KR820000142B1 - Process for preparing novel penicillin and cephalosporin derivatives - Google Patents

Abstract

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Description

Method for preparing novel penicillin and cephalosporin derivatives

The present invention relates to the preparation of new penicillin and cephalosporin derivatives represented by structural formula (I) and nontoxic salts thereof.

는

,

또는

이고, ℓ과 n은 0 또는 1이고 그 합계는 0 또는 1이며 m은 1 또는 2이다.Wherein Ar is a halogen atom or a phenyl or heterocycle group which may be substituted with a hydroxyl or lower alkoxy group, R is a hydrogen atom or hydroxyl group, X is CH or N,

Is

,

or

And l and n are 0 or 1, the sum is 0 or 1 and m is 1 or 2.

It is an object of the present invention to provide novel penicillin and cephalosporin derivatives represented by Structural Formula (I) having excellent antibacterial effect and useful for the treatment of bacterial diseases and nontoxic salts thereof.

Non-toxic salts of the compounds of formula (I) include metal salts such as sodium, potassium, magnesium, calcium and aluminum salts and amine salts of ammonia, alkylamines, amine sulfates and the like. Structural formula (I) compounds include optical isomers, with the D-form being particularly preferred among the D-, L- and DL-forms.

The present compounds of formula (I) are divided into the following groups according to l, m, n.

는 위에서 규정한 것과 같다.Ar, R, X,

Is as defined above.

Compounds of formula (I) and their nontoxic salts can be produced by the following reaction models.

l, m과 n은 위에서 규정한 것과 같다.Ar, R, X,

l, m and n are as defined above.

The compound of formula (I) is made by reacting a compound of formula (IV), a salt thereof, or a carboxylic acid of structure (IV) or a reaction derivative thereof. The compound of formula (VII) is usually used as a free acid or a water-soluble salt. However, protective compounds in which the protecting groups in the 3 or 4 positions are easily removed without destroying the penicillin structure or the cephalosporin structure are also useful. Suitable protecting groups for producing compounds in the form of penicillin or cephalosporin are carboxyl groups (e.g., 2, 2, 2-trichloroethyl, P-nitrobenzyl, P-methoxybenzyl, phenacyl, diphenicyl), organic Silin (e.g., trimethylsilyl), organostannyl (e.g., trimethylstannyl), organophosphorus (e.g., ethylene phosphoryl), organobromine group (e.g., ethylene bromine group).

-아미노기는 보통 유리형태로 반응 하지만 유기은(銀)기(예, 트리메칠실릴기), 유기인기(예, 에칠렌포스포릴기), 유기브롬기(예, 에칠렌보닐기)와는 활성화된다.

-Amino groups usually react in free form but are activated with organosilver (eg trimethylsilyl), organophosphorus (eg ethylenephosphoryl) and organobromine (eg ethylenecarbonyl).

It is used as a reaction derivative of the structural formula to form a peptide-based amide bond in the chemistry of penicillin or cephalosporin, for example, halide acid, hydrochloric acid, bromic acid, azide acid, anhydrous acid, aryl sulfate and Anhydrous mixed acid, alkyl carboxylic acid, alkyl phosphoric acid and aliphatic carboxylic acid, active ester (e.g., P-nitrophenyl ester, P-nitrophenylthioester, N-hydroxy succinimide ester), acid amide with imidazole, dimethyl Pyrazoles and triazoles. Condensing agents are required when using the free carboxylic acid of structural formula, such as N, N'-dicyclohexylcarbodiimide, isoxazolium salt, pyridinium salt and diphenylphosphoro azide acid to form a peptide bond. It is used widely.

The reaction is induced in a solvent such as an organic solvent or a liquid organic solvent that does not inhibit the reaction. Preferred among them are tetrahydrofuran, acetone, dioxane, dimethylformamide, dimethylacetamide, dichloromethane, chloroform, dimethylsulfoxide, isobutyl ketone and benzene.

The reaction proceeds at a temperature between -50 and 50 ° C., but is suitable between -20 ° and room temperature. If the acid is too strong during the reaction, the following inorganic bases are recommended. That is, alkali hydrogen carbonates, alkali carbonates, tertiary organic bases (e.g., triethylamine, pyridine, picoline, N-methyl piperazine, dimethylaniline). The compound has excellent antibacterial effects and can be used for diseases caused by bacteria.

The antibacterial effects of the invention are shown in the table below.

Initial growth inhibitory concentration (MIC) (㎍ / mol)

Species of bacteria

A: Staphylococcus aureus ATCC 6538

B: Escherichia coli NIHJ

C: modified bacteria ATCC 6897

D: Phenitis Bacillus ATCC 10031

E: Pseudomonas aeruginosa IFO 3080

-(찰콘-4-카복스아미도)벤질페닐실 포타슘 염Compound 1: D (-)-

-(Chalcon-4-carboxamido) benzylphenylsil potassium salt

-(찰콘-4-카복스아미도) P-하이드록시 벤질페니실린 포타슘 염Compound 2: D (-)-

-(Chalcon-4-carboxamido) P-hydroxy benzylpenicillin potassium salt

-(찰콘-4'-카복스아미도)벤질페니실린 소디움 염Compound 3: D (-)-

-(Chalcon-4'-carboxamido) benzyl penicillin sodium salt

-(찰콘-4'-카복스아미도) P-하이드록시 벤질페니실린 소디움 염Compound 4: D (-)-

-(Chalcon-4'-carboxamido) P-hydroxy benzylphenicillin sodium salt

-(P-스티릴벤즈아미도)벤질페니실린 소디움 염Compound 5: D (-)-

-(P-styrylbenzamido) benzyl penicillin sodium salt

-(P-스티릴벤즈아미도) P-하이드록시 벤질페니실린 소디움 염Compound 6: D (-)-

-(P-styrylbenzamido) P-hydroxy benzylpenicillin sodium salt

-(4'-메톡시찰콘-4-카복스아미도)벤질페니실린 소디움 염Compound 7: D (-)-

-(4'-methoxychalcon-4-carboxamido) benzylpenicillin sodium salt

-(2-클로로찰콘-4'-카복스아미도)벤질페니실린 소디움 염Compound 8: D (-)-

-(2-chlorochalcon-4'-carboxamido) benzyl penicillin sodium salt

-(4-클로로찰콘-4'-카복스아미도)벤질페니실린 소디움 염Compound 9: D (-)-

-(4-chlorochalcon-4'-carboxamido) benzylpenicillin sodium salt

-(4-클로로찰콘-4'-카복스아미도) P-하이드록시 벤질페니실린 소디움 염Compound 10: D (-)-

-(4-chlorochalcon-4'-carboxamido) P-hydroxy benzylpenicillin sodium salt

-[P-(5-페닐펜타-2, 4-디에노일)벤즈아미도]벤질페니실린 소디움 염Compound 11: D (-)-

-[P- (5-phenylpenta-2,4-dienoyl) benzamido] benzylphenicillin sodium salt

-[P-(5-페닐펜타-2, 4-디에노일)벤즈아미도] P-하이드록시 벤질페니실린 소디움 염Compound 12: D (-)-

-[P- (5-phenylpenta-2,4-dienoyl) benzamido] P-hydroxy benzylpenicillin sodium salt

-[P-[

-(2-키에닐)아크릴오일]벤즈아미도]벤질페니실린 소디움 염Compound 13: D (-)-

-[P- [

-(2-chienyl) acrylic oil] benzamido] benzyl penicillin sodium salt

-[P-

-(2-피리딜)아크릴오일]벤즈아미도]벤질페니실린 소디움 염Compound 14: D (-)-

-[P-

-(2-pyridyl) acrylic oil] benzamido] benzyl penicillin sodium salt

-(6-스티릴니코틴아미도)벤질페니실린 소디움 염Compound 15: D (-)-

-(6-styrylnicotinamido) benzyl penicillin sodium salt

-[6-(2-티엔-2-일에테닐)니코틴아미도] P-하이드록시 벤질페니실린 소디움 염Compound 16: D (-)-

-[6- (2-thien-2-ylethynyl) nicotinamido] P-hydroxy benzylphenicillin sodium salt

-[P-(4-페닐부타-1, 3-디에닐)벤즈아미도] P-하이드록시 벤질페니실린 소디움 염Compound 17: D (-)-

-[P- (4-phenylbuta-1,3-dienyl) benzamido] P-hydroxy benzylphenicillin sodium salt

-[P-(4-페닐부타-1, 3-디에닐)니코틴아미도]벤질페니실린 소디움 염Compound 18: D (-)-

-[P- (4-phenylbuta-1,3-dienyl) nicotinamido] benzyl penicillin sodium salt

As can be seen from the above results, the compound of the present invention shows a very good effect on the modified bacteria as compared to amoxicillin widely used as antibiotics all over the world.

The compounds of the present invention and their nontoxic salts can be used as medicaments in human medicine as pharmaceutical compositions. Dosage forms can be administered orally in the form of intravenous, intramuscular, same injections or tablets, powders, capsules, syrups. Usually, the compound is administered once or several times in an amount of 150 mg to 3000 mg per day, depending on the condition of the disease, age, weight and route of administration.

The present invention is described in more detail by the following examples, but the present invention is not limited to the examples.

Example 1

-(찰콘-4-카복사미도)-벤질페니실린 포타슘 염 : 252mg의 찰콘-4-카복실린산과 한방울의 디메틸포름 아마이드와 1.5ml의 옥살린클로라이드 혼합물을 실온에서 한시간 동안 교반하고 저압하여 농축 건조시킨다. 350mg의

-아미노벤질페니실린 3수화물에 80%액체 테트라하이드로푸란 10ml를 가하고 트리에틸아민을 가해서 용액의 pH를 8.0∼8.5로 맞춘다. 이 용액에 테트라하이드로푸란 5ml에 용해시킨 위에서 말한 찰콘-4-카복실산 클로라이드를 방울씩 빙냉 교반하면서 가한다. 방울씩 가하는 동안 용액의 pH는 트리에틸아민으로 pH 7.5∼8.0 사이로 유지한다. 모두 가한후 혼합물을 빙냉시키면서 1시간동안 교반한다. 저압하에서 테트라하이드로푸란을 실온에서 증발시키고 잔사를 물 30ml를 가해서 용해 시킨다.D (-)-

-(Calcon-4-carboxamido) -benzylphenicillin potassium salt: 252 mg of chalcon-4-carboxylic acid, a drop of dimethylformamide, and 1.5 ml of oxalin chloride mixture are stirred at room temperature for 1 hour, and concentrated to dryness under low pressure. . 350mg

10 ml of 80% liquid tetrahydrofuran is added to the aminobenzyl penicillin trihydrate, and triethylamine is added to adjust the pH of the solution to 8.0 to 8.5. The above-mentioned chalcone-4-carboxylic acid chloride dissolved in 5 ml of tetrahydrofuran was added to this solution with dropwise ice stirring. During dropwise addition, the pH of the solution is maintained between pH 7.5 and 8.0 with triethylamine. After the addition, the mixture is stirred for 1 hour while ice-cooling. Under low pressure, tetrahydrofuran is evaporated at room temperature and the residue is dissolved by adding 30 ml of water.

The solution is washed twice with ethyl acetate and ethyl acetate is added to the solution and the pH is adjusted to 1.5 by adding hydrochloric acid.

(첼콘-4-카복사미도)-벤질페니실린 카리움염을 얻는다.The ethyl acetate layer is taken, washed twice with water and dried over anhydrous sodium sulfate. The solvent is evaporated at low pressure. The residue is dissolved in acetone and 2 ml of acetone containing 200 mg of 2-ethyl-hexanoic acid carium salt is added to this solution. The white crystals were separated by ether and added together. D (-)-with a melting point of 180-190 ° (decomposition) of 400 mg (yield 82%).

(Celcon-4-carboxamido) -benzylpenicillin carium salt is obtained.

