CN100343260C

CN100343260C - Cephem compounds

Info

Publication number: CN100343260C
Application number: CNB2003801026422A
Authority: CN
Inventors: 大木秀德; 奥田真也; 山中敏夫; 大垣胜; 户田彩子; 川端浩二; 井上敏; 三隅启司; 伊藤健治; 佐藤贤治
Original assignee: Wakunaga Pharmaceutical Co Ltd; Yamanouchi Pharmaceutical Co Ltd
Current assignee: Wakunaga Pharmaceutical Co Ltd; Yamanouchi Pharmaceutical Co Ltd
Priority date: 2002-10-30
Filing date: 2003-10-27
Publication date: 2007-10-17
Anticipated expiration: 2023-10-27
Also published as: CN1708502A; AU2002952355A0; ZA200504181B

Abstract

The present invention relates to a compound of the formula [I]: wherein R<1> is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R<2> is hydrogen or amino protecting group, or R<1> and R<2> are bonded together and form lower alkylene or lower alkenylene; R<3> is hydrogen or lower alkyl; R<4> IS ; R<5> is carboxy or protected carboxy; and R<6> is amino or protected amino, or a pharmaceutically acceptable salt thereof, a process for preparing a compound of the formula [I], and a pharmaceutical composition comprising a compound of the formula [I] in admixture with a pharmaceutically acceptable carrier.

Description

Cephem compounds

Invention field

The present invention relates to new cephem (cephem) compound and pharmacologically acceptable salt thereof.More particularly, the present invention relates to have the new cephem compounds and the pharmacologically acceptable salt thereof of antimicrobial acivity, its preparation method comprises their pharmaceutical composition, and in humans and animals the method for treatment infectious diseases.

Disclosure of the Invention

An object of the present invention is to provide the new cephem compounds and the pharmacologically acceptable salt thereof of high activity with anti-multiple pathogenic microbes.

Another object of the present invention provides the method for described cephem compounds of preparation and salt thereof.

Another object of the present invention provides pharmaceutical composition, and described pharmaceutical composition comprises described cephem compounds or its pharmacologically acceptable salt as active ingredient.

Another object of the present invention provides the method for the infectious diseases that is caused by pathogenic microbes, and described method comprises to the human or animal who infects uses described cephem compounds.

Cephem compounds of the present invention is new, and can be represented by following general formula [I]:

Wherein

R ¹Be low alkyl group, hydroxyl (rudimentary) alkyl or halo (rudimentary) alkyl, and

R ²Be hydrogen or amino protecting group, perhaps

R ¹With R ²Be bonded together and form low-grade alkylidene or lower alkenylene;

R ³Be hydrogen or low alkyl group;

R ⁴Be

Wherein

A is

Wherein X is O or NH,

R ⁷Be hydrogen, low alkyl group or amino protecting group,

R ⁸Be hydrogen or hydroxyl,

R ⁹Be amino, the guanidine radicals of amino, one or two (rudimentary) alkylamino, protection, the guanidine radicals or the saturated 3-8 unit heterocyclic radical of protection, described heterocyclic radical contains 1-4 nitrogen-atoms, and optional by the amino replacement of amino or protection,

K, m, n and q are 0 or 1 independently, and

P is 0,1,2 or 3;

R ⁵It is the carboxyl of carboxyl or protection; And

R ⁶Be amino amino or protection.

For The compounds of this invention [I], point out following some.

That is to say that The compounds of this invention [I] comprises cis-isomeride (Z-shaped formula), trans-isomer(ide) (E form) and composition thereof.Cis-isomeride (Z-shaped formula) is meant a kind of geometrical isomer, and it has the ad hoc structure of following formula representative:

R wherein ⁵And R ⁶Respectively as defined above,

And trans-isomer(ide) (E form) is meant another kind of geometrical isomer, and it has the ad hoc structure of following formula representative:

R wherein ⁵And R ⁶Respectively as defined above,

And geometrical isomer that all are such and composition thereof is included in the scope of the present invention.

For the purpose of convenient, in present specification and claims, the ad hoc structure of these geometrical isomers and composition thereof is represented by following formula:

R wherein ⁵And R ⁶Respectively as defined above.

It may be noted that on the other hand the pyrazoles subbase part of compound [I] also exists with tautomeric form, and such tautomeric equilibrium can be represented by following formula

R wherein ¹, R ², R ³And R ⁴Respectively as defined above.

Above two kinds of tautomers all be included in the scope of the present invention, yet in present specification and claim, for convenience's sake, The compounds of this invention [I] is represented with the pyrazoles subbase of formula (A).

Cephem compounds of the present invention [I] can make by method as follows.

Method 1

Method 2

Method 3

Method 4

R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, A, k, m, n, p and q respectively as defined above,

R ¹⁰Be the carboxyl of protection,

Y is a leavings group,

Z ^Be negatively charged ion,

R ¹A is hydroxyl (rudimentary) alkyl of protection,

R ¹B is hydroxyl (rudimentary) alkyl,

R ⁹A be protection amino, protection guanidine radicals or contain the first heterocyclic radical of the protected amino saturated 3-8 that replaces of 1-4 nitrogen-atoms, and

R ⁹B is amino, guanidine radicals or the first heterocyclic radical of the saturated 3-8 by amino replacement that contains 1-4 nitrogen-atoms.

