CN1073444A

CN1073444A - Cephalosporin compound and preparation method thereof

Info

Publication number: CN1073444A
Application number: CN91111604.4A
Authority: CN
Inventors: 齐藤邦夫; 高村则夫; 松下忠弘; 山口东太郎
Original assignee: Tanabe Seiyaku Co Ltd
Current assignee: Tanabe Seiyaku Co Ltd
Priority date: 1990-08-09
Filing date: 1991-12-18
Publication date: 1993-06-23
Also published as: JPH0686461B2; JPH04261182A

Abstract

The cephalosporin compound of formula [I] or its pharmaceutical salts,

R in the formula ¹Be amino or protected amino, R ²Be hydroxyl, protected hydroxyl or low-carbon alkoxy, R ³Be carboxyl or protected carboxyl, R ⁴Be hydrogen, low-carbon alkyl, low-carbon (LC) thiazolinyl or formula-CH ₂R ⁴¹The group of expression, R ⁴¹Be nucleophilic group, R ⁵Be carboxyl, protected carboxyl or-the COO base, R ⁶Be hydrogen or low-carbon alkyl, dotted line is represented the existence of two keys or does not exist that described compound or pharmaceutically acceptable salt thereof has good anti-microbial activity and is useful antibacterials.

Description

Cephalosporin compound and preparation method thereof

The present invention relates to have the active new cephalosporin compound of excellent antibacterial, prepare the method for these compounds and intermediate thereof.

Many so far cephalosporinses are known to be antiseptic-germicide, for example report (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-((2-carboxyl-2-propyl group) the oxo imido grpup) acetamido]-the 3-(1-picolyl)-cephalo-3-alkene-4-carboxylate salt (generic name: ceftazidime) potent antimicrobial acivity [referring to Japanese patent laid-open publication gazette No.5916/1987] is arranged.

An object of the present invention is to provide cephalosporin compounds with good antimicrobial acivity.Another object of the present invention provides the method for these new cephalosporin compounds of preparation.A further object of the present invention provides the intermediate of these cephalosporin compounds of preparation.From following explanation, these and other objects of the present invention and advantage thereof are conspicuous to the people who is familiar with this area.

Shown in the following formula I of cephalosporin compound of the present invention:

R in the formula ¹Be amino or protected amino, R ²Be hydroxyl, protected hydroxyl or low-carbon alkoxy, R ³Be carboxyl or protected carboxyl, R ⁴Be hydrogen atom, low-carbon alkyl, low-carbon (LC) thiazolinyl) or be by formula-CH ₂R ⁴¹Represented group (R in the formula ⁴¹Be the nucleophilicity residue), R ⁵Be carboxyl, protected carboxyl or be-COO ^-, R ⁶Be hydrogen atom or low-carbon alkyl, dotted line represents that two keys exist or do not exist.

Cephalosporin compound (I) that the present invention is new and pharmaceutical salts thereof are to gram-positive microorganism and negative bacterium, and particularly the broad-spectrum micro-organisms to gram-positive microorganism has good antimicrobial acivity.Cephalosporin compound of the present invention (I) produces bacterium to various β-Nei Xiananmeis also very high stability, and body tissue is had very high absorbability.Its therapeutic action is long lasting in addition.According to these advantages, The compounds of this invention (I) can be used as antimicrobial agents, for example comprises human mammiferous transmissible disease as chemotherapeutics prevention and treatment by what above-mentioned various microorganisms caused, also can be used as the fodder additives of animal.

Purpose compound of the present invention includes, for example: formula I compound, wherein R ⁴Be hydrogen atom, or low-carbon alkyl, for example methyl, or low-carbon (LC) thiazolinyl, for example vinyl, or formula-CH ₂R ⁴¹Group { the R in the formula of representative ⁴¹Be this area nucleophilicity residue commonly used, low carbon chain acyloxy for example is as acetoxyl group; Nitrogenous heterocyclic radical, pyridyl, 5,6,7,8-tetrahydric quinoline group or 2,3-pentamethylene pyridyl, quinolyl, isoquinolyl, 2, [these heterogeneous ring compounds can randomly have one or two to be selected from following substituting group to 3-trimethylene pyridyl: halogen atom (chlorine for example, bromine, fluorine etc.), low-carbon alkyl (as methyl etc.), low-carbon alkoxy (as methoxyl group etc.), low-carbon (LC) carbalkoxy (as methoxycarbonyl etc.), amino, formamyl, cyano group, formamido group and hydroxyl (low-carbon (LC)) alkyl (as methylol etc.)]; The thio group that is replaced by nitrogen heterocycle, thiadiazoles sulfenyl for example, tetrazole sulfenyl and pyridine sulfenyl [these nitrogen heterocycles can have a substituting group that is selected from the following group with appointing: low-carbon alkyl (for example methyl etc.), low-carbon (LC) thiazolinyl (for example vinyl, allyl group etc.)] }.

In addition, The compounds of this invention (I) also comprises for example compound of formula I, R in the formula ¹Be amino, R ³Be carboxyl, R ⁵For carboxyl or-COO ^-, R ⁶Be hydrogen atom or methyl.

Moreover The compounds of this invention (I) also comprises for example compound of formula I, R in the formula ²Be hydroxyl or methoxyl group, it is replaced in 2-oxo-1H-quinoline ring or 2-oxo-1,2,3, on the 8-position of 4-tetrahydroquinoline ring.

The present invention is the formula I compound as the more preferred compound of medicine, R in the formula ⁴Be formula-CH ₂R ⁴¹Group (the R in the formula of representative ⁴¹Be acetoxyl group, pyridyl, 3-chloropyridine base, 3-amino-2-methyl pyridyl or quinolyl).

The present invention is the compound of formula I as the most preferred of medicine, R in the formula ⁴Be formula-CH ₂R ⁴¹The group of representative (R wherein ⁴¹Be pyridyl, 3-chloropyridine base, 3-amino-2-methyl pyridyl or quinolyl).

R when compound of the present invention (I) ¹Be protected when amino, this amino protecting group comprises various peptide synthetic protecting group, for example the low carbon chain acyl groups of being generally used for; One-, two-or three-halo (low-carbon (LC)) chain acyl; The low-carbon (LC) carbalkoxy; That replace or unsubstituted phenyl (low-carbon (LC)) carbalkoxy, for example carbobenzoxy-(Cbz) is right-(low-carbon (LC)) alkoxy benzyl carbonyl; That replace or unsubstituted phenyl (low-carbon (LC)) alkyl, for example benzyl is right-(low-carbon (LC)) alkoxy benzyl, and 3,4-two (low-carbon (LC)) alkoxy benzyl; With two-or three-phenyl (low-carbon (LC)) alkyl, etc.

R when The compounds of this invention (I) ²When being protected hydroxyl, the protecting group of this hydroxyl includes, for example: phenyl replacement or unsubstituted (low-carbon (LC)) alkyl, for example benzyl, diphenyl-methyl etc.; Low carbon chain acyl group such as ethanoyl and benzoyl etc.

Moreover, the R of The compounds of this invention (I) ³Or/and R ⁵When being protected carboxyl, preferably available ordinary method of the protecting group of this carboxyl such as hydrolysis, the protecting group that acid treatment and reduction reaction etc. are removed on carboxyl easily.This class protecting group for example is a low-carbon alkyl; That replace or unsubstituted phenyl (low-carbon (LC)) alkyl, right-(low-carbon (LC)) alkoxy benzyl, right-nitrobenzyl as benzyl, diphenyl-methyl etc.; And three (low-carbon (LC)) alkyl tin groups, alkyl silane groups.

According to the present invention, the preparation of its purpose compound (I) and pharmaceutical salts thereof can be with oxygen imido grpup acetic acid compound, its salt or its reactive derivative of formula II

The amino cephalosporin compound of 7-or its salt condensation with formula III:

The definition of symbol is the same in the formula, perhaps with hydroxyl imido grpup cynnematin or its salt of formula IV

Quinolone compounds or its reactant salt with formula (V):

The definition of the symbol in (IV) formula is the same, and Z is active residue in the formula (V), R ², R ³, R ⁶The same with the definition of dotted line.

In the middle of the purpose compound of the present invention (I), R ⁴Be formula-CH ₂R ⁴¹The compound of the group of representative can prepare with nucleophilicity compound (VII) or its reactant salt with cephalosporin compound or its salt of formula VI:

X in the formula ¹Be active residue, R ¹, R ², R ³, R ⁵, R ⁶The same with the definition of dotted line.

R when the purpose compound (I) of such preparation ¹Be protected amino, R ²Be protected hydroxyl, and and/or R ³And/or R ⁵When being protected carboxyl, if need, described blocking group can randomly be removed.In addition, this purpose compound (I) can randomly be transformed into its pharmaceutical salts.

Initial compounds (II), (III), (IV), the salt of (V) and (VI) can be any salt that forms with the inorganic or organic amine of routine.

Initial nucleophilicity compound (VII) comprises any common compounds of using in the art usually; low-carbon (LC) alkanoic acid (as acetate etc.) for example; nitrogen-containing heterocycle compound is (as pyridine; quinoline; isoquinoline 99.9,2,3-trimethylene pyridine; tetrahydroquinoline; 2-3-pentamethylene pyridine etc.), can randomly be replaced on the heterocycle: halogen atom, low-carbon alkyl by following group; low-carbon alkoxy; the low-carbon (LC) carbalkoxy, amino, formamyl; cyano group; formamido-and hydroxyl (low-carbon (LC)) alkyl, and the nitrogen-containing heterocycle compound that replaces of sulfydryl or sulphur (dimercaptothiodiazole for example, mercapto tetrazole; sulfo-pyridone etc.), can randomly be replaced on the heterocycle: low-carbon alkyl and low-carbon (LC) thiazolinyl by following group.The form of available its salt of these nucleophilicity compounds (VII), for example inorganic acid salt or an alkali metal salt.

Condensation reaction between the amino cephalosporin compound of free oxygen imido grpup acetate (II) and 7-(III) can be carried out in the presence of dewatering agent, this dewatering agent can be the dewatering agent of arbitrary routine, dicyclohexylcarbodiimide for example, phosphorus oxychloride, thionyl chloride, oxalyl chloride or by dimethyl formamide and phosphorus oxychloride, oxalyl chloride, David Smail reagent Wei (Vilsmeier reagent) that phosgene or protochloride sulfuric acid reaction generate.This reaction is preferably in cooling or the room temperature to be carried out.

Condensation reaction between the amino cephalosporin compound (III) of active derivative of oxygen imido grpup acetic acid compound (II) (for example acid anhydrides, mixed acid anhydride, active ester etc.) and 7-or its salt can be carried out under the situation that alkali exists or do not have alkali to exist.Preferred alkali for example includes: alkali metal hydroxide, alkaline carbonate, alkali metal hydrocarbonate, two (TMS) ethanamide, trialkylamine, N, N-dialkyl aniline, pyridine or the like.This reaction is preferably in carries out (for example-60 ℃ to 25 ℃) under cooling or the room temperature.

