KR810000186B1 - -lactam antibiotics process for their preparation - Google Patents

Abstract

Title compds. [I; R = H or methoxy; Z = R1R2C=N- or R1R2COHNH-; R1,R2 = H, alkyl, alkenyl, cycloalkyl, cycloalkadienyl, aralkyl or -SO2N(CH3)2; A = -CH2CH2-, -CH2CHCH2- or C6H5; B = phenyl, cyclohexenyl or cyclohexadienyl; X = S, O, SO, SO2 or -CH2-; Y = -CHCOOH(CH3)2C-, -C(COOH)CCH2TCH2-; T = H, alkyl, -CO2-, cyano, W = halogen or azide were prepd. by reaction of II and III. I had ED50 against Escherichia coli C 165, Klibsiella, pseudomonas aeruginosa infections in mice of 100,000, 2x7500, and 4x150,000 units S.C.

Description

Method for preparing β-lactam antibiotics

The present invention relates to a method for the preparation of novel β-lactam antibiotics, which are particularly antimicrobial agents and are also easy to promote animal growth and promote food use.

It is already known that some α- (imidazolidine-2-oxo-1-yl-carbonylamino) -benzyl penicillins have antimicrobial activity. (See Belgium Patent Specification 767,647, 767,648, Dutch Patent Specification 7,114,254, German Publication No. 2,152,968).

The novel β-lactam antibiotics according to the present invention differ chemically from the known compounds of the reference in that the N3 of the imidazolidinone radical is overlapped with the atoms of the imino group.

The present invention provides β-lactam antibiotics of the general formula (I).

In the above formula

R represents hydrogen or methoxy

=N- 또는

Z is

= N- or

Indicates

here

R ¹ and R ² are the same or different and are hydrogen, optionally substituted alkyl or alkenyl, optionally substituted cycloalkyl or cycloalkenyl and cycloalkadienyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heterocycle Reel, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, nitro, lower alkylcarbonyl, -CONH ₃ , -CONH CH ₃ , -CON (CH ₃ ) ₂ , -SO ₂ -NH ₂ , -SO ₂ —NH CH ₃ or —SO ₂ N (CH ₃ ) ₂ , or R ¹ and R ² together with their bonded carbons may form a saturated or unsaturated 3-7 membered carbocyclic or heterocyclic ring; Can be formed, and A is -CH ₂ -CH _2- , -CH ₂ -CH ₂ -CH ₂ -or

이며,

Is,

B represents optionally substituted phenyl, cyclohexenyl or cyclohexadienyl, X represents SOSO.SO ₂ or -CH _2- ,

및

Y is

And

To indicate

here

The carbon atom bonded to the carboxyl group is bonded to the nitrogen atom of the β-lactam ring,

T is hydrogen, alkyl-CO-0-, pyridinium, amino-pyridinium, carbamoyloxy, azido, cyano,

Hydroxyl, optionally substituted -S-phenyl or -S-Het group,

Het represents an optionally substituted 5-6 membered heterocycle;

=N-이고 R1과 R2가 서로 다른 때에는 이미 노기에 대해서 Syn-형이나 anti-형으로 존재할 수 있으며, 또한 일반식(Ⅰ)의 화합물은 여러 수화물의 형태나 염의 형태로서 존재할 수 있다.The compound of the general formula (I) may be present in the double configuration of the R and S forms with respect to the subsidiary core carbon ^* C, may also exist as a diastereomeric mixture, Z is

When N = and R1 and R2 are different from each other, they may already exist in Syn-type or anti-form with respect to the furnace, and the compound of general formula (I) may exist in the form of various hydrates or salts.

The compounds of the present invention of general formula (I) and their salts exhibit potent antimicrobial activity and improve the growth of animals and the availability of food. Pharmaceutically nontoxic salts of the salts of the compounds of the invention are important and preferred.

The compound of the present invention is obtained by reacting a compound of the following general formula (II) or a salt thereof with the compound of the following general formula (III) in the presence of a solvent, optionally in the presence of an acid binder, at -20 ° to 50 ° C, and β-lactam The antibiotic is optionally converted or the free acid is prepared from the salt obtained if necessary.

In the above formula

R, B, ^* C, X, Y, A, Z are as described above and W represents halogen or azide or other removable nucleophilic group.

Surprisingly, the compounds of the present invention exhibit more potent and broader antimicrobial activity, ie, activity against a wider range of Gram-negative bacteria than known β-lactam antibiotics.

When using D-α-amino benzyl penicillin and 1-chlorocarbonyl-3-benzylideneamino-imidazolidin-2-one as starting materials, the reaction process can be represented by the following formula.

Alkyl R ¹ and R ² optionally substituted in the description of general formula (I) are preferably straight or branched chain alkyl of 1 to 6 carbon atoms, especially 1 to 4 carbon atoms. And optionally substituted methyl, ethyl, n- and isopropyl, n-, iso-, and tertiary butyl.

The optionally substituted alkenyl R ¹ and R ² are preferably straight or branched chain alkenyls having 2 to 6 carbon atoms, especially 2 to 4 carbon atoms, for example optionally substituted ethenyl, propenyl- (1), propenyl- (2) and butenyl (3).

The optionally substituted cycloalkyl, cycloalkenyl and cyclo alkadienyl R1 and R2 are preferably monocyclic, bicyclic and tricyclic having 3 to 10 carbon atoms, especially 3,5 or 6 carbon atoms. Examples include substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, bicyclo 2,2-yl-heptyl, bicyclo [2,2, 2,]-octyl and adamantyl.

The optionally substituted aryl R ¹ and R ² are preferably aryl having 6 to 10 carbon atoms in the aryl moiety. Examples are optionally substituted phenyl or naphthyl. The substituent of the phenyl ring is 0-, m- or P-position;

및

를 들 수 있다.

And

Can be mentioned.

Optionally substituted aralkyl R ¹ and R ² are aralkyl in which the aryl moiety and / or the alkyl moiety are optionally substituted, wherein the aryl moiety preferably has 6 to 10, especially 6, carbon atoms of the alkyl moiety is preferably 1 To 4, in particular 1 or 2, the alkyl moiety being straight or branched. And optionally substituted benzyl and phenylethyl.

Optionally substituted heterocycles R ¹ and R ² are 5-7 membered rings, preferably 5 or 6-membered rings, hetero-paraffinic, hetero containing preferably 1 to 3, especially 1 or 2, identical or different heteroatoms; -Aromatic, hetero-olefin ring. Heteroatoms include oxygen, sulfur or nitrogen atoms. For example optionally substituted thienyl, furyloxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxdiazolyl, thiadiazolyl, triazolyl, oxtriazolyl, tithiazolyl, tetrazolyl, pyri Dill, pyrazinyl, pyramidinyl, tetrahydrofuranyl, dioxanyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl-2 and pyridyl-4 and the like.

Alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl and aralkyl R ¹ and R ² carry one or more, preferably 1 to 3, in particular 1 to 2, identical or different radicals R ³ . can do. It is particularly preferred that the radicals R ¹ and R ² contain an unsubstituted or substituted substituent.

The heterocycles R ¹ and R ² may carry one or more, preferably 1 to 3, in particular 1 to 2, identical or different R ⁴ . It is especially preferred when heterocycles R ¹ and R ² are unsubstituted or carry one substituent R ⁴ .

"Lower alkyl" (lower alkoxy, HCON- (lower alkyl) and the like) preferably represents straight chain alkyl having 1 to 6 carbon atoms, in particular 1 to 4 carbon atoms. Examples are optionally substituted methyl, ethyl, n- and isopropyl, n-, iso- and tert-butyl. “Lower alkyl” may be substituted with the same or different halogen atoms 1 to 5, especially 1 to 3, with fluorine chlorine and bromine being particularly preferred as halogen. Examples include trifluoromethyl, chlorodifluoromethyl, bromomethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.

R ³ is halogen, preferably fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine, bromine, amino, mono-lower alkylamino, preferably methylamino, and ethylamino, especially methylamino, dilower alkylamino, Especially dimethylamino and diethylamino, especially dimethylamino; Pyrrolidyl; Piperidyl; HCO-NH-; Lower alkyl-CO-NH-, preferably CH ₃ -CO-NH-; H-CO-N- (loweralkyl)-, preferably H-CO-N (CH ₃ )-or H-CO-N (C ₂ H ₅ )-; Loweralkyl-CO-N- (loweralkyl)-, preferably CH ₃ -CO-N (CH ₃ )-; (Lower alkyl) ₂ C═N—; Loweralkyl-SO ₂ -NH-, preferably CH ₃ -SO ₂ -NH- and C ₂ H ₅ -SO ₂ -NH-, and especially CH ₃ -SO ₂ -NH-; Loweralkyl-SO ₂ -N- (loweralkyl)-, preferably CH ₃ -SO ₂ -N (CH ₃ )-; HO-SO ₂ -NH-HO-SO ₂ -N (lower alkyl)-, preferably HO-SO ₂ -N (CH ₃ )-and HO-SO ₂ -N (CH ₅ )-; Amidino; (Lower alkyl) ₂ -N-CH = N-, in particular (CH ₃ ) ₂ N-CH = N-;

, 구아니도, 니트로, 아지도, 하이드록실, 저급알킬옥시, 바람직하게는 CH₃-O- 및 C₂H₅-O- 특히 CH₃O-; H-CO-O-; 저급알킬-CO-O- 바람직하게는 CH₃-CO-O, C₂H₅-CO-O 및 (CH₃)₃C-CO-O-; 저급알킬-O-CO-O-, 바람직하게는 CH₃-O-CO-O-, C₂H₅-O-CO-O- 및 (CH₃)₃C-O-CO-O-; H₂N-CO-O-; 저급알킬-NH-CO-O-,

, Guanido, nitro, azido, hydroxyl, lower alkyloxy, preferably CH ₃ -O- and C ₂ H ₅ -O- in particular CH ₃ O-; H-CO-O-; Loweralkyl-CO-O- preferably CH ₃ -CO-O, C ₂ H ₅ -CO-O and (CH ₃ ) ₃ C-CO-O-; Lower alkyl-O-CO-O-, preferably CH ₃ -O-CO-O-, C ₂ H ₅ -O-CO-O- and (CH ₃ ) ₃ CO-CO-O-; H ₂ N-CO-O-; Lower alkyl-NH-CO-O-,

Preferably CH ₃ -NH-CO-O- and C ₂ H ₅ -NH-CO-O-; Loweralkyl-NH-CO-O-, preferably CH ₃ -NH-CO-O- and C ₂ H ₅ -NH-CO-O-; (Lower alkyl) ₂ N-CO-O- preferably (CH ₃ ) ₂ N-CO-O- (C ₂ H ₅ ) ₂ N-CO-O-,

및 H₂N-SO₂-O-; 저급알킬-NH-SO₂-O-, 바람직하게는 CH₃-NH-SO₂-O- 및 C₂H₅-NH-SO₂-O-; (저급알킬)₂N-SO₂-O-, 바람직하게는 (CH₃)₂N-SO₂-O- 및 (C₂H₅)₂N-SO₂-O-; HOOC- 및 H₂N-CO; (저급알킬)₂N-CO-, 특히 (CH₃)₂N-CO- 및 (C₂H₅)₂N-CO-; OHC-; HO-SO₂-O- 및 HS-, 저급알킬-S-, 바람직하게는 CH₃-S-, CF₃-S-, C₂H₅-S- 및 (CH₂)₂CH-S-,

, 바람직하게는

및

저급알킬-SO₂-, 바람직하게는 CH₃-SO₂-, CF₃,-SO₂- 및 C₂H₅-SO₂-; H₂N-SO₂- 그룹; 저급알킬-NH-SO₂-, 바람직하게는 CH₃-NH-SO₂및 C₂H₅-NH-SO₂-; (저급알킬)₂N-SO₂-, 바람직하게는 (CH₃)₂N-SO₂- 및 (C₂H₅)₂N-SO₂-;

HO-SO₂-S-그룹;

And H ₂ N-SO ₂ -O-; Loweralkyl-NH-SO ₂ -O-, preferably CH ₃ -NH-SO ₂ -O- and C ₂ H ₅ -NH-SO ₂ -O-; (Lower alkyl) ₂ N-SO ₂ -O-, preferably (CH ₃ ) ₂ N-SO ₂ -O- and (C ₂ H ₅ ) ₂ N-SO ₂ -O-; HOOC- and H ₂ N-CO; (Lower alkyl) ₂ N-CO-, in particular (CH ₃ ) ₂ N-CO- and (C ₂ H ₅ ) ₂ N-CO-; OHC-; HO-SO ₂ -O- and HS-, lower alkyl-S-, preferably CH ₃ -S-, CF ₃ -S-, C ₂ H ₅ -S- and (CH ₂ ) ₂ CH-S-,

, Preferably

And

Loweralkyl-SO _2- , preferably CH ₃ -SO _2- , CF ₃ , -SO ₂ -and C ₂ H ₅ -SO _2- ; H ₂ N-SO ₂ -group; Loweralkyl-NH-SO _2- , preferably CH ₃ -NH-SO ₂ and C ₂ H ₅ -NH-SO _2- ; (Lower alkyl) ₂ N-SO _2- , preferably (CH ₃ ) ₂ N-SO ₂ -and (C ₂ H ₅ ) ₂ N-SO _2- ;

HO-SO ₂ -S-group;

Straight or branched chain alkyl of 1 to 6 carbon atoms, especially methyl, ethyl, propyl, isopropyl, n-butyl, secondary-butyl or tert-butyl, preferably methyl, furyl-2, phenyl or phenoxy.

; HOOC- 그룹, HO₃-S-; 저급알킬-NH-SO₂-, 특히 CH₃-NH-SO₂-; (저급알킬) NSO₂-, 특히 (CH₃)₂NSO₂-; HCO-; 저급알킬-CO-, 바람직하게는 CH₃-CO-; 저급알킬-O-CO-, 바람직하게는 CH₃-O-CO- 및 C₂H₅-O-CO-; 및 -CN, 저급알킬-O-CO-CH₂, 바람직하게는 CH₃-O-COCH₂-나 C₂H₅-OCOCH₂-; (저급알킬-O)₂CH-, 바람직하게는 (C₂H₅O)CH-;HO-저급알킬-, 바람직하게는 HO-CH₂-,

및

티에닐, 푸릴, 옥사졸릴, 이속사졸릴, 티아졸릴, 이소티아졸릴, 피롤릴, 이미다졸릴, 옥스디아졸릴, 티아디아졸릴, 트리아졸릴, 옥스트리아졸릴, 티아트리아졸릴, 테트라졸릴, 피롤리디닐, 피페리디닐, 므르폴리닐, 바람직하게는 푸릴이다.When R ⁴ is present at one or more carbon atoms of the heterocyclic radicals R ¹ and R ² , R ⁴ is lower alkyl, preferably methyl, ethyl, isopropyl, especially methyl; Cycloalkyl having 3 to 7, preferably 3 to 6 carbon atoms, in particular cyclopropyl; Trifluoromethyl; Halogen, preferably fluorine, chlorine, or bromine; Nitro; Amino; Lower alkylamino, preferably CH ₃ -NH- and C ₂ H ₅ -NH-di-lower alkylamino, preferably (CH ₃ ) ₂ N- and (C ₂ H ₅ ) ₂ N-; Formylamino; Acetylamino; CH ₃ O—CO—NH— and C ₂ H ₅ O—CO—NH—; CH ₃ -SO ₂ -NH-; Hydroxyl, methoxy, ethoxy, methylthio and ethylthio; CH ₃ -SO _2- ; CH ₃ -SO-, lower alkyl-NH-SO ₂ , preferably CH ₃ -NH-SO _2- ; Lower alkoxy-CH ₂ , in particular CH ₃ -CH ₂ and C ₂ H ₅ O-CH _2- ; Heterocycle-aldimino (heterocycle as defined in R ¹ and R ² ), in particular furyl-2-aldimino, alkenyl (as defined in R ¹ and R ² ), in particular allyl,

; HOOC- group, HO ₃ -S-; Lower alkyl-NH-SO _2- , in particular CH ₃ -NH-SO _2- ; (Lower alkyl) NSO _2- , in particular (CH ₃ ) ₂ NSO _2- ; HCO-; Lower alkyl-CO-, preferably CH ₃ -CO-; Loweralkyl-O-CO-, preferably CH ₃ -O-CO- and C ₂ H ₅ -O-CO-; And —CN, lower alkyl-O—CO—CH ₂ , preferably CH ₃ —O—COCH ₂ — or C ₂ H ₅ —OCOCH ₂ —; (Lower alkyl-O) ₂ CH-, preferably (C ₂ H ₅ O) CH-; HO-lower alkyl-, preferably HO-CH _2- ,

And

Thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, oxdiazolyl, thiadiazolyl, triazolyl, oxtriazolyl, tithiazolyl, tetrazolyl, pyrroly Dinil, piperidinyl, merpolyyl, preferably furyl.

When R ⁴ is present as a substituent on at least one of R ¹ and R ² , which is a heterocyclic group containing nitrogen, R ⁴ is lower alkyl; Preferably methyl, ethyl, propyl, isopropyl, especially methyl and ethyl; -C≡N group, -CHO; -COO-loweralkyl, preferably -COO-CH ₃ , -COOC ₂ H ₅ , -COOCH (CH ₃ ) ₂ and -COO-C (CH ₃ ) ₃ ); -CO-NH ₂ ; -CO-NH-lower alkyl, preferably -CO-NH-CH ₃ , -CO-NH-C ₂ H ₅ and -CO-NH-CH (CH ₃ ) ₂ and -CO-loweralkyl, preferably -CO-CH ₂ , -CO-C ₂ H ₅ and -CO-CH (CH ₃ ) ₂ .

R ¹ and R ² together with the carbon to which they are attached form a saturated or unsaturated ring. The unsaturated ring preferably has a double bond of 1 or 2. The ring contains one or more, preferably 1 to 2, in particular one heteroatom or heterogroup. Heteroatoms include oxygen, sulfur and / or nitrogen. Examples of the hetero group include SO ₂ -and lower alkyl-N-, and in the case of 6-membered ring, it is preferable that one hetero atom or hetero group is in the 4-position.

(The following rings are particularly preferable for the carbon atom to which R ¹ and R ² are bonded.)

The ring formed by R ¹ and R ² together with the carbon atom to which they are attached may contain one or more, preferably 1 to 3, especially 1 to 2, identical or different substituents R ⁵ .

R ⁵ is halogen, preferably fluorine, chlorine, bromine; Hydroxyl; lower alkoxy, preferably methoxy, ethoxy, lower alkylthio, preferably methylthio, ethylthio, amino, lower alkylamino, preferably CH ₃ -NH-, C ₂ H ₅ -NH- , Di-lower alkylamino, preferably dimethylamino, diethyl amino, -CN; -COOH; -COOCH ₃ and COOC ₂ H ₅ ; Linear or branched lower alkyl, preferably methyl, ethyl and the like.

Especially preferably, at least one of R ¹ and R ² represents hydrogen.

를 나타낸다.Particularly preferably Z is

Indicates.

라디칼을 함유하는 화합물은, 그 기를 함유한 구조식(Ⅲ)의 화합물을 사용하거나 수성용매중에서 반응시켜 제조할 수 있다.

The compound containing a radical can be manufactured using the compound of structural formula (III) containing the group, or by making it react in an aqueous solvent.

Phenyl B may carry one or more, preferably 1 to 3, especially 1 to 2, identical or different substituents.

Substituents may be at the O-, m- and / or P-positions. Preferably the substituent is at the P- or m-position. Examples of substituents include halogens such as fluorine, chlorine, bromine and iodine, fluorine, chlorine bromine, alkyl having 1 to 6 carbon atoms, preferably 1 to 4 especially alkyl having 1 to 2, cyano and methylsulfonyl . Examples of the substituted phenyl group B include hydroxy phenyl group (preferably P-hydroxyphenyl), methylphenyl group (preferably P-methylphenyl), cyanophenyl group (preferably m- and P-cyano phenyl group), Methylsulfonyl groups (preferably P-methylsulfonylphenyl) and fluorophenyl groups (preferably O-fluorophenyl and m-fluorophenyl).

In the definition of T, alkyl of alkyl-CO-O- refers to alkyl of 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms.

For example, methyl, ethyl, methyl is more preferred.

The heterocyclic Het (definition of T) of -S-Het contains the same or different heteroatoms 1 to 4, preferably 1 to 3, in 5- or 6-membered rings, and heteroatoms include oxygen and sulfur nitrogen. It is preferable that a heterocycle becomes unsaturated, and it is especially preferable to contain one double bond. This heterocycle preferably has one or more preferably 1 to 2, in particular one substituent. Examples of the substituent include halogens such as fluorine, chlorine and bromine iodine, preferably chlorine and bromine, amino, lower alkylamino, di-lower alkylamino, lower alkyl, and cycloalkyl (cycloalkyl ring having 3 to 7, preferably 5-6), lower alkoxy, trifluoromethyl, phenyl, benzyl, acylamino (2 to 5 carbon atoms, especially 2 to 3).

Particularly preferred cases as -S-Het are as follows.

The -S-phenyl group in T may carry one or more, preferably 1 to 3, in particular 1 to 2, identical or different substituents, preferred substituents being those listed as possible substituents of -S-Het.

^* C is particularly preferred that the D- = R- coordination compound.

All crystalline hydrates and their salts of the compounds of general formula (I) of the present invention likewise have an antibacterial action.

Halogen W represents fluorine, chlorine and bromine, with bromine, chlorine, especially chlorine being preferred.

Removable dinuclear groups in the definition of W are both possible in organic chemistry and in particular those described in Angewandte Chemie 81 (1969) 10 543.

Pharmaceutically nontoxic salts of compounds of formula (I) are inorganic or organic bases with carboxyl groups of these compounds or salts of carboxyl and sulfonic acids. In general, all bases used in weak chemistry, particularly antibiotic chemistry can be used. For example, inorganic bases are hydroxides, carbonates and alkali metal bicarbonates of alkali and alkaline metals, sodium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, potassium hydrogen carbonate, aluminum hydroxide and ammonium hydroxide. There is this. As organic amines, primary, secondary, tertiary, aliphatic amines and heterocyclic amines can be used. For example, di- and tri-lower alkylamines such as diethylamine, triethylamine, tri-β-hydroxy ethylamine, procaine, dibenzylamine, N, N'-dibenzylethylenediamine, N-benzyl -β-phenylethylamine, N-methylmorpholine and N-ethylmorpholine, 1-ephenamine, dehydroabiethylamine, N, N'-bis-dehydroabiethylenediamine, N-lower alkylpiperidine Etc. Basic amino acids such as lysine and arginine may also be usefully used as bases. In particular, sodium salt is preferable.

Particularly preferred compounds of general formula (I) are those in which the definition of radicals is as follows and their sodium salts:

R represents hydrogen

또는

를 나타내는데Z is

or

To indicate

From above

R ¹ represents hydrogen,

R ² is halogen (fluorine, chlorine, bromine) alkyl having 1 to 4 carbons (particularly methyl), alkoxy having 1 to 4 carbon atoms (particularly methoxy), nitro, cyano, alkylsulfonyl having 1 to 4 carbon atoms (particularly methyl Sulfonyl), or phenyl optionally substituted with CH ₃ OOC-; Furyl or thienyl rings of 4- or ₅ -position optionally substituted with halogen (especially chlorine or bromine), NO ₂ , alkyl or alkoxycarbonyl having 1 to 4 carbon atoms, or CH ₃ COOCH ₂ -are 2- And preferably bonded at the 3-position, or represents pyridyl (preferably pyridyl-3);

A represents -CH ₂ -CH _2- ;

B represents phenyl, hydroxyphenyl (preferably P-hydroxyphenyl), and saclohexadienyl (preferably cyclohexa-1,4-dien-1-yl);

및

을 나타내는데Y is

And

To indicate

From above

T is hydrogen, —OCO—CH ₃ , hydroxyl, thiadiazolylthio or tetrazolylthio, optionally substituted with alkyl or CF ₃ of 1 to 4 carbon atoms;

^* C has a D- = R- configuration.

Compounds of the general formula (II) used as starting materials may be known compounds or may be prepared by known methods.

All crystalline forms, hydrates, and salts of compounds of formula II can be used as starting materials.

Examples include α-aminobenzylphenicillin, α-amino-P-hydroxybenzylpenicillin, α-amino-P-methylbenzylphenicillin, α-amino-P-chlorobenzylphenicillin, 6- [2-amino-2- (1,4-cyclohexadien-l-yl) acetamido] -phenylanic acid, 7- (α-amino-phenylacetamido) -3-methyl-ce-3-fem-4-carboxylic acid, 7 -(α-amino-phenylacetamido) -3-acetoxymethyl-ce-3-fem-4-carboxylic acid and the like.

As a salt of the compound of general formula (II), the salt with the base listed as a suitable base for preparing the salt of general formula (I) can be used. Sodium salts are particularly preferred.

Compounds of general formula (III) used as starting materials can be prepared according to known methods. For example, it can manufacture by the following method (refer J.A.C.S. 78, (1956)).

For example, the compound of the general formula (III) used as a starting material is as follows.

1-chlorocarbonyl-2-oxo-3-benzalamino-imidazolidine,

1-azidocarbonyl-2-oxo-3-benzalimino-imidazolidine,

1-chlorocarbonyl-2-oxo-3- (4-chloro) -benzylimino-imidazolidine,

1-chlorocarbonyl-2-oxo-3- (4-methoxy) -benzalmino-imidazolidine,

1-chlorocarbonyl-2-oxo-3- (4-nitro) -benzalmino-imidazolidine,

1-chlorocarbonyl-2-oxo-3- (4-cyano) -benzalmino-imidazolidine,

1-chlorocarbonyl-2-oxo-3- (4-methylsulfonyl) -benzalmino-imidazolidine,

1-azidocarbonyl-2-oxo-3- (thiophen-2-alamino) -imidazolidine,

1-chlorocarbonyl-2-oxo-3- (furan-2-aldehydeamino) -imidazolidine,

1-azidocarbonyl-2-oxo-3- (furan-2-aldehydeamino) -imidazolidine,

The compound of the general formula (III) wherein W is an azide can be produced by, for example, reacting a compound of the general formula (III) wherein W is halogen with an alkali metal azide or the like.

Diluents which can be used in the present invention are water and all inert organic solvents, preferably water-miscible.

These include, among others, lower dialkyl ketones such as acetone, methyl ethyl ketone, cyclic ethers such as tetrahydrofuran, dioxane, nitriles such as acetonitrile, lower dialkylformamides such as dimethylform Amide lower alkyl alcohols such as ethanol and isopropanol, dimethyl sulfoxide.

These solvents can also be used in mixtures thereof and in mixtures of water and one or more of the desired solvents. The process of the present invention can therefore be carried out in the presence of (1) in the presence of only water, (2) in the presence of only one or more solvents, and (3) in the presence of water and one or more organic solvents. If the pH can be measured by the presence of water during the reaction, it is preferable to add a base or maintain the pH at 6.5 to 7.5 using a buffer. However, the room is very easily performed in other pH ranges, for example pH 4.5-9.0, or pH 2.0-4.5. The reaction may also be carried out by adding an organic base, preferably a lower alkylamine such as triethylamine or diethylamine, or a cyclic base such as N-ethylpiperidine, to a water immiscible solvent such as a halogenated hydrocarbon such as chloroform or methylene chloride. Can be done. It may also be carried out in a mixture of water and a water-immiscible solvent, for example lower alkyl ethers such as diethyl ether, halogenated hydrocarbons such as chloroform and methylene chloride, esters such as carbon disulfide, isobutyl methyl ketone, ethyl acetate, Aromatic hydrocarbons such as benzene, in which case it is advantageous to maintain the pH at 4.5 to 9.0 or 2.0 to 4.5 by vigorously stirring and adding a base or adding phosphate, acetate, citric acid and a buffer solution. However, the reaction can be carried out using only water in the absence of an organic solvent, in the presence of organic or inorganic, base or in the presence of a conventional buffer.

Any acid binder used in conventional antibiotic chemistry can be used. These include inorganic or organic bases that are difficult to acylate due to steric hindrance. Examples of inorganic bases include sodium hydroxide and potassium hydroxide. Organic bases that can be used also include almost all ring-opening or cyclic amines and hetero-aromatic bases that cannot be acylated or are difficult to be acylated. Examples of such bases are tertiary amines, preferably lower alkylamines such as triethylamine and / or secondary amines such as cyclic bases such as pyridine and dicyclohexyl amine which are difficult to acylate.

The addition of a base in the process of the invention is only necessary if an acid is produced during the reaction, such as when W is halogen or azide.

The reaction temperature can vary within a significant range and is generally carried out at -20 ° C to 50 ° C, preferably 0 to 20 ° C. However, as in most chemical reactions, in principle high or low temperatures outside the above ranges are also possible.

The reaction can proceed at atmospheric pressure and under pressure or reduced pressure but generally uses atmospheric pressure.

In carrying out the present reaction, the ratio of the compound of formula (II) to the reactant of formula (III) can be varied within limits that do not adversely affect the reaction. For example, starting materials can be reacted using the same amount (water). However, the excess use of one of the two reactants is convenient to enhance the yield by facilitating the purification or preparation (in pure form) of the desired penicillin.

For example, using 0.1 to 0.3 molar equivalents of the reactant of general formula (II) can reduce the decomposition of the reactant of general formula (III) in the aqueous solvent mixture. The excess reactant of general formula (II) is easily dissolved in the aqueous inorganic acid, so that the reaction mixture can be completed and easily removed.

On the other hand, the reactant of general formula (III) may be used in an excess of 0.1 to 1.0 molar equivalents. This enhances the efficiency of the reactants of general formula (II) and counteracts the decomposition of the reactants of general formula (III) that occur as side reactions in aqueous solvents. The compound of formula III added in excess is rapidly converted into a neutral heterocyclic compound containing nitrogen in water, which can be easily removed so that the purity of the antibiotic is not significantly reduced.

The amount of base used depends on the desired maintenance pH value. It is preferable to add 2 molar equivalents of base when there is not enough water in the diluent to measure or control the pH, or if it is not meaningful.

Completion of the reaction batch to prepare other compounds and their salts in the present invention is carried out by methods known for these compounds. The separation and purification of the compounds according to the invention, the free acid free from the salts, the conversion of the free acid to the salts are also carried out according to conventional organic chemistry methods known to the expert.

It is a free acid form water or anhydride and has the same antibacterial activity.

The following table is an example of novel active substances.

TABLE A

(A) I) R1 represents hydrogen.

(A) II) R ¹ represents hydrogen; B represents phenyl; R ² represents the following.

(A) III) B represents phenyl. ;

(A) IV) B represents cyclohexa-1,4-dien-1-yl.

(A) V) B represents phenyl;

은 다음을 나타낸다.

Indicates the following:

(B) I) R ¹ represents hydrogen; T represents -O-COCH ³ .

(B) II) R ¹ represents hydrogen; B represents phenyl;

T represents -O-CO-CH ₃

R ₂ represents the following.

(B) III) B represents phenyl; T represents -O-CO-CH ₃ .

(B) IV) B represents cyclohexa-1,4-dien-1-yl and T represents O-CO-CH ₃ .

는 다음을 나타낸다.(B) V) B represents phenyl; T represents -O-CO-CH ₃

Indicates the following.

(B) Ⅵ)

(B) i) B represents phenyl.

The active compounds according to the invention have strong and broad antimicrobial activity while low toxicity. Because of this property, it is used as a chemotherapeutic agent as a medicine and is used as a preservative of inorganic and organic substances, especially preservatives of all organic substances such as polymers, lubricants, paints, fibers, leather, paper, wood, food and water.

The active substance according to the invention has a very broad antimicrobial activity. It can be used to kill Gram-negative and Gram-positive and bacterial microorganisms, as well as to prevent, alleviate and / or cure diseases caused by these pathogens.

In particular, the compounds according to the invention have potent activity against bacteria and bacterial microorganisms. Therefore, it is suitable for the prevention and treatment of local and systemic infections caused by these pathogens in medicine and veterinary medicine.

For example, local and systemic infections caused by the following pathogens or combination infections can be treated and / or prevented. Micrococcases such as Staphylococcus aureus, Staphylococcus epidermis, Staphylococcus aerogenes, and Gafka tetragena;

Strapcoccus pyogenes, α- or β-hemolytic Streptococcus, non- (γ) -hemolytic Streptococcus, Streptococcus viridans, Streptococcus pecalis (Enterococcus), Streptococcus agalactiae, Streptococcus lac Lactobacillus, such as Streptococcus and Diflococcus pneumoniae (Pneumococcus), such as this, Streptococcus equ, Streptococcus anerobis;

Neisseria such as Neisseria gonorrea (gonococcus), Neisseria meningitidis (meningococcus), Neisseria catarrhalis, Neisseria pollava, etc.

Corynebacterium diphtheriae, Corynebacterium piogenes, Corynebacterium diphtheroides, Corynebacterium acrones, Corynebacterium parboom, Corynebacterium boris, Corynebacterium lenale, Corynebacterium such as Corynebacterium orbis and Corynebacterium myricepticum, Listeria bacteria such as Listeria monocytogenes, Erysipelotrix bacteria such as Erysefelotrix insidioza, Kurtia zeppei, etc. Corynebacterial such as protea bacteria;

Mycobacterial pathogens such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium avium and so-called dysplastic mycobacteria and mycobacterium of the lunin groups I, II, III and IV Mycobacterial such as teprae;

Enterobacteriaceae such as E. coli Escherichia bacteria; this. Escherichia bacteria such as E. coli, Enterobacter bacteria such as Enterobacter erogenes and Enderobacter cloase, Klebsiella bacteria such as Klebsiella pneumoniae and Klebsiella ozaeena, and Erbinia Erwinia, Seratia such as Serratia marsense, Proteas of the Proteus group Bacteria: Proteus vulgaris, Proteus morgani, Proteus retgeri, Proteus mirabilis, Proteus, etc. Salmonella; Salmonella bacteria such as Salmonella paratype A and B, Salmonella typhi, Salmonella enteritidis, Salmonella cholera suis, Salmonella typhimurium, Shigella disgentriae, Shigella ammigua, Shigella flexneri, Shigella Shigella bacteria such as La Boyi, Shigella Johnnai, etc .:

Pseudomonas, such as Pseudomonas bacteria, such as Pseudomonas eruginoza and Pseudomonas pseudolay, aeromonas bacteria, such as aeromonas liquifaciens and aeromonas hydrophila;

Spirillaces, such as Vibrio cholera, Vibrio bacteria, such as Vibrio proteus, Vibrio petus, and Spirilum bacteria, such as Spirilum minus;

Pasteurella bacteria, such as Pasteurella mulloscida, Pasteurella pestis (Ercinia), Pasteurella pseudotubercosis, Pasteurella tullarensis, Brucella abbottus, Brucella melithensis, Brucella suis Brucellella bacteria such as Brucella bacteria, Haemophilus influenzae, Haemophilus ducray, Haemophilus suis, Haemophilus canis, Haemophilus bacteria such as Haemophilus edgepiticus, Bordetella pertussis, Bordetella bronchiceptica, etc. Parvobacterial or brucellase, such as Moraxella bacteria, such as Moraxella lacunata;

Bacteroides bacteria such as Bacteroides pragilis and Bacteroides serpens, and fuziforme bacteria such as fusobacterium fuziforme, spherophorus necrophorus, spherophorus necroticus, sphero Bacterioidase such as spherophorus bacteria such as Forus pyrogenes;

Aerobic spore-producing bacteria such as Bacillus anthracis (Bacillus subtilis and Bacillus cereus) and Clostridium petprings, Clostridium septicum, Clostridium edematien, Clostridium histolyticum, clostri Basilases such as anaerobic spore-producing Clostridium, such as dium tetany and coulostridium botulinum;

Borrelia bacteria such as Borrelia Licerentia and Borrelia Vincenti, Treponema bacteria such as Treponema palladium, Treponema petrinue, Treponema catateum, Leptospira interogans, Leptospira ectero hemoresia Spirochiras such as leptospira bacteria such as leptospira canicola, leptospira grippoty spores, leptospira pomona, leptospira mys, leptospira bovis and the like.

The above listed pathogens are examples only and should not be construed as limiting them.

Diseases that can be prevented, alleviated and cured with the active compounds of the present invention include the following.

Diseases of the respiratory and pharyngeal cavity, otitis, pharyngitis, pneumonia, peritonitis, pyelonephritis, cystitis, endocarditis, systemic infection, bronchitis, arthritis, local infection.

A pharmaceutical composition is prepared by mixing the active substance of the present invention with a solid or liquefied gas diluent or with a liquid diluent (but in the absence of a surfactant, a solvent having a molecular weight of 200 (preferably 350) or more).

In addition, a pharmaceutical composition is prepared by using the active substance of the present invention as a sterile or isotonic solution.

Unit dosage forms are prepared either alone or in admixture with a diluent.

In addition, the compounds of the present invention alone or mixed with a diluent to provide a dosage form in the form of tablets (including lozenges, granules), dragees, capsules, pills, ampoules suppositories.

As used herein, "drug" means a physically distinct cohesive moiety suitable for medical administration. Dosage unit drug means a physically discrete cohesive portion suitable for administration containing a daily dose or multiples (up to 4 times) or dilution (up to 1/40) of a compound of the invention. . Whether the drug contains a daily dose or 1/2, 1/3 or 1/4 thereof depends on whether the drug is administered once or twice, three or four times daily.

The pharmaceutical composition according to the present invention comprises ointments, gels, creams, pastes, sprays (including aerosols), lotions, suspensions, liquids and emulsions of active substances in aqueous or non-aqueous diluents, syrups, granules, powders and the like.

Diluents which can be used in pharmaceutical compositions (eg, granules) for the preparation of tablets, dragees, capsules, pills, are the following:

(A) Excipients: starch, sugar mannitol, silicic acid,

(B) binders: carboxy methylcellulose and other cellulose derivatives, alginates, gelatin, polyvinyl pyrrolidone,

(C) humectant: glycerol

(D) Sealants, agar-agar, calcium carbonate, sodium bicarbonate

(E) dissolution inhibitors; paraffin

(E) Absorbents. Quaternary ammonium compounds,

(G) surfactants. Cetyl alcohol, glycerol, monostearate,

(H) Adsorbent carriers: kaolin, bentonite,

(I) Lubricants: talc, calcium and magnesium stearate, solid polyethylene glycols.

Diluents that can be used in pharmaceutical compositions for the preparation of suppositories include conventional water soluble or water insoluble diluents such as polyethylene glycol and fats (e.g. cocoa oil and higher esters (e.g. C16-fatty acid esters of C14-alcohol). ) Or mixtures thereof.

Ointments, pastes, creams, gels and the like may be conventional diluents, for example, animal and vegetable fats, lead, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicon bentonite, talc silicate, zinc oxide, or mixtures thereof. It may contain.

Powders or sprays may contain conventional diluents, for example lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder or mixtures thereof. Aerosol sprays may contain, for example, conventional propellers, chlorofluoro hydrocarbons.

Liquids and emulsions are conventional diluents (of course solvents with a molecular weight of 200 or less are used only in the presence of surfactants). Examples of solvents, solubilizers and emulsifiers, such diluents include water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl Formamides, oils (eg peanut oil) glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycol, fatty acid esters of sorbitol and mixtures thereof.

For parenteral administration, liquids or emulsions must be sterilized and, if appropriate, isotonic with blood.

Suspending agents include water, ethyl alcohol, propylene glycol, surfactants (e.g., ethoxylated isostearyl alcohol, polyoxyethylene sorbite, sorbitan esters) microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- Agar, tragacanth or mixtures thereof.

In addition, the pharmaceutical composition according to the present invention may contain colorants, preservatives, fragrances and flavoring agents (eg, peppermint oil, cloves), sweeteners (saccharin) and the like.

The pharmaceutical composition according to the invention contains from about 0.1 to 99.5% by weight of the total composition, more preferably from 0.5 to 95% of the active ingredient.

The pharmaceutical compositions and formulations according to the invention may contain other pharmaceutically active substances in addition to the compounds of the invention, and may also contain various compounds of the invention.

In the present formulation, any of the diluents mentioned above for the pharmaceutical composition of the present invention may be used, and a solvent having a molecular weight of less than 200 may be used as a single diluent.

The individual cohesive portions of the formulations according to the invention (whether or not in dosage units) are as follows: tablets (including lozenges and granules), pills, dragees, capsules, suppositories, ampoules, some of these formulations It may also be prepared to delay the release of the active ingredient. Capsules and the like have a protective film that makes the formulation physically distinct and cohesive.

Preferred daily dosages of the formulations of the invention are 50 mg to 25 g of active ingredient.

The preparation of the aforementioned pharmaceutical compositions and formulations mixes the active ingredient (s) with a diluent to produce a composition (eg granules) and formulates it into a formulation (eg tablets).

The present invention also provides a method for treating the aforementioned diseases (including prevention and alleviation) in humans and animals by administering the compounds of the present invention alone or in admixture with a diluent or in the form of a formulation.

These active compounds are orally, parenterally (muscle, intraperitoneal, intravenous), rectal and topical, preferably orally or parenterally. Therefore, pharmaceutical compositions and formulations suitable for oral and parenteral administration are preferred.

The present invention also encompasses the use in the veterinary field as a drug feed containing the compounds and nutrients of the present invention. Examples of suitable nutrients include jelly, cereals (eg barley), fish meal, soybean wheat, waste sugar bee tailings, silage hay and skim milk.

In general, in medicine and veterinary medicine it has been found to be advantageous to administer the active compounds of the invention every 5 hours at 5 to 1000 mg, preferably 20 to 300 mg per kg body weight, optionally in several dosage forms for the desired result. . Each dose contains 1 to 250 mg, preferably 10 to 100 mg, per kg body weight of the active compound of the present invention. However, the dose can be varied depending on the weight and type of disease, the type of agent, the route of administration, the interval and frequency of administration. In some cases, it may be added or subtracted from the above-described dose. Those skilled in the art can easily determine how to administer the active compound and the actual lowest dose based on his expertise.

When used as an additive to feed, it is administered with the feed formulation or in water at the usual concentration and formulation. In this way, infection by Gram-negative or Gram-positive bacteria can be prevented, alleviated and / or treated, while at the same time promoting growth and increasing feed utilization.

New penicillins and cephalosporins are characterized by potent antimicrobial activity and oral absorptivity demonstrated in in vivo and in vitro tests.

The penicillins and cephalosporins according to the present invention can be used in combination with other antibiotics, for example penicillinlinase-resistant penicillins, especially in order to broaden the range of action and enhance the action in the case of β-lactamase producing bacteria.

Examples of such combinations include combinations with oxacillin or dicloxacillin.

The penicillin and cephalosporin of the present invention may also be used in combination with aminoglycoside antibiotics such as gentamicin, sisomycin, kanamycin amikacin, and tobramycin in order to broaden the range and enhance the action.

The formation of β-lactam antibiotics according to the present invention can be investigated by the following in vivo and in vitro experiments.

1. In vitro experiment

0.1% glucose is added to the compounds of Examples 1.3,2.3 and 2.4, which can be considered as typical representative antibiotics of the present invention, and diluted with Mueller-Hinton nutrient medium to 100 μg / ml. In each case, 1 ml of bacteria contains 1 × 10 ⁵ to 2 × 10 ⁵ per ml of nutrient solution. Test tubes containing this mixture are incubated for 24 hours and turbidity is measured. Not turbid means that there is activity of the compound. At the dose of 100 μg / ml, the next culture medium is not turbid.

