KR930007812B1 - Process for preparing alkenyl cephalosporin - Google Patents

Abstract

Alkenyl cephalosporin derivs. of formula (I) and their pharmaceutical salts are new. 3-cephem compds. were obtained by witting reaction from a phosphonium cpd. of formula (II) with an aldehyde cpd. of formula (III) and then were deacylated to produce 7- amino-3-cephem derivs. The formula (I) derivs. are prepd. by acylation of 7-amino-3-cephem derivs with 2- aminothiazolyl-2-hydroxyimino- acetic acid compds. In (I), R1=H or a protecting gp. as in cephalosporin and penicillin cpds.; R2=H, C1-4 alkyl or substd. alkyl; R3=H or a deriv. of a carboxy gp., an atom for prepn. of a salt or carboxy protecting gp.

Description

Alkenyl cephalosporins and preparation methods thereof

The present invention relates to novel cephalosporins and pharmaceutically acceptable salts represented by the general formula (I) and methods for their preparation. These compounds exhibit a wide range of antibacterial properties and can be useful for cephalosporin-based medicines.

Wherein R ₁ is hydrogen or a protecting group commonly used in penicillin or cephalosporin compounds, for example trityl, tert-butoxycarbonyl (t-BOC), benzyl, chloroacetyl, trichloroacetyl, benzyl Oxycarbonyl, para-methoxybenzyloxycarbonyl, formyl, and trioleacetyl, R ₂ is hydrogen, an alkyl group having 1 to 4 carbon atoms, or a substituted alkyl group, for example alkoxycarbonylmethyl, carboxy Methyl, 1-carboxyethyl, 1-carboxy-1-methylethyl, a cycloalkyl group having 3 to 7 carbon atoms, and R ₃ is a derivative of hydrogen or a carboxy group, which is mainly a group forming an ester or useful as an atom or a carboxy protecting group forming a salt. Qi. The carboxyprotecting groups herein are those which can be introduced or removed without particularly adversely affecting other parts of the molecule in the field of penicillin or cephalosporin compounds. Salts include inorganic salts and organic salts. Typical inorganic salts include sodium and potassium salts, and organic salts include alkylamines (lower alkylamines such as ethylamine, diethylamine, and triethylamine). Salts, salts of tetracyclic amines (salts such as aniline, dimethylaniline) and salts of aromatic bases (salts of picoline, lutidine, quinoline). Moreover, as a protecting group of a carboxy group, the alkyl ester containing the case where C1-C8 is substituted (for example, methyl, methoxymethyl, ethyl, methoxyethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hexyl Esters) or esters of phenyl, indanyl, benzyl, cyanobenzyl, halobenzyl, methylbenzyl, nitrobenzyl, para-methoxybenzyl, phenylbenzyl.

Carboxylic derivatives useful as pharmaceuticals are metal salts or pharmaceutically useful esters, which are used as oral or injectables, and have an antibiotic effect. Specifically, alkyl esters having 1 to 3 carbon atoms are substituted. Alkanoyloxyalkyl esters (more specifically acetoxymethyl, acetoxyethyl, propionyloxyethyl, pivaloyloxymethyl, pivaloyloxyethyl, tetrahydrofuryl, tetrahydropyranyl ester) Alkoxyformyloxyalkyl esters (e.g., ethoxycarbonyloxyethyl esters, etc.) of 8 to 8, substituted alkalkyl esters of 7 to 15 carbon atoms (e.g., phenacyl, phthalidyl esters), and substitutions of 6 to 12 carbon atoms Aryl esters (eg phenyl, xylyl, indanyl ester), and 2-alkenyl esters (eg allyl, 2-oxo-1, 3-dioxol-4-ylmethyl Scotland are Termini). R <_4> , R <_5> is a protecting group or acyl group of hydrogen or phenolic hydroxyl group, and R <_4> , R <_5> may be same or different from each other. Examples are acetyl, para-methoxybenzyl, benzyl, methylene and the like.

In the general formula (I), two isomers of cis and trans may exist according to the three-dimensional structure of the double bond in the ethenyl group of the cephalosporin derivative. All isomers are included within the scope of the present invention.

Looking at the manufacturing process of the present invention as follows.

In the method for preparing alkenyl cephalosporin of the present invention, the 3-cefe derivative (R) of Formula (IV) is reacted by Wittig reaction between a phosphonium salt of Formula (II) and an aldehyde compound of Formula (III). ₃ = protecting group). In this Wittich reaction, an organic solvent and water may be used as a solvent, or a solvent mixed with an organic solvent and water may be used. In this case, various organic solvents may be used, but dichloromethane, chloroform, carbon tetrachloride, ethyl ether, and tetrahydrofuran may be used. Etc., and these solvents may be used alone or mixed with water. In the case of mixed solvents, the ratio with water may be from 1: 10 to 10: 1 (organic solvent: water), but 2: 1 A ratio of about 4: 1 is appropriate. Many bases can be used, but for example, lower alkylamines such as triethylamine, diisopropylethylamine and dibi oil (DBU (1,8-Diazabicyclo [5,4,0] undec-7-ene)] , Organic bases such as morpholine, lithium carbonate (Li ₂ CO ₃ ), sodium carbonate (Na ₂ CO ₃ ), potassium carbonate (K ₂ CO ₃ ), cesium carbonate (Cs ₂ CO ₃ ), sodium hydroxide (NaOH), hydroxide Bases such as potassium (KOH) or strong bases NaOMe, NaOEt, KOt-Bu, nBuLi, Lithium diisopropylamide (LDA), NaH, KH are all possible In the present invention sodium carbonate (Na ₂ CO ₃ ) and carbonic acid Potassium (K ₂ CO ₃ ) is the most efficient, the temperature can be from 0 ℃ to 100 ℃, 0 ℃ ~ 30 ℃ is most suitable.