Reaction between hydroxyl imide base cephalosporin compound (IV) and the quinolone compounds (V) can be carried out in the presence of dewatering agent or alkali.Active residue Z is in the quinolone compounds (V), hydroxyl for example, halogen atom, low-carbon alkyl sulfonyloxy or the like.Dewatering agent can be the mixture of phosphorus compound (as triphen phosphorus, diphenyl methyl phosphine, diphenyl-ethyl phosphine etc.) and diazonium carboxylic acid two (low-carbon (LC)) alkane ester for example.Alkali is alkali metal hydroxide preferably, trialkylamine, N, N-dialkyl aniline, pyridine or the like.This reaction be preferably in cooling or warm under carry out (for example-40 ℃ to 30 ℃).

Reaction between cephalosporin compound (VI) and nucleophilicity compound (VII) is preferably carried out in appropriate solvent.Active residue X in this reaction in the cephalosporin compound (VI) ¹Can be carbamoyloxy for example, low carbon chain acyloxy or halogen atom.This reaction is cooled off or warm (for example-40 to 40 ℃) down preferably in room temperature, and pH2-8 preferably carries out under the pH5-8 situation.If need, can in reactive system, add alkali metal halide for quickening this reaction, three (low-carbon (LC)) alkyl tin groups, alkyl silane groups trifluoromethayl sulfonic acid ester, alkali-metal thiocyanate-, alkali-metal supercarbonate has surface-active quaternary ammonium salt (as three (low-carbon (LC)) alkyl benzyl ammonium halogenide) or phosphate buffer soln or the like.

If need, above-mentioned reaction can be in The suitable solvent, dimethyl formamide for example, and N,N-DIMETHYLACETAMIDE ， diox, acetone, ethanol, acetonitrile, methylene dichloride, chloroform, pyridine, methyl-sulphoxide, toluene, tetrahydrofuran (THF) carries out in water or their mixture.

With optically active initial compounds (II), (V) or (VI) can obtain optically active compound of the present invention (I) in the above-mentioned reaction.

The R of compound (I) ¹Be protected amino, R ²Be protected hydroxyl, and/or R ³And/or R ⁵During for protected carboxyl, can randomly remove these protecting groups.Available ordinary method is removed these protecting groups, for example hydrolysis, solvolysis, acid treatment, reduction or the like, or the combination of these methods.Select to remove the method for protecting group according to the kind of the protecting group that is removed.

Compound of the present invention (I) and pharmaceutical salts thereof are to gram-positive microorganism enterococcus spp (as enterococcus faecalis) for example, Staphylococcus is (as streptococcus aureus, staphylococcus epidermidis), morganella morganii belongs to (as morganella morganii strain) and Rhodopseudomonas (as Pseudomonas aeruginosa) and Gram-negative bacteria broad spectrum of bacteria good antimicrobial acivity.Especially different with the cephalosporin compound of above-mentioned conventional usefulness is that compound of the present invention (I) and pharmaceutical salts thereof have potent antimicrobial acivity (as staphylococcus microorganism belonging to genus etc.) to gram-positive microorganism.

For example, compare with aforesaid ceftazidime, compound 73-of the present invention (Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl)-(carboxyl) methoxy imino] acetamido }-3-3(1-quinoline methyl)-3-cephem-4-carboxylic acid has good anti-microbial activity, restraining effect to streptococcus aureus 209P JC-1 is stronger 32 times than ceftazidime, and 7 β-(Z)-2-(2-amino-4-thiazolyl)-2[(8-hydroxyl-2-oxo-1H-5-quinolyl ((carboxyl-methoxy imino] acetamido]-the 3-(1-picolyl)-3-cephem-4-carboxylic acid and 7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl)-(carboxyl) methoxy imino] acetamido }-3-(3-amino-2-methyl-1 picolyl-3-cephem-4-carboxylic acid has the excellent antibacterial effect to staphylococcus epidermidis, is eager to excel 16 times than aforesaid ceftazidime.

In addition, purpose compound of the present invention (I) and pharmaceutical salts thereof have the characteristic that various β-Nei Xiananmeis generation bacterium is had higher stability.For example The compounds of this invention 7 β-(Z) 2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl) (carboxyl) methoxy imino] acetamido-the 3-(1-quinoline methyl of 3-cephem-4-carboxylic acid) derivative and 3-(1-picolyl) derivative has good anti-microbial activity to Fu Shi citric acid bacterium GN346, it is active higher 4 times than ceftazidime.Purpose compound of the present invention (I) and pharmaceutical salts thereof are to proteus (as proteus morganii), Citrobacter (as the Fu Shi citric acid bacterium), Escherichia (as intestinal bacteria), Klebsiella (as klebsiella pneumoniae) or enterobacter, serratia, Shigella and salmonella have good anti-microbial activity.

The most important characteristics of these compounds is that the drug-fast staphylococcus aureus of 6-Staphcillin (MRSA) has potent anti-microbial effect to isolated to 2 clinically.MRSA is drug-fast to many beta-lactam antibioticss.For example 7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl)-(carboxyl) methoxy imino] acetamido-3-(3-amino-2-methyl-1-picolyl)-3-cephem-4-carboxylic acid is stronger 16 times than ceftazidime for the anti-microbial activity (90% inhibition concentration) of clinical isolated M RSA.Further, above-claimed cpd of the present invention is stronger 2 times than ceftazidime to the anti-microbial activity (90% inhibition concentration) of clinical isolating Pseudomonas aeruginosa.

And purpose compound of the present invention (I) or its pharmaceutical salts have very high absorbability in body tissue, long lasting therapeutic action is arranged.Therefore, The compounds of this invention (I) has the good effect of resisting to the transmissible disease that is caused by the various microorganisms that comprise staphylococcus aureus and Pseudomonas aeruginosa.In addition, purpose compound of the present invention (I) and pharmaceutical salts thereof are low as medicine toxicity, safe, for example, 7 β-(Z)-2-(2-amino-4-thiazolyl)-the 2-[(8-hydroxyl)-2-oxo-1H-5-quinolyl)-(carboxyl) methoxy imino] acetamido }-3-(3-amino-2-methyl-1-picolyl)-acute toxicity test of 3 cephems-4-carboxylic acid, behind 5 mouse mainline 1g/Kg dosage, none is only dead after five days.

Also available its pharmaceutical salts of the both available free type of cephalosporin compound of the present invention (I).Pharmaceutical salts includes, for example avirulent metal-salt, and as sodium salt, sylvite, calcium salt, magnesium salts, aluminium salt etc.; Avirulent amine salt is as trialkylamine (for example triethylamine), pyridine, thanomin, trolamine, dicyclohexylamine etc.; With the salt of mineral acid formation, for example with hydrochloric acid, sulfuric acid, the salt that Hydrogen bromide etc. form; With the salt of organic acid formation, for example with oxalic acid, the salt that tartrate etc. form; With amino acid whose adduct, for example with glycine, Methionin, arginine, Aspartic Acid, the salt that L-glutamic acid etc. form etc.

The salt of compound (I) also can be the salt with resin formation, for example with contain amino, the salt that quaternary ammonium group or sulfonic polystyrene resin form, or with the salt of the resin formation that contains carboxyl, for example salt that forms with polyacrylic resin.The compounds of this invention (I) also can form complex compound with metal, for example with iron, copper etc. or with the ammonium salt complex compound that forms such as ammonium chloride for example.Therefore, purpose compound of the present invention (I) and salt thereof comprise inner salt, adduct, complex compound, solvate and hydrate.

Cephalosporin compound of the present invention (I) or its pharmaceutical salts can or oral administration usefulness, or parenteral medication (for example vein, muscle or subcutaneous injection).Use for the pharmaceutical dosage form that is suitable for oral or parenteral medication, they can make for example tablet, granule, capsule, pulvis, injection or the like with pharmaceutical carrier or mixing diluents.

The compounds of this invention (I) every day dosage by route of administration, patient age, the body weight and the state of an illness and kinds of Diseases and decide, but common scope of medication is per kilogram of body weight 2-200mg, preferably per kilogram of body weight 5-40mg.

In this specification sheets and claims, if NOS, then formula

Part-structure mean it is geometrical isomer or its mixture of following formula.

Yet the oxygen imido grpup in compound (I) or its salt is preferably used as medicine with (Z)-configuration and has than superior bioactive.

Purpose compound of the present invention (I), initial compounds (II) and (VI) because they have the part-structure of following formula, therefore include optical isomer or raceme:

Asterisk * in the formula represents unsymmetrical carbon, R ², R ³, R ⁶The same with the definition of dotted line.

Initial compounds (II) is new compound, its method for making can the existence of for example alkali and cooling or warm down, with the quinolone compounds and the reaction of formula (VIII) compound of formula (V), production [II-a] compound, and then choose wantonly

In the formula-when COOY was carboxyl or protected carboxyl, this protecting group can be above-mentioned R ³And R ⁵The protecting group of example any.In addition, compound (II) also can be used the compound of low-carbon alkyl hydrazine reaction mixture production (IX) then through quinolone compounds (V) and N-hydroxybenzene imide or its an alkali metal salt prepared in reaction under cooling,

Exist or do not exist down in alkali again, the blocking group in the product is randomly removed in cooling or warm down with the glyoxalated compound reaction of compound (IX) with formula (X) again.

The definition of symbol is the same in the formula.

In this specification sheets and claims, low-carbon alkyl, the low-carbon (LC) thiazolinyl, low-carbon alkoxy and low carbon chain acyl group have 1-6 carbon atom respectively, 2-6 carbon atom, 1-6 carbon atom and 2-6 carbon atom.

The following examples and reference example are done more detailed explanation to the present invention, but should not think to be only limited to this.

Embodiment 1

(1)-(a) under argon atmospher and 5-10 ℃, diazonium carboxylic acid diethyl ester (36.6g) is added drop-wise to 2-(8-phenylbenzene methoxy base-2-oxo-1H-5-quinolyl)-benzhydryl ester (47.7g) of 2-oxyacetic acid, N-hydroxybenzene dicarboximide (41.2g), in the mixture of triphenyl phosphine (55.2g) and tetrahydrofuran (THF) (2000ml), stirred the mixture 1 hour under the same temperature, under room temperature, stirred 70 hours again.After mixture concentrates, residuum is through purification by silica gel column chromatography (elutriant: ethane/ethyl acetate and chloroform), with chloroform/ether recrystallization, 2-(8-two benzyloxies-2-oxo-1H-5-quinolyl) 2-(Phthalimide oxygen base) benzhydryl ester (44.5g) of acetate.

M.P.206-207 ℃ (decomposition).