Klebsiella pneumoniae; Enterobacter erogenes species; Providencia; Serratia Marsense; this. E. coli BE Salmonella spp .; Shigella species; Proteus; Indole-negative and indole-positive; Pasteurella pseudo-tuberculosis; Brucella species; Haemophilus influenzae; Bordetella bronchiceptica; Staphylococcus aureus 133; Neisseria catatalis species; Diplococcus pneumoniae species; Streptococcus piogenes W; Enterococcus species; Lactobacillus species; Gravure on corynebacterium diphtheria; Corynebacterium piogenes M; Clostridium tetany; Pseudomonas aeruginosa strains; Bacteroides pragilis species.

2. In vivo experiment

In experiments using white mice, the action of some compounds of the compounds of the present invention is shown in Table 1 below. Each bacterium is infected intraperitoneally with CF1 white mice.

TABLE 1

Animal experiment using white mouse

ED100 measurement after 24 hours

Treatment: Two administrations, 30 and 90 minutes after infection.

ED ₁₀₀ is the capacity that 100% of the animals survive after 24 hours. The method according to the invention is illustrated by the following examples.

The α-amino benzyl-penicillin used in the following examples contains about 14% water, but anhydrous α-amino benzyl-penicillin (compare US Pat. No. 3,144,445) may likewise be used.

The α-aminoP-hydroxy benzylpenicillin used in the examples contains about 13% water, but anhydrous α-amino-P-hydroxy benzyl penicillin may likewise be used.

The 6- [2-amino-2- (1,4-cyclohexadien-1-yl) acetamido] phenylanic acid used in the examples is almost anhydrous.

The 7- (α-amino-phenylacetamido) -3-methyl-ce-3-fem-4-carboxylic acid used in the examples is anhydrous 7- (α-amino-phenylacetacean) containing about 5% water. Amido) -3-methyl-ce3-fem4-carboxylic acid can likewise be used.

The 7- (α-amino-phenylacet amido) -3-acetoxymethyl-ce-3-fem-4-carboxylic acid used in the examples contains 8% water but is anhydrous 7- (α-amino-phenyl Acetamido) -3-acetoxy-methyl-ce-3-fem-4-carboxylic acid can likewise be used.

The moisture content of the starting material is not critical to the process of the present invention.

“Ampicillin” means a specific α-amino benzylphenicillin with side chains having a D = R-configuration and “adoxicillin” means a specific α-amino-P-hydroxy-benzylphenicillin with side chains having a D = R-configuration “Epicycin” refers to a specific α-amino-α- (1,4-cyclohexadien-1-yl) -methylphenicillin in which the side chain has a D = R-configuration.

“Separexin” refers to a specific 7- (α-amino-phenylacetamido) -3-methyl-ce-3-fem-4-carboxylic acid with side chains having a D = R-configuration, and “cephaloglycine” Means 7- (α-amino-phenylacetamido) -3-acetoxy-methyl-ce-3-fem-4-carboxylic acid with side chains having a D = R-configuration.

NMR spectra were taken in a CD ₃ OD solution unless otherwise indicated. The symbols in parentheses mean the following:

IR spectra were taken in paraffin oil suspension unless otherwise indicated.

Abbreviations used in the examples have the following meanings.

Example 1

[1.1]

31.5 parts of 2-oxo-imidazolidine was dissolved in 1000 parts (volume) of 2N sulfuric acid, cooled to 3 to 6 ° C, and 25.25 parts of sodium nitrite solution in 50 parts (volume) of water was stirred and continued to cool 31 Dropped over minutes, the mixture was further stirred for 1 hour on an ice bath and 55 parts of purified zinc powder were introduced over 1 hour. The mixture is stirred under ice cooling for 30 minutes and then at room temperature for 1 hour. Unconverted zinc is filtered off, washed with a small amount of water and 35 parts of benzaldehyde is added to the combined filtrate and stirred vigorously for 30 minutes. Precipitated 1-benzylimino-2-oxo-imidazolidine is filtered off and dried and recrystallized from ethanol. (49.2 parts, melting | fusing point = 194-200 degreeC).

11.7 parts of 1-benzylimino-2-oxo-imidazolidine (see 1.1), a mixture of 120 parts (volume) of benzene and 13.8 parts (volume) triethylamine are heated and boiled in 50 parts (volume) of benzene. 10 parts of trimethylchlorosilane solution is added over 1 hour with stirring. The mixture is continued to boil for 5.5 hours and the isolated triethyl ammonium hydrochloride is filtered under heat and washed with hot benzene. A 6.3 parts phosgene solution in 30 parts (volume) of benzene is cooled, added to the combined benzene filtrates, and the mixture is left to stand overnight at room temperature. Excess phosgene is almost eliminated by passing through a dry air stream and dried by filtration of 1-chlorocarbonyl-2-oxo-3-benzalimino-imidazolidine.

14 parts of ampicillin are suspended in 140 parts (volume) of 80% aqueous tetra hydrofuran and dissolved by addition of the required minimum amount of triethylamine. (pH becomes 8.0), 7.8 parts of 1-chloro-carbonyl-2-oxo-3-benzylimino-imidazolidine (see 1.2) is stirred while stirring, and at the same time the pH is properly adjusted to triethylamine. Addition is maintained at 7.0-7.5. Triethylamine is then added and stirred until it is necessary to maintain the pH. (About 1 to 2 hours) The mixture is diluted with 200 parts (volume) of water, the pH is adjusted to 6.5, the tetrahydrofuran is almost evaporated in vacuo and the residual aqueous solution is washed once with ether in aliquots and then ethyl acetate And acidify to pH 2 with stirring with dilute hydrochloric acid. The organic phase was separated and washed with saturated aqueous NaCl solution, dried over MgSO ₄ , diluted with an equivalent volume of ether, and stopped with precipitation of about 1 mole of sodium 2-ethylhexanoate solution in ether containing methanol until the formation of precipitate was stopped. Process. Sodium 6- [D-α-[(2-oxo-benzalimino-imidazolidin-1-yl) -carbonylamino] -phenylacetamido] -peniclanate was filtered off and washed with ether and ether After washing with a mixture of methanol (5 to 10%) and isopropanol, it is dried.

Yield 6.2 parts β-lactam content 91%

According to the spectra 2.5 moles of H ₂ O, 0.1 moles of isopropanol and 0.04 moles of sodium 2-ethyl-hexanoate are still contained in the material. The analytical value considering this is as follows.

Calculated Value: C 51.5 H 5.3 N 13.0 S 5.0

Found: C 50.9 H 5.2 N 12.9 S 5.1

NMR τ (CD ₂ OD) 2.1-2.8 (11H), 4.3 4.65 (3H), 5.8 (1H), 6.1-6.35 (4H) and 8.3-8.6 ppm (6H)

In the IR (paraffin oil) (carbonyl part): 1,770, 1,730, 1,605, 1,610, 1,540 cm ^-1

Penicillin of the above formula is prepared from 6.1 parts of amoxicillin trihydrate and 3.6 parts of 1-chlorocarbonyl-2-oxo-3-benzalmino-imidazolidine (see 1.2) in the same manner as in Example 1.3. When the aqueous solution is acidified to pH 1.5 with about 20% dilute hydrochloric acid, some of the free penicillin-acids are not dissolved in ethyl acetate. This is filtered, washed with water and dried (yield: 5.2 parts), and then a part of the sodium salt of penicillin can be precipitated from ethyl acetate with sodium 2-ethyl hexanoate.

(Yield 1.4 parts)

6- {D-α-[(2-oxo-3-benzalimino-imidazolidin-1-yl) -carbonylamino] -4-hydroxyphenylacetamino} -phenicylic acid

Yield: 5.2 parts

β-lactam content: (measured by iodine loading method): 81%

(From NMR spectrum): 89%

NMR spectra show that 3.4 moles of water and 0.5 moles of ether per mole of material. Taking this into account, we obtain the following analysis:

Calculated Value: C 51.2 H 5.9 N 12.44 S 4.7

Found: C 50.7 H 5.5 N 12.8 S 4.8

NMR τ (CD ₃ OD) = 2.2-3.3 (10H), 4.3-4.64 (3H), 5.7 (1H), 6.15-6.4 (4H), 8.35-8.6ppm (6H)

IR (in paraffin oil) (carbonyl part): 1780, 1740 (shoulder), 1725, 1645, 1520 cm ^-1

Sodium 6- {D-α-[(2-oxo-3-benzalimino-imidazolidin-1-yl) -carbonylamino] -4-hydroxyphenylacetamido} -phenylsilanate

Yield: 1.4 parts

β-lactam content (measured by iodine titration method): 96%

(From NMR spectrum): 87%

NMR spectra contain 2.5 moles of water and 0.25 moles of sodium 2-ethylhexanoate per mole of material. Taking into account the identified impurities (in addition to the unknown impurities derived from the used Amoksil and present in unknown amounts), the following analytical values are obtained.

Calculated Value: C 50.6 H 5.2 N 12.2 S 4.6

Found: C 51.2 H 6.0 N 11.7 S 4.5

NMR τ (CDOD) = 2.1-3.3 (10H), 4.4-.7 (3H), 5.8 (1H), 6.1-6.4 (4H) and 8.3-8.6 ppm (6H).

IR (in paraffin oil) (carbonyl moiety) = 1,770, 1,735, 1,670, 1,600, 1,560-1,520 cm ^-1

Penicillin of the above formula is prepared from 1.5 parts of epicillin and 1.1 parts of 1-chlorocarbonyl-2-oxo-3-benzylimino-imidazolidine in the same manner as in Example 1.3.

Yield: 1.7 parts of sodium 6- {D-α-[(2-oxo-3-benzalimino-imidazol-1-yl) -carbonylamino] -cyclohex-1,4-dienyl (1)- Acetamido} -penicilanate is obtained. β-lactam content, 90% (91% by NMR)

According to the NMR spectrum, this material contains 2.5 mol of water, 0.072 mol of sodium 2-ethylhexanoate. The elemental analysis value considering this is as follows.

Calculated Value: C 51.2 H 5.4 N 13.0 S 4.9

Found: C 50.9 H 5.7 N 13.6 S 4.6

NMR τ (CD ₃ OD) = 2.0-2.65 (5H), 4.0 (1H), 4.25 (2H), 4.45 (2H), 4.95 (1H), 5.75 (1H), 6.0-6.3 (4H), 7.1-7.4 (4H) and 8.25-8.5 ppm (6H).

IR (in paraffin oil) (carbonyl moiety), 1,765, 1,730, 1,660, 1,600, 1,530 cm ^-1

2.25 parts of cephaloglycine dihydrate was suspended in 50 ml of 80% aqueous THF and reacted with 12.6 parts of 1-chlorocarbonyl-2-oxo-3-benzalimino-imidazolidine to complete as in Example 13. 7- {D-α-[(2-oxo-3-benzalimino-imidazolidin-1-yl) -carbonylamino] -phenylacetamido} by acidification with a dibasic acid (eg 2N hydrochloric acid)} 3-Acetoxymethyl-ce-3-fem-4-carboxylic acid is precipitated. (1.9 parts, corresponding to 61.4%) of this material was dissolved in 5 parts (volume) of dimethylacetamide, 3 parts of methanolic 1M sodium 2-ethyl-hexanoate solution was added and 30 parts (volume) of the mixture was stirred. Ether: methanol = 10: 1 sodium 7- {D-α-[(2-oxo-3-benzalimino-imidazolidin-1-yl) -carbonylamino at a decomposition point of 80 to 185 ° C. when added to the mixture -Phenylacetamido} -3-acetoxymethyl-ce-3-fem-4-carboxylate 1.7 parts is obtained by precipitation.

The ethyl acetate layer was completed as in Example 1.3 to further obtain 0.9 part (corresponding to 28%) of sodium salt.

Determination of C ₂₉ H ₂₇ N ₆ NaO ₈ SH ₂ O

Calculated Value: C 52.72 H 4.42 N 12.71 S 4.85

Found: 2.5 4.9 12.2 4.6

IR (KBr): 1,760, 1,725, 1,670, 1,605 1,520 cm-1

NMR (CD ₃ OD / D ₂ O): 7.75 and 7.40 (m, 1H), 5.75 (d, 1H), 5.57 (S, 1H), 5.00 (d, 1H), 4.87 (duplicate exchangeable hydrogen) , 3.82 (m, 4 H), 2.08 (S, 3 H) δ.

The peak of the CD ₃ OD solvent overlaps with C-2 hydrogen. β-lactam content is 80 to 85%.

Example 2

15.8 parts 2-oxo-imidazolidine, 12.6 parts sodium nitrite, 27.5 parts zinc powder are reacted as in Example 1.1 and stirred overnight with 23.2 parts 4-chlorobenzaldehyde. 20.5 parts of 1- (4-chloro-benzylimino-2-oxo-imidazolidine having a melting point of 233 to 235 ° C are obtained.

Analyzes of C ₁₀ H ₁₀ ClN ₃ O

Calculated Value: C 53.70 H 4.51 N 18.79 Cl 15.85

Found: 53.9 4.5 18.7 16.0

IR (KBr): 3,250, 3,130, 1,735, 1,705 and 1,595 cm ^-1

NMR (d ₆ -DMSO): 7.66 and 7.45 (AB, 4H), 7.60 (S, 1H), 7.15 (S, Broad, 1H), 3.6 centered (4H) δ

A 31.0 parts trimethylchlorosilane solution in 100 parts (volume) of dioxane anhydride was added to 21.4 parts of 1- (4-chloro-benzylimino-2-oxo-imidazolidine and 31.0 parts in 240 parts (volume) of dioxane anhydride. Add to the boiling solution of triethylamine over 1 h with stirring The mixture is heated to reflux overnight and the separated triethylammonium hydrochloride is filtered over hot and washed with hot dioxane 60 parts (after cooling) 9.9 parts of phosgene solution in anhydrous dioxane is added, and after standing at room temperature for 12 hours, excess phosgene is removed through dry air, the precipitate is filtered off and the filtrate is concentrated to recrystallize the residue from anhydrous acetonitrile. Decomposition point: 8.9 parts of 1-chlorocarbonyl-2-oxo-3- (4-chloro) -benzylimino-imidazolidine at 188 to 192 ° C are obtained.

IR (in paraffin oil): 1,800 and 1,700 cm ^-1

7.9 parts of ampicillin trihydrate in 80 parts (volume) of 80% aqueous THF was prepared in the same manner as in Examples 1, 3 and 2.8 parts of 1-chlorocarbonyl-2-oxo-3- (4-chloro) -benzylimino React with imidazolidine. Decomposition point: Sodium 6- {D-α-[(2-oxo-3- {4-chloro} -benzalmino-imidazolidin-1-yl) carbonylamino] at 210-215 ° C.-phenylacet Amido} -penicilanate 1.4 parts are obtained. β-lactam content: 87%

IR (KBr): 1,760, 1,725, 1,665, 1,595 cm ^-1

NMR (CD ₃ OD) 7.6-7.2 (m, 10H), 5.60 (S, 1H), 5.45 (q-2H), 4.15 (S, 1H), 3.80 (Broad S, 4H), 1.57 (S, 3H) , 1.48 (S, 3H) δ.

2.0 parts sodium epicillin in 40 parts (volume) of 80% aqueous THF was prepared in the same manner as in Example 1.5, 3.5 parts 1-chlorocarbonyl-2-oxo-3- (4-chloro) -benzylimino-imida Reacted with zolidine to sodium 6- {D-α-[(2-oxo-3- {4-chloro} -benzylmino-imidazolidin-1-yl) -carbonylamino-cyclohex-1, 4-Dienyl (1) -acetamido} -penicilanate is obtained. β-lactam content: 92%

IR (KBr): 1,770, 1,730, 1,670, 1,605 cm ^-1

NMR (CD ₃ OD) 7.78 (S, 1H), 7.76 and 7.36 (AB, 4H), 5.95 (m, 1H), 5.72 (S, 2H), 5.50 (S, 2H), 5.00 (S, 1H), 4.20 (S, 1H), 3.95 (S, Broad, 4H), 2.75 (S, Broad, 4H), 1.65 (S, 3H), and 1.58 (S, 3H) δ.

2.25 parts of cephaloglycine was dissolved in a solution of 40 parts of 80% THF of dihydrate, and 3.5 parts of 1-chlorocarbonyl-2-oxo-3- (4-chloro-benzylimino-imidazolidine and Example 1.6. And reacted with sodium 7- {D-α-[(2-oxo-3-4-chloro-benzalmino-imidazolidin-1-yl) carbonylamino] -phenylacetamido} -3-ace 0.6 parts of methoxymethyl-ce-3-fem-4-carboxylate are obtained: β-lactam content: 80 to 85%

IR (KBr) 1,760, 1,720, 1,660, 1,595 cm ^-1

NMR (CD ₃ OD) 7.7 and 7.4 (m, 10H), 5.65 (d, 1H), 5.60 (S, 1H), 5.0-4.8 (overlapping exchangeable hydrogens) 3.88 and 3.70 (overlapping multiplets), 2.03 (S, 3H) δ.

H₂O·

디메틸아세트-아미드의 분석치C ₂₉ H ₂₆ ClN ₆ NaO ₈ S

H ₂ O

Analysis of Dimethyl Acetamide

Calculated Value: C 50.25 H 4.22 N 11.72 S 4.48

Found: 50.1 4.5 11.1 5.4

A solution of 80 parts of 80% aqueous THF (volume) of negative amoxicillin trihydrate was prepared in 2.9 parts of 1-chlorocarbonyl-2-oxo-3- (4-chloro) -benzylamino-imidazolidine as in Example 1.4. React with Sodium 6- {D-α-[(2-oxo-3- {4-chloro} -benzalmino-imidazolidin-1-yl) -carbonylamino] at a decomposition point of 220 to 224 ° C.-4- 4.6 parts of hydroxyphenyl-acetamido} -peniclanate are obtained.

IR (KBr): 1,775, 1,730, 1670, 1615cm-1

NMR (CD ₃ OD) 6.7-8.0 (9H), 5.4-5.6 (3H), 4.95 (3 exchangeable hydrogens), 4.15 (1H), 3.80 (4H), 1.58 (3H), 1,52 (3H) δ.

Analytical Value of C ₂₇ H ₂₆ CIN ₆ NaO ₇ S · 2H ₂ O

Calculated: C 48.18 H 4.49 N 12.49 S 4.77

Found: C 48.7 H 5.1 N 12.6 S 4.5

Example 3

15.8 parts 2-oxo-imidazolidine 12.6 parts sodium nitrite and 27.5 parts zinc powder are completed as in Example 2.1 and reacted with 22.4 parts 4-methoxy benzaldehyde. 1.8 parts of 1- (4-methoxy) -benzylimino-2-oxo-imidazolidine of melting point 179-181 degreeC are obtained.

IR (KBr): 3,250, 3,130, 1,725, 1,700, 1,605 cm-1

NMR (d ₆ -DMSO): 7.56 and 6.92 (AB, 4H), 7.52 (S, 1H), 7.04 (S, 1H), 3.72 (S, 3H), m 3.52 (4H) δ centered on 3.52.

Analytical Value of C ₁₁ H ₁₃ N ₃ O ₂

Calculated Value: C 60.7 H 5.97 N 19.7

Found: C 60.3 H 5.9 N 18.9

20.0 parts of trimethylchlorosilane solution in 50 parts (capacity) of anhydrous benzene, 13.6 parts of 1- (4-methoxy) -benzylimino-2-oxo-imidazoli in 120 parts (capacity) of anhydrous benzene Dean and 27.6 parts of triethyl amine were added dropwise and the mixture was reacted as in Example 1.2 to complete. 6.2 parts of 1-chlorocarbonyl-2-oxo-3- (4-methoxy) -benzylimino-imidazolidine having a melting point of 204 to 208 ° C are obtained.

IR (in paraffin oil): 1,800 cm ^-1

6.9 parts ampicillin and 70 parts (dose) of 80 parts aqueous THF and 2.4 parts of 1-chlorocarbonyl-2-oxo-3- (4-methoxy) -benzylimino-imidazolidine React together. Sodium 6- {D-α-[(2-oxo-3- {4-methoxy} -benzalimino-imidazolidin-1-yl having a decomposition point of 213 to 223 DEG C and a 87% β-lactam content 4.5 parts of) -carbonylamino] -phenylacetamido} -peniclanate is obtained.

IR (KBr) 1,770,, 730, 1,675, 1,605 cm ^-1

NMR (CD ₃ O): 7.60 and 6.85 (AB, 4H), 7.4 (m, 5 + 1H), 5.60 (S, 1H), 5.45 (q, 2H), 4.15 (S, 1H), 3.72 (S, 3H), 3.63 (broad S, 4H), 1.55 (S, 3H), 1.50 (S, 3H) δ.

2.0 parts sodium epicillin in 40 parts (dose) of 80% aqueous THF and 2.1 parts 1-chlorocarbonyl-2-oxo-3- (4-methoxy) -benzylimino-imidazolidine React in the same manner as Sodium 6- {D-α-[(2-oxo-3- {4-methoxy} -benzylmino-imidazolidin-1-yl) -carbonylamino] having a P-lactam content of 568% 3.5 parts of cyclohex-1,4-dienyl (1) -acetamido} -phenylanate are obtained.

IR (KBr): 1,760, 1,720, 1,655, 1,600 cm ^-1

NMR (CD ₃ OD): 7.60 and 6.85 (AB, 4H), 7.40 (S, overlapped on AB system, 1H), 5.90 (Broad S, 1H), 5.50 (S, 2H), 5.50 (S, 2H ), 5.00 (S, 1H), 4.20 (S, 1H), 3.77 (broad S, 4H), 2.72 (broad S, 4H), 1.65 (S, 3H), 1.57 (S, 3H) S.

2.25 parts of cephaloglycine dihydrate in which 1.41 parts of 1-chloro-carbonyl-2-oxo-3- (4-methoxy) -benzylimino-imidazolidine was suspended in 40 parts (dose) of 80% THF The reaction is carried out in the same manner as in Example 1.6.