The following reaction conditions are required to obtain general formula (V), which is a 7-aminocefem compound, by grinding an amido bond from the general formula (IV) compound. First, in order to obtain imido chloride, phosphorus pentachloride (PCl ₅ ) and pyridine are reacted with the general formula (IV) compound, which is an amide compound, at a reaction temperature of -20 to 50 ° C for a reaction time of 1 to 5 hours. In this case, although a conventional solvent is used, it is preferable to use a halohydrogenated carbon solvent such as methylene chloride and chloroform.

Treatment of the obtained iminochloride compound with an alcohol such as methanol, ethanol, propanol or butanol yields a 7-amino-3-cepem compound of formula (V) through acid hydrolysis. The reaction time in this process is about 10 to 90 minutes, and the reaction temperature is preferably -60 to 20 ° C. As shown in (c), the alkylation reaction of the compound of formula (V) and the acid compound of formula (VI) produces an alkenyl cephalosporin of the present invention of formula (I). When the compounds of formula (VI) are activated in the acylation reaction and reacted, the usable reaction solvents are water, acetone, dioxane, acetonitrile, chloroform, dichloromethane, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine and the like are useful and react in the presence of an organic base or an inorganic base.

Examples of bases that can be used are alkali metal hydroxides, alkali metal acetates, tri- (lower) alkylamines, pyridine, N-lower alkylmorpholines, N, N-di- (lower) alkylbenzylamines, N, N- And di- (lower) -acylaniline. The reaction temperature is generally about -20 ° C to 30 ° C.

Here, activation of the carboxylic acid of general formula (VI) may include activation processes that are typically used for the synthesis of cephalosporins. Examples of the activated derivatives include acid anhydrides such as symmetrical or mixed anhydrides. At this time, the compounds forming the carboxylic acid and acid anhydride of formula (VI) are inorganic acids (e.g. phosphoric acid, sulfuric acid, halogen acid, carbonyl half acid, etc.), organic acids (e.g., alkanoic acid, araalkanoic acid, Sulfonic acids), intramolecular acid anhydrides (e.g., anhydrides with ketene, isocyanates, etc.), acid halides, reactive alkenyl esters (e.g. vinyl esters, isopropenyl esters), aryl esters (e.g. Diester, benzotriazolyl ester), ester with N-hydroxy compound, diacylhydroxyamine ester (e.g., N-hydroxysuccinimide ester, N-hydroxyphthalimide ester), thioester ( For example aralkylthiol esters, heterools with heterocycles, or reactive amides (e.g., amides with imidazole, triazole, 2-ethoxy-1, 2-dihydroquinoline, dia It may be the anilide).

In addition, in the acylation reaction, acylation reaction can be directly induced by using a binding aid in an organic acid or salt state. For example N, N-dicyclohexylcarbodiimide, N-cyclohexyl-N-morpholino-ethylcarbodiimide, N-cyclohexyl-N- (4-diethylaminocyclohexyl) carbodiimide, N , N'-carbonylbis (2-methylimidazole), pentamethyleneketene-N-cyclohexylamine, ethoxyacetylene, ethylpolyphosphate, phosphorous trichloride, phosphorus oxcyclolide, thionyl chloride, Oxalyl chloride and the method by a triphenyl phosphine are mentioned. Finally by the general formula (I) cephalosporins of the carboxyl group is reacted of the compound in the base or the acid present R ₃ represents the formula (I) is a hydrogen atom, if you want to remove the protective group from the protected compound group R ₃ of the Compounds can be prepared. At this time, a suitable acid is Lewis acid such as acetic acid, formic acid, trifluoroacetic acid or aluminum chloride, and the addition amount is preferably 1 to 1000 times the acid equivalent to the cephalosporin compound of general formula (I). 5 to 100 times is good.

In addition, when looking at the structure of the groups linked to the imine group in the substituent at position 7 of the cephalosporin of the general formula (I), there can be two types of isomers of syn and anti in three dimensions. In consideration of syn isomers, syn isomers are effective from the standpoint of their utility value, since syn isomers show much higher antimicrobial activity than anti isomers. In addition, the 2-aminotazole structure may exist in a tautomer form and thus have a structure of 2-iminothiazolinyl.

Examples of the representative compounds having the structure of formula (I) obtained in the present invention are as follows.

