KR830001278B1 - Process for preparing cephalosporin compound - Google Patents

Abstract

The cephalosproins I(R1 = H, CH3O; R2 = phthalimido, succineimido; R13 = -CO-C6H5, C1-4 alkyl, etc.), useful as fungicides, were prepd. by reacting compd. II (R = C1-3 alkyl, C4-6 cycloalkyl, amino) with S-contg. uncleophilic reagent III (R14 = H, or thiourea with R13) in anhydrous arg.solvent. Thus, 3-(((1-methyl-1H-tetrazol-5-yl)thio)methyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid was prepd. from 7-(2(2-thienyl)acetamido)cephalosporanic acid and l-methyl-1H-tetrazol-5-thiol in acetonitrile.

Description

Process for the preparation of cephalosporin compounds

The present invention relates to a method for producing a cephalosporin compound having the following general formula (1) having antibacterial activity.

In the general formula

R ¹³ is

R < ¹ > is hydrogen or methoxy

R ² is phthalimido, succinimido,

의 기(여기에서 L은 수소 또는 니트로소임),In general formula

(Wherein L is hydrogen or nitroso),

기이고,Or a general formula

Lt; / RTI &

R < ³ > is 1) hydrogen,

2) alkyl having 1 to 6 carbon atoms,

3) -CH2- (chloroalkyl of 1 to 3 carbon atoms),

4) -CH2- (fluoroalkyl having 1 to 3 carbon atoms),

5) cyanoalkyl having 1 to 4 carbon atoms,

6) a hydroxyalkyl having 1 to 4 carbon atoms,

7) p-nitrobenzyloxy,

8) tert-Butoxy,

9) (2,2,2-trichloroethoxy),

의 보호된 4-아미노-4-카복시부틸기(여기에서 A¹은 보호된 아미노그룹이고 R¹²는 수소 또는 탄소수 1 내지 4의 알킬임),10) General formula

Amino-4-carboxybutyl group wherein A ¹ is a protected amino group and R ¹² is hydrogen or an alkyl having 1 to 4 carbon atoms,

11) 4-oxo-4-carboxybutyl,

12) 3-carboxypropyl,

의 기(여기에서 a 및 a¹은 각기 수소, 탄소수 1 내지 4의 알킬, 탄소수 1 내지 4의 알콕시, 할로겐, 하이드록시 또는 A¹CH₂-(여기에서 A1은 상기에서와 같이 보호된 아미노임)이머, Z는 산소 또는 황원자이고 m은 0 또는 1임,13) General formula

Wherein each of a and a ¹ is independently selected from the group consisting of hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halogen, hydroxy or A ¹ CH ₂ - Z is an oxygen or sulfur atom and m is 0 or 1,

의 기, (여기에서 P는 a) 2-티에닐, b) 3-티에닐 또는 c) 일반식

의 페닐그룹이고(a 및 a¹은 상기에서 정의된 바와 같다), Q는 a) 하이드록시, b) 포르밀옥시, c) 아세톡시, d) 일반식

의 카복시이고(여기에서 A²는 디페틸메틸, P-니트로벤질, 벤질, 2,2,2-트리클로로에틸, 3급-부틸, 또는 p-메톡시벤질), e) 알카리금속 옥시설포닐, f) 보호된 아미노그룹, g) 일반식

의 아실화된 아미노그룹이고,14) General formula

, Wherein P is a) 2-thienyl, b) 3-thienyl or c)

(A and a ¹ are as defined above), Q is a) hydroxy, b) formyloxy, c) acetoxy, d)

Carboxy, wherein A ² is diphenylmethyl, P-nitrobenzyl, benzyl, 2,2,2-trichloroethyl, tert-butyl or p-methoxybenzyl, e) , f) a protected amino group, g)

Lt; / RTI > is an acylated amino group,

Wherein T is amino,

(Wherein R < ⁷ > is hydrogen or alkyl having 1 to 3 carbon atoms,

R ⁸ is phenyl, halophenyl, furyl, mono-methyl amino, dimethyl amino, diethyl amino, diethylamino, methyl-ethylamino, propylamino, dipropylamino, diisopropylamino, phenylamino or diphenylamino,

R ⁹ is hydrogen, alkyl having 1 to 4 carbon atoms or phenyl,

R ¹⁰ is hydrogen, alkyl having 1 to 3 carbon atoms or methylsulfonyl,

R < ¹¹ > is methylene, trimethylene or vinylene)],

의 기이고(여기에서 P'은 상기에서 정의된 바와 같은 P, 보호된 2-아미노-4-티아졸일 또는 2-푸릴이다),(15) General formula

(Wherein P ' is P, protected 2-amino-4-thiazolyl or 2-furyl as defined above),

(16) a group of the general formula VS (O) _a -CH ₂ -, wherein V is -CF ₃ or -CH ₂ -X and X is hydrogen, methyl, CF ₃ , CN or N ₃ and n is 0 , 1 or 2), or

(17) a group of the general formula Y-CH ₂ -, wherein Y is selected from 2-thienyl, 3-thienyl, 2-furyl, 2-oxazolyl, 2-thiazolyl, Thiazolylthio, 1,2,3-triazol-5-ylthio, 1,3,4-triazol-2-ylthio, 1,3,4-thia Thiadiazol-2-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio, 1, Thiadiazol-5-ylthio, 3-methyl-1,2,4-thiadiazol-5-ylthio, 1,2,5-thiadiazol- 4-oxadiazol-2-ylthio, 1-methyl-5-tetrazolylthio, pyridylthio, 4-cyano- 3-cyano-1,2,4-triazol-1-yl or protected 2-amino-4-thiazolyl),

Each R ⁴ is hydrogen, alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 3 carbon atoms, cyclohexyl or phenyl,

Each R ⁵ is independently selected from the group consisting of alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, hydroxy, nitro, cyano, methanesulfonamido or trifluoromethyl,

R < ⁶ > is an optionally substituted 5- or 6-membered heteroaromatic ring having 1 to 4 total heteroatoms selected from Units,

의 구조를 갖는 단위이다.One nitrogen and zero or one oxygen or sulfur, two nitrogen and zero or one oxygen or sulfur, three nitrogen and zero or one oxygen or four nitrogen; Or benzimidazolyl, 2-benzothiazolyl, 2-benzoxazolyl or an oil of the general formula

. ≪ / RTI >

The present invention provides a method for replacing an acetoxy group of cephalosporanic acid with a sulfur containing nucleophilic reagent under anhydrous conditions in an organic solvent.

Substitution of acetoxy groups in cephalosporins by sulfur containing nucleophilic reagents is a known reaction (US Pat. No. 3,278,531). This patent and other publications (J. D. Cockey, J. Chem. Soc., 1965, 5015) suggest that this reaction occurs only in aqueous media. The sulfur-containing nucleophilic reagent or salt thereof is used at pH 5-8 with a salt of cephalosporanic acid in water to effect actual displacement. Rising temperatures (35-870 ° C), neutral to basic pH, and reaction conditions of the aqueous medium largely destroy the cephalosporin nucleus, so the products produced in this manner often require extensive purification procedures.

Replacement of Cephalosporanic acid in water at low pH (pH 2 to 3) results in the formation of a side-reaction lactone and a very low yield of the desired product.

It has been found that substitution of the acetoxy group (and other 3-acyloxy groups) of the cephalosporic acid with sulfur containing nucleophilic reagents can be achieved in an organic solvent under anhydrous conditions. In the reaction under these conditions, no lactone is formed, the yield is high and the product can be easily separated. Some of the products are naturally precipitated from the reaction mixture. This process is a general method, and any of sulfur-containing nucleophilic reagent and cephalosporanic acid can be applied to this process.

It is an object of the present invention to provide an improved process for preparing 3- (thiomethyl) cephalosporin.

According to the present invention, the cephalosporin compound of formula (I) is obtained by reacting a compound of formula (II) with sulfur-containing nucleophilic reagent of formula (III) in an organic solvent under anhydrous conditions.

In the general formula

R ¹ and R ² are as defined above,

R is alkyl having 1 to 3 carbon atoms, cycloalkyl having 4 to 6 carbon atoms, amino, mono or di (alkyl having 1 to 3 carbon atoms)

R < ¹³ > is as defined above,

R ¹⁴ is hydrogen or when R ¹³ is a methylenammonium group, then R ¹⁴ combines with R ¹³ to form thiourea.

The products obtained according to the process of the present invention exhibit antibacterial activity, and most of these products are also used as intermediates for other cephalosporin products which also exhibit antibacterial activity. (See U.S. Patent No. 3,932,393)

In the above definition, " alkyl " is a straight chain and branched chain alkyl group. The "alkyl having 1 to 6 carbon atoms" in R ³ is a group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, amyl, isoamyl, hexyl, 2,3-dimethyl butyl and the like.

The term "-CH ₂ - (chloroalkyl of 1 to 3 carbon atoms)" and "-CH ₂ - (fluoroalkyl of 1 to 3 carbon atoms)" means chloroethyl, fluoroethyl, 3-fluoropropyl, and 4-chlorobutyl. The "cyanoalkyl having 1 to 4 carbon atoms" is a group such as cyanomethyl, 2-cyanoethyl, 3-cyanopropyl and 2-cyanopropyl. The "hydroxyalkyl of 1 to 4 carbon atoms" is a group such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and 2-hydroxypropyl.

In the 3- (acyloxymethyl) cephalosporin and sulfur-containing nucleophilic reagent of the general formula (II), the amino group is preferably protected. Methods for protecting amino groups are known.

[Protective Groups In Organic Chemistry, edited by J.T.W. McOmie (Plenum Press, London and New York, 1973).

In general, protection of the amino group means the ability to remove the protecting group. However, in the subsequent separation from the cephalosporin,

의 7-아실아미도기의 경우에는 보호그룹의 제거가 필요하지 않다.

In the case of the 7-acylamido group of the formula, removal of the protecting group is not necessary.

의 아미노그룹은 벨기에 특허 제771,694호에 기술된 방법으로 보호Suitable groups for protecting this group include alkanoyl having 2 to 4 carbon atoms, chloro or fluoroalkanoyl having 3 to 4 carbon atoms, benzoyl and substituted benzoyl. The term " alkanoyl having 2 to 4 carbon atoms " means acetyl, propionyl, butyryl and the like, and " chloro or fluoroalkanoyl having 3 to 4 carbon atoms " means 3-chloropropionyl, 3-fluoropropionyl, Refers to halo-substituted benzoyl groups such as 4-chlorobenzoyl, 4-bromobenzoyl and 2,4-dichlorobenzoyl. This group can also be used to protect amino groups at other positions of 3- (acyoxymethyl) cephalosporin and sulfur containing nucleophilic reagents. However, when recovery of the free amino group is required, the protecting group should be an easily controlled group [see above McOmie]. Suitable protecting groups that can be easily removed include benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxy Carbonyl and diphenylmethoxycarbonyl. In general formula

Is protected by the method described in Belgian Patent No. 771,694

&Quot; Halogen " and " halo " refer to fluoro, chloro, bromo or iodo. The term "alkoxy having 1 to 4 carbon atoms" means methoxy, ethoxy, isopropoxy, n-butoxy, and the like. Preferred " alkali metal " s are sodium, potassium and lithium.

그룹의 예를 들면 포름아미드, 아세트아미도, 프로피온 아미도, 부티르아미도, α-메틸프로피온아미도, 발레르아미도, α-메틸부티르아미도, 트리메틸아세트아미도, 헥산아미도, 헵탄아미도, 3-클로로프로피온아미도, 3-클로로부티르아미도, 4-플루오로부티르아미도, 5-클로로 발레르아미도, 시아노아세트아미도, 2-시아노프로피온아미도, 3-시아노프로피온아미도, 4-시아노부티르아미도, 하이드록시 아세트아미도, 2-하이드록시프로피온아미도, 3-하이드록시 부티르아미도, p-니트로벤질옥시 카보닐아미노, 3급-부톡시카보닐아미노, (2,2,2-트리클로로에톡시) 카보닐아미노, 5-(2,5-디클로로벤즈아미도)-5-카복시발레르아미도, 5-아세트아미도-5-카복시발레르아미도, 5-카보메톡시-5-(2,4-디클로로벤즈아미도) 발레르아미도, 5-카보-n-부톡시-5-(2,4-디클로로벤즈아미도) 발레르아미도, 5-카복시-5-(2,4-디클로로벤즈 아미도)-발레르아미도, 5-(p-클로로 벤즈아미도)-5-카복시발레르아미도, 5-프로피온아미도-5-카복시발레르아미도, 5-(3-클로로 피로피온아미도)-5-카복시발레르아미도, 5-벤즈아미도-5-카복시발레르아미도, 5-옥서-5-카복시발레르아미도 및 4-카복시부티르아미도가 있다.Wherein R < ³ > is any one of the groups (1) to (12)

Groups such as formamide, acetamido, propionamido, butyrylamido,? -Methylpropionamido, valeramido,? -Methylbutyramido, trimethylacetamido, 3-chlorobutyrimido, 4-fluorobutyrimido, 5-chloropervalidamido, cyanoacetamido, 2-cyanopropionamido, 3- Hydroxypropionamido, 3-hydroxybutyramido, p-nitrobenzyloxycarbonylamino, tert-butyloxycarbonylamino, tert-butyloxycarbonylamino, (2,5-dichlorobenzamido) -5-carboxy valeramido, 5-acetamido-5-carboxy Valeramide, 5-carbomethoxy-5- (2,4-dichlorobenzamido) valeramido, 5-carbo-n-butoxy-5- (2,4- (P-chlorobenzamido) -5-carboxyvaleramido, 5-propionamido, 5- 5-carboxy valeramido, 5-carboxy valeramido, 5- (3-chloropyrropionamido) -5-carboxy valeramido, 5-benzamido- And 4-carboxybutyramido.

의 예를들면 다음과 같다.R < ³ > is a group of the following general formula, m is 0

For example:

2- (p-methylphenyl) acetamido, 2- (p-isopropylphenyl) acetamido, 2- 2- (2,4-dichlorophenyl) acetamido, 2- (p-bromophenyl) acetamido, 2- 2- (3,4-dihydroxyphenyl) acetamido, 2- (p-fluorophenyl) acetamido, 2- (p-hydroxyphenyl) acetamido, 2- (m-hydroxyphenyl) acetamido, 2- (2,6- dimethoxyphenyl)

Examples of the case where m = 1 and Z is oxygen in the above general formula include phenoxyacetamido, 2- (p-methylphenoxy) acetamido, 2- (m-ethylphenoxy) acetamido, 2- (p-chlorophenoxy) acetamido, 2- (p-bromophenoxy) acetamido, 2- (p- 2- (o-bromophenoxy) acetamido, 2- (p-fluorophenoxy) acetamido, 2- (o- 2- (m-ethoxyphenoxy) acetamido, 2- (p-methoxyphenoxy) acetamido, 2- Amido, 2- (3,4-dimethoxyphenoxy) acetamido, 2- (p-tert-butoxyphenoxy) acetamido, 2- (o-butoxyphenoxy) acetamido, 2- (3-chloro-4-methylphenoxy) acetamido, 2- (3-hydroxy-4-methylphenoxy) acetamido, 2- , 2- (p-isopropoxyphenoxy) acetamido, 2- (3-hydroxyphenoxy) acetamido, 2- acetamidomethyl) phenoxy) acetamido and 2- (p-tert-butoxycarbonylaminomethyl) phenoxy) acetamido.

(M-ethylphenylthio) acetamido, 2- (m-ethylphenylthio) acetamido, m-ethylphenylthio) acetamido in which m is 1 in the above general formula and Z is sulfur, 2- (p-chlorophenylthio) acetamido, 2- (p-bromophenylthio) acetamido, 2- 2- (p-fluorophenylthio) acetamido, 2- (2,4-dichlorophenylthio) acetamido, 2- 2- (3,4-dihydroxyphenylthio) acetamido, 2- (p-hydroxyphenylthio) acetamido, 2- 2- (m-ethoxyphenylthio) acetamido, 2- (p-methoxyphenylthio) acetamido, 2 (p-methoxyphenylthio) acetamido, 2- - (3,4-dimethylphenylthio) acetamido, 2- (p-tert-butoxyphenylthio) acetic acid 2- (3-chloro-4-methylphenylthio) acetamido, 2- (3,4-dimethylphenylthio) acetamido, 2- (3-fluoro-4-chlorophenylthio) acetamido, 2- (3-fluorophenylthio) acetamido, 2- 2- (o-fluorophenylthio) acetamido, 2- (2,6-difluorophenylthio) acetamido, 2- (Acetamidomethyl) phenylthio) acetamido and 2- (p-tert-butoxycarbonylaminomethyl) phenylthio) acetamido.

의 그룹을 나타내는 경우, 일반식

를 갖는 그룹의 예를들면 만델아미도그룹, 이의 o-포르밀 및 o-아세틸유도체, 2-카복시-2-페닐아세트 아미도그룹, 2-설포-2-페닐아세트아미도그룹, 보호된 2-아미노-2-페닐아세트 아미도그룹, (여기에서 보호된 아미노그룹은 카보닐아미노, 3급-부톡시카보닐아미노, 트리클로로에톡시 카보닐아미노 또는 p-니트로벤질옥시카보닐R < ^{3 &}

, The group represented by the general formula

Carboxy-2-phenylacetamido group, 2-sulfo-2-phenylacetamido group, protected 2 < RTI ID = 0.0 > -Amino-2-phenylacetamido group, wherein the protected amino group is selected from the group consisting of carbonylamino, tert-butoxycarbonylamino, trichloroethoxycarbonylamino or p-nitrobenzyloxycarbonyl

Examples of such acetamido groups include mandelamide, p-methyl mandelamide, p-hydroxymandelamido, m-hydroxymandelamido, p-methoxymandelamido, m- Bromomandelamido, p-chloromandelamido, 3-methyl-4-fluoromandelamido, o-fluoromandelamido, p-fluoromandelamido, p- M-isopropoxy-o-formylmandelamide, m-bromo-aminomethylamido, p-chloro-o- o-formylmandelamido, o-formylmandelamido, 3,4-dimethoxy-o-formylmandelamido, o-acetylmandelamido, p-

그룹의 예를 들면, 2-(하이드록시이미노)-2-페닐아세트아미도, 2-(메톡시아미노)-2-페닐아세트아미도, 2-(아세톡시이미노)-2-페닐아세트아미도, 2-(하이드록시이미노)-2-(2-티에닐) 아세트아미도, 2-(하이드록시이미노-2-(2-푸릴) 아세트아미도, 2-(메톡시이미노)-2-(3-티에닐) 아세트아미도, 2-(메톡시이미노)-2-(2-푸릴) 아세트아미도, 2-(메톡시이미노)-2-(p-하이드록시페닐)-아세트아미도, 2-(하이드록시이미노)-2-(2-(2,2,2-트리플루오로에톡시카보닐아미노)-4-티아졸일) 아세트아미도, 2-(하이드록시이미노)-2-(2-(2,2,2-트리클로로에톡시카보닐이미노-4-티아졸린-4-일)아세트아미도)와의 호변이성체), 2-(메톡시이미노)-2-(2-(p-니트로벤젠옥시카보닐아미노)-4-티아졸일아세트아미도[2-(메톡시이미노)-2-(2-(p-니트로벤질옥시카보닐이미노)-4-티아졸일-4-일) 아세트아미도)와의 호변이성체] 및 2-(메톡시이미노)-2-(4-클로로페닐)아세트-아미도가 있다.And R < ³ >

Groups such as 2- (hydroxyimino) -2-phenylacetamido, 2- (methoxyamino) -2-phenylacetamido, 2- (acetoxyimino) 2- (2-thienyl) acetamido, 2- (hydroxyimino-2- (2-furyl) acetamido, 2- (methoxyimino) -2- 2- (methoxyimino) -2- (p-hydroxyphenyl) -acetamido, 2- (methoxyimino) 2- (hydroxyimino) -2- (2- (2,2,2-trifluoroethoxycarbonylamino) -4- thiazolyl) acetamido, 2- (Tautomer with 2- (2,2,2-trichloroethoxycarbonylimino-4-thiazolin-4-yl) acetamido), 2- (methoxyimino) -2- nitrobenzenoxycarbonylamino) -4-thiazolylacetamido [2- (methoxyimino) -2- (2- (p-nitrobenzyloxycarbonylimino) Yl) acetamido) And 2- (methoxyimino) -2- (4-chlorophenyl) acet-amido.