When acidified, 1.2 parts of 7- {D-α-[(2-oxo-3- {4-methoxy} -benzylmino-imidazolidin-1-yl) -carbonylamino] -phenylacetamido} 3-Acetoxymethyl-ce-3-fem-4-carboxylic acid is precipitated and reacted with 1.9 parts (volume) of 1M sodium 2-ethyl-hexanoate solution in the same manner as in Example 1.4 to give sodium 7- {D -α-[(2-oxo-3- {4-methoxy} -benzylamino-imidazolidin-1-yl) -carbonylamino] -phenylacetamido} -3-acetoxymethyl-ce 0.7 parts of 3-fem-4-carboxylate are obtained.

The ethyl acetate phase was completed as in Example 1.3 to further obtain 1.6 parts of sodium salt at a decomposition point of 220 to 230 ° C.

β-lactam content: 80%

IR (KBr): 1,770, 1,730, 1,660, 1,610cm ^-1

NMR (CD ₃ OD / D ₂ O): 7.55 and 6.85 (AB, 4H), 7.40 (overlap on S, AB system, 1H), 5.67 (d, 1H), 5.47 (S, 1H), 5.15-4.85 (m, overlapping exchangeable hydrogen), 3.76 (broad S, 4H), 2.05 (S, 3H) S.

Analytical Value of C ₃₀ H ₂₉ N ₆ NaO ₉ SH ₂ O (690.6)

Calculation: C 52.18 H 4.52 N 12.17 S 4.65

Found: C 51.9 H 4.4 N 11.8 S 5.1

Example 4

15.8 parts 2-oxo-imidazolidine 12.6 parts sodium nitrite 27.5 parts zinc mal and 24.9 parts 4-nitrobenzaldehyde are reacted as in Example 2.1. The resulting 1- (4-nitro) -benzylmino-2-oxo-imidazolidine impurities are removed by boiling with ethanol.

37.6 parts having a melting point of 265 to 267 ° C

IR (KBr): 3,430, 3,260, 1,720, 1,595, 1,570 cm ^-1

NMR (d ₆ -DMSO): 8.20 and 7.88 (AB, 4H), 7.68 (S, 1H), 7.37 (Broad S, 1H), m (4H) δ centered at 3.65

Calculated Value: C 51.28 H 4.31 N 23.92

Found: C 51.2 H 4.3 N 23.9

8.8 parts 1- (4-nitro) -benzylimino-2-oxo-imidazolidine 12.1 parts triethylamine 12.0 parts trimethyl chlorosilane and 3.9 parts phosgene are reacted in the same manner as in Example 2.2. Recrystallization from anhydrous acetonitrile yields 2.6 parts of 1-chloro-carbonyl-2-oxo-3- (4-nitro) -benzylimino-imidazolidine at a decomposition point of 188 to 192 ° C.

IR (in paraffin oil): 1,800, 1,760, 1,700 cm ^-1

6.8 parts ampicillin, trihydrate in 70 parts (dose) of 80% aqueous THF with 2.5 parts 1-chlorocarbonyl-2-oxo-3- (4-nitro) -benzalmino-imidazolidine React as in 1.3. Sodium 6- {D-α-[(2-oxo-3- {4-nitro} -benzalimino-imidazolidin-1-yl having a decomposition point of 220 to 225 ° C and a 98% β-lactam content 3.0 parts of) -carbonylamino] -phenylacetamido} -peniclanate is obtained.

IR (KBr): 1,765, 1,730, 1,670, 1,600 cm ^-1

NMR (CD ₃ OD): 8.2H), 4.20 (S, 1H), 3.88 (Broad S, 4H), 1.58 (S, 3H), 1.50 (S, 3H) S.

Analytical Value of C ₂₇ H ₂₆ N ₇ NaO ₈ S2.5H ₂ O

Calculated Value: C 47.93 H 4.62 N 14.50 S 4.74

Found: C 47.7 H 4.3 N 14.4 S 4.8

6.5 parts cephaloglycine in 80 parts (dose) 80% aqueous THF was mixed with 4.4-part 1-chlorocarbonyl-2-oxo-3- (4-nitro) -benzalmino-imidazolidine and Example 3.5. Reaction in the same manner to 7- {D-α-[(2-oxo-3- {4-nitro} -benzalmino-imidazolidin-1-yl) -carbonylamino at a decomposition point of 220 to 225 ° C -Phenylacetamido} -3-acetoxymethyl-ce-3-fem-4-carboxylate 9.3 parts are obtained.

IR (KBr): 1,760, 1,730, 1,660, 1,605 cm ^-1

Determination of C ₂₉ H ₂₉ N ₇ NaO ₁₀ S · 2H ₂ O

Calculated Value: C 48.13 H 4.19 N 13.56 S 4.42

Found: C 48.0 H 4.1 N 13.4 S 4.4

Example 5

12.6 parts 2-oxo-imidazolidine, 21.8 parts sodium nitrite and 21.8 parts zinc powder were operated in the same manner as in Example 2.1 to react with 17.3 parts 4-cyano benzaldehyde.

26.2 parts of 1- (4-cyano) -benzylimino-2-oxo-imidazolidine are obtained and are continuously washed with water, ethanol and ether to remove impurities.

Melting Point: 265-267 ℃

IR (KBr): 3,210, 3,120, 2,220, 1,720, 1,590 cm ^-1

NMR (d ₆ -DMSO): 7.88 (S, 4H), 7.66 (S, 1H), 7.30 (Broad S, 1H), m (4H) δ, with an emphasis on 3.7.

Calculated Value: C 61.68 H 4.71 N 26.15

Found: C 59.8 H 4.6 N 25.9

7.5 parts 1- (4-cyano) -benzylimino-2-oxo-imidazolidine and 12.1 parts triethylamine in 60 parts (volume) anhydrous dioxane and 12.0 parts trimethylamine in 25 parts anhydrous dioxane And 3.9 parts of phosgene 3.9 parts are reacted in the same manner as in Example 2.2. Recrystallization from anhydrous acetonitrile yields 4.7 parts of 1-chlorocarbonyl-2-oxo-3- (4-cyano) -benzylimino-imidazolidine having a melting point of 260 to 264 占 폚.

IR (paraffin wax): 1800㎝ ^-1

Calculated Value: C 52.09 H 3.28 N 20.25 Cl 12.82

Found: C 52.0 H 3.3 N 20.3 Cl 12.5

7.9 parts of ampicillin trihydrate in 80 parts (capacity) of 80% tetrahydrofuran was combined with 2.7 parts of 1-chlorocarbonyl-2-oxo-3- (4-cyano) -benzylimino-imidazolidine The reaction was carried out in the same manner as in Example 1.3, with sodium 6- {D-α [(2-oxo-3- {4-cyano} benzalimino-imid having a decomposition point of 225 to 230 ° C and 88% of a β-lactam content. 2.3 parts of dazolidin-1-yl) -carbonylamino] -phenylacetamido} -penicilanate are obtained.

IR (KBr), 2,220, 1,770, 1,730, 1,665, 1,00 cm ^-1

NMR (CD ₃ OD): 7.95-7.20 (10H), 5.56 (S, 1H), 5.42 (g, 2H), 4.12 (S, 1H), 3.87 (Broad S, 4H), 1.57 (S, 3H), 1.48 (S, 3 H) δ.

Anal for C ₂₈ H ₂₆ N ₇ NaD ₆ S.2.5H ₂ O.

Calculated Value: C 51.21 H 4.76 N 14.93

Found: C 51.6 H 4.9 N 14.4

Example 6

This material is prepared from 15.8 parts of imidazolidone and 31.0 parts of 4-methylsulfonyl benzaldehyde by reaction in the same manner as in Example 1.1 except that the material is reacted in a mixture of water and dichloromethane 1: 1. Recrystallization of the crude product from nitro methane yields 9.2 parts of 1- (4-methylsulfonyl) -benzylmino-2-oxo-imidazolidine having a melting point of 264 ° C.

NMR τ: 2.0 (4H), 2.2 (1H), 5.9-6.65 (4H), 6.7 ppm (3H).

Calculated Value: C 49.4 H 4.9 N 15.7 O 18.0 S 12.0

Found: C 48.6 H 5.0 N 15.7 O 18.3 S 12.1

This material is prepared by the same method as Example 1.2 from 9.2 parts of 1- (4-methylsulfonyl) -benzylmino-2-oxo-imidazolidine. The crude product is recrystallized from nitromethane and acetonitrile. 5.4 parts of 1-chlorocarbonyl-2-oxo-3- (4-methylsulfonyl) -benzylmino-imidazolidine of melting | fusing point 208-213 degreeC are obtained.

Calculated Value: C 43.7 H 3.6 Cl 10.8 N 12.8 S 9.7

Found: C 43.8 H 4.9 Cl 10.2 N 12.5 S 9.5

This penicillin is prepared from 2.0 parts of ampicillin trihydrate and 1.6 parts of 1-chlorocarbonyl-2-oxo-3- (4-methylsulfonyl) -benzylmino-imidazolidine in the same manner as in Example 1.3. . Penicillin-acids are separated by crystalline precipitation insoluble in water and 1.6 parts of ethyl acetate.

This penicillin acid is dissolved in a small amount of dimethylformamide, a calculated amount of sodium 2-ethylhexanoate in ether containing methanol is added and the mixture is poured into a large amount of ether to precipitate penicillin sodium salt by precipitation.

Yield: 0.85 parts of sodium D-α-{[2-oxo-3- (4-methyl-sulfonyl) -benzylmino-imidazolidin-1-yl] -carbonylamino} -benzylphenicillin are obtained. β-lactam content: 90%

According to the NMR spectrum, this penicillin contains about 1.5 moles of water about 0.2 moles of ethyl acetate, 0.25 moles of dimethylformamide and 0.15 moles of sodium-2-ethyl hexanoate. The elemental analysis value considering this is as follows.

Calculated Value: C 49.1 H 5.1 N 11.6 S 8.5

Found: C 48.5 H 4.8 N 11.8 S 8.4

NMR τ = 2.05 (4H), 2.2 (1H), 2.2-2.8 (5H), 4.3-4.65 (3H), 5.8 (1H), 5.9-6.4 (4H), 6.85 (3H), 8.2-8.7 ppm (6H ),

This penicillin was derived from 1.5 parts of ampicillin and 1.8 parts of 1-chlorocarbonyl-2-oxo-3- (4-methylsulfonyl) -benzylmino-imidazolidine, as described in Examples 1,3 and 6.3. It is obtained first as penicillin-acid crystals and later as sodium salt.

Yield: 2.0 parts of sodium D-α-{[2-oxo-3- (4-methylsulfonyl) -benzylmino-imidazolidin-1-yl)]-carbonylamino} -hydroxybenzylphenicillin, β-lactam content: 85%

According to the NMR spectrum, this penicillin contains 2.0 moles of water, 0.25 moles of ethyl acetate, 0.7 moles of dimethylformamide, and 0.08 moles of sodium 2-ethylhexanoate. The elemental analysis value considering this is as follows.

Calculated Value: C 47.4 H 5.1 N 11.7 S 8.0

Found: C 47.2 H 5.0 N 11.1 S 7.9

NMRτ = 2.1 (4H), 2.2 (1H), 2.5-3.3 (4H), 4.35-4.65 (3H), 5.8 (1H), 5.9-6.4 (4H), 6.85 (3H), 8.2-8.7 (ppm (6H) ).

Penicillin of the above formula was initially derived from 1.0 parts of epicillin and 0.94 parts of 1-chlorocarbonyl-2-oxo-3- (4-methylsulfonyl) benzalmino-imidazolidine as described in Examples 1.3 and 6.3. Penicillin-acid crystals, which are then obtained as sodium salts. Yield: sodium D-α-{[2-oxo-3- (4-methylsulfonyl) -benzylmino-imidazolidin-1-yl] -carbonylamino} -α- (1,4-cyclo Hexadien-1-yl] methyl penicillin 1.6 parts, β-lactam content: 81%

According to the NMR spectrum, this penicillin contains 3.0 moles of water, 0.3 moles of ethyl acetate, 0.4 moles of dimethylformamide, and 0.12 moles of sodium 2-ethylhexanoate. The elemental analysis value considering this is as follows.

Calculated Value: C 47.3 H 5.5 N 11.3 S 8.1

Found: C 46.9 H 5.5 N 11.3 S 8.1

NMRτ = 2.0 (4H), 2.15 (1H), 4.0 (1H), 4.25 (2H), 4.45 (2H), 5.0 (1H), 5.8 (1H), 5.8-6.3 (4H), 6.8 (3H), 7.0 -7.4 (4H), 8.2-8.7 ppm (6H).

Crystalline acid initially from 1.5 parts cephaloglycine and 1.0 part 1-chlorocarbonyl-2-oxo-3- (4-methylsulfonyl) -benzalmino-imidazolidine as described in Examples 1.3 and 6.3 1.0 part (part insoluble in ethyl acetate and water) as a part, 0.75 part is obtained in part as a sodium salt (precipitating with sodium salt from the part which melt | dissolves in ethyl acetate). A sodium salt is also prepared from penicillin-acid in the same manner as in Example 6.3. Total yield: Sodium D-α-{[2-oxo-3- (4-methylsulfonyl) -benzylmino-imidazolidin-1-yl] -carbonylamino} -phenylacetamido / 3- 1.85 parts of acetoxymethyl-ce-3-fem-4-toxylate are obtained. β-lactam: 84%

According to the NMR spectrum, this cephalosporin contains 1.7 moles of water, 0.4 moles of dimethylformamide, 0.4 moles of ethyl acetate, and 0.16 moles of sodium 2-ethylhexanoate. The analysis values considering this are as follows.

Calculated Value: C 47.4 H 4.6 N 10.5 S 7.5

Found: C 47.3 H 4.2 N 10.8 S 8.1

NMRτ = 2.1 (4H), 2.25 (1H), 2.5-2.9 (5H), 4.3-4.6 (2H), 5.05-5.3 (3H), 6.0-6.3 (4H), 6.7 (2H), 6.9 (3H), 8.0 ppm (3H).

Example 7

15.8 parts 2-oxo-imidazolidine, 12.6 parts sodium nitrite, 27.5 parts zinc mal and 18.5 parts thiophene-2-aldehyde are reacted in the same manner as in 1.1. The resulting 1- (thiophene-2-aldimino) -2-oxo-imidazolidine was purified by boiling with ethanol or recrystallized from dimethylformamide to give 22.4 parts of a compound having a melting point of 263 to 265 ° C.

IR (KBr): 3,240, 1,705㎝ ^-1

NMR (d ₆ -DMSO): 7.88 (S, 1 H), 7.3-7.0 (heteroaromatic hydrogen, NH, 4H), m (4H) centered at 3.6.

Calculated: C 49.22 H 4.65 N 21.52 S 16.42

Found: C 49.4 H 4.6 N 21.4 S 16.1

9.8 parts of 1- (thiophene-2-aldimino) -2-oxo-imidazolidine, 16.2 parts of triethylamine, 16.1 parts of trimethylchlorosilane, and 5.1 parts of phosgene were reacted in the same manner as in Example 1.2 to decompose 7.7 parts of 1-chlorocarbonyl-2-oxo-3- (thiophene-2-aldimino) -imidazolidine at points 184-188 ° C are obtained.

IR (paraffin wax): 1830, 1720cm ^-1

This chlorocarbonyl compound contains a starting material that has not been removed since it does not interfere with the next step reaction.

Example 1.3 Example 1 -Chlorocarbonyl-2-oxo-3- (thiophene-2-aldimino) -imidazolidine and 4.1 parts Ampicillin trihydrate in 40 parts (dose) of 80% aqueous Reacted with a room bubble such as sodium 6- {D-α-[(2-oxo-3- {thiophen-2-alminomino} -imidazolidin-1-yl) -carbonylamino] -phenyl 0.4 part of acetamido} phenylanate is obtained. Decomposition point: 210 to 220 ℃ β-lactam content: 89%

IR (KBr): 1,760, 1,720, 1,660, 1,600 cm ^-1

NMR (CD ₃ OD): 7.90 (S, 1H), 7.5-6.8 (aromatic and heteroaromatic hydrogen 8H), 5.551 (S, 3H overlapped m near 5.4), 4.12 (S, 1H), 3.79 (broad S, 4H), 1.57 (S, 3H), 1.48 (S, 3H), 1.48 (S, 3H) δ.

Analytical value of C ₂₅ H ₂₅ NaO ₆ S ₂ .2.5H ₂ O.0.25 ether (656.1)

Calculated Value: C 47.60 H 5.00 N 12.81 S 9.79

Found: C 47.6 H 5.5 N 12.4 S 10.0

Method of 1.5 parts of 1-chlorocarbonyl-2-oxo-3- (thiophene-2-aldimino-imidazolidine and 2.0 parts of sodium episilin in 40 parts (dose) of 80% aqueous THF 6- {D-α-[(2-oxo-3- {thiophene-2-aldimino} -imidazolidine-1- at a decomposition point of 205 to 215 DEG C and 80% of β-lactam. I) -carbonylamino] -cyclohex-1,4-dienyl (1) -acetamido} -penicilanate 0.8 parts are obtained.

IR (KBr): 1,770, 1,730, 1,665, 1,605 cm ^-1

NMR (CD ₃ OD): 8.00 (S, 1H), 7.5-7.0 (Heteroaromatic hydrogen, 3H), 5.95 (Broad S, 1H), 5.70 (S, 2H), 5.50 (S, 2H), 5.00 (S , 1H), 4.20 (S, 1H), 3.86 (broad S, 4H), 2.73 (broad S, 4H), 1.64 (S, 3H), 1.57 (S, 3H) δ.

Analytical value of C ₂₅ H ₂₇ N ₆ NaO ₆ S ₂ .2H ₂ O (550.6).

Calculated Value: C 47.61 H 4.95 N 13.31 S 10.16

Found: C 47.6 H 5.1 N 13.0 S 10.2

Implement 150 parts of 1-chlorocarbonyl-2-oxo-3- (thiophene-2-aldimino) -imidazolidine and 2.25 parts of cephaloglycine dihydrate in 40 parts (dose) of 80% aqueous THF React as in Example 1.4. Acidification results in 7- {D-α-[(2-oxo-3- {thiophen-2-aldimino} -imidazolidin-1-yl) -carbonylamino] -phenylacetamino} -3- 0.6 parts of acetoxymethyl-ce-3-fem-4-carboxylic acid precipitated out as a precipitate, which was reacted with 3 parts (volume) of 1 sodium 2-ethyl-hexanoate solution in the same manner as in Example 1.4 to form p-lactam. Sodium 7- {D-α-[(2-oxo-3- {thiophen-2-alminomino} -imidazolidin-1-yl) -carbonylamino] with a content of 75 to 80% -phenyl Acetamido} -3-acetoxymethyl-ce-3-fem-4-carboxylate is obtained.

IR (KBr): 1,755, 1,720, 1,660, 1,600 cm ^-1

NMR (CD ₃ OD): 1.795 (S, 1H), 7.5-6.8 (aromatic and heteroaromatic hydrogen, 8H), 5.75-5.00 (m, 3H), 4.8 (overlapped exchangeable hydrogen), 3.82 (broad S , 4H), 2.00 (S, 3H) δ.

Example 8

15.8 parts 2-oxo-imidazolidine, 12.6 parts sodium nitrite, 27.5 parts zinc dust and 15.8 parts furan-2-aldehyde are reacted in the same manner as in Example 1.1. 17.5 parts of 1-furylidene amino-2-oxo-imidazolidine of melting point 218-220 degreeC are obtained.

IR (KBr): 3,200, 3,110, 1,715, 1,585 cm ^-1

NMR (d ₆ -DMSO): 7.70 (m, 1H), 7.50 (S, 1H), 7.5 (Broad S, 1H), 6.50-6.775 (m, 2H), m (4H) centered at 3.55.

Calculated Value: C 56.63 H 5.06 N 23.45

Found: C 53.7 H 5.0 B 23.2

11.5 parts of 1-furylideneamino-2-oxo-imidazolidine, 10.0 parts of triethylamine, 13.2 parts of trimethylchlorosilane, and 6.2 parts of phosgene were reacted in the same manner as in Example 1.2, and the decomposition point was 188 to 192 ° C. 3.8 parts of 1-chlorocarbonyl-2-oxo-3-furylideneamino-imidazolidine of is obtained.

IR (Paris pinyu): 1,800, 1,700㎝ ^-1

Example 1.3 Example 1-Chlorocarbonyl-2-oxo-3- (furan-2- aldimino) -imidazolidine and 20.4 parts ampicillin trihydrate in 200 parts (dose) of 80% aqueous THF React in the same manner as Decomposition point: 220-207 ° C., sodium 6- {D-α-[(2-oxo-3-furylideneamino-imidazolidin-1-yl) -carbonylamino having a β-lactam content of 81% -Phenylacetamido} -peniclanate 2.3-part is obtained.

IR (KBr): 1,760, 1,715, 1,660, 1,600 cm ^-1

NMR (CD ₃ OD): 7.60 (S, 1H), 7.50-6.35 (aromatic and heteroaromatic baths, 8H), 5.55 (S, 1H), 5.40 (q, 2H), 4.12 (S, 1H), at 3.75 Centered m (4H), 1.55 (S, 3H), 1.481 (S, 3H) δ.

Analysis of C ₂₄ H ₂₅ N ₆ NaO ₇ S1.5H ₂ O0.25 ether

Calculated Value: C 49.22 H 5.04 N 13.76 S 5.26

Found: C 49.5 H 4.8 N 13.5 S 5.2

Example 1.6 A solution of 100 parts (volume) of 10.0 parts of cephaloglycine dihydrate in 100 parts of 80% aqueous THF and 6.1 parts of 1-chlorocarbonyl-2-oxo-3-furylideneamino-imidazolidine React and manipulate in the same way. Sanalizing with 0.1 N hydrochloric acid at 5 to 10 DEG C gradually precipitates 13.1 parts of crystalline acid (Q = H). Dissolve it in 500 parts (volume) of acetone, filter out a small amount of insoluble material, and concentrate the filtrate. The residue is suspended in 120 parts (volume) of water and dissolved completely while adding pH 1.5N sodium hydroxide solution to maintain the pH between 7.5 and 8.0. The solution is filtered to add 940 parts (volume) of acetone and 190 parts of ethyl acetate, and then 380 (volume) of ether is added dropwise to precipitate the sodium salt. Decomposition point 215 to 220 ° C,

Crystalline sodium 7- {D-α-[(2-oxo-3-furylideneamino-imidazolidin-1-yl) -carbonylamino] -phenylacetamino} having a β-lactam content of 95% 7.8 parts of 3-acetoxymethyl-ce-3-fem-4-carboxylate are obtained.