A: para-methoxybenzyl (6R, 7R) -phenylacetamido-3- [2- {3- (3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cefem -4-carboxylate

B: para-methoxybenzyl (6R, 7R) -amino-3- [2- {3- (3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cef-4- Carboxylate

C: (6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamide} -3- [2- {3- (3 , 4-dihydroxyphenyl) isoxazol-5-yl} vinyl] -3-cefe-4-carboxylic acid and its sodium salt

D: (6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2- (carboxymethoxyimino} -acetamido-3- [2- {3- (3,4-dihydroxyphenyl) isoxazol-5-yl} vinyl] -3-cefe-4-carboxylic acid and its sodium salt

E: (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-{(1S) -1-carboxyethoxyimino}]-acetamido-3 -[2- {3- (3,4-dihydroxyphenyl) isoxazol-5-yl} vinyl] -3-cepem-4-carboxylic acid and its sodium salt

F: (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methoxyethoxyamino)} acetamido- 3- [2- {3- (3,4-dihydroxyphenyl) isoxazol-5-yl} vinyl] -3-cepem-4-carboxylic acid and its sodium salt

G: (6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino} acetamido-3- [2- {3- (3 , 4-dihydroxyphenyl) isoxazol-5-yl} vinyl] -3-cefe-4-carboxylic acid and its sodium salt

The following examples illustrate the invention in more detail but are not intended to limit the scope thereof.

Example 1

Para-methoxybenzyl (6R, 7R) -7-phenylacetamido-3- [2- {3- (3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cefem Preparation of 4-carboxylate

{(Para-methoxybenzyl 7-phenylacetamido-3-cefe-4-carboxylate) -3-yl} 17.6 g (0.021 mol) of methylphosphonium iodine was dissolved in 12 ml of methylene chloride and then 0 to 12 ml of 5% sodium bicarbonate solution was added while maintaining the temperature at 5 ° C. 5 g (0.017 mol) of 5-formyl-3- (3,4-diacetoxyphenyl) isoxazole was dissolved in 24 ml of methylene chloride and added dropwise thereto. Stir at 10 ° C. Stirring for 1.5 hours completes the reaction. This was washed three times with 20 ml of brine, the organic layer was separated, dried over anhydrous magnesium sulfate, concentrated by distillation under reduced pressure, and then separated by column chromatography using a solvent of hexane: ethyl acetate (1: 1) to give the target compound 8.2g (0.014). mol) was obtained.

Yield: 65%

¹ HNMR (CDCl ₃ , δppm): 2.2 (6H, s, -COCH ₃ ), 3.2-3.5 (2H, dd, C ₂ -H), 3.6 (2H, s, øCH _2- ), 3.7 (3H, s , CH ₃ O-), 5.0 (1H, d, C ₆ -H), 5.1 (2H, s, PMB-CH ₂ ), 5.8 (1H, q, C ₇ -H), 6.4 (1H, s, isoxazole -C ₄ -H), 6.4 (1H, d, -CNH), 6.5 (1H, d, C ₃ -C = CH-), 6.6 (1H, d, C ₃ -CH = C-), 6.8 (2H , d, PMB-), 7.3-7.6 (10H, m, Ph + PMB + catechol)

Example 2

Para-methoxybenzyl (6R, 7R) -7-amino-3- [2- {3- (3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cef-4- Preparation of Carboxylate

Phosphorus pentachloride 435 mg (2.09 mmol) was dissolved in 6 ml of methylene chloride, cooled to -40 ° C, 0.56 ml (6.96 mmol) of pyridine was added dropwise, stirred for 30 minutes while maintaining at -40 ° C, and then para-methoxybenzyl 7 -Phenylacetamido-3- {2- [3- (3,4-diacetoxyphenyl) -isoxazol-5-yl] -vinyl} -3-cepem-4-carboxylate 500 mg (0.696 mmol) ) Is dissolved in 8 ml of methylene chloride and added dropwise, the mixture is stirred at 0 to 10 ° C. for 1.5 hours, cooled to −40 ° C., and 60 ml of methanol is added at once and stirred for about 1 hour. 50 ml of methylene chloride was added thereto, washed three times with 70 ml of brine, and then the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated by distillation under reduced pressure, and then crystallized using methylene chloride and isopropyl ether (350 ml (0.585 mmol). )

Yield: 84%

Example 3

Para-methoxybenzyl (6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2-methoxyimino} acetamide-3- [2- {3- ( Preparation of 3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cefe-4-carboxylate

100.5 mg (0.5 mmol) of 2--2-aminothiazol-4-yl) -2-methoxyiminoacetic acid was dissolved in 4 ml of dimethylformamide, cooled to 0 ° C., and 95 mg (0.5 mmol) of para-toluenesulfonyl chloride. Was added and 0.038 ml (0.5 mmol) of triethylamine was added dropwise, followed by para-methoxybenzyl 7-amino-3- [2- [3- (3,4-diacetoxyphenyl) isoxazol-5-yl} Dissolve 300 mg (0.5 mmol) of vinyl] -3-cef-4-carboxylate in 3 ml of dimethylformamide, add dropwise, stir at 0 to 10 ° C for 2 hours, add 500 ml of ethyl acetate, wash 3 times with 50 ml of brine, and organic layer. The mixture was dried over anhydrous magnesium sulfate, filtered, concentrated, and separated by column chromatography using n-hexane: ethyl acetate (1: 3), followed by crystallization using methylene chloride and isopropyl ether to obtain 220 mg of the target compound. 0.28 mmol).