7.2-8.2(16H, m's, 방향족과 올레핀양성자), 8.6-9.0(2H, m's, NH's)NMR (DMSO-d ₆ ) δ: 1.40 (3H, s, Cα-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.82 (1H, s, C ₃ -CH), 5.4 (2H , m's, C ₅ -CH and C ₆ -CH), 5.88 (1H, d,

7.2-8.2 (16H, m's, aromatic and olefin protons), 8.6-9.0 (2H, m's, NH's)

Example 2

-(첼콘-4-카복스아미도)-P-하이드록시벤질페니실린 카리움염 :D (-)-

-(Chelcon-4-carboxamido) -P-hydroxybenzylphenicillin carium salt:

-아미노-P-하이드록시 벤질페니실린 삼수화물 420mg에 80%액체 테트라하이드로푸란 10ml를 가하고 트리에틸아민으로 pH를 8.0∼8.5로 조절한다. 이 용액에 위에서 언급한 첼콘-4-카복실산 클로라이드를 테트라하이드로푸란 5ml에 용해시킨 것을 방울씩 빙냉교반하면서 가한다. 방울씩 가하는 동안 혼합물을 1시간 동안 빙냉하면서 교반한다. 저압실온에서 테트라하이드로푸란을 증발시키고 얻은 잔사를 물 30ml를 가해서 용해시킨다. 용액을 에틸아세테이트로 2번 세척하고, 이 용액에 에틸아세테이트를 가하고 염산으로 pH를 1.5로 조절한다. 에틸아세테이트층을 합하고 물로 2번 세척하고 무수황산나트륨 상에서 건조한다. 용매는 저압으로해서 증발시킨다. 잔사를 아세톤에 용해시키고 나서 2-에틸-헥사노익산 포타슘염 200mg을 함유한 아세톤 2ml를 가한다. 에테르로 흰색 결정을 분리하고 합해서 533mg(수율 84%)로 융점 200-210℃(분해)인 D(-)-

-(첼콘-4-카복사미도)-P-하이드록시 벤질페니실린 포타슘염을 얻는다.A mixture of 252 mg of chalcon-4-carboxylic acid, a drop of dimethylformamide, 1.5 ml of oxalyl chloride is stirred at room temperature for 1 hour and concentrated to dryness under low pressure.

10 ml of 80% liquid tetrahydrofuran is added to 420 mg of -amino-P-hydroxy benzylpenicillin trihydrate, and the pH is adjusted to 8.0-8.5 with triethylamine. To this solution, the above-mentioned chelcon-4-carboxylic acid chloride dissolved in 5 ml of tetrahydrofuran is added dropwise with ice-cooling. The mixture is stirred with ice cooling for 1 hour while dropwise addition. Tetrahydrofuran was evaporated at low pressure room temperature, and the obtained residue was dissolved by adding 30 ml of water. The solution is washed twice with ethyl acetate, ethyl acetate is added to the solution and the pH is adjusted to 1.5 with hydrochloric acid. The ethyl acetate layers are combined, washed twice with water and dried over anhydrous sodium sulfate. The solvent is evaporated to low pressure. The residue is dissolved in acetone and 2 ml of acetone containing 200 mg of 2-ethyl-hexanoic acid potassium salt are added. Separate white crystals with ether and add 533 mg (84% yield) of D (-)-with melting point 200-210 ° C (decomposition).

-(Celcon-4-carboxamido) -P-hydroxy benzylphenicillin potassium salt is obtained.

6.72(2H, d, 방향족 양성자), 7.26(2H, d, 방향족 양성자), 7.5-8.2(11H, m's, 방향족과 올레핀 양성자), 8.6-8.9(2H, m's, NH's)1.42 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C2β-CH ₃ ), 3.8 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.76 (1 H, d,

6.72 (2H, d, aromatic protons), 7.26 (2H, d, aromatic protons), 7.5-8.2 (11H, m's, aromatic and olefin protons), 8.6-8.9 (2H, m's, NH's)

Example 3

-(찰콘-4'-카복사미도)-벤질페니실린 소디움 염 : 찰콘-4'-카복실산 252mg, 디메틸포름 아마이드 한방울, 옥살릴클로라이드 1.5ml의 혼합물을 마른 공기중에서 실온에서 1시간 동안 교반하고 실온에서 저압으로 농축건조한다.D (-)-

-(Chalcon-4'-carboxamido) -benzylphenicillin sodium salt: A mixture of chalcon-4'-carboxylic acid 252 mg, a drop of dimethylformamide, 1.5 ml of oxalyl chloride was stirred in dry air for 1 hour at room temperature and at room temperature Concentrate to dryness at low pressure.

-아미노벤질페니실린 삼수화물 404mg를 80% 액체 테트라하이드로푸란 10ml에 현탁시키고 이 혼합물 트리에틸아민으로 pH를 8.0-8.5로 조절한다. 이 용액에 위에서 언급한 찰콘-4'-카복실산클로라이드를 녹인 테트라하이드로푸란 5ml를 방울씩 빙냉 교반하면서 가한다. 모두 가한뒤 혼합물을 빙냉시키면서 1시간 교반한다. 가하는 동안 용액의 pH는 트리에틸아민으로 7.5-8.0 사이로 유지시킨다. 저압실은 중에서 테트라하이드로푸란을 증발시키고 얻은 잔사에 물 30ml를 가하고 탄산수소나트륨 용액으로 pH를 9로 조절한다. 용액을 에틸아세테이트 20ml로 세척하고 이 용액에 에틸아세테이트 30ml를 가하고 10%염산으로 빙냉하면서 pH를 1.5로 조절한다.

404 mg of aminobenzylphenicillin trihydrate is suspended in 10 ml of 80% liquid tetrahydrofuran and the mixture is adjusted to pH 8.0-8.5 with triethylamine. To this solution, 5 ml of tetrahydrofuran dissolved in the aforementioned chalcone-4'-carboxylic acid chloride was added dropwise with ice-cooling stirring. After adding all, the mixture was stirred for 1 hour while ice-cooling. During the addition the pH of the solution is maintained between 7.5-8.0 with triethylamine. In the low pressure chamber, 30 ml of water is added to the residue obtained by evaporating tetrahydrofuran in the medium, and the pH is adjusted to 9 with sodium hydrogencarbonate solution. The solution was washed with 20 ml of ethyl acetate and 30 ml of ethyl acetate was added to the solution, and the pH was adjusted to 1.5 with ice cooling with 10% hydrochloric acid.

-(찰콘-4'-카복사미도)-벤질페니실린 나트륨염의 백색분말을 얻는다. 융점 190-220℃(분해)The ethyl acetate layer was washed twice with 20 ml of water and dried over anhydrous sodium sulfate. The solvent is evaporated under low pressure. The residue was dissolved in 2 ml of acetone and 2 ml of ethyl acetate solution containing 200 mg of 2-ethyl sodium hexanoic acid salt was added. Separate white precipitate with 30 ml of ether, filter, combine and wash with ether to give 434 mg (72% yield) of D (-)-

White powder of-(chalcon-4'-carboxamido) -benzyl penicillin sodium salt is obtained. Melting Point 190-220 ° C (Decomposition)

7.2-8.3(16H, m's, 방향족과 올레핀 양성자), 8.98(1H, d, NH), 9.14(1H, d, NH)NMR (DMSO-d ₆ ) δ: 1.42 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.98 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.98 (1H, d,

7.2-8.3 (16H, m's, aromatic and olefin protons), 8.98 (1H, d, NH), 9.14 (1H, d, NH)

Example 4

(찰콘-4'-카복사미도)-P-하이드록시벤질 페니실린나트륨염 : 찰콘-4'-카복실린산 252mg, 디메틸포름아마이드 한방울, 옥샅일 클로라이드 1.5ml의 혼합물을 싱온 건조공기중에서 1시간 교반하고 저압 실온에서 건조농축시킨다.

-아미노-P-하이드록시-벤질 페니실린 삼수화물 420mg을 80%액체 테트라하이드로푸란 10ml에 현탁시키고 이 혼합물을 트리에틸아민을 가해서 PH를 8.0-8.5로 조절한다.D (-)-

(Calcon-4'-carboxamido) -P-hydroxybenzyl penicillin sodium salt: A mixture of 252 mg of chalcon-4'-carboxylinic acid, a drop of dimethylformamide, and 1.5 ml of oxalyl chloride was stirred for 1 hour in a dry air. Dry concentrated at low pressure room temperature.

420 mg of -amino-P-hydroxy-benzyl penicillin trihydrate is suspended in 10 ml of 80% liquid tetrahydrofuran and the mixture is adjusted to pH 8.0-8.5 by addition of triethylamine.

-(찰콘-4'-카복사미도) P-하이드록시벤질페니실린 나트륨염의 백색 분말을 얻는다. 융점 205-240°C(분해)To this solution, the chalcone-4'-carboxylic acid chloride dissolved in 5 ml of tetrahydrofuran mentioned above was added dropwise with ice-cooling stirring. After all additions, the mixture is ice-cooled for 1 hour. During dropwise addition, the pH of the solution is adjusted to between 7.5 and 8.0 by the addition of triethylamine. 30 ml of water is added to the residue obtained by evaporating tetrahydrofuran at low pressure room temperature, and the pH is adjusted to 9 with sodium bicarbonate solution. The solution was washed with 20 ml of ethyl acetate, 30 ml of ethyl acetate was added to the solution, and the pH was adjusted to 1.5 with 100% hydrochloric acid. The ethyl acetate layers are combined, washed twice with 20 ml of water and dried over anhydrous sodium sulfate. The solvent is evaporated under low pressure. The residue was dissolved in 2 ml of acetone, and 2 ml of ethyl acetate containing 200 mg of 2-ethyl-hexanoic acid salt in this solution was added, white precipitate was separated with 30 ml of ether, filtered, washed with ether, 600 mg (yield 96%) of D (-)-

A white powder of-(chalcon-4'-carboxamido) P-hydroxybenzylphenicillin sodium salt is obtained. Melting Point 205-240 ° C (Decomposition)

6.68(2H, d, 방향족 양성자), 7.22(2H, d, 방향족 양성자). 7.3-8.2(11H, m's, 방향족과 올레핀 양성자), 8.66(1H, d, NH), 8.88(1H, d, NH)NMR (DMSO-d ₆ ) δ: 1.44 (3H, s, C ₂ -CH ₃ ), 1.52 (3H, s, C ₂ -CH ₃ ), 3.86 (1H, s, C ₃ -CH), 5.34 (2H , m's, C ₅ -CH and C ₆ -CH), 5.74 (1H, d,

6.68 (2H, d, aromatic protons), 7.22 (2H, d, aromatic protons). 7.3-8.2 (11H, m's, aromatic and olefin protons), 8.66 (1H, d, NH), 8.88 (1H, d, NH)

Example 5

(P-스티릴벤즈아마이드)-벤질 페니실린 소디움 염 : P-스티릴벤조익산 224mg, 디메틸포름아마이드 한방울, 테트라하이드로푸란 5ml, 옥살릴클로라이드 0.17ml의 혼합물을 건조공기하에서 30분간 빙냉 교반한다. 80%액체 테트라하이드로 푸란에

-아미노벤질 페니실린 삼수화물 404mg을 가하고 트리에틸아민을 가해서 용액의 pH를 8.0-8.5사이로 조절한다. 이 용액에 위에서 언급한 P-스티릴 벤조익산클로라이드 용액을 빙냉교반하면서 방울씩 가한다. 방울씩 가하는 동안 용액의 pH는 트리에틸아민을 가해서 7.5-8.0사이로 유지한다. 1시간 후 점적이 끝나면 저압실온에서 테트라하이드로 푸란을 증발시키고 잔사를 얻는다. 여기에 물을 가하고 탄산수소나트륨 용액으로 pH를 8정도로 조절한다. 용액을 에틸아세테이트를 가하고 10% 염산을 가해서 빙냉 교반하면서 pH를 1.5로 조절한다. 에틸 아세테이트 층을 합하고 수세하고 무수황산나트륨 상에서 건조시킨다. 저압실온으로 해서 에틸 아세테이트를 증발시킨다. 잔사를 아세톤 5ml에 용해시키고 2-에틸-헥사노익산 소디움 염 200mg을 함유한 에틸아세테이트 2ml를 가해서 에테르로 침전을 분리하고 여과해서 합하여 527mg(수율 ; 91%)의 D(-)-α-(P-스티릴벤즈아마이드-벤질페니실린 소디움염의 백색 분말을 얻는다.D (-)-