The IR(Nujol mull): 3170,3130,3065,3030,1790,1760,1730,1660,1610cm ^-1

MS（m/z）：713（MH ⁺）

(1)-(b) 2-(8-two benzyloxies-2-oxo-1H-5 quinolyl)-benzhydryl ester (0.57g) and the lime carbonate (0.2 gram) of 2-oxyacetic acid is cooled to-5 to 0 ℃ in the suspension of tetrahydrofuran (THF) (10ml), under argon atmospher, stir, drip tribromide phosphine (0.38 gram) in this mixture again, this mixture of restir 1 hour, stir down, mixture is poured in the cold mixing liquid of the ethyl acetate (10ml) that is lower than 2 ℃ and 2N aqueous sodium hydroxide solution (3ml), the adding saturated sodium bicarbonate solution makes and is alkalescence, and separates.The water layer ethyl acetate extraction merges above-mentioned ethyl acetate layer that obtains and acetic acid ethyl acetate extract, with sodium chloride solution washing, drying, then toward wherein adding lime carbonate (5 milligrams).Evaporating mixture desolvates to remove, and obtains 2-bromo-2-(8-two benzyloxies-2-oxo-1H-5-quinolyl) benzhydryl ester of acetate.

Diformamide (2ml) suspension with N-hydroxybenzene dicarboximide sylvite (0.25 gram) under argon atmospher is cooled to-10 ℃, then toward the solution that wherein drips the dimethyl formamide (3ml) of top compound, stir this mixture after 1 hour in 0-2 ℃, its impouring is fallen in the mixture of frozen water (20ml)/ethyl acetate (30ml), and separate.Collected organic layer, after sodium bicarbonate aqueous solution and water washing, drying concentrates.The residuum that obtains obtains 2-(8-two benzyloxies-2-oxo-1H-5-quinolyl through purification by silica gel column chromatography)-2-(Phthalimide oxygen base) benzhydryl ester (0.30 gram) of acetate.The physicochemical property of this product go on foot prepare identical with front (a).

(2) under argon atmospher will above the solution that in methylene dichloride (500ml), obtains of the product (36.5 gram) that obtains be cooled to-60 ℃, to wherein dripping methyl hydrazine (3.0ml).Mixture stirred 1.5 hours in-60-0 ℃, stirred 30 minutes in 0 ℃ again, and washed with dichloromethane use in the crystallization that filtering is separated out, and merges washings and filtrate, evaporates.Residuum ether crystallization, filter is assembled brilliant, the ether washing; After the drying 2-amino oxygen base-2-(8-two benzyloxies-2-oxo-1H-5-quinolyl) benzhydryl ester (29.8 gram) of acetate, be colourless crystallization.

M.P.178-180 ℃ (decomposition)

The IR(Nujol mull): 3230,3160,1750,1730,1650,1600cm ^-1

MS（m/z）：583（MH ⁺）

The crystallization that this product obtains with recrystallizing methanol has different infrared spectras.

M.P.170-171℃

The IR(Nujol mull): 3650,3550,3300,3240,1760,1740,1660,1610cm ^-1

(3) product that obtains above (28.0 gram) and 2-triphenyl amine base-4-thiazolyl-oxoethanoic acid (18.05 gram) are dissolved in the mixed solution of tetrahydrofuran (THF) (800ml), acetonitrile (280ml) and water (280ml), stirred the mixture under the room temperature 5 hours, steaming desolventizes, residuum ether crystallization, the crystallization that the filter collection is separated out, the ether washing, dry, get 2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-two benzyloxies-2-oxo-1H-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino] acetate (41.6 gram), be colourless crystallization.

M.P.154-156 ℃ (decomposition)

The IR(Nujol mull): 3400,3200,3060,3030,2800-2400,1740,1720,1600,1610cm ^-1

MS（m/z）：979（MH ⁺）

(4) under ice-cooled and argon atmospher, successively phosphorous oxychloride (2.85 gram) and methylene dichloride (10ml) are added in the dimethyl formamide (2.23 gram), this mixture of stirring at room 1 hour is cooled to-55 to-50 ℃ then.In this mixture, drip 2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-two benzyloxies-2-oxo-1H-5-quinolyl) (hexichol methoxycarbonyl) methoxyl group imido grpup] acetate (13 gram) is in the solution of methylene dichloride (300ml), and this mixture stirs 2 hours (solution of generation is called reaction soln A) down in-60 to-50 ℃.In addition, under ice-cooled and argon atmospher, two-(TMS) ethanamide (14.8ml) is added to the amino cephalo acid of 7-(5.43g) in methylene dichloride (48ml) suspension, under same temperature, stirs 1.5 hours (solution of generation is called reaction soln B) of this mixture.In-60 to-55 ℃ are added drop-wise to reaction soln B among the reaction soln A, and mixture stirred 1 hour in-60 to-30 ℃, stirred 1.5 hours in-30 ℃ again.After reacting completely, mixture is poured in the frozen water, and separates.The water layer dichloromethane extraction merges dichloromethane extraction liquid and dichloromethane layer.Wash with salt solution, dry back is steamed and is desolventized, obtain 7 β-(z)-2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-two benzyloxies-2-oxo-1H-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino] acetamido cephalo acid (16.48 gram), be buff powder.

M.P.160-162 ℃ (decomposition)

The IR(Nujol mull): 3380,3230,2800-2400,1790,1740,1670,1610cm ^-1

MS（m/z）：1233（MH ⁺）

Embodiment 2

7 β-(Z)-2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-two benzyloxies-2-oxo-1H-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino] acetamido } cephalo acid (12.48 gram) is dissolved in the formic acid (160ml), ice-cooled down to wherein adding entry (40ml), under room temperature, stirred this mixture 8.5 hours, the precipitation that filtering is separated out, and wash with 80% aqueous formic acid.Merging filtrate and washings steam and desolventize, add ethanol in the residuum, filter and collect the solid of separating out, with ethanol and ether washing, after the drying, be dissolved in the sodium bicarbonate aqueous solution, add saturated sodium bicarbonate solution to regulate the PH to 8.0 of mixture, with non-ionic type polymeric adsorbent (trade(brand)name Diaion HP-20, Mitsubishi Kasei company produces, to call HP-20 in the following text) column purification, (elutriant: water and 5% methanol aqueous solution), merge the part contain the purpose compound, after concentrated freeze-dried 7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl) (carboxyl) methoxy imino] acetamido cephalo acid disodium salt (4.2 gram), be buff powder.

M.P.230-240 ℃ (decomposition)

The IR(Nujol mull): 3320,3200,1770,1730,1650,1600cm ^-1

MS（m/z）：703（MH ⁺）

NMR（D ₂O）δ：2.11 and 2.12（3H，sx2），2.88 and 2.92（1H，dx2，J＝18Hz and 18Hz），3.36 and 3.39（1H，dx2，J＝18Hz and 18Hz），4.66（1H，d，J＝12Hz），4.83（1H，d，J＝12Hz），4.89 and 4.92（1H，dx2，J＝4.9Hz and 4.4Hz），5.56 and 5.66（1H，dx2，J＝4.9Hz and 4.4Hz），5.97（1H，s），6.75 and 6.76（1H，dx2，J＝9.8Hz and 9.8Hz），6.99-7.05（2H，m），7.21 and 7.23（1H，dx2，J＝8.3Hz and 7.8Hz），8.28 and 8.35（1H，dx2，J＝9.8Hz and 9.8Hz）

Embodiment 3

(1) under argon atmospher, TMS trifluoromethayl sulfonic acid fat (1.1ml) is added to quinoline (900mg) in the solution of methylene dichloride (9ml), this mixture of stirring at room 10 minutes.Adding 7 β in this mixture-(Z)-2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-two benzyloxies-2-oxo-1H-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino] acetamido } cephalo acid (1.0 gram), stirred the mixture under the room temperature 45 minutes, and refluxed 1.5 hours in stirring down again.Steaming desolventizes, and residuum is dissolved in formic acid (12ml), adds entry again.This mixture of stirring at room 6.5 hours.The precipitation that filtering separation is separated out, and wash this precipitation with 80% aqueous formic acid, merging filtrate and washings, steaming desolventizes, residuum is dissolved in saturated sodium bicarbonate aqueous solution and the acetonitrile, regulates its PH to 8.0, steams and removes acetonitrile, water layer washs with chloroform, through HP-29 column chromatography purification (elutriant: water and 5-30% methanol aqueous solution).Merge the part that contains the purpose compound, concentrate, freeze-drying, obtain 7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl) (carboxyl) methoxy imino]-acetamido-3-(1-quinoline methyl)-3-cephem-4-carboxylic acid sodium salt (160mg), be buff powder.

M.P.205-210 ℃ (decomposition)

The IR(Nujol mull): 3350,3200,1770,1660,1610cm ^-1

MS（m/z）：750（MH ⁺）

NMR（D ₂O）δ：2.58 and 2.65（1H，dx2，J＝19Hz and 19Hz），3.12 and 3.15（1H，dx2，J＝19Hz and 19Hz），4.91 and 4.94（1H，dx2，J＝4.9Hz and 4.9Hz），5.62 and 5.68（1H，dx2，J＝4.9Hz and 4.9Hz），5.70 and 5.85（2H，each br d），5.93（1H，s），6.60 and 6.64（1H，dx2，J＝9.8Hz and 9.8Hz），6.71 and 6.86（1H，dx2，J＝8.3Hz and 8.3Hz），6.92 and 6.94（1H，sx2），7.12 and 7.18（1H，dx2，J＝8.3Hz and 8.3Hz），7.80-8.34（6H，m），8.98-9.10（2H，m）

(2) product that obtains above (100mg) again through the HP-20 column chromatography purification, obtains alpha-isomer and β-isomer through high performance liquid chromatography separating isomerism body respectively.