Yield: 56%

¹ HNMR (CDCl ₃ , δ ppm): 2.3 (6H, s, -COCH ₃ ), 3.4-3.7 (2H, C ₂ -H), 3.8 (3H, s, PMB-OCH ₃ ), 4.0 (3H, s, CH ₃ ON = C), 5.2 (2H, s, PMB-CH _2- ), 5.2 (1H, d, C ₆ -H), 6.0 (1H, q, C ₇ -H), 6.4 (1H, s, isoxazole-C ₄ -H), 6.5 (1H, d, C ₃ -C = CH-), 6.7 (1H, d, C ₃ -CH = C-), 6.8 (2H, d, PMB), 6.9 (1H , s, aminothiazole-H), 7.2-7.7 (7H, m, PMB, catechol)

Example 4

Para-methoxybenzyl (6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2- (1-t-butoxycarbonylmethoxyimino) acetamido } -3- [2- {3- (3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cefe-4-carboxylate

468 mg (1.2 mmol) of 2- (2-aminothiazol-4-yl) -2- (1-t-butoxycarbonylmethoxyimino) acetic acid was dissolved in 8 ml of dimethylformamide, cooled to 0 ° C., and then para- Toluenesulfonyl chloride 296 mg (1.2 mmol) was added, and 0.12 ml (1.2 mmol) of triethylamine was added dropwise, followed by para-methoxybenzyl 7-amino-3- [2- {3- (3,4-diacetoxy 650 mg (1.0 mmol) of phenyl) isoxazol-5-yl} vinyl] -3-cefe-4-carboxylate was dissolved in 6 ml of dimethylformamide, and added dropwise, stirred for 1 hour while maintaining at 0 to 10 DEG C, and then raised to room temperature. After stirring for 1 hour, 50 ml of ethyl acetate was added, washed three times with 50 ml of brine, and then the organic layer was separated, dried over anhydrous magnesium sulfate, filtered, concentrated and separated by column chromatography using n-hexane: ethyl acetate (1: 2). Then, crystallization was carried out using methylene chloride and isopropyl ether to obtain 380 mg (0.5 mmol) of the target compound.

Yield: 50%

¹ HNMR (CDCl ₃ , δ): 1.4 (9H, s, t-butyl), 2.3 (6H, d, -COCH ₃ ), 3.3-3.7 (2H, dd, C ₂ -H), 3.8 (3H, s , CH ₃ O-), 4.7 (2H, s, C = N-OCH _2- ), 5.2 (2H, s, PMB-CH _2- ), 5.2 (1H, d, C ₆ -H), 5.9 (1H , q, C ₇ -H), 6.4 (1H, s, isoxazoleC ₄ -H), 6.4 (1H, d, C ₃ -C = CH-), 6.7 (1H, d, C ₃ -CH = C-) , 6.8 (2H, d, PMB), 7.0 (1H, s, aminothiazole-H), 7.2-7.7 (5H, m, PMB, catechol), 8.7 (1H, d, -C-NH-)

Example 5

Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-{(1S) -1-diphenylmethoxycarbonylethoxyimino } Acetamido-3- [2- {3- (3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cefe-4-carboxylate

2- (2-aminothiazol-4-yl) -2-{(1S) -1-diphenylmethoxycarbonylethoxyimino] 551 mg (1.3 mmol) of acetic acid was dissolved in 10 ml of dimethylformamide, Add 247 mg (1.3 mmol) of para-toluene sulfonyl chloride and 0.1 ml (1.3 mmol) of triethylamine, and add para-methoxybenzyl 7-amino-3- [2- {3- (3,4-diacetoxyphenyl A solution of 650 mg (1.081 mmol) of isoxazol-5-yl} vinyl] -3-cef-4-carboxylate in 6 ml of dimethylformamide was added, stirred at 0 to 10 ° C. for 1 hour, and heated to room temperature. Stir for time. 50 ml of ethyl acetate was added, washed three times with 50 ml of brine, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated, and then separated by column chromatography using a solvent of hexane: ethyl acetate (1: 2). Chloride and isopropylene ether were used to crystallize to obtain 500 mg (0.54 mmol) of the target compound.