Initial compounds [II] and [VI] can make by following method.

Method A

Method B

R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ¹⁰, Y and Z ^Respectively as defined above,

R ¹¹Be the amino of protection,

R ¹²Be the carboxyl of protection, and

R ¹³Be amino protecting group or low alkyl group.

Initial compounds [VII] and [XI] or its salt can make by disclosed method or similar approach among the preparation example 3-6, the 8-47 that describe in the back and the 49-102.

In the application's context, being explained as follows in detail of the suitable example of various definition.

Except as otherwise noted, used term " rudimentary " is meant to have 1-6, the group of preferred 1-4 carbon atom.

Suitable " low alkyl group " and " low alkyl group " part in " hydroxyl (rudimentary) alkyl ", " hydroxyl of protection (rudimentary) alkyl ", " aryl (rudimentary) alkyl ", " halo (rudimentary) alkyl " and " one or two (rudimentary) alkylamino " comprises the straight or branched alkyl with 1-6 carbon atom; for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, tert-pentyl and hexyl, wherein C ₁-C ₄Alkyl is preferred.

Suitable " hydroxyl (rudimentary) alkyl " comprises hydroxyl (C ₁-C ₆) alkyl for example hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxyl amyl group and 6-hydroxyl hexyl, wherein hydroxyl (C ₁-C ₄) alkyl is preferred.

Suitable " halo (rudimentary) alkyl " comprises by 1-5 the halogen atom straight or branched alkyl with 1-6 carbon atom that replaces of chlorine, bromine, iodine and fluorine for example.The preferred embodiment of " halo (rudimentary) alkyl " comprises methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, brooethyl, 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl, 2-chloroethyl, 2,2-Dichloroethyl, 2,2,2-three chloroethyls, 3-fluoropropyl and 2,2,3,3,3-five fluoropropyls, wherein halo (C ₁-C ₄) alkyl is preferred.

Suitable " one or two (rudimentary) alkylamino " comprises one or two (C ₁-C ₆) alkylamino for example methylamino, dimethylamino, ethylamino, diethylamino, N-ethyl-N-methylamino, propyl group amino, butyl amino and N-ethyl-N-propyl group amino, wherein one or two (C ₁-C ₄) alkylamino is preferred.

By R ¹And R ²Suitable " low-grade alkylidene " that forms comprises having 1-6, the straight-chain alkyl-sub-of preferred 2-4 carbon atom, and for example methylene radical, ethylidene, trimethylene and tetramethylene, the straight-chain alkyl-sub-that wherein has 2 or 3 carbon atoms is preferred.

By R ¹And R ²Suitable " lower alkenylene " that forms comprises having 2-6, the straight chain alkenylene of preferred 2-4 carbon atom, and for example vinylidene and propenylidene, the straight chain alkenylene that wherein has 2 or 3 carbon atoms is preferred.

Suitable " the first heterocyclic radical of saturated 3-8 that contains 1-4 nitrogen-atoms " comprises azetidinyl (for example 1-azetidinyl and 3-azetidinyl), pyrrolidyl (for example 1-pyrrolidyl and 3-pyrrolidyl), imidazolidyl (for example 1-imidazolidyl and 4-imidazolidyl), piperidyl (for example piperidino and 4-piperidyl) and piperazinyl (for example 1-piperazinyl), and the first heterocyclic radical of saturated 4-6 that wherein contains 1-4 nitrogen-atoms is preferred.

The first heterocyclic radical of saturated 3-8 that contains 1-4 nitrogen-atoms can be chosen wantonly by the amino replacement of amino or protection.Choose the first heterocyclic radical of the saturated 3-8 that contains 1-4 nitrogen-atoms that is replaced by the amino of amino or protection wantonly and comprise 1-azetidinyl, 3-amino-1-azetidinyl, 3-tert-butoxycarbonyl amino-1-azetidinyl, 3-azetidinyl, 1-pyrrolidyl, 3-amino-1-pyrrolidyl, 3-tert-butoxycarbonyl amino-1-pyrrolidyl, 3-pyrrolidyl, piperidino, 4-piperidyl and 1-piperazinyl.

Suitable " aryl " part in " aryl (rudimentary) alkyl " comprises C ₆-C ₁₂Aryl is phenyl and naphthyl for example, and wherein phenyl is preferred.

Suitable " aryl (rudimentary) alkyl " comprises one, two or triphenyl (rudimentary) alkyl for example benzyl, styroyl, diphenyl-methyl and trityl.

Suitable " lower alkane acyl group " and " lower alkane acyl group " in " lower alkane acyl amino " part comprise the straight or branched alkanoyl with 1-6 carbon atom; for example formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, isovaleryl, valeryl and caproyl, wherein C ₁-C ₄Alkanoyl is preferred.

Suitable " lower alkoxy " part in " elementary alkoxy carbonyl " and " elementary alkoxy carbonyl amino " comprises the straight or branched alkoxyl group with 1-6 carbon atom, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, uncle's pentyloxy and hexyloxy, wherein C ₁-C ₄Alkoxyl group is preferred.

Suitable " amino protecting group " in " amino of protection " comprises acyl group as described below, replacement or unsubstituted aryl (rudimentary) alkylidene group [for example benzylidene, hydroxyl benzylidene etc.], aryl (rudimentary) alