 ° C (Decomposition)

IR (New sol): 3400, 3300, 3190, 1770, 1720, 1650, 1620, 1580, 1520, 1480cm ^-1

NMR (DMSO-d6, δ): 2.02 (3H, s), 3.58 (2H, wide s), 4.75 and 4.98 (2H, ABq, J = 13 Hz), 5.22 (1H, d, J = 5 Hz), 5.87 ( 1H, dd, J = 5 and 8 Hz), 7.27 (2H, d, J = 9 Hz), 8.42 (2H, d, J = 9 Hz), 8.28 (2H, wide s), 9.85 (1H, d, J = 8 Hz ).

(4) 7-1-4chlorophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3 [4- (2-carboxyethyl) -2-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting Point 135-140 ° C (Decomposition)

IR (New sol): 3400, 3270, 3190, 1770, 1680, 1620, 1585, 1520, 1480cm ^-1

NMR (DMSO-d6, S): 2.70-3.10 (2H, m), 3.70 (2H, wide s), 4.10-4.60 (4H, m), 5.20 (1H, d, J = 5 Hz 5.87 (1H, dd, J = 5 and 8 Hz), 7.28 (2H, d, J = 9 Hz), 7.45 (2H, d, J = 9 Hz), 8.30 (2H, wide s), 9.85 (1H, d, J = 8 Hz).

(5) 7- [2- (4-chlorophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [2-carboxymethyl -3-oxo-2,3-dihydro-1,2,4-triazolo [4,3-b] pyridazin-6-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 140-145 ° C (decomposition)

IR (New sol): 3400, 3300, 3190, 1765, 1700, 1620, 1580, 1540, 1520, 1480cm ^-1

NMR (DMSO-d6, δ): 3.80 (2H, wide s), 4.28 (2H, wide s), 4.73 (2H, s), 5.27 (1H, d, J = 5 Hz), 5.90 (1H, dd, J = 5 and 8 Hz), 7.12 (1H, d, J = 10 Hz), 7.32 (2H, d, J = 9 Hz), 7.72 (1H, d, J = 10 Hz), 8.30 (2H, wide s), 9.92 (1H , d, J = 8 Hz).

(6) 7- [2- (4-chlorophenoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3-tetrazolo- [1 , 5-b] pyridazin-6-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting Point 140-145 ° C (Decomposition)

IR (New sol): 3350, 3240, 1780, 1685, 1625, 1530, 1490cm ^-1

NMR (DMSO-d6, δ): 3.70 (2H, wide s), 4.22 and 4.62 (2H, ABq, J = 13 Hz), 5.22 (1H, d, J = 5 Hz), 5.93 (1H, dd, J = 5 And 8 Hz), 7.27 (2H, d, J = 9 Hz), 7.42 (2H, d, J = 9 Hz), 7.73 (1H, d, J = 9 Hz), 8.28 (2H, wide s), 8.59 (1H, d , J = 9 Hz), 9.87 (1H, d, J = 8 Hz)

(7) 7- [2- (α-butoxycarbonylbenzyloxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1 , 3,4-thiadiazol-3-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 105-110 ° C. (decomposition)

IR (New sol): 3400, 3300, 3180, 1780, 1720, 1680, 1620, 1520cm ^-1

NMR (DMSO-d6, δ): 1.40 (9H, s), 3.50-3.83 (2H, m), 4.37 and 4.60 (2H, ABq, J = 13 Hz), 5.10 and 5.18 (1H, d, J = 5 Hz) , 5.63 (1H, s), 5.67-6.0 (1H, m), 7.47 (5H, s), 8.20 (2H, wide s), 9.62 (1H, s), 9.64 (1H, s), 9.47-9.77 ( 1H, m).

(8) 7-[(α-t-butoxycarbonylbenzyloxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3-cepem- 3-carboxylic acid (syn isomer), melting point 90-95 ° C. (decomposition)

IR (New sol): 3400, 3380, 3230, 1780, 1730, 1685, 1635, 1530 cm ^-1

NMR (DMSO-d6, δ): 1.38 (9H, s), 3.60 (2H, wide s), 5.0-5.20 (1H, m), 5.63 (1H, wide s), 5.72-6.03 (1H, m), 6.37-6.67 (1H, m), 7.47 (5H, s), 8.18 (2H, wide s), 9.43-9.70 (1H, m).

(9) 7- [2- (α-butoxycarbonylbenzyloxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1 -[2-t-butoxycarbonylamino) ethyl-1H-tetrazol-5-yl] thio-3-methylcepem-4-carboxylic acid (syn isomer). Melting Point 105-110 ° C (Decomposition)

IR (New sol): 3360. 3220. 1785, 1690, 1625, 1525cm ^-1

NMR (DMSO-d6, δ): 1.38 (18H, s), 3.17-3.87 (4H, m), 4.17-4.65 (4H, m), 5.0-5.28 (1H, m), 5.12 (1H, s), 5.58-6.0 (1H, m), 7.47 (5H, s), 8.17 (2H, wide s), 9.45-9.75 (1H, m).

(10) 7-2 [-(2-tpropynyloxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] 3- [4- (2 -Carboxyethyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting Point 125-130 ° C (Decomposition)

IR (New sol): 3400, 3260, 3190, 2580, 1765, 1710, 1670, 1620, 1520cm ^-1

NMR (DMSO-d6, δ): 2.92 (2H, t, J = 6 Hz), 3.47 (1H, t, J = 2 Hz), 3.67 (2H, wide s), 4.17-4.60 (4H, m), 4.77 ( 2H, d, J = 2 Hz, 5.08 (1H, d, J = 5 Hz), 5.77 (1H, dd, J = 5 and 8 Hz), 8.08 (2H, wide s), 9.57 (1H, d, J = 8 Hz )

(11) 7- [2- (2-propynyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] cephalosporanic acid (syn isomer ),

IR (New sol): 3400, 3270, 3180, 1770, 1720, 1655, 1520 cm ^-1

NMR (DMSO-d6, δ): 1.98 (3H, δ), 2.45 (1H, t, J = 2 Hz), 3.48 (2, wide s), 4.72 (2H, d, J = 2 Hz), 4.67 and 4.92 ( 2H, ABq, J = 13 Hz, 5.08 (1H, d, J = 5 Hz), 5.77 (1H, dd, J = 5 and 8 Hz), 8.07 (2H, wide s) 9.55 (1H, d, J = 8 Hz) .

(12) 7- [2-t-butoxycarbonylphenoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3-cepem-4-carboxylic acid (syn isomers). Melting Point 165-170 ° C (Decomposition)

IR (New sol): 3350, 3250, 3180, 1790, 1720, 1660, 1630, 1620, 1520 cm ^-1

NMR (DMSO-d6, δ): 1.40 (9H, s), 3.57 (2H, wide s), 4.60 (1H, s), 5.07 (1H, d, J = 4 Hz), 5.83 (1H, dd, J = 4 and 8 Hz), 6.47 (1H, wide s), 8.13 (2H, s), 9.50 (1H, d, J = 8 Hz)

(13) 7- [2-thiolin-1.1-dioxide-3-yl) oxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer). Melting Point 170-175 ° C (Decomposition)

IR (New sol): 3300, 3200, 1770, 1670, 1620, 1520cm ^-1

NMR (DMSO-d6, δ): 2.30-2.50 (2H, m), 3.0-3.57 (4H, m), 3.70 (2H, wide s), 4.33 and 4.57 (2H, ABq, J = 13 Hz), 5.0- 5.15 (1H, m), 5.17 (1H, d, J = 4 Hz), 5.85 (1H, dd, J = 4 and 8 Hz), 8.23 (2H, s), 9.60 (1H, s), 9.67 (1H, d , J = 8 Hz).

(14) 7- [2-allyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1-carboxymethyl-1H-tetrazole -5-yl) tinomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 140-145 ° C. (decomposition)

IR (New sol): 3300, 3200, 1770, 1720, 1670, 1620, 1520cm ^-1

NMR (DMSO-d6, δ): 3.63 (2H, wide s), 4.23 and 4.43 (2H, ABq, J = 14 Hz), 4.60-4.73 (2H, m), 5.10 (1H, d, J = 4 Hz), 5.30 (2H, s), 5.07-5.50 (2H, m), 5.67-5.20 (2H, m), 8.15 (2H, s), 9.63 (1H, d, J = 8 Hz).

(15) 7- [2- (2-propynyloxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1-carboxymethyl -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (sym isomer), melting point 135-140 ° C. (decomposition)

IR (New sol): 3250, 3150, 1770, 1720, 1670, 1620, 1520cm ^-1

NMR (DMSO-d6, δ: 3.47 (1H, t, J = 2Hz), 3.63 (2H, wide s), 4.22 and 443 (2H, .ABq, J = 14Hz), 5.07 (1H, d, J = 4Hz ), 5.28 (2, Hs), 5.80 (1H, dd, J = 4 and 8 Hz), 8.15 (2H, s), 9.63 (1H, d, J = 8 Hz).

(16) 7- [2-allyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- [1- (2-carboxymethyl)- 1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 140-145 ° C. (decomposition)

IR (New sol): 3300, 3200, 1770, 1720, 1670, 1620, 1520cm ^-1

NMR (DMSO-d6, δ): 2.87 (2H, t, J = 6 Hz), 3.63 (2H, wide s), 4.37 (2H, t, J = 6 Hz), 4.20 and 4.47 (2H, ABq, J = 14 Hz ), 4.57-4.67 (2H, m), 5.07 (1H, d, J = 4 Hz), 5.10-5.43 (2H, m), 5.67-6.13 (2H, m), 8.10 (2H, s), 9.58 (1H) , d, J = 8 Hz)

(17) 7- [2- (t-butoxycarbonylmethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (2-carboxyethyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 150-155 ° C. (decomposition)

IR (New sol): 3300, 3200, 1770, 1720, 1700, 1620, 1520cm ^-1

NMR (DMSO-d6, δ): 1.50 (9H, s), 3.00 (2H, t, J = 6 Hz), 3.73 (2H, wide s), 4.43 (2H, wide s), 4.50 (2H, t, J = 6 Hz), 4.67 (2H, s) 5.17 (1H, d, J = 4 Hz), 5.87 (1H, dd, J = 4 and 8 Hz), 8.18 (2H, s), 9.53 (1H, d, J = 8 Hz ).

(18) 7- [2- (t-butoxycarbonylmethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3-1- [ 3- (4-Methyl-1-piperidinyl) propyl [-1 H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 220-115 ° C. (decomposition)

IR (New sol): 3300, 1700, 1680, 1605, 1520cm ^-1

NMR (DMSO-d6, δ): 1.40 (9H, s), 1.96-2.10 (2H, m), 2.38-2.50 (4H, m), 2.60 (3H, s), 2.95-3.10 (6H, m), 3.52 and 3.65 (2H, ABq, J = 16 Hz), 4.20-4.40 (4H, m), 4.60 (2H, s), 5.06 (1H, J = 4 Hz), 5.70 (1H, dd, J = 4 and 8 Hz) , 8.12 (2H, s), 9.44 (1H, doublet, J = 8 Hz).

(19) 7- [2- (1-t-butoxycarbonyl-2-methylpropoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido ] Sephalosporanic acid (syn isomer), melting point 130-140 ° C (decomposition)

IR (New sol): 3400, 3300, 3200, 1780, 1720-1680, 1620, 152, 146, 1370, 1230, 1150, 1030, 730cm ^-1

NMR (DMSS-d ₆ , δ: 1.03 (6H, d, J = 7Hz), 1.43 (9H, s,), 2.03 (3H, s), 1.9-2.2 (1H, m), 3.6 (2H, m) , 4.26 and 4.34 (1H, d, J = 6 Hz), 4.68 and 5.05 (2H, ABq, J = 13 Hz), 5.19 (1H, d, J = (5 Hz), 5.87 (1H, dd, J = 5 and 8 Hz) ), 8.10 (2H, broad s), 9.48 (1H, d, J = 8 Hz).

(20) 7- [2- (1-t-butoxycarbonylpropoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] cephalospo Lanic acid (syn isomer), melting point 95-105 ° C (decomposition)

IR (New sol): 3400, 3300, 3200, 1780, 1720, 1620, 1530, 1230, 1150, 1010, 890, 840, 740cm ^-1

NMR (DMSO-d ₆ , δ): 0.95 (3H, t, J = 7Hz), 1.39 (9H, s), 1.8 (2H, m), 2.02 (3H, s), 3.5 (2H, m), 4.47 (1H, m), 4.67 and 5.03 (2H, ABq, J = 13 Hz), 5.14 (1H, d, J = 5 Hz), 5.83 (1H, dd, J = 5 and 8 Hz), 8.07 (2H, wide s) , 9.37 and 9.43 (1H, d, J = 8 Hz)

(22) 7- [2- (1-tbutoxycarbonylethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- ( 1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 120-128 ° C. (decomposition)

IR (New sol): 3280, 3180, 1770, 1720, 1680, 1620, 1520, 1240, 1150, 1000, 740, 720cm ^-1

NMR (DMSO-d (, δ): 1.4 (12H, m), 3.76 (2H, m), 4.30 and 4.67 (2H, ABq, J = 13Hz), 4.70 (1H, δ, J = 7Hz), 5.22 ( 1H, d, J = 5 Hz, 5.88 (1H, dd, J = 5 and 8 Hz), 8.20 (2H, wide s), 9.47 (1H, m), 9.60 (1H, s).

(23) 7-2- (1-butoxycarbonylethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] cephalosporanic acid ( syn isomer), melting point 138-145 ° C (decomposition)

IR (New sol): 3280, 3180, 1780, 1720, 1680, 1620, 1520, 1230, 1150, 840cm ^-1

NMR (DMSO-d ₆ , δ), 1.47 (12, H, m), 2.07 (3, H, s), 5.58 (2H, m), 4.5-5.1 (3H, m), 5.19 (1H, d, J = 5 Hz), 5.87 (1H, dd, J = 5 and 8 Hz), 8.10 (2H, wide s), 9.40 and 9.50 (1H, d, J = 8 Hz).

(24) 7- [2- (1-methyl-1-t-butoxycarbonylethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido ] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 115-120 ° C. (decomposition)

IR (New sol): 3280, 3170, 1780, 1720, 1680, 1520, 1140, 990, 750cm ^-1

NMR (DMSO-d ₆ , δ): 1.40 (9H, s), 1.46 (6H, s) 3.7 (2H, m), 4.26 and 4.63 (2H, ABq, J = 13 Hz), 5.18 (1H, d, J = 5 Hz), 5.83 (1H, dd, J = 5 and 8 Hz), 8.13 (2H, wide s), 9.40) 1H, d, J = 8 Hz, 9.53 (1H, s)

(25) 7-2- (1-t-butoxycarbonyl-cyclopentyloxyimino) -2-5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 140-143 ° C. (decomposition)

IR (New sol): 3300, 3180, 1770, 1720, 1670, 1620, 1520, 1245, 1150, 1060, 995, 840cm ^-1

NMR (DMSO-d ₆ , δ): 1.40 (9H, s), 1.8 (4H, m), 2.1 (4H, m), 3.7 (2H, m), 4.27 and 4.68 (2H, ABq, J = 13Hz) , 5.18 (1H, d, J = 5 Hz), 5.85 (1H, dd, J = 5 and 8 Hz), 8.1 (2H, wide s), 3.39 (1H, d, J = 8 Hz), 9.53 (1H, s) .

(26) 7- (2- (1-methyl-1-t-butoxycarbonylethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido Cephalosparan acid (syn isomer), melting point 135-140 ° C (decomposition)

IR (New sol): 3400, 3300, 3180, 1780, 1720, 1690, 1620, 1540, 1300, 1220, 1140, 1030, 990, 840, 740cm ^-1

NMR (DMSO-d ₆ , δ): 1.57 (9H, s, 1.62 (6H, s), 2.03 (3H, s), 3.57 (2H, m), 4.69 and 5.06 (2H, ABq, J = 13Hz), 5.19 (1H, d = J = 5 Hz), 5.89 (1H, dd, J = 5 and 8 Hz), 8.21 (2H, wide s), 6.32 (1H, d, J = 8 Hz)

(27) 7- [2- (1-t-butoxycarbonyl-1-cyclopentyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] Sepharose blue acid (syn isomer), melting point 98-102 ° C (decomposition)

IR (New sol): 3350, 3230, 1790, 1730, 1630, 1530, 1340, 1160, 1070, 1040, 1000cm ^-1

NMR (DMSO-d ₆ , δ): 1.47 (9H, s), 1.80 (4H, m), 2.10 (4H, m), 2.13 (3H, s), 3.60 (2H, m), 4.73 and 5.1 (2H , ABq, J = 14 Hz), 5.22 (1H, d, J = 5 Hz), 5.88 (1H, dd, J = 5 and 8 Hz), 8.15 (2H, m), 9.43 (1H, d, J = 8 Hz).

(28) 7- [2- (1-methyl-1-t-butoxycarbonylethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido ] -3- [1- (Nt-butoxycarbonylamino] ethyl] -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 96-100 ° C. (decomposition) )

IR (New sol): 3300, 3150, 1780, 1680, 1570, 1240, 1160, 990cm ^-1

NMR (DMSO-d ₆ , δ): 1.45 (18H, s), 1.52 (6H, s), 3.33 (2H, m), 3.67 (2H, m), 4.30 (4H, m), 5.10 (1H, d , J = 5 Hz), 5.85 (1H, dd, J = 5 and 8 Hz), 6.92 (1H, m), 8.13 (2H, m), 9.40 (1H, d, J = Hz).

(29) 7- [2- (1-methyl-1-t-butoxycarbonylethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido ] -3-cepem-4-carboxylic acid (syn isomer) at melting point of 215 ° C (decomposition)

IR (New sol): 3400, 3300, 3150, 1780, 1710, 1690, 1620, 1520, 1240, 1140, 980cm ^-1

NMR (DMSO-d ₆ , δ): 1.40 (9H, s), 1.47 (5H, s), 3.60 (2H, m), 5.17 (1H, d, J = 5 Hz), 5.92 (1H, dd, J = 5 and 8 Hz), 6.50 (1H, m), 8.22 (2H, m), 9.50 (1H, d, J = 8 Hz).