The retention time of alpha-isomer (Rt): 25 minutes

The retention time of β-isomer (Rt): 40 minutes

(condition)

Stationary phase: C ₁₈Silica gel (trade(brand)name: YMC-Pack S-343)

Moving phase: acetonitrile: 30mM phosphate buffered saline buffer (pH=7.0)=8.5: 91.5

Flow velocity: 5ml/ minute

Alpha-isomer output: 30mg

M.P.＞175 ℃ (decomposition)

The IR(Nujol mull): 3380,3200,1770,1660,1610cm ^-1

MS（m/z）：750（MH ⁺）

NMR（D ₂O）δ：2.62，3.17（2H，dx2，J＝18Hz and 18Hz），4.94（1H，d，J＝4.9Hz），5.62（1H，d，J＝4.9Hz），5.75，5.91（2H，dx2，J＝16Hz and 16Hz），5.95（1H，s），6.66（1H，d，J＝9.8Hz），6.79（1H，d，J＝8.3Hz），6.99（1H，s），7.13（1H，d，J＝8.3Hz），7.90-8.40（6H，m），9.10（2H，m）

β-isomer

Output: 27mg

M.P.＞175 ℃ (decomposition)

The IR(Nujol mull): 3380,3200,1770,1660,1610cm ^-1

MR（m/z）：750（MH ⁺）

NMR（D ₂O）δ：2.57，3.13（2H，dx2，J＝18Hz and 18Hz），4.91（1H，d，J＝4.9Hz），5.69（1H，d，J＝4.9Hz），5.73，5.88（2H，dx2，J＝16Hz and 16Hz），5.96（1H，s），6.68（1H，d，J＝10Hz），6.94（1H，d，J＝8.3Hz），6.98（1H，s），7.20（1H，d，J＝8.3Hz），7.80-8.38（6H，m），9.12（2H，m）

Embodiment 4

With acetate be added to 7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl) (carboxyl) methoxy imino]-acetamido cephalo acid disodium salt (0.59 gram), pyridine (0.34ml) and the pH value of sodium iodide (1.25 gram) with the adjusting mixture in the mixed solution of water (6ml) be 6.6.Stir this mixture 30 minutes down in argon atmospher and 70 ℃, cool off it then.With saturated sodium bicarbonate solution the pH value of this mixture is adjusted to 7.9, and through HP-20 column chromatography purification (elutriant: water and 5% methanol aqueous solution).Initial wash-out part, middle portion and the last wash-out part that will contain the purpose compound merge respectively, concentrate.After the residuum freeze-drying that every part obtains be respectively 7 β-(Z)-2-(2 amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl) (carboxyl) methoxy imino]-acetamido-the 3-(1-picolyl)-alpha-isomer of 3-cephalo-4-carboxylic acid sodium salt, α-and 3-isomer mixture and β-isomer.

Alpha-isomer

Output: 24mg M.P.＞200 ℃ (decomposition)

The IR(Nujol mull): 3350,3320,1770,1660-1620,1600cm ^-1

MS（m/z）：722（MNa ⁺），700（MH ⁺）

NMR（D ₂O）δ：2.61（1H，d，J＝18Hz），3.34（1H，d，J＝18Hz），4.96（1H，d，J＝4.9Hz），5.28（1H，d，J＝14Hz），5.49（1H，d，J＝14Hz），5.70（1H，d，J＝4.9Hz），5.96（1H，s），6.67（1H，d，J＝9.8Hz），6.90（1H，d，J＝8.3Hz），7.19（1H，d，J＝8.3Hz），8.13（2H，m），8.32（1H，d，J＝9.8Hz），8.60（1H，m），8.90（2H，m）

β-isomer

Output: 16mg

M.P.＞200 ℃ (decomposition)

The IR(Nujol mull): 3350,3320,1770,1660-1620,1600cm ^-1

MS（m/z）：722（MNa ⁺），700（MH ⁺）

NMR（D ₂O）δ：2.64（1H，d，J＝18Hz），3.34（1H，d，J＝18Hz），4.97（1H，d，J＝4.4Hz），5.28（1H，d，J＝15Hz），5.51（1H，d，J＝15Hz），5.61（1H，d，J＝4.4Hz），5.96（1H，s），6.64（1H，d，J＝8.3Hz），6.69（1H，d，J＝9.8Hz），7.06（1H，d，J＝8.3Hz），8.13（2H，m），8.22（1H，d，J＝9.8Hz），8.60（1H，m），8.90（2H，m）

Alpha-isomer and β-mixture of isomers

Output: 91mg

M.P.＞200℃

The IR(Nujol mull): 3350,3200,1770,1660-1620,1600cm ^-1

MS（m/z）：722（MNa ⁺），700（MH ⁺）

NMR（D ₂O）δ：2.16 and 2.64（1H，dx2，J＝18Hz and 18Hz），3.34（1H，d，J＝18Hz），4.96 and 4.97（1H，dx2，J＝4.9Hz and 4.4Hz），5.28（1H，br d），5.49 and 5.51（1H，dx2，J＝14Hz and 15Hz），5.61 and 5.70（1H，dx2，J＝4.4Hz and 4.9Hz），5.96（1H，br d），6.66 and 6.90（2H，m and d，J＝8.3Hz），7.00（1H，s），7.06 and 7.19（1H，dx2，J＝8.3Hz and 8.3Hz），8.13（2H，m），8.22 and 8.32（1H，dx2，J＝9.8Hz and 9.8Hz），8.60（1H，m），8.90（2H，m）

Embodiment 5-26

7 β-(Z)-2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-two benzyloxies-2-oxo-1H-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino] acetamido } same quadrat method processing that cephalo acid and nitrogen-containing heterocycle compound are pressed embodiment 3, obtain the compound shown in the table 1.

Embodiment 27

(1) under ice-cooled and argon atmospher, phosphorous oxychloride (0.48 gram) and methylene dichloride (2.2ml) are added drop-wise in the dimethyl formamide (0.38 gram), stirred 1.5 hours under the mixture room temperature, be cooled to-55 to-50 ℃ then, in this mixture, drip 2-(2-trimethylbenzene amido-4-thiazolyl)-2-[(8-two benzyloxies-2-oxo-H-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino] acetate (2.2 gram) is in the solution of methylene dichloride (54ml).Mixture stirred 1.5 hours in-65 to-55 ℃, and in-55 to-50 ℃ are stirred 30 minutes (solution that obtains is called reaction soln A) then.In addition, will two (TMS) ethanamides (3.08 gram) under ice-cooled and argon atmospher be added to 7 beta-aminos-3-(3-amino-2-methyl-1-picolyl)-3-cephem-4-carboxylicesters (1.57 gram) in the suspension of methylene dichloride (32ml), under same temperature, stir 2 hours (solution that obtains is called reaction soln B) of this mixture.Reaction soln B is added drop-wise among the reaction soln A, and mixture stirred 40 minutes in-55-30 ℃, stirred 1.5 hours in-30 ℃ again.After reacting completely, in mixture impouring water, steam and remove methylene dichloride.Filter to collect the precipitation of separating out, should precipitate washing and drying, the residuum that obtains is in 15-20 ℃ of mixture that is added to methyl-phenoxide (10ml) and trifluoroacetic acid (10ml), and this mixture of stirring is 2 hours under room temperature.Under ice-cooled isopropyl ether (180ml) is added in this mixture, stirred 15 minutes.Filter and collect the precipitation of separating out, wash with isopropyl ether, after the drying, suspend in water, regulate the pH value to 7.7 of this suspension with saturated sodium bicarbonate aqueous solution, and through HP-20 column chromatography purification (elutriant: water and 20% methanol aqueous solution), merge the part that contains the purpose compound, after concentrated freeze-dried, obtain 7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl) (carboxylic acid) methoxy imino] acetamido-3-(3-amino-2-methyl-1-picolyl)-3-cephem-4-carboxylic acid sodium salt (0.75 gram), be buff powder.

M.P.＞160 ℃ (decomposition)

The IR(Nujol mull): 3360,3200,1770,1650,1610cm ^-1

MS（m/z）：751（MNa ⁺），729（MH ⁺）

NMR（D ₂O）δ：2.50 and 2.52（3H，sx2），2.54 and 2.57（1H，dx2，J＝17Hz and 18Hz），3.06 and 3.09（1H，dx2，J＝17Hz and 18Hz），4.92 and 4.95（1H，dx2，J＝4.4Hz and 4.4Hz），5.22（1H，d，J＝15Hz），5.50 and 5.51（1H，d，J＝15Hz and 15Hz），5.60 and 5.68（1H，dx2，J＝4.4Hz and 4.4Hz），5.99（1H，s），6.71 and 6.74（1H，dx2，J＝9.8Hz and 9.8Hz），6.91 and 7.01（1H，dx2，J＝8.3Hz and 8.3Hz），7.01（1H，s），7.18 and 7.22（1H，dx2，J＝8.3Hz and 8.3Hz），7.52-7.62（1H，m），7.69 and 7.71（1H，dx2，J＝8.3Hz and 8.3Hz），8.00（1H，d，J＝6.3Hz），8.24 and 8.34（1H，d，J＝9.8Hz and 9.8Hz）

(2) product that obtains above (70mg) separates each isomer through high performance liquid chromatography, uses the HP-20 column chromatography purification, obtains α-and β-isomer respectively.

The retention time of alpha-isomer: 45 minutes

The retention time of β-isomer: 75 minutes

(condition)

Stationary phase: C ₁₈Silica gel (trade(brand)name: YMC-Pack D-ODS-10)

Moving phase: acetonitrile: 30mM phosphate buffered saline buffer (PH 7.0)=6: 94

Flow velocity: 5ml/ minute

Alpha-isomer

Output: 20mg

M.P.＞160 ℃ (decomposition)

The IR(Nujol mull): 3360,3200,1770,1650,1610cm ^-1

MS（m/z）：751（MNa ⁺），729（MH ⁺）

NMR（D ₂O）δ：2.52（3H，s），2.57，3.09（2H，ABq，J＝18Hz），4.95（1H，d，J＝4.4Hz），5.22，5.51（2H，ABq，J＝15Hz），5.60（1H，d，J＝4.4Hz），5.98（1H，s），6.71（1H，d，J＝9.8Hz），6.91（1H，d，J＝8.3Hz），7.01（1H，s），7.18（1H，d，J＝8.3Hz），7.59（1H，dd，J＝8.3Hz，5.9Hz），7.71（1H，d，J＝8.3Hz），8.00（1H，d，J＝5.9Hz），8.24（1H，d，J＝9.8Hz）

β-isomer

Output: 20mg

M.P.＞160 ℃ (decomposition)

The IR(Nujol mull): 3360,3200,1770,1660,1610cm ^-1

MS（m/z）：751（MNa ⁺），729（MH ⁺）

NMR（D ₂O）δ：2.50（3H，s），2.54，3.06（2H，ABq，J＝17Hz），4.92（1H，d，J＝4.4Hz），5.22，5.50（2H，ABq，J＝15Hz），5.68（1H，d，J＝4.4Hz），5.99（1H，s），6.74（1H，d，J＝9.8Hz），7.01（1H，s），7.01（1H，d，J＝8.3Hz），7.22（1H，d，J＝8.3Hz），7.56（1H，dd，J＝7.8Hz，6.3Hz），7.69（1H，d，J＝7.8Hz），8.00（1H，d，J＝6.3Hz），8.34（1H，d，J＝9.8Hz）

Embodiment 28-33

2-(2-triphenyl amine base-4-thiazolyl)-and 2-[(8-two benzyloxies-2-oxo-1H-5-quinolyl) (hexichol methoxycarbonyl)-methoxy imino] acetate and corresponding starting raw material press the same methods processing of embodiment 27; just when removing protecting group, carry out, generate the listed compound of table 2 with 80% aqueous formic acid.