IR (KBr): 1,765, 1,730, 1,670, 1,615, 1,530, 1,480, 1,390, 1,265, 1,230, 1,020, 740, 695 cm ^-1

NMR (D ₂ O / CD ₃ OD): 7.5 (S, 2H), 7.30 (S, 5H), 6.65 (1H), 6.45 (1H), 5.56 (d, 1H), 5.38 (S, 1H), 4.91 (Pseudo-d, exchangeable hydrogen overlaps), 3.76 (6H), 2.03 (S, 3H) δ

Analytical Value of C ₂₇ H ₂₅ N ₆ NaO ₉ SH ₂ O

Calculated Value: C 49.84 H 4.18 N 12.91 S 4.92

Found: C 49.4 H 4.6 N 12.9 S 4.9

9.4 parts of amoxisilane in 100 parts of 80% aqueous THF are reacted with 5.5 parts of 1-chlorocarbonyl-2-oxo-3- (furan-2- aldimino) -imidazolidine as in Example 1.4. . As a result 0.1 part sodium-6- {D-α [(2-oxo-3-furylideneamino-imidazolidin-1-yl) -carbonylamino] -4-hydroxyphenyl acetamido}- Obtain penicillate.

IR (KBr): 1,775, 1,730, 1670, 1615cm-1

NMR (CD ₃ OD): 7.7-6.6 (8H), 5.5 (3H), 4.18 (S, 1H), 3.90 (S, 4H), 1.58 (S, 3H), 1.50 (S, 3H) δ

Example 9

18.9 parts 2-oxo-imidazolidine, 15.2 parts sodium nitrite and 33.2 parts zinc powder are reacted with 2.1 parts 2-chlorothiophene-5-aldehyde following the same procedure as in Example 2.1. 36.0 parts of 1- (2-chlorothiophen-5-aldiimino) -2-oxo-imidazolidine are obtained and purified by washing with water, ethanol and ether.

Melting Point: 194-197 ℃

IR (KBr): 3,260, 1,700 (Broad), 1,580 cm ^-1

NMR (d ₆ -DMSO): 7.92 and 7.78 (S, 1H, Syn and anti: forms), 7.16 and 7.10 (AB, 3H overlapping NH) m (4H) δ centered on 3.6.

Calculated Value: C 41.84 H 3.51 N 18.28 S 13.96

Found: C 41.9 H 3.8 N 18.0 S 14.3

In the same manner as in Example 2.2, 8.6 parts of 1- (2-chlorothiophen-5-aldimino) -2-oxo-imidazolidine and 12.1 parts of triethylamine in 60 parts (dose) of anhydrous dioxane and 25 12 parts trimethylchlorosilane in a part (volume) of dioxane anhydride is reacted with 3.9 parts of phosgene. The precipitate was separated and dried to yield 5.1 parts of 1-chlorocarbonyl-2-oxo-3- (2-chlorothiophen-2-aldimino) -imidazolidine (decomposition point: 215-220 ° C.)

IR (paraffin wax): 1800㎝ ^-1

13.9 parts of ampicillin trihydrate in 140 parts (volume) of 80% aqueous THF was mixed with 5 parts of 1-chlorocarbonyl-2-oxo-3- (2-chloro-thiophen-5-aldimino) -imidazoli React with Dean.

As a result, 7.5 parts of sodium 6- {D-α-[(2-oxo-3- {2-chlorothiophen-5-alamino} -imidazolidin-1-yl) -carbonylamino] -phenylacet Amido} -penicilanate is obtained.

(Decomposition point: 215 to 225 ° C, β-lactam content: 90%)

IR (KBr): 1,765, 1,730, 1,670, 1,605 cm ^-1

NMR (CD ₃ OD): 7.77 (S, 1H), m (1H) centered at 7.32, 7.06 and 6.83 (AB, 2H), 5.55 (S, 1H), 5.42 (g, 2H), 4.13 (S , 1H), 3.77 (Broad S, 4H), 1.56 (S, 3H), 1.48 (S, 3H) δ

에테르의 분석치 _{C 25 H 24 Cl 6 NaO 6} S 2 · H 2 O ·

Analysis of ether

Calculated Value: C 47.10 H 4.33 N 12.68 S 9.68 Cl 5.35

Found: C 47.0 H 4.2 N 12.5 S 9.5 Cl 4.9

2.5 parts of cephaloglycine dihydrate in 2.5 parts of 50% (dose) of 80% aqueous THF, in Example 1.6 and 1.7 parts of 1-chloro-carbonyl-2-oxo-3- (2-chlorothiophene- React with 5-aldimino) -imidazolidine. As a result, 2.5 parts of sodium 7- {D-α [(2-oxo-3- {2-chlorothiophen-5-aldimino} -imidazolidin-1-yl) carbonylamino] -phenylacetamino } -3-acetoxymethyl-ce-3-fem-4-carboxylate is obtained.

IR (KBr): 1,760, 1,730, 1,670, 1,600 cm ^-1

NMR (CD ₃ OD / D ₂ O): 7.87 (S, 1H), 7.50 (S, 5H), 7.18 (d, 1H), 5.65 (d, 1H), 5.53 (S, 1H), 5.05 (exchangeable) Overlapping hydrogen), 3.83 (6H), 2 (10 (S3H) δ

C ₂₇ H ₂₄ clN ₆ O ₈ S ₂ H ₂ O

Calculated: C 46.26 H 3.74 N 11.99 S 9.14 Cl 5.07

Found: C 46.3 H 3.9 N 11.9 S 9.5 Cl 5.0

Example 10

15.8 parts 2-oxo-imidazolidine, 12.6 parts sodium nitrite and 27.5 parts zinc powder are reacted with the process of Example 2.1 and 31.5 parts 3-bromothiophene-5-aldehyde. 41.2 parts of 1- (3-bromothiophen-5-aldimino-2-oxo-imidazolidine is obtained, washed with water, ethanol, ether and recrystallized from DMF.

(Melting point: 253 ° C to 255 ° C)

IR (KBr): 3230 and 1710 cm ^-1

NMR (d6-DMSO): 7.77 (S, 1H), 7.6 (S, 1H), 7.28 (S, 1H), 7.24 (S, 1H), m (4H) centered on 3.6

Calculated: C 35.04 H 2.93 N 15.33 S 11.70 Br 29.15

Found: C 34.7 H 2.9 N 15.5 S 11.8 Br 29.1

12.2 parts 1- (3-bromothiophen-5-aldimino) -2-oxo-imidazolidine and 120 parts (dose) of anhydrous 14.1 parts triethylalmine and 50 parts (dose) of anhydrous di 14 parts of trimethylchlorosilane in oxane and 4.6 parts of phosgene were reacted with each of Example 2.2. After removal of excess phosgene, the precipitate was concentrated by filtration, the residue was triturated with ether and filtered to afford 7.5 parts of 1-chlorocarbonyl-2-oxo-3- (3-bromothiophen-5-aldimino)- Obtain imidazolidine.

(Melting point is 165-170 ° C. and still contains some starting material)

IR (paraffin wax): 1780 and 1690cm ^-1

6.5 parts of ampicillin trihydrate and 2.7 parts of 1-chlorocarbonyl-2-oxo-3- (3-bromothiophen-5-aldimino) -imidazolidine in 80% aqueous THF 70 (dose) Example 1.3 The reaction was carried out by the method. As a result, 2.2 parts of 6- {D-α-[(2-oxo- {3-bromothiophen-5-aldimino} -imidazolidin-1-yl) -carbonylamino] -phenylacetamido } -Penicylanate

(Melting point: 210-220 degreeC) is obtained.

(85% β-lactam content)

IR (KBr): 1,765, 1,730, 1,675, 1,610 cm ^-1

NMR (CD ₃ OD): 7.83-7.20 (8H), 5.53 (S (1H), 5.42 (g, 2H), 4.12 (S (1H), 3.78 (Broad S, 4H), 1.55 (S, 3H), 1.48 (S, 3 H) δ.

6.5 parts of cephaloglycine dihydrate in 80 parts (dose) of 80% aqueous THF were combined with 1-chlorocarbonyl-2-oxo-3- (3-bromothiophen-5-aldimino) -imidazolidine React. As a result, sodium 7- {D-α-[(2-oxo-3} bromothiophen-5-aldimino} -imidazolidin-1-yl) -carbonylamino] -phenylacetamido}- 3-acetoxymethyl-ce-3-fem-4-carboxylate is obtained.

(Decomposition point: 190 to 195 ℃)

IR (KBr): 1,760, 1,725, 1,670, 1,605 cm ^-1

Analysis of the _{C 27 H 24 BrN 6 NaO 8} S 2 · H 2 O

Calculated Value: C 43.50 H 3.52 N 11.28 S 8.59

Found: C 43.8 H 3.8 N 10.8 S 8.1

7.5 parts of amoxicillin trihydrate in 100 parts (volume) of 80% aqueous THF was mixed with 6.0 parts of 1-chlorocarbonyl-2-oxo-3- (3-bromothiophen-5-aldimino) -imidazolidine Reaction was followed by 4.3 parts of sodium 6- {D-α [(2-oxo-3- {3-bromothiophen-5-aldimino} -imidazolidin-1-yl) -carbonylamino] -4- Hydroxyphenyl-acetamido} -peniclanate is obtained.

IR (KBr): 1,760, 1,720, 1,670, 1,605 cm ^-1

NMR (CD ₃ OD): 7.80 (S, 1H), 6.6-7.4 (6H), 5.5 (m, 3H), 4.12 (S, 1H), 3.78 (S, Broad 4H), 1.54 (S, 3H), 1.48 (S, 3 H) δ.

C ₂₅ H ₂₄ BrN ₆ NaO ₇ S ₂ H ₂ O

Calculated Value: C 41.50 H 3.91 N 8.84

Found: C 41.7 H 4.3 N 8.3

Example 11

18.5 parts of cinnamic aldehyde was added to 150 parts (volume) of 1N sodium hydroxide solution in 21 parts of 1-amino-2-oxo-imidazolidine hydrochloride with stirring at 20 ° C., and this dimixture was further stirred for 90 minutes and thereafter. Let stand 16 hours.

The separated precipitate is filtered off, washed well with water and dried over a P ₄ O ₁₀ desiccator.

Yield: 29.6 parts, decomposition point 206 to 210 ° C (Coppler bench)

It contains 0.28 molar equivalents of water. The analytical value considering this is as follows.

Calculated Value: C 65.4 H 6.1 N 19.1

Found: C 65.5 H 6.1 N 19.1

4.3 parts (volume) of phosgene liquid in 15 parts (volume) of benzonitrile and 10 parts 1- (cinnamilide-amino) -2-oxo-imidazolidine and 50 parts (volume) of benzonitrile and 7.7 parts The mixture was added dropwise while stirring to a mixture of triethylamine (volume), and cooled with ice water.

Continue to cool and stir for 4.5 hours. The resulting precipitate is filtered, stirred at 20 ° C. in about 30 parts (volume) of methylene chloride for 2 hours, refiltered and dried over a P ₄ O ₁₀ desiccator.

Yield: 8.2 parts, Melting point: 227-230 ° C. (Coppler bench)

The compound still contains triethylamine hydrochloride, but it does not interfere with subsequent reactions.

IR spectrum (-CO-Cl): 1800 cm ^-1 (in paraffin oil)

Penicillin of the above formula was prepared in the same manner as in Example 1.3 with 2 parts of ampicillin trihydrate and 1-chlorocarbonyl-2-oxo-3- (cinnamylideneamino) -imidazolidine Is prepared by reacting triethylamine).

Yield: 2.1

D-α-[(2-oxo-3-cinnamylideneamino-imidazolidin-1-yl) -carbonylamino] -benzyl-penicillin, β-lactam content: 82%

According to NMR analysis, this compound contains 2.6 molar equivalents of water and 0.56 molar equivalents of sodium 2-ethylhexanoate.

Calculated Value: C 53.6 H 5.6 N 11.22 S 4.3

Found: C 53.6 H 5.6 N 11.8 S 4.3

NMR τ: 2.3-3.2 (13H), 4.45 (1H), 4.45-4.75 (AB, 2H), 5.9 (1H), 6.1-6.4 (4H), 8.5 (3H), 8.55ppm (3H)

IR (in paraffin oil): 1,770, 1,730, 1,670, 1,6101, 525 cm ^-1

Penicillin of the above formula was reacted with 1.5 parts of amoxicillin trihydrate and 1.49 parts of 1-chlorocarbonyl-2-oxo-3- (cinnamylidene-amino) -imidazolidine in the same manner as in Example 1.3 to give 1.3 parts of sodium D-α [(2oxo-3-cinnamylidene-amino-imidazolidin-1-yl) carbonylamino] -P-hydroxy-benzylphenicillin is prepared. β-lactam content: 88%

Here, 1.5 molar equivalents of water and 0.36 molar equivalents of 2-ethylhexanoate are contained, and the analysis values considering this are as follows.

Calculated Value: C 53.6 H 5.2 N 11.8 S 4.5

Found: C 53.6 H 5.7 N 11.7 S 4.6

IR spectrum (in paraffin wax): 1,770, 1,740, 1,670, 1,615, 1,555-1,520 cm ^-1

Penicillin of the above formula is 1.5 parts of epicillin and 1-chloro carbonyl-2-oxo-3- (cinnamilidene-amino) -imidazolidine (since 1.77 parts of excess contains triethylamine hydrochloride) Was reacted in the same manner as in Example 1.3 to give 1.6 parts of sodium

D-α [(2-oxo-3-cinnamylidene-amino-imidazolidin-1-yl) -carbonylamino] -α- (1,4-cyclohexadien-1-yl) -methyl Prepare penicillin. β-lactam content: 82%

NMR analysis showed 2 molar equivalents of water and 0.36 molar equivalents of sodium 2-ethylhexanoate.

Calculated Value: C 54.0 H 5.6 N 11.8 S 4.5

Found: C 54.0 H 5.7 N 11.7 S 4.5

IR spectrum (in paraffin wax): 1772, 1670, 1610, 1530cm ^-1

NMR τ: 2.25-3.15 (8H), 4.05 (1H), 4.3 (2H), 4.5 (2H), 5.0 (1H), 5.8 (1H), 6.05-6.4 (4H), 7.15-7.45 (4H), 8.4 (3H), 8.46 (ppm, 3H).

Cephalosporin of the above formula was prepared in the same manner as in Examples 1.3 and 1.6 with 1.5-pack cephaloglycine dihydrate and 1-chlorocarbonyl-2-oxo-3- (cinnamylidene-amino) -imidazoline (1.08 parts The reason for the excessive use is because it contains triethylamine hydrochloride), tetrahydrofuran is removed in PH7, the insoluble precipitate and ethyl acetate are filtered off and stirred in PH2.0 with a mixture of water and ethyl acetate. do. After filtration the product is stirred with 10 parts (volume) of dimethylformamide, the insoluble material is filtered off and diluted with 150 parts (volume) of ether to precipitate sodium salts.

Yield: sodium 7- {| -α-[(2-oxo-3-cinnamylidene-amino-imidazolidin-1-yl) -carbonylamino} -phenyl-acetamido} -3-acetoxy Methyl-ce-3-fem-4-carboxylate0.5part, β-lactam

Content: 80%

NMR analysis showed 3 molar equivalents of water and 0.65 molar equivalents of natre 2-ethylhexanoate. The analytical value to consider is as follows.

Calculated Value: C 52.3 H 5.4 N 1.1 S 3.9

Found: C 52.4 H 5.6 N 10.3 S 3.8

IR spectrum (in paraffin oil) (carbonyl moiety): 1,770, 1,730, 1,668, 1,612, 1,540 cm ^-1

NMR (in deuterated DMF): 2.1-2.9 (13H), 3.9-4.3 (2H), 4.75-5.1 (3H), 4.0 (4H), 6.6 (2H), 7.9ppm (3H)

Example 12

10.7 parts of pyridine-3-aldehyde is added to 10.1 parts of 1-amino-2-oxo-imidazolidine in a mixture of methanol and water (50 parts each: capacity) and stirred at 20 ° C. for 20 hours.

The precipitate is filtered off, washed with water and a small amount of methanol and dried over P ₄ O ₁₀ .

Yield: 16.5 parts Melting point: 195 ° (Coppler bench)

Calculated Value: C 56.9, H 5.3, N 29.5, O 8.4

Found: C 56.9, H 5.2, N 30.0, O 8.0

1.35 parts (volume) of phosgene solution in 10 parts (volume) of tetrahydrofuran was added to 3 parts 1- (3-pyridyl-methylideneamino) -2-oxo- in a mixture of 30 parts benzonitrile and 2.6 parts triethylamine. To a suspension of imidazolidine is added by cooling with ice water. After 20 minutes, the mixed radish is brought to 20 ° C. and stirred overnight at this temperature. The resulting precipitate is filtered off, washed with ether and then dried over dichloromethane. Yield: 4.2

IR spectrum (CO. Cl): 1,800 cm ^-1 (in paraffin oil) Melting point: 252 ° C (Coppler bench)

Penicillin of the above formula was prepared in the same manner as in Example 1.3 from 1.0 part Ampicillin trihydrate and 0.63 part 1-chlorocarbonyl-2-oxo-3- (3-pyridyl-methylidene amino) -imidazolidine do. The solution from which tetrahydrofuran was removed is acidified and ethyl acetate is added to give some penicillin free acid which is insoluble in ethyl acetate. (Yield 0.2 parts).

IR spectrum carbonyl moiety: 1,775, 1,725, 1670, 1520 cm ^{-1 The} organic phase is precipitated with sodium 2-ethylhexanoate solution to give sodium salt.

Yield: 0.7 parts of sodium D-α {[(2-oxo-3- (3-pyridyl-methylideneamino) -imidazolidin-1-yl] -carbonylamino} -benzylphenicillin, β-lactam content : 90%

According to NMR analysis, it contains 3.3 molar equivalents and 0.13 molar equivalents of sodium-2-ethylenesanoate. The analytical value considering this is as follows.

Calculated Value: C 48.6, H 5.3, N 14.7, S 4.8

Found: C 48.5, H 5.8, N 14.5, S 4.8

IR spectrum (in paraffin wax): 1768, 1722, 1667, 1625, 1600, 1550 and 1525cm ^-1

NMR (τ): 1.0-1.2 (1H), 1.35-1.55 (1H), 1.6-1.85 (1H), 2.15 (1H), 2.3-2.8 (6H), 4.3 (1H), 4.3-4.6 (AB, 2H ), 5.8 (1H), 5.9-6.2 (4H), 8.4 (3H) and 8.45 ppm (3H).

Example 13

To a mixture of 14 parts 1-amino-2-oxo-imidazolidine hydrochloride and 100 parts 1N sodium hydroxide solution, 3-methylbenzaldehyde is added and stirred at 20 ° for 5 hours. The precipitate is filtered off and washed with water. Yield: 20.3 parts Melting point: 205 to 207 ° C (Coppler bench)

9.65 parts trimethylchlorosilane solution in 50 parts (volume) of benzene was added 12 parts 1- (3-methyl-benzylidene-amino) -2-oxo-imidazolidine, 150 parts (vol.) Benzene and 13.4 parts triethyl To the lightly boiled mixture of amines is added dropwise over 1 hour. The mixture is boiled under reflux for 30 hours. Triethylamine hydrochloride is warm filtered and washed with hot benzene. 4.7 parts (capacity) of phosgene solution in 4.7 parts (capacity) of 30 parts of benzene (capacity) was added to the combined benzene filtrate cooled to 10 ° C, and left standing at 20 ° C for 48 hours.

The precipitate is then filtered off, washed with benzene, triturated with 40 parts (volume) of methylene chloride and dried. Yield: 3.2 parts Melting point: 209 to 210 ° C (Coppler bench)

Calculated Value: C 54.3, H 4.5, Cl 13.4, N 15.8

Found: C 54.5, H 4.6, Cl 13.5, N 15.4

IR spectra (CO, Cl) (in paraffin wax): 1810 cm ^-1

Penicillin of the above formula was reacted with penicillin by reacting 2 parts ampicillin trihydrate and 1.6 parts 1-chlorocarbonyl-2-oxo-3- (3-methylbenzylidene-amino) -imidazolidine as in Example 1.3. To prepare.

Yield: 2.55 parts of sodium D-α-{[2-oxo-3- (3-methylbenzylidene-amino) -imidazolidin-1-yl] -carbonylamino} -benzylphenicillin is obtained. β-lactam content: 90%

NMR analysis showed about 0.06 molar equivalents of 2-ethylhexanoate and 3 molar equivalents of water.

The analysis values considering this are as follows.

Calculated Value: C 52.1, H 15.4, N 12.6, S 4.8

Found: C 51.9, H 6.3, N 12.4, S 4.9

IR spectrum (in paraffin oil) (carbonyl moiety): 1,770, 1,675, 1,612, 1,530 cm ^-1

NMRτ (CD ₃ , OD): 2.25-2.9 (10H), 4,35 (1H), 4.35-4.65 (AB, 2H), 5.85 (1H), 6.1-6.4 (4H), 7.7- (3H), 8.5 ppm (3H).

Penicillin of the above formula was prepared by reacting 1 amoxicillin trihydrate and 0.73 parts of 1-chlorocarbonyl-2-oxo-3- (3-methylbenzylidene-amino) -imidazolidine from the same method as in Example 1.3. do.

Yield: 1.1 parts of crystalline sodium D-a-{[2-oxo-3- (3-methylbenzylidene-amino) -imidazolidin-1-yl] carbonylamino} -P-hydroxybenzylphenicillin are obtained. β-lactam content: 90%

NMR analysis showed about 0.16 molar equivalents of sodium 2-ethylhexanoate and 2.9 molar equivalents of water. The analysis values considering this are as follows.

Calculated Value: C 50.5, H 5.3, N 12.1, S 4.6

Found: C 50.5, H 5.4, N 11.9, S 4.6

IR spectrum (from paraffin oil: carbonyl moiety): 1,790, 1,765, 1,720, 1,690, 1,660, 1,612, 1,590, 1,550, 1,510 cm ^-1

NMR τ (CD ₃ OD): 2.2-3.3 (9H), 4.4-4.65 (3H), 5.85 (1H), 6.0-6.3 (4H), 7.65 (3H), 8.4 (3H), 8.5 mm (3H).

Penicillin of the above formula is prepared by reacting 1 part epicylin with 0.91 part 1-chlorocarbonyl-2-oxo-3- (3-methylbenzylidene-amino) -imidazolidine in the same manner as in Example 1.3. . At the time of precipitation of the sodium salt, an amorphous penicillin salt was first obtained and 0.9 parts of crystalline D-α-{[2-oxo-3- (3-methylbenzylidene-amino) -imidazolidin-1-yl] from the mother liquor Further obtain -carbonylamino} -α- (1,4-cyclohexadien-1-yl) -methylphenicyl.

IR spectrum of amorphous salt (from paraffin oil: carbonyl moiety): 1,770, 1,730, 1,670, 1,610, 1,252 cm ^-1

IR spectrum of crystalline salt (from paraffin oil: carbonyl moiety): 1,790 (1,775), 1,740, 1,712, 1,660, 1,600, 1,575, 1,520 cm ^-1

NMR (CD ₃ OD) τ: 2.1-2.8 (5H), 4.05 (1H), 4.3 (2H), 4.5 (2H), 5.0 (1H), 5.8 (1H), 6.1 (4H), 7.25 (4H), 7.65 (3H), 8.35 (3H), 8.45 (3 ppm (3H)

The cephalosporin of the above formula is 1.0 parts of cephaloglycine dihydrate and 0.69 parts of 1-chlorocarbonyl-2-oxo-3- (3-methyl benzylideneamino) -imidazolidine in Example 1.3 and 1.6. It is made by reacting by the method. The sodium salt is then separated into precipitates in the form of gel which are not filtered. For this reason, the residue is treated with dry ether after removing all volatiles. As a result, the cephalosporin salt was obtained with the analyzed white powder.

Yield: 1.2 parts of 7 {D-α-[(2-oxo-3-methyl-methyl-benzylideneamino-imidazolidin-1-yl) -carbonylamino] -phenylacetamino} -3-acetoxy Methyl-ce-3-fem-4-carboxylate β-lactam content: 90%

It contains 2.9 molar equivalents of water. The analysis values considering this are as follows.

Calculated Value: C 51.2, H 4.9, N 11.9, S 4.6

Found: C 51.4, H 5.5, N 11.7, S 4.7

IR spectrum (in paraffin oil) (carbonyl moiety): 1,765 (shoulder), 1,740, 1,660, 1,610, 1535 cm ^-1

NMR τ (d ₇ -DMF): 1.85-2.8 (10H), 3.9-4.3 (2H), 4.75-5.0 (3H), 5.8-6.1 (4H), 6.4-6.7 (2H), 7.5 (3H), 7.8 ppm (3H)

Example 14

14.0 parts of 1-amino-2-oxo-imidazolidine hydrochloride and 12.8 parts of 4-fluoro benzaldehyde are prepared and reacted in the same manner as in Example 13.1. Yield: 20.4 parts Melting point: 229 to 230 ° (Coppler bench)

A 4.2 parts (volume) phosgene solution in 10 parts (volume) of benzonitrile was prepared by 6 parts 1- (4-fluorobenzylidene-amino) -2-oxo-imidazolidine and 50 parts (volume) of benzonitrile. And 8 parts (volumes) of triethylamine were added dropwise with cooling with ice water, and further stirred at 820 ° C. for 3 hours. The precipitate is filtered, suspended in 240 parts (volume) of methylene chloride, refiltered and dried.

Yield: 0.9 parts (partially contained in mother liquor) This contains some triethylamine hydrochloride but does not affect subsequent reactions.

IR spectrum (CO. Cl): 1820/1810 cm ^-1 (in paraffin oil) Melting point: 240 to 247 ° C (decomposition) (Coppler bench)

Penicillin of the above formula is 1.0 part Ampicillin trihydrate and 0.8 part 1-chlorocarbonyl-2-oxo-3- (4-fluoro-benzylidene-amino) -imidazolidine in the same manner as in Example 1.3 Reaction to obtain. As a result, 1.2 parts of crystalline sodium D-α-{[2-oxo-3- (4-fluorobenzylidene-amino) -imidazolidin-1-yl] -carbonylamino} -benzylphenicillin are obtained . β-lactam content: 90%

According to the NMR spectrum, it contains 1.7 molar equivalents of water. The analysis values considering this are as follows.

Calculated Value: C 51.1, H 4.6, N 13.2, S 5.0

Found: C 51.1, H 5.4, N 13.2, S 5.1

IR spectrum (paraffin oil: carbonyl moiety): 1,790 (1,767), 1,730, 1,702, 1,670 (shoulder), 1,660, 1,602 cm ^-1

NMR (CD ₃ OD) τ: 2.1-3.1 (10H), 4.4 (1H), 4.4-4.65 (AB, 2H), 5,85 (1H), 6.0-6.3 (4H), 8.45 (3H), 8.55ppm (3H)

Cephalosporins of the above formula are prepared in the same manner as in Examples 1.3 and 1.6 with 1 part cephaglycine dihydrate and 0.7 part 1 chlorocarbonyl-2oxo-3- (4-fluorobenzylidene-amino) -imidazolidine. Obtained by reaction. The sodium salt is separated into an unfiltered gel form, so all volatiles are removed in vacuo and the residue is treated with a mixture of ether and methanol (10: 1).

As a result, the sodium salt turns into a pale white powder.

Yield: 0.5 parts of sodium 7- {D-α-[(2-oxo-3-P-fluoro-benzylideneamino-imidazolidin-1-yl) -carbonylamino] -phenylacetamido}- 3-acetoxymethyl-ce-3-fem-4-carboxylate. β-lactam content: 91%

According to the NMR spectrum, it contains 0.13 molar equivalents of sodium 2-ethylhexanoate and 1.7 molar equivalents of water. The analysis values considering this are as follows.

Calculated Value: C 50.7, H 4.4, N 11.8, S 4.5

Found: C 50.7, H 4.4, N 11.8, S 4.6

IR spectrum (from paraffin oil: carbonyl moiety): 1,775 (shoulder), 1,160 (shoulder), 1,735, 1,680, 1,610, 1,550, 1,520 cm ^-1

NMR (CD ₃ OD) τ: 2.1-2.9 (10), 4.2-4.35 (1H), 4.4 (1H), 5.0-5.2 (3H), 6.1 (4H), 6.5-6.7 (2H), 8.0ppm (3H )

Example 15

This compound is obtained in the same manner as in Example 13.1 with a yield of 17.6 parts from 14 parts of 1-amino-2-oxo-imidazolidine hydrochloride and 12.7 parts of 2-fluorobenzaldehyde. Melting Point: 214 to 216 ° C (Coppler Bench)

A 4.2 parts (volume) solution of phosgene in 10 parts (volume) of benzonitrile was added to 6 parts 1- (2-fluorobenzylidene-amino) -2-oxo-imidazolidine and 50 parts benzonitrile and 8 parts tris To the mixture of ethylamine, it is added dropwise with cooling and stirring with ice water. The mixture is stirred at 20 ° C. for 3 hours, the product is filtered off, washed with ether, suspended in 120 parts (volume) of methylene chloride, refiltered and dried.

Yield: 5.6 parts

Melting Point: 230 ° C (Coppler Bench)

IR spectrum (COCl): 1,800 (Shoulder at 1,815) cm ^-1

It contains a small amount of triethylamine hydrochloride but does not affect subsequent reactions.

Penicillin of the above formula was obtained by reacting 1 part of ampicillin trihydrate with 0.8 parts of 1-chlorocarbonyl-2-oxo-3- (2-fluorobenzylidene-amino) -imidazolidine as in Example 1.3. do.

Yield: 0.55 parts of crystalline sodium D-α-{[2-oxo-3- (2-fluorobenzylidene-amino) -imidazolidin-1-yl] -carbonylamino} -benzyl penicillin

β-lactam content: 90%

According to the NMR spectrum, it contains 2.9 molar equivalents of water. The analysis values considering this are as follows.

Calculated Value: C 49.4 H 4.9 N 12.8 S 4.9

Found: C 49.4 H 4.9 N 12.6 S 5.3

IR spectrum (from paraffin oil: carbonyl moiety): 1,793 (1,775), 1,740, (1,700, 1,680: all shoulders), 1,660, 1,610, 1,560, 1,520 cm ^-1

NMR (CD ₃ OD) τ: 1.8-3.1 (10), 4.4 (1H), 4.4-4.65 (2H), 5.8 (1H), 6.0-6.3 (4H), 8.45 (3H), 8.55PPm (3H)

Cephalosporin of the above formula is 1.5 parts of cephaloglycine dihydrate and 1.07 parts of 1-chlorocarbonyl-2-oxo-3- (2-fluorobenzylidene-amino) -imidazolidine in Example 1.3 and Obtained by reaction as in 1.6.

Acidification to pH 2 in the final tablets yields some cephalosporins as free acids that do not dissolve in water and ethyl acetate. (0.2 parts, IR spectrum (carbonyl part): 1,780, 1,745, 1,670, 1,540 cm < -1 >) The resulting cephalosporin is dissolved to some extent in the organic phase, from which sodium 7 {-D-α-[(2- Oxo-3-0-fluorobenzylideneamino-imidazolidin-1-yl) -carbonylamino] -phenylacetamido} -3-acetoxymethyl-ce-3-fem-4-carboxylate 0.8 parts are obtained. The following data is for sodium salts.

β-lactam content: 91%

According to the NMR spectrum, this cephalosporin contains 2.8 molar equivalents of water and 0.05 molar equivalents of sodium-2-ethylhexanoate.

Calculated Value: C 49.2 H 4.5 N 11.7 S 4.5

Found: C 49.1 H 4.3 N 11.7 S 4.9

IR spectrum (from paraffin oil: carbonyl moiety): 1,780, 1,730, 1,670, 1,610, 1,530 cm ^-1

NMR (d ₇ -DMF) τ: 1.8-2.9 (10H), 4.0-4.4 (2H), 4.8-5.1 (3H), 5.8-6.2 (4H), 6.5-6.75 (2H), 7.95ppm (3H)

Example 16

47.5 parts 2-oxo-imidazolidine, 83.0 parts sodium nitrite and 82.5 parts zinc powder were reacted with 64.0 parts 2-chlorobenzaldehyde in the same manner as in Example 2.1 to give 65 parts 1- (2-chloro) -benzylamino 2-oxo-imidazolidine is obtained and recrystallized from ethanol. Melting Point: 216 ~ 217 ℃

50 parts of 1- (2-chloro-)-benzylimino-2-oxo-imidazolidine and 73 parts of triethylamine [in 400 parts (dose) of dioxane] and 72.7 parts of trimethylchlorosilane [150 parts ( 34.5 parts of 1-chlorocarbonyl-2-oxo-3- (2-chloro) -benzylimino-imidazolidine is reacted with 44.5 parts of phosgene in the same manner as in Example 2.2. Obtained and recrystallized from acetonitrile, melting | fusing point is 233-237 degreeC.

IR (from paraffin wax): 1,800 cm ^-1

Calculated Value: C 49.18 H 3.17 N 14.68 Cl 24.78

Found: C 46.1 H 3.2 N 14.6 Cl 24.7

Example 1.1.3 parts ampicillin trihydrate in 150 parts (dose) of 80% aqueous THF was mixed with 5.0 parts 1-chlorocarbonyl-2-oxo-3- (2-chloro) -benzylimino-imidazolidine Example 1.3 And reacted as described above to form 11.3 parts of sodium 6- {D-α-[(2-oxo-3- (2-chloro) -benzylimino-imidazolidin-1-yl) -carbonylamino] -phenylacetami To obtain penicilanate (decomposition point: 215 to 220 ° C).

β-lactam content: 83%

IR (KBr): 1,765, 1,730, 1,675, 1,605 cm ^-1

NMR (CD ₃ OD): 7.92 (exchangeable m and S, 2H), m (8H) centered on 7.3, 5.55 (S, 1H), 5.42 (AB series, 2H), 4.12 (S, 1H), 3.83 (S, Broad, 4H), 1.58 (S, 3H), 1.50 (S, 3H) δ.

Analytical Value of C ₂₇ H ₂₆ ClN ₆ NaO ₆ S.2H ₂ O

Calculated Value: C 49.36 H 4.60 N 12.79

Found: C 49.4 H 4.6 N 12.7

6.3 parts of amoxicillin trihydrate and 2.9 parts of 1-chlorocarbonyl-2-oxo-3- (2-chloro) -benzylimino-imidazolidine in 80 parts (dose) of 80% THF were prepared as in Example 1.4. Reaction to react with 8.5 parts of sodium 6- {D-α-[(2-oxo-3- {2-chloro} -benzylmino-imidazolidin-1-yl) carbonylamino] -4-hydroxyphenylacet Amido} -penicilanate is obtained.

IR (KBr): 1,760, 1,720, 1,655, 1,600 cm ^-1

NMR (CD ₃ OD): 7.95 (S, 1H), 7.5-6.8 (8H), 5.5 (m, 3H), 4.2 (S, 1H), 3.92 (S, Broad 4H), 1.60 (S, 3H), 1.5 (S, 3H) δ.

10.9 parts sodium in 100 parts (dose) of 80% THF was reacted with 5.7 parts 1-chlorocarbonyl-2-oxo-3- (2-chloro) -benzylmino-imidazolidine to react 10.9 parts sodium 7- {D-α-[(2-oxo-3- {2-chloro} -benzylmino-imidazolidin-1-yl) -carbonylamino] -cyclohexa-1,4-dienyl ( 1) -acetamido} -3-methyl-ce-3-fem-4-carboxylate is obtained (decomposition point: 222 ° C.).

IR (KBr): 1,770, 1,735, 1,665, 1,590 cm ^-1

Analysis of the _{C 27 H 26 ClN 6 NaD 6} S · 2H 2 O

Calculated Value: C 49.36 H 4.66 N 12.79 S 4.88 Cl 5.39

Found: C 48.9 H 4.5 N 12.4 S 4.4 Cl 5.3

Five parts of cephaloglycine dihydrate in 100 parts (dose) of 80% aqueous THF was added with 3.3 parts of 1-chlorocarbonyl-2-oxo-3- (2-chloro) -2-benzalimino-imidazolidine. 6.7 parts of sodium 7- {D-α-[(2-oxo-3- {2-chloro} -benzylimino-imidazolidine-1 having a decomposition point of 195 to 200 ° C by reaction in the same manner as in Example 1.6 -Yl) -carbonylamino] -phenylacetamido} -3-acetoxymethyl-ce-3-fem-4-carboxylate.

IR (KBr): 1,760, 1,725, 1670, 1600cm ^-1

NMR (CD ₃ OD / D ₂ O): 7.2-8.0 (aromatic minority and -CH = N-), 5.65 (d, H), 5.50 (S, 1H), 5.05 (d, overlapping exchangeable hydrogen) 3.8 (6H), 2.10 (S, 3H) S.

Analyzes of C ₂₉ H ₂₆ ClN ₆ NaD ₈ SH ₂ O

Calculated Value: C 50.11 H 4.21 N 12.09 S 4.63

Found: C 50.1 H 4.1 N 12.1 S 4.8

Example 17

In the same manner as in Example 1.1, 47.6 parts of 2-oxo-imidazolidine, 34.5 parts of sodium nitrite and 78.4 parts of zinc powder are reacted and stirred overnight with 77 parts of 3-chlorobenzaldehyde. 65.7 parts of 1- (3-chloro) -benzylmino-2-oxo-imidazolidine having a melting point of 210 to 212 ° C are obtained.

IR (KBr): 3,230, 3,120, 1,715, 1,475, 1,405 cm ^-1

NMR (d ₆ -DMSO): m centered at 7.5 (aromatic hydrogen, -CH = N- and NH; 6H), 3.65 (m, 4H) δ.

Calculated Value: C 53.70 H 4.51 N 18.79 Cl 15.85

Found: C 54.0 H 4.7 N 18.4 Cl 16.2

43.3 parts of trimethyl-chlorosilane solution in 80 parts of dioxane anhydride (capacity) was mixed with 30 parts of 1- (3-chloro) -benzylmino-2-oxo-imidazolidine and 43.4 parts of triethylamine (capacity) ) Is added dropwise to boiling solution in dioxane anhydride. The mixture was reacted with 26.4 parts of phosgene in the same manner as in Example 2.2 to give 1-chlorocarbonyl-2-oxo-3- (3-chloro) -benzylimino-imidazolidine (decomposition point 190 °). Part is obtained.

It still contains a small amount of starting material.

IR (from paraffin wax): 1,800 cm ^-1

In 100 parts (dose) of 80% aqueous THF, 9.3 parts of ampicillin trihydrate was added to 8.7 parts of 1-chlorocarbonyl-2-oxo-3- (3-chloro) -benzylamino-imidazolidine. Reacted with 5.0 parts of sodium 6- {D-α-[(2-oxo-3- {3-chloro} benzalimino-imidazolidin-1-yl) -carbonylamino] -phenylacetamido} Obtain penicylanate.

IR (KBr): 1,760, 1,720, 1,660, 1,600 cm ^-1

3.3 parts of cephaloglycine dihydrate and 2.5 parts of 1-chlorocarbonyl-2-oxo-3- (3-chloro) benzalmino-imidazolidine in 100 parts (dose) of 80% aqueous THF And react together to 2.1 parts of sodium 7- {D-α-[(2-oxo-3- {3-chloro} -benzylmino-imidazolidin-1-yl) -carbonyl amino] -phenylacetamido } -3-acetoxymethyl-ce-3-fem-4-carboxylate is obtained (melting point: 212 to 218 ° C: decomposition).

IR (KBr): 1,765, 1,735, 1,665, 1,610cm ^-1

Analyzes of C ₂₉ H ₂₆ ClN ₆ NaO ₈ S · 3H ₂ O

Calculated Value: C 47.65 H 4.42 N 11.49

Found: C 47.6 H 4.8 N 11.5

Example 18

47.6 parts of 2-oxo-imidazolidine, 34.5 parts of sodium nitrite, 78.4 parts of zinc powder and 87.5 parts of 3,4-dichloro benzaldehyde were reacted as in Example 1.1 to give 50.4 parts of 1- ( 3,4-Dichloro) -benzylimino-2-oxo-imidazolidine is obtained.

IR (KBr): 3,240, 1,710 (Broad), 1,470 1,400, 1,260 cm ^-1

NMR (d ₆ -DMSO): 7.95 (S, 1H), 7.7 (m, 3H), 7.37 (S, Broad, 1H), m (4H) centered at 3.7

Calculated Value: C 46.46 H 3.52 N 16.28 Cl 27.48

Found: C 46.4 H 3.6 N 16.1 Cl 27.4

37.8 parts triethylamine in 30 parts 1- (3,4-dichloro) -benzylimino-2-oxo-imidazolidine and 250 parts (volume) of anhydrous dioxane, 37.7 in 80 parts (volume) of dioxane anhydride The negative trimethylchloro silane is reacted with 23.1 parts of forTMgen as in Example 2.2. As a result, 11.2 parts of 1-chlorocarbonyl-2-oxo-3- (3,4-dichloro) -benzylmino-idazolidine having a decomposition point of 224 to 230 ° C are obtained.

IR (Parispin You),: 1,800 cm ^-1

Calculated Value: C 41.80 H 2.82 N 13.07 Cl 33.07

Found: C 41.9 H 2.8 N 12.9 Cl 32.8

In 100 parts (dose) of 80% aqueous THF (9.4 parts of ampicillin trihydrate and 5 parts of 1-chloro carbonyl-2-oxo-3- (3,4-dichloro) -benzylimino-imidazolidine Reaction was carried out in the same manner as in Example 1.3, and 5.3 parts of sodium 6- {D-α-[(2-oxo-3- {3,4-dichloro} -benzylmino-imidazolidin-1-yl) -carbo Nylamino] -phenyl acetamido} -penicylanate is obtained.

IR (KBr): 1,765, 1,725, 1,660, 1605 cm ^-1

NMR (CD ₃ OD): 7.3-7.7 (aromatic hydrogen and -CH = N-), 5.61 (S, 1H), 5.50 (q, 2H), 4.18 (S, 1H), 3.85 (S, Broad, 4H) , 1.58 (S, 3H), 1.50 (S, 3H) δ

7 parts of cephaloglycine dihydrate in 100 parts (capacity) of 80% aqueous THF were prepared in the same manner as in Example 1.6 with 5.0 parts of 1-carbonyl-2-oxo-3- (3,4-dichloro) -benzylimino- 7.7 parts of sodium- {D-α-[(2-oxo-3- {3,4-dichloro} -benzylamino-imidazolidin-1-yl) -carbonylamino] by reaction with imidazolidine -Phenyl acetamido} -3-acetoxymethyl-ce-3-fem-4-carboxylate is obtained (decomposition point: 190 to 195 ° C).