(P-styrylbenzamide) -benzyl penicillin sodium salt: A mixture of 224 mg of P-styrylbenzoic acid, a drop of dimethylformamide, 5 ml of tetrahydrofuran, and 0.17 ml of oxalyl chloride is stirred under ice-cooling for 30 minutes under dry air. 80% Liquid Tetrahydrofuran

Add 404 mg of aminobenzyl penicillin trihydrate and triethylamine to adjust the pH of the solution between 8.0 and 8.5. To this solution is added dropwise the above-mentioned P-styryl benzoic acid chloride solution under ice-cooling stirring. During dropwise addition, the pH of the solution is maintained between 7.5 and 8.0 with the addition of triethylamine. After 1 hour the drip is completed, the tetrahydrofuran is evaporated at low pressure room temperature to obtain a residue. Add water and adjust the pH to 8 with sodium bicarbonate solution. Ethyl acetate was added to the solution, and 10% hydrochloric acid was added to adjust the pH to 1.5 with ice-cooling stirring. The ethyl acetate layers are combined, washed with water and dried over anhydrous sodium sulfate. Ethyl acetate is evaporated at low pressure room temperature. The residue was dissolved in 5 ml of acetone, 2 ml of ethyl acetate containing 200 mg of 2-ethyl-hexanoic acid sodium salt was added, the precipitate was separated by ether, filtered and combined to give 527 mg (yield; 91%) of D (-)-α- ( A white powder of P-styrylbenzamide-benzylphenicillin sodium salt is obtained.

7.2-7.9(16H, m's, 방향족과 올레핀 양성자), 8.86(2H, d's, NH)NMR (DMSO-d ₆ ): 1.44 (3H, s, C ₂ α-CH ₃ ), 1.54 (3H, s, C ₂ β-CH ₃ ), 3.88 (1H, s, C ₃ -CH), 5.4 ( 2H, m's, C ₅ -CH and C ₆ -CH), 5.92 (1H, d,

7.2-7.9 (16H, m's, aromatic and olefin protons), 8.86 (2H, d's, NH)

Example 6

D (-)-α- (P-styrylbenzoamide) P-hydroxybenzylphenicillin sodium salt,

518 mg (yield 87%) of D (-)-α- was obtained in the same manner as in Example 5, except that 224 mg of P-styrylbenzoic acid and 420 mg of α-amino-P-hydroxybenzyl penicillin trihydrate were used. A white powder of (P-styrylbenzamide) P-hydroxybenzyl penicillinsodium salt is obtained.

6.66(2H, d, 방향족 양성자), 7.1-7.9(13H, m's, 방향족과 올레핀 양성자), 8.62(2H, d's, NH'S)NMR (DMSO-d ₆ ) δ: 1.44 (3H, s, C ₂ α-CH ₃ ), 1.52 (3H, s, C ₂ β-CH ₃ ), 3.86 (1H, s, C ₃ -CH), 5.3 (2H, m's, C ₅ -CH and C ₆ -CH), 5.72 (1H, d,

6.66 (2H, d, aromatic protons), 7.1-7.9 (13H, m's, aromatic and olefin protons), 8.62 (2H, d's, NH'S)

Example 7

D (-)-α- (4'-methoxychalcon-4-carboxamido) benzyl penicillin sodium salt:

531 mg (83% yield) of D (-)-α- (except that 282 mg of 4'-methoxychalcon-4-carboxylic acid and 404 mg of α-aminobenzylphenicillin trihydrate were used. A white powder of 4'-methoxychalcon-4-carboxyamide) benzylphenicillin sodium salt is obtained.

7.0-8.1(15H, m, 방향족과 올레핀 양성자), 8.9(2H, d, NH)NMR (DMSO-d ₆ ) δ: 1.42 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.8 (1H, s, C ₃ -CH), 3.84 (3H, s, OCH ₃ ) 5.3 (2H, m, C ₅ -CH and -CH), 5.92 (1H, d,

7.0-8.1 (15H, m, aromatic and olefin protons), 8.9 (2H, d, NH)

Example 8

D (-)-α- (4'-methoxychalcon-4-carboxamido) P-hydroxybenzyl penicillin sodium salt:

Except using 282 mg of 4'-methoxychalcon-4-carboxylic acid and 420 mg of α-amino-P-hydroxybenzyl penicillin trihydrate, the procedure was the same as in Example 5, yielding 476 mg (yield 73%) of D (- A white powder of) -α- (4'-methoxychalcon-4-carboxamido) -P-hydroxybenzyl penicillin sodium salt is obtained.

6.78(2H, d, 방향족 양성자), 7.10(2H, d, 방향족 양성자), 7.32(2H, d, 방향족 양성자), 7.74(1H, d, 올레핀 양성자), 8.00(4H, s, 방향족 양성자), 약 8.00(1H, d, 올레핀 양성자), 8.20(2H, d, 방향족 양성자), 8.8(2H, d's, NH)NMR (DMSO-d ₆ ) δ: 1.44 (3H, s, C ₂ α-CH ₃ ), 1.54 (3H, s, C ₂ β-CH ₃ ), 3.88 (3H, s, OCH ₃ ), 3.92 (1H , s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.80 (1H, d,

6.78 (2H, d, aromatic protons), 7.10 (2H, d, aromatic protons), 7.32 (2H, d, aromatic protons), 7.74 (1H, d, olefin protons), 8.00 (4H, s, aromatic protons), About 8.00 (1H, d, olefin protons), 8.20 (2H, d, aromatic protons), 8.8 (2H, d's, NH)

Example 9

D (-)-α- (2-chlorochalcon-4'-carboxamido) benzyl penicillin sodium salt:

-아미노벤질페니실린 삼수화물 404mg을 사용하는 것을 제외하고 실시예 5와 같은 진행을 하여 529mg(수율 83%)의 D(-)-α-(2-클로로찰콘-4'-카복스아미도)벤질 페니실린 소디움염의 백색 분말을 얻는다.286.5 mg of 2-chlorochalcon-4'-carboxylic acid

529 mg (yield 83%) of D (-)-α- (2-chlorochalcon-4'-carboxamido) benzyl with the same procedure as in Example 5 except that 404 mg of aminobenzyl penicillin trihydrate was used. Obtain white powder of penicillin sodium salt.

7.2-7.6(8H, m's, 방향족과 올레핀 양성자), 8.0-8.3(7H, m's, 방향족과 올레핀 양성자), 8.96(1H, d, NH), 9.26(1H, d, NH)NMR (DMSO-d ₆ ) δ: 1.38 (3H, s, C ₂ α-CH ₃ ), 1.48 (3H, s, C ₂ β-CH ₃ ), 3.86 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.96 (1H, d,

7.2-7.6 (8H, m's, aromatic and olefin protons), 8.0-8.3 (7H, m's, aromatic and olefin protons), 8.96 (1H, d, NH), 9.26 (1H, d, NH)

Example 10

D (-)-α- (2-chlorochalcon-4'-carboxamido) P-hydroxy benzyl penicillin sodium salt:

-아미노-P-하이드록시 벤질 페니실린 삼수화물 420mg을 사용하는 것을 제외하고는 실시예 5와 같은 진행을 하여 582mg(수율 89%)으로 D(-)-α-(2-클로로찰콘-4'-카복스아미도)P-하이드록시벤질 페니실린 소디움 염의 백색분말을 얻는다.286.5 mg of 2-chlorochalcon-4'-carboxylic acid

Proceed as in Example 5, except that 420 mg of amino-P-hydroxy benzyl penicillin trihydrate was used to obtain D (-)-α- (2-chlorochalcon-4'- at 582 mg (89% yield). A white powder of the carboxamido) P-hydroxybenzyl penicillin sodium salt is obtained.

6.68(2H, d, 방향족 양성자), 7.22(2H, d, 방향족 양성자), 7.3-7.5(3H, m's, 방향족과 올레핀 양성자), 7.9-8.2(7H, m's, 방향족과 올레핀 양성자), 8.68(1H, d, NH), 8.90(1H, d, NH)NMR (DMSO-d ₆ ) δ: 1.44 (3H, s, C ₂ α-CH ₃ ), 1.52 (3H, s, C ₂ β-CH ₃ ), 3.88 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.76 (1H, d,

6.68 (2H, d, aromatic protons), 7.22 (2H, d, aromatic protons), 7.3-7.5 (3H, m's, aromatic and olefin protons), 7.9-8.2 (7H, m's, aromatic and olefin protons), 8.68 ( 1H, d, NH), 8.90 (1H, d, NH)

Example 11

D (-)-α- (4-chlorochalcon-4'-carboxamido) benzylpenicillin sodium salt:

-아미노벤질페니실린 삼수화물 404mg을 사용하는 것을 제외하고 실시예 5와 같은 진행을 하여 523mg(수율 82%)의 D(-)-α-(4-클로로찰콘-4'-카복스아미도)벤질페니실린 소디움 염의 백색 분말을 얻는다.286.5 mg of 4-chlorochalcon-4'-carboxylic acid

523 mg (yield 82%) of D (-)-α- (4-chlorochalcon-4'-carboxamido) benzyl was carried out in the same manner as in Example 5 except that 404 mg of aminobenzyl penicillin trihydrate was used. Obtain white powder of penicillin sodium salt.

7.2-8.2(15H, m's, 방향족과 올레핀 양성자), 8.92(1H, d, NH), 9.12(1H, d, NH)NMR (DMSO-d ₆ ) δ: 1.40 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.86 (1H, s, C ₃ -CH), 5.34 (2H, m's, C ₅ -CH and C ₆ -CH), 5.94 (1H, d,

7.2-8.2 (15H, m's, aromatic and olefin protons), 8.92 (1H, d, NH), 9.12 (1H, d, NH)

Example 12

D (-)-α- (4-chlorochalcon-4'-carboxamido) P-hydroxy benzylpenicillin sodium salt:

-아미노-P-하이드록시 벤질페니실린 삼수화물 420mg을 사용하는 것을 제외하고 실시예 5와 같은 진행을 하여 623mg(수율 : 95%)의 D(-)-α-(4-클로로찰콘-4'-카복스아미도) P-하이드록시벤질 페니실린 소디움 염의 백색분말을 얻는다.286.5 mg of 4-chlorochalcon-4'-carboxylic acid

623 mg (yield: 95%) of D (-)-α- (4-chlorochalcon-4'- was obtained in the same manner as in Example 5 except that 420 mg of amino-P-hydroxy benzylphenicillin trihydrate was used. Carboxamido) to obtain a white powder of P-hydroxybenzyl penicillin sodium salt.

6.68(2H, d, 방향족 양성자), 7.20(2H, d, 방향족 양성자), 7.4-8.2(10H, m's, 방향족과 올레핀 양성자), 8.66(1H, d, NH), 8.86(1H, d, NH)NMR (DMSO-d ₆ ) δ: 1.44 (3H, s, C ₂ α-CH ₃ ), 1.54 (3H, s, C ₂ β-CH ₃ ), 3.88 (1H, s, C ₃ -CH), 5.33 (2H, m's, C ₅ -CH and C ₆ -CH), 5.74 (1H, d,

6.68 (2H, d, aromatic protons), 7.20 (2H, d, aromatic protons), 7.4-8.2 (10H, m's, aromatic and olefin protons), 8.66 (1H, d, NH), 8.86 (1H, d, NH )

Example 13

D (-)-α- [P- (5-phenylpenta-2,4-dienoyl) benzamido] benzylphenicillin sodium salt:

-아미노벤질 페니실린 삼수화물 404mg을 사용하는 것을 제외하고는 실시예 5와 같은 진행을 하여 533mg(수율 : 84%)의 D(-)-α-[P-(5-페닐펜타-2, 4-디에노일)벤즈아미도]벤질페니실린 소디움 염의 황색 분말을 얻는다.278 mg of P- (5-phenylpenta-2,4-dienoyl) benzoic acid

533 mg (yield: 84%) of D (-)-α- [P- (5-phenylpenta-2, 4-, except that 404 mg of aminobenzyl penicillin trihydrate was used. A yellow powder of dienoyl) benzamido] benzylphenicillin sodium salt is obtained.