(30) 7- [2-1-t-butoxycarbonylethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- ( 1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 96-100 ° C. (decomposition)

IR (New sol): 3300, 3150, 1780, 1720, 1680, 1620, 1520, 1240, 1150, 1090, 1000cm ^-1

NMR (DMSO-d ₆ δ): 1.40 (12H, wide s), 3.67 (2H, m), 4.2 and 4.50 (2H, ABq, J = 13 Hz), 4.67 (1H, s, J = 6 Hz), 4.93 ( 2H, m), 5.07 (1H, d, J = 5 Hz), 5.13-5.37 (2H, m), 5.83 (1H, dd, J = 5 and 8 Hz), 5.83-6.22 (1H, m), 8.10 (2H , Wide s), 9.40 and 9.52 (1H, d, J = 8 Hz)

(31) 7- [2- (1-phenylethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1, 3, 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), decomposed at 175 ° C

IR (New sol): 3400, 3250, 3150, 1750, 1650, 1610, 1520, 1400, 1240, 1160, 1060, 1000, 700cm ^-1

WMR (DMSO-d ₆ , δ): 1.57 (3H, d, J = 8 Hz), 3.73 (2H, m), 4.32 and 4.72 (2H, ABq, J = 13 Hz), 5.22 (1H, d, J = 5 Hz ), 5.3-5.5 (1H, m), 5.93 (2H, dd, J = 5 and 8 Hz, 7.36 (5H, m), 8.13 (2H, m), 9.57 (1H, s), 9.72 (1H, d, J = 8 Hz).

(32) 7- [2- (3,4-dichlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cepem-4 Carboxylic acid (syn isomers), decomposed at 210 ° C

IR (New sol): 3450, 3300, 3200, 1760, 1660, 1560, 1290, 1210, 1000, 970, 940, 730 cm ^-1

NMR (DMSO-d ₆ , δ): 3.63 (2H, m), 5.17 (1H, d, J = 5 Hz), 5.91 (1H, dd, J = 5 and 8 Hz), 6.41 (1H, m), 7.13- 7.73 (3H, m), 8.28 (2H, s), 9.87 (1H, d, J = 8 Hz).

(33) 7- [2- (p-trilyloxyimino) -2- (5-amino-1-2, 4-thiadiazol-3-yl) acetamido] -3- (13, 4-thia Diazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), admixed with decomposition 0-tolyl isomer at 150 ° C.

IR (New sol): 3350, 3250, 1780, 1680, 1630, 1530, 1510, 1230, 1059, 910, 820cm ^-1

NMR (DMSO-d ₆ , δ: 2.23 (15H, s), 2.27 (1 / 5H, s), 3.71 (2H, m), 4.21 and 4.61 (2H, ABq, J = 13 Hz), 5.23 (1H, d , J = 5 Hz, 5.90 (1H, m), 7.16 (4H, m), 8.23 (2H, m), 9.56 (1H, s), 9.86 (1H, d, J = Hz).

(34) 7- [2- (3-trifluoromethylphenoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1 -Allyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), decomposed at 155 ° C.

IR (New sol): 3300, 3200, 1770, 1680, 1620, 1520, 1320, 1160, 1120, 1060, 980, 930, 700cm ^-1

NMR (DMSO-d ₆ , δ): 3.56 and 3.82 (2H, ABq, J = 18 Hz), 4.20 and 4.60 (2H, ABq, J = 14 Hz), 4.95 (2H, m), 5.18 (1H, d, J = 5 Hz), 5.12-5.24 (2H, m), 5.92 (1H, dd, J = 5 and 8 Hz), 5.72-5.12 (1H, m), 7.50 (4H, m), 8.26 (2H, m), 9.84 (1H, d, J = 8 Hz).

(35) 7- [2- (3-trifluoromethylphenoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1-methyl -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) decomposes at 170 ° C.

IR (New sol): 3300, 3200, 1770, 1680, 1620, 1520, 1320, 1160, 1120, 1060, 930, 790, 700cm ^-1

NMR (DMSO-d ₆ , δ): 3.77 (2H, m), 3.97 (3H, s), 4.37 (2H, m), 5.27 (1H, d, J = 5 Hz), 5.95 (1H, dd, J = 5 and 8 Hz), 7.60 (4H, m), 8.33 (2H, m), 9.97 (1H, d, J = 8 Hz).

(36) 7- [2- (4-fluorophenoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1-methyl- 1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), decomposed at 170 ° C

IR (New sol): 3450, 3350, 3200, 1780, 1710, 1680, 161011510, 1590, 1240, 1200, 1170, 1090, 990, 910, 840cm ^-1

NMR (DMSO-d ₆ , δ): 3.73 (2H, m), 3.93 (3H, s), 4.33 (2H, m), 5.23 (1H, d, J = 5 Hz), 5.90 (1H, dd, J = 5 and 8 Hz), 7.17 (-7.28 (4H, m), 8.37 (2H, m), 9.87 (1H, d, J = 8 Hz).

(37) 7- [2- (2,4-dichlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cepem-4 -Carboxylic acid (syn isomers), decomposed at 240

IR (New sol): 3250, 1770, 1660, 1620, 1540, 1520, 1280, 1230, 1100, 1050, 970, 920, 810, 750cm ^-1

NMR (DMSO-d ₆ , δ): 3.56 (2H, m), 5.11 (1H, d, J = 5 Hz), 5.91 (1H, dd, J = 5 and 8 Hz), 6.47 (1H, m), 7.47- 7.63 (3H, m), 8.21 (2H, m), 9.81 (1H, d. J = 8 Hz).

(38) 7- [2- (2,4-dichlorophenoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1, 3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), decomposed at 165 ° C.

IR (New sol): 3300, 3200, 1770, 1680, 1620, 1520, 1250, 1230, 1100, 1060, 960, 910, 810cm ^-1

NMR (DMSO-d ₆ , δ): 3.71 (2H, m), 4.23 and 4.67 (2H, ABq, J = 14 Hz), 5.25 (1H, d, J = 5 Hz), 5.93 (1H, dd, J = 5 And 8 Hz), 7.50-7.67 (3H, m), 8.25 (2H, m), 9.57 (1H, s), 9.88 (1H, d, J = 8 Hz).

(39) 7- [2- (2-cyclopenten-l-yloxyimino) -2- (5-amino-l, 2,4-thiadiazol-3-yl) acetamido] -3-methyl 3-cefe-4-carboxylic acid (syn isomer), melting point 165-218 ° C. (decomposition)

IR (New sol): 3350, 3250, 3140, 3050, 1750, 1705, 1665, 1625, 1550, 1535cm ^-1

NMR (DMSO-d ₆ + D ₂ O, δ): 1.6-2.6 (4H, m), 2.00 (3H, s), 3.0-3.9 (2H, m), 5.05 (1H, d, J = 4.5 Hz) , 5.2-5.5 (1H, m), 5.70 (1H, d, J = 4.5 Hz), 5.7-6.3 (2H, m).

(40) 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3-methyl-3-cepem-4-carboxylic acid (syn isomer), melting point 170-212 ° C (decomposition)

IR (New sol): 3350, 3120, 3050, 1750, 1705, 1668, 1625, 1556, 1534 cm ^-1

NMR (DMSO-d ₆ + D ₂ O, δ): 1.3-2.2 (8H, m), 2.03 (3H, s), 3.0-3.9 (2H, m), 4.77 (1H, wide s), 5.10 (1H , d, J = 4.5 Hz), 5.73 (1H, d, J = 4.5 Hz).

(41) 7- [2- (2-cyclohexene-1 yloxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3-methyl- 3-cefe-4-carboxylic acid (syn isomer), melting point 180-205 ° C. (decomposition)

IR (New sol): 3300, 3250, 3120, 3050, 1750, 1765, 1665, 1625, 1535cm ^-1

NMR (DMSO-d ₆ + D ₂ O, δ): 1.3-2.4 (5H, m), 2.03 (3H, s), 3.1-3.7 (2H, m), 4.70 (1H, wide s), 5.10 (1H , d, J = 4.5 Hz), 5.73 (1H, d, J = 4.5 Hz), 5.7-6.0 (2H, m).

(42) 7- [2- (2-cyclopenten-l-yloxyimino) -2- (5-amino-l, 2,4-thiadiazol-3-yl) acetamido] -2-methyl- 3-cepem-4-carboxylic acid (syn isomer), melting point 142-148 ° C (decomposition)

IR (New sol): 3300, 3200, 1775, 1650, 1630, 1525cm ^-1

NMR (DMSO-d ₆ + D ₂ O, δ): 1.41 (3H, d, J-7.5 Hz), 1.9-2.6 (4H, m), 3.5-4.1 (1H, m), 5.16 (1H, d, J = 4.5 Hz), 5.2-5.5 (1H, m), 5.6-6.4 (3H, m), 6.62 (1H, d, J = 6 Hz)

(43) 7- [2- (3 (Nt-butoxycarbonylamino) fufufucimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-semfem-4-carboxylic acid (syn isomer).

IR (New sol): 3200, 3160, 1773, 1685, 1620cm ^-1

NMR (DMSO-d ₆ + D ₂ O, δ): 1.41 (1H, s), 1.6-2.1 (2H, m), 2.8-3.3 (2H, m), 3.75 (2H, wide s), 4.0-4.5 (2H, m) 4.35 and 4.65 (2H, ABq, J = 14 Hz), 5.20 (1H, d, J = 5 Hz), 9.58 (1H, s).

(44) 7- [2- (3- (Nt-butoxycarbonylamino) furoxyimino] -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1- (2-hydroxyethyl) 1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer)

IR (New sol): 3200, 3160, 1775, 1720, 1700, 1675, 1620cm ^-1

NMR (DMSO-d ₆ + D ₂ O, δ): 1.37 (9H, s), 1.5-1.9 (2H, m), 2.6-3.2 (2H, m), 3.4-3.9 (4H, m), 3.9- 4.4 (6H, m), 5.10 (1H, J = 5 Hz), 5.80 (1H, d, J = 5 Hz).