그룹의 예에는 2-(트리플루오로메틸티오) 아세트아미도, 2-(메틸설포닐)-아세트아미도, 2-(시아노메틸티오) 아세트아미도, 2-(아지도메틸티오) 아세트아미도, 2-(에틸설포닐) 아세트아미도, 2-(2,2,2-트리플루오로에틸티오) 아세트아미도, 2-(메틸설피닐) 아세트아미도 및 2-(시아노메틸설포닐) 아세트 아미도가 있다.R < ³ > is the group of the above (16)

Examples of groups include 2- (trifluoromethylthio) acetamido, 2- (methylsulfonyl) -acetamido, 2- (cyanomethylthio) acetamido, 2- Amido, 2- (ethylsulfonyl) acetamido, 2- (2,2,2-trifluoroethylthio) acetamido, 2- (methylsulfinyl) acetamido and 2- Sulfonyl) acetamido.

그룹의 예를들면 2-(2-티에닐) 아세트아미도, 2-(3-티에닐)아세트아미도, 2-(2-푸릴) 아세트아미도, 2-(2-옥사졸일) 아세트아미도, 2-(2-티아졸일) 아세트아미도, 2-(1-테트라졸일)아세트아미도, 2-(1-벤조트리아졸일) 아세트아미도, 2-(2-옥사졸일티오 아세트아미도, 2-(2-티아졸일티오) 아세트아미도, 2-(1,2,3-트리아졸-2-일티오) 아세트아미도, 2-(1,3,4-트리아졸-2-일티오) 아세트아미도, (1,3,4-티아디아졸-2-일티오) 아세트아미도, 2-(5-(보호된 아미노)-1,3,4-티아디아졸-2-일티오) 아세트아미도, 2-(5-메틸-1,3,4-티아디아졸-2-일티오)아세트아미도, 2-(1,2,4-티아디아졸-5-일티오) 아세트아미도, 2-(3-메틸-1,2,4-티아디아졸-5-일티오) 아세트아미도), 2-(1,2,5-티아디아졸-3-일티오) 아세트아미도, 2-(1,3,4-옥사디아졸-2-일티오) 아세트아미도, 2-(5-메틸-1,3,4-옥사디아졸-2-일티오) 아세트아미도, 2-(1-메틸-5-테트라졸일티오)아세트아미도, 2-(피리딜티오)아세트아미도, 2-(4-시아노-1,2,3-트리아졸-1-일)아세트아미도, 2-(3-시아노-1,2,4-트리아졸-1-일) 아세트아미도 및 2-(2-(보호된 아미노)-4-트리아졸일)아세트아미도[2-(2-이미노-4-티아졸린-4-일) 아세트아미도와의 호변이성체]가 있다.R ³ is Y-CH ₂ -

Groups such as 2- (2-thienyl) acetamido, 2- (3-thienyl) acetamido, 2- (2-furyl) acetamido, 2- (2-thiazolyl) acetamido, 2- (1-tetrazolyl) acetamido, 2- (1-benzotriazolyl) acetamido, 2- , 2- (2-thiazolylthio) acetamido, 2- (1,2,3-triazol-2-ylthio) acetamido, 2- Thio) acetamido, (1,3,4-thiadiazol-2-ylthio) acetamido, 2- (5- (protected amino) -1,3,4-thiadiazol- Thio) acetamido, 2- (5-methyl-1,3,4-thiadiazol-2-ylthio) acetamido, 2- (1,2,4-thiadiazol- Acetamido, 2- (3-methyl-1,2,4-thiadiazol-5-ylthio) acetamido), 2- (1,2,5-thiadiazol- Amido, 2- (1,3,4-oxadiazol-2-ylthio) acetamido, 2- (5-methyl-1,3,4-oxadiazol- (1-methyl-5-tetrazolylthio) acetamido, 2- (pyridylthio) acetamido, 2- (4-cyano-1,2,3-triazol- ) Acetamido, 2- (3-cyano-1,2,4-triazol-1-yl) acetamido and 2- (2- (protected amino) Tautomer of 2- (2-imino-4-thiazolin-4-yl) acetamido].

Many cephalosporanic acids used as starting materials in the present preparation process are known compounds and can be prepared according to conventional methods in the art.

See, for example, Cephalosporins and Penicillins, Chemistry and Biology, edited by Edwin H. Flynn (Academic Press, New York, 1972), especially Chapters 3,4 and 15 and the patents cited therein, U.S. Patent 3,914,157 and South African Patents 71/3229)

인 경우이다.Preferred sulfur-containing nucleophilic reagents of formula (III) are those wherein R < ^{13 &}

.

Suitable 5-membered heteroaromatic rings of the above formula include pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole , 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole , 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, oxatriazole, and tetrazole. Suitable 6-membered rings include pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5- 1,2,4,5-tetrazine.

Alkylthiols and phenylthiols of the general formula (III) as well as heteroarylthiol are actually present as thionates or as tautomeric mixtures of thiols and thiones. For example, the compound of 2-methyl-1,3,4-thiadiazole-5-thiol exists as the following tautomer.

However, since the present invention proceeds with a given sulfur-containing nucleophilic reagent in either thiol or thion form, the present invention falls within the scope of the present invention to perform a given reaction using a thione or thiol-thione tautomer of a given reagent.

The heteroarylthiol may be unsubstituted or substituted with one or more substituents. In general, the substituent itself is not a problem. For best results, all primary or secondary amino groups must be protected. If the heteroarylthiol contains one or more thiol groups, the group that is not to be reacted should be protected. Methods for protecting thiols are well known (McOmie supra). In protecting this group, the reaction proceeds regardless of the substituent.

It is desirable to avoid excessive substitution. In general, substitutions that do not exceed a molecular weight of about 500 are preferred. The most commonly substituted heteroaromatic rings contain a substitution with a total molecular weight of 250 or less.

Suitable substituents include alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 4 carbon atoms, alkynyl having 2 to 4 carbon atoms, cycloalkyl having 5 to 6 carbon atoms, benzene, and phenethyl. Aryl including phenyl and substituted phenyl as defined above, halo, -CF ₂ , = O, -OH, protected amino or alkylamino having from 1 to 4 carbon atoms, -COOH, -COOA ² , -CONH ₂ , Aminomethyl or alkylaminomethyl of 1 to 4 carbon atoms, -CH ₂ SO ₃ -alkali metal, -CH ₂ COOH, -CH ₂ COOA ² or - (CH ₂ ) ₂ N (CH ₃ ) ₂ .

Representative sulfur containing nucleophilic reagents of formula (III) are as follows.

Thiourea

N, N'-di-n-butyl thiourea, N, N'-di-tert-butyl thiourea, N, N'-dicyclohexyl thiourea, Thiourea, N, N'-dimethylthiourea, N-methylthiourea, N, N, N ', N'-tetraethylthiourea, N, N, N' , N-phenylthiourea, N, N'-diphenylthiourea, N, N'-dimethylthiourea.

Thiobenzoic acid

Alkyl thiols

Methanethiol, ethanethiol, 1- or 2-propanethiol, 1- or 2-butanethiol, 2-methyl-

Benzene thiol

Benzene thiol, 4-bromo-3-methylbenzene thiol, p-bromobenzene thiol, p-chlorobenzene thiol, 2,5-dichlorobenzene thiol, 3,4-dichlorobenzene thiol, m-methoxybenzenethiol, p-methoxybenzenethiol, p-nitrobenzenethiol, p-methylbenzenethiol.

Heteroaryl thiols

2-imidazole thiol, 4-oxazole thiol, 3-isoxazole thiol, 2-methyl thiazole thiol, 2-methyl thiazole thiol, Thiazole thiol, 3-isothiazole thiol, 1-methyl-1,2,3-triazole-5-thiol, 1-benzyl-1,2,3-triazole- Triazole-4-thiol, 3,5-dimethyl-1,2,3-triazole-5-thiol, 1,2,4-triazole- Triazole-5-thiol, 3-methyl-1,2,4-triazole-5-thiol, 3,4-dimethyl- Triazol-5-thiol, 2-benzyl-1,2,4-triazole-5-thiol, 2,3-dimethyl-

Most of the sulfur-containing nucleophilic reagents used in the present process are known compounds and can be prepared according to the methods of the prior art. Heteroaryl thiols and each heterocyclic system are described in the following references. Edited by Robert C. Elderfield (John Wiley and Sons, Inc., NY), as well as a variety of heterocyclic systems in the series " The Chemistry of Heterocyclic Compounds, " edited by Weissberger et al. (John Wiley and Sons, N. Y.).

It is important in the present invention to carry out the reaction in an organic solvent. However, the choice of solvent is not a problem as it can produce satisfactory results with various organic solvents. In general, the following solvents give satisfactory results. Such as hydrocarbons, aliphatic and aromatic alcohols, amides, ethers, ketones, carboxylic acids, carboxylic acid esters, halogenated hydrocarbons, nitro compound nitriles and thioethers. Because some nucleophilic reagents are liquids, an excess of this reactant can be used as a solvent.

In view of not competing with any of the reactants, the solvent must be inert.

Suitable solvents which are carried out in accordance with the present process include but are not limited to pentane, cyclopentane, hexane, heptane, octane, benzene, toluene, o-, m- or p-xylene, cumene, mesitylene, p- Methyl ethyl ketone, 2-butanone, 2-pentanone, methyl isobutyl ketone, cyclohexanone, acetic acid, propionic acid, butyric acid, isobutyric acid, valerol But are not limited to, acid, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, ethyl propionate, butyl acetate, isoamyl acetate,

hydrocarbon

Benzene, toluene, o-, m-, or p-xylan, cumene, mesitylene,

Halogenated hydrocarbons;

Dichloroethane, carbon tetrachloride, 1, 2- or 3-chloropentane, methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride, , 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, fluorobenzene, chlorobenzene, bromobenzene, o-, m-, or p -Fluorotoluene, o-, m-, or p-chlorotoluene, o-, m-, or p-bromotoluene, o-, m-, or p- dichlorobenzene.

Mountain:

Acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid,

Ester:

Methyl acetate, ethylene glycol diacetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, pentyl acetate, ethyl propionate, methyl butyrate, n-butyl formate, , Ethylene carbonate.

Nitro compounds:

Nitrobenzene, nitromethane, nitroethane, nitropropane.

Nitrile:

Acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, benzonitrile, phenylacetonitrile.

Ketone:

Methyl isobutyl ketone, methyl ethyl ketone.

Particularly preferred solvents are acetonitrile, 1,2-dichloroethane, methylene chloride, propionitrile, nitromethane, nitroethane, acetic acid, isopropyl acetate, butyl acetate and methyl isobutyl ketone.

The 3- (acyloxymethyl) cephalosporin of formula (II) is defined as the acid. Generally, since the cephalosporin salt is not dissolved in the organic solvent, the reaction is regarded as an acid. As an exception, the cephalosporin salt is dissolved in a carboxylic acid solvent such as acetic acid. Thus, the present reaction can be achieved by dissolving a 3- (acyloxymethylheparosporin salt such as a metal salt in a carboxylic acid solvent.

It is necessary to carry out the present manufacturing process under anhydrous conditions regardless of the solvent. Generally, the reaction mixture should contain no more than 5% water, preferably no more than 1% water. It is more preferable that the content of water is 0.5% or less. The commercially available reagents and solvents that are not sufficiently dehydrated can be dehydrated according to known methods, that is, azeotropic mixing and dehydrating agents such as alumina, silica gel, anhydrous calcium sulfate salts and the like.

This production reaction proceeds at a wide range of temperatures. Generally, a temperature of 50 to 140 캜 can be used, but good results can be obtained at 70 to 120 캜. It can cause a reaction at elevated pressure, but there is no advantage. For convenience, atmospheric pressure is generally preferred.

The amount of reactants is not a problem at all. It is generally desirable to use an excess of sulfur containing nucleophilic reagent. Namely 1.0 to 5.0 molar equivalents of sulfur-containing nucleophilic reagent per molar equivalent of 3- (acyloxymethyl) cephalosporin reactant.

The present process is particularly effective for introducing 30 heteroarylthio groups into cephalosporin, in particular the following.

Methyl-1H-tetrazol-5-ylthio-, 1-carboxymethyl-1H-tetrazol-5-ylthio Methyl-6-hydroxy-5-oxo-1,2,4-triazine-3-ylthio-, 1-methyl-1,3,4- Methyl-1,3,4-triazol-5-ylthio, -1,2-dimethyl-1,3,4-triazol-5-ylthio- Triazole-5-ylthio-, 2,3-dimethyl-1,3,4-triazol-5-ylthio-, 1-methyl- Methyl-2-carboxamido-1,3,4-triazol-5-ylthio-1-methyl-2-carboxymethyl-1,3,4-triazole -1-methyl-2-carboalkoxy-1,3,4-triazol-5-ylthio-, 1-methyl- 2- (protected aminomethyl) 1-methyl-2- (protected amino) -1,3,4-triazol-5-ylthio-, 1-methyl- -Triazol-5-ylthio-, 1-H-tetrazol-5-ylthio-, 1- (2- dimethylaminoethyl) Methyl-1, 3, 4-oxadiazol-2-ylthio-, 1, 3,4-thiadiazol-2-ylthio-, 3-methyl-1,2,4-thiadiazol-5-ylthio- and 2- (protected aminomethyl) -1,3,4-thiadiazol-

Among the cephalosporin compounds of the general formula (I) that can be prepared according to the synthesis method including the present manufacturing process, the important important compounds are as follows.

The products of the present invention, their deprotected derivatives, and the pharmaceutically non-toxic salts are effective to control infectious organisms in warm-blooded mammals when administered parenterally at a non-toxic dose of 10 and 500 mg / kg body weight. This compound is formulated in a conventional manner. The following examples are illustrative of the present invention and those skilled in the art will be able to carry out the method.

[Example 1]

Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem- Recipe.

2.2 g (5.5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 1.0 g (8.6 mmol) of 1-methyl-1H-tetrazole- Was added to 25 ml of acetonitrile in a dry glass tube equipped with a dry tube containing calcium sulfate anhydrate, and the reaction mixture was refluxed with stirring, and the progress of the reaction was confirmed by thin layer chromatography (TLC). After 90 minutes of reflux, TLC solids and about 2/3 of the starting material cephalosporanic acid, 1/3 of the desired product were found to be present. After refluxing for 3 hours, the starting material was about 1/3 and the product was 2/3 by TLC. After 6 hours, the reaction with TLC was actually completed. The reaction mixture is cooled to room temperature and allowed to stand overnight. Removal of the solvent with a rotary evaporator leaves a residue on the foam which is dissolved in 10 ml of ethanol. When a solution of 1 ml of dicyclohexylamine in 10 ml of ethanol is added dropwise thereto, the product precipitates as a diacyclohexylamine salt. The mixture is stirred for 15 minutes and then separated by filtration. The separated product is washed with 15 ml of ethanol and the product is vacuum dried at 40 DEG C for 2 hours to obtain 2.5 g (yield: 76.1%). Melting point: 183-184 占 폚 (decomposition)

The NMR, IR, and TLC results of this product were the same as those of the product prepared by aqueous substitution, which is a method of prior art. _{NMR (DMSO-d 6) δ} 3.52 (m, 2, 2-CH 2), 3.76 (s, 2, -CH 2 CONH-) 3.92 (s, 3, tetrazole _{-CH 3), 4.35 (s,} 2 _{, 3-CH 2 s-),} 5.00 (s, 2, 3-C 6 -H, J = 5Hz), 5.55 (q, 1, C 7 -H, J = 5Hz, J = 9Hz), 6.95 (s , 2, thiophene 3 and 4-H, J = 3 Hz), 7.35 (t, 1, thiophene 5-H, J = 3 Hz) and 8.75 (d, 1, -CH ₂ CONH, J = 9 Hz).

[Example 2]

Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem- Recipe.

(10 mmol) 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 5.8 g (millimoles) of 1-methyl-1H-tetrazole-5-thiol were dissolved in anhydrous acetonitrile Treated with an anhydrous sulfonic acid resin, commercially available under the trade name of Lite 15) in anhydrous atmosphere for 8 3/4 hours, followed by TLC, the reaction was almost complete at the end of 8 3/4 hour.

The solvent is removed by evaporation and 125 ml of ethanol are added to the residue. When 75 ml of ethanol and 6 ml of dicyclohexylamine are added, the product precipitates as a dicyclohexylamine salt. Separated by filtration, washed, and dried to obtain 4.50 g (Yield: 71.0%).

IR, NMR, and TLC.

NMR was also the same as the NMR analysis of the product of Example 1.

[Example 3]

Methyl-1H- tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem in 1, 2-dichloroethane, -4-carboxylate.

2.0 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 1.2 g (10 mmol) of 1-methyl-1H-tetrazole-5-thiol were dissolved in 1,2- Ethane and refluxed for a total of 5.5 hours under anhydrous conditions. After removing the solvent with a rotary evaporator, 25 ml of ethanol is added to the filtrate, and 2 ml of dicyclohexylamine is added dropwise to 25 ml of ethanol. The precipitated product as dicyclohexylamine salt was stirred at room temperature for 20 minutes, filtered, washed with 25 ml of ethanol and dried at 40 캜 under vacuum to obtain 2.34 g (yield: 73.8%) of an off-white solid.

IR < / RTI > and NMR. NMR was also the same as NMR of the product of Example 1.

[Example 4]

Methyl-1H- tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem in 1, 2-dichloroethane, -4-carboxylate.

(20 mmol) of 1-methyl-1H-tetrazole-5-thiol were added to 50 ml of 1,2-dichloroethane, and the mixture was stirred do. The reaction mixture is cooled to room temperature and allowed to stand overnight at room temperature to precipitate a red gossy solid.

The product is identified by removing the 7-formyl group as follows.

That is, the solvent is removed with a rotary evaporator, and the residue is dissolved in methanol (25 ml), then concentrated hydrochloric acid (2.8 ml) is added, and the mixture is allowed to stand at room temperature overnight. The solution is diluted with 50 ml of water, then starts at pH 0.9, and triethylamine is added dropwise to 3.6. The pale brown crystals are filtered, washed with water and dried to obtain 2.10 g (yield: 64%).

NMR analysis was the same as that of the product prepared by aqueous substitution. _{NMR (D 2 O, NaHCO 3} ), δ 3.65 (q, 2, 2-CH 2, J AB = 16.5Hz), 4.08 (s, -CH 3 of three phases, tetrazole), 4.16 (q, 2, 3 _{-CH 2 s-, J AB = 12.5Hz} ), 5.05 (d, 1, C 6 -H, J = 5Hz) and _{5.45 (d, 1, C 7} -H, J = 5Hz).

[Example 5]

Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem- Recipe.

2.0 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 1.2 g (10 mmol) of 1-methyl-1H-tetrazole-5-thiol were dissolved in 25 ml of isopropyl acetate And refluxed with stirring for 23 hours.

The reaction mixture is cooled to room temperature. TLC and cephalosporanic acid, the starting material, remained. The pale creamy solid material was separated by filtration, washed with isopropyl acetate and dried to give 1.60 g (yield: 70.8%). As a result of the NMR, the product was found to contain less than 1% of the starting material cephalosporanic acid.