7.2-7.6(14H, m's, 방향족과 올레핀 양성자), 8.06(4H, s, 방향족 양성자), 8.92(1H, d, NH), 9.10(1H, d, NH)NMR (DMSO-d ₆ ) δ: 1.40 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.88 (1H, s, C ₃ -CH), 5.44 (2H, m's, C ₅ -CH and C ₆ -CH), 5.94 (1H, d,

7.2-7.6 (14H, m's, aromatic and olefin protons), 8.06 (4H, s, aromatic protons), 8.92 (1H, d, NH), 9.10 (1H, d, NH)

Example 14

D (-)-α- [P- (5-phenylpenta-2,4-dienoyl) benzamido] P-hydroxy benzyl penicillin sodium salt:

-아미노-P-하이드록시 벤질 페니실린 삼수화물 420mg을 사용하는 것을 제외하고는 실시예 5와 같은 진행을 하여 527mg(수율 81%)의 D(-)-α-[P-(5-페닐펜타-2, 4-디에노일)벤즈아미도] P-하이드록시 벤질 페니실린 소디움 염의 황색분말을 얻는다.278 mg of P- (5-phenylpenta-2,4-dienoyl) benzoic acid

527 mg (yield 81%) of D (-)-α- [P- (5-phenylpenta-) was obtained in the same manner as in Example 5, except that 420 mg of amino-P-hydroxy benzyl penicillin trihydrate was used. 2,4-dienoyl) benzamido] A yellow powder of P-hydroxy benzyl penicillin sodium salt is obtained.

6.72(2H, d, 방향족 양성자), 7.2-7.7(11H, m's, 방향족과 올레핀 양성자), 8.04(4H, s, 방향족 양성자), 8.72(1H, d, NH), 8.94(1H, d, NH)NMR (DMSO-d ₆ ) δ: 1.42 (3H, s, C ₂ α-CH ₃ ), 1.52 (3H, s, C ₂ β-CH ₃ ), 3.88 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.78 (1H, d,

6.72 (2H, d, aromatic protons), 7.2-7.7 (11H, m's, aromatic and olefin protons), 8.04 (4H, s, aromatic protons), 8.72 (1H, d, NH), 8.94 (1H, d, NH )

Example 15

D (-)-α- [P- [β- (2-furyl) acryloyl] benzamido] benzyl penicillin sodium salt:

Except using 242 mg of P- [β- (2-furyl) acryloyl] benzoic acid and 404 mg of α-amino benzyl penicillin trihydrate, 534 mg (yield 90%) of D (- A pale yellow powder of) -α- [P- [β- (2-furyl) acryloyl] benzamido] benzyl penicillin sodium salt is obtained.

6.64(1H, dd, 방향족 양성자), 7.1-8.1(13H, m's, 방향족과 올레핀 양성자), 8.90(1H, d, NH), 9.10(1H, d, NH)NMR (DMSO-d ₆ ) δ: 1.40 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.88 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.94 (1H, d,

6.64 (1H, dd, aromatic protons), 7.1-8.1 (13H, m's, aromatic and olefin protons), 8.90 (1H, d, NH), 9.10 (1H, d, NH)

Example 16

D (-)-α- [P- [β- (2-furyl) acryloyl] benzamido] P-hydroxy benzyl penicillin sodium salt:

-아미노-P-하이드록시벤질 페니실린 삼수화물 420mg을 사용하는 것을 제외하고는 실시예 5와 같은 진행을 하여 501mg(수율 82%)의 D(-)-α-[P-[β-(2-푸릴)아크릴오일]벤즈아미도] P-하이드록시 벤질 페니실린 소디움 염의 연 황색분말을 얻는다.242 mg of P [β- (2-furyl) acrylic oil] benzoic acid

501 mg (yield 82%) of D (-)-α- [P- [β- (2-, except that 420 mg of -amino-P-hydroxybenzyl penicillin trihydrate was used. Furyl) acrylic oil] benzamido] light yellow powder of P-hydroxy benzyl penicillin sodium salt.

6.7(3H, m's, 방향족 양성자), 7.10(1H, d, 방향족 양성자), 7.28(2H, d, 방향족 양성자), 7.54(5H, s, 올레핀 양성자), 7.8-8.1(5H, m's, 방향족 양성자), 8.72(1H, d, NH), 8.96(1H, d, NH)NMR (DMSO-d ₆ ) δ: 1.42 (3H, s, C ₂ α-CH ₃ ), 1.52 (3H, s, C ₂ β-CH ₃ ), 3.88 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.78 (1H, d,

6.7 (3H, m's, aromatic protons), 7.10 (1H, d, aromatic protons), 7.28 (2H, d, aromatic protons), 7.54 (5H, s, olefin protons), 7.8-8.1 (5H, m's, aromatic protons ), 8.72 (1H, d, NH), 8.96 (1H, d, NH)

Example 17

D (-)-α- [P- [β- (2-thienyl) acryloyl] benzamido] benzyl penicillin sodium salt:

551 mg (90% yield) of D was obtained in the same manner as in Example 5, except that 258 mg of P- [β- (2-thienyl) acryloyl] -benzoic acid and 404 mg of α-amino benzyl penicillin trihydrate were used. A light yellow powder of (-)-α- [P- [β- (2-thienyl) acryloyl] benzamido] benzyl penicillin sodium salt is obtained.

7.2-8.2(14H, m's, 방향족과 올레핀 양성자), 8.94(1H, d, NH), 9.16(1H, d, NH)NMR (DMSO-d ₆ ) δ: 1.42 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 33.88 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.96 (1H, d,

7.2-8.2 (14H, m's, aromatic and olefin protons), 8.94 (1H, d, NH), 9.16 (1H, d, NH)

Example 18

D (-)-α- [P- [β- (2-thienyl) acryloyl] benzoamido] P-hydroxy benzyl penicillin sodium salt:

-아미노-P-하이드록시 벤질 페니실린 삼수화물 420mg을 사용하는 것을 제외하고는 실시예 5와 같은 진행을 하여 530mg(수율 : 84%)의 D(-)-α-[P-[β-(2-티에닐)아크릴오일]벤즈아미도] P-하이드록시 벤질 페니실린 소디움 염의 연황색 분말을 얻는다.258 mg of P [β- (2-thienyl) acryloyl] benzoic acid

530 mg (yield: 84%) of D (-)-α- [P- [β- (2) was carried out in the same manner as in Example 5 except that 420 mg of amino-P-hydroxy benzyl penicillin trihydrate was used. -Thienyl) acryloyl oil] benzamido] light yellow powder of P-hydroxy benzyl penicillin sodium salt.

6.76(2H, d, 방향족 양성자), 7.2-8.2(11H, m's, 방향족과 올레핀 양성자), 8.78(1H, d, NH), 9.00(1H, d, NH)NMR (DMSO-d ₆ ) δ: 1.42 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.88 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.80 (1H, d,

6.76 (2H, d, aromatic protons), 7.2-8.2 (11H, m's, aromatic and olefin protons), 8.78 (1H, d, NH), 9.00 (1H, d, NH)

Example 19

D (-)-α- [3-3- (2-thienyl) prop-1-ene 3-oil] benzoamido] benzyl penicillin sodium salt:

522 mg was prepared in the same manner as in Example 5, except that 258 mg of P- [β- (2-tinyl) prop-1-ene-3-onyl] -benzoic acid and 404 mg of α-amino benzyl penicillin trihydrate were used. A white powder of D (-)-α- [P-3- (2-thienyl) prop-1-ene-3-onyl] benzoamido] benzyl penicillin sodium salt of (yield 85%) is obtained.

7.3-8.1(13H, m's, 방향족과 올레핀 양성자), 8.32(1H, d, 방향족 양성자), 8.9(2H, d's, NH's)NMR (DMSO-d ₆ ) δ: 1.40 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.86 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.92 (1H, d,

7.3-8.1 (13H, m's, aromatic and olefin protons), 8.32 (1H, d, aromatic protons), 8.9 (2H, d's, NH's)

Example 20

D (-)-α- [P-3- (2-thienyl) prop-1-enene 3-greenhouse] benzamido] P-hydroxy benzyl penicillin sodium salt:

-아미노-P-하이드록시 벤질 페니실린 삼수화물 420mg을 사용하는 것을 제외하고는 실시예 5와 같은 진행을 하여 540mg(수율 : 86%)의 D(-)-α-[P-3-(2-티에닐)프로프-1-엔네 3-온닐]벤즈아미도] P-하이드록시 벤질 페니실린 소디움 염의 백색분말은 얻는다.258 mg of P- [3- (2-thienyl) prop-1-ene-3-onyl] benzoic acid

540 mg (yield: 86%) of D (-)-α- [P-3- (2-) was obtained in the same manner as in Example 5, except that 420 mg of amino-P-hydroxy benzyl penicillin trihydrate was used. A white powder of thienyl) prop-1-ene 3-onyl] benzamido] P-hydroxy benzyl penicillin sodium salt is obtained.

6.74(2H, d, 방향족 양성자), 7.28(3H, m's, 방향족 양성자), 7.6-8.1(9H, m's, 방향족과 올레핀 양성자), 8.34(1H, d, 방향족 양성자), 8.8(2H, d's, NH'S)NMR (DMSO-d ₆ ) δ: 1.44 (3H, s, C ₂ α-CH ₃ ), 1.52 (3H, s, C ₂ β-CH ₃ ), 3.90 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.78 (1H, d,

6.74 (2H, d, aromatic protons), 7.28 (3H, m's, aromatic protons), 7.6-8.1 (9H, m's, aromatic and olefin protons), 8.34 (1H, d, aromatic protons), 8.8 (2H, d's, NH'S)

Example 21

D (-)-α- [P- [β- (2-pyridyl) acryloyl] benzamido] benzylphenicillin sodium salt:

447 mg (yield 74%) of D was obtained in the same manner as in Example 5 except that 253 mg of P- [β- (2-pyridyl) acryloyl] -benzoic acid and 404 mg of α-aminobenzyl penicillin trihydrate were used. A light yellow powder of (-)-α- [P- [β- (2-pyridyl) acryloyl] benzamido] benzyl penicillin sodium salt is obtained.

7.3-8.3(14H, m's, 방향족과 올레핀 양성자), 8.72(1H, m, 방향족 양성자), 8.96(1H, d, NH), 9.18(1H, d, NH)NMR (DMSO-d ₆ ) δ: 1.40 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.88 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.98 (1H, d,

7.3-8.3 (14H, m's, aromatic and olefin protons), 8.72 (1H, m, aromatic protons), 8.96 (1H, d, NH), 9.18 (1H, d, NH)

Example 22

D (-)-α- (6-styryl nicotinamido) -benzylpenicillin sodium salt: proceed as in Example 5 except that 225 mg of 6-styryl nicotinic acid and 404 mg of α-aminobenzyl penicillin trihydrate are used. To give a light yellow powder of 458 mg (yield: 79%) of D (-)-α- (6styryl nicotinamido) -benzylphenicillin sodium salt.

7.3-7.9(13H, m's, 방향족과 올레핀 양성자), 8.36(1H, dd, 방향족 양성자), 9.14(1H, d, 방향족 양성자), 9.1(2H, d's, NH's)NMR (DMSO-d ₆ ) δ: 1.42 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.92 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 6.00 (1H, d,

7.3-7.9 (13H, m's, aromatic and olefin protons), 8.36 (1H, dd, aromatic protons), 9.14 (1H, d, aromatic protons), 9.1 (2H, d's, NH's)

Example 23

D (-)-α (6-styryl nicotinamido) P-hydroxy benzyl penicillin sodium salt:

503 mg (yield: 85%) of D (-)-α- (6-styryl nicotinamido, except using 225 mg of 6-styryl nicotinic acid and 420 mg of α-amino-P-hydroxy benzyl penicillin trihydrate ) White powder of P-hydroxy benzyl penicillin sodium salt.