IR (KBr): 1,765, 1,740, 1,665, 1,615, cm ^-1

Calculated Value: C 48.95 N 11.80 O 17.99

Found: C 49.0 N 11.7 O 18.1

Example 19

27.8 parts 2-oxo-imidazolidine, 20.0 parts sodium nitrite, 83.0 parts zinc powder, 54.0 parts 4-bromobenzaldehyde were reacted in the same manner as in Example 1.1 to 22.4 parts 1- (4-bromo) -benzal Amino-2-oxo-imidazolidine is obtained. Melting Point: 250-252 ° C

IR (KBr),: 3,240, 3,120, 1,740, 1,705, 1,595, 1,475, 1,415 and 1,270 cm ^-1

NMR (d ₆ -DMSO): 7.67 (aromatic hydrogenation -CH = N-), 7.30 (S, Broad, 1H), m (4H) δ centered at 3.6

Calculated Value: C 44.80 H 3.76 N 15.67

Found: C 44.9 H 3.7 N 15.3

26.2 parts of 1- (4-bromo) -benzylimino-2-oxo-imidazolidine and 26.3 parts of triethylamine in 80 parts (dose) of dioxane anhydride and 26.2 parts of 80 parts (dose) of dioxane anhydride Partial chlorotriethylsilane and 16.0 parts of phosgene are reacted according to Example 2.2 to obtain 4.2 parts of 1-chlorocarbonyl-2-oxo-3- (4-bromo) -benzalamino-imidazolidine. Melting Point: 177 to 180 ° C

IR (paraffin oil): 1,800 cm ^-1

3.6 parts of sodium 7- was reacted with 5.7 parts of cephaloglycine dihydrate and 4.2 parts of 1-chlorocarbonyl-2-oxo-3- (4-bromo) -benzylimino-imidazolidine in accordance with Example 18.3. {D-α-[(2-oxo-3- {4-bromo} -benzylmino-imidazolidin-1-yl) -carbonylamino] -phenylacetamido} -3-acetoxy methyl -3-3-fem-4-carboxylate is obtained. Decomposition point: 190 ~ 193 ℃

IR (KBr): 1760, 1725, 1655 and 1600 cm ^-1

Example 20

47.6 parts 2-oxo-imidazolidine, 34.5 parts sodium nitrite, 78.4 parts zinc powder, 60.1 parts 4-methylbenzaldehyde were reacted according to Example 1.1 to give 52.2 parts 1- (4-methyl) -benzylimino-2 -Oxo-imidazolidine is obtained. Melting Point: 235-236 ° C

IR (KBr): 3,320, 3,110, 1,710 (broad), 1,475, 1,410, 1,270 (broad) cm ^-1

NMR (d ₆ -DMSO): 7.2-7.8 (aromatic hydrogen, -CH = N-, NH, 6H), m (4H) centered at 3.7, 2.40 (S, 3H) S.

Calculated Value: C 65.00 H 6.45 N 20.68

Found: C 65.0 H 6.3 N 20.8

20.3 parts 1- (4-methyl) -benzylimino-2-oxo-imidazolidine, 33.3 parts triethylamine, 32.1 parts chlorotrimethylsilane and 19.8 parts phosgene were reacted according to Example 19.2 to give 19.6 parts 1- Chlorocarbonyl-2-oxo-3- (4-methyl) -benzylimino-imidazolidine is obtained. Melting Point: 265-268 ℃

IR (paraffin oil): 1,800 cm ^-1

Calculated Value: C 54.24 H 4.55 N 15.82 Cl 13.34

Found: C 54.2 H 4.5 N 15.8 Cl 13.6

5.0 parts of sodium 6- {D was reacted by reacting 8.1 parts of ampicillin trihydrate and 2.7 parts of 1-chlorocarbonyl-2-oxo-3- (4-methyl) -benzylimino-imidazolidine according to Example 2.3. -α-[(2-oxo-3- {4-chloro} -benzylimino-imidazolidin-1-yl) -carbonylamino] -phenylacetamido} -penicilanate is obtained.

Decomposition Point: 220 ~ 225 ℃

IR (KBr): 1760, 1,725, 1,660, 1,900 cm ^-1

NMR (CD ₃ OD): 7.1-7.8 (aromatic hydrogen and -CH = N-), 5.60 (S, 1H), 5.45 (q, 2H), 4.17 (S, 1H), 3.60 (S, broad, 4H) 2.18 (S, 3H), 1.58 (S, 3H), 1.50 (S, 3H) S.

Analyzes of C ₂₈ H ₂₉ N ₆ NaO ₆ S · 2H ₂ O

Calculated Value: C 52.82 H 5.22 N 13.20 S 5.03

Found: C 52.6 H 5.3 N 12.8 S 5.2

5.5 parts of amoxicillin trihydrate and 3.2 parts of 1-chlorocarbonyl-2-oxo-3- (4-methyl) -benzylimino-imidazolidine were reacted according to Example 10.5 to 6.8 parts of sodium 6- {D- α-[(2-oxo-3- {4-methyl} -benzylimino-imidazolidin-1-yl) -carbonylamino] -4-hydroxyphenyl-acetamido} -penicilanate To obtain. Decomposition Point: 230 ~ 235 ℃

IR (KBr): 1,765, 1,730, 1,665, 1,610 cm ^-1

NMR (CD ₃ OD): 7.6-6.7 (aromatic hydrogen and -CH = N-), 5.5 (m, 3H), 4.18 (S, 1H), 3.6 (m, 4H), 3.25 (S, 3H), 1.55 (S, 3H), 1.50 (S, 3H) δ.

Analyzes of C ₂₈ H ₂₉ N ₆ NaO ₇ S · 2H ₂ O

Calculated Value: C 51.53 H 5.09 N 12.87 S 4.91

Found: C 51.2 H 5.2 N 12.7 S 5.1

5.0 parts of cephalo-glycine dihydrate in 50 parts (volume) of 80% THF solution with 3.0 parts of 1-chlorocarbonyl-2-oxo-3- (4-methyl) -benzylimino-imidazolidine Reaction according to Example 1.6, where 5.5 parts of sodium 7- {D-α-[(2-oxo-3- {4-methyl} -benzylmino-imidazolidin-1-yl) -carbonylamino]- Phenylacetamido} -3-acetoxymethyl-ce-3-fem-4-carboxylate is obtained. Decomposition Point: 178 to 180 ℃

IR (KBr): 1,760, 1,725, 1,660, 1,625 cm ^-1

Analyzes of C ₃₀ H ₂₉ N ₆ NaO ₈ SH ₂ O

Calculation: C 53.41 N 12.47

Found: C 53.4 N 12.5

Example 21

47.6 parts 2-oxo-imidazolidine, 34.5 parts sodium nitrite, 78.4 parts zinc powder 77.1 parts 4-carboxy-benzaldehyde was reacted according to Example 1.1 to 82.8 parts 1- (4-carboxy) -benzylino-2 -Oxo-imidazolidine is obtained. It is suspended in 200 parts (volume) of methanol and the diazomethane solution in ether is added until yellow color is maintained. After a while a clear solution is produced and 1- (4-methoxycarbonyl) -benzylmino-2-oxo-imidazolidine precipitates out as crystals. Melting point 245 ~ 246 ℃

IR (KBr): 2,240, 1,700, 1,720, cm ^-1

NMR (d ₆ -DMSO): 7.6-8.1 (S, 5H in AB systems and 7.63), 7.20 (S, Broad, 1H), 3.88 (S, 3H), m (4H) S centered at 3.7

Calculated: C 58.29 H 5.30 N 17.00 O 19.41

Found: C 58.7 H 5.2 N 17.3 O 19.6

17.4 parts 1- (4-methoxy carbonyl) -benzylimino-2-oxo-imidazolidine, 22.8 parts triethylamine, 22.7 parts chloro trimethylsilane and 13.9 parts phosgene were reacted according to Example 19.2 to give 21.0 Negative 1-chlorocarbonyl-2-oxo-3- (4-methoxycarbonyl) -benzylimino-imidazolidine is obtained. Decomposition Point: 210 to 215 ℃

IR (paraffin oil): 1,800 cm ^-1

6.2 parts of ampicillin trihydrate and 4.6 parts of 1-chlorocarbonyl-2-oxo-3- (4-methoxycarbonyl) -benzylimino-imidazolidine were reacted according to Example 2.3 to 5.4 parts of sodium 6 -{D-α-[(2-oxo-3- {4-methoxycarbonyl} -benzylmino-imidazolidin-1-yl) -carbonylamino] -phenylacet amido} -penicila Obtain the nate. Decomposition Point: 215 ~ 220 ℃

IR (KBr): 1,760, 1,720, 1,665, 1,595 cm ^-1

NMR (CD ₃ OD): 8.0-7.1 (aromatic hydrogen and -CH = N-, 10H), 5.58 (S, 1H), 5.45 (q, 2H), 4.15 (S, 1H), m (4H) near 3.8 ), 2.30 (S, 3H), 1.57 (S, 3H), 1.58 (S, 3H) δ

Analyzes of C ₂₉ H ₂₉ N ₆ NaD ₈ S · 3H ₂ O

Calculated Value: C 49.86 H 5.05 N 12.02 S 4.58

Found: C 49.7 H 5.2 N 11.9 S 4.4

2.3 parts of cephalo-glycine dihydrate in 40 parts (volume) of 80% THF solution was added to 2.2 parts of 1-chlorocarbonyl-2-oxo-3- (4-methoxycarbonyl) -benzylimino-imida. 1.0 part sodium 7- {D-α-[(2-oxo-3- {4-methoxycarbonyl} -benzalmino-imidazolidin-1-yl) reacted with zolidine according to Example 1.6 -Carbonylamino] -phenylacetamido} -3-acetoxy methyl-ce-3-fem-4-carboxylate.

IR (KBr): 1,755, 1,665, 1,600 cm ^-1

Analyzes of C ₃₁ H ₂₉ N ₆ NaG ₀ S · 3H ₂ O

Calculated Value: C 49.34 H 4.67 N 11.14 S 4.25

Found: C 49.1 H 4.5 N 11.1 S 4.4

Example 22

A solution obtained by dissolving 3.0 parts of 1-amino-2-oxo-imidazolidine in 30 parts (volume) of water was suspended in 50 parts (volume) of 5.0 parts of 5-acetoxymethyl-furan-2-aldehyde. The suspension was added with cooling over iced water with stirring over 30 minutes. The mixture is stirred for 20 more hours at 20 ° C. and the precipitate is filtered off, washed with isopropanol and dried over 70 ° C. in vacuo.

Yield: 6.6 parts Melting point: 146 ° C

Calculated Value: C 52.6, H 5.2, N 16.7, S 25.5

Found: C 52.6, H 5.3, N 16.8, S 25.8

6.6 parts of 1- (5-acetoxymethyl-furfurylideneamino) -2-oxo-imidazolidine, 60 parts (volume) of benzene which boils a solution of 2.2 parts of trimethylchlorosilane in benzene under reflux To 4.1 parts (volume) of triethylamine mixture is added dropwise and the mixture is boiled for another 20 hours. The triethylamine hydrochloride was filtered off when hot and washed with benzene and a solution of 1.6 parts (volume) of phosgene dissolved in 10 parts (volume) of benzene was added to the combined filtrates while cooling. The mixture is left at 20 ° C. for 20 hours, and then the product is filtered off.

Yield: 4.3 parts, Melting point: 184 to 185 ° C

IR (paraffin oil) (carbonyl part): 1,810, 1,745 cm ^-1

Calculated Value: C 45.9, H 3.8, Cl 11.3, N 13.4, O 25.5

Found: C 46.4, H 3.9, Cl 11.1, N 13.4, O 25.3

2.8 parts sodium by reacting 2.0 parts of empicillin trihydrate with 1.75 parts of 1-chlorocarbonyl-2-oxo-3- (5-acetoxymethyl-furfurylidene-amino) imidazolidine according to Example 1.3. D-α-{[2-oxo-3- (5-acetoxymethylfurfurylideneamino) -imidazolidin-1-yl] -carbonylamino} -benzylphenicillin is obtained. Melting point: It decomposes gradually by sticking together from about 190 ℃.

NMR T: 2.37 (1H), 2.5-2.85 (5H), 3,15-3,30 (d, 1H), 3.40-3.55 (d, 1H), 4.43 (1H), 4.43-4,70 (AB, 2H), 4.93 (2H), 5,87 (1H), 5.98-6.30 (4H), 7.94 (3H), 8.45 (3H), and 8.52 ppm (3H)

IR (paraffin wax) (carbonyl part): 1,767 (shoulder), 1,734, 1,660, 1,600 and 1,530-1,510 cm ^-1

β-lactam content: 92%

This cephalosporin contains 2.0 parts of cephaloglycin dihydrate and 1.5 parts of 1-chlorocarbonyl-2-oxo-3-5) -acetoxymethylfurylideneamino) -imidazolidine in Examples 1.3 and 1.6. It is obtained by reacting accordingly. Part of the cephalosporin upon acidification is obtained as a precipitate insoluble in water and organic phase (ethyl acetate).

(Yield: 0.1 parts, Melting point: Viscosity at 205 ° C, gradually degrades to 260 ° C, but not completely dissolved.

IR (carbonyl moiety): 1,770, 1,726, 1,678, 1,600-1,528 cm ^-1 , in paraffin oil)

This cephalosporin can precipitate from the organic phase.

Yield: 2.7 parts sodium 7-D-α-{[2-oxo-3- (5-acetoxymethyl-furfurylidene-amino) -imidazolidin-1-yl] -carbonylamino} -phenyl Acetamido-3-acetoxymethyl-ce-3-fem-4-carboxylate

β-lactam content: 86%

IR (carbonyl part): 1,770 (Shoulder), 1,760 (Shoulder), 1,730, 1,668, 1,610, 1,550 (Shoulder) and 1,530 cm ^-1

NMRτ: 2.33 (1H), 2.45-2.85 (5H), 3.15-3.25 (1H), 3.4-3.52 (1H), 4.24-4.48 (2H), 4.92 (2H), 5.0-5.22 (3H), 6.0-6.27 (4H), 6.55-6.75 (2H), 7.96 (3H), and 8.02 ppm (3H)

Melting point: Decomposes and drops from 220 ℃.

Example 23

2-chlorofuran-5-aldehyde is reacted with 1-amino-2-oxo-imidazolidine according to Example 1.1 to give 1- (5-chlorofurylideneamino) -2-oxo-imidazolidine To obtain.

Melting Point: 173 ~ 175 ℃

NMR (δ ₆ -DMSO): 7.45 (S, 1H), 7.26 (S, Broad, 1H), 6.77 (d, 1H), 6.60 (1H), 3.55 (m, 4H) δ

Calculated Value: C 45.0, H 3.7, N 19.7, Cl 16.6

Found: C 45.5, H 3.8, N 38.8, Cl 16.2

20.0 parts 1- (5-chlorofurylideneamino) -2-oxo-imidazolidine, 31.8 parts triethylamine, 31.8 parts chlorotrimethylsilane and 18.6 parts phosgene are reacted according to Example 1.2 and recrystallized from acetonitrile 16.5 parts of 1-chlorocarbonyl-2-oxo-3- (5-chlorofurylideneamino) -imidazolidine are obtained.

Decomposition Point: 193 to 196 ℃

Calculation: Cl 25.68

Found: Cl 25.7

5.0 parts of ampicillin trihydrate was prepared in 3.9 parts of 1-chlorocarbonyl-2-oxo-3- (5-chlorofurylideneamino) -imidazolidine and 100 parts (volume) of 80% THF solution. Reaction was carried out according to the following procedure and 4.7 parts of sodium 6- {D-α-[(2-oxo-3- {5-chlorofurylideneamino} -imidazolidin-1-yl) -carbonylamino] -phenylacetami To obtain penicilanate.

Decomposition Point: 210 ~ 220 ℃

IR (KBr): 1,67, 1,720, 1,660, 1,660, 1,525, 1,470, 1,405, 1,270 and 1,225 cm ^-1

NMR (CD3OD): 7.55 (S, 1H), 7.3 (m, 5H), 6.28 (d, 1H), 6,35 (d, 1H), 5.56 (S, 1H), 5.43 (Pseudo-q, 2H) , 4.12 (S, 1H), 3.82 (Broad S, 4H), 1.55 (S, 3H), 1.48 (S, 3H) δ

의 분석치C ₂₅ H ₂₄ Cl N ₆ N ₆ O ₇ S

Analysis value of

Calculated Value: C 47.06, H 4.27, N 13.18, S 5.04

Found: C 47.1, H 4.7, N 13.2, S 5.2

100 parts (volume) of 80% THF 5.0 parts of cephaloglycine dihydrate and 3.5 parts of 1-chlorocarbonyl-2-oxo-3- (5-chlorofurylideneamino) -imidazolidine are shown in Example 1.6. Reaction was carried out to make 4.3 parts of sodium 7D- {α-[(2-oxo-3- {5-chlorofurylideneamino} -imidazolidin-1-yl) -carbonylamino] -phenylacetamido}- 3-acetoxymethyl-ce-3-fem-4-carboxylate is obtained. Decomposition Point: 185 to 190 ℃

IR (KBr): 1,765, 1,720, 1,660, 1,595, 1,520, 1,405 cm-1, 1,225 cm ^-1

NMR (CD ₃ OD / D ₂ O): 7.48 (S) and 7.37 (m, 6H total), 6.78 (1H), 6.34 (1H), 5.43 (1H), 4.95 (signal of exchangeable hydrogen overlaps) , 3.8 (S, Broad, 4H), 3.6 (solvent peaks overlap). 2.06 (S, 3 H) δ.

Example 24

33.5 parts of 2-bromofuran-5-aldehyde dissolved in 100 parts (volume) of THF was dissolved 1-amino-2-oxo-imidazolidine hydrochloride in 350 parts (volume) of water, followed by sodium hydroxide solution. Add to solution adjusted to pH 5 and stir the mixture overnight. The precipitate is filtered off, washed with water and recrystallized from methanol to yield 30.0 parts of 1- (5-bromo furylideneamino) -2-oxo-imidazolidine.

Decomposition Point: 153 ~ 158 ℃

IR (KBr): 1,720, 1,580, 1,410, 1,265, 1,245 cm ^-1

NMR (b ₆ -DMSO): 7.55 (S, 1 H), 7.31 (S, 1 H), 6.80 (AB, 2 H), 3.6 (m, 4 H) δ.

30.0 parts 1- (5-bromofurylideneamino) -2-oxo-imidazolidine, 37.8 parts triethylamine, 36.8 parts chlorotrimethylsilane and 23.0 parts phosgene are reacted according to Example 1.2. Recrystallization from acetonitrile affords 21.6 parts of 1-chlorocarbonyl-2-oxo-3- (5-bromofurylideneamino) -imidazolidine.

Decomposition Point: 190 ~ 194 ℃

IR (paraffin wax): 1,815cm ^-1

Example 1.3 Ampicillin Trihydrate and 3.2 Parts 1-Chlorocarbonyl-2-oxo-3- (5-bromofurylideneamino) -imidazolidine in 80 parts (volume) of 80% THF aqueous solution Example 1.3 3.7 parts of sodium 6- {D-α-[(2-oxo-3- {5-bromo-furylideneamino} -imidazolidin-1-yl) -carbonylamino} -phenyl Acetamido] -penicilanate is obtained.

Decomposition Point: 220 ~ 228 ℃

IR (KBr): 1,760, 1,725, 1,660, 1,600, 1,400, 1,225

NMR (CD ₃ OD): 7.60 (S, 1H), 7.46 (S, 5H), 6.83 (d, 1H), 6.52 (d, 1H), 5.58 (S, 1H), 5.50 (AB, 2H), 4.18 (S, 1 H), 3.85 (S, broad, 4H), 1.57 (S, 3H), 1.50 (S, 3H) δ.

4.5 parts of cephaloglycine dihydrate and 3.3 parts of 1-chlorocarbonyl-2-oxo-3- (5-bromofurylideneamino) -imidazolidine in 100 parts (dose) of 80% THF Example 1.6 And reacted according to the above procedure, and 3.3 parts of sodium 7- {D-α-[(2-oxo-3- {5-bromofurylideneamino} -imidazolidin-1-yl) -carbonylamino] -phenylacetami Obtain 3-acetoxymethyl-ce-3-fem-4-carboxylate.

Decomposition Point: 187 to 196 ℃

IR (KBr): 1,775, 1,715, 1,655, 1,450, 1,275cm ^-1

NMR (CD ₃ OD / D ₂ O): 7.55 (S, 1H), 7.4 (m, 5H), 6.80 (d, 1H), 6.50 (d, 1H), 5.68 (d, 1H), 5.50 (S, 1H), 4.96 (d, 1H), 4.92 (overlapping signals of exchangeable hydrogen), 3.80 (S, broad, 4H), 3.4 (overlapping solvent peaks), 2.08 (S, 3H) δ.

Example 25

98.3 parts of 2-methylfuran-5-aldehyde is dissolved in 1 part of amino-oxo-imidazolidine hydrochloride in 1000 parts (volume) of water, and the mixture is added to a solution having a pH of 4.5 with sodium hydroxide. Stir overnight. The precipitate is filtered, washed with water and recrystallized from ethanol to give 126 parts of 1- (5-methylfurylideneamino) -2-oxo-imidazolidine. Melting point: 194-196 degreeC.

IR (KBr): 3,320, 1,735, 1,710, 1,480, 1,420, 1,395, 1,245 cm ^-1

NMR (b ₆ -DMSO): 7.57 (S, 1H), 7.22 (S. Brodo 1H), 6.67 and 6.25 (AB, 2H), 3.65 (m, 4H), 2.38 (S, 3H) δ.

Calculated Value: C 55.95 H 5.74 N 21.75

Found: C 56.0 H 5.8 N 21.3

50.0 parts 1- (5-methylfurylideneamino) -2-oxo-imidazolidine, 84.3 parts trimethylamine, 84.0 parts chlorotrimethylsilane and 51.4 parts phosgene are reacted according to Example 1.2. Recrystallization from acetonitrile gives 50.7 parts of 1-chlorocarbonyl-2-oxo-3- (5-methylfurylideneamino) -imidazolidine.

Decomposition Point: 180 ~ 186 ℃

IR (paraffin wax): 1,815cm ^-1

Example 1.3 Ampicillin Trihydrate and 2.6 Parts 1-Chlorocarbonyl-2-oxo-3- (5-methylfurylideneamino) -imidazolidine in 80 parts (weight) of 80% THF aqueous solution Example 1.3 And reacted according to the above procedure, and 4.2 parts of sodium 6- {D-α-[(2-oxo-3- {5-methylfurylideneamino} -imidazolidin-1-yl) -carbonylamino] -phenylacetami To obtain penicilanate.