(45) 7- [2- (3- (Nt-butoxycarbonylamino) puroxyimino] -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-carboxylic acid (syn isomer)

IR (New sol): 3300, 3150, 1775, 1710, 1700, 1670, 1650, 1620cm ^-1

NMR (DMSO-d ₆ + D ₂ O, δ): 1.40 (9H, s), 1.6-2.1 (2H, m), 2.71 (3H, s), 2.9-3.3 (2H, m), 3.71 (2H, Wide s), 4.0-4.8 (4H, m), 5.18 (1H, d, J = 4.5 Hz), 5.88 (1H, d, J = 4.5 Hz).

(46) 7- [2- (3- (Nt-butoxycarbonylamino) puroxyimino] -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 81-119 ° C. (decomposition)

IR (New sol): 3300, 3180, 1773, 1715, 1700, 1670, 1620cm ^-1

NMR (DMSO-d ₆ + D ₂ O, δ): 1.35 (9H, s), 1.5-2.0 (2H, m), 2.7-3.2 (2H, m), 3.68 (2H, wide s), 3.9-4.5 (2H, m), 3.92 (3H, m, 3.92 (H, s), 5.12 (1H, d, J = 4.5 Hz), 5.83 (1H, d, J = 4.5 Hz)

(4) 7- [2 [4- (Nt-butoxycarbonylaminomethyl) -benzyloxyimino] -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido -3-Methyl-3-cepem-4-carboxylic acid (syn isomer)

IR (New sol): 3300, 3170, 1760, 1680cm ^-1

NMR (DMSO-d ₆ , δ): 1.65 (9H, s), 2.0 (3H, s), 3.4 (2H, m), 4.14 (2H, d, J = 6Hz), 5.1 (1H, d, J = 4.5 Hz), 4.2 (2H, s), 7.75 (1H, dd, J = 4.5 and 8 Hz).

(48) 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -4-hydroxy-cefe-4-carboxylic acid ( syn isomer), melting point 169-173 ° C. (decomposition)

IR (New sol): 3440, 3250, 1750, 1660, 1520, 1400, 1060, 990, 720cm ^-1

NMR (DMSO-d ₆ , δ): 1.78 (8H, m), 2.77 (1H, m), 3.0-3.5 (1H, m), 3.7-3.5 (1H, dd, J = 5 and 8 Hz), 8.02 ( 2H, broad s), 9.33 (1H, d, J = 8 Hz).

(49) 7- [2- (1-cyclohexyloxycarbonyl) ethoxyimino] -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- Cefem-4-carboxylic acid (syn isomer), melting point 169-173 ° C (decomposition)

IR (New sol): 3440, 3250, 1750, 1660, 1520, 1400, 1240, 1060, 990, 720cm ^-1

NMR (DMSO-d ₆ , δ): 1.7 (8H, m), 2.77 (1H, m), 3.0-3.5 (1H, m), 3.7-4.1 (1H, s), 4.43 (1H, d, J = 6 Hz), 4.73 (1H, m), 5.16 (1H, d, J = 5 Hz), 5.47 (1H, dd, J = 5 and 8 Hz), 8.02 (2H, wide s), 9.33 (1H, d, J = 8 Hz).

(49) 7- [2- (1-cyclohexyloxycarbonyl) ethoxyimino] -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- Cefem-4-carboxylic acid (syn isomer), melting point 160-163 ° C (decomposition)

IR (New sol): 3420, 3300, 3180, 1775, 1720, 1685, 1610, 1520, 1290, 1230, 1040, 980, 740cm ^-1

NMR (DMSO-d ₆ , δ): 1.50 (3H, d, J = 6 Hz), 1.0-2.1 (10H, m), 3.62 (2H, m), 4.80 (1H, q, J = 6 Hz), 4.6- 5.0 (1H, m), 5.15 (1H, d, J = 5 Hz), 5.90 (1H, d, J = 5 and 8 Hz), 6.50 (1H, m), 8.13 (2H, wide s), 9.39 (1 / 2H, d, J = 8 Hz).

(50) 7- [2- (1H-t-butoxycarbonyl-1-cyclopentyloxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido 3-Cefem-4-carboxylic acid (syn isomer), melting point 165-169 ° C (decomposition)

IR (New sol): 3400, 3300, 3200, 1770, 1710, 1680, 1610, 1520, 1290, 1240, 1150, 1000, 970, 740cm ^-1

NMR (DMSO-d ₆ , δ): 1.42 (9H, s), 1.77 (4H, m), 2.05 (4H, m), 3.60 (2H, m), 5.13 (1H, d, J = 5Hz), 5.87 (1H, dd, J = 5 and 8 Hz), 6.47 (1H, m), 8.13 (2H, m), 9.33 (1H, d, J = 8 Hz).

(51) 7- [2-carboxymethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (2- (NNdimethyl Amino) ethyl-1-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 170-173 ° C (decomposition)

IR (New sol): 3400, 3280, 3150, 1760, 1665, 1610, 1520cm ^-1

(52) 7- [2-carboxymethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [3- (N, N-dimethyl Amino) furophyll] -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 170-175 ° C (decomposition)

IR (New sol): 3400, 3280, 3160, 1760, 1665, 1610, 1520cm ^-1

(53) 7- [2- (2-propynyloximino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- (3 -(Nt-butoxycarbonylamino) furophyll-1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 85-90 占 폚 (decomposition)

IR (New sol): 3400, 3290, 3200, 1770, 1680, 1620, 1520cm ^-1

(54) 7- [2-carboxymethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (Nt-butoxycarbo Nylamino) furophyll] -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 185-190 占 폚 (decomposition)

IR (New sol): 3300, 3200, 1770, 1680, 1620, 1520cm ^-1

(55) 7- [2- (2, 2, 2-trifluoroethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3 -(1-4-carboxylic acid (syn isomer), melting point 130-132 ° C (decomposition)

IR (New sol): 3300, 3200, 1770, 1720, 1670, 1620, 1520cm ^-1

(56) 7- [2- (1-carboxy-2-methylpropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamino> 3-1- ( Nt-butoxycarbonylamino) propyl] -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid, (syn isomer), melting point 192-195 ° C. (decomposition)

IR (New sol): 3400, 1780, 1680, 1520, 1450, 1360, 1240, 1160, 1620, 1020, 730m ^-1

(57) [2- (1-carboxypropoxyimino] -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (3- ( Nt-butoxycarbonylamino) propyl] -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 185-192 占 폚 (decomposition)

IR (New sol): 3300, 3200, 1770, 1680, 1620, 1520, 1450, 1360, 1250, 1160, 1000, 730, 710cm ^-1

(58) 7- [2- (3- (Nt-butoxycarbonylamino) propoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido- 3- [1- (3- (Nt-butoxycarbonylamino) furophyll] -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer)

IR (New sol): 3300, 3150, 1775, 1715, 1675, 150, 1615cm ^-1

(59) 7- [2- (1-carboxyethoxyimino] -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido-3- [1- (3- (Nt-butoxycarbonylamino) propyl] -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 110-115 占 폚 (decomposition)

IR (New sol): 3300, 3200, 1770, 1680, 1600, 1520, 1250, 100, 720cm ^-1

(60) 7- [2- (1- (1-carboxy-1-cyclopentyloxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3 -1- (3- (Nt-butoxycarbonylamino) propyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 20 0 -205 ° C (decomposition) )

IR (New sol): 3300, 3200, 1770, 1680, 1520, 1250, 1160, 1000cm ^-1

(61) 7- [2-carboxymethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (3-morpholino Propyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 190-194 ° C (decomposition)

IR (New sol): 3300, 3200, 1770, 1680, 1610, 1530, 1240, 1180, 1090, 1060, 880, 760cm ^-1

(62) 7- [2- (2-carboxy-1-methylethoxyimino] -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [ 1 (3- (Nt-butoxycarbonylamino) propyl] -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer),

IR (New sol): 3300, 3150, 1770, 1680, 1520, 1240, 1160, 990cm ^-1

(63) 7- [2-carboxymethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido) -3- (4-methyl-5-oxo- 6-hydroxy-4.5-dihydro-1,2,4-triazin-3-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 210-21 ° C. (decomposition)

IR (New sol): 3250, 3180, 1720, 1660, 1590, 1520, 1240, 1090, 1050, 720cm ^-1

(64) 7- [2-carboxymethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (4- (Nt- Butoxycarbonylamino) butyl] -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer)

IR (New sol): 3300, 3200, 1770, 1680, 1620, 1520, 1240, 1160, 1090, 890cm ^-1

(65) 7- [2-carboxymethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (3-piperidino Propyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 22-228 ° C (decomposition)

IR (New sol): 3300, 3200, 1770, 1570, 1610, 1520cm ^-1

(66) 7- [2-carboxymethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1- (1-carboxymethyl- 1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 170-175 ° C. (decomposition)

IR (New sol): 3300, 3200, 1765, 1720, 1660, 1620, 1520cm ^-1

(67) 7-2-carboxymethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (6- (Nt-part Methoxycarbonylamino) hexyl] -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), light yellow powder