6.74(2H, d, 방향족 양성자), 7.2-7.9(10H, m's, 방향족과 올레핀 양성자), 8.26(1H, dd, 방향족 양성자), 8.74(1H, d, NH), 9.0(1H, d, NH) 9.02(1H, d, 방향성 양성자)NMR (DMSO-d ₆ ) δ: 1.42 (3H, s, C ₂ α-CH ₃ ), 1.52 (3H, s, C ₂ β-CH ₃ ), 3.88 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.80 (1H, d,

6.74 (2H, d, aromatic protons), 7.2-7.9 (10H, m's, aromatic and olefin protons), 8.26 (1H, dd, aromatic protons), 8.74 (1H, d, NH), 9.0 (1H, d, NH ) 9.02 (1H, d, directional protons)

Example 24

D (-)-α- (2'-hydroxychalcon-4-carboxamido) benzylpenicillin sodium salt:

501 mg (yield: 81%) of D (-)-α- was obtained in the same manner as in Example 5 except that 268 mg of 2'-hydroxychalcon-4-carboxylic acid and α-amino benzyl penicillin trihydrate were used. A light yellow powder of (2'-hydroxychalcon-4-carboxamido) benzylphenicillin sodium salt is obtained.

6.9-8.2(15H, m's, 방향족과 올레핀 양성자), 9.0(2H, d's, NH's)NMR (DMSO-d ₆ ) δ: 1.40 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.88 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.96 (1H, d,

6.9-8.2 (15H, m's, aromatic and olefin protons), 9.0 (2H, d's, NH's)

Example 25

D (-)-α- [P- (2-thien-2-ylethynyl) benzamido] benzylphenicillin sodium salt:

Except for using 115 mg of P- (2-thien-2-ylethynyl) benzoic acid and 202 mg of α-aminobenzyl penicillin trihydrate, 215 mg (yield: 74%) of D ( A white powder of-)-α- [P- (2-thien-2-ylethynyl) benzamido] benzylphenicillin sodium salt is obtained.

6.9-8.0(14H, m's, 방향족과 올레핀 양성자), 8.9(2H, d's, NH's)NMR (DMSO-d ₆ ) δ: 1.42 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.92 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.92 (1H, d,

6.9-8.0 (14H, m's, aromatic and olefin protons), 8.9 (2H, d's, NH's)

Example 26

D (-)-α- [P- (2-thien-2-ylethynyl) benzamido] P-hydroxy benzyl penicillin sodium salt:

190 mg (yield: 63%) of D (-)-except that 115 mg of P- (2-thien-2-ylethynyl) benzoic acid and 210 mg of α-amino-P-hydroxy benzylpenicillin trihydrate were used. A white powder of α- [P- (2-thien-2-ylethynyl) benzamido] P-hydroxy benzyl penicillin sodium salt is obtained.

6.6-7.8(13H, m's, 방향족과 올레핀 양성자), 8.56(2H, d's, NH'S)NMR (DMSO-d ₆ ) δ: 1.44 (3H, s, C ₂ α-CH ₃ ), 1.52 (3H, s, C ₂ β-CH ₃ ), 3.86 (1H, s, C ₃ -CH), 5.3 (2H, m's, C ₅ -CH and C ₆ -CH), 5.68 (1H, d,

6.6-7.8 (13H, m's, aromatic and olefin protons), 8.56 (2H, d's, NH'S)

Example 27

D (-)-α- [6- (2-thien-2-ylethynyl) nicotinamido] benzyl penicillinsodium salt:

450 mg of D (-)-α- [6 was carried out in the same manner as in Example 5, except that 231 mg of 6- (2-thien-2-ylethynyl) nicotinic acid and 404 mg of α-aminobenzylphenicillin trihydrate were used. -(2-thien-2-ylethenyl) nicotinamido] A light yellow powder of benzylphenicillinsodium salt is obtained.

7.0-8.2(12H, m's, 방향족과 올레핀 양성자), 8.92(1H, d, NH), 8.98(1H, d, 방향족양성자), 9.14(1H, d, NH).NMR (DMSO-d ₆ ) δ: 1.42 (3H, s, C ₂ α-CH ₃ ), 1.52 (3H, s, C ₂ β-CH ₃ ), 3.88 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.94 (1H, d,

7.0-8.2 (12H, m's, aromatic and olefin protons), 8.92 (1H, d, NH), 8.98 (1H, d, aromatic protons), 9.14 (1H, d, NH).

Example 28

D (-)-α- [6- (2-thien-2-ylethynyl) nicotinamido] P-hydroxy benzylphenicillin sodium salt:

460 mg (yield 77%) in the same manner as in Example 5, except that 231 mg of 6- (2-thien-2-ylethynyl) nicotinic acid and 420 mg of α-amino-P-hydroxy benzylphenicillin trihydrate were used. White powder of D (-)-α- [6- (2-thien-2-ylethynyl) nicotinamido] P-hydroxybenzyl penicillin sodium salt of

6.74(1H, d, 방향족양성자), 6.9-7.6(7H, m's, 방향족과 올레핀 양성자), 7.92(1H, d, 올레핀양성자), 8.22(1H, dd, 방향족양성자), 8.74(1H, d, NH), 8.96(1H, d, NH) 8.98(1H, d, 방향족양성자).NMR (DMSO-d ₆ ) δ: 1.42 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.88 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.78 (1H, d,

6.74 (1H, d, aromatic protons), 6.9-7.6 (7H, m's, aromatic and olefin protons), 7.92 (1H, d, olefin protons), 8.22 (1H, dd, aromatic protons), 8.74 (1H, d, NH), 8.96 (1H, d, NH) 8.98 (1H, d, aromatic protons).

Example 29

D (-)-α- [P- (4-phenylbuta-1, 3-dienyl) benzamido] benzyl penicillin sodium salt:

246 mg (yield: 81%) was obtained in the same manner as in Example 5, except that 125 mg of P- (4-phenylbuta-1, 3-dienyl) benzoic acid and 202 mg of -α-aminobenzyl penicillin trihydrate were used. A pale yellow powder of D (-)-α- [P- (4-phenylbuta-1,3-dienyl) benzamido] benzyl penicillin sodium salt of is obtained.

6.7-8.0(18H, m's, 방향족과 올레핀 양성자), 8.88(2H, d's, NH's).NMR (DMSO-d ₆ ) δ: 1.40 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.86 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.92 (1H, d,

6.7-8.0 (18H, m's, aromatic and olefin protons), 8.88 (2H, d's, NH's).

Example 30

D (-)-α- [P- (4-phenylbuta-1, 3-dienyl) benzamido] P-hydroxybenzylphenicillin sodium salt:

The same procedure as in Example 5 was carried out except that 231 mg of P- (4-phenylbuta-1,3-dienyl) benzoic acid and 210 mg of -α-amino-P-hydroxybenzyl penicillin trihydrate were used. Yield: 77%) of white powder of D (-)-α- [P- (4-phenylbuta-1, 3-dienyl) benzoamido] P-hydroxybenzylphenicillinsodium salt.

6.7-8.0(17H, m's, 방향족과 올레핀 양성자), 8.70(2H, d's, NH'S).NMR (DMSO-d ₆ ) δ: 1.42 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.90 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.76 (1H, d,

6.7-8.0 (17H, m's, aromatic and olefin protons), 8.70 (2H, d's, NH'S).

Example 31

D (-)-α- [6- (4-phenylbuta-1, 3-dienyl) nicotinamido] benzyl penicillin sodium salt:

Except for using 126 mg of 6- (4-phenylbuta-1,3-dienyl) nicotinic acid and 202 mg of α-amino benzylphenicillin trihydrate, the procedure was the same as in Example 5, yielding 232 mg (yield: 77%) A light yellow powder of D (-)-α- [6- (4-phenylbuta-1,3-dienyl) nicotinamido] benzylphenicillin sodium salt is obtained.

6.8-7.7(15H, m's, 방향족과 올레핀 양성자), 8.24(1H, dd, 방향족양성자), 8.92(1H, d, NH), 9.00(1H, d, 방향족양성자), 9.14(1H, d, NH)NMR (DMSO-d ₆ ) δ: 1.40 (3H, s, C ₂ α-CH ₃ ), 1.50 (3H, s, C ₂ β-CH ₃ ), 3.88 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.94 (1H, d,

6.8-7.7 (15H, m's, aromatic and olefin protons), 8.24 (1H, dd, aromatic protons), 8.92 (1H, d, NH), 9.00 (1H, d, aromatic protons), 9.14 (1H, d, NH )

Example 32

D (-)-α- [6- (4-phenylbuta-1, 3-dienyl) nicotinamido] P-hydroxybenzylpheny silinsodium:

232 mg (yield) in the same manner as in Example 5, except that 126 mg of 6- (4-phenylbuta-1, 3-dienyl) nicotinic acid and 210 mg of -α-amino-P-hydroxybenzylphenicillin trihydrate were used. : 75%) of D (-)-α- [6- (4-phenylbuta-1, 3-dienyl) nicotinamido] white powder of P-hydroxybenzylphenicillin sodium salt was obtained.

6.8-7.7(14H, m's, 방향족과 올레핀 양성자), 8.22(1H, dd, 방향족양성자), 8.76(1H, d, NH), 8.98(1H, d, NH), 9.00(1H, d, 방향족양성자).NMR (DMSO-d ₆ ) δ: 1.42 (3H, s, C ₂ α-CH ₃ ), 1.52 (3H, s, C ₂ β-CH ₃ ), 3.90 (1H, s, C ₃ -CH), 5.4 (2H, m's, C ₅ -CH and C ₆ -CH), 5.82 (1H, d,

6.8-7.7 (14H, m's, aromatic and olefin protons), 8.22 (1H, dd, aromatic protons), 8.76 (1H, d, NH), 8.98 (1H, d, NH), 9.00 (1H, d, aromatic protons ).

Example 33

D (-)-7- [α- (chalcon-4-carboxamido) phenylacetamido] cephalosporanic acid:

A mixture of 252 mg of chalcone-4-carboxylic acid, a drop of dimethylformamide, 5 ml of anhydrous tetrahydrofuran, and 0.17 ml of oxalin chloride is ice-cooled stirred in dry air for 30 minutes.

406 mg of D (-)-7- (α-aminophenylacetamido) cephalosporanic acid is added to 80% aqueous tetrahydrofuran and the pH of the solution is adjusted to between 8.0 and 8.5 with triethylamine. The above-mentioned chalcone-4-carboxylic acid chloride solution is added dropwise with ice-cooling stirring.

The pH of the solution during the deposition is adjusted to between 7.5-8.0 with triethylamine. After one hour, after completion of the drop, tetrahydrofuran was evaporated under low pressure at room temperature, water was added to the residue, and the pH of the solution was adjusted to about 8 with sodium hydrogencarbonate solution.

The solution was washed with ethyl acetate and ethyl acetate was added to the solution, and the pH was adjusted to 1.5 by adding 10% hydrochloric acid under ice-cooling stirring. The ethyl acetate layer is taken, washed with water and dried over anhydrous sodium sulfate. Ethyl acetate is evaporated at room temperature under low pressure to obtain 140 mg (yield: 22%) of white powder of D (-)-7- [α- (chalcon-4-carboxamido) phenylacetamido] cephalos foranoic acid. .

7.3-8.2(16H, m's, 방향족과 올레핀양성자), 8.92(1H, d's, NH), 9.24(1H, d, NH).NMR (DMSO-d ₆ ) δ: 2.02 (3H, s, COCH ₃ ), 3.44 (2H, q, C ₂ -CH ₂ ), 4.80 (2H, q, C ₃ -CH ₂ ), 5.02 (1H, d , C ₆ -CH) 5.8 (2H, m's, C ₇ -CH and

7.3-8.2 (16H, m's, aromatic and olefin protons), 8.92 (1H, d's, NH), 9.24 (1H, d, NH).