Yield: 50%

¹ HNMR (CDCl ₃ , δ): 1.6 (3H, d, -CH ₃ ), 2.3 (6H, d, -COCH ₃ ), 3.3-3.6 (2H, dd, C ₂ -H), 3.8 (3H, s , CH ₃ O-), 5.1 (1H, q, O-CH-), 5.2 (1H, d, C ₆ -H), 5.3 (2H, s, PMB-CH ₂ ), 6.0 (1H, q, C _7- H), 6.4 (1H, S, isoxazole-H), 6.5 (1H, d, C ₃ -C = CH-), 6.7 (1H, d, C ₃ -CH = C-), 6.8 (1H, s, DPM-CH-), 6.85 (2H, d, PMB), 6.9 (1H, s, aminothiazole-H), 7.2-7.3 (13H, DPM + PMB + catechol), 7.6 (2H, d, catechol), 8.2 (1H, d, -CNH-)

Example 6

Paramethoxybenzyl (6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2- (1-t-butoxycarbonyl-1-methylethoxyimino) } Acetamido-3- [2- {3- (3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cefe-4-carboxylate

217 mg (0.658 mmol) of 2- (2-aminothiazol-4-yl) -2- (1-t-butoxycarbonyl-1-methylethoxyimino) acetic acid was dissolved in 5 ml of dimethylformamide, 125 mg (0.656 mmol) of para-toluenesulfonyl chloride and 0.05 ml (0.65 mmol) of triethylamine were added, followed by para-methoxybenzyl 7-amino-3- [2- {3- (3,4-diacetoxy Phenyl) isoxazol-5-yl} vinyl] -3-cefe-4-carboxylate 330 mg (0.549 mmol) was added to 5 ml of dimethyl formamide, and then stirred at 0 to 10 ° C. for 1.5 hours, followed by acetic acid. 50 ml of ethyl was added, washed three times with 50 ml of brine, and then the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated. Then, the column was chromatographed using hexane: ethyl acetate (1: 2) solvent, followed by methylene chloride and Crystallization using isopropyl ether gave 200 mg (0.25 mmol) of the desired material.

Yield: 47%

¹ H-NMR (CDCl ₃ , δ): 1.4 (6H, s, C- (CH ₃ ) ₂ ), 1.6 (9H, st-butyl), 2.3 (6H, d, -COCH ₃ ), 3.3-3.7 ( 2H, dd, C ₂ -H), 3.8 (3H, s, OCH ₃ ), 5.2 (2H, s, PMB-CH ₂ ), 5.2 (1H, d, C ₆ -H), 5.7 (2H, br- s, NH ₂ ), 6.1 (1H, q, C ₇ -H), 6.4 (1H, s, isoxazole-H), 6.5 (1H, d, C ₃ -C = CH-), 6.7 (1H, d, C ₃ -CH =-), 6.8 (2H, d, PMB), 6.9 (1H, s, aminothiazole-H), 7.3 (3H, m, PMB + catechol), 7.6 (2H, d, catechol), 8.1 ( 1H, d, amide)

Example 7

Para-methoxybenzyl (6R, 7R) -7-{(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyimino} acetamido-3- [2- Preparation of {3- (3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cepem-4-carboxylate

376 mg (0.56 mmol) of 2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetic acid was suspended in 5 ml of methylene chloride, cooled to 0 ° C., and para-methoxybenzyl 7-amino 336 mg (0.56 mmol) of 3- [2- {3- (3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cef-4-carboxylate are added. Pyridini 0.34 ml (2.8 mmol) was added dropwise, stirred at 0 ° C. for 1 hour, phosphorus oxcyclolide 0.06 ml (0.6 mmol) was added dropwise at −10 ° C., and stirred at −10 ° C. for 1 hour. Remove, add ethyl acetate and wash with brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated, and then separated by column chromatography with hexane: ethyl acetate (5: 1), followed by crystallization using methylene chloride and isopropyl ether to give the desired compound 280mg (0.22mmol). )

Yield: 40%

¹ H-NMR (CDCl ₃ , δ): 2.1 (3H, s, -OCCH ₃ ), 2.3 (3H, s-COCH ₃ ), 3.2 (1H, d, C ₂ -H), 3.6 (1H, d, C ₂ -H), 3.8 (3H, s, -OCH ₃ ), 5.2 (2H, s, PMB-CH ₂ ), 5.2 (1H, d, C ₆ -H), 6.2 (1H, q, C _7- H), 6.4 (1H, s, isoxazole-H), 6.5 (1H, d, C ₃ -C = CH), 6.7 (1H, d, C ₃ -CH = C-), 6.8 (1H, s, aminothiazol -H), 6.8 (2H, d, PMB), 7.2-7.7 (35H, m, trityl + PMB + catechol)

Example 8

(6R, 7R) -7-{(Z) -2-aminothiazol-4-yl) -2-methoxyimino} acetamido-3- [2- {3- (3, 4-diacetoxy Preparation of Phenyl) isoxazol-5-yl} vinyl] -3-cepem-4-carboxylic acid

3.62 ml (47 mmol) trifluoroacetic acid and 0.76 ml (7.05 mmol) anisole were cooled to 0 ° C. and para-methoxybenzyl 7- {2- (2-aminothiazol-4-yl) -2-methoxy 370 mg (0.47 mmol) of Mino} acetamido-3- [2- {3- (3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cef-4-carboxylate After dissolving in 5 ml of methylene chloride, the mixture is stirred at room temperature for 1 hour. After removing the solvent, crystallization was performed using methanol and isopropyl ether to obtain 180 mg (0.27 mmol) of the target compound.