(68) 7- [2- (1-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [5- (Nt -Butoxycarbonylamino) methyl-1,3,4-thiadiazol-2-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 210-215 ° C. (decomposition)

IR (New sol): 3300, 1770, 1680, 1620, 1520, 1240, 1140cm ^-1

(69) 7- [2- (2-propynyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- (3 -Aminopropyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 165-170 占 폚 (decomposition)

IR (New sol): 3450, 3300, 3210, 1770, 1670, 1620, 1525cm ^-1

(70) 7- [2- (2-carboxymethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (3- Aminopropyl-1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 165-170 ° C (decomposition)

IR (New sol): 3450, 3300, 3210, 1770, 1670, 1620, 1525cm ^-1

(70) 7- [2-carboxy-2- (5-methylpropoxyimino) -2-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- ( 3-aminopropyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 195-200 ° C. (decomposition)

IR (New sol): 3150, 1760, 1660, 1640, 1520cm ^-1

(71) 7- [2- (1-carboxy-2-propoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1 -(3-aminopropyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 183-189 ° C. (decomposition)

IR (New sol): 3400-3100, 3150, 1770, 1670, 1620, 1520, 1380, 1280, 1230, 1180, 1100, 1020, 900, 730cm ^-1

(72) 7- [2- (1-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- (3 -Aminopropyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 183-188 ° C. (decomposition)

IR (New sol): 3400-3150, 1770, 1670, 1620, 1530, 1380, 1280, 1230, 1180, 1100, 1050, 1010, 730cm ^-1

(73) 7- [2- (1-carboxymethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- (3 -Aminobutyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 185-188 deg. C (decomposition)

IR (New sol): 3300, 3150, 1760, 1660, 1620, 1520, 1230, 1000, 720cm ^-1

(74) 7- [2-carboxymediepoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido]-[1- (4-aminopropyl) -1H -Tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 191-194 ° C (decomposition)

IR (New sol): 3300, 3150, 1760, 1670, 1620, 1520, 1230, 1170, 1050, 890, 740, 720cm ^-1

(75) 7- [2- (1-carboxy-1-methylepoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3 [1- (3-aminopropyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 200-203 ° C. (decomposition)

IR (New sol): 3300, 3150, 1760, 1660, 1620, 1520, 1150, 99cm ^-1

(76) 7- [2- (1-carboxy-1-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1 -(3-aminomethyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 202-205 占 폚 (decomposition)

IR (New sol): 3300, 3200, 1760, 1660, 1620, 1520, 1180, 1060, 1000, 730cm ^-1

(77) 7- [2- (1-carboxymethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- (5-aminohexyl- 1,3,4-tetrazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 207-210 ° C. (decomposition)

IR (New sol): 3300, 3150, 1760, 1660, 1620, 1520, 1230, 1170, 1090, 1060, 1040, 99cm ^-1

(78) 7- [2-aminopropoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (6-aminohexyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 185-188 deg. C (decomposition)

IR (New sol): 3300, 3200, 1760, 1670, 1620, 1520, 1240, 1180, 1060cm ^-1

(79) 7- [2- (3-aminopropoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1,3, 4-Vyadizol-2-yl) biomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 165-183 ° C. (decomposition)

IR (New sol): 3150, 1765, 1660, 1630, 1570, 1520cm ^-1

(80) 7- [2-3 (3-Apinopropoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- [1- (2-hydroxyethyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 170-185 ° C. (decomposition)

IR (New sol): 31400, 1760, 1660, 1580, 1520cm ^-1

(81) 7- [2- (3-aminopropoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] 3- (5-methyl-1 , 3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 192-195 ° C. (decomposition)

IR (New sol): 3250, 3140, 1760, 1640, 1620, 1585, 1525cm ^-1

(82) 7- [2- (3-aminopropoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1-methyl- 1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 180-184 ° C. (decomposition)

IR (New sol): 3160, 1760, 1660, 1590cm ^-1

(83) 7- [2- (4-aminomethylbenzyloxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3-methyl-3- Cefem-4-carboxylic acid formate (syn isomer), melting point 230-240 ° C (decomposition)

IR (New sol): 1750cm ^-1

(84) 7- [2- (3-aminopropoxyimino) -2- (5-amino-1, 2, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (3-aminopropyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer)

IR (New sol): 3300, 3150, 1760, 1660, 1607, 1595, 1520cm ^-1

(85) 7- [2- (α-carboxybenzyloxyimino) -2-5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (1, 3, 4 -Thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 150-155 占 폚 (decomposition)

IR (New sol): 3400, 3290, 3160, 2500, 1770, 1720, 1615, 1520cm ^-1

(86) 7- [2- (α-carboxybenzyloxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3-cepem-4-carboxylic acid (syn isomer), melting point 170-175 ° C (decomposition)

IR (New sol): 3400, 3280, 3160, 2600, 1770, 1720, 1670, 1625, 1525cm ^-1

(87) 7- [2- (α-carboxybenzyloxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- [1- (2 -Aminoethyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 190-195 ° C. (decomposition)

IR (New sol): 3400, 3300, 3150, 1765, 1670, 1610, 1520cm ^-1

(88) 7- [2-carboxymethoxyimino-2- (5-amino-1, 2,4-thiadiazol-3-ylacetamido] -3-cepem-4-carboxylic acid (syn isomer), Melting Point 180-185 ° C (Decomposition)

IR (New sol): 3350, 3250, 1770, 1720, 1680, 1630, 1530 cm ^-1

(89) 7- [2-carboxymethoxyimino-3- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [1- (3- (4- Methyl-1-piperidinyl) propyl] -1-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 185-190 deg. C (decomposition)

IR (New sol): 3300, 1760, 1670, 1600, 1520cm ^-1

(90) 7- [2- (1-carboxy-2-methylpropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -cephalospo Lanic acid (syn isomer),

IR (New sol): 3400-3150, 1770, 1730-1670, 1720, 1620, 1460, 1370, 1230, 1030, 730cm ^-1

(91) 7- [2- (10carboxypropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1, 3, 4 -Thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 153-158 占 폚 (decomposition)

IR (New sol): 3300, 3180, 1770, 1720, 1670, 1602, 1520, 1220, 1060, 1000, 900, 730 cm ^-1

(92) 7- [2- (1-carboxypropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] cephalosporonic acid (syn isomer ), Melting point 115-120 ° C (decomposition)

IR (New sol): 3400, 3300, 3200, 1770, 1720-1670, 1620, 1520, 1230, 1030-1010, 890, 740-720cm ^-1

(93) 7- [2- (1-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3, 4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 165-168 ° C. (decomposition)

IR (New sol): 3400-3200, 1770, 1710, 1670, 1620, 1520, 1230, 1170, 1000, 900, 720cm ^-1

(94) 7- [2- (1-carboxy-1-methylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- ( 1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 164-167 ° C. (decomposition)

IR (New sol): 3300, 3200, 2800-2300, 1770, 1720-1660, 1620, 1520, 1160, 1060, 990, 800cm ^-1

(95) 7- [2- (1-carboxy-1-cyclopentyloxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- (1 , 3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 165-169 ° C. (decomposition)

IR (New sol): 3300, 3180, 1770, 1720-1660, 1620, 1520, 1240, 1180, 1060, 1000, 720cm ^-1

(96) 7 [2- (1-carboxy-1-methylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cepem- 4-carboxylic acid (syn isomer), melting point 215-22 ° C (decomposition)

IR (New sol): 3400, 3250, 3200, 1770, 1670, 1520, 1290, 1240, 1160, 1000, 980, 740c ^-1

(97) 7- [2- (1-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-allyl- 1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 180 deg. C (decomposition)

IR (New sol): 3300, 3150, 770, 1680, 1610, 1520, 1260, 1100, 1040, 1000cm ^-1

(98) 7- [2-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cepem-4-carboxylic acid (syn isomer ), Melting point 230-235 ° C (decomposition)

IR (New sol): 3400, 3250, 3150, 1760, 1720, 1660, 1610, 1550, 1290, 1240, 1170, 970, 740cm ^-1

(99) 7- [2- (1-carboxy-1-cyclopentyloxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3-cepem 4-carboxylic acid (syn isomer), melting point 212-217 ° C (decomposition)

IR (New sol): 3300, 3200, 1770, 1670, 1620, 1520, 1280, 1240, 1180, 1000, 970, 730cm ^-1

(100) 7- [2- (1-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] cephalosporanic acid (syn isomer ),

IR (New sol): 3300, 3200, 1770, 1710, 1670, 1520, 1230, 1040cm ^-1

(101) 7- [2 (1-carboxy-1-methylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1 -(2-aminoethyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 195-200 ° C. (decomposition)

IR (New sol): 3150, 1760, 1670, 1920, 1520, 1170, 990cm ^-1

(102) 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-ylacetamido] -3- [1- (3- (4- Methyl-1-piperazinyl) propyl] -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 175-180 ° C. (decomposition)

IR (New sol): 3300, 1770, 1650, 1610, 1520cm ^-1

NMR (DMSO-d ₆ , δ: 1.50-1.80 (8H, m), 1.80-2.10 (2H, m), 2.30-2.50 (4H, m), 2.60 (3H, s), 2.8-3.3 (6H, m ), 3.60 (2H, wide s), 4.30-4.50 (4H, m), 4.67-4.83 (1H, m), 5.10 (1H, d, J = 4 Hz), 5.77 (1H, dd, J = 4 and 8 Hz ), 8.17 (2H, s), 9.50 (1H, d, J = 8 Hz).