Example 34

D (-)-7- [α [(chalcon-4'-carboxamido) phenylacetamido, cephalosporanic acid sodium salt:

527 mg (yield: 80%) by the same procedure as in Example 5 except for using 252 mg of chalcone-4'-carboxylic acid and D (-)-7- (α-aminophenylacetamido) cephalosporanoic acid A white powder of D (-)-7- [α- (chalcon-4'-carboxamido] phenylacetamido] cephalosporanic acid sodium salt of.

7.2-8.2(16H, m's, 방향족과 올레핀양성자), 9.2(2H, d's, NH's).NMR (DMSO-d ₆ ) δ: 1.98 (3H, s, COCH ₃ ), 3.24 (2H, q, C ₂ -CH ₂ ), 4.86 (2H, q, C ′ ₃ -CH ₂ ), 4.90 (1H, d, C ₆ -CH) 5.54 (1H, dd, C ₇ -CH), 5.90 (1H, d,

7.2-8.2 (16H, m's, aromatic and olefin protons), 9.2 (2H, d's, NH's).

Example 35

-(P-스티릴벤즈아미도)페닐아세트아미도] 세팔로스포라닌산 :D (-)-7- [

-(P-styrylbenzamido) phenylacetamido] cephalosporanic acid:

-아미노페닐아세트 아미도)세팔로스포라닌산 406mg을 사용하는 것을 제외하고 실시예 33과 같은 진행을 하여 211mg(수율 34%)의 D(-)-7-[

-(P-스티릴벤즈아미도)페닐아세트아미도] 세팔로스포라닌산의 백색분말을 얻는다.223 mg of P-styrylbenzoic acid and D (-)-7- (

211 mg (34% yield) of D (-)-7- [was proceeded in the same manner as in Example 33 except that 406 mg of aminophenylacetamido) cephalosporanic acid was used.

-(P-styrylbenzamido) phenylacetamido] White powder of cephalosporanic acid is obtained.

7.3-8.0(16H, m's, 방향족과 올레핀양성자), 8.84(1H, d, NH), 9.24(1H, d, NH).NMR (DMSO-d ₆ ) δ: 2.02 (3H, s, COCH ₃ ), 3.44 (2H, wide range C ₂ -CH ₂ ), 4.80 (2H, q, C ′ ₃ -CH ₂ ), 5.04 (1H, d , C ₆ -CH), 5.74 (1H, dd, C ₇ -CH), 5.88 (1H, d

7.3-8.0 (16H, m's, aromatic and olefin protons), 8.84 (1H, d, NH), 9.24 (1H, d, NH).

Example 36

-4'-메톡시찰콘-4-카복스아미도)페닐아세트아미도]세팔로스포라닌산소디움염 :D (-)-7- [

-4'-methoxychalcon-4-carboxamido) phenylacetamido] cephalosporanine sodium salt:

-아미노페닐아세트아미도)세팔로스포라닌산 406mg을 사용하는 것을 제외하고는 실시예 5와 같은 진행을 하여 443mg(수율 : 64%)의 D(-)-7-[

-(4'메톡시찰콘-4-카복스아미도)페닐아세트아미도]세팔로스포라닌산소디움염의 백색분말을 얻는다.282 mg of 4'-methoxychalcon-4-carboxylic acid and 282 mg of 4'-methoxychalcon-4-carboxylic acid, D (-)-7- (

443 mg (yield: 64%) of D (-)-7- [was proceeded in the same manner as in Example 5 except that 406 mg of aminophenylacetamido) cephalosporanic acid was used.

White powder of-(4'methoxychalcon-4-carboxamido) phenylacetamido] cephalosporanine sodium salt is obtained.

7.0-8.2(15H, m's, 방향족과 올레핀 양성자), 9.00(1H, d, NH), 9.24(1H, d, NH).NMR (DMSO-d ₆ ) δ: 1.98 (3H, s, COCH ₃ ), 3.26 (2H, q, C ₂ -CH ₂ ), 3.86 (3H, s, OCH ₃ ), 4.88 (2H, q, C ' ₃ -CH ₂ ), 4.92 (1H, d, C ₆ -CH), 5.56 (1H, dd, C ₇ -CH), 5.92 (1H, d,

7.0-8.2 (15H, m's, aromatic and olefin protons), 9.00 (1H, d, NH), 9.24 (1H, d, NH).

Example 37

-(2-클로로찰콘-4'-카복스아미도)페닐 아세트아미도] 세팔로스포라닌산 소디움염 :D (-)-7- [

-(2-Chlorochalcone-4'-carboxamido) phenylacetamido] cephalosporanic acid sodium salt:

-아미노 페닐아세트아미도)세팔로스포라닌산 406mg을 사용하는 것을 제외하고는 실시예 5와 같은 진행을 하여 592mg(수율 : 85%)의 D(-)-7-[

-(2-클로로찰콘-4'-카복스아미도)페닐아세트아미도]세팔로스 포라닌산 소디움염의 백색분말을 얻는다.286.5 mg of 2-chlorochalcon-4'-carboxylic acid and D (-)-7- (

592 mg (yield: 85%) of D (-)-7- [was proceeded in the same manner as in Example 5, except that 406 mg of aminophenylacetamido) cephalosporanic acid was used.

White powder of-(2-chlorochalcon-4'-carboxamido) phenylacetamido] cephalosporanic acid sodium salt is obtained.

7.3-7.6(8H, m's, 방향족과 올레핀 양성자), 8.0-8.2(7H, m's, 방향족과 올레핀 양성자), 9.2(2H, d's, NH's).NMR (DMSO-d ₆ ) δ: 1.98 (3H, s, COCH ₃ ), 3.26 (2H, q, C ₂ -CH ₂ ), 4.88 (2H, q, C ′ ₃ -CH ₂ ), 4.92 (1H, d, C ₆ -CH), 5.58 (1H, dd, C ₇ -CH), 5.92 (1H, d,

7.3-7.6 (8H, m's, aromatic and olefin protons), 8.0-8.2 (7H, m's, aromatic and olefin protons), 9.2 (2H, d's, NH's).

Example 38

-(4-클로로찰콘-4'-카복스아미도)페닐아세트아미도]세팔로스포라닌산 :D (-)-7- [

-(4-chlorochalcon-4'-carboxamido) phenylacetamido] cephalosporanic acid:

-아미노페닐아세트아미도)세팔로스포라닌산 406mg을 사용하는 것을 제외하고는 실시예 33와 같은 진행을 하여 229mg(수율 : 34%)의 D(-)-7-[

-(4-클로로찰콘-4'-카복스아미도)페닐아세트아미도]세팔로스포라닌산의 백색분말을 얻는다.286.5 mg of 4-chlorochalcon-4'-carboxylic acid and D (-)-7- (

229 mg (yield: 34%) of D (-)-7- [was proceeded as in Example 33, except that 406 mg of aminophenylacetamido) cephalosporanic acid was used.

White powder of-(4-chlorochalcon-4'-carboxamido) phenylacetamido] cephalosporanic acid is obtained.

7.3-8.3(15H, m's, 방향족과 올레핀양성자), 9.08(1H, d, NH), 9.30(1H, d, NH).NMR (DMSO-d ₆ ) δ: 2.02 (3H, s, COCH ₃ ), 3.46 (2H, broad range C ₂ -CH ₂ ), 4.80 (2H, q, C ′ ₃ -CH ₂ ), 5.04 (1H, d , C ₆ -CH), 5.76 (1H, dd, C ₇ -CH), 5.90 (1H, d,

7.3-8.3 (15H, m's, aromatic and olefin protons), 9.08 (1H, d, NH), 9.30 (1H, d, NH).

Example 39

-[P-(5-페닐펜타-2, 4-디에노일)벤조아미도]페닐아세트아미도] 세팔로스포라닌 산소디움염 :D (-)-7- [

-[P- (5-phenylpenta-2,4-dienoyl) benzoamido] phenylacetamido] cephalosporanine oxygenate salt:

-아미노페닐아세트아미도)세팔로스포라닌산 406mg을 사용하는 것을 제외하고는 실시예 5와 같은 진행을 하여 579mg의 D(-)-7-[

-[P-(5-페닐펜타-2, 4-디에노일)벤즈아미도]펙닐아세트아미도]세팔로스포라닌산소디움염의 황색분말을 얻는다.278 mg of P- (5-phenylpenta-2,4-dienoyl) benzoic acid and D (-)-7- (

579 mg of D (-)-7- [was proceeded as in Example 5, except that 406 mg of aminophenylacetamido) cephalosporanic acid was used.

-Yellow powder of [P- (5-phenylpenta-2,4-dienoyl) benzamido] phenylacetamido] cephalosporanic acid sodium salt is obtained.

7.3-7.7(14H, m's, 방향족과 올레핀양성자), 8.16(4H, s, 방향족양성자), 9.3(2H, d's, NH's).NMR (DMSO-d ₆ ) δ: 1.98 (3H, s, COCH ₃ ), 3.26 (2H, q, C ₂ -CH ₂ ), 5.0 (3H, m's, C ' ₃ -CH ₂ and C ₆ -CH) , 5.62 (1H, doublet of doublets, C ₇ -CH), 5.98 (1H, d,

7.3-7.7 (14H, m's, aromatic and olefin protons), 8.16 (4H, s, aromatic protons), 9.3 (2H, d's, NH's).

Example 40

-[P-[

-(2-푸릴)아크릴오일]벤즈아미도)페닐아세트아미도] 세팔로스포라닌 산소디움염 :D (-)-7- [

-[P- [

-(2-furyl) acrylic oil] benzamido) phenylacetamido] cephalosporanine oxygenium salt:

-(2-푸릴)아크릴오일]벤조인산 242mg과 D(-)-7-(

-아미노페닐아세트아미도)세팔로스포라닌산 406mg을 사용하는 것을 제외하고는 실시예 5과 같은 진행을 하여 535mg(수율 : 82%)의 D(-)-7-[

-[P-[

-(2-푸릴)아크릴오일]벤즈아미도]페닐아세트아미도]세팔로스포라닌산 소디움염의 백색분말을 얻는다.P- [

-(2-furyl) acryloyl] benzoic acid 242 mg and D (-)-7- (

535 mg (yield: 82%) of D (-)-7- [except that 406 mg of aminophenylacetamido) cephalosporanic acid was used.

-[P- [

White powder of-(2-furyl) acrylic oil] benzamido] phenylacetamido] cephalosporanic acid sodium salt is obtained.

6.68(1H, dd, 방향족양성자), 7.12(1H, d, 방향족양성자),7.3-8.1(12H, m's, 방향족과 올레핀양성자), 9.2(2H, d's, NH's).NMR (DMSO-d ₆ ) δ: 1.98 (3H, s, COCH ₃ ), 3.26 (2H, q, C ₂ -CH ₂ ), 4.88 (2H, q, C ′ ₃ -CH ₂ ), 4.92 (1H, d, C ₆ -CH), 5.56 (1H, dd, C ₇ -CH), 5.92 (1H, d,

6.68 (1H, dd, aromatic protons), 7.12 (1H, d, aromatic protons), 7.3-8.1 (12H, m's, aromatic and olefin protons), 9.2 (2H, d's, NH's).

Example 41

-[P-[

-(2-티엘)아크릴오일]벤즈아미도)페닐아세트아미도] 세팔로스포라닌 산소디움염 :D (-)-7- [

-[P- [

-(2-Tiel) acrylic oil] benzamido) phenylacetamido] cephalosporanine oxygenium salt:

-(2-티에닐)아크릴오일]벤조인산 258mg과 D(-)-7-(

-아미노페닐아세트아미도)세팔로스포라닌산 406mg을 사용하는 것을 제외하고는 실시예 5과 같은 진행을 하여 534mg(수율 : 80%)의 D(-)-7-[

-[P-[

-(2-티에닐)아크릴오일]벤즈아미도]페닐아세트아미도]세팔로스포라닌산 소디움염의 연황색 분말을 얻는다.P- [

258 mg of-(2-thienyl) acryloyl] benzoic acid and D (-)-7- (

534 mg (yield: 80%) of D (-)-7- [was obtained in the same manner as in Example 5 except that 406 mg of aminophenylacetamido) cephalosporanic acid was used.