Embodiment 34

With 4-(7-amino-3-methyl-3-cephem-4-carboxymethyl) phenylmethylether (502mg), 2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-two benzyloxies-2-oxo-1H-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino] mixture of acetate (979mg), dicyclohexylcarbodiimide (227mg), butanols (149mg) and tetrahydrofuran (THF) (15ml) stirred under room temperature 18 hours.Remove by filter the precipitation of separating out, concentrated filtrate, (elutriant: the spumescence product that toluene/ethyl acetate=1: 1) obtains is dissolved in the methyl-phenoxide (5ml) residuum through the silica gel column chromatography chromatography purification, ice-cooled down to wherein being added dropwise to trifluoroacetic acid (5ml), this mixture stirred under room temperature 2 hours.The mixed solution that adds isopropyl ether (100ml) and hexane (30ml) in this reaction mixture filters and collects the precipitation of separating out, and with the isopropyl ether washing, dry back is soluble in water.Add saturated sodium bicarbonate aqueous solution and regulate the pH value of this mixture to about 8.0, through HP-20 column chromatogram chromatography purifying (elutriant: water and 20% methanol aqueous solution), the part that will contain the purpose compound merges and concentrates, freeze-drying, obtain 7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl) (carboxyl) methoxy imino] acetamido-3-methyl-3-cephem-4-carboxylic acid disodium salt (400mg), be buff powder.

M.P.185-210 ℃ (decomposition)

The IR(Nujol mull): 3320,3200,1755,1650,1600cm ^-1

MS（m/z）：645（MH ⁺）

NMR（D ₂O）δ：1.87 and 1.88（3H，sx2），2.74 and 2.76（1H，dx2，J＝18Hz），3.30（1H，dx2，J＝18Hz），4.87 and 4.88（1H，dx2，J＝4.5Hz），5.49 and 5.58（1H，dx2，J＝4.5Hz），5.98 and 5.99（1H，sx2），6.76 and 6.77（1H，dx2，J＝9.8Hz），7.02 and 7.03（1H，sx2），7.04 and 7.05（1H，dx2，J＝8Hz），7.22 and 7.24（1H，dx2，J＝8Hz），8.29 and 8.37（1H，dx2，J＝9.8Hz）

Embodiment 35-36

Press the same quadrat method of embodiment 34 and handle 2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-two benzyloxies-2-oxo-1H-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino] acetate and corresponding raw material, obtain the listed compound of table 3.

Embodiment 37

(1) 5-oxalyl-8-benzyloxy quinolone (3.23 gram), wet 10% palladium-carbon (4 grams; Water capacity 50%) and tetrahydrofuran (THF) (100ml), water (50ml) and acetate 50ml) mixture jolting 40 hours under 45 ℃ and 4 hydrogen-pressure, remove by filter catalyzer then, and use the tetrahydrofuran aqueous solution washing catalyst.Washings and filtrate merge, and steaming desolventizes, and residuum is dissolved in 50% tetrahydrofuran aqueous solution (200ml).To wherein adding diphenyl diazomethane (2.9 gram), this mixture of stirring at room 20 hours.Steaming desolventizes, and adds ether in the residuum smashing solid to pieces, solid collected by filtration, and with ether washing, drying under reduced pressure.The solid that obtains is dissolved in the dimethyl formamide (20ml), and to wherein adding salt of wormwood (2.6 gram).Dripping diphenyl-bromomethane (4.64 gram) in this mixture in the solution of dimethyl formamide (5ml), stirred 5 hours under the room temperature.In the reaction mixture impouring frozen water (100ml), and use chloroform extraction.Extraction liquid order water and saturated common salt solution washing, drying.Steaming desolventizes, and the residuum that obtains is through purification by silica gel column chromatography (elutriant: hexane/ethyl acetate), obtain 2-(8-two benzyloxies-2-oxo-1,2,3,4-tetrahydrochysene-5-quinolyl)-benzhydryl ester (2.85 grams of 2-oxyacetic acid, 50%), is colourless crystallization.

M.P.165-166℃

The IR(Nujol mull): 3250,1750,1670,1610,1590cm ^-1

MS（m/z）：570（MH ⁺）

(2) product that obtains above is by embodiment 1, and the method for (1)-(a) is handled, and obtains 2-(8-two benzyloxies-2-oxo-1,2,3,4-tetrahydrochysene-5-quinolyl)-2-(Phthalimide oxygen) benzhydryl ester of acetate.

M.P.180-183℃

The IR(Nujol mull): 3240,1790,1760,1740,1670,1610,1590cm ^-1

MS（m/z）：715（MH ⁺）

(3) compound that obtains above is by embodiment 1-(2) same method handles and obtains 2-amino oxygen base-2-(8-two benzyloxies-2-oxo-1,2,3,4-tetrahydrochysene-5-quinolyl)-benzhydryl ester of acetate.

M.P.166-168℃

The IR(Nujol mull): 3410,3320,3240,1750,1680,1610,1590cm ^-1

MS（m/z）：585（MH ⁺）

(4) product that obtains above is by embodiment 1-(3) same method processing, obtain 2-2-triphenyl amine base-4-thiazolyl)-2-[(8-two benzyloxies-2-oxo-1,2,3,4-tetrahydrochysene-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino] acetate.

M.P.142-144 ℃ (decomposition)

The IR(Nujol mull): 3400,3220,1760,1740,1700(sh), 1680cm ^-1

MS（m/z）：981（MH ⁺）

(5) product that obtains above is by embodiment 1-(4) same method processing, obtain 7 β-(Z)-2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-two benzyloxies-2-oxo-1,2,3,4-tetrahydrochysene-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino] acetamido } Cephalosporanic acid.

M.P.138-142 ℃ (decomposition)

The IR(Nujol mull): 3400,3250,1790,1740,1690cm ^-1

MS（m/z）：1235（MH ⁺）

Embodiment 38

Corresponding raw material is pressed the same quadrat method of embodiment 2 and is handled, obtain 7 β-(Z)-2-(2-amino-4 thiazolyl)-2-[(8-hydroxyl-2-oxo-1,2,3,4-tetrahydrochysene-5-quinolyl) (carboxyl) methoxy imino] acetamido Cephalosporanic acid.

M.P＞170 ℃ (decomposition)

The IR(Nujol mull): 3300(br), 3200(sh), 1780,1730,1670(br) cm ^-1

MS（m/z）：661（MH ⁺）

The disodium salt of this product

M.P.＞170 ℃ (decomposition)

The IR(Nujol mull): 3340(br), 3200(sh), 1760,1660,1600cm ^-1

MS（m/z）：727（MNa ⁺），7.05（MH ⁺）.

NMR（D ₂O）δ：2.13 and 2.15（3H，sx2），2.61-2.68（2H，m），3.01-3.13（2H，m），2.96，3.46（2H，ABq，J＝18Hz），4.68 and 4.71（1H，dx2，J＝13Hz and 12Hz），4.77 and 4.89（1H，dx2，J＝13Hz and 12Hz），5.01 and 5.03（1H，dx2，J＝4.4Hz and 4.4Hz），5.64 and 5.68（1H，dx2，J＝4.4Hz and 4.4Hz），5.69 and 5.70（1H，s），6.82 and 6.83（1H，dx2，J＝8.3Hz and 8.3Hz），6.96 and 6.99（1H，dx2，J＝8.3Hz and 8.3Hz），7.02（1H，s）

Embodiment 39

(1) diphenyl diazomethane (15.6g) is added to 2-(8-hydroxyl-2-oxo-1H-5 quinolyl)-2-oxyacetic acid (11.8g) is in the suspension of 17% tetrahydrofuran aqueous solution, and this mixture of stirring is 3 days under the room temperature.Steaming desolventizes, and adds ether (250ml) in the residuum that obtains, so that solid is cracked, solid collected by filtration, with ether washing (300ml), decompression is dry down, obtains 2-(8-hydroxyl-2-oxo-1H-5-quinolyl)-benzhydryl ester (17.16g) of 2-oxyacetic acid.

M.P.218.5-219.5 ℃ (decomposition)

The IR(Nujol mull): 3365,3240,2720-2580,1730,1645,1630,1590cm ^-1

MS（m/z）：402（MH ⁺）

(2) product that obtains above (16.15g) adds salt of wormwood (4.2g) and methyl iodide (7.8ml) successively in the solution of dimethyl formamide (81ml), this mixture stirred under room temperature 7 hours.Down frozen water (480ml) is added in this mixture ice-cooled, stirs.Filter to collect the precipitation of separating out, water washing, and drying under reduced pressure obtains 2-(8-methoxyl group-2-oxo-1H-5-quinolyl)-benzhydryl ester (16.05g) of 2-oxyacetic acid.

M.P.177-182℃

The IR(Nujol mull): 3330,3160,1740,1650,1630,1600cm ^-1

MS（m/z）：416（MH ⁺）

(3) product that obtains is above handled with quadrat method by embodiment (1)-(a), obtains 2-(8-methoxyl group-2-oxo-1H-5-quinolyl)-2-(Phthalimide oxygen base) benzhydryl ester of acetate.

M.P.206-209℃

The IR(Nujol mull): 3170,1790,1740,1660,1610cm ^-1

MS（m/z）：561（MH ⁺）

(4) corresponding raw material is pressed example 1-(2) identical method handles, and obtains 2-amino oxygen base-2-(8-methoxyl group-2-oxo-1H-5-quinolyl) benzhydryl ester of acetate.

M.P.166-168℃

The IR(Nujol mull): 3280,3230,3150,1750,1660,1610cm ^-1

MS（m/z）：431（MH ⁺）

(5) corresponding raw material is pressed embodiment 1-(3) same procedure handle, obtain 2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-methoxyl group-2-oxo-1H-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino] acetate.

M.P.157-158.5 ℃ (decomposition)

The IR(Nujol mull): 3380,3220(br), and 1740,1670,1610cm ^-1

MS（m/z）：827（MH ⁺）

(6) corresponding raw material is pressed embodiment 1-(4) same procedure handle, obtain 7 β-(Z)-2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-methoxyl group-2-oxo-1H-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino]-acetamido Cephalosporanic acid.

M.P.154-156℃

The IR(Nujol mull): 3220(br), 1790,1740,1660,1610cm ^-1

MS（M/Z）：1081（MH ⁺）

Embodiment 40

Corresponding initial compounds is pressed the identical methods of embodiment 2 handles, obtain 7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-methoxyl group-2-oxo-1H-5-quinolyl) (carboxyl) methoxy imino] acetamido Cephalosporanic acid.