_{NMR (DMSO-d 6) δ} 3.72 (s, 2, 2-CH 2), 3.80 (s, 2-CH 2 CONH-) 3.95 (s, -CH ₃ of 3, tetrazole), 4.30 (s, 2 _{, 3-CH 2 S-),} 5.10 (d, 1, C 6 -H, J = 5Hz), 5.70 (q, 1, C 7 -H, J = 5Hz, J = 8Hz), 6.92 (d, 2 , Thiophene 3- and 4-H, J = 3 Hz), 7.35 (t, 1, thiophene 5-H, J = 3 Hz) and 8.78 (d, 1, -CH ₂ CONH, J = 8 Hz).

[Example 6]

(2-thienyl) acetamido) -3-cephem-4-carboxylate in propionitrile was added to a solution of 3- ( quite.

2.0 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 1.2 g (10 mmol) of 1-methyl-1H-tetrazole-5-thiol were dissolved in 25 ml of anhydrous propionitrile And refluxed at 79 [deg.] C by TLC until cephalosporanic acid, the starting material, is completely absent (4.5 hours).

The reaction mixture is cooled to room temperature and the solvent is removed using a rotary evaporator. Part of the solution was lost due to boiling during the reaction. 35 ml of warmed ethanol was dissolved, and a solution of 10 ml of ethanol and 2 ml of disilecylhexylamine was added. The product is precipitated as a dicyclohexylamine salt. The mixture was stirred at room temperature for 10 minutes, filtered, washed with ethanol and dried to obtain 1.24 g (yield: 39.0%, product not lost by rotary evaporator). The NMR analysis of the product was identical to that of the product of Example 1.

[Example 7]

3 - (((1 -methyl-1 H -tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) thiophene in acetonitrile ) Acetamido) -3-cephem-4-carboxylic acid.

2.0 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid, 0.87 g (7.5 mmol) of 1-methyl- 0.122 g (0.5 mmol) of phenyldihydrogenphosphate was added to 25 ml of anhydrous acetonitrile at 70 占 폚, heated overnight, and then evaporated to 8 to 10 ml with a rotary evaporator to remove the solvent. The product begins to crystallize. After stirring for 30 minutes, 25 ml of isopropyl acetate is added dropwise for 30 minutes to further induce crystallization. After stirring for an additional 30 minutes, the product is separated by filtration, washed with isopropyl acetate and dried to give 0.8 g (yield: 43.4%). The NMR of the product was the same as that of the product of Example 5.

[Example 8]

Preparation of 3 - (((1H-tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem-4-carboxylic acid in acetic acid.

2.0 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 0.87 g (5 mmol) of 1-methyl-1H-tetrazole-5-thiol are added to 25 ml of glacial acetic acid . When the reaction mixture is heated to 60 < 0 > C and maintained at ionic strength for one hour, only trace amounts of the product appear on the TLC.

The reaction mixture is heated to 80 < 0 > C and held at ionic strength for 5 hours and allowed to stand overnight. The product was separated by filtration, washed with acetic acid and dried to give 0.71 g (yield: 31%). The NMR of the product was the same as that of the product of Example 5.

[Example 9]

(4, 5-dihydro-6-hydroxy-4-methyl-5-oxo-1,2,4-triazin-3- yl) thio) methyl) Preparation of 2- (2-thienyl) acetamido) -3-cephem-4-carboxylic acid.

Dihydro-6-hydroxy-4-methyl-5-oxo-1,2,3,4-tetrahydroisoquinoline (2.0 g, 1.2 g (7.5 mmol) of 4-triazine-3-thiol are added to 25 ml of anhydrous acetonitrile in a reaction flask immersed on an oil bath at 84-85 < 0 > C. A flask is equipped with a drying tube and a cooler containing anhydrous calcium sulfate, marketed under the trade name Dreyertree. The reaction mixture is maintained under this condition for 16 hours with gentle stirring with a magnetic stirrer.

The product is crystallized from the hot solution. The reaction mixture is cooled to room temperature, filtered, washed with acetonitrile, washed with acetone and dried under vacuum to give 1.81 g (yield: 72.6%). This product is an off-white crystal. Melting point: 161 캜 (decomposition)

Upon leaving the filtrate, the second crystal product is deposited. The product is separated by filtration, washed with acetonitrile and dried to give 0.26 g (Yield: 10.5%).

The melting point of this second product is also 161 [deg.] C (decomposition). The total yield is 83.1%.

[Example 10]

Methyl-7- (2- (2-thienyl) acetamido) -1,2-dichloroethane, ) -3-cephem-4-carboxylic acid.

2.0 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 0.87 g (7.5 mmol) of 5-methyl-1,3,4-oxydiazole- 1, 2-dichloroethane in 25 ml of dry tetrahydrofuran is placed in a prism equipped with a magnetic stirrer and a dryer tube containing calcium sulfate anhydride sold under the trade name of Triire and a cooler.

The flask was immersed in an oil bath at 84 to 85 ° C, left for 8 hours, and then frozen for 2 days. When a part of the product crystallizes, it is separated by filtration, washed with 1, 2-dichloroethane and dried to obtain 1.10 g (yield 48.7%). This is dissolved in 15 ml of acetone and filtered to remove insoluble products. 75 nl of deionized water is added dropwise, the product is separated by filtration and dried to obtain 0.61 g. Melting point: 114 캜 or higher (decomposition)

Evaporation of the solvent from the filtrate gives 0.23 g of a mixture of the product and the starting material.

[Example 11]

Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem- Recipe.

2.0 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 0.87 g (7.5 mmol) of 1-methyl-1H-tetrazole-5-thiol were added to anhydrous nitromethane , The flask is immersed in an oil bath at 100 to 101 DEG C for 4.5 hours and then cooled to room temperature.

The completion of the reaction is confirmed by TLC. Solvent is removed with a rotary evaporator and the residue is dissolved in 75 ml of warm ethyl acetate. The solution is filtered to remove small amounts of insoluble matter and then extracted twice with 25 ml of 5% aqueous sodium bicarbonate solution. The extracts are combined, treated with 50 ml of ethyl acetate and acidified with a 70% aqueous solution of methanesulfonic acid to a pH of about 1.0. The ethyl acetate layer is separated and the aqueous layer is extracted with 25 ml of ethyl acetate. The combined ethyl acetate layers were dehydrated with anhydrous sodium sulfate and concentrated to 25 ml with a rotary evaporator.

50 ml of diethyl ether is added dropwise thereto to obtain a crystallized product. Filtered off, washed with diethyl ether and dried to give 1.27 g (yield 56.2%) of off-white crystals. Melting point: 156 to 159 占 폚 (decomposition)

The product is identified by NMR.

[Example 12]

Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem- Recipe.

11.9 g (30 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 7.0 g (60 mmol) of 1-methyl-1H-tetrazole-5-thiol were dissolved in methylene chloride ) And placed in a 1 l stainless steel autoclave equipped with a heater. The reaction mixture is stirred and heated at 83-86 < 0 > C for 16 h at 42 psi and then cooled to room temperature. TLC showed conversion to the product, but the starting material, cephalosporanic acid trace, remained. The reaction mixture is allowed to stand at room temperature to obtain crystals of the product which are then concentrated to 200 ml. The crystals were filtered off and washed with methylene chloride to give 7.37 g (yield: 54.3%) of white crystals.

Melting point: 163.5-164 占 폚 (decomposition)

The filtrate is diluted with 100 ml of diethyl ether to give a pale yellow-brown crystal, which is filtered, washed with diethyl ether and dried to give 1.40 g (yield: 10.3%).

Dilution of the filtrate with isopropyl acetate gives 1.18 g (yield: 8.7%) of the third product. Therefore, the total yield is 73.3%.

[Example 13]

Methyl-1H- tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem- Preparation of carboxylic acid.

2.0 g (5.04 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 1.2 g (10 mmol) of 1-methyl-1H-tetrazole-5-thiol were dissolved in fluorobenzene 85.1 < 0 > C) and added to a flask equipped with a condenser and a drying tube containing calcium sulfate anhydride sold under the trade name Darierite. The mixture is heated to reflux and the progress of the reaction is confirmed by TLC using a 7: 1 mixed solvent of ethyl acetate: acetic acid. The reaction in the uneven state is completed in 72 hours.

The reaction mixture is cooled to room temperature and filtered to separate the precipitated product. The product is washed with fluorobenzene and dried at 40 < 0 > C for 5 hours under vacuum. 2.13 g (yield: 93.4%) of off-white crystals were obtained.

Melting point: 161 to 162 占 폚 (decomposition)

The product is identified by NMR.

[Example 14]

Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem- Recipe.

2.0 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 0.87 g (7.5 mmol) of 1-methyl-1H-tetrazole-5-thiol were added to 25 ml of thiophene Reflux for 7 hours then crystallizes the product.

The reaction mixture is cooled to room temperature and stirred for 30 minutes to complete the crystallization. The separated product was washed with 0.5 ml of thiophene and then vacuum-dried for 2 hours. (Yield: 80.2%) of white crystals. Melting point: 163 to 163 캜 (decomposition). TLC showed that the filtrate contained an additional product.

[Example 15]

Methylthio) -7- (2- (1H-tetrazol-1-yl) acetamido (2-methyl- ) -3-cephem-4-carboxylic acid.

0.76 g (2 mmol) of 7- (2- (1H-tetrazol-1-yl) acetamido) secaprosporanic acid and 0.33 g 2.5 mmol) is added to anhydrous acetonitrile (10 ml) and refluxed for 2 hours and 40 minutes to crystallize the product. The reaction mixture is cooled on ice bath and filtered to isolate the product, which is then washed with 3 ml of acetonitrile and dried under vacuum at 40 [deg.] C to give 0.61 g (yield: 67%).

The product is identified by NMR.

_{NMR (DMSO-d 6) δ} 2.68 (s, 3, tetrazol-of _{-CH 3), 3.72 (s,} 2, 2-CH 2), 4.40 (q, 2, 3-CH 2 S, J AB = 13Hz ), 5.12 (d, 1, C 6 -H, J = 5Hz), 5.38 (s, 2, -CH 2 CONH-), 5.72 (q, 1, C 6 -H, J = 3Hz, J = 9Hz) , 9.00 (s, 1, tetrazole-5-H) and _{9.17 (d, 1, -CH 2} CONH-).

[Example 16]

Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2-formyloxy-2-phenyl-acetamido) -3 - < / RTI > cephem-4-carboxylic acid.

2.17 g (5 mmol) of 7- (2-formyloxy-2-phenyl-acetamido) cephalosporanic acid and 0.87 g (7.5 mmol) of 1-methyl- -Dichloroethane and the resultant reaction mixture is refluxed for 6 hours. At 3 hours and 6 hours, samples are taken and TLC is performed. The reaction mixture is heated for an additional hour and then allowed to stand overnight to cool. The solvent is removed by evaporation, and when diethyl ether is added to the residue, it is transformed to a solid phase and then to a solid phase. The product was isolated by filtration, washed with diethyl ether and dried to give 1.90 g (Yield: 77.0%).

), 7.26(s, 5, 페닐-H) 및 8.28(s, 1,

). _{NMR (DMSO-d 6) δ} 3.52 (s, 2, 2-CH 2), 3.88 (s, 3, tetrazol-of _{-CH 3), 4.10 (s,} 2, 3-CH 2 S), 4.92 (d _{, 1, C 6 -H),} 5.62 (q, 1, 1, C 7 -H), J = 5Hz), J = 9Ha), 6.06 (s, 1,

), 7.26 (s, 5, phenyl-H) and 8.28 (s, 1,

).

[Example 17]

(1-methyl-1H-tetrazol-5-yl) thio) methyl) -7- (5-carboxy-5- (2, 4-dichlorobenzamido) -valeramido) -3-cephem-4-carboxylic acid.

(A) 7- (5-Carboxy-5- (2,4-dichlorobenzamido) valeramido) 2.9 g (5 mmol) Sepharosporanic acid and 1-methyl-1H-tetrazole-5-thiol 1.2 g (10 mmol) and 50 ml of acetonitrile are refluxed for 18 hours. TLC showed that the reaction was completed at 90%. The reaction mixture is evaporated, the residue is treated with ethyl acetate and filtered to give 1.51 g (yield: 48.3%).

(B) 7- (5-carboxy-5- (2,4-dichlorobenzamido) valeramido) 2.9 g (5 mmol) cephalosporanic acid and 1-methyl-1H-tetrazole-5-thiol 1.2 g (10 mmol) and 50 ml of 1,2-dichloroethane are refluxed for 5 hours and 30 minutes.

TLC showed that the reaction was completed at 90%. When the solvent is tilted from the reaction mixture, a solid material in the form of a plastic remains, which is treated under ether reflux. The product was separated by filtration to give 2.83 g (Yield: 89.3%) of yellowish brown crystals.

The product was identified by NMR, but the ether appeared.

NMR (DMSO-d ₆₎ δ1.78 and 2.26 (each m, adipoyl side chain), 3.66 (m, 2, 2-CH 2), 3.95 (s, 3, of the tetrazol-CH _3), 4.30 (m, 2, 3-CH ₂ S-), 5.08 (d, 1, C ₆ -H, J = 5 Hz), 5.68 (q, 1, C ₇ -H, J = 5 Hz), 7.50 and 7.62 , 4-dichlorophenyl) and 9.00 (m, 2, two -CONH).

[Example 18]

(1-methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3- Preparation of cephem-4-carboxylic acid.

시간 환류시킨후, 반응혼합물을 실온으로 냉각하고 여과한다. 얻은 솜같은 침상의 생성물은 1, 2-디클로로에탄 10ml로 세척(5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 0.58 g (5 mmol) of 1-methyl-1H-tetrazole- Is added to 12.5 ml of dichloroethane and the reaction mixture is refluxed. Refluxing to remove the by-product of acetic acid, which can be accomplished by recycling 1,2-dichloroethane reflux through calcium oxide.

After refluxing, the reaction mixture is cooled to room temperature and filtered. The resulting cotton-like bed product was washed with 10 ml of 1, 2-dichloroethane

Evaporation of the filtrate gives 0.04 g of product (yield: 3.5%). The product is identified by TLC, the main product being identified by NMR. The analytical value of NMR was the same as that of the product of Example 5.

[Example 19]

3- ((5-methyl-1,3,4-thiadiazol-2-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3- Preparation of cephem-4-carboxylic acid.

2.0 g (2.5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 2.64 g (20 mmol) of 5-methyl-1,3,4- Is added to 25 ml of acetonitrile and refluxed at 79 ° C overnight. TLC shows only trace amounts of cephalosporanic acid, the starting material. The reaction mixture is filtered to remove the oily residue and the solvent is removed with a rotary evaporator. The residue was crystallized from acetonitrile: isopropyl acetate (1: 1), filtered and separated, and dried in vacuo to give 1.59 g (yield: 33.9%). Melting point 166 ° C

The product is identified by IR, UV, NMR, MS and elemental analysis.

_{NMR (DMSO-d 6) δ2.68} (S, 3, tetrazol-of _{-CH 3), 3.68 (S,} 2, 2-CH 2), 3.76 (S, 2, -CH 2 CONH-), 4.38 ( _{q, 2, 3-CH 2} S-, J = 13Hz), 5.10 (d, 1, C 6 -H, J = 5Hz), 5.70 (q, 1, C 7 -H, J = 5Hz, J = 9Hz ), 6.92 (d, 2, thiophene 3- and 4-H), 7.37 (t, 1, thiophene 5-H) and 9.10 (d, a, -CH ₂ CONH, J = 9 Hz).

[Example 20]

(1-methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3 - < / RTI > cephem-4-carboxylic acid.

2.0 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 1.2 g (10 mmol) of 1-methyl-1H-tetrazole- Is added to 25 ml of 2-trichloroethane, and the mixture is heated at 100 to 101 DEG C for 4 hours while stirring at 100 to 101 DEG C, followed by TLC. It can be seen that the starting material, cephalosporanic acid, remains in the TLC. The reaction mixture is cooled to room temperature with stirring. Crystals are added and the reaction mixture is stirred overnight to crystallize the product. The solvent is removed by evaporation and 25 ml of 1, 2-dichloroethane are added. Again filtered

[Example 21]

(1-methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2-methyl- (2-thienyl) acetamido) -3-cephem-4-carboxylic acid.

(A) 7- (2- (2-thienyl) acetamido) 2.0 g (5 mmol) cephalosporanic acid and 1.2 g (10 mmol) 1- methyl- Add 25 ml of ketone and reflux for 48 hours. TLC shows only trace amounts of the starting material cepharosporanic acid. The reaction mixture is washed with a solution of 2.5 g of sodium bicarbonate dissolved in 50 ml of water, the aqueous layer is treated with 1 g of carbon, and then 50 ml of ethyl acetate is added. The pH is lowered to 1.6 with 30 ml of water and 4 ml of methanesulfonic acid. The ethyl acetate layer is dehydrated with sodium sulfate and the oil is obtained on a rotary evaporator. The product is dissolved in 50 ml of ether to make crystals. The product is separated by filtration, washed and dried in vacuo to give 0.94 g (yield: 41.6%).

The analytical value of NMR was the same as that of the product of Example 5.

(B) The reaction is repeated using the same starting materials and amounts as in (A), except that 50 ml of 1, 1, 2-trichlorethylene is used as the solvent. The reaction mixture was refluxed for 16 h, at which time TLC showed no cephalosporanic acid as starting material. The product is isolated as described in part (A) to give 0.47 g (Yield: 20.8%). The NMR analysis was the same as the NMR analysis of the product of Example 5.

[Example 22]

(1-methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2-phenylacetamido) -7-methoxy- -4-carboxylic acid.

(0.5 mmol) of 7- (2-phenylacetamido) -7-methoxycephalosporanic acid, 87 mg (0.75 mmol) of 1-methyl-1H-tetrazole-5-thiol and 15 ml of 1,2- And refluxed for 6 hours in the presence of nitrogen. At this time, as a result of TLC, there was a trace amount of cephalosporanic acid starting material. To this was added 29 mg (0.25 mmol) of 1-methyl-1H-tetrazole-5-thiol and the reaction mixture was further refluxed for 3 hours. There was no appreciable change in TLC. The reaction mixture is washed four times with saturated sodium bicarbonate and the bicarbonate layer is washed three times with ethyl acetate, then ethyl acetate is added again and cooled to 0 < 0 > C. The pH is adjusted to 2.2 with 20% hydrochloric acid and the layers are separated. The aqueous layer was washed with ethyl acetate, and the combined acetate layers were washed with saturated sodium chloride, dehydrated with magnesium sulfate, filtered and evaporated to leave a pale green residue on the foam. 199 mg (83.6% yield). The product is identified by TLC and NMR.

NMR (CDCl ₃ + 1d acetone _{-d 6) δ3.45 (S, 3} , -OCH 3), 3.55 (S, 2, 2-CH 2), 3.75 (S, 2, ψCH 2 CO-), 3.9 ( S, 3, on the tetrazole _{CH 3), 4.4 (S,} 2, 3-CH 2 -S-), 5.15 (S, 1, C 6 -H) 7.35 (S, 5, ψ), 8.0 (S, 1, -CH ₂ CONH-, and 11.2 (S, 1, J = O Hz, -COOH).

[Example 23]

Preparation of 3 - (((2-benzthiazolyl) thio) -7- (2- (2-thienyl) acetamido) -3-cephem-4-carboxylic acid in 2-dichloroethane .

1.2 g (2.5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 0.625 g (3.75 mmol) of 2- and mercaptobenzothiazole were placed in a flask and air replaced with nitrogen After adding 25 ml of 1, 2-dichloroethane, the reaction mixture is refluxed with stirring for 24 hours. The reaction mixture is cooled and filtered to give 1.1 g (yield: 88%) of the product as off-white material. Melting point: 190.5-191 占 폚 (decomposition)

And dried overnight at 40 캜 in a vacuum to prepare an analytical sample. The product is identified by NHR, UV, mass spectrometry, IR and elemental analysis.