-[P- [

A light yellow powder of-(2-thienyl) acrylic oil] benzamido] phenylacetamido] cephalosporanic acid sodium salt is obtained.

7.2-8.2(14H, m's, 방향족과 올레핀양성자), 9.2(2H, d's, NH's).NMR (DMSO-d ₆ ) δ: 1.98 (3H, s, COCH ₃ ), 3.26 (2H, q, C ₂ -CH ₂ ), 4.86 (H, q, C ′ ₃ -CH ₂ ), 4.92 (1H, d, C ₆ -CH), 5.56 (1H, dd, C ₇ -CH), 5.92 (1H, d,

7.2-8.2 (14H, m's, aromatic and olefin protons), 9.2 (2H, d's, NH's).

Example 42

-[P-[3-(2-티에닐)프로파-1-엔네-3-온일]벤즈아미도)페닐아세트아미도] 세팔로스포라닌산 :D (-)-7- [

-[P- [3- (2-thienyl) propa-1-enene-3-onyl] benzamido) phenylacetamido] cephalosporanoic acid:

-아미노페닐아세트아미도) 세팔로스포라닌산 406mg을 사용하는 것을 제외하고는 실시예 33과 같은 진행을 하여 255mg(수율 : 39%)의 D(-)-7-[

-[P-3-(2-티에닐)프로파-1-엔네-3-온일]벤즈아미도]페닐아세트아미도 세팔로스포라닌산의 흰색 분말을 얻는다.258 mg of P- [3- (2-thienyl) propa-1-ene-3-onyl benzoic acid and D (-)-7- (

Aminophenylacetamido) 255 mg (yield: 39%) of D (-)-7- [was proceeded in the same manner as in Example 33 except that 406 mg of cephalosporanic acid was used.

White powder of [P-3- (2-thienyl) propa-1-ene-3-onyl] benzamido] phenylacetamido cephalosporanic acid is obtained.

7.3-8.1(13H, m's, 방향족과 올레핀 양성자), 8.40(1H, d, 방향족 양성자), 9.02(1H, d, NH), 9.30(1H,d, NH).NMR (DMSO-d ₆ ) δ: 2.02 (3H, s, COCH ₃ ), 3.48 (2H, broad S, C ₂ -CH ₂ ), 4.82 (2H, q, C ′ ₃ -CH ₂ ), 5.06 (1H , d, C ₆ -CH), 5.8 (2H, m's, C ₇ -CH and

7.3-8.1 (13H, m's, aromatic and olefin protons), 8.40 (1H, d, aromatic protons), 9.02 (1H, d, NH), 9.30 (1H, d, NH).

Example 43

-(6-스티릴니코틴아미도)페닐 아세트아미도]세팔로스포라닌산 :D (-)-7- [

-(6-styrylnicotinamido) phenyl acetamido] cephalosporanic acid:

-아미노페닐아세트아미도 세팔로스포라닌산 : 406mg을 사용하는 것을 제외하고는 실시예 33과 같은 진행을 하여 248mg(수율 : 40%)의 D(-)-7-[

-스티릴니코틴아미도)페닐 아세트아미도]세팔로스포라닌산의 연 황색분말을 얻는다.225 mg of 6-styrylnicotinic acid and D (-)-7- (

-Aminophenylacetamido cephalosporanic acid: 248 mg (yield: 40%) of D (-)-7- [except that 406 mg was used.

Styryl nicotin amido) phenyl acetamido] light yellow powder of cephalosporanic acid.

7.3-7.9(13H, m's, 방향족과 올레핀 양성자), 8.34(1H, dd, 방향족 양성자), 9.12(1H, d, 방향족 양성자), 9.16(1H, d, NH), 9.38(1H,d, NH).NMR (DMSO-d ₆ ) δ: 2.00 (3H, S, COCH ₃ ), 3.46 (2H, broad S, C ₂ -CH ₂ ), 4.84 (2H, q, C ′ ₃ -CH ₂ ), 5.08 (1H , d, C ₆ -CH), 5.80 (1H, dd, C ₇ -CH), 5.92 (1H, d,

7.3-7.9 (13H, m's, aromatic and olefin protons), 8.34 (1H, dd, aromatic protons), 9.12 (1H, d, aromatic protons), 9.16 (1H, d, NH), 9.38 (1H, d, NH ).

Example 44

-(2'-하이드록시찰콘-4-카복스아미도)페닐아세트아미도]세팔로스포라닌산소디움염 :D (-)-7- [

-(2'-hydroxychalcon-4-carboxamido) phenylacetamido] cephalosporanic acid sodium salt:

-아미노페닐 아세트아미도)세팔로스포라닌산 406mg을 사용하는 것을 제외하고는 실시예 35와 같은 진행을 하여 473mg(수율 : 70%)의 D(-)-7-[

-(2'-하이드록시찰콘-4-카복스아미도)페닐아세트아미도]세팔로스포라닌산 소디움염의 연 황색 분말을 얻는다.268 mg of 2'-hydroxychalcon-4-carboxylic acid and D (-)-7- (

473 mg (yield: 70%) of D (-)-7- [except that 406 mg of aminophenyl acetamido) cephalosporanic acid was used.

A pale yellow powder of-(2'-hydroxychalcon-4-carboxamido) phenylacetamido] cephalosporanic acid sodium salt is obtained.

6.9-8.2(15H, m's, 방향족과 올레핀 양성자), 9.10(1H, d, NH), 9.30(1H,d, NH).NMR (DMSO-d ₆ ) δ: 1.98 (3H, S, COCH ₃ ), 3.26 (2H, q, C ₂ -CH ₂ ), 4.9 (3H, m's, C ' ₃ -CH ₂ and C ₆ -CH) , 5.6 (1H, m, C ₇ -CH), 5.94 (1H, d,

6.9-8.2 (15H, m's, aromatic and olefin protons), 9.10 (1H, d, NH), 9.30 (1H, d, NH).

Example 45

-[P-(2-티엔-2-일에테닐)벤즈아미도]페닐 아세트 아미도]세팔로스포라닌산 소디움 염 :D (-)-7- [

-[P- (2-thien-2-ylethynyl) benzamido] phenyl acetamido] cephalosporanic acid sodium salt:

-아미노페닐 아세트아미도) 세팔로스포라닌산 406mg을 사용하는 것을 제외하고는 실시예 35와 같은 진행을 하여 304mg(수율 : 48%)의 D(-)-7-[

-[P-(2-티엔-2-일에테닐)벤즈아미도]페닐 아세트 아미도] 세팔로스포라닌산 소디움염의 백색 분말을 얻는다.230 mg of P- (2-thien-2-ylethynyl) -benzoic acid and D (-)-7- (

Aminophenyl acetamido) The same procedure as in Example 35 was conducted except that 406 mg of cephalosporanic acid was used, and 304 mg (yield: 48%) of D (-)-7- [

A white powder of [P- (2-thien-2-ylethynyl) benzamido] phenyl acet amido] cephalosporanic acid sodium salt is obtained.

6.9-8.0(14H, m's, 방향족과 올레핀 양성자), 8.9(1H, d, NH), 9.3(1H,d, NH).NMR (DMSO-d ₆ ) δ: 1.98 (3H, s, COCH ₃ ), 3.26 (2H, q, C ₂ -CH ₂ ), 4.86 (2H, q, C ′ ₃ -CH ₂ ), 4.90 (1H, d, C ₆ -CH), 5.6 (2H, m, C ₇ -CH), 5.88 (1H, d,

6.9-8.0 (14H, m's, aromatic and olefin protons), 8.9 (1H, d, NH), 9.3 (1H, d, NH).

Example 46

-[6-(2-티엔-2-일에테닐)니코틴아미도]페닐 아세트아미도]세팔로스포라닌산 :D (-)-7- [

-[6- (2-thien-2-ylethynyl) nicotinamido] phenyl acetamido] cephalosporanic acid:

-아미노세팔로스포라닌산 406mg을 사용하는 것을 제외하고는 실시예 33과 같은 진행을 하여 252mg(수율 : 41%)의 D(-)-7-[

-[6-(2-티엔-2-일에테닐)니코틴아미도]페닐아세트아미도]세팔로스포라닌산의 황색 분말을 얻는다.231 mg of 6- (2-thien-2-ylethynyl) nicotinic acid and D (-)-7- (

-252 mg (yield: 41%) of D (-)-7- [except that 406 mg of aminocephalosporanic acid was used.

A yellow powder of-[6- (2-thien-2-ylethynyl) nicotinamido] phenylacetamido] cephalosporanic acid is obtained.

7.0-7.6(10H, m's, 방향족과 올레핀 양성자), 7.94(1H, d, 올레핀 양성자), 8.24(1H, dd, 방향족 양성자), 9.00(1H, d, 방향족 양성자), 9.06(1H,d, NH), 9.30(1H, d, NH).NMR (DMSO-d ₆ ) δ: 2.00 (3H, s, COCH ₃ ), 3.46 (2H, broad, C ₂ -CH ₂ ), 4.80 (2H, q, C ′ ₃ -CH ₂ ), 5.04 (1H, d, C ₆ -CH), 5.74 (1H, dd, C ₇ -CH), 5.86 (1H, d,

7.0-7.6 (10H, m's, aromatic and olefin protons), 7.94 (1H, d, olefin protons), 8.24 (1H, dd, aromatic protons), 9.00 (1H, d, aromatic protons), 9.06 (1H, d, NH), 9.30 (1H, d, NH).

Example 47

D (-)-7- [α- [P- (4-phenylbuta-1, 3-dienyl) benzamido] phenyl acetamido] cephalosporanoic acid:

-아미노페닐아세트아미도) 세팔로스포라닌산 203mg을 사용하는 것을 제외하고는 실시예 33과 같은 진행을 하여 135mg(수율 42%)의 D(-)-7-[α-[P-(4-페닐부타-1, 3-디에닐)벤즈아미도]페닐 아세트아미도] 세팔로스포라닌산의 연황색 분말을 얻는다.125 mg of D- (4-phenylbuta-1,3-dienyl) benzoic acid and D (-)-7- (

Aminophenylacetamido) 135 mg (42% yield) of D (-)-7- [α- [P- (4 -Phenylbuta-1,3-dienyl) benzamido] phenyl acetamido] light yellow powder of cephalosporanic acid.

6.7-8.0(18H, m's, 방향족과 올레핀 양성자), 8.82(1H,d, NH), 9.28(1H, d, NH).NMR (DMSO-d ₆ ) δ: 2.02 (3H, s, COCH ₃ ), 3.46 (2H, q, C ₂ -CH ₂ ), 4.82 (2H, q, C ′ ₃ -CH ₂ ), 5.06 (1H, d, C ₆ -CH), 5.76 (1H, dd, C ₇ -CH), 5.88 (1H, d,

6.7-8.0 (18H, m's, aromatic and olefin protons), 8.82 (1H, d, NH), 9.28 (1H, d, NH).

Example 48

D (-)-7- [α- [6- (4-phenylbuta-1,3-dienyl) nicotinamido] phenylacetamido] cephalosporanic acid:

-아미노페닐아세트아미도) 세팔로스포라닌산 203mg을 사용하는 것을 제외하고는 320mg(수율 : 100%)의 D(-)-7-[α-[6-(4-페닐부타-1, 3-디에닐)니코틴아미도]페닐아세트아미도]세팔로스포라닌산의 황색 분말을 얻는다.126 mg of 6- (4-phenylbuta-1,3-dienyl) nicotinic acid and D (-)-7- (

Aminophenylacetamido) 320 mg (yield: 100%) of D (-)-7- [α- [6- (4-phenylbuta-1,3) except that 203 mg of cephalosporanoic acid was used -Yellow powder of dienyl) nicotinamido] phenylacetamido] cephalosporanic acid is obtained.