Yield: 57%

¹ H-NMR (DMSO, δ): 2.3 (6H, s, -COCH ₃ ), 3.5 (1H, d, C ₂ -H), 3.7 (1H, d, C ₂ -H), 3.8 (3H, s , CH ₃ O-), 5.3 (1H, d, C ₆ -H), 5.8 (1H, q, C ₇ -H), 6.6 (1H, d, C ₃ -C = CH), 6.8 (1H, s , isoxazole-H), 6.9 (1H, d, C ₃ -CH = C-), 7.0 (1H, s, aminothiazole), 7.2 (2H, s, NH ₂ ), 7.4 (1H, m, catechol), 7.8 (2H, m, catechol), 9.7 (1H, d, -CNH-)

Example 9

(6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2-carboxymethoxyimino} acetamido-3- [2- {3- (3, Preparation of 4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cefe-4-carboxylic acid

2.62 ml (34 mmol) of trifluoroacetic acid and 0.38 ml (2.55 mmol) of anisole were cooled to 0 ° C. and para-methoxybenzyl 7- {2- (2-aminothiazol-4-yl) -2- (1 -t-butoxycarbonylmethoxyimino)} acetamido-3- [2- {3- (3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cef-4 -130 mg (0.17 mmol) of carboxylate are dissolved in 3 ml of methylene chloride and added dropwise, followed by stirring at room temperature for 1 hour to complete the reaction. This was distilled under reduced pressure to remove the solvent, and crystallization with methanol and isopropyl ether gave 92 mg (0.135 mmol) of the title compound.

Yield: 80%

¹ H-NMR (D ₂ O, δ): 2.3 (6H, s-COCH ₃ ), 3.5 (1H, d, C ₂ -H), 3.7 (1H, d, C ₂ -H), 4.6 (2H, s, C = NO-CH ₂ ), 5.3 (1H, d, C ₆ -H), 5.9 (1H, q, C ₇ -H), 6.5 (1H, d, C ₃ -C = CH-), 6.7 (1H, d, C ₃ -CH = C-), 6.8 (1H, s, isoazole-H), 7.0 (1H, s, aminothiazole), 7.4 (1H, d, catechol), 7.8 (1H, s, catechol ), 7.9 (1H, d, catechol), 9.7 (1H, d, -CNH-)

Example 10

(6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2-{(1S) -1-carboxyethoxyimino} acetamido-3- [2- Preparation of {3- (3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cepem-4-carboxylic acid

5.5 ml (71.4 mmol) of trifluoroacetic acid and 0.6 ml (5.36 mmol) of anisole were cooled to 0 ° C. and para-methoxybenzyl-7- [2- (2-aminothiazol-4-yl) -2- { (1S) -1-diphenylmethoxycarbonylethoxyimino} acetamido-3- [2- {3- (3,4-diacetoxyphenyl) -isoxazol-5-yl} vinyl]- 360 mg (0.357 mmol) of 3-cefe-4-carboxylate was dissolved in 6 ml of methylene chloride, added dropwise, stirred at room temperature for 1 hour, and distilled under reduced pressure to remove the solvent, followed by vacuum drying and crystallization using methanol and isopropyl ether. 230 mg (0.318 mmol) of compound were obtained.

Yield: 89%

Example 11

(6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2-(-1-carboxy-1-methylethoxyimino)} acetamido-3- [ Preparation of 2- {3- (3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cepem-4-carboxylic acid

5.85 ml of trifluoroacetic acid and 0.63 ml (5.69 mmol) of anisole were cooled to 0 ° C. and para-methoxybenzyl 7- {2- (2-aminothiazol-4-yl) -2- (1-t- Butoxycarbonyl-1-methylethoxyimino)} acetamido-3- [2- {3- (3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cefem- 300 mg (0.379 mmol) of 4-carboxylate was dissolved in 5 ml of methylene chloride and added dropwise. After raising to room temperature, the mixture was stirred for 1 hour, distilled under reduced pressure, the solvent was removed, dried in vacuo, and crystallized using methanol and isopropyl ether. 0.271 mmol).

Yield: 72%

Example 12

(6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyimino} acetamido-3- [2- {3- (3, 4- Preparation of Diacetoxypheny) isoxazol-5-yl} vinyl] -3-cefe-4-carboxylic acid

1.47 ml (19.1 mmol) of trifluoroacetic acid and 0.3 ml (2.87 mmol) of anisole were cooled to 0 ° C. and para-methoxybenzyl 7- {2- (2-tritylaminothiazol-4-yl) -2 -Trityloxyimino} acetamido-3- [2- {3,4-diacetoxyphenyl) isoxazol-5-yl} vinyl] -3-cefe-4-carboxylate 240 mg (0.191 mmol) Was added dropwise to 3 ml of methylene chloride, stirred for about 1 hour, distilled under reduced pressure to remove the solvent, dried in vacuo, and crystallized with methanol and isopropyl ether, which was dissolved in 0.5 ml of 90% formic acid and dissolved for 1 hour at room temperature. The mixture was stirred and filtered to remove insoluble matters, and then dried in vacuo and crystallized using methanol and isopropyl ether to obtain 80 mg (0.123 mmol) of the title compound.