(103) 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-ylacetamido-] 3-carbamoyloxymethyl-3-cepem-4 Carboxylic acid (syn isomer), melting point 175-180 ° C (decomposition)

IR (New sol): 3400, 3300, 3180, 1770, 1710, 1670, 1620, 1520cm ^-1

NMR (DMSO-d ₆ , δ): 1.40-2.0 (8H, m), 3.53 (2H, wide s), 4.67 and 4.85 (2H, ABq, J = 13Hz), 4.67-5.07 (1H, m), 5.15 (1H, d, J = 5 Hz). 5.78 (1H, dd, J = 5 and 8 Hz), 6.55 (2H, wide s) 8.08 (2H, wide s), 9.45 (1H, d, J = 8 Hz).

(104) 7- [2- (2-cyclopenten-l-yloxyimino) -2- (5-amino-l, 2,4-thiadiazol-3-yl) acetamido] -3- cover Moyloxymethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 165-170 占 폚 (decomposition)

IR (New sol): 3400, 3300, 3180, 1770, 1710, 1670, 1615, 1520 cm ^-1

NMR (DMSO-d ₆ ,): 1.97-2.47 (4H, m), 3.50 (2H, wide s), 4.65 and 4.85 (2m, ABq, J = 13 Hz), 5.12 (1H, d, J = 5 Hz), 5.17-5.50 (1H, m), 5.67-6.27 (3H, m), 6.55 (2H, wide s), 8.10 (2H, wide s), 9.47 (1H, d, J = 8 Hz).

(105) 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido-]-2-methyl-3-cepem-4 Carboxylic acids (syn isomers),

IR (New sol): 3420, 3400, 3270, 3180, 2430, 1790, 1775, 1690, 1675, 1640, 1615, 1600, 1495cm ^-1

NMR (DMSO-d ₆ , δ): 1.43 (3H, d, J = 7 Hz), 1.5-2.1 (8H, m), 3.73 (1H, z, J = 7 Hz), 4.5-4.9 (1H, m) , 5.07 (1H, d, J = 5 Hz), 5.84 (1H, dd, J = 5 and 9 Hz), 6.50 (1H, wide s), 9.38 (1H, d, J = 9 Hz)

(106) 7- [2- (2-oxo-3-tetrahydrofuryloxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 165-170 ° C (decomposition)

IR (New sol): 3300, 3200, 1770, 1680, 1620, 1525cm ^-1

NMR (DMSO-d ₆ , δ): 2.27-2.70 (2H, m), 3.70 (2H, wide s), 4.17-4.73 (4H, m), 5.15 (1H, d, J = 4 Hz) 5.18 (1H, t, J = 7 Hz), 5.83 (1H, dd, J = 4 and 8 Hz), 8.13 (2H, s), 9.50 (1H, s), 9.60 (1H, d, J = 8 Hz).

(107) 7- [2- (2-oxo-3-tetrahydrofuryloxyimino) -2- (5 ² -amino-1, 2,4-thiadiazol-3-yl) acetamido-] 3 Cefem-4-carboxylic acid (syn isomer), melting point 175-180 ° C. (decomposition)

IR (New sol): 3300, 3200, 1775, 1670, 1620, 1530cm ^-1

NMR (DMSO-d ₆ , δ): 2.35-2.67 (2H, m), 3.57 (2H, wide s), 4.17-4.50 (2H, m), 5.07 (1H, d, J = 4Hz), 5.15 (1H , t, J = 8 Hz). 5.82 (1H, dd, J = 4 and 8 Hz), 6.43 (1H, t, J = 5 Hz), 8.17 (2H, wide s), 9.60 (1H, d, J = 8 Hz)

(108) 7- [2- (1-cyclohexylcarbonylethoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- [1 -3- (Nt-butoxycarbonylamino) furophyll] -1H-tetrazol-5yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 145-150 ° C. (decomposition)

IR (New sol): 3400-3250, 1780, 1680, 1620, 1520, 1240, 1220, 1160, 1100, 1,000, 740, 720cm ^-1

NMR (DMSO-d ₆ , s): 1.0-2.3 (15H, m), 1.40 (9H, s), 3.0 (2H, m), 3.7 (2H, m), 4.5-5.0 (1H, m), 4.77 (1H, q, J = 7 Hz), 5.13 (1H, d, J = 5 Hz), 5.86 (1H, m), 6.83 (1H, m), 8.12 (2H, wide s) 9.37 (1 / 2H, d, J = 8 Hz), 9.51 (1 / 2H, d, J = 8 Hz)

(109) 7- [2- (1-benzyloxycarbonylethoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido-3-cepem-4 Carboxylic acid (syn isomer), melting point 177-180 ° C (decomposition)

IR (New sol): 3400, 3300, 3200, 1770, 1730, 1680, 1610, 1520, 1240, 1160, 1040, 980, 740cm ^-1

NMR (DMSO-d ₆ , δ): 1.47 (3H, d, J = 7 Hz), 3.57 (2H, m), 4.88 (1H, m), 4.88 (1H, q, J = 7 Hz), 5.10 (1H, d, J = 5 Hz), 5.18 (2H, s), 5.87 (1H, dd, J = 5 and 8 Hz), 6.45 (1H, m) 7.31 (5H, wide s), 8.10 (2H, wide s), 9.40 And 9.55 (1H, d, J = 8 Hz)

(110). 7- [2- (1-Benzyloxycarbonylethoxyamino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [ 1-3- (N-butoxycarbonylamino) furophyll] -1H-tetrazol-5yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 113-117 ° C (decomposition)

IR (New sol): 3300, 3200, 1780, 1680, 1620, 1250, 1250, 1160, 1100, 1040, 1000, 740, 700cm ^-1

NMR (DMSO-d ₆ , δ), 1.43 (9H, s), 1.53 (3H, d, J = 6Hz), 2.0 (2H, m), 3.03 (2H, m), 3.70 (2H, m), 4.10 -4.67 (4H, m), 4.88 (1H, q, J = 6 Hz), 5.10 (1H, d, J = 5 Hz), 5.17 (2H, s), 5.08 (1H, dd, J = 8 Hz) 6.53 (1H , m), 7.30 (5H, m), 7.30 (5H, s), 8.10 (2H, wide s), 9.40 and 9.55 (1H, d, J = 8 Hz)

(111) 7- [2- (1-butoxycarbonylethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -sefe-4- Carboxylic acid (syn isomer), melting point 147-151 ° C (decomposition)

IR (New sol): 3400, 3300, 3200, 1170, 1720, 1680, 1610, 1520, 1280, 1235, 1150, 1045, 980, 740cm ^-1

NMR (DMSO-d ₆ , s): 0.87 (3H, t, J = 6 Hz) 1.46 (3H, d, J = 7 Hz), 0.8-1.8 (4H, m), 3.6 (2H, m), 4.08 (2H , t, J = 6 Hz), 4.74 (1H, q, J = 7 Hz), 5.08 (1H, d, J = 5 Hz), 5.83 (1H, dd, J = 5 and Hz), 6.4 (1H, m), 8.07 (2H, wide s), 9.39 and 9.44 (1H, d, J = 6 Hz)

(112) 7- [2- (1-butoxycarbonylethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [3 -(Nt-butoxycarbonylamino) furophyll] -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 149-155 ° C (decomposition)

IR (New sol): 3300, 3200, 1780, 1700, 1620, 1520, 1520, 1160, 1100, 1040, 1000, 740, 720cm ^-1

NMR (DMSO-d ₆ , δ): 0.26 (3H, t, J = 7 Hz), 1.40 (9H, s), 1.0-1.7 (4H, m), 1.43 (3H, d, 77 Hz), 1.7-2.3 ( 2H, m), 3.0 (2H, m), 3.7 (2H, m), 4.0-4.5 (6H, m), 4.77 (1H, q, J = 7 Hz), 5.15 (1H, d, J = 6 Hz), 5.8 (1H, m), 6.9 (1H, m), 8.13 (2H, wide s), 9.5 (1H, m)

(113) 7- [2- (2-D-pinylglyciylaminoethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -2- Methyl-3-cepem-4-carboxylic acid (syn isomer), melting point 204-222 占 폚 (decomposition)

IR (New sol): 3260, 3150, 1760, 1665, 1616, 1512, 1400, 1045cm ^-1

(114) 7- [2- (3-G-phenylglycosylaminofurooxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -2- Methyl-3-cepem-4-carboxylic acid (syn isomer), melting point 203-231 ° C. (decomposition)

IR (New sol): 3280, 1170, 1760, 1660, 1600, 1520, 1400cm ^-1

NMR (D ₂ O + DCl, δ): 1.47 (3H, d, J = 7.5 Hz), 1.7-2.3 (2H, m), 3.40 (2H, t, J = 7 Hz), 3.88 (1H, q, J = 7.5 Hz), 4.33 (2H, t, J = 6 Hz), 5.18 (1H, d, J = 4.5 Hz), 5.20 (1H, s), 5.95 (1H, d, J = 4.5 Hz), 6.90 (1H , d, J = 6.0 Hz), 7.57 (5H, s)

(115) 7- [2- (1-cyclohexyloxycarbonylethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [ 1- (3-aminofurophyll) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 175-178 ° C (decomposition)

IR (New sol): 3400-3200, 1765, 1680-1610, 1520, 1220, 1100, 1000, 890, 790cm ^-1

NMR (DMSO-d ₆ , δ): 0.9-2.0 (13H, m), 2.2 (2H, m), 2.9 (2H, m): 3.6 (2H, m), 4.0-5.1 (5H, m), 4.76 (1H, s, J = 7 Hz), 5.30 (1H, d, J = 5 Hz), 5.77 (1H, m), 8.17 (2H, broad s), 9.45 (1H, m).