_{NMR (DMSO-d 6) δ3.74} (S, 2, 2-CH 2), 3.80 (S, 2, -CH 2 CONH-), 4.58 (q, 2, 3-CH 2 s-, J = 13Hz ), 5.14 (d, 1, C 6 -H, J = 5Hz), 5.73 (q, 1, C 7 -H), J = 5Hz, J = 8Hz), 6.96, 7.43 and 7.96 (each m, phenyl and Thienyl ring), 9.10 (d, 1, -CH ₂ CONH-, J = 8 Hz).

[Example 24]

1 - ((5-N-methylacetamido) 1,3,4-thiadiazol-2-yl) thio) methyl-7- (2- ) Acetamido) -3-cephem-4-carboxylic acid.

(5 mmol) and 5-N-methylacetamido) 1,3,4-thiadiazole-2-thiol 1.42 (5 mmol) g (7.5 mmol) of 1, 2-dichloroethane was added, and the reaction mixture was refluxed for 10 hours. The reaction mixture was cooled, filtered, washed with 1, 2-dichloroethane, and then vacuum-dried to obtain 2.06 g (yield: 78.3%). The product is identified by IR, UV, NHR, mass spectroscopy and elemental analysis.

_{NMR (DMSO-d 6) δ2.42} (S, 3, -COCH 3), 3.74 (m, 7, 2-CH 2, the tetrazole -CH ₃ - and _{-CH 2 CONH-, 4.35 (q,} 2 _{, 3-CH 2, J =} 13Hz), 5.10 (d, 1, C 6 -H, J = 5Hz), 5.70 (q, 1, C 7 -H, J = 5Hz, J = 9Hz), 6.96, 7.36 (Each m, 3, thiophene H) and 9.10 (d, 1, -CH ₂ CONH-, J = 9 Hz).

[Example 25]

Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (N-tert-butoxycarbonyl) -2-phenylglycine Amide) -3-cephem-4-carboxylic acid.

45 ml of 1, 2-dichloroethane are refluxed to remove the water solvent azeotropic mixture, and the mixture is cooled by distillation until the volume of the solution becomes 30 ml. 235 mg (0.5 mmol) of cefacrosporanic acid was added and the solution was further distilled to 15 ml and the reaction mixture was refluxed in the presence of nitrogen TLC. At the 16th hour, only traces of starting material appeared when TLC was performed. The reaction mixture is washed three times with saturated sodium bicarbonate, the bicarbonate layers are combined and washed twice with ethyl acetate. To the washed bicarbonate layer was added ethyl <

The product is identified by TIC and NMR. A small amount (less than 10%) of cephalosporanic acid, the starting material, was found in NMR. The product is suspended in 10 ml of diethyl ether and ground for 1 hour. The ether is decanted off, 10 ml of diethyl ether is added, the mixture is ground for 1 hour, the ether is tilted, evaporated to dryness to give a white powder product. The product is identified by TLC and NMR.

), 5.75(q, 1, J=4Hz, C₇-H), 6.2(d, 1, J=8Hz,

), 7.4(s, 5, ψ), 7.65(d, 1, J=8Hz, -CONH 및 ~9.3(s, 1, COOH). _{NMR (CDCl 3) δ 1.45 (} s, 9, -COO 3 Grade _{C 4 H 9), 3.6 (} s, 2, 2-CH 2), 3.95 (s, 3, of the tetrazol-CH _3), 4.3 (s _{, 2, 3-CH 2 S-} ), 4.9 (d, 1, J = 5Hz, C 6 -H), 5.4 (d, 1, J = 8Hz,

), 5.75 (q, 1, J = 4 Hz, C ₇ -H), 6.2 (d,

), 7.4 (s, 5,?), 7.65 (d, 1, J = 8 Hz, -CONH and ~9.3 (s, 1, COOH).

[Example 26]

Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (N-tert-butoxycarbonyl) -2- (p- Hydroxyphenyl) glycylamide-3-cephem-4-carboxylic acid.

1, 45 ml of 2-dichloroethane is refluxed with a trap, and 15 ml of solvent is removed. The remaining 30 ml was cooled, and 260.5 mg (0.5 mmol) of 7- (N-tert-butoxycarbonyl) -2- (p-hydrophenyl) -glycylamidocephalosporanic acid , The solution is further distilled to leave 15 ml and then cooled again. 87 mg (0.75 mmol) of 1-methyl-1H-tetrazole-5-thiol are added and the reaction mixture is heated to 65-70 ° C. before TLC. After 3 hours, TLC showed that the starting material was almost absent. The reaction mixture is TLC at the end of 4 h.

The performance and purification of the reaction are carried out as described in the above examples. The yield is 189 mg (65.5%) as the crude product and 46 mg (about 16%) of the purified product.

), 5.75(d, 1, J=6Hz,

), 6.4(s, 1, COCH), 6.8(d, 2, J=8Hz,

) 및 7.9(d, 1, -CONH-).NMR (CDCl ₃ + 2d acetone _{d 6) δ 1.45 (s,} 9, -COO 3 Grade _{C 4 H 9), 3.35 (} s, 2, 2-CH 2), 3.85 (s, ₃ of CH 3, tetrazol ), 4.3 (s, 2, 3-CH 2 S-), 4.9 (d, 1, J = 6Hz, C 6 -H), 5.3 (q, 1, J = 3Hz, C 7 -H), 5.4 ( s, 1,

), 5.75 (d, 1, J = 6 Hz,

), 6.4 (s, 1, COCH), 6.8 (d, 2, J = 8 Hz,

) And 7.9 (d, 1, -CONH-).

[Example 27]

Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2-phenoxyacetamido) -3-cephem- Recipe.

60 ml of 1, 2-dichloroethane is refluxed with a trap, 15 ml of the solvent is removed, and the remaining 45 ml is cooled.

7 (2-phenoxyacetamido) cephalosporanic acid (406 mg, 1 mmol) was added, the solution was further distilled, concentrated to 30 ml and cooled again. 174 mg (1.5 mmol) of 1-methyl-1H-tetrazole-5-thiol are added and the reaction mixture is refluxed in the presence of nitrogen for 12 hours.

At this time, TLC with a mixed solvent of 10: 3 diethyl ether: (3: 1 = acetic acid: water) showed that an excessive amount of thiol, a small amount of cephalosporanic acid and an unknown compound were present in the product. The reaction mixture is carried out in the manner described in the two examples above. The TLC of the final product was found to be the same as that of the product prepared by the method of the prior art.

_{NMR (CDCl 3) δ 3.65 (} s, 2, 2-CH 2), 3.9 (s, ₃ of CH 3, tetrazole), 4.35 (s, 2, 3-CH 2 S-), 4.65 (s, 2 _{, ψOCH 2), 5.1 (d} , 1, J = 4Hz, C 6 -H), 5.9 (q, 1, J = 4Hz, C 7 -H), 7.1 (m, 5, ψ-), 7.6 (d , 1, J = 10 Hz, -CONH-), and ~ 9 (s, 1, COOH).

[Examples 28-31]

Methyl-1H- tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem- Recipe.

(2-thienyl) acetamido) -3-cephem-4-carboxylic acid was prepared by the same method as in Separosporanic acid is used as the starting material and produced in four different reactions.

28: 3- (Propionyloxymethyl) -7- (2- (2-thienyl) acetamido) -3-cephem-4-carboxylic acid (41 mg: 0.1 mmol).

29: 3- (2-Methylpropionyloxymethyl) -7- (2- (2-thienyl) -acetamido) -3-cephem-4- carboxylic acid (42 mg; 0.1 mmol).

30: 3- (n-Butyloxymethyl) -7- (2- (2-thienyl) acetamido) -3-cephem-4- carboxylic acid (42 mg: 0.1 mmol).

31: 3-Cyclobutylcarbonyloxymethyl) -7- (2- (2-thienyl) -acetamido) -3-cephem-4- carboxylic acid (43 mg: 0.1 mmol).

Each compound was suspended in 10 ml of a flow of benzene (dehydrated with an aluminosilicate dehydrating agent commercially available under the trade name 4-A Lindde molecular sieves) and 18 mg (0.15 mmol) of 1-methyl-1H-tetrazole- After each addition, the reaction mixture is refluxed for 24 hours.

The precipitated product in each reaction is separated by filtration and dried. The product was found to be displaced by TLC (using ethyl acetate: acetic acid) in a quantitative manner.

The NMR of each product was consistent with the NMR indicated in the sample of the product prepared by aqueous substitution.

[Example 32]

(3-methyl-1,2,4-oxadiazol-5-yl) thio) methyl) -7- (2- (2-thienyl) Amide) -3-cephem-4-carboxylic acid.

396 mg (1 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid was suspended in 40 ml of 1,1, 2-trichloroethane and 3-methyl-1,2,4- 116 mg (1 mmol) of the sol-5-thiol are added. The reaction mixture is heated on an oil bath at 113 [deg.] C for 3 hours, allowed to stand overnight, cooled and evaporated to obtain an oil phase.

Ethyl acetate and saturated sodium bicarbonate were added and the ethyl acetate layer was washed again with saturated sodium bicarbonate, then the combined aqueous layers were extracted with ethyl acetate. The aqueous layer is again treated with ethyl acetate, cooled on ice-bath and the pH is adjusted to 2.5 with 20% hydrochloric acid. The layers are separated and the aqueous layer is extracted again. The ethyl acetate layer is washed and the sodium hypochlorite is combined, dehydrated with magnesium sulfate, filtered and evaporated.

When 1,1,1,2-trichloroethane is added to the residue, a solid product is formed. Yield: 220 mg (48%).

NMR, IR, UV and bio-agram are used to identify the product.

_{NMR (DMSO-d 6) δ} 2.35 (s, CH 3 on the third, oxadiazole), 3.7 (q, 2, J = 18Hz, 2-CH 2), 3.8 (s, 2, -CH 2 CONH-) , 4.4 (q, 2, J = 14Hz, 3-CH 2 S-), 5.1 (d, 1, J = 5Hz, C 6 -H), 5.6 (q, 1, J = 4Hz, C 7 -H) , 6.9, 7.3 (t, d, 3, thiophene H), and 9.1 (d, 1, J = 8 Hz, -CH ₂ CONH).

[Example 33]

((1H-1,3,4-triazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido- Preparation of 3-cephem-4-carboxylic acid.

396 mg (1 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid was suspended in 30 ml of 1,1,2-trichloroethane and 1H-1,3,4- 100 mg (1 mmol) of 5-thiol are added. The reaction mixture is heated to 105 < 0 > C within 30 minutes to precipitate the product. Heating is continued again at 100 DEG C for 6 hours, and the reaction mixture is cooled to room temperature. The product was collected by filtration and washed with 1, 1, 2-trichloroethane to obtain 380 mg (yield: 87%).

The product is identified by IR, NMR, UV and biotite. Also in biotoglomer, the presence of the cephalosporanic acid starting material was found and 6.8% of the cephalosporanic acid was present in high pressure liquid chromatography.

) 및 9.13(d, 1, J=8Hz, -CH₂CONH). _{NMR (DMSO-d 6) δ} 3.7 (s, 2, 2-CH 2), 3.88 (s, 2, -CH 2 CONH-), 4.2 (q, 2, J = 5Hz, 3-CH 2 S-) , 5.1 (d, 1, J = 5 Hz, C ₆ -H), 5.7 (q, 1, J = 4 Hz, C ₇ -H), 7.0, 7.4 (t, s, 3, triazole

) And 9.13 (d, 1, J = 8 Hz, -CH ₂ CONH).

[Example 34]

Preparation of 3 - (((1-methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2-phenylacetamido-3-cephem-4-carboxylic acid in chloroform.

195 mg (0.5 mmol) of 7- (2-phenylacetamido) cephalosporanic acid are suspended in 75 ml of chloroform and 75 mg (0.65 mmol) of 1-methyl-1H-tetrazole-5-thiol are added. The reaction mixture is heated on an oil bath to 80-85 < 0 > C for 3 hours and 60 ml is distilled. TLC shows very small amounts of product, where 20 ml of 1, 2-dichloroethane are added and heating is continued overnight, and the reaction mixture is then subjected to TLC to confirm that a small amount of starting material of the cephalosporanic acid is present. After a total reaction time of 26 hours, the reaction mixture is cooled to room temperature. The product is obtained in the same manner as described in Example 32 to give 80 mg of the purified material (yield: 35%).

NMR, IR, UV and bio-agram are used to identify the product.

NMR (DMSO-d ₆ )? 3.6 (s, 2, 2-CH ₂ ), 3.7 (s, 2 -CH ₂ CONH-), 4.0 (s, 3, CH ₃ on tetrazole) _{, 3-CH 2 S-),} 5.1 (d, 1, J = 5Hz, C 6 -H), 5.7 (q, 1, J = 4Hz, C 7 -H), 7.3 (s, 5, ψ) , and 9.13 (s, 1, J = 8Hz, -CH 2 CONH).

[Example 35]

Preparation of 3 - (((1-methyl-1H-tetrazol-5-yl) thio) methyl) -7-acetamido-3-cephem-4-carboxylic acid in 2-dichloroethane.

314 mg (1 mmol) of 7-acetamidoseparosporanic acid and 98 mg (0.65 mmol) of 1-methyl-1H-tetrazole-5-thiol were added to 70 ml of 1,2-dichloroethane and 50 ml of the mixture was distilled The reaction mixture is refluxed for 24 hours. The reaction mixture is carried out in the same manner as in Example 32 to give 120 mg (yield: 32%) of the product.

NMR, IR, UV and bio-agram are used to identify the product.

_{NMR (DMSO-d 6) δ} 1.97 (s, 3, CH 3 CONH-), 3.7 (s, 2, 2-CH 2), 4.0 (s, 3, CH 3 on tetrazole), 4.35 (s, 2 _{, 3-CH 2 S-),} 5.1 (d, 1, J = 5Hz, C 6 -H), 5.7 (q, 1, J = 4Hz, C 7 -H) , and 8.8 (d, 1, J = 8Hz , -CH ₂ CONH).

[Example 36]

(3-methyl-1,2,4-thiadiazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido ) -3-cephem-4-carboxylic acid.

(0.5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 85 mg (0.65 mmol) of 3-methyl-1,2,4-methylthiadiazol- 1. Add 50 ml of 2-dichloroethane and mix, then heat to 95 ° C on oil bath. The temperature of the base phase is maintained at 90 占 폚 for 19 hours. The reaction mixture is transferred from the bath, allowed to cool, then placed in a cold for 1 day. Add 3 volumes of ethyl acetate and wash twice with 50 ml each of saturated sodium bicarbonate.

The combined aqueous solution is treated with ethyl acetate and then cooled on an ice bath. The pH is adjusted to 2.0, the layers are separated and the aqueous layer is extracted again with ethyl acetate. The combined ethyl acetate is washed with saturated sodium chloride, dehydrated with magnesium sulfate, filtered and evaporated to give 252 mg of the product as a foam. Crystallization with a mixed solvent of acetone: diethyl ether afforded 153 mg (Yield: 65%).

NMR, IR, UV and bio-agram are used to identify the product.

_{NMR (DMSO-d 6) δ} 3.7 (s, 2, 2-CH 2), 3.8 (s, 2, -CH 2 CONH), 4.5 (q, 2, J = 5Hz, 3-CH 2 S-), 5.1 (d, 1, J = 5Hz, C 6 -H), 5.7 (q, 1, J = 4Hz, C 7 -H), 6.96, 7.38 (t, d, 3, thiophene H) and 9.13 (d , 1, J = 8Hz, -CH 2 CONH).

[Example 37]

Preparation of 3 - (((2-pyrimidinyl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem-4- carboxylic acid in acetonitrile.

2.0 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 0.62 g (5.5 mmol) of 2-methacrylopyrimidine were added to 25 ml of anhydrous acetonitrile, Is refluxed with stirring overnight (16 hours). TLC confirmed complete conversion of the mixture to the product. The reaction mixture is cooled to room temperature and filtered to separate the product, which is washed with 50 ml of acetonitrile and vacuum dried at 50 ° C for 4 hours to give 1.86 g (yield: 83.0%) of off-white crystalline material. Melting point: 217 캜 (decomposition).

In DMSO-d ₆ NMR did not show any of the starting materials.

The product is identified by IR, UV and NMR.

_{NMR (DMSO-d 6) δ} 3.55 (q, 2, 2-CH 2, J = 18Hz), 3.74 (s, 2, -CH 2 CONH), 4.28 (q, 2, 3-CH 2 S-, J = 13Hz), 5.00 (d, 1, C 6 -H, J = 5Hz), 5.64 (q, 1, C 7 -H, J = 5Hz) J = 9Hz, 7.08 (m) and 8.52 (d) (6 , Thiophene and pyrimidine H) and 9.00 (d, 1, -CH ₂ CONH, J = 9 Hz).

[Example 38]

Preparation of 3 - (((2-pyrimidinyl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem-4- carboxylic acid in acetic acid.

2.0 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid, 0.6 g (5.4 mmol) of 2-methacrylopyrimidine and 0.41 g (5 mmol) And heated at 85 캜 for 4 hours. The product crystallizes during the reaction. The reaction mixture is cooled to room temperature and filtered to separate the product, which is washed with acetic acid and dried to give 1.58 g (Yield: 70.5%) of white crystalline material.

Melting point: 218 캜 (decomposition).

IR, UV and NMR and elemental analysis are performed to confirm the product.

The NMR was the same as the NMR of the product of Run-37.

[Example 39]

Preparation of 3 - (((1-methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) cephalosporanic acid in acetic acid.

2.0 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid, 0.81 g (7 mmol) of 1-methyl-1H- tetrazole-5-thiol and 0.41 g 5 mmol) is added to 25 ml of glacial acetic acid and heated to 75-77 [deg.] C for 8 hours. When TLC was performed every hour, the reaction was completed at TLC at 8 hours. The reaction mixture is cooled to 40-45 < 0 > C and the acetic acid is removed under vacuum. 50 ml of ethyl acetate and 50 ml of water are added to the residue, and the aqueous layer is adjusted to pH 1.5 with 1 N sulfuric acid. The ethyl acetate layer was separated and dehydrated with anhydrous sodium sulfate, and then the ethyl acetate was removed with a rotary evaporator. A trace amount of the oil residue is redissolved in 50 ml of ethanol and a solution of 2 ml (10.2 mmol) of dicyclohexylamine in 10 ml of ethanol is added thereto. The product precipitates immediately as the dicyclohexylamine salt. Stirring is continued for 15 minutes, the product is separated by filtration, washed with ethanol and dried to obtain 1.2 g (yield: 37.8%). Boiling point: 185 to 186 ° C.

IR, NMR and UV were consistent with the same product samples prepared above.

[Example 40]

(1-benzyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem in 1, 2- -4-carboxylic acid.

2.0 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid were added to 25 ml of 1,2-dichloroethane and the reaction mixture was heated to 85 ° C on an oil bath, Keep this temperature overnight.

As a result of TLC, the starting material, cephalosporanic acid, did not appear. Removal of the dissolution with a rotary evaporator leaves a residue on the foam. To this is added 15 ml of methanol and warmed on a steam bath until the mixture is dissolved.

When the solvent is evaporated with a rotary evaporator, the product is crystallized. The product was stirred for 15 minutes and then filtered to separate the product. The product was washed with methanol and vacuum dried to obtain 1.6 g (yield: 60.6%).

Melting point: 171-171.5 < 0 > C.

[Example 41]

Preparation of 3-amidinothiomethyl-7- (2- (2-thienyl) acetamido) -3-cephem-4-carboxylic acid in acetonitrile.

3.12 g (8 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 912 mg (12 mmol) of thiourea were dissolved in acetonitrile (trade name: Aluminosilicate Dehydrated with dehydrating agent) and heated to 87 DEG C for 24 hours with stirring. Within 1 hour the precipitate begins to form in the reaction mixture. At the end of 24 hours, the hot reaction mixture is filtered to separate the product and then dried to obtain 2.5 g (yield: 76%).

Elemental analysis:

LRonci: C 43.68, H 3.91, N 13.58

Actual value: C 43.50, H 4.03, N 13.29

The product is identified by NMR.