Yield: 64%

¹ H-NMR (DMSO, δ): 2.3 (6H, s, -COCH ₃ ), 3.4 (1H, d, C ₂ -H), 3.7 (1H, d, C ₂ -H), 5.3 (1H, d , C ₆ -H), 5.8 (1H, d, C ₇ -H), 6.6 (1H, d, C ₃ -C = CH-), 6.7 (1H, s, isoxazole-H), 6.8 (1H, d , C ₃ -CH = C-), 7.0- (1H, S, aminothiazole-H), 7.2 (2H, s, NH ₂ ), 7.4 (1H, d, catechol), 7.8 (1H, s, catechol), 7.8 (1H, d, catechol), 9.6 (1H, d, -CNH-)

Example 13

(6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2-methoxyimino} acetamido-3- [2- {3- (3, 4- Preparation of Na Salt of Dihydroxyphenyl) isoxazol-5-yl} vinyl] -3-cepem-4-carboxylic acid

7- {2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido} -3- [2- {3- (3,4-diacetoxyphenyl) isoxazole- 180 mg (0.27 mmol) of 5-yl} vinyl] -3-cef-4-carboxylic acid was dissolved in 1.5 ml of water, and then 2 ml of 7% NaHCO ₃ (pH 8) was added at 0 ° C., followed by stirring at room temperature for about 3 hours. Then separated using Sepralite ^TM C ₁₈ column chromatography (water: methanol = 7: 3), concentrated and freeze-dried to give the title compound 130mg (0.216mmol).

Yield: 80%

¹ H-NMR (D ₂ O, δ): 3.2 (1H, d, C ₂ -H), 3.6 (1H, d, C ₂ -H), 3.9 (3H, s, CH ₃ O-), 5.3 ( 1H, d, C ₆ -H), 5.8 (1H, q, C ₇ -H), 6.5 (1H, d, C ₃ -C = CH-), 6.7 (1H, d, C ₃ -CH = C- ), 6.8 (1H, s, isoazole), 7.0 (1H, s, aminothiazole), 7.1 (1H, d, catechol), 7. (1H, s, catechol)

Example 14

(6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2-carboxymethoxyimino} acetamido-3-2- {3- (3, 4- Preparation of Na Salt of Dihydroxyphenyl) -Isoxazol-5-yl} vinyl] -3-cepem-4-carboxylic Acid

7- {2- (2-aminothiazol-4-yl) -2-carboxymethoxyimino} acetamido-3- [2- {3,4-diacetoxyphenyl) isoxazol-5-yl } Vinyl] -3-cepem-4-carboxylic acid 300mg (0.443mmol) was dissolved in 2ml of water, cooled to 0 ° C, 4ml of 7% sodium bicarbonate (pH 8) was added and stirred at room temperature for 4 hours, followed by 7% Add 1 ml of sodium bicarbonate and stir for 3 hours. After separation using Sepralyte ^TM C ₁₈ column chromatography, the product was freeze-dried to obtain 230 mg (0.345 mmol) of the title compound.

Yield: 78%

¹ H-NMR (D ₂ O, δ): 3.2 (1H, d, C ₂ -H), 3.6 (1H, d, C ₂ -H), 4.6 (2H, s, -O-CH ₂ ), 5.3 (1H, d, C ₆ -H), 5.8 (1H, d, C ₇ -H), 6.5 (1H, d, C ₃ -C = Cl-), 6.6 (1H, d, isoxazole-H), 6.7 (1H, d, C ₃ -CH = C-), 6.8 (1H, d, isozazole-H), 7.0 (1H, s, aminothiazole), 7.1 (1H, d, catechol-H), 7.2 (1H, s , catechol)

Example 15

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-{(1S) -1-carboxyethoxyimino}] acetamido-3- [2 Preparation of Na Salt of-{3- (3,4-Dihydroxyphenyl) isoxazol-5-yl} vinyl] -3-cepem-4-carboxylic acid

7- [2- (2-aminothiazol-4-yl) -2-{(1S) -1-carboxyethoxyimino}]-acetamido-3- [2- {3- (3, 4- 230 mg (0.312 mmol) of diacetoxyphenyl) -isoxazol-5-yl} vinyl] -3-cef-4-carboxylic acid are suspended in 1.5 ml of water and then cooled to 0 ° C. 3 ml of 7% sodium hydrogen carbonate was added and stirred at room temperature for 4 hours. Then, 1 ml of 7% sodium hydrogen carbonate was added and stirred for 3 hours, followed by separation using Sepralyte ^TM C ₁₈ column chromatography (water: methanol = 7: 3). Lyophilization gave 190 mg of the target compound.