Decomposition Point: 210 ~ 220 ℃

IR (KBr): 1,760, 1,720, 1,660, 1,600, 1,525, 1,410 cm ^-1

NMR (CD ₃ OD): 7.62 (S, 1H), 7,35 (m, 5H), 6.75 (d, 1H), 6.13 (d, 1H), 5.60 (S, 1H), 5.45 (AB, 2H) , 4.18 (S, 1H), 3,83 (S, Broad, 4H), 2.35 (S, 3H), 1.56 (S, 3H), 1.49 (S, 3H),

4.4 parts of cephaloglycine 2-hydrate and 2.6 parts of 1-chlorocarbonyl-2-oxo-3- (5-methylfurylideneamino) -imidazolidine were administered in 80 parts (volume) of 80% THF aqueous solution 4.4 parts of sodium 7- {D-α-[(2-oxo-3- {5-methylfurylideneamino} -imidazolidin-1-yl) -carbonylamino] -phenyl were reacted according to Example 1.6. Acetamido} -3-acetoxymethyl-ce-3-fem-4-carboxylate is obtained.

IR (KBr): 1,760, 1,725, 1,660, 1,660, 1,525, 1,405, 1,225 cm ^-1

NMR (CD ₃ OD): 7.70 (S, 1H), 7.40 (m, 5H), 6.80 (d, 1H), 6.20 (d, 1H), 5.75 (d, 1H), 5.68 (S, 1H), 4.95 (m, overlapping signals of exchangeable hydrogen), 3.88 (S, Broad, 4H), 3.45 (solvent peaks overlapping), 2.35 (S, 3H), 2.04 (S, 3H) δ.

Example 26

14.0 parts 5-methyl-3-formyl-isoxazole is reacted according to Example 25.1 in 25.6 parts 1-amino-2-oxo-imidazolidine hydrochloride in 100 parts (volume) of water. After 90 minutes, the precipitate is filtered off, washed with water and dried over anhydrous acetic nitrile to recrystallize 12.5 parts of 1- (5-methyl-isoxazol-3-yl-methyleneamino) -2-oxo-imidazolidine. Melting Point: 195-197 °

IR (Parispin You): 3,220, 2,695, 1,610 cm ^-1

NMR (CD ₃ OD): 7.65 (S, 1H), 7.47 (S, Broad, 1H), 6.53 (S, 1H), 3.7 (m, 4H), 2.20 (S, 3H) δ.

Calculated Value: C 49.48 H 5.19 N 28.85

Found: C 49.6 H 5.2 N 29.2

12.0 parts 1- (5-methyl-isoxazol-3-yl-methyleneamino) -2-oxo-imidazolidine, 21.0 parts triethylamine, 20.8 parts chlorotrimethylsilane and 12.3 parts phosgene according to Example 1.2 19.8 parts of 1-chlorocarbonyl-2-oxo-3- (5-methyl-isoxazol-3-yl-methyleneamino) -imidazolidine are obtained by reaction. Melting point: 199 to 203 캜. The compound still contains a small amount of triethyl-amine hydrochloride, but the next reaction does not interfere and does not need to be removed.

IR (paraffin wax): 1790cm ^-1

80% THF of 100 parts (dose) of 16.5 parts of ampicillin trihydrate and 9.5 parts of 1-chlorocarbonyl-2-oxo-3- (5-methylisosazol-3-yl-methyleneamino) -imidazolidine 1.0 part of sodium 6- {D-α-[(2-oxo-3- {5-methyl-isoxazol-3-yl-methylamino} -imidazolidine-3- I) -carbonylamino] -phenylacetamido} -peniclanate.

IR (KBr): 1,760, 1,730, 1,660, 1,600, 1,525, 1,395, 1,22 cm ^-1

NMR (CD ₃ CO / D ₂ O): 7.72 (S, 1H), 7.38 (S, 5H), 6.62 (S, 1H), 5.53 (S, 1H), 5.43 (m, 2H), 4.13 (S, 1H), 3.90 (m, 4H), 2.45 (S, 3H), 1.53 (S, 3H), 1.48 (S, 3H) δ.

80 parts THF of 150 parts (dose) of 18.1 parts of cephaloglycine dihydrate and 9.5 parts of 1-chlorocarbonyl-2-oxo-3- (methylisoxazol-3-yl-methyleneamino) -imidazolidine 2.2 parts of sodium 7- {D-α-[(2-oxo-3- {5-methylisoxazol-3-yl-methyleneamino} -imidazolidine-1- I) -carbonylamino] -phenylacetamido} -3-acetoxymethyl-ce-3-fem-4-carboxylate. Decomposition Point: 215 ~ 220 ℃

IR (KBr): 1,760, 1,730 (Shoulder), 1,670, 1,595, 1,395 cm ^-1

NMR (CD ₃ OD / D ₂ O): 7.74 (S, 1H), 7.38 (S, 5H), 6.63 (S, 1H), 5.65 (d, 1H), 5.50 (S, 1H), 4.95 (exchangeable) Overlapping signals of hydrogen), 3.90 (S, Broad, 4H), 3.4 (solvent peaks overlapping), 2.45 (S, 3H), 2.05 (S, 3H) δ.

Example 27

48.6 parts of 1- (diacetoxymethyl) -5-nitro-furan was boiled for 15 minutes under N ₂ in a mixture of 216 parts (volume) of water and 108 parts (volume) of concentrated sulfuric acid and the mixture was cooled and 5-nitro-furfuraldehyde is dissolved in ether, and the ether is removed and then dissolved in 100 parts (volume) of methanol. A solution of 27.5 parts of 1-amino-2-oxo-imidazolidine hydrochloride dissolved in water (100 parts, capacity) is added to the solution. After 4.5 hours the separated product is filtered off and washed with water. Yield: 42.1 parts Melting point: 259 to 260 ° C (Coflo heating bench)

Calculated Value: C 42.9 H 3.6 N 25.0 O 28.6

Found: C 42.8 H 3.7 N 25.2 O 29.1

8.0 parts of the product obtained in 27.1 are silylated according to Example 1.2 and reacted with 2.6 parts (volume) of phosgene.

Yield: 5.2 parts Melting point: 188 to 190 ° C (Coppler bench)

The compound still contains a small amount of triethylamine hydrochloride (most triethylamine hydrochloride is washed off with methylene chloride) but does not interfere with the next reaction.

This penicillin is obtained by reacting 1.5 parts of ampicillin trihydrate with 1.1 parts of 1-chlorocarbonyl-2-oxo-3- (5-nitro-furylideneamino) -imidazolidine according to Example 1.3. 0.7 parts of the crude product sodium salt is obtained after completion of the reaction. To purify it, it is suspended in a small amount of water, and insoluble materials are filtered off and dried (once yield: 0.3 parts). The aqueous filtrate is covered with ethyl acetate and acidified to pH 1.5 and the sodium salt is precipitated according to the method described above. (2 times yield: 0.2 part)

Total yield: 0.5 parts sodium D-α-{[2-oxo-3- (5-nitro-furylidene-amino) -imidazolidin-1-yl] -carbonylamino} -benzylphenicillin

β-lactam content (according to NMR and elemental analysis): 44% This material contains 44% of the product of the ring-opened β-lactam ring. (The reaction mixture is acidified and left for a while at 20 ° C.)

According to NMR and elemental analysis, this substance contains 4.8 molar equivalents of water (including water consumed when the β-lactam ring is ring-opened). The analysis values considering this are as follows.

Calculated Value: C 42.4 H 4.8 N 13.8 S 4.5

Found: C 42.1 H 4.8 N 13.8 S 4.3

IR (carbonyl part): 1,775 (Shoulder), 1,745, 1,665, 1,590, 1,515 cm ^-1

This cephalosporin contains 4.0 parts of cephaloglycine dihydrate and 2.5 parts of 1-chlorocarbonyl-2-oxo-3- (5-nitro-furylidene-amino) -imidazolidine in Examples 1.3 and 1.6. It is obtained by reacting accordingly. Acidification of the reaction mixture from which the tetrahydrofuran is removed causes only part of cephalosporan acid to be dissolved in ethyl acetate, and the rest precipitates. Sodium salt is obtained from both fractions according to the method described above.

Yield: 2.8 parts sodium 7- {D-α-[(2-oxo-3-5-nitro-furylideneamino-imidazolidin-1-yl) -carbonylamino] -phenylacetamido}- 3-acetoxymethyl-ce-3-fem-4-carboxylate

Melting Point: Decomposes at 230 ~ 260 ℃ but does not dissolve completely (Coppler Heating Bench)

β-lactam content (quantified by iodine titration method): 84%

NMR (d ₆ -DMF) τ: 1.95-2.9 (8H), 4.1-4.5 (2H), 4.9-5.23 (H), 6.0 (4H), 6.6-6.85 (2H and 80ppm / 3H)

IR (carbonyl moiety): 1,765 (Shoulder), 1,725, 1,670, 1,600 and 1,510 cm ^-1 (Newsol method)

Example 28

1.2 parts of this substance was reacted with 1-amino-2-oxo-imidazolidine and 1.8 parts of 5-methoxycarbonyl-furfural in an aqueous methanol solution (1: 1,12 parts by volume) at 20 ° C. within 60 minutes. To obtain. Yield 2.7 parts

Melting Point: Sticks firmly from 88 ℃ (Coppler Bench)

2.6 parts of the product of Example 28.1 parts above were silylated according to Example 1.2 and reacted with 0.8 parts (volume) of phosgene.

Melting point: (Crude product-still contains some triethylamine hydrochloride): Decomposition at about 220 ° C (Coppler bench)

This penicillin was reacted according to Example 1.3 with 0.87 parts Ampicillin trihydrate and 0.65 parts 1-chlorocarbonyl-2-oxo-3- (5-methoxycarbonyl-furylideneamino) -imidazolidine. Can be obtained.

Yield: 0.5 parts sodium D-α-{[2-oxo-3- (5-methoxycarbonyl-furylideneamino) -imidazolidin-1-yl] -carbonylamino} -benzylphenicillin

β-lactam content (quantified by iodine titration method): 80% melting point 185 to 210 ° C (decomposition) (Coppler bench)

IR (carbonyl moiety): 1,770, 1,730, 1,670, 1,605, 1,530 cm ^-1 (New sol method)

Example 29

1.3 parts of 1-amino-2-oxo-imidazolidine and 2.6 parts of 5-ethoxycarbonyl-furfuryl are obtained by reacting in an aqueous methanol solution. Yield: 3.1 parts Melting point (crude product): 135-138 ° C.

2.85 parts of the product obtained in Example 1 was silylated according to Example 1.2 (but using dioxane as solvent) and reacted with 0.9 parts (volume) of phosgene. Yield: 1.1 parts Melting point 230-233 ° C. (Coppler bench) (crude product)

This penicillin was reacted with 1.3 parts of ampicillin trihydrate with 1.0 part of 1-chlorocarbonyl-2-oxo-3- (5-ethoxycarbonyl-furylideneamino) -imidazolidine according to Example 1.3. To obtain.

Yield: 0.8 parts sodium D-α-{[(2-oxo-3- (5-ethoxycarbonyl-furylideneamino) -imidazolidin-1-yl] -carbonylamino} -benzyl penicillin

β-lactam content (quantified by iodine titration method): 92% (this material contains about 6% of the product of the ring-opened β-lactam ring)

Melting Point: Approx. 220 ℃, Decomposition (Coppler Bench)

IR spectrum (carbonyl portion): 1,775-1,790, 1,740, 1,675, 1,610, 1,520, 1,540 cm ^-1 (New sol method)

According to elemental analysis and NMR, the penicillin contains about 4.3 molar equivalents of water and 0.16 molar equivalents of sodium 2-ethylhexanoate.

The analysis values considering this are as follows.

Calculated Value: C 46.7 H 5.3 N 11.2 S 4.3

Found: C 46.7 H 5.6 N 11.2 S 4.5

Example 30

This intermediate was dissolved in 50 parts (volume) of 1N sodium hydroxide solution in 1-amino-2-oxo-imidazolidine hydrochloride and 8.0 parts (volume) of 4-tert-butyl-benzaldehyde was added to the mixture at 20 ° C. Obtained by stirring for 24 hours. The precipitated product is recrystallized from acetonitrile. Yield: 5.9 parts Melting point 208 ° C (Coppler bench)

This material is obtained by silylating 5.5 parts of the product obtained in Example 30.1 with 4.4 parts triethyl chlorosilane according to Example 1.2 and then reacting with 2.1 parts (volume) of phosgene using dioxane as solvent.

This material still contains some triethylamine hydrochloride.

IR (C0Cl): 1,808 cm ^-1 (New sol method)

This penicillin is obtained by reacting 2.2 parts of ampicillin trihydrate with 2.0 parts of 1-chlorocarbonyl-2-oxo-3- (4-tertbutyl-benzalimino) -imidazolidine according to Example 1.3. .

Yield: 2.7 parts of sodium 6- {D-α-[(2-oxo-3- / 4-tert-butyl-benzylimino / -imidazolidin-1-yl) -carbonylamino] -phenylacetamino } -Phenylsilanate.

β-lactam content (by iodine titration method): 83% (this penicillin contains about 10% of a product in which the β-lactam ring is ring-opened)

Melting point: Viscosity from about 240 ° C. Dark fusion at about 259 ° C. is formed and quickly solidifies again as a result of decomposition.

NMR (CD ₃ OD): 2.15-2.8 (10H), 4.4 (1H), 4.4-4.65 (2H), 5.85 (1H), 6.3 (Broad, 4H), 8.45 (3H), 8.52 (3H), 8.75ppm (9H)

According to NMR this material contains about 1.8 molar equivalents of water. The analysis values considering this are as follows.

Calculated Value: C 55.1 H 5.8 N 12.4 S 4.7

Found: C 55.1 H 5.9 N 12.4 S 4.8

IR spectrum (carbonyl moiety): 1,772, 1,730, 1,672, 1,610, 1,515-1,530 cm ^-1

Example 31

To prepare this cephalosporin, 1,5 parts of cephaloglycine dihydrate and 0.8 parts of 1-chlorocarbonyl-2-oxo-3- (3-pyridyl-methylideneamino) -imidazolidine React according to 1.3 and 1.6. After tetrahydrofuran is removed and acidified to pH 1.5, 0.8 parts of free cephalosporranic acid are separated by precipitation insoluble in water and ethyl acetate. Melting Point: It does not melt completely to about 200 ° C (Korlor Heating Bench).

IR: 1,770, 1,745, 1,675, 1,520-1,550 cm ^-1 (New sol method)

This acid is dissolved in a small amount of dimethylformamide, and 1.3 parts (capacity) of 1 M solution in which sodium 2-ethylhexanoate is dissolved is added to an ether containing methanol, and the sodium salt of cephalosporin is precipitated with ether.

Yield: 0.6 parts sodium 7- {D-α-[(2-oxo-3- / 3-pyridyl-methylideneamino / -imidazolidin-1-yl) -carbonylamino] -phenylacet amido } -3-acetoxymethyl-ce-3-fem-4-carboxylate.

Melting point: When spraying fine powdery material on the coppler heating bench, it melts simply and transparently at 242 ° C or higher, but it is decomposed and solidified and does not melt until 260 ° C.

IR (carbonyl moiety): 1,770 (Shoulder), 1,760, 1,730, 1,670, 1,605 and 1,530-1550 cm ^-1 (New sol method)

NMR contains about 5.5 molar equivalents of water and 0.26 molar equivalents of sodium 2-ethylhexanoate. The analysis values considering this are as follows.

Calculated Value: C 45.9 H 5.2 N 12.5

Found: C 45.9 H 5.3 N 12.4

β-lactam content (by iodine titration method): 82%

Example 32

11.0 parts 7- (D-α-amino-phenylacetamido) -3-hydroxymethyl-ce-3-fem-4-carboxylic acid and 6.1 parts 1-chlorocarbonyl in 100 parts (capacity) of 80% THF aqueous solution 2-oxo-3-furylidene amino-imidazolidine is reacted and completed according to Example 1.6. 5.2 parts sodium 7- {D-α-[(2-oxo-3-furylideneamino-imidazolidin-1-yl) -carbonylamino] -phenylacet amido} -3-hydroxymethyl- Cet-3-fem-4-carboxylate is obtained.

Decomposition Point: 215 ~ 220 ℃

NMR (CD ₃ OD): 7.80 (S, 1H), 7.70 (S, 1H), 6.97 (g, 1H), 5.75 (d, 1H), 5.63 (S, 1H), 5.37 (exchangeable hydrogen overlaps) ), 4.40 (S, 2H), 3.95 (S, Broad, 4H) and solvent pit (S) overlap with C-2-hydrogen.

Example 33

7.5 parts of 7- (D-α-amino-phenylacetamido) -3-[(3-methyl-thiadiazol-5-yl) -thiomethyl] -ce-3 in 100 parts (capacity) of 80% THF Fem-4-carboxylic acid and 6.1 parts of 1-chlorocarbonyl-2-oxo-3-furylideneamino-imidazolidine were completed in the same manner as in Example 1.6.

5.2 parts Sodium 7- {D-α-[(2-oxo-3-furylidene amino-imidazolidin-1-yl) -carbonylamino] -phenylacet amido} -3-[(3- Methyl-thiadiazol-5-yl) -thiomethyl] -ce-3-fem-4-carboxylate is obtained.

Decomposition Point: 210 to 215 ℃

IR (KBr): 1,760, 1,720, 1,660, 1,595, 1,525, 1,475, 1,410, 1,275, 1,230 cm ^-1

NMR (CD ₃ OD): 7.70 (S, 1H), 7.64 (d, 1H), 7.33 (m, 5H), 6.86 (d, 1H), 6.50 (dd, 1H), 5.65 (d, 1H), 5.55 (S, 1H), 4.90 (d, 1H), 4.20 (pseudog, 2H), 3.85 (S, broad, 4H), 3.4 (solvent peaks overlapped), 2.52 (S, 3H) δ.

Example 34

5.0 parts of 7- (D-α-amino-phenylacetamino) -3-[(1-methyl-tetrazol-5-yl) -thiomethyl] -ce-3 in 100 parts (volume) of 80% THF aqueous solution -Fem-4-carboxylic acid and 6.1 parts of 1-chlorocarbonyl-2-oxo-3-furylideneamino-imidazolidine are complete according to Example 1.6. 3.2 parts sodium 7- {D-α-[(2-oxo-3-furylidene amino-imidazolidin-1-yl) -carbonylamino] -phenylacetamido} -3-[(1- Methyl-tetrazol-5-yl) -thiomethyl] -ce-3-fem-4-carboxylate is obtained.

Decomposition point: 210 to 22O ℃

IR (KBr): 1,760, 1,720, 1,660, 1,610, 1,520, 1,475, 1,410, 1,230 cm ^-1

NMR (CD ₃ OD): 7.73 (S, 1H), 7.63 (d, 1H), 7.38 (m, 5H), 6.88 (d, 1H), 6.54 (q, 1H), 5.67 (d, 1H), 5.56 (S, 1H), 4.9 (exchangeable interchangeable hydrogen), 4.32 (S, 2H), 3.95 (S, 3H), 3.85 (S, broad, 4H), 3.45 (solvent peaks overlap) δ.

Example 35

8.0 parts 7- (D-α-amino-phenylacetamido) -3-[(5-trifluoromethyl-1,3,4-thiadiazole-2 in 100 parts (volume) of 80% THF solution -Yl) thiomethyl] -ce-3-fem-carboxylic acid and 6.0 parts of 1-chlorocarbonyl-2-oxo-3-furylideneamino-imidazolidine were reacted according to Example 1.6 to complete 7.8 parts of sodium. 7- {D-α-[(2-oxo-3-furylideneamino-imidazolidin-1-yl) -carbonylamino] -phenylacet amido} -3-[(5-trifluoro Methyl-1,3,4-thiadiazol-2-yl) -thiomethyl] -ce-3-fem-4-carboxylate (decomposition point: 220 degreeC, (beta) -lactam content 76%) is obtained.

IR (paraffin oil): carbonyl moiety: 1,765, 1,720, 1,660, 1,600 and 1,530 cm ^-1

Claims (1)

A method of producing β-lactam antibiotics of the following general formula (I), characterized by reacting a compound of the following general formula (II) with a compound of the following general formula (III).

Wherein R represents hydrogen or methoxy, Z is

or

Wherein R ¹ and R ² are the same or different and are hydrogen, optionally substituted alkyl or alkenyl, optionally substituted cycloalkyl or cycloalkenyl and cycloalkadienyl, optionally substituted aralkyl, optionally substituted aryl, optionally Substituted heterocyclyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, nitro, lower alkylcarbonyl, -CONH ₂ , -CONHCH ₃ , -CON (CH ₃ ) ₂ , SO ₂ NH ₂ ,- R ² and R ² represent SO ₂ -NHCH ₃ or -SO ₂ N (CH ₃ ) ₂ , or R ¹ and R ² together with the carbon to which they are attached, represent a substituted or unsaturated 3-7 membered carbocyclic or heterocyclic ring; Can be formed, and A is -CH ₂ -CH _2- , -CH ₂ -CH-CH ₂ -or

B represents optionally substituted phenyl, cyclohexenyl or cyclohexadienyl, X represents S, O, SO, SO ₂ or -CH _2- , and Y is

And

Wherein the carbon atom to which the carboxyl group is bound is bound to the nitrogen atom of the β-lactam ring, and T is hydrogen, alkyl-CO-O-, pyridinium, amino-pyridinium, carbamoyloxy, azido, cyano, hydr Hydroxyl, optionally substituted -S-phenyl or -S-Het group wherein Het represents an optionally substituted 5- to 6-membered heterocycle and W represents a halogen, azide or other nucleophilic group that may be removed Indicates.