6.8-7.7(15H, m's, 방향족과 올레핀 양성자), 8.22(1H, dd, 방향족 양성자), 9.00(1H, d, 방향족 양성자), 9.06(1H,d, NH), 9.30(1H, d, NH).NMR (DMSO-d ₆ ) δ: 2.00 (3H, s, COCH ₃ ), 3.44 (2H, broad, C ₂ -CH ₂ ), 4.88 (2H, q, C ′ ₃ -CH ₂ ), 5.04 (1H, d, C ₆ -CH), 5.74 (1H, dd, C ₇ -CH), 5.86 (1H, d,

6.8-7.7 (15H, m's, aromatic and olefin protons), 8.22 (1H, dd, aromatic protons), 9.00 (1H, d, aromatic protons), 9.06 (1H, d, NH), 9.30 (1H, d, NH ).

Example 49

-(찰콘-4-카복스아미도)페닐아세트아미도]-3-디아세톡시 세팔로스포라닌산 포타슘염 :D (-)-7- [

-(Chalcon-4-carboxamido) phenylacetamido] -3-diacetoxy cephalosporanic acid potassium salt:

-아미노페닐 아세트아미도)-3-디아세톡시 세팔로스포라닌산 348mg과 2-에틸-헥사노익산 포타슘 염 200mg을 사용하는 것을 제외하고는 실시예 5와 같은 진행을 하여 207mg(수율 : 33%)의 D(-)-7-[

-(찰콘-4-카복스아미도)페닐아세트아미도]-3-디아세톡시 세팔로스포라닌산 포타슘염의 백색분말을 얻는다.252 mg of chalcone-4-carboxylic acid and D (-)-7- (

207 mg (Yield: 33) was carried out in the same manner as in Example 5, except that 348 mg of aminophenyl acetamido) -3-diacetoxy cephalosporanic acid and 200 mg of 2-ethyl-hexanoic acid potassium salt were used. %) Of D (-)-7- [

White powder of (chalcon-4-carboxamido) phenylacetamido] -3-diacetoxy cephalosporanic acid potassium salt was obtained.

7.2-8.2(6H, m's, 방향족과 올레핀 양성자), 9.0-9.4(2H, m's, NH's).NMR (DMSO-d ₆ ) δ: 1.88 (3H, s, C ′ ₃ -CH ₃ ), 3.14 (2H, q, C ₂ -CH ₂ ), 4.84 (1H, d, C ′ ₆ -CH), 5.48 (1 H, dd, C ₇ -CH), 5.92 (1 H, d,

7.2-8.2 (6H, m's, aromatic and olefin protons), 9.0-9.4 (2H, m's, NH's).

Example 50

-(찰콘-4'-카복스아미도)페닐아세트아미도]-3-디아세톡시-세팔로스포라닌산 소디움염 :D (-)-7- [

-(Chalcon-4'-carboxamido) phenylacetamido] -3-diacetoxy-cephalosporanic acid sodium salt:

-아미노페닐 아세트아미도)-3-디아세톡시-세팔로르스포라닌산 일수화물 366mg을 사용하는 것을 제외하고는 실시예 5와 같은 진행을 하여 485mg(수율 : 80%)의 D(-)-7-[

-(찰콘-4'-카복스아미도)페닐아세트아미도]-3-디아세톡시-세팔로스포라닌산 소디움염의 연황색분말을 얻는다.252 mg of chalcone-4'-carboxylic acid and D (-)-7- (

485 mg (yield: 80%) of D (-) was proceeded in the same manner as in Example 5 except that 366 mg of aminophenyl acetamido) -3-diacetoxy-cephalosporanic acid monohydrate was used. -7- [

-(Chalcon-4'-carboxamido) phenylacetamido] -3-diacetoxy-cephalosporanic acid sodium salt of light yellow powder is obtained.

7.2-8.2(16H, m's, 9.1(2H, m's, NH'S).NMR (DMSO-d ₆ ) δ: 1.92 (3H, s, C ′ ₃ -CH ₃ ), 3.16 (2H, q, C ₂ -CH ₂ ), 4.82 (1H, d, C ₆ -CH), 5.44 ( 1H, dd, C ₇ -CH), 5.90 (1H, d,

7.2-8.2 (16H, m's, 9.1 (2H, m's, NH'S).

Example 51

-(4-스티릴벤즈아미도)페닐아세트아미도]-3-디아세톡시-세팔로스포라닌산 :D (-)-7- [

-(4-styrylbenzamido) phenylacetamido] -3-diacetoxy-cephalosporanic acid:

-아미노페닐아세트아미도)-3-디아세톡시-세팔로스포라닌산 일수화물 366mg을 사용하는 것을 제외하고는 실시예 33과 같은 진행을 하여 324mg(수율 : 58%)의 D(-)-7-[

-(4-스티릴벤즈아미도)-3-디아세톡시-세팔로스포라닌산의 백색분말을 얻는다.224 mg of 4-styrylbenzoic acid and D (-)-7- (

324 mg (yield: 58%) of D (-)-was proceeded as in Example 33, except that 366 mg of aminophenylacetamido) -3-diacetoxy-cephalosporanic acid monohydrate was used. 7- [

White powder of-(4-styrylbenzamido) -3-diacetoxy-cephalosporanic acid is obtained.

7.3-8.0(16H, m's, 방향족과 올레핀 양성자), 8.84(1H, d, NH), 9.26(1H, d, NH).NMR (DMSO-d ₆ ) δ: 1.98 (3H, s, C ′ ₃ -CH ₃ ), 3.36 (2H, q, C ₂ -CH ₂ ), 5.00 (1H, d, C ₆ -CH), 5.68 ( 1 H, dd, C ₇ -CH), 5.92 (1 H, d,

7.3-8.0 (16H, m's, aromatic and olefin protons), 8.84 (1H, d, NH), 9.26 (1H, d, NH).

Example 52

-(4'-메톡시찰콘-4-카복스아미도) 페닐아세트아미도]-3-디아세톡시-세팔로스포라닌산 소디움염 : 4'-메톡시찰콘-4-카복실산 292mg과 D(-)-7-(

-아미노페닐아세트아미도)-3-디아세톡시-세팔로스포라닌산 일수화물 366mg을 사용하는 것을 제외하고는 실시예 5와 같은 진행을 하여 424mg(수율 : 67%)의 D(-)-7-[

-(4'-메톡시찰콘-4-카복스아미도) 페닐아세트아미도]-3-디아세톡시-세팔로스포라닌산 소디움염의 백색분말을 얻는다.D (-)-7- [

-(4'-methoxychalcon-4-carboxamido) phenylacetamido] -3-diacetoxy-cephalosporanic acid sodium salt: 292 mg of 4'-methoxychalcon-4-carboxylic acid and D ( -)-7- (

424 mg (yield: 67%) of D (-)-in the same manner as in Example 5, except that 366 mg of aminophenylacetamido) -3-diacetoxy-cephalosporinic acid monohydrate was used. 7- [

A white powder of-(4'-methoxychalcon-4-carboxamido) phenylacetamido] -3-diacetoxy-cephalosporanic acid sodium salt is obtained.

7.0-8.1(15H, m's, 방향족과 올레핀 양성자), 8.96(1H, d, NH), 9.16(1H, d, NH).NMR (DMSO-d ₆ ) δ: 1.90 (3H, s, C ′ ₃ -CH ₃ ), 3.16 (2H, q, C ₂ -CH ₂ ), 3.86 (3H, s, OCH ₃ ), 4.84 (1H, d, C ′ ₆ -CH), 5.46 (1H, dd, C ₇ -CH), 5.92 (1H, d,

7.0-8.1 (15H, m's, aromatic and olefin protons), 8.96 (1H, d, NH), 9.16 (1H, d, NH).

Example 53

-(2-클로로찰콘-4'-카복스아미도)페닐 아세트아미도]-3-디아세톡시-세팔로스포라닌산 :D (-)-7- [

-(2-Chlorochalcon-4'-carboxamido) phenyl acetamido] -3-diacetoxy-cephalosporanoic acid:

-아미노페닐 아세트아미도)세팔로스포라닌산 일수화물 366mg을 사용하는 것을 제외하고는 실시예 33과 같은 진행을 하여 453mg(수율 : 74%)의 D(-)-7-[

-(2-클로로찰콘-4'-카복스아미도)페닐 아세트아미도]-3-디아세톡시-세팔로스포라닌산의 백색분말을 얻는다.286.5 mg of 2-chlorochalcon-4'-carboxylic acid and D (-)-7- (

453 mg (yield: 74%) of D (-)-7- [was proceeded in the same manner as in Example 33 except that 366 mg of aminophenyl acetamido) cephalosporanic acid monohydrate was used.

A white powder of-(2-chlorochalcon-4'-carboxamido) phenyl acetamido] -3-diacetoxy-cephalosporanoic acid is obtained.

7.3-7.6(8H, m's, 방향족과 올레핀 양성자), 8.0-8.3(7H, m's, 방향족과 올레핀 양성자), 9.08(1H, d, NH), 9.16(1H, d, NH).NMR (DMSO-d ₆ ) δ: 1.98 (3H, s, C ′ ₃ -CH ₃ ), 3.36 (2H, q, C ₂ -CH ₂ ), 4.98 (1H, d, C ' ₆ -CH), 5.66 (1 H, dd, C ₇ -CH), 5.92 (1 H, d,

7.3-7.6 (8H, m's, aromatic and olefin protons), 8.0-8.3 (7H, m's, aromatic and olefin protons), 9.08 (1H, d, NH), 9.16 (1H, d, NH).

Example 54

-(4-클로로찰콘-4'-카복스아미도)페닐 아세트아미도]-3-디아세톡시-세팔로스포라닌산 :D (-)-7- [

-(4-chlorochalcon-4'-carboxamido) phenyl acetamido] -3-diacetoxy-cephalosporanoic acid:

-아미노페닐 아세트아미도)세팔로스포라닌산 일수화물 366mg을 사용하는 것을 제외하고는 실시예 33과 같은 진행을 하여 235mg(수율 : 38%)의 D(-)-7-[

-(4-클로로찰콘-4'-카복스아미도)페닐 아세트아미도]-3-디아세톡시-세팔로스포라닌산의 연황색 분말을 얻는다.286.5 mg of 4-chlorochalcon-4'-carboxylic acid and D (-)-7- (

235 mg (yield: 38%) of D (-)-7- [except that 366 mg of aminophenyl acetamido) cephalosporanic acid monohydrate was used.

A light yellow powder of-(4-chlorochalcon-4'-carboxamido) phenyl acetamido] -3-diacetoxy-cephalosporanoic acid is obtained.

7.2-8.2(15H, m's, 방향족과 올레핀 양성자), 9.08(1H, d, NH), 9.16(1H, d, NH).NMR (DMSO-d ₆ ) δ: 2.00 (3H, s, C ′ ₃ -CH ₃ ), 3.36 (2H, q, C ₂ -CH ₂ ), 4.98 (1H, d, C ₆ -CH), 5.66 ( 1 H, dd, C ₇ -CH), 5.96 (1 H, d,

7.2-8.2 (15H, m's, aromatic and olefin protons), 9.08 (1H, d, NH), 9.16 (1H, d, NH).

Claims (1)

A method for preparing novel penicillin and cephalosporin derivatives represented by the general formula (I) below by reacting a compound represented by the general formula (VII) below or a salt thereof with a carboxylic acid or a derivative thereof represented by the general formula (VII) below .

In the above formula, Ar is a phenyl group or a heterocycle group which may be substituted with a halogen atom, a hydroxyl group or a lower alkoxy group, R is a hydrogen atom or a hydroxyl group, X is CH or N,

Is

ℓ and n are 0 or 1 and m is 1 or 2.