[Example 42]

Preparation of 3-Benzoylthiomethyl-7- (2- (2-thienyl) acetamido) -3-cephem-4-carboxylic acid in isopropyl acetate.

3.12 g (8 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 510 mg (3.7 mmol) of thiobenzoic acid are suspended in 20 ml of isopropyl acetate anhydride, . At this time, all the reactants are in a solution state. The solvent was evaporated in vacuo and the TLC of the remaining residue showed that the product and unreacted starting material were present as a 60:40 mixture. Acetone as elution agent; Acetic acid = 16: 1 is used, and the product is purified by preparative thin-layer chromatography on a silica plate.

_{NMR (DMSO-d 6 / D} 2 O) δ 3.50 (ABq, 2H, z-CH 2, J = 6Hz, J = 19Hz), 3.82 (s, 2H, -CH 2 CONH-), 4.20 (d, 2H _{, 3-CH 2 S-, J} = 5Hz), 5.03 (d, 1H, C 6 -H, J = 5Hz), 5.69 (d, 1H, C 7 -H, J = 5Hz) 6.89-8.0 (m, 8H, aromatic H).

[Example 43]

Preparation of 3 - ((phenylthio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem-4-carboxylic acid in 1, 2-dichloroethane.

2.0 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 0.75 ml (7.5 mmol) of benzenethiol are added to 25 ml of 1,2-dichloroethane. The reaction mixture was refluxed overnight and TLC showed that no starting material, cephalosporanic acid, remained. The solvent is evaporated with a rotary evaporator, 25 ml of ethanol is added to the residue, and the residue is heated to obtain a partially residue. To obtain a complete solution, add 25 ml of methanol and heat.

The resulting solution was filtered through cotton, treated with 2.0 g of carbon, stirred for 5 minutes, and filtered through a filter aid. Solvent was removed with a rotary evaporator and the residue was NMR to confirm the presence of some thiol starting material. The residue is treated with 25 ml of isopropyl acetate, filtered and placed in a cry overnight. The filtrate is diluted with 25 ml of ethyl acetate and washed with 25 ml of dilute sodium bicarbonate to remove the thiol. The ethyl acetate layer is then added with 25 ml of water and the pH 8.5 is adjusted to 1.4 with sulfuric acid. The ethyl acetate layer was washed with sulfuric acid

_{NMR (DMSO-d 6) δ3.58} (m, 2, 2-CH 2,), 3.75 (s, 2, -CH 2 CONH-), 4.12 (q, 2, 3-CH 2 S-, J = 13Hz), 5.08 (d, 1 , C 6 -H, J = 5Hz), 5.66 (q, 1, C 7 -H, J = 5Hz, J = 9Hz), 7.15 (m, 8, thiophene and phenyl H H), and 9.10 (d, 1, -CH ₂ CONH-, J = 9 Hz).

[Example 44]

(2-phenylacetamido) -3-cephem-1, 2-dichloroethane in the presence of 3 - ((5-methyl- Preparation of 4-carboxylic acid.

19.5 g (5 mmol) of 7- (2-phenylacetamido) cephalosporanic acid and 0.99 g (7.5 mmol) of 5-methyl-1,3,4-thiadiazole-2-thiol were dissolved in 1,2- Ethane and refluxed for 16 hours. As a result of TLC, it was found that there was a trace amount of Cephalosporanic acid starting material. The product crystallizes during the course of the reaction. The reaction mixture is cooled to 0-5 < 0 > C and filtered, and the product is washed with cold 1,2-dichloroethane and dried in vacuo to give 1.82 g (yield: 78.8%). Melting point 171-172 ° C

_{NMR (DMSO-d 6) 2.70} (s, 3, of jolil thiadiazole _{-CH 3), 3.58 (s,} 2, -CH 2 CONH-), 3.70 ( broad _{s, 2, 2-CH 2} ), 4.40 ( _{q, 2, 3-CH 2} S-, J = 13Hz), 5.12 (d, 1, C 6 -H, J = 5Hz), 5.72 (q, 1, C 7 -H, J = 5Hz, J = 9Hz ), 7.28 (s, 5, phenyl H), and 9.08 (d, 1, -CH ₂ CONH-, J = 9 Hz).

[Example 45]

Preparation of 3 - ((methylthio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem-4-carboxylic acid in methylene chloride.

24 g (60 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid, 7.0 ml of methanethiol and 600 ml of methylene chloride were stirred and heated in a bomb at 84-86 DEG C for 18 hours The reaction mixture is cooled to room temperature.

A small amount of insoluble matter is filtered out, and the filtrate is evaporated. The residue is treated with ethyl acetate and heated. 150 ml of water is added to the filtrate to form a layer, which is then stirred, and 1N sodium hydroxide is added dropwise to adjust the pH to 5.5. Separate the aqueous phase, concentrate to about 75 ml, and dilute with water to 700 ml. The pH is adjusted to 3.8 by adding glacial acetic acid. The precipitated amorphous solid material is stirred on an ice bath for 3 hours and placed in a cry overnight. The solid material is filtered off and the filtrate is diluted with 100 ml of ethyl acetate and adjusted to pH 2.0 with concentrated hydrochloric acid. The organic phase is separated and extracted once with 150 ml of ethyl acetate once with 100 ml of ethyl acetate. The combined organic phases are dehydrated with magnesium sulfate and the solvent is removed to give an amber foamy substance. This material is dissolved in 50 ml of ethyl acetate, crystal nuclei are added to the desired product, and crystals are formed when the crystals are left in a dark overnight. The crystals were separated by filtration, washed with cold isopropyl acetate and dried in vacuo at 50 DEG C to give 3.2 g (yield: 14%).

The product is identified by NMR.

_{NMR (DMSO-d 6) δ2.00} (s, 3, 3-CH 2 SCH 3), 3.74 (m, 3-CH 2 S, 2-CH 2 and _{-CH 2 CONH-), 5.14 (d} , 1 _{, C 6 -H, J = 5Hz} ), 6.64 (q, 1, C 7 -H, J = 5Hz, J = 9Hz), 7.15 (m, 3, thiophene H) and 9.12 (d, 1, -CH ₂ CONH-, J = 9 Hz).

[Example 46]

A solution of 7- (2-formyloxy-2-phenylacetamido) -3 - (((1 -methyl-1 H-tetrazol-5-yl) thio) Preparation of sodium salt.

2.77 g (4.65 mmol) of 7- (2-formyloxy-2-phenylacetamido) cephalosporanic acid and 0. 87 g (7.5 mmol) of 1-methyl-1H-tetrazole- Benzene and refluxed at about 80 < 0 > C for 12 hours. During the reaction, a soft plastic layer is deposited in the glass container. As it cools, the soft plastic layer is deposited in the glass container while the plastic material is solid on the glass. As it cools, the plastic material cures to a solid material in the form of glass. Only a trace amount of the product was contained in the solution by TLC, and most of the plastic material was found to be a deformed product. The reaction mixture was dissolved in 35 ml of anhydrous acetone, which was obtained by adding acetone to the reaction mixture, and treated with 10 ml of a solution of 1.25 g (7.5 mmol) of sodium 2-ethylhexanoate dissolved in acetone. The product crystallizes as a sodium salt. After one hour, the product is filtered, washed with 20 ml of acetone and dried to give 1.38 g (yield: 58%).

The product is identified by TLC and NMR.

3. 48(q, 2,2-CH₂, J=18Hz), 4. 00(s, 3, 테트라졸일의 -CH₃), 4. 10(m, 2, 3-CH₂S-), 5. 05(d, 1, C₆H, J=5Hz), 5. 70(d, 1, C₇-H, J=5Hz), 6. 24(s, 1, -CH₂CONH-), 7. 50(m, 5, 페닐 H) 및 8. 33g(s, 1,

)NMR (D ₂ O)

3. 48 (q, 2,2-CH 2, J = 18Hz), 4. 00 (s, 3, -CH 3 of tetrazolyl), 4. 10 (m, 2 , 3-CH 2 S-), 5. 05 (d, 1, C 6 H, J = 5Hz), 5. 70 (d, 1, C 7 -H, J = 5Hz), 6. 24 (s, 1, -CH 2 CONH-), 7. 50 (m, 5, phenyl H) and 8.33 g (s, 1,

)

[Example 47]

(1-methyl- (1H-tetrazol-1-yl) thio) methyl) -3-cephem- Preparation of 4-carboxylic acid.

2.87 g (4.65 mmol) of 7- (2-formyloxy-2-phenylacetamido) -ceparosporanic acid and 0. 87 g of 1-methyl-1H-tetrazole-5-thiol in 25 ml of carbon tetrachloride And refluxed at about 77 캜 for 12 hours. The reaction mixture is cooled to room temperature and the supernatant is tilted away from the cured semi-solid material. Addition of 25 ml of 1,2-dichloroethane to this solid material causes the product to crystallize. The reaction mixture was cooled to room temperature, stirred for about 1 hour and then filtered to separate the product, washed with 10 ml of 1,2-dichloroethane, and then vacuumed at 45 [

NMR and TLC are performed to confirm the product.

A small amount of the deformylated product appeared on the TLC.

The NMR was consistent with the NMR of the product of Example 16.

[Example 48]

Preparation of 3-methyl-1,2,4-oxadiazole-5-thiol.

30 ml of acetamidooxime (0.4 mmol), 100 ml (1.66 mmol) of carbon disulfide and 56 ml (0.4 mmol) of triethylamine are added to 1 liter of pyridine and mixed. Nitrogen gas is passed through the carbon disulfide solution into the reaction mixture. The mixture is heated on an oil bath at 70 占 폚 for 3 days and evaporated to obtain an oily substance. Here, ethyl acetate and saturated sodium bicarbonate are added. The sides are separated and the organic layer is washed again with saturated sodium bicarbonate. The combined sodium bicarbonate washings are extracted with ethyl acetate and the ethyl acetate extract is discarded. The aqueous portion is again layered with ethyl acetate and allowed to cool on an ice bath. After adjusting to pH 2.5 with 20% hydrochloric acid, sodium chloride is added to the saturated solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, and dehydrated with anhydrous magnesium sulfate. The solution is filtered and evaporated to half of its original volume. A carbon tetrachloride equivalent is added and the product is continuously evaporated until crystallization to give 24.8 g (52% yield).

[Example 49]

(3-methyl 1,2,4-oxathiazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) 1,2- -3-cephem-4-carboxylic acid.

100 mg (0.25 mmol) of 7- (2- (2-thienyl) acetamido) -3- (carbamoyloxymethyl) -3-cephem-4- carboxylic acid was suspended in 25 ml of 1,2- , 35 mg (0.30 mmol) of 1,2,4-oxadiazole-5-thiol are added with stirring. The reaction mixture is heated to 110 DEG C on an oil bath and 5 ml of a solvent containing a small amount of water is distilled. The oil bath temperature is lowered to 90-95 < 0 > C, at which the reaction mixture is maintained for 19 hours and then cooled to room temperature. Filter to remove insoluble material and wash with 1,2-dichloroethane and diethyl ether. As a TLC,

The filtrate is evaporated and the residue oil is partitioned with sodium bicarbonate solution and ethyl acetate. The aqueous solution is further added with ethyl acetate to form a layer, cooled on an ice bath, adjusted to pH 2.5 with 20% hydrochloric acid, and then the organic layer is removed. The aqueous layer was extracted again with ethyl acetate, and the combined ethyl acetate solution was washed with saturated sodium chloride, dehydrated with magnesium sulfate, filtered and evaporated to obtain an oily substance. Crystallization with a 1: 1 solution of hexane and diethyl ether gives 13 mg (11.5% yield) of product. Generated with NMR and IR

[Example 50]

Methyl-1H- tetrazol-5-yl) thio) methyl) -7- (2- (tert- butoxycarbonyl) -2-phenylacetamido) - Preparation of 3-cephem-4-carboxylic acid.

(49 mmol) of 4- (2- (tert-butoxycarbonyl) -2-phenylacetamido) -separosporanic acid and 145 mg (1.25 mmol) of 1-methyl-1H-tetrazole- Mmol) are added to 15 ml of anhydrous nitromethane and heated at 85-90 < 0 > C for 8 hours in the presence of nitrogen. TLC showed excessive thiol reactants and decarboxylated products, but no cephalosporanic acid starting material. Nitromethane is removed by evaporation. The orange foamed beverage is dissolved in 10 ml of saturated sodium bicarbonate, 20 ml of water are added and the reaction mixture is washed successively with ethyl acetate until the washings are clear.

Add the ethyl acetate wash, add 20 ml of water, cool the mixture to 0 ° C and adjust to pH 2.2 with 20% hydrochloric acid. The layers are separated and the aqueous layer is washed with ethyl acetate. The ethyl acetate washings are combined, washed with saturated sodium chloride, and then dried over magnesium sulfate, filtered and evaporated to give 455 mg of brown foam (yield 83%). In TLC, there was a trace amount of thiol and decarboxylated product in addition to the product. 455 mg (0.88 mmol) of the product was dissolved in 7 ml of ethyl acetate and 0. 833 ml of lithium acetate was added with stirring

The product is identified by TLC, NMR, bio-agram, elemental analysis, IR and UV. TLC revealed a trace of decarboxylated sulfurized material.

1.4(s, 9, -COO3급 C₄H₉), 3.6(s, 2,2-CH₂), 3. 85(s, 3, 테트라졸의 CH₃), 4.3(s, 2, 3-CH₂S-), 4. 44 및 4. 45 (2s, 1,

C₁H-) 4. 9(d, 1, J=6Hz, C₆-H), 5. 8(q, 1, J=6Hz, C₇-H), 7. 35(s, 5,

), 8.2 및 7.8(2d, 1, J=9Hz, -CONH-) 및 9.3(s, 1, -COOH).NMR (CDCl ₃₎

1.4 (s, 9, -COO3 tert _{C 4 H 9), 3.6 (} s, 2,2-CH 2), 3. 85 (s, 3, of the _{tetrazol-CH 3), 4.3 (s,} 2, 3- CH ₂ S-), 4.44 and 4.45 (2s, 1,

_{C 1 H-) 4. 9 (d} , 1, J = 6Hz, C 6 -H), 5. 8 (q, 1, J = 6Hz, C 7 -H), 7. 35 (s, 5,

), 8.2 and 7.8 (2d, 1, J = 9 Hz, -CONH-) and 9.3 (s, 1, -COOH).

[Example 51]

Methyl-1H-tetrazol-5-yl) thio) methyl) -7 - ((N- (1,3- dimethylureido) carbonyl) -2-phenylglycine in nitromethane 3-cephem-4-carboxylic acid.

130 mg (0.25 mmol) of 7- (N - ((1,3-dimethylureido) carbonyl) -2-phenylglycylamido) -Tetrazol-5-thiol 43.5 mg (0.375 mmol) are added. The reaction mixture is heated in the presence of nitrogen at 85 占 폚 for 12 hours and then left at room temperature for one week. The reaction mixture was filtered, and the solid material was washed with a small amount of nitromethane and then vacuum-dried in an oven at 35 ° C to give 83 mg (yield: 58%). The product is identified by TLC, NMR, IR, UV, elemental analysis and vio- grams.

2. 65(d, 3, J=4Hz, -CONH CH₃), 3. 15(s, 3, CONH₃CO-), 3. 6(s, 2, 2-CH₂), 3. 9(s, 3, 테트라졸의 CH₃), 4. 3(s, 2, 3-CH₂S-), 5. 0(d, 1, J=5Hz, C₆-H), 5. 5(d, 1, J=7Hz,

), 5. 7(q, 1, C₇-H), 5. 8(q, 1, -CONHCH₃), 7. 4(s, 5,

), 9. 3(d, 1, J=8Hz,

CHCONH-)및 10(d, 1, J=8Hz,“

)NMR (DMSO-d ₆₎

2. 65 (d, 3, J = 4Hz, -CONH CH 3), 3. 15 (s, 3, CONH 3 CO-), 3. 6 (s, 2, 2-CH 2), 3. 9 ( s, 3, CH ₃ on tetrazole), 4. 3 (s, 2, 3 _CH-2 S-), 5. 0 (d, 1, = J 5Hz, C ₆ -H), 5. 5 (d , 1, J = 7 Hz,

), 5.7 (q, 1, C ₇ -H), 5.8 (q, 1, -CONHCH ₃ ), 7.4 (s,

), 9. 3 (d, 1, J = 8 Hz,

CHCONH-) and 10 (d, 1, J = 8 Hz, "

)

[Example 52]

Methyl-1H- tetrazol-5-yl) -thio) methyl) -7- (2- (2-thienyl) acetamido) acetonitrile (with tetrabutylammonium iodide) -3-cephem-4-carboxylic acid.

(5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid, 1.2 g (10 mmol) of 1-methyl-1H-tetrazole-5-thiol, and tetrabutylammonium iodide Are added to 25 ml of anhydrous acetonitrile and mixed and heated at reflux for 8 hours, then the reaction mixture is cooled to room temperature and the solvent is removed by rotary evaporator. The residue is treated with a hot mixture of 25 ml of isopropyl acetate and 5 ml of acetonitrile, filtered and allowed to cool slowly. The product precipitated from the pale cream-colored crystals was filtered off, washed with isopropyl acetate and dried to give 1.30 g (57.5%) of the product. NMR was consistent with NMR of the product of Example 5.

[Example 53]

((1-methyl-1H-tetrazol-5-yl) thio) methyl-7- (2- (2-thienyl) acetamidine -3-cephem-4-carboxylic acid.

The preparation process of Example 52 is repeated using 1,2-dichloroethanol as a solvent. Dicyclohexylamine (2 ml) was added to obtain 1.5 g of a dicyclohexylamine salt (yield: 48.9%). NMR was consistent with NMR of the product of Example 1.

[Example 54]

((Phenylthio) methyl-7- (2- (2-thienyl) acetamido) -methanol in 1,2-dichloroethane (1-methyl- Preparation of 3-cephem-4-carboxylic acid.

(5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid, 0.75 ml (7.5 mmol) of benzenethiol and 1-methyl- Tetrazole (0.65 g) was added to 25 ml of 1,2-dichloroethane, and the mixture was heated to reflux. After TLC, the reaction was completed in 14 hours. Solvent is removed with a rotary evaporator and the residue is extracted repeatedly with diethyl ether. Removal of the solvent gives 1.66 g (74% yield) of a brown solid product. IR and NMR were consistent with the same products prepared by the methods described in the above examples.

[Example 55]

A mixture of 3 - ((1-methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) quite.

2.0 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 0. 87 g (7.5 mmol) of 1-methyl-1H-tetrazole-5-thiol were dissolved in isopropanol , And the mixture is placed in a flask (with a drying tube and a cooler containing commercial anhydrous calcium sulfate sold under the trade name Darierite). The flask is placed on an oil bath at 84 to 85 占 폚. The reaction is confirmed by TLC. After 40 hours at 83 to 83 ° C only the cephalosporanic acid 1/2 was reacted.

[Example 56]

Preparation of 3 - ((2-oxazolylthio) methyl-7- (2- (1H-tetrazol-1-yl) acetamido) -3-cephem-4-carboxylic acid in nitromethane.

0.85 g (1.0 mmol) of 7- (2- (1H-tetrazol-1-yl) acetamido) -ceparosporanic acid and 0.1 g (1.1 mmol) of 2-oxazol- To 5 ml of nitromethane, the mixture is immersed in an oil bath at 90 to 91 ° C. The reaction mixture is left under a nitrogen atmosphere. After 20 minutes the entire reaction is dissolved and after 35 minutes the product is going to crystallize. After 6 hours, the reaction mixture was cooled to room temperature and the product was filtered, washed with 7 ml of nitromethane, dried in air and then dried in vacuo at 40 < 0 > C for 3 hours to give 0.36 g (yield 85.7% . Melting point 196 DEG C (decomposition) NMR showed 70% of the desired product and 30% of the cephalosporanic acid starting material. The product was recrystallized from 5 ml of DMSO-d ₆ and 10 ml of water, separated by filtration and washed with 5 ml of a solution of water: DMSO-d ₆ = 2: 1, followed by air drying and vacuum drying at 50 ° C for 6 hours, Is generated. NMR showed 87% of the desired product and 13% of the starting material cephalosporanic acid. The mixture was stirred again with 3 ml of DMSO-d ₆ and ₆ ml of water for 1 hour, and then recrystallized to obtain 0. 21 g.