M.P.＞160 ℃ (decomposition)

The IR(Nujol mull): 3300(br), 3200(br), 1780,1730,1660(br), 1610cm ^-1

MS（m/z）：673（MH ⁺）

The disodium salt of this product

M.P.＞160 ℃ (decomposition)

The IR(Nujol mull): 3350(br), 3200(sh), 1770,1730(sh), and 1660,1610cm ^-1

MS（m/z）：717（MH ⁺）

NMR（D ₂O）δ：2.12 and 2.13（3H，sx2），2.87 and 2.93（1H，dx2，J＝18Hz and 18Hz），3.38 and 3.41（1H，dx2，J＝18Hz and 18Hz），4.01 and 4.02（3H，sx2），4.68 and 4.69（1H，dx2，J＝13Hz and 13Hz），4.85 and 4.87（1H，dx2，J＝13Hz and 13Hz），4.93 and 4.95（1H，dx2，J＝4.9Hz and 4.9Hz），5.60 and 5.68（1H，dx2，J＝4.9Hz and 4.9Hz），5.99（1H，s），6.77 and 6.79（1H，dx2，J＝9.8Hz and 9.8Hz），7.02 and 7.03（1H，sx2），7.18 and 7.20（1H，dx2，J＝8.3Hz and 8.3Hz），7.34 and 7.36（1H，dx2，J＝8.3Hz and 8.3Hz），8.29 and 8.37（1H，dx2，J＝9.8Hz and 9.8Hz）

Embodiment 41

(1) under argon atmospher and in 25 minutes with 2-(8-two benzyloxies-2-oxo-1H-5-quinolyl)-2-(Phthalimide oxygen base) benzhydryl ester (10.6g) of acetate is added to sodium hydride (750mg) in the suspension of dimethyl formamide (50ml) in the drips of solution of dimethyl formamide (60ml), stirred this mixture 1.5 hours under the room temperature, reaction soln is cooled to 0 ℃, to wherein dripping methyl iodide (8.44g), under same temperature, stirred this mixture 1.5 hours.Mixture is poured in the 0.05N hydrochloric acid (330ml), and with the ethyl acetate extraction precipitation, behind the extract washing and drying, steaming desolventizes.The residuum that obtains is through purification by silica gel column chromatography (elutriant: hexane/ethyl acetate) obtain 2-(8-two benzyloxies-1-methyl-2-oxo-1H-5-quinolyl)-2-(Phthalimide oxygen base) benzhydryl ester (5.28g) of acetate.

The IR(Nujol mull): 1790,1760,1740,1660,1610,1590cm ^-1

MS（m/z）：727（MH ⁺）

NMR（CDCl ₃）δ：3.89（3H，s），6.21（1H，s），6.41（1H，s），6.70（1H，d，J＝9.8Hz），6.82-7.40（23H，m），7.69-7.80（4H，m），8.34（1H，d，J＝9.8Hz）

(2) product that will obtain above is by embodiment 1, and (1)-(a) identical method is handled, and obtains 2-amino oxygen base-2-(8-two benzyloxies-1-methyl-2-oxo-1H-5-quinolyl) benzhydryl ester of acetate.

The IR(Nujol mull): 3310,3240,1750,1660,1610,1590,1560cm ^-1

MS（m/z）：597（MH ⁺）

NMR（CDCl ₃）δ：3.88（3H，s），5.55（1H，s），5.91（2H，brs），6.20（1H，s），6.61（1H，d，J＝9.9Hz），6.79-7.43（23H，m），8.00（1H，d，J＝9.9Hz）

(3) product that will obtain above is by embodiment 1-(2) identical method processing, obtain 2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-two benzyloxies-1-methyl-2-oxo-1H-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino] acetate.

M.P.140-145 ℃ (decomposition)

The IR(Nujol mull): 3220(br), 1740,1660,1610(sh) 1590cm ^-1

MS（m/z）：993（MH ⁺）

NMR（CDCl ₃）δ：3.83（3H，s），6.16（1H，s），6.19（1H，s），6.52（1H，d，J＝9.8Hz），6.70（1H，s），6.79-7.36（38H，m），7.50（1H，br），8.02（1H，d，J＝9.8Hz）

(4) product that obtains above is by embodiment 1-(3) identical method handle, obtain 7 β-(Z)-2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-two benzyloxies-1-methyl-2-oxo-1H-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino] acetamido Cephalosporanic acid.

M.P.139-141 ℃ (decomposition)

The IR(Nujol mull): 3240(br), 1790,1740,1690,1660cm ^-1

MS（m/z）：1247（MH ⁺）

NMR（DMSO-d ₆）δ：2.00 and 2.03（3H，sx2），3.00-3.60（2H，m），3.86（3H，s），4.65 and 4.68（1H，dx2，J＝13Hz and 13Hz），4.90 and 4.98（1H，dx2，J＝13Hz and 13Hz），4.94 and 5.08（1H，dx2，J＝4.9Hz and 4.9Hz），5.64（1H，m），6.18（1H，s），6.50 and 6.51（1H，dx2，J＝9.8Hz and 9.8Hz），6.67，6.75，6.78，6.80 and 6.82（3H，each s），7.03-7.57（37H，m），8.08 and 8.10（1H，dx2，J＝9.8Hz and 9.8Hz），8.87 and 8.90（1H，sx2），9.59 and 9.63（1H，dx2，J＝7.8Hz and 7.8Hz）

Embodiment 42

The compound that embodiment 41 obtains is handled by the identical methods of embodiment 2, obtain 7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-1-methyl-2-oxo-1H-5-quinolyl) (carboxyl) methoxy imino] acetamido Cephalosporanic acid.

M.P.＞170 ℃ (decomposition)

The IR(Nujol mull): 3300-3200,1780,1740,1650,1590cm ^-1

The disodium salt of this product

M.P.＞145 ℃ (decomposition)

The IR(Nujol mull): 3340(br), 3200,1770,1650,1590cm ^-1

NMR（D ₂O）δ：2.13 and 2.14（3H，sx2），2.87 and 2.94（1H，dx2，J＝18Hz and 18Hz），3.37 and 3.40（1H，dx2，J＝18Hz and 18Hz），3.96 and 3.99（3H，sx2），4.69（1H，brd，J＝11Hz），4.79-4.93（1H，m），4.87 and 4.91（1H，dx2，J＝4.9Hz and 4.9Hz），5.56 and 5.66（1H，dx2，J＝4.9Hz and 4.9Hz），5.99（1H，s），6.76 and 6.78（1H，dx2，J＝9.8Hz and 9.8Hz），7.02 and 7.03（1H，sx2），7.14 and 7.15（1H，dx2，J＝8.3Hz and 8.3Hz），7.25 and 7.28（1H，dx2，J＝8.3Hz and 8.3Hz），8.16 and 8.25（1H，dx2，J＝9.8Hz and 9.8Hz）

Embodiment 43-48

Identical method according to embodiment 3 is handled corresponding initial compounds, obtains the compound of table 4.

Embodiment 49

The compound (disodium salt) that embodiment 39 is obtained and 1-allyl group-4-sulfo-pyridone are pressed embodiment 4 identical methods and are handled, just make solvent with 50% acetonitrile solution, obtain 7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-methoxyl group-2-oxo-1H-5-quinolyl) (carboxyl) methoxy imino] acetamido-3-(1-allyl group-4-pyridine sulfenyl)-3-cephem-4-carboxylic acid sodium salt.

M.P.＞175 ℃ (decomposition)

The IR(Nujol mull: 3370(br), 3200(sh), 1770,1660,1630,1610cm ^-1

MS（m/z）：808（MNa ⁺），786（MH ⁺）

NMR（D ₂O）δ：2.94 and 2.96（1H，dx2，J＝18Hz and 18Hz），3.28 and 3.34（1H，dx2，J＝18Hz and 18Hz），4.15（1H，d，J＝14Hz），4.23 and 4.34（1H，dx2，J＝14Hz and 14Hz），4.91-4.98（3H，m），5.38（1H，d，J＝17Hz），5.49（1H，d，J＝10Hz），5.56 and 5.61（1H，dx2，J＝4.9Hz and 4.9Hz），5.92-6.12（1H，m），5.96 and 5.97（1H，sx2），6.71 and 6.74（1H，dx2，J＝9.8Hz and 9.8Hz），6.95（1H，s），7.08 and 7.13（1H，dx2，J＝8.3Hz and 8.3Hz），7.29 and 7.36（1H，dx2，J＝8.3Hz and 8.3Hz），7.77（2H，d，J＝6.8Hz），8.24-8.39（3H，m）

Embodiment 50-52

7 beta-aminos-3-(3-amino-2-methyl-1-picolyl)-and same procedure processing that 3-cephem-4-carboxylicesters and corresponding initial compounds press embodiment 27, obtain the compound of table 5.

Embodiment 53

(1) with 2-(8-two benzyloxies-2-oxo-1H-5-quinolyl)-benzhydryl ester (5.03g) of 2-oxyacetic acid is dissolved in 17% tetrahydrofuran aqueous solution (96ml), under ice-cooled and stirring, in this solution, drip 2.0N aqueous sodium hydroxide solution (8.8ml), stirred this mixture 2 hours under the room temperature.The ice-cooled 2.4N hydrochloric acid (7.4ml) that drips in mixture down adds tetrahydrofuran aqueous solution (in right amount) again, makes mixture become homogeneous phase.Steam and remove tetrahydrofuran (THF), filter and collect the precipitation of separating out, water, ether washing behind 60 ℃ of drying under reduced pressure, obtain 2-(8-two benzyloxies-2-oxo-1H-5-quinolyl successively)-2-oxyacetic acid (3.42g), be colorless solid.

M.P.186-188 ℃ (decomposition)

The IR(Nujol mull): 3360,3160,1710,1640,1600cm ^-1

MS（m/z）：401（M ⁺）

(2) product that obtains above (145.8g) with (R)-2-amino-3-methyl isophthalic acid, 1-phenylbenzene-butanols-1(92.8g) reaction, twice of recrystallizing methanol of the salt that generates, obtain photoactive 2-(8-two benzyloxies of tool-2-oxo-1H-5-quinolyl)-(the R)-2-amino-3-methyl isophthalic acid of 2-oxyacetic acid, 1-phenylbenzene-butanols-1 salt (47.7g) is colourless crystallization.

M.P.208.5-209.5 ℃ (decomposition)

The IR(Nujol mull): 3440,3400,3360,3460,1660,1630,1600,1590cm ⁺

MS（m/z）：657（MH ⁺）

[α] D ²⁰-53.6 ⁰(c=1.00, methyl alcohol)

(3) diphenyl diazomethane (49.2g) is added to the compound (111g) that obtains above in the suspension of tetrahydrofuran (THF) (3.3 liters), stirred 2 days under the room temperature, the deep purple solution that obtains is evaporated to remove tetrahydrofuran (THF), residuum and ether (200ml) azeotropic steams and slips 2 times, obtains crystallization.In crystallization, add isopropyl ether (1 liter) so that crystallization is cracked, filter and collect crystallization, ether washing (1 liter), 45 ℃ of drying under reduced pressure obtain optically active 2-(8-two benzyloxies-2-oxo-1H-5-quinolyl)-benzhydryl ester (94.6g) of 2-oxyacetic acid.