(116) 7- [2- (1-benzyloxycarbonylethoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- [1 -(3-aminofurophyll) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 162-166 占 폚 (decomposition)

IR (New sol): 3300, 3200, 1760, 1680, 1620, 1520, 11, 1040, 1000, 740cm ^-1

NMR (DMSO-d ₆ , δ): 1.47 (3H, d, J = 6Hz), 2.23 (2H, m), 2.90 (2H, m), 3.60 (2H, m), 4.43 (4H, m), 4.90 (1H, q, J = J = 6 Hz), 5.07 (1H, d, J = 5 Hz), 5.20 (2H, s), 5.77 (1H, m) 7.43 (5H, s), 8.23 (2H, m), 9.57 (1 H, m)

(117) 7- [2- (1-carbonylaminofuroxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido]]-3- [1 -(3-hydroxyethyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 158-163 ° C. (decomposition)

IR (New sol): 3400-3200, 1770, 1680, 1610, 1530, 1300, 1290, 1050, 1040, 1000, 960, 900, 790, 740, 720cm ^-1

(118) fibiloyloxymethyl 7- [2- (3-aminofurooxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -2- Methyl-3-cepem-4-carboxylate hydrochloride (syn isomer) Melting point 91-156 ° C (decomposition)

IR (New sol): 3150, 1780, 1745, 1670, 1625, 1525cm ^-1

(119) pivaloyloxymethyl 7- [2- (3-aminofuroxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3 -(1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylate hydrochloride (syn isomer), melting point 110-125 ° C. (decomposition)

IR (New sol): 1780, 1745, 1670, 1625, 1525cm ^-1

(120) pivaloyloxymethyl 7- [2- (3-aminofuroxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (5-Methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylate hydrochloride (syn isomer), melting point 88-153 ° C. (decomposition)

IR (New sol): 2150, 1780, 1745, 1650, 1625, 1525cm ^-1

NMR (DMSO-d6 + D ₂ O ₂ δ): 1.16 (9H, s), 1.6-2.2 (2H, m), 2.6-3.1 (2H, m), 2.68 (3H, s), 3.76 (2H, s ), 4.20 and 4.53 (2H, ABq, J = 18 Hz), 4.24 (2H, wide s), 5.12 (1H, d, J = 4.5 Hz), 5.6-6.0 (3H, m)

(121) pivaloyloxymethyl 7- [2- (3-aminofuroxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- [1- (2-hydrooxyethyl) -1-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylate hydrofluoride (syn isomer), melting point 150-175 ° C. (decomposition)

IR (New sol): 3150, 1780, 1740, 1670, 1630, 1520cm ^-1

(122) pivaloyloxymethyl 7- [2- (3-aminofurooxyimino) -2-) (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3 -(1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylate hydrochloride (syn isomer), melting point 96-155 ° C. (decomposition)

IR (New sol): 3300, 3150, 1775, 1730, 1670, 1625, 1530cm ^-1

(123) pivaloyloxymethylaminomethyl 7- [2- [2- (4-benzyloxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido 3-Methyl-3-cepem-4-carboxylate hydrochloride acid (syn isomer), melting point 160-168 ° C. (decomposition)

IR (New sol): 1780, 1745, 1670, 1628cm ^-1

(124) pivaloyloxymethyl 7- [2-allyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3-1- (2-amino Ethyl) -1H-tetrazol-5-yl] thiomethyl-3-cepem-4-carboxylate formate (syn isomer), melting point 95-105 ° C. (decomposition)

IR (New sol): 1790, 1735, 1452, 1370, 1118, 990cm ^-1

NMR (DMSO-d6 + D ₂ O, δ): 1.2 (9H, s), 3.2-3.35 (2H, m), 3.7 (2H, s), 4.2-4.6 (2H.m), 4.1-4.6 (2H , m), 4.7 (2H, s), 4.8-5.2 (1H, m), 5.25 (1H, d, J = 4.5 Hz), 5.45 (2H, m), 5.7-6.25 (2H, m), 5.8 ( 1H, d, J = 4.5 Hz)

(125) 1-acetoxyethyl 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -2methyl-3-cepem 4-carboxylate (syn isomer)

IR (New sol): 3400, 3310, 3150, 1780, 1770, 175, 1675cm ^-1

(126) 1-isobutyryloxyethyl 7- [2-cyclopentyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -2-methyl- 3-cefe-4-carboxylate (syn isomer) amorphous powder.

IR (New sol): 3400, 3300, 3170, 1780, 1745, 1675, 1620, 1525cm ^-1

NMR (DMSO-d6, δ), 1.08 (6H, d, J = 7 Hz), 1.2-2.2 (14H, m), 2.2-2.9 (1H, m), 3.88 (1H, q, J = 7 Hz), 4.6 -5.0 (1H, m), 5.12 (1H, dd, J = 4.5 Hz), 5.90 (1H, dd, J = 4.5 and 8 Hz), 6.63 (1H, d, J = 7 Hz), 8.06 (2H, wide s ), 9.43 (1H, doublet, J = 8 Hz).

(127) 1-acetoxyfurophyl 7- [2- (2-cyclopenten-l-yloxyimino) -2- (5-amino-l, 2,4-thiadiazol-3-yl) acetami Fig.]-2-Methyl-3-cepem-4-carboxylate (syn isomer), melting point 110-128 ° C. (decomposition)

IR (New sol): 3400, 3280, 3150, 1780, 1750, 1730, 1620cm ^-1

(128) 1- (2-azidoethoxycarbonyloxy) ethyl 7- [2- (2-cyclopenten-1-yloxyimino) -2- (5-amino-1, 2, 4-thiadia Zol-3-yl) acetamido]]-2-methyl-3-cepem-4-carboxylate, (syn isomer), melting point 85-100 ° C. (decomposition)

IR (New sol): 3310, 2200, 1760-1785, 1680cm ^-1

NMR (DMSO-d6 + D ₂ D, δ): 1.48 (3H, d, J = 6 Hz), 1.5 (3H, d, J = 4.5 Hz), 2.0-2.5 (4H, m), 3.5-4.1 (1H , m), 3.63 (2H, t, J = 4 Hz), 4.30 (2H, t, J = 4 Hz), 5.16 (1H, d, J = 4.5 Hz), 5.2-5.45 (1H, m), 5.7-6.2 (2H, m), 6-6.2 (1H, m), 6.6-6.8 (1H, m), 6.7 (1H, d, J = 6 Hz)

(129) 1-ethoxycarbonyloxyethyl 7- [2- (2-cyclopenten-1-yloxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) Acetamido] -2methyl-3-cepem-4-carboxylate (syn isomer)

IR (New sol): 3420-3300, 3150, 1780, 1760, 1675, 1620cm ^-1

(130) pivaloyloxymethyl 7- [2- [3- (Nt-butoxycarbonyl-amino) propoxyimino] -2- (5-amino-1, 2, 4-thiadiazole-3- (I) acetamido] -2-methyl-3-cepem-4-carboxylate (syn isomer) powder, melting point 66-75 占 폚 (decomposition)

IR (New sol): 3300, 1780, 1745, 1680, 1620cm ^-1

(131) pivaloyloxymethyl 7- [2- [3- (Nt-butoxycarbonyl-amino) propoxyimino] -2- (5-amino-1, 2, 4-thiadiazole-3- (I) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cepem-4-carboxylate (syn isomer) powder.

IR (New sol): 3300, 1780, 1745, 1680, 1620cm ^-1

(132) pivaloyloxymethyl 7- [2- [3- (Nt-butoxycarbonyl-amino [puroxyimino] -2- (5-amino-1, 2, 4-thiadiazole-3- I) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylate (syn isomer)

IR (New sol): 3300, 3150, 1783, 1745, 1675, 1615cm ^-1

NMR (DMSO-d6 + D ₂ O, δ): 1.15 (9H, s), 1.37 (9H, S), 1.5-2.0 (2H, m), 2.65 (3H, s), 2.8-3.2 (2H, m ), 3.5-3.8 (2H, m), 3.9-4.3 (2H, m), 4.16 and .53 (2H, ABq, J = 13 Hz), 5.17 (1H, d, J = 4.5 Hz) 5.6-6.0 (3H , m)

(133) pivaloyloxymethyl 7- [2- [3- (Nt-butoxycarbonylamino) furoxyimino] 2- (5-amino-1, 2, 4-thiadiazol-3-yl) Acetamido] -3-1- (2-hydroxyethyl) -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylate (syn isomer), powder, melting point 88-101 占 폚 ( decomposition)

IR (New sol): 3300, 1780, 1750, 1675, 1620cm ^-1

(134) pivaloyloxymethyl 7- [2- [3- (Nt-butoxycarbonyl-amino) propoxyimino] 2- (5-amino-1, 2, 4-thiadiazol-3-yl Acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylate (syn isomer), powder, melting point 71-84 ° C. (decomposition)

IR (New sol): 3300, 1780, 1745, 1680, 1615cm ^-1

(135) pivaloyloxymethyl 7- [2- (2-cyclohexen-1-yloxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido -Cephalosporanate (syn isomer), melting point 93-101 ° C. (decomposition)