3. 75(s, 2, 2-CH₂), 4. 34(q, 2, 3-CH₂S-, J=14Hz), 5. 16(d, 1, C₆-H, J=5Hz), 5. 76(q, 1, C₇-H, J=5Hz, J=9Hz), 5. 44(s, 2, -CH₂CONH-), 7. 28(s, 1, 옥사졸 C₄-H), 8. 14(s, 1, 옥사졸 C₅-H), 9. 37(s, 1, 테트라졸 H), alc 9. 53(d, 1, -CONH-, J=9Hz).NMR showed that the starting material, cephalosporanic acid, was 5% reduced and the desired product was identified by NMR. NMR (DMSO-d ₆₎

3. 75 (s, 2, 2 -CH 2), 4. 34 (q, 2, 3-CH 2 S-, J = 14Hz), 5. 16 (d, 1, C 6 -H, J = 5Hz ), 5.46 (s, 2, -CH ₂ CONH-), 7. 28 (s, 1, C ₇ -H, J = 5 Hz, J = 9 Hz) _4- H), 8. 14 (s, 1, oxazole C ₅ -H), 9.37 (s, 1, tetrazole H), alc 9. 53 ).

[Example 57]

Preparation of 3 - ((2-oxazolylthio) methyl) -7- (2-formyloxy-2-phenylacetamido) -3-cephem-4-carboxylic acid in 1,2-dichloroethane.

7- (2-formyloxy-2-phenylacetamido) -separosporanic acid methylene chloride Solvent 0. 52 g (1 mmol) and 0. 21 g (1.1 mmol) of 2-oxazolethiol are added to 20 ml of 1,2-dichloroethane, refluxed for about 16 hours and then cooled to room temperature. The product was completely converted by TLC. Concentrate the reaction mixture to 10 ml with a rotary evaporator, then leave the column to form gelatinous crystals. The crystalline material is filtered, washed with 1,2-dichloroethane and dried to give 0. 21 g of a gray solid material. Removal of the solvent from the filtrate

The product is identified by NMR.

3. 56(m, 2, 2-CH₂), 4. 24(q, 2, 3-CH₂S-, J=13Hz), 5. 00(d, 1, C₆-H, J=5Hz), 5. 70(q, 1, C₇-H), J-5Hz, J=9Hz), 6. 14(S, 1,

) 7. 25(S, 1, 옥사졸 C₄-H), 7. 45(m, 5, 페닐 H), 8. 12(S, 1, 옥사졸 C₅-H), 8. 35(S, 1, -CHO) 및 9. 40(d, 1, -CONH-, J=9Hz).NMR (d-DMSO ₆₎

3. 56 (m, 2, 2 -CH 2), 4. 24 (q, 2, 3-CH 2 S-, J = 13Hz), 5. 00 (d, 1, C 6 -H, J = 5Hz ), 5.70 (q, 1, C ₇ -H), J = 5 Hz, J = 9 Hz), 6. 14 (S,

) 7. 25 (S, 1, oxazole _{C 4 -H), 7. 45 (} m, 5, phenyl H), 8. 12 (S, 1, oxazole _{C 5 -H), 8. 35 (} S , 1, -CHO) and 9.40 (d, 1, -CONH-, J = 9 Hz).

[Example 58]

Preparation of 3 - (((4-phenyl-2-thiazolyl) thio) methyl-7- (2- (2-thienyl) acetamido) -3-cephem-4- carboxylic acid in acetonitrile.

(5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 1.44 g (7.5 mmol) of 4-phenyl-2-thiazolthiol were dissolved in 35 ml of acetonitrile And refluxed for 16 hours (a dewatering tube containing dreyerite anhydrous calcium sulfate is attached to block moisture in the atmosphere). TLC indicated that the product was completely transferred. The reaction mixture is cooled to room temperature and stirred for 2 hours to crystallize the product. This is filtered, washed with acetonitrile and dried to give 2.5 g (85.6% yield). A melting point of 180 캜 (decomposition), a product of NMR

[Example 59]

((5-methyl-1,3,4-thiadiazol-2-yl) thio) methyl) -7- (2- (1H-tetrazol-1-yl) acetamido ) -3-cephem-4-carboxylic acid.

(5 mmol) of 5-methyl-1, 3,4-thiadiazole-2-thiol, 1.92 g (6 mmol) were added to 25 ml of alumina-treated nitromethane and the reaction mixture was heated to 95 ° C on an oil bath and left to stir for 4 hours. TLC showed conversion of the product and contained trace amount (less than 2%) of cephalosporanic acid starting material. The reaction mixture is cooled to room temperature, filtered, washed with nitromethane and dried in vacuo to give 11.11 g (92. 5% yield). Melting point: 183. 5 캜 (decomposition), NMR revealed product

[Example 60]

((5-methyl-1,3,4-thiadiazol-2-yl) thio) methyl) -7- (2- (1H-tetrazol-1-yl) acetamide -3-cephem-4-carboxylic acid.

(5 mmol) of 5-methyl-l, 3, 4-thiadiazole-2-thiol < / RTI > 99 g (7.5 mmol) is added to 25 ml of propionitrile (treated with neutral alumina) and heated to reflux (97 ° C). The reaction mixture is refluxed with stirring for 9 hours. TLC shows only trace amounts of the starting material of cephalosporanic acid. The reaction mixture is cooled to room temperature, filtered, washed with propionitrile and then vacuum dried to give 2. 04 g (89. 5% yield). Melting point 186. Determine the product by NMR at 5 캜 (decomposition).

[Example 61]

Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2-formyloxy-2-phenylacetamido) -3- Preparation of cephem-4-carboxylic acid.

(0.05 mol) of 7-ACA (7-amidoseparasporanic acid) are suspended in 100 ml of 1,2-dichloroethane and 26.25 g (0.20 mol) of trimethylsilylacetamide are added. The reaction mixture is heated to 40 < 0 > C and the solid is dissolved until it becomes a suspended solution and cooled to 20 < 0 > C. A solution of 10.92 g (0.055 mol) of 2-formyloxy-2-phenyl-acetyl chloride in 25 ml of 1,2-dichloroethane was added dropwise over 20 minutes, and the temperature was raised to 30 ° C. The reaction mixture is stirred for 2 hours, 100 ml of 1,2-dichloroethane are added, and the reaction mixture is washed three times with 100 ml of water. water

[Example 62]

Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2-formyloxy) -2-phenylacetamido) -3 - < / RTI > cephem-4-carboxylic acid.

2.33 g (5 mmol) of 7- (2-formyloxy-2-phenylacetamido) cephalosporanic acid and 0.64 g (5.5 mmol) of 1-methyl-1H-tetrazole- To 25 ml of 1,2-dichloroethane, the mixture is refluxed for 12 hours. The reaction mixture is cooled to room temperature, reheated by reflux, 10 ml of solvent is distilled off, and 10 ml of carbon tetrachloride is added dropwise at around reflux temperature (77 ° C). The resulting mixture is allowed to cool to room temperature and stirred for 1 hour. The product is isolated by filtration, washed with 14 ml of 40% sodium chloride in 1,2-dichloroethane and dried at 50 < 0 > C under vacuum to give 2. 12 g (yield 86. 5%) of a pale solid. NMR was consistent with NMR of the product prepared by the method of Example 16. < tb > < TABLE >

[Example 63]

(3-benzyloxycarbonylaminomethyl) -1,2,4-triazol-5-yl) thio) methyl) -7- (2-2-thienyl) - acetamide -3-cephem-4-carboxylic acid.

2 g (5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 2 g (5 mmol) of 3- (benzyloxycarbonylaminomethyl) -1,2-4-triazol- 7.6 mmol) is added to 35 ml of nitromethane and heated at 80-90 < 0 > C for 6 hours with stirring. The reaction mixture is cooled and filtered to isolate the product. Recrystallization twice with acetone solution yields 1.2 g (40% yield) of creamy crystals. Melting point: 174-178 占 폚 (decomposition).

Elemental analysis: C ₂₅ H ₂₄ C ₆ O ₆ S ₃

Calculated values: C 49.99, H 4.30, N 13.99, S 16. 01

Actual value: C 50. 20, H 4. 03, N 13. 76, S 15. 68

[Example 64]

(2-thienyl) acetamido) -3-cephem-4-carboxylic acid in acetonitrile was added to a solution of 3 - ((1-carboxymethyl-1H-tetrazol- Recipe.

(2.5 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 0.61 g (2.5 mmol) of 1- (carboxymethyl) -1H-tetrazole-5-thiol. 8 mmol) is added to 75 ml of acetonitrile, which is heated until it boils, and 35 ml of the solvent is distilled off. The reaction mixture is refluxed for 13 hours, then cooled, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid and brine, dehydrated with sodium sulfate, and hexane was added to separate the resulting precipitate and treated with ether to yield 0.475 g (yield 38%) of brown solid. The product is identified by comparison with a certified sample prepared by other synthetic methods.

[Example 65]

(5-methyl-1,3,4-thiadiazol-2-yl) thio) methyl) -7- (3- chloropropionamido) -3-cephem-4-carboxylic acid in nitromethane quite.

(2.5 mmol) of 7- (3-chloropionamido) -separasporanic acid and 0. 4 g of 5-methyl-1,3,4-thiadiazole-2-thiol in 20 ml of nitromethane (3 mmol) is added to the oil bath at 95-96 占 폚. In TLC, the reaction appeared to be complete within 3 hours. The reaction mixture was cooled to room temperature, filtered and evaporated in vacuo to give a pale red oil which crystallized on standing at room temperature for 2 hours. Treatment with 15 ml of ethyl acetate, filtration, washing with ethyl acetate again and evaporation yielded 0.64 g of product (yield 55.2:). The product was confirmed by IR, UV, titrimetry, trace analysis and NMR.

Elemental analysis: C ₁₆ H ₁₉ CIN ₄ O ₄ S ₃

Calculated values: C 41. 51, H 4. 14, N 12. 10, S 20. 78, Cl 7.66

Actual values: C 41.70, H 4.23, N 11.84, S.20.15, Cl 7.88

[Example 66]

Synthesis of 3 - (((1-benzyl-1H-1,2,3-triazol-5-yl) thio) methyl-7- (2- (2-thienyl) acetamido ) -3-cephem-4-carboxylic acid.

200 mg (0.5 mmol) of 7- (2- (thienyl) acetamido) cephalosporanic acid and 140 mg (0.7 mmol) of 1-benzyl-1H-1,2,3- Is mixed with 15 ml of 1,2-dichloroethane and heated at 65-70 [deg.] C for 21 hours. The solvent is removed under reduced pressure, 25 ml of a saturated solution of sodium bicarbonate are added and the mixture is extracted twice with ethyl acetate. Ethyl acetate is again added to the remaining aqueous solution, cooled in an ice bath and the pH is adjusted to 2.5 with 20% hydrochloric acid solution. The acidic product was extracted twice with ethyl acetate and the extract was washed with a saturated solution of NaCl

[Examples 67 to 72]

7-Methoxy-7- (2- (1H-tetrazol-1-yl) acetamido) cephalosporanic acid in nitromethane with various thiols.

7-methoxy-7- (2-1H-tetrazol-1-yl) acetamido) cephalosporanic acid is reacted with various thiols in nitromethane. The method is carried out in the same manner as described above, with the exception that the product is purified from unreacted starting material using high pressure liquid chromatography. The products and identification are as follows.

Methyl-1H-tetrazol-5-yl) thio) methyl) -7-methoxy-7- (2- (1H- Cephem-4-carboxylic acid, UV max (ethanol) 273m (epsilon 9,082)

7-methoxy-7- (2- (1H-tetrazol-1-yl) acetamido ) -3-cephem-4-carboxylic acid, UV max (ethanol) 273m (epsilon 12,785)

Elemental analysis: C ₁₆ H ₁₆ N ₈ O ₅ S ₃

Calculated values: C 37. 18, H 3.33, N 23. 13

Actual value: C 36. 99, H 3.31, N 22. 86

Methyl) -7-methoxy-7- (2- (1H-tetrazol-1-yl) acetamide 3-cephem-4-carboxylic acid, UV max (ethanol) 269m (epsilon 8,910)

Elemental analysis: C ₁₅ H ₁₆ N ₈ O ₆ S ₂

Calculated value: C 38. 46, H 3.44, N 23. 92

Actual value: C 38. 58, H 3.69, N 23. 91

Methyl-7-methoxy-7- (2- (1H-tetrazol-1-yl) acetamido) -3H-tetrazol- - cephem-4-carboxylic acid, UV max (ethanol) 269m (epsilon 7,669)

Elemental _{analysis: C 15 H 16 N 10 O} 7 S 2

Calculated values: C 35.16, H 3.15, N 27. 33

Actual value: C 35. 42, H 3. 38, N 27. 39

Synthesis of 3 - (((4,5-dihydro-6-hydroxy-4-methyl-5-oxo-1,2,4-triazin- 2- (1H-tetrazol-1-yl) acetamido) -3-cephem-4-carboxylic acid.

UV max (ethanol) 274m (? 11,967)

Elemental analysis: C ₁₆ H ₁₇ N ₉ O ₇ S ₂

Calculated values: C 37. 57, H 3.35, N 24. 65

Actual value: C 36. 96, H 3.80, N 27. 63

(3- ((1,3,4-triazol-5-yl) thio) methyl) -7-methoxy- Cephem-4-carboxylic acid.

Elemental analysis: C ₁₄ H ₁₅ N ₉ O ₅ S ₂

Calculated: C 37.08, H 3.33, N 27.80

Actual value: C 36. 78, H 3.43, N 27. 79

[Example 73]

Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- (4-ethyl-2,3-dioxo-1-piperazinylcarbo 2-phenylacetamido) < / RTI > 3-cephem-4-carboxylic acid.

(0.5 mmol) of 7- (2- (4-ethyl-2,3-dioxopiperazinylcarbonylamino) -2- phenylacetamido) cephalosporanic acid hydrate and 1-methyl-1H (0.625 mmol) of tetrazol-5-thiol was added to 6 ml of nitromethane, followed by dehydration to alumina and heating the mixture at 85 占 폚 under nitrogen for 12 hours. After evaporation of the nitromethane, the remaining brown foam is redissolved in sodium bicarbonate solution and washed twice with ethyl acetate. Wash the newly ethyl acetate. The ethyl acetate layers were combined and washed with a saturated solution of sodium chloride,

1.2(t,3,-NCH₂CH₃, J=7Hz), 3.65(m, 6, N-CH₂CH₃및 피페라지닐 H), 4.0(s, 3, 테트라졸의 -CH₃), 4.4(s, 2,3-CH₂S), 5.1(d, 1, C₆-H, J=6Hz), 5.8(d, 1, C₇-H, J=8Hz), 6.0(d, 1,

, J=6Hz), 7.4(m, 5, 페닐-H), 8.4(d, 1, -CHCONH, -J=8Hz), 및 10.0(d, 1,

, J=6Hz).

N, N-CH ₂ CH ₃ and piperazinyl H), 4.0 (s, 3, -CH _{3 of} tetrazole), 1.2 (t, 3, -NCH ₂ CH ₃ , J = 7 Hz) _{4.4 (s, 2,3-CH 2} S), 5.1 (d, 1, C 6 -H, J = 6Hz), 5.8 (d, 1, C 7 -H, J = 8Hz), 6.0 (d, 1 ,

, J = 6 Hz), 7.4 (m, 5, phenyl-H), 8.4 (d, 1, -CHCONH,

, J = 6 Hz).

[Example 74]

1 - ((1-carboxymethyl-1H-tetrazol-5-yl) thio) methyl-7- (2- -Piperazinyl-carbonylamino) -2-phenylacetamido) -3-cephem-4-carboxylic acid.

(0.5 mmol) of cepharosporanic acid hydrate was added to 45 ml of 1,2, 3-dioxopiperazinecarbonylamino) -2-phenylacetamido) After dissolving in dichloroethane and dehydrating with alumina, the solution is heated to 95 DEG C to remove the azeotrope. After collecting 40 ml of the solvent, 10 ml of nitromethane and 0.160 g (1 mmol) of 1- (carboxymethyl) -1H-tetrazole-5-thiol are added and the reaction mixture is maintained at 90 ° C in the presence of nitrogen for 12 hours. The reaction mixture is filtered and the solvent is evaporated to give a gum, followed by the addition of a saturated solution of ethyl acetate and sodium bicarbonate. The mixture is washed twice with ethyl acetate and fresh ethyl acetate is added, then the mixture is cooled to 0 C and the pH is adjusted to 2.3 using 20% HCl. The layers are separated and the aqueous layer is washed with ethyl acetate. The ethyl acetate layers were combined and washed with a saturated solution of HCl, then dried over anhydrous magnesium sulfate, filtered, evaporated and dried at room temperature to give 123 mg of product. The product is confirmed by NMR.

), 7.4(m, 5, 페닐 H), 및 9.9(d, 1,

, J=7Hz).1.2 (t, 3, -NCH ₂ CH ₃ , J = 7 Hz), 3.6 (m, 4, N-CH ₂ CH ₃ and piperazinyl 5-H) ), 4.4 (s, 2, 3-CH ₂ S), 5.1 (d, 1, C ₆ -H, J = 5 Hz), 5.3 (s, 2, tetrazole 1 -CH ₂ COOH) d, 1, C ₇ -H, J = 6 Hz), 5.9 (d,

), 7.4 (m, 5, phenyl H), and 9.9 (d, 1,

, J = 7 Hz).

[Example 75]

(((4,5-dihydro-4-methyl-6-hydroxy-5-oxo-1,2,4-triazin-3- yl) thio) methyl) Preparation of 2- (4-ethyl 2, 3-dioxo-1-piperazinylcarbonylamino) -2-phenylacetamido) -3-cephem-4- carboxylic acid.

(0.5 mmol) of 7- (2- (4-ethyl-2,3-dioxo-1- piperazinylcarbonylamino) -2- phenylacetamido) cephalosporanic acid hydrate and 4 (0.625 mmol) of 5-dihydro-4-methyl-6-hydroxy-5-oxo-1,2,4-triazine-3-thiol was dissolved in 10 ml of nitromethane After dissolution, the reaction mixture is heated at 85 < 0 > C for 12 hours. It is discarded when brown precipitates form. The solvent is slowly evaporated to form a yellow precipitate. The residue was cooled, then filtered and washed with diethyl ether to give two pale yellow solid which was identified on TLC

1.1(t, 3, -NCH₂CH₃, J=6Hz), 3.3(s, 3, 트리아진-CH₃), 3.65(m, 4, N-CH₂CH₃및 피페라지닐 5-H), 4.0(m, 2, 피페라지닐 6-H), 4.6(s, 2, 3-CH₂S-), 5.1(d, 1, C₆-H, J=5Hz), 5. 75(m, 2,

, 및 C₇-H), 7. 45(m, 5, 페닐 H), 9.5(d, 1, -CHCONH, J=8Hz) 및 10. 0(d, 1,

, J=Hz).

_{1.1 (t, 3, -NCH 2} CH 3, J = 6Hz), 3.3 (s, 3, triazine _{-CH 3), 3.65 (m,} 4, N-CH 2 CH 3 and piperazinyl 5-H) , 4.0 (m, 2, piperazinyl, 6-H), 4.6 (s , 2, 3-CH 2 S-), 5.1 (d, 1, C 6 -H, J = 5Hz), 5. 75 (m , 2,

, And C ₇ -H), 7.45 (m, 5, phenyl H), 9.5 (d, 1, -CHCONH, J = 8 Hz)

, J = Hz).