Yield: 89%

¹ H-NMR (D ₂ O, δ): 1.4 (3H, d, -CH ₃ ), 3.2 (1H, d, C ₂ -H), 3.6 (1H, d, C ₂ -H), 4.6 (1H , q, -CH-CH ₃ ), 5.3 (1H, d, C ₆ -H), 5.8 (1H, d, C ₇ -H), 6.5 (1H, d, C ₃ -C = CH-), 6.6 (1H, s, Isoxazole-H), 6.7 (1H, d, C ₃ -CH = C-), 6.8 (1H, d, catechol), 7.0 (1H, s, aminothiazole), 7.2 (1H, d, catechol ), 7.3 (1H, s, catechol)

Example 16

(6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2-(-1-carboxy-1-methylethoxyimino)} acetamido-3- [ Preparation of Na Salt of 2- {3- (3,4-Dihydroxyphenyl) -isoxazol-5-yl} vinyl] -3-cepem-4-carboxylic acid

7- {2- (2-aminothiazol-4-yl) -2-(-1-carboxy-1-methylethoxyimino)} acetamido-3- [2- {3- (3, 4- 160 mg (0.217 mmol) of diacetoxyphenyl) isooxtkzol-5-yl} vinyl] -3-cefe-4-carboxylic acid was suspended in 2 ml of water, cooled to 0 ° C., and 3 ml of 7% sodium hydrogencarbonate was added. After stirring for 4 hours at room temperature, 1 ml of 7% sodium hydrogen carbonate was added, stirred for about 3 hours, separated using Sepralyte ^TM C ₁₈ column chromatography (water: methanol = 7: 3), and freeze-dried to obtain 100 mg of the target compound (0.143). mmol).

Yield: 66%

¹ H-NMR (D ₂ O, δ): 1.5 (6H, s, -C- (CH ₃ ) ₂ ), 3.3 (1H, d, C ₂ -H), 3.6 (1H, d, C ₂ -H ), 5.3 (1H, d, C ₆ -H), 5.8 (1H, d, C ₇ -H), 6.5 (1H, d, C ₃ -C = CH-), 6.6 (1H, s, isoazole-H ), 6.7 (1H, d, C ₃ -CH = C-), 6.9 (1H, d, catechol), 7.0 (1H, s, aminothiazole), 7.2 (1H, d, catechol), 7.3 (1H, s, catechol)

Example 17

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyimino} acetamido-3- [2- {3- (3,4- Preparation of Na Salt of Dihydroxyphenyl) isoxazol-5-yl} vinyl] -3-cepem-4-carboxylic acid

7- {2- (2-aminothiazol-4-yl) -2-hydroxyimino} acetamido-3- [2- {3- (3,4-diacetoxyphenyl) isoxazole-5 80 mg (0.123 mmol) of -yl} vinyl] -3-cef-4-carboxylic acid are suspended in 0.5 ml of water, cooled to 0 ° C., and 1 ml of 7% sodium hydrogencarbonate (pH = 8). After raising to room temperature, the mixture was stirred for 3 hours and freeze-dried using Sepralyte ^™ C ₁₈ column chromatography (water: methanol = 7: 3) to obtain 60 mg (0.0924 mmol) of the target compound.

Yield: 75%

¹ H-NMR (D ₂ O, δ): 3.2 (1H, d, C ₂ -H), 3.6 (1H, d, C ₂ -H), 5.3 (1H, d, C ₆ -H), 5.8 ( 1H, d, C ₇ -H), 6.4 (1H, d, C ₃ -C = CH-), 6.5 (1H, s, isoxazole-H), 6.7 (1H, d, C ₃ -CH = C-) , 6.8 (1H, d, Catechol), 6.9 (1H, s, aminothiazole-H), 7.1 (1H, d, catechol), 7.2 (1H, s, catechol)

Claims (3)

Alkenyl cephalosporins represented by the following general formula (I) and pharmaceutically acceptable salts thereof. In General Formula (I), R ₁ is hydrogen, trityl group, tert-butoxycarbonyl group or formyl group, R ₂ is hydrogen, alkyl group having 1 to 4 carbon atoms, alkoxycarbonylmethyl group, carboxymethyl group, 1-carboxyethyl group, 1-carboxy-1-methylethyl group, 3 to 9 carbon atoms is a cycloalkyl group, R ₃ is hydrogen, Na, K, para-methoxybenzyl group, diphenylmethyl group and R ₄ and R ₅ are hydrogen, acetyl group, para -A methoxybenzyl group, benzyl group, methylene group or acyl group. After reacting the aldehyde compound of general formula (III) with the phosphonium salt of general formula (II) to obtain 3-cefem compound of general formula (IV), the compound (IV) is subjected to deacylation reaction. 7-amino-3-cepem derivatives of). Wherein R ₃ , R ₄ and R ₅ are the same as defined in claim 1, respectively. A method for producing an alkenylcephalosporin of formula (I) wherein the compound of formula (VI) and a compound of formula (V) are subjected to acylation reaction. Wherein R ₂ , R ₃ , R ₄ and R ₅ are the same as defined in claim 1, respectively.