IR (New sol): 3400, 3300, 3180, 1740, 1675, 1615, 1525cm ^-1

(136) 7- [2-cyclopenten-l-yloxyimino) -2- (5-amino-l, 2,4-thiadiazol-3-yl) acetamido] -2-methyl-3- Prilyl-3-yl ester of cefem-4-carboxylic acid (syn isomer melting point 131-144 ° C (decomposition)

IR (New sol): 3420, 3210, 3150, 1780, 1740, 1675, 1620, 1525cm ^-1

(137) pivaloyloxymethyl 7- [2- (2-cyclopenten-l-yloxyimino) -2- (5-amino-l, 2,4-thiadiazol-3-yl) acetamido 2-methyl-3-cepem-4-carboxylate (syn isomer), melting point 111-124 ° C. (decomposition)

IR (New sol): 3400, 3300, 3270, 1775, 1740, 1670, 1620, 1520 cm ^-1

(138) 1-benzoyloxyethyl 7- [2- (2-cyclopenten-l-yloxyimino) -2- (5-amino-l, 2,4-thiadiazol-3-yl) acetamido 2-methyl-3-cepem-4-carboxylate (syn isomer), melting point 132-137 ° C. (decomposition)

IR (New sol): 3400, 3300, 3160, 1780, 1738, 1680, 1620cm ^-1

NMR (DMSO-d6 + D ₂ O, δ): 1.43 (3H, d, J = 7 Hz) 1.62 (3H, d, J = 5 Hz), 1.7-2.4 (4H, m), 3.8 (1H, q, J = 7 Hz), 5.0-5.4 (1H, m), 5.13 (1H, d, J = 4.5 Hz), 5.6-6.3 (3H, m), 6.70 (1H, d, J = 6 Hz), 7.16 (1H, q , J = 5 Hz), 7.3-8.2 (5H, m)

(139) Pivaloyloxymethyl 7- [2- [4- (Nt-butoxycarbonyl-amino) methylbenzyloxyimino-2- (5-amino-1, 2, 4-thiadiazole-3- (I) acetamido-3-methyl-3-cepem-4-carboxylate (syn isomer) powder.

IR (New sol): 3300, 1780, 1750, 1680cm ^-1

(140) pivaloyloxymethyl 7- [2-allyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- [1-2- ( Nt-butoxycarbonylimino] ethyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylate (syn isomer) powder.

IR (New sol): 3300, 1780, 1750, 1680cm ^-1

(141) 7- [2- [2- (N-tN-t-butoxycarbonyl) -D-phenylglycyl-amino) ethoxyimino-2- (5-amino-1, 2, 4-thia Diazol-3-ylacetamido] -2-methyl-3-cepem-4-carboxylic acid (syn isomer), melting point 77-91 占 폚 (decomposition)

IR (New sol): 3300, 3160, 1775, 1680, 1660, 1630, 1525cm ^-1

N.M.R. (DMSO-d 6, δ): 1.37 (9H, s), 1.40 (3H, d, J = 8 Hz) 3.1-4.2 (5H, m). 5.08 (1H, d, J = 4.5 Hz), 5.10 (1H, d, J = 8 Hz), 5.90 (1H, dd, J = 4.5 and 9 Hz), 6.53 (1H, d, J = 7.5 Hz), 7.32 ( 5H, s), 8.13 (2H, s), 9.48 (1H, d, J = 9 Hz)

(142) 7- [2- [3- (N- (2- (1-amino-1-cyclohexyl) acetyl) -amino) furoxyimino] -2-amino-1, 2, 4-thiadiazole 3-yl) acetamido-2-methyl-3-cepem-4-carboxylic acid (syn isomer), melting point 198-224 ° C. (decomposition)

IR (New sol): 3250, 3150, 1760, 1640, 1580, 1520cm ^-1

(143) 7- [2- [3- (N- (Nt-butoxycarbonyl-D-phenylglycitylimino) furoxyimino] -2- (5-amino-1, 2, 4-thiadia Zol-3-yl) acetamido] -2-methyl-3-cepem-4-carboxylate (syn isomer),

IR (New sol): 3300, 3200, 1775, 1700, 1650, 1525cm ^-1

NMR (DMSO-d6 + D ₂ O, δ): 1.3-1.6 (12H, m), 1.6-2.0 (2H, m), 2.8-3.4 (2H, m), 3.82 (1H, q, J = 7.5 Hz ), 3.9-4.3 (2H, m), 5.05 (1H, d, J = 4.5 Hz), 5.83 (1H, d, J = 4.5 Hz), 6.48 (1H, d, J = 6 Hz),

(144) 7- [2-carboxymethoxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- [1- (2-carboxyethyl) -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 215-220 ° C.

IR (New sol): 3300, 3200, 1770, 1720, 1680, 1620, 1520cm ^-1

NMR (DMSO-d6, δ): 2.93 (2H, t, J = 6 Hz), 3.67 (2H, br.s), 4.33 (2H, cr.s), 4.43 (2H, t, J = 6 Hz), 4.67 (2H, s), 5.10 (1H, d, J = 4 Hz), 5.83 (1H, dd, J = 4 and 8 Hz), 8.13 (2H, s), 9.50 (1H, d, J = 8 Hz)

Example 20

The following compounds are obtained according to methods analogous to the above examples.

(1) 7- [2- (2-oxo-3-tetrahydrofuryloxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -2- (1- (3- (Nt-butoxycarbonylamino) -propyl-1H-tetrazol-5-yl-thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 130-135 ° C (decomposition)

(2) 7- [2- (2-oxo-3-tetrahydrofuryloxy imino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -2 -(1- (3-aminopropyl) -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 210 to 215 ° C (decomposition)

IR (New sol): 3300, 3200, 1770, 1670, 1620, 1525cm ^-1

(3) 7-2- (1-methyl-1-carboxyethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido) cephalosporonic acid (syn isomer) Melting point 210 to 210 ° C (decomposition)

IR (New sol): 3402, 3300, 3200, 1770, 1720, 1700-1670, 1620, 1520, 1230, 1150, 1060, 1020, 995, 975, 920, 740, 720cm ^-1

(4) pivaloyloxymethyl 7- (2-cyclopentyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -2-methyl-3- Cefem-4-carboxylic acid (syn isomer) anhydrous powder.

IR (New sol): 3450, 3360, 6200, 1790, 1750, 1680, 1625, 1530 cm ^-1

(5) 7- (2- (1-methyl-1-t-butoxycarbonylethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido ) -3- (1- (3-aminopropyl) -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 198 to 203 캜 (decomposition)

IR (New sol): 3450-3300, 3200, 1770, 1680, 1600-1615, 1525, 1140, 990, 970, 750, 720cm ^-1

(6) 7-2- (1-carboxymethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido) -2- (5- (2- (Nt-butoxycarbonylamino) ethyl) -1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (syn isomer) Melting point 202-204 DEG C (decomposition)

IR (New sol): 3350, 3200, 1780, 1680, 1620, 1520, 1250, 1170, 1100, 1050, 1000cm ^-1

(7) 7-2- (1-carboxymethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido-3- (5- (2-amino Ethyl) -1,3,4-thiadiazol-2-yl) -thiomethyl-3-cepem-4-carboxylic acid (syn isomer), melting point 200-204 DEG C (decomposition)

IR (New sol): 3350, 3200, 1770, 1680, 1620, 1520, 1180, 1100, 1060, 1040, 1000cm ^-1

(8) N- (7- (2 (-cyclopenten-1-yloxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido) -3- Cefem-3-almethyl) -4-carbaoyl-pyridinium-4-carboxylate (syn isomer), melting point 155-160 ° C. (decomposition)

IR (New sol): 3350, 3150, 1770, 1675, 1610, 1560, 1520cm ^-1

(9) N- (7- (2- (1-methyl-1-carboxymethoxyimino) -2- (5-amino-1, 2, 4-thiadiazol-3-yl acetamido) -3 Cefem-4'-ylmethyl-4-carbaoyl-pyridinium carboxylate (syn isomer), melting point 180-185 ° C. (decomposition)

IR (New sol): 3300, 1770, 1680, 1620, 1560, 1520cm ^-1

Claims (1)

A compound of the following formula (I) or a salt thereof is prepared by reacting with a compound of the following formula (II), a reaction derivative or salt thereof in an amino group thereof, and a compound of the following formula (III), a reaction derivative thereof or a salt thereof Way.

In the above formula R ¹ is an amino or protected amino group, R ² is hydrogen, acyl, aryl which may be substituted with suitable substituents, lower alkyl, lower alkenyl, lower alkynyl, suitable substituents which may be substituted with suitable substituents Cycloalkyl which may be substituted, cyclo (lower) alkenyl, 5-membered cyclic group containing S or O substituted with oxo group, R ³ is hydrogen or lower alkyl, R ⁴ is hydrogen, alkyloxy (lower) alkyl , Alkylthio (lower) alkyl, pyridinium (lower) alkyl which may be substituted with suitable substituent, heterocyclic thio (lower) alkyl which may be substituted by suitable substituent, halogen, hydroxy group; R ⁵ is a carboxy or protected carboxy group; If R ⁴ is pyridinium (lower) alkyl which may be substituted with a suitable substituent, then R ⁵ is a COO ^- group, and the thick line means a single or double bond.