[Example 76]

A solution of 3 - (((5-methylthio-1,3,4-thiadiazol-2-yl) thiomethyl) -7- (2- (1H-tetrazol- ) -3-cephem-4-carboxylic acid.

(39.2 mmol) and 5- methylthio) -1,3,4-thiadiazol-2 (2-fluorophenyl) (39.2 mmol) of thiol are suspended in 500 ml of nitromethane passed through a column of neutral calmina, then the mixture is heated to 95 DEG C and the reaction mixture is maintained at 95 DEG C for 6 hours, After filtration, it is washed with 250 ml of nitromethane and dried at 45 DEG C for 4 hours to obtain 18. 08 g of product.

(Yield: 94.9%)

This product is added to 150 ml of water and 4. 0 ml of acetic acid. The pH is adjusted to 6.3 with 1 N sodium hydroxide (107 ml required) and the mixture is stirred for 1 hour. A mixed solution of 257 ml of 60% sodium lactate and 65 ml of ethanol was added and the mixture was left for 45 minutes. Stir for 45 minutes, filter, wash three times with ethanol and dry to obtain 18.1 g of product. The product is confirmed by HPLC.

[Examples 77 to 84]

Methylthio) methyl) -7- (2-1H-tetrazol-1-yl) acetamido) -7- -3-cephem-4-carboxylic acid.

7- (2-1H-tetrazol-1-yl) acetamido) cephalosporanic acid is reacted with 5-methyl-1,3,4-thiadiazole-2-thiol in various solvents. The reaction conditions and results are summarized below. (Other reaction procedures are carried out according to the typical methods of the above examples)

* With sodium salt

[Example 85]

(2-hydroxy-2-phenylacetamido) -3-cephem-4-carboxylate in glacial acetic acid How to rate.

7- (2-hydroxy-2-phenylacetamido) cephalosporanic acid. And 0.5 g (4.3 mmol) of 1-methyl-1H-tetrazole-5-thiol are reacted in 15 ml of glacial acetic acid at 84 to 86 ° C for 8 hours. The reaction mixture is cooled to room temperature and 0.4 g (1.6 mmol) of iodine is added to convert unreacted thiol to disulfide. The mixture is stirred at room temperature for 20 minutes, poured into 100 ml of ethyl acetate and 50 ml of water, and excess sodium iodide is removed by adding sodium sulphate. The layers are separated and the ethyl acetate layer is washed twice with 100 ml portions of water, then once with 50 ml portions of 20% sodium chloride solution and then over anhydrous sodium sulfate. Ethyl acetate is removed on a rotary evaporator and the residue is dissolved in 10 ml of methanol. 0.20 g (2 mmol) of lithium acetate dihydrate was added, followed by stirring at room temperature for 20 minutes. The product was crystallized and separated by filtration, washed with 5 ml of methanol and dried to give 0.34 g of white crystals. (Yield: 69.4%). The product was confirmed by NMR.

3. 50(ABq, J=17Hz), 3.92(s, 테트라졸의 -CH₃), 4. 20(s, 3-CH₂S-), 5. 04(d, C₆-H, J=5Hz), 5. 24(s,

CHCONH-), 5. 64(d, C₇-H, 5Hz), 및 7. 44(s,

-H).

3. 50 (ABq, = J 17Hz), 3.92 (s, tetrazole -CH ₃ in), 4. 20 (s, 3 _CH-2 S-), 5. 04 (d, ₆ C -H, J = 5 Hz), 5.24 (s,

CHCONH-), 5.64 (d, C ₇ -H, 5 Hz), and 7.44 (s,

-H).

The above NMR spectrum was consistent with the NMR spectrum of the certified sample of the product prepared by aqueous titration.

[Example 86]

Methyl-1H- tetrazol-5-yl) thio) methyl) -7- (2- (0-3-butoxycarbonylaminomethyl) phenyl) acetamide in nitromethane ) -3-cephem-4-carboxylic acid.

(0.386 mmol) and 1-methyl-1H-tetrazol-5-ylmethyl-2- (4- (2- (O- (tert- 0.47 g (0.405 mmol) of thiol were reacted in 5 ml of nitromethane at 85 ° C under nitrogen for 12 hours to give 3 - ((1 -methyl-1H-tetrazol-5-yl) (2- (tert-butoxycarbonylaminomethyl) phenyl) acetamido-3-cephem-4-carboxylate. The product is confirmed by NMR.

1. 45(s, 9,-C(CH₃)₃), 3.65(s, 4,2-CH₂및 -CH₂CONH-), 3.85(s, 3, 테트라졸의 -CH₃), 4.3(m, 4,3-CH₂S-및 -CHNHCOO-3급-C₄H₉), 5.0(d, 2, C₆-H, J=4Hz), (5.7(q, 1, C₇-H), 7.25(s, 5, 페닐-H 및 -CONH-), 및 8.9(s, 1, -COOH).

1. 45 (s, 9, -C (CH 3) 3), 3.65 (s, 4,2-CH 2 and _{-CH 2 CONH-), 3.85 (s} , -CH ₃ of 3, tetrazole), 4.3 (m, 4,3-CH ₂ S- and -CHNHCOO-3 tert _{-C 4 H 9), 5.0 (} d, 2, C 6 -H, J = 4Hz), (5.7 (q, 1, C 7 - H), 7.25 (s, 5, phenyl-H and -CONH-), and 8.9 (s, 1, -COOH).

[Example 87]

(1-methyl-1H-tetrazol-5-yl) thio) methyl) 7- (2-ureido-2-phenylacetamido) -3-cephem- quite.

0.49 g (0.5 mmol) of 1- (2-thienyl) -2-phenylacetamido) cephalosporanic acid and 0.61 g (0.552 mmol) of 1- methyl- Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2-ureido-2-phenylacetamido ) -3-cephem-4-carboxylic acid. The product is confirmed by NMR.

3.5(d, 2, 2-CH₂, J=3Hz), 3. 83(s, 3, 테트라졸의 -CH₃), 4. 17(d, 2, 3-CH₂S-, J=3Hz), 4.9(d, 1, C₆-H, J=5Hz), 5.4(d, 1-CH₂CONH-, J=8Hz), 5.6(m, 3, C₇-H 및 -NH₂), 6.7(d, 1,

, J=8Hz), 7. 25(m, 5, H), 및 9. 2(d, 1, -CH₂CONH-, J=8Hz).

3.5 (d, 2, 2- CH 2, J = 3Hz), 3. 83 (s, 3, tetrazol-of _{-CH 3), 4. 17 (d} , 2, 3-CH 2 S-, J = 3Hz ), 4.9 (d, 1, C 6 -H, J = 5Hz), 5.4 (d, 1-CH 2 CONH-, J = 8Hz), 5.6 (m, 3, C 7 -H and -NH _2), 6.7 (d, 1,

, J = 8 Hz), 7.25 (m, 5, H), and 9. 2 (d, 1, -CH ₂ CONH-, J = 8 Hz).

[Example 88]

Preparation of 3 - (((1-methyl-1H-tetrazol-5-yl) -thio) methyl-7- (2-cyanoacetamido) -3-cephem-4-carboxylic acid in nitromethane.

0.93g (1 mmol) of 7- (2-cyanoacetamido) cephalosporanic acid and 0. 122g (1.5mmol) of 1-methyl-1H-tetrazole- Methyltetrah-5-yl) thio) methyl) -7- (2-cyanoacetamido) -3-cephem-4 -Carboxylic acid. ≪ / RTI > The product is confirmed by NMR.

3.5(s, 2, 2-CH₂) 3. 65(s, 2, CHCH₂, CONH-), 3. 95(s, 3, 테트라졸의 -CH₃), 5. 35(s, 2, 3-CH₂S-), 5.1(d, 1, C₆-H, J=6Hz), 5. 75(q, 1, C₇-H, J=4Hz), 7.9(s, 1, -COOH) 및 8.7(d, 1, -CH₂CONH-, J=9Hz).

3.5 (s, 2, 2- CH 2) 3. 65 (s, 2, CHCH 2, CONH-), 3. 95 (s, -CH ₃ of 3, tetrazole), 5. 35 (s, 2 , _{3-CH 2 S-), 5.1} (d, 1, C 6 -H, J = 6Hz), 5. 75 (q, 1, C 7 -H, J = 4Hz), 7.9 (s, 1, -COOH ) And 8.7 (d, 1, -CH ₂ CONH-, J = 9 Hz).

[Example 89]

Methyl-1H- tetrazol-5-yl) thio) methyl) -7- (2- (N-chlorophenylthio) acetamido) -3- Preparation of carboxyl.

0.90 g (0.855 mmol) of 7- (2- (m-chlorophenylthio) acetamido) cephalosporanic acid and 0. 104 g (0.9 mmol) of 1-methyl-1H-tetrazole- Methyl-1H-tetrazol-5-yl) thio) methyl-7- (2-m-chlorophenylthio) acetamide was reacted under nitrogen atmosphere at 85 ° C for 12 hours in 10 ml of nitromethane. ) -3-cephem-4-carboxylic acid. The product is confirmed by NMR.

3.6(s, 2, 2-CH₂), 3. 75(s, 2, -CH₂CONH-), 3.9(s, 3, 테트라졸의 -CH₃), 4.4(s, 2, 3-CH₂S), 5.0(d, 1, C₆-H, J=5Hz), 5.8(q, q, C₇-H, J=4Hz), 7.15(m, 4, 페닐-H), 7.7(d, 1, -CH₂CONH-, J=8Hz) 및 8. 5(s, 1, COOH).

3.6 (s, 2, 2- CH 2), 3. 75 (s, 2, -CH 2 CONH-), 3.9 (s, 3, tetrazol-of _{-CH 3), 4.4 (s,} 2, 3-CH _{2 S), 5.0 (d,} 1, C 6 -H, J = 5Hz), 5.8 (q, q, C 7 -H, J = 4Hz), 7.15 (m, 4, phenyl -H), 7.7 (d , 1, -CH ₂ CONH-, J = 8 Hz) and 8.5 (s, 1, COOH).

[Example 90]

Preparation of 3 - (((1-methyl-1H-tetrazol-5-yl) thio) methyl-7- (2- (phenylthio) acetamido) -3-cephem-4-carboxylic acid in nitromethane.

0.42 g (1 mmol) of 1-methyl-1H-tetrazole-5-thiol and 0. 122 g (1.5 mmol) of 1-methyl- Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2-phenylthio) acetamido) -3-cephem- Carboxylic acid. ≪ / RTI > The product is confirmed by NMR.

3.7(s, 4, -CH₂CONH-및 2-CH₂), 3.9(s, 3, 테트라졸의 -CH₃), 4. 35(s, 2, 3-CH₂S-), 4.9(d, 1, C₆-H, J=6Hz), 5.8(q, 1, C₇-H, J=4Hz), 7. 25(s, 5, 페닐-H), 7.7(d, 1, -CH₂CONH-, J=8Hz) 9.4(s, 1,-COOH).

_{3.7 (s, 4, -CH 2} CONH- , and _{2-CH 2), 3.9 (} s, -CH ₃ of 3, tetrazole), 4. 35 (s, 2 , 3-CH 2 S-), 4.9 ( (d, 1, C ₆ -H, J = 6 Hz), 5.8 (q, 1, C ₇ -H, J = 4 Hz), 7.25 CH ₂ CONH-, J = 8 Hz) 9.4 (s, 1, -COOH).

[Example 91]

methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) -3-cephem- Preparation of 4-carboxylic acid.

3.96 g (10 mmol) of 7- (2- (2-thienyl) acetamido) cephalosporanic acid and 1.28 g (11 mmol) of 1-methyl-1H-tetrazole- Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) 3-cephem-4-carboxylic acid. Melting point: 167.5 ° to 168 ° C Yield: 79.9% The NMR spectrum of the product was in agreement with the NMR spectrum of the product of Example 5.

[Example 92]

A solution of 3 - ((1-methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- (2-thienyl) acetamido) quite.

The procedure of Example 91 is repeated, except that 150 ml of toluene is used and the reaction is carried out at 84 to 86 占 폚 for 136 hours. The product melts at 163 to 163.5 [deg.] C with a yield of 88.5%. The NMR spectrum of the product was consistent with the NMR spectrum of the product of Example 5.

[Example 93]

Preparation of 3 - (((1 -methyl-1 H -tetrazol-5-yl) thio) methyl) -7- (tert- butoxycarbonylamido) -3-cephem-4-carboxylic acid in nitromethane .

(1 mmol) of 7- (tert-butoxycarbonylamino) cephalosporanic acid and 0. 122 g (1.5 mmol) of 1-methyl-1H-tetrazole- (1-methyl-1H-tetrazol-5-yl) thio) methyl) -7- (tert-butoxycarbonylamido) -3-cephem- -Carboxylic acid is produced. The product is identified by NMR.

1. 45(s, 9, -C(CH₃)₃), 3.7(s, 2,2-CH₂), 3.95(s, 3, 테트라졸의 -CH₃0, 4.4(s, 2, 3-CH₂S), 5.0(s, 1, C₆-H), 5.6(s, 2, C₇-H 및 -CH₂CONH) 및 13(s, 1, -COOH).

1. 45 (s, 9, -C (CH 3) 3), 3.7 (s, 2,2-CH 2), 3.95 (s, -CH 3 0, 4.4 of 3, tetrazol (s, 2, 3 _{-CH 2 s), 5.0 (s} , 1, C 6 -H), 5.6 (s, 2, C 7 -H and -CH ₂ CONH) and 13 (s, 1, -COOH) .

[Example 94]

Methyl-1H- tetrazol-5-yl) thio) methyl) -7- (2- (4-ethyl-2,3-dioxopiperazinylcarbonylamido) -2- p-hydroxyphenyl) acetamino) -3-cephem-4-carboxylic acid

0.80 g (0. 306 mmol) of 7- (2- (4-ethyl-2,3-dioxopiperazinylcarbonylamino) -2- (p- hydroxyphenyl) acetamino) (0.3274 mmol) of methyl-1H-tetrazole-5-thiol were reacted in 6 ml of nitromethane at 80 ° C for 12 hours to give 3 - (((1- ) Thio) methyl) -7- (2- (4-ethyl-2,3-dioxopiperazinylcarbonylamido) -2- (p-hydroxyphenyl) acetamino) Is generated. The product is identified by NMR.

1.2(t, 3, N-CH₂CH₃), 3.6(m, 6, 2-CH₂, 피페라지닐 6-H 및 N-CH₂CH₃), 3.9(m, 2, 피페라지닐 5-H), 3. 95(S, 3, 테트라졸의 -CH₃), 4.4(S, 2, 3-CH₂S-), 5.0(d, 1, C₆-H, J=6Hz), 5.6(d, 1, C₇-H, J=6Hz), 5.8(d, 1, CHCONH-, J=8Hz), 6.8(d, 2, 페닐-H, J=8Hz), 7.3(d, 2, 페닐-H, J=8Hz), 8.3(d, 1, -CHCONH-, J=8Hz) 및 9.9(d, 1,

).

1.2 (t, 3, N-CH ₂ CH ₃ ), 3.6 (m, 6, 2-CH ₂ , piperazinyl 6-H and N-CH ₂ CH ₃ ) -H), 3. 95 (S, 3, -CH 3), 4.4 (S, 2, 3-CH 2 S-), 5.0 (d, 1, C 6 -H, J = 6Hz) of tetrazole, _{5.6 (d, 1, C 7} -H, J = 6Hz), 5.8 (d, 1, CHCONH-, J = 8Hz), 6.8 (d, 2, phenyl -H, J = 8Hz), 7.3 (d, 2 , Phenyl-H, J = 8 Hz), 8.3 (d, 1, -CHCONH-, J = 8 Hz)

).

[Example 95]

(3- (((1,3,4-thiadiazol-2-yl) thio) methyl) -7- (2- (lH-tetrazol- l-yl) acetamido) -3- Preparation of cephem-4-carboxylic acid.

0.38 g (1 mmol) of 7- (2- (1H-tetrazol-1-yl) acetamido) cephalosporanic acid and 0.15 g of 1,3,4-thiadiazole- 27 mmol) was reacted in 15 ml of acetonitrile under reflux under nitrogen for 24 hours to give 3 - (((1,3,4-thiadiazol-2-yl) thio) methyl) -7- (2-1H-tetrazole -1-yl) acetamido) -3-cephem-4-carboxylic acid. The product is identified by NMR.

3. 74(m, 2, 2,-CH₂-), 4. 48(q-23-CH₂S-, J_AB=14), 5. 16(d, 1, C₆-H, J=5), 5. 42(S, 2, 테트라졸일의 -CH₃), 5. 76(q, 1, C₇-H, J₆,₇=5, J_7NH=8), 8, 87(S, 1, 테트라졸링), 9. 40(S, 1, 티아디아졸티올 출발물질), 9. 53(d, 1,-CH₂CONH-J=8Hz) 및 9. 57(S, 1, 티아디아졸링).

3. 74 (m, 2, 2 , -CH 2 -), 4. 48 (q-23-CH 2 S-, J AB = 14), 5. 16 (d, 1, C 6 -H, J = 5), 5.42 (S, 2, -CH ₃ of tetrazolyl), _5.76 (q, 1, C ₇ -H, J ₆ , ₇ = 5, J _{7 NH} = 8) , 1, tetrazolyl), 9.40 (S, 1, thiadiazole thiol starting material), 9. 53 (d, 1, -CH ₂ CONH-J = 8 Hz) Diazolyl).

[Example 96]

(5-methyl-1,3,4-thiadiazol-2-yl) thio) methyl-7- (5-carbomethoxy- -Dichlorobenzamido) valeramido-3-cephem-4-carboxylic acid.

(5.0 mmol) of 5- (5-carbomethoxy-5- (2,4-dichlorobenzamido) valeramido) cephaloranoic acid and 5-methyl-1,3,4-thia 0. 1 g (0.75 mmol) of diazo-2-thiol was reacted in 1,2-dichloroethane under reflux for 30 minutes to give 3 - (((5-methyl-1,3,4-thiadiazol- -Yl) thio) methyl) -7- (5-carbomethoxy-5- (2,4-dichlorobenzamido) valeramido) -3-cephem-4- carboxylic acid.

[Example 97]

Methylthiazol-5-yl) thio) methyl) -7- (2- (1H-tetrazol-1-yl) acetamido) -3- Cephem-4-carboxylate.

(5 mmol) of 7- (2- (1H-tetrazol-1-yl) acetamido) cephalosporanic acid and 0.7 g (6 mmol) of 1-methyl- Added to 50 ml of acetonitrile, refluxed for 24 hours and cooled to room temperature. The solvent was removed by a rotary evaporator, and 40 ml of ethanol was added to the remaining 10 ml of the solution. Then, a solution of 0.3 g of lithium hydroxide dissolved in 10 ml of methanol was added. The product, lithium 3 - ((1 -methyl-1 H -tetrazol-5-yl) thio) methyl) -7- 4-carboxylate is determined. The reaction mixture was stirred at room temperature for 45 minutes and then filtered to separate the product. The product was washed with ethanol and then vacuum-dried at 40 DEG C to obtain 1.60 g (yield 72%). The product is identified by NMR.

[Example 98]

((5-methyl-1,3,4-thiadiazol-2-yl) thio) methyl) -7- (2-formyloxy-2-phenylacetamido -3-cephem-4-carboxylic acid.

4.6 g (8.8 mmol) of 7- (2-propylmethyl-2-phenylacetamido) cephalosporanic acid and 1. 52 g of 5-methyl-1,3,4-thiadiazole-2-thiol (11. 5 mmol) is added to 50 ml of 1,2-dichloroethane and refluxed for 12 hours and cooled to room temperature. The product, 3 - (((5-methyl-1,3,4-thiadiazol-2-yl) thio) methyl) -4-carboxylic acid as a concentrated paste. The mixture is diluted with 50 ml of 1,2-dichloroethane and stirred at room temperature for 4 hours. The product was separated by filtration and washed with 1,2-dichloroethane until the filtrate was clear

[Example 99]

((4,5-dihydro-6-hydroxy-4-methyl-5-oxo-1,2,4-triazin-3- yl) thio) methyl) - (1H-tetrazol-1-yl) acetamido) -3-cephem-4-carboxylic acid.