M.P.194-196℃

The IR(Nujol mull): 3320,1740,1640,1600cm ^-1

MS（m/z）：568（MH ⁺）

[α] D ²⁰-6.2 ⁰(C=1.00, chloroform)

Optical purity:＞98%ee[measures with high performance liquid chromatography, and (stationary phase: the Mierocrystalline cellulose derivation is applied and covered silicagel column; Trade(brand)name: Opti-Pak XC; Moving phase: ethane/ethanol=3: 2]

(4) product that obtains above is by embodiment 1, and the same procedure of (1)-(a) is handled, and obtains optically active 2-(8-two benzyloxies-2-oxo-1H-5-quinolyl)-2-(Phthalimide oxygen base) benzhydryl ester of acetate.

M.P.194-196℃

The IR(Nujol mull): 3180,3060,3020,1790,1760,1740,1650,1610cm ^-1

MS（m/z）：713（MH ⁺）

(5) product that obtains above is by embodiment 1-(2) same procedure handle, obtain optically active 2-amino oxygen base-2-(8-two benzyloxies-2-oxo-1H-5-quinolyl) benzhydryl ester of acetate.

M.P.182-184 ℃ (decomposition)

The IR(Nujol mull): 3320,3300,3220,3160,1750,1730,1650,1610cm ^-1

MS（m/z）：583（MH ⁺）

(6) product that obtains above is by embodiment 1-(3) same procedure handle, obtain optically active 2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-two benzyloxies-2-oxo-1H-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino] acetate.

M.P.154-156℃

The IR(Nujol mull): 3400,3200(br), and 1740,1670,1610cm ^-1

MS（m/z）：979（MH ⁺）

(7) product that obtains above is by embodiment 1-(4) same procedure handle, obtain optically active 7 β-(Z)-2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-two benzyloxies-2-oxo-1H-5-quinolyl) (hexichol methoxycarbonyl) methoxy imino] acetamido Cephalosporanic acid.

M.P.142-145 ℃ (decomposition)

The IR(Nujol mull): 3400,3250(br), and 1790,1740,1670,1600cm ^-1

MS（m/z）：1233（MH ⁺）

NMR（DMSO-d ₆）δ：1.99（3H，s），3.09，3.35（2H，ABq，J＝18Hz），4.62，4.91（2H，ABq，J＝13Hz），4.94（1H，d，J＝4.9Hz），5.62（1H，dd，J＝7.8Hz，4.9Hz），6.13（1H，s），6.46（1H，d，J＝9.8Hz），6.77-7.38，7.72-7.76（40H，m），8.15（1H，d，J＝9.8Hz），8.90（1H，brs），9.59（1H，d，J＝7.8Hz），11.0（1H，brs）

Embodiment 54-55

By embodiment 53-(7) optically active Cephalosporanic acid compound of obtaining and corresponding initial compounds be by embodiment 3-(1) identical method handles, and obtains following compound.

(54) optically active 7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl) (carboxyl) methoxy imino] acetamido-3-(1-quinoline methyl)-3-cephem-4-carboxylic acid sodium salt.

The physicochemical property of top compound and embodiment 3-(2) physicochemical property of β-isomer of obtaining are identical.

(55) optically active 7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl) (carboxyl) methoxy imino] acetamido-3-(3-chloro-1-picolyl)-3-cephem-4-carboxylic acid sodium salt.

The physicochemical property of top compound are identical with the physicochemical property of β-isomer that embodiment 26 obtains.

Embodiment 56

Embodiment 53-(6) the optically active oxygen imines acetic acid compound that obtains and corresponding initial compounds are by implementing just 27(1) same procedure handle, obtain optically active 7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl) (carboxyl) methoxy imino] acetamido-3-(3-amino-2-methyl-1-picolyl)-3-cephem-4-carboxylic acid sodium salt.

The physicochemical property of top compound and embodiment 27-(2) physicochemical property of β-isomer of obtaining are identical.

Embodiment 57

(1) in argon atmospher and ice-cooledly down I-hydroxybenzotriazole (405mg) and dicyclohexylcarbodiimide (567mg) are added to embodiment 53-(6) compound (2.45g) that obtains in the solution of tetrahydrofuran (THF) (20ml), 3 hours (suspension that obtains is called reaction soln A) of this mixture of stirring under the room temperature.In addition, under argon atmospher with the 4-methoxybenzyl alcohol ester (1.58g) of 7 β-phenylacetyl amido-3-chloromethyl-3-cephem-4-carboxylic acid in the solution of ethylene dichloride (40ml) with ice-cooled, to wherein adding pyridine (0.49ml) and phosphorus pentachloride (1.01g), this mixture stirred 1 hour under same temperature, and stirring at room is 30 minutes then.In this mixture, drip methyl alcohol (24ml) under ice-cooled, at room temperature reacted then 15 minutes.After ice-cooled, to the potassium dihydrogen phosphate aqueous solution that wherein adds 0.5N (48ml), this mixture of stirring at room 1.5 hours.The reaction soln dichloromethane extraction, extraction liquid washs with common salt aqueous solution, and dry back is steamed and is desolventized.The residuum that obtains (1.87g) is dissolved in the tetrahydrofuran (THF) (15ml) and (is called reaction soln B).Reaction soln B is added drop-wise among the reaction soln A, stirred 17 hours under the mixture room temperature.The filtering precipitation, solvent is removed in the filtrate evaporation.The oily residuum through purification by silica gel column chromatography (elutriant: hexane/ethyl acetate), obtain optically active 7 β-(Z)-2-(2-triphenyl amine base-4-thiazolyl)-2-[(8-two benzyloxies-2-oxo-1H-5-quinolyl) the hexichol methoxycarbonyl) methoxy imino] acetamido-the 3-(chloromethyl)-the 4-methoxy benzyl ester (2.12g) of 3-cephem-4-carboxylic acid.

The IR(Nujol mull): 3380,3280,3200,1790,1740,1660,1610cm ^-1

In N,N-DIMETHYLACETAMIDE (8ml) solution of the product that (2) obtains upward (800mg), add zinc iodide (77mg) and 1-allyl group-4-sulfo-pyridone (272mg) successively under ice-cooled and argon atmospher, mixture stirred 22 hours under same temperature.Under ice-cooled, in reaction mixture, add the entry (20ml) and the saturated common salt aqueous solution (20ml), filter collection precipitation, water and ethyl acetate washing successively, spend the night in the room temperature decompression, be concentrated into driedly, the solid that obtains (840mg) is ice-cooled down to join in the mixture of trifluoroacetic acid (2.5ml)/methyl-phenoxide (2.5ml) stirring at room 2 hours.With ice-cooled, add isopropyl ether (50ml), stirred this mixture 15 minutes, filter collection precipitation is with isopropyl ether washing, reduced pressure at room temperature.The solid that obtains (555mg) is suspended in the water (5ml), add saturated sodium bicarbonate aqueous solution and regulate its PH to 8.0, through HP-20 column chromatography purification (elutriant: water and 20% methanol aqueous solution), merge the part that contains the purpose compound, concentrate, freeze-drying, obtain optically active 7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl) (carbonyl) methoxy imino] acetamido-3-[(1-allyl group-4-pyridyl) sulphomethyl]-3-cephem-4-carboxylic acid sodium salt (104mg).

M.P.＞165 ℃ (decomposition)

The IR(Nujol mull): 3350(dr), 3180(br), 1770,1660,1630,1610cm ^-1

NMR（DMSO-d ₆）δ：2.96，3.34（2H，ABq，J＝18Hz），4.79（2H，brs），4.90-4.93（3H，m），5.33（1H，d，J＝17Hz），5.47（1H，d，J＝9.8Hz），5.90-6.10（1H，m），5.97（1H，s），6.74（1H，d，J＝9.8Hz），6.95（1H，s），7.01（1H，d，J＝8.3Hz），7.23（1H，d，J＝8.3Hz），7.73（2H，d，J＝6.8Hz），8.29（2H，d，J＝6.8Hz），8.35（1H，d，J＝9.8Hz）

Embodiment 58

Argon atmospher and ice-cooled down, sodium iodide (164mg) and 3-chloropyridine (454mg) are added to the 57-(1 by embodiment) (1: 33g) in the solution of acetonitrile (13ml), mixture stirs at 8 ℃ and trembled 14 hours, removes acetonitrile under reduced pressure for the compound that obtains; Under ice-cooled, add the mixed solution of trifluoroacetic acid (8ml)/methyl-phenoxide (8ml) in the residuum that obtains, stirred 2 hours under the room temperature, mixture adds isopropyl ether (150ml) with ice-cooled, stirs 15 minutes.Filter collection precipitation is with isopropyl ether washing, drying under reduced pressure under the room temperature.The solid suspension that obtains is in water (20ml), add saturated sodium bicarbonate aqueous solution and regulate its PH to 8.0, through HP-20 column chromatography purification (elutriant: water and 20% methanol aqueous solution), merge the part that contains the purpose compound, concentrate, freeze-drying, obtain optically active 7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl) (carbonyl) methoxy imino] acetamido-3-(3-chloro-1-picolyl)-3-cephem-4-carboxylic acid sodium salt (220mg).

[preparation of initial compounds]

Reference example 1

(1) 5-(2; 2-dihydroxyl ethanoyl)-and the 8-(phenoxy group) quinolone (58g) is suspended in butyl alcohol-tert (1000ml) and 5% potassium dihydrogen phosphate aqueous solution (650ml); following to the mixture that wherein drips potassium permanganate (56.3g) and water (930ml) in 5-7 ℃ with stirring; stirred the mixture 7 hours in 5-7 ℃, under room temperature, stirred 17 hours again.Under ice-cooled,, add concentrated hydrochloric acid to regulate its PH to 1-2, stirred 30 minutes to wherein adding saturated sodium bisulfite solution (535ml).Filter collection precipitation, washing, drying gets 5-oxalyl-8-(benzyloxy) quinolone (36.7g)

M.P.217-219 ℃ (decomposition)

The IR(Nujol mull): 3200-2400,1700,1670,1640,1600cm ^-1

MS（m/z）：323（M ⁺）

(2) product that obtains upward (74g) is in the solution of tetrahydrofuran (THF) (2000ml) and water (1500ml), add wet 10% palladium-carbon (37g, humidity 50%), under nitrogen atmosphere, stirred 3 hours, filtration catalizer with tetrahydrofuran (THF) and water mixed liquid washing catalyst, merges washings and filtrate, steaming desolventizes, and gets 2-hydroxyl-2-(8-hydroxyl-2-oxo-1H-5-quinolyl after the drying) acetate (54g).

M.P.259-261 ℃ (decomposition)

The IR(Nujol mull): 3160,3080,2780-2560,1725,1695,1640,1600cm ^-1

MS（m/z）：236（MH ⁺）

(3) product that obtains above (39g) heating for dissolving is cooled to 40 ℃ then in tetrahydrofuran (THF) (3000ml) and water (600ml), add diphenyl diazomethane (96.6g), again in 55 ℃ of stirrings 20 hours, added diphenyl diazomethane (96.6g) restir in this mixture again 24 hours after stirring the mixture 1 hour.Steaming desolventizes, and adds ether in the residuum and obtains crystallization.The crystallization that filter collection is separated out,, dry 2-(8-two benzyloxies-2-oxo-1H-5-quinolyl) with the ether washing-benzhydryl ester (57.2g) of 2-oxyacetic acid.

M.P.183-185 ℃ (decomposition)

The IR(Nujol mull): 3330,1750,1650,1600cm ^-1

MS（m/z）：568（MH ⁺）

[effect of the present invention]

The compounds of this invention (I) and pharmaceutical salts thereof have good anti-microbial activity to the multiple microorganism of the wide spectrum that comprises gram-positive microorganism and Gram-negative bacteria, particularly β-Nei Xiananmei is produced bacterium very high stability is arranged, therefore, these compounds can be used to treat the mammiferous multiple transmissible disease that comprises the mankind that mentioned microorganism causes as chemotherapeutics, also can be used as the additive of animal-feed.

* 1: each isomer separates [stationary phase: C through high performance liquid chromatography ₁₈Silica gel YMC Pack S-343); Moving phase: acetonitrile/30mM phosphate buffered saline buffer (PH7.0)=1: 9]

* 2: each isomer separates [stationary phase: C through high performance liquid chromatography ₁₈Silica gel (YMC Pack D-ODS-10); Moving phase: acetonitrile/30mM phosphate buffered saline buffer pH7.0)=6: 94]

Table 2

In table 2, the R among the embodiment 28-31 ⁵Be COO ^-,

R among the embodiment 32-33 ⁵Be COONa

* isomer with high performance liquid chromatography separate [stationary phase:

C ₁₈Silica gel (YMC-Pack D-ODS-10), moving phase: acetonitrile/30mM phosphate buffered saline buffer (pH=7.0)=6: 94]

* isomer separates [stationary phase: C18-silica gel (YMC-Pack D-ODS-10), moving phase: acetonitrile/30mM phosphate buffered saline buffer (pH 7.0)=1: 9] through high performance liquid chromatography

* isomer separates [stationary phase: C18 silica gel (YMC Pack D-ODS-10), moving phase: acetonitrile/30mM phosphate buffer soln (pH 7.0)=8: 92] through high performance liquid chromatography

Claims

1, the cephalosporin compound of formula [I] or its pharmaceutical salts

In the formula, R ¹Be amino or protected amino, R ²Be hydroxyl, protected hydroxyl or low-carbon alkoxy, R ³Be carboxyl or protected carboxyl, R ⁴Be hydrogen atom, low-carbon alkyl, low-carbon (LC) thiazolinyl or formula-CH ₂R ⁴¹Group (the R in the formula of expression ⁴¹Be the nucleophilicity residue), R ⁵Be carboxyl, protected carboxyl or formula-COO ^-The group of expression, R ⁶Be hydrogen atom or low-carbon alkyl, dotted line is represented the existence of two keys or is not existed.

2, according to the compound of claim 1, wherein, R ⁴¹It is the low carbon chain acyloxy; Has optional substituent nitrogen heterocycle; Or quilt is contained the sulfenyl that optional substituent nitrogen heterocyclic ring group replaces.

3, according to the compound of claim 2, wherein, R ⁴¹It is the low carbon chain acyloxy; Pyridyl, quinolyl, isoquinolyl, 2,3-trimethylene pyridyl, 5,6,7,8-tetrahydric quinoline group or 2,3-pentamethylene pyridyl, one or two substituting group that can randomly be selected from following radicals on the ring replaces: halogen atom, low-carbon alkyl, low-carbon alkoxy, low-carbon (LC) carbalkoxy, amino, carbamyl, cyano group, formamido-and hydroxyl (low-carbon (LC)) alkyl; Can be by optional thiadiazoles sulfenyl or the tetrazole sulfenyl that replaces of low-carbon alkyl; Or can be by the optional pyridine sulfenyl that replaces of low-carbon (LC) thiazolinyl.

4, according to the compound of claim 3, R wherein ⁴Be hydrogen atom, methyl, vinyl or formula-CH ₂R ⁴¹The group of representative (R wherein ⁴¹It is acetoxyl group; Pyridyl, quinolyl, isoquinolyl, 2,3-trimethylene pyridyl, 5,6,7,8-tetrahydric quinoline group or 2,3-pentamethylene pyridyl can replace by selected one or two substituting group in following group on the ring: halogen atom, methyl, methoxyl group, methoxycarbonyl, amino, carbamyl, cyano group, formamido-and methylol; Can choose wantonly by methyl substituted 5-(1,2, the 3-thiadiazolyl group) sulfenyl or 5-tetrazole base sulfenyl; Or 1-allyl group-4-pyridine sulfenyl).

5, according to claim 1, the compound one of in 2,3,4, wherein, R ¹Be amino, R ³Be carboxyl, R ⁵Be carboxyl or formula-COO ^-The group of representative, R ⁶Be hydrogen atom or methyl.

6, according to the compound of claim 5, wherein, R ²Be hydroxyl or methoxyl group, R ²Can be in 2-oxo-1H-quinoline ring or 2-oxo-1,2,3, the 8-position of 4-tetrahydroquinoline ring replaces.

7, according to the compound of claim 6, wherein, R ²Be hydroxyl, R ⁶Be hydrogen atom, the existence of the two keys of dotted line representative.

8, according to the compound of claim 7, wherein, R ⁴Be formula-CH ₂R ⁴¹The group of representative (R wherein ⁴¹Be acetoxyl group, pyridyl, 3-chloropyridine base, 3-amino-2-methyl pyridyl or quinolyl).

9, according to the compound of claim 8, wherein, R ⁴¹Be pyridyl, 3-chloropyridine base, 3-amino-2-methyl pyridyl or quinolyl.

10,7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl) (carboxyl) oxygen imido grpup] acetamido-3-(1-quinoline methyl)-3-cephem-4-carboxylic acid or its pharmaceutical salts.

11,7 β-(Z)-2-(2-amino-4-thiazolyl)-2-[(8-hydroxyl-2-oxo-1H-5-quinolyl) (carboxyl) methoxy imino] acetamido-3-(3-chloropyridine methyl)-3-cephem-4-carboxylic acid or its pharmaceutical salts.

12,7 β-(Z)-2-(2-amino-4-thiazolyl)-2[(8-hydroxyl-2-oxo-1H-5-quinolyl) (carboxyl) methoxy imino] acetamido-3-(3-amino-2-methyl-1-picolyl)-3-cephem-4-carboxylic acid or its pharmaceutical salts.

13, the preparation method of formula [I] cephalosporin compound and pharmaceutical salts thereof:

R in the formula ¹Be amino or protected amino, R ²Be hydroxyl, protected hydroxyl or alkoxyl group, R ³Be carboxyl or protected carboxyl, R ⁴Be hydrogen atom, low-carbon alkyl, low-carbon (LC) thiazolinyl or formula-CH ₂R ⁴¹The group of representative (R wherein ⁴¹Be the nucleophilicity residue), R ⁵Be carboxyl, protected carboxyl or formula-COO ^-The group of representative, R ⁶Be hydrogen atom or low-carbon alkyl, dotted line is represented the existence of two keys or does not exist that this method comprises, with the oxygen imido grpup acetic acid compound of formula [II] or the amino cephalosporin compound of 7-or its salt condensation of its salt or its active derivative and formula [III], then product randomly is transformed into its pharmaceutical salts

R in the formula [II] ¹, R ², R ³, R ⁶The same with the definition of dotted line, the R in the formula [III] ⁴And R ⁵Definition the same.

14, the cephalosporin compound of formula [I] or the preparation method of its pharmaceutical salts:

R in the formula ¹Be amino or protected amino, R ²Be hydroxyl, protected hydroxyl or low-carbon alkoxy, R ³Be carboxyl or protected carboxyl, R ⁴Be hydrogen atom, low-carbon alkyl, low-carbon (LC) thiazolinyl or formula-CH ₂R ⁴¹The group of representative (R wherein ⁴¹Be the nucleophilicity residue), R ⁵Be carboxyl, protected carboxyl or-COO ^-Base, R ⁶Be hydrogen atom or low-carbon alkyl, dotted line is represented the existence of two keys or does not exist that this method comprises, with the compound or its salt of formula [IV] and the compound or its salt reaction of formula [V], then product randomly is transformed into its pharmaceutical salts,

R in the formula [IV] ¹, R ⁴And R ⁵Definition the same, the Z in the formula [V] is active residue, R ², R ³, R ⁶The same with the implication of dotted line.

15, the cephalosporin compound of formula [I-a] or the preparation method of its pharmaceutical salts:

R in the formula ¹Be amino or protected amino, R ²Be hydroxyl, protected hydroxyl or low-carbon alkoxy, R ³Be carboxyl or protected carboxyl, R ⁴¹Be the nucleophilicity residue, R ⁵Be carboxyl, protected carboxyl or-COO ^-Base, R ⁶Be hydrogen atom or low-carbon alkyl, dotted line is represented the existence of two keys or does not exist that this method comprises, with cephalosporin compound or its salt and the reaction of nucleophilicity compound or its salt of formula [VI], and then randomly product is transformed into its pharmaceutical salts;

X in the formula [VI] ¹Be active base, R ¹, R ², R ³, R ⁵, R ⁶The same with the definition of dotted line.

16, the thiazole acetic acid derivative of formula [II-a] or its salt:

R in the formula ¹Be amino or protected amino, R ²Be hydroxyl, protected hydroxyl or low-carbon alkoxy, R ³Be the group (formula-COOY is carboxyl or protected carboxyl) of carboxyl or protected carboxyl or formula-COOY representative, R ⁶Be hydrogen atom or low-carbon alkyl, dotted line is represented the existence of two keys or is not existed.

17, the quinolone compounds of formula [V] or its salt:

R in the formula ²Be hydroxyl or protected hydroxyl, R ³Be carboxyl or protected carboxyl, R ⁶Be hydrogen atom or low-carbon alkyl, Z is active residue, and dotted line is represented the existence of two keys or do not existed.

18, the cephalosporin compound of formula [VI] or its salt:

R in the formula ¹Be amino or protected amino, R ²Be hydroxyl, protected hydroxyl or low-carbon alkoxy, R ³Be carboxyl or protected carboxyl, R ⁵Be carboxyl, protected carboxyl or-COO ^-Base, R ⁶Be hydrogen atom or low-carbon alkyl, X ¹Be active residue, dotted line is represented the existence of two keys or is not existed.

19, a kind of pharmaceutical composition, said composition contain the sterilization significant quantity of any one compound or pharmaceutically acceptable salt thereof in the claim 1 to 12 and their pharmaceutical carrier.