8.9 g (23.2 g millimoles) of 7- (2- (1H-tetrazol-1-yl) acetamido) cephalosporanic acid and 4.5-dihydro-6-hydroxy- -1,2,4-triazine-3-thiol was added to 200 ml of acetonitrile, refluxed for 23 hours, and then cooled to room temperature. The product crystallizes during the course of the reaction. The product is separated by filtration, washed with 50 ml of acetonitrile and then vacuum dried at 40 to 45 ° C to obtain 9.70 g (yield 86.6%). NMR confirmed the title product.

[Examples 100-144]

According to the process of the present invention, the reaction can be carried out as follows:

Methyl-1H-tetrazole-5-thiol to give 3 - (((1-methyl-1H-tetrazole- 5-yl) thio) methyl) -7- (2- (4-pyridylthio) acetamido) -3-cephem-4- carboxylic acid sodium salt.

Methyl-1H-tetrazole-5-thiol to give 3 - (((1-methyl-1H-tetrazole- Yl) thio) methyl) -7- (2- (4-pyridylthio) acetamido) -3-cephem-4- carboxylic acid.

7- (5-Carbo-n-butoxy-5- (2,4-dichlorobenz-amido) valeramido) cephalosporanic acid was reacted with 5-methyl-1,3,5-thiadiazole- Thiol reacted to give 3 - (((5-methyl-1,3,4-thiadiazol-2-yl) thio) -Dichlorobenzamido) valeramido) -3-cephem-4-carboxylic acid is produced.

(5-Carbo-n-butoxy-5- (2,4-dichlorobenzamido) -valeramido) cephalosporanic acid is reacted with 1-methyl-1H-tetrazole- -7- (5-carbo-n-butoxy-5- (2,4-dichlorobenzamido) valeramido) 3-cephem-4-carboxylic acid is produced.

2- (methoxyamino) acetamido) cephalosporanic acid was reacted with l-methyl-lH-tetrazole-lH-pyrazole- Thiol to give 3 - (((1 -methyl-1 H -tetrazol-5-yl) thio) methyl) -7- (2- (2- (P-nitrobenzyloxycarbonylamino) 4-yl) -2-methoxyimino) acetamido) -3-cephem-4-carboxylic acid.

7- (2- (2-P-Nitrobenzyloxycarbonylamino) thiazol-4-yl) acetamido) cephalosporanic acid was reacted with l- Methyl-1H-tetrazol-5-yl) thio) methyl) -7- (2- ( 2-P-nitrobenzyloxycarbonylamino) -thiazol-4-yl) acetamido) -3-cephem-4- carboxylic acid.

Reaction of 7 - (((2,2,2-trichloroethoxy) carbonylamino) cephalosporanic acid with 6-hydroxypyridazine-3-thiol gave 3 - (((6-hydroxypyridazine- Yl) thio) methyl) -7 - (((2,2,2-trichloroethoxy) carbonylamino) -3-cephem-4- carboxylic acid is produced.

Hydroxypyridazin-3-thiol to give 3 - (((6-hydroxypyridazin-3-yl) Thio) methyl) -7- (2- (2-thienyl) -acetamido) -3-cephem-4- carboxylic acid is produced.

The reaction of 7 - (((2,2,2-trichloroethoxy) carbonylamino) cephalosporanic acid with tetrazolo [1,5- b] pyridazin-6-thiol gave 3 - (((tetrazolo [ 1,5-b] pyridazin-6-yl) thiol) methyl) -7 - (((2,2,2-trichloroethoxy) carbonylamino) -3-cephem-4-carboxylic acid.

Reaction of 7- (2- (2-thienyl) acetamido) cephalosporanic acid with tetrazolo [1,5-b] pyridazin-6-thiol gave 3 - (((-tetrazolo [ -b] pyridazin-6-yl) thio) methyl) 7- (2- (2-thienyl) acetamido-3- cephem-4- carboxylic acid.

The reaction of 7 - (((2,2,2-trichloroethoxy) carbonylamino) cephalosporanic acid with 1- (sulfomethyl) -1H-tetrazole- (2, 2, 2-trichloroethoxy) carbonylamino) -3-cephem-4-carboxylic acid sodium salt Is generated.

The reaction of 7- (2- (2-thienyl) acetamido) cephalosporanic acid with 1- (sulfomethyl) -1H-tetrazole-5-thiol sodium salt gave 3 - (((1- -1H-tetrazol-5-yl) thio) methyl-7- (2- (2-thienyl) acetamino) -3-cephem-4- carboxylic acid sodium salt.

Ethyl) -1H-tetrazol-5-yl) thio) methyl) - (2,2,2-trichloroethoxy) carbonylamino) 7 - (((2,2,2-trichloroethoxy) carbonylamino) -3-cephem-4-carboxylic acid is produced.

Reaction of 7- (2- (2-thienyl) acetamido) cephalosporanic acid with 1- (2-dimethylamino) ethyl-1H-tetrazole- (2-dimethylamino (ethyl)) - 1H-tetrazol-5-yl) thio) methyl-7- (2- (2-thienyl) acetamino) -3-cephem-4-carboxylic acid.

7-2) - (2-thienyl) acetamido) Sepharosporanic acid was reacted with p-methoxybenzenethiol to give 3 ((- (p- methoxyphenyl) thio) methyl) (2-thienyl) acetamido) 3-cephem-4-carboxylic acid is produced.

(3- ((p-chlorophenyl) -7- (2- (2-thienyl) acetamido) cephalosporanic acid was reacted with p- Amido) 3-cephem-4-carboxylic acid.

7- (2- (2-thienyl) acetamido) cephalosporanic acid is reacted with o-toluenethiol to give 3 (((o- tolyl) Yl) acetamido) 3-cephem-4-carboxylic acid.

3 - (((1, 3-dihydro-1 H-pyrazol-3-yl) Methylthiazol-2-yl) thio) methyl) -7- (2-1H-tetrazol-1-yl) acetamido) -3-cephem-4- carboxylic acid is produced.

7-phthalimidoheparosporanic acid is reacted with 5-methyl-1,3,4-thiadiazole-2-thiol to give 3 - (((5-methyl-1,3,4-thiadiazol- Yl) thio) methyl-7-phthalimido-3-cephem-4-carboxylic acid.

The reaction of 7- (2-hydroxy-2-phenylacetamido) cephalosporanic acid with 5-methyl-1,3,4-thiadiazole- Thiadiazol-2-yl) thio) methyl) -7- (2- (trifluoromethylthio) acetamido) -3-cephem-4- carboxylic acid is produced.

Methyl-1,3,4-thiadiazole-2-thiol to give 3 - (((5-methyl-1,3,2- 4-thiadiazol-2-yl) thio) methyl) -7- (2-acetoxy-2-phenylacetamino) -3-cephem-4- carboxylic acid.

Methyl-1H-tetrazole-5-thiol to give 3 - (((1-methyl-1H-tetrazole- Yl) thio) methyl) -7- (2-trifluoromethylthio) acetamido) -3-cephem-4-carboxylic acid is produced.

2- (methoxyimino) acetamidocephalosporanic acid was reacted with 4,5-dihydro-6-hydroxynaphthalene-2-carboxylic acid Methyl-5-oxo-1,2,4-triazine-3-thiol to give 3 - (((4,5- dihydro- Yl) thio) methyl) -7- (2- (2-p-nitrobenzyloxycarbonylamino) -3-cephem-4- carboxylic acid is produced.

(2-dimethylamino) ethyl) -1H-tetrazole-5-carboxylic acid ethyl ester was prepared in accordance with the general method of example 1 from 7- (2- (2-p-nitrobenzyloxycarbonylamino) -Thiol to give 3 - (((1- (2- (dimethylamino) ethyl) -1H-tetrazol-5-yl) thio) methyl) Ylamino) acetamido) -3-cephem-4-carboxylic acid is produced.

When 7- (2- (o- (tert-butoxycarbonylaminomethyl) phenyl) -acetamido) cephalosporanic acid is reacted with tetrazolo- [1,5- b] pyridazin-6-thiol Methyl) -7- (2- (o- (tert-butoxycarbonylaminomethyl) phenyl) acetamido To a solution of 3 - ((tetrazolo [1,5- b] pyridazin-6-yl) thio) ) -3-cephem-4-carboxylic acid.

The reaction of 7- (2-formyloxy-2-phenylacetamido) cephalosporanic acid with 1- (sulfomethyl) -1H-tetrazole-5-thiol, Sulfomethyl) -1H-tetrazol-5-yl) thio) methyl) -7- (2-hydroxy-2-phenylacetamido) -3-cephem-4- carboxylic acid.

The reaction of 7- (2-hydroxy-2-phenylacetamido) cephalosporanic acid with 1- (sulfomethyl) -1H-tetrazole-5-thiol, sodium salt gave 3 - (( Methyl) -1H-tetrazol-5-yl) thio) methyl) -7- (2-hydroxy-2-phenylacetamido) -3-cephem-4- carboxylic acid.

7- (2- (2-thienyl) acetamido) cephalosporanic acid is reacted with 2-oxazolethiol to give 3 - ((oxazol- (2-thienyl) acetamido) -3-cephem-4-carboxylic acid.

Reaction of 7- (2-formyloxy-2-phenylacetamido) cephalosporanic acid with 1- (carboxymethyl) -1H-tetrazole-5-thiol gave 3 - ((1- (carboxymethyl) -1H-tetrazol-5-yl) thio) methyl) -7- (2-formyloxy-2-phenylacetamido) -3-cephem-4- carboxylic acid.

Methyl-1H-tetrazole-5-thiol to give 3 - (((1-methyl-1H-tetrazole- -Yl) thio) methyl) -7- (2-trifluoromethylthio) acetamido) -3-cephem-4-carboxylic acid.

Methyl-1H-tetrazole-5-thiol to give 3 - (((1-methyl-1H-tetrazole- -Yl) thio) methyl) -7- (2- (cyanomethylthio) acetamido) -3-cephem-4-carboxylic acid.

Reaction of 7-methoxy-7- (2- (cyanomethylthio) acetamido) cephalosporanic acid with 1-methyl-1H-tetrazole-5-thiol gave 3 - (( -Tetrazol-5-yl) thio) methyl) -7-methoxy-7- (2- (cyanomethylthio) acetamido) -3-cephem-4- carboxylic acid.

1 - ((carboxymethyl) -1H-tetrazole-5-thiol to give 3 - (((1- (carboxymethyl) -1H-tetrazol-5-yl) thio) methyl) -7- (2- (o-benzoylaminomethylphenyl) acetamido) -3-cephem-4-carboxylic acid.

7 (2-ureido-2-thienylacetamido) cephalosporanic acid is reacted with 1-methyl-1H-tetrazole-5-thiol to give 3 - (( Yl) thio) methyl) -7- (2-ureido-2-thienylacetamido) -3-cephem-4- carboxylic acid is produced.

Reaction of 7- (2- (2-amino-4-thiazolyl) acetamido) cephalosporanic acid with 1- (2-dimethylamino) ethyl-1H-tetrazole- (2-dimethylamino) ethyl) -1 H-tetrazol-5-yl) thio) methyl) -7- .

7- (5-benzoylamino-5-carboxy valeramido) cephalosporanic acid was reacted with 4,5-dihydro-6-hydroxy-4-methyl- -Thiol to give 3 - (((4,5-dihydro-6-hydroxy-4-methyl-5-oxo- (5-benzoylamino-5-carboxy valeramido) -3-cephem-4-carboxylic acid is produced.

Methyl-1H-1,2,3-triazole-5-thiol to give 3 - (((1-methyl) -1H-1,2,3-triazol-5-yl) thio) methyl) -7- (5-benzoylamino-5-carboxy valeramido) -3-cephem-4- carboxylic acid.

The reaction of 7- (5-benzoylamino-5-carboxy valeramido) cephalosporanic acid with 1- (carboxymethyl) -1H-tetrazole- Yl) thio) methyl) -7- (5-benzoylamino-5-carboxy valeramido) -3-cephem-4- carboxylic acid is produced.

(5-benzoylamino-5-carboxy valeramido) cephalosporanic acid is reacted with 5-methyl-1,2,4-oxadiazole-2-thiol to give 3 - (( 1H-1,3,4-oxadiazol-2-yl) thio) methyl) -7- (5-benzoylamino-5-carboxy valeramido) -3-cephem-4- carboxylic acid is produced.

5-carboxy valeramido) cephalosporanic acid was reacted with 1-benzyl-1H-tetrazole-5-thiol to give 3 - (((1-benzoyl- -Yl) thio) methyl) -7- (5-benzoylamino-5-carboxy valeramido) cephalosporanic acid.

7- (5-benzoylamino-5-carboxy valeramido) parosporanic acid is reacted with thiourea to give 3-amidinothiomethyl-7- (5-benzoylamino- -4-carboxylic acid is produced.

Reaction of 7-methoxy-7- (5-benzoylamino-5-carboxy valeramido) -separasporanic acid with 1-methyl-1H-tetrazole 5-thiol gave 3 - (( -Tetrazol-5-yl) thio) methyl) -7- (5-benzoylamino-5-carboxy valeramido) -3-cephem-4- carboxylic acid.

Reaction of 7-methoxy-7- (5-benzoylamino-5-carboxy valeramido) -separasporanic acid with 5-methyl-1,3,4-thiadiazole- (5-methyl-1,3,4-thiadiazol-2-yl) thio) methyl) -7-methoxy- 7- (5-benzoylamino-5-carboxy valeramido) -3- -Carboxylic acid is produced.

7-methoxy-7- (5-benzoylamino-5-carboxy valeramido) cephalosporanic acid was reacted with 4,5-dihydro-6-hydroxy-4-methyl- 3-thiol to give 3 - (((4,5-dihydro-6-hydroxy-4-methyl- Methyl) -7-methoxy-7- (5-benzoylamino-5-carboxy valeramido) -3-cephem-4- carboxylic acid.

7-methoxy-7- (5-benzoylamino-5-carboxy valeramido) -separasporanic acid is reacted with thiourea to give 3-amidinothiomethyl-7-methoxy- 7- 5-carboxy valetamido) -3-cephem-4-carboxylic acid is produced.

The reaction of 7- (5-butoxycarbonylamino-5-carboxy valeramido) -3-carbamoyloxymethyl-3-cephem-4- carboxylic acid with thiourea gave 3-amidinothiomethyl-7- (5 -Butoxycarbonylamino-5-carboxy valeramido) -3-cephem-4-carboxylic acid.

The reaction of 7- (5-butoxycarbonylamino-5-carboxy valeramido) -3-carbamoyloxymethyl-3-cephem-4- carboxylic acid with 1-methyl-1H-tetrazole- - (((1-methyl-1H-tetrazol-5-yl) thio) methyl) butoxycarbonylamino-5-carboxy valeramido) -3-cephem-4-carboxylic acid.

Carboxyvaleramido) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid was reacted with 5-methyl-1,3,4-thiadiazole-2- (5-methyl-1,3,4-thiadiazol-2-yl) thio) methyl) -7 (5-butoxycarbonylamino-5-carboxy valeramido) - 3-cephem-4-carboxylic acid is produced.

Carboxy valylamido) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid with 1- (carboxymethyl) -1H-tetrazole-5- (5-butoxycarbonylamino-5-carboxy valeramido) -3-cephem-5-yl) thio) methyl) 4-carboxylic acid is produced.

Claims (1)

A process for the preparation of a cephalosporin compound of the general formula (I), characterized in that a compound of the general formula (II) is reacted with a sulfur-containing nucleophilic reagent of the general formula (III) in an organic solvent under anhydrous conditions.

In the general formula, R < ¹³ >

R ¹ is hydrogen or methoxy and R ² is phthalimido,

(Wherein L is hydrogen or nitroso). Or a general formula

Fluoroalkyl (1 to 3 carbon atoms - a group where, R ³ is 1) hydrogen, 2) C 1 -C 6 alkyl, 3) -CH ₂ - (C 1 -C 3 alkyl, chloro), 4) -CH ₂ Alkyl, cyanoalkyl having 1 to 4 carbon atoms, 6) hydroxyalkyl having 1 to 4 carbon atoms, 7) p-nitrobenzyloxy, 8) tert- 10) a compound represented by the general formula

Amino-4-carboxybutyl group wherein A ¹ is a protected amino group and R ¹² is hydrogen or alkyl of 1 to 4 carbon atoms. 11) 4-oxo-4-carboxybutyl, 12) 3-carboxypropyl. 13) General formula

The group [herein, each of a and a ¹ are respectively hydrogen, alkoxy, halogen, hydroxy, or A ¹ CH ₂ C 1 -C 4 alkyl, C 1 -C 4 - (wherein A ¹ is protected, as in the Lt; / RTI > z is oxygen or sulfur atom, and m is 0 or 1. 14) General formula

(Wherein p is a) 2-thienyl b) 3-thienyl or c)

(A and a ¹ are as defined above) Q) is a) hydroxy b) formyloxy c) acetoxy d) a phenyl group of formula

Carboxy wherein A ² is diphenylmethyl, p-nitrobenzyl, benzyl, 2,2,2-trichloroethyl, tertiary butyl or p-methoxybenzyl e) an alkali metal oxysulfonyl, f) a protected amino group, g)

Lt; / RTI > amino group, wherein T is amino,

Wherein R ⁷ is hydrogen or alkyl having 1 to 3 carbon atoms and R ⁸ is phenyl, halophenyl, furyl, monomethylamino, dimethylamino, monoethylamino, diethylamino, methylethylamino, Diisopropylamino, phenylamino or diphenylamino. R ⁹ is hydrogen, alkyl having 1 to 4 carbon atoms or phenyl, R ¹⁰ is hydrogen, alkyl having 1 to 3 carbon atoms or methylsulfonyl, and R ¹¹ is ethylene, trimethylene or vinylene) 15) General formula

Wherein P 'is P, protected 2-amino-4-thiazolyl or 2-furyl as defined above. 16) a group of the general formula VS (O) n-CH ₂ -, wherein V is -CF ₃ or -CH ₂ -X, X is hydrogen, methyl, CF ₃ , CN or N ₃ , 1 or 2; or 17) a group of the general formula Y-CH ₂ -, wherein Y is selected from the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 2-oxazolyl, 2-thiazolyl, , 1-benzotriazolyl, 2-oxazolylthio, 2-thiazolylthio, 1,2,3-triazol-5-ylthio, Thiadiazol-2-ylthio, protected -5-amino-1,3,4-thiadiazol-2-ylthio, 5-methyl-1,3,4- Thiadiazol-5-ylthio, 3-methyl-1,2,4-oxadiazole-2-ylthio, 5-methyl-5-tetrazolylthio, pyridylthio , 4-cyano-1,2,3-triazol-1-yl, 3-cyano-1,2,4-triazol-1-yl or protected 2-amino-4-thiazolyl). R ⁴ is each independently hydrogen, alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 3 carbon atoms, cyclohexyl or phenyl, R ⁵ is alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, Nitro, cyano, methanesulfonamido or trifluoromethyl, and R < ⁶ > is an optionally substituted 5- or 6-membered heteroaromatic ring having a total of 1 to 4 heteroatoms selected from the group consisting of

One nitrogen and zero or one oxygen or sulfur, two nitrogen and zero or oxygen or sulfur. Three nitrogen and zero or one oxygen or four nitrogen; Or 2-benzoxazolyl or a group containing a group of the formula

Structure

R is alkyl having 1 to 3 carbon atoms, cycloalkyl having 4 to 6 carbon atoms, amino, mono or di alkyl) amino having 1 to 3 carbon atoms,

or

ego, R ¹⁴ is hydrogen or when R ¹³ is a methylenammonium group, then R ¹⁴ combines with R ¹³ to form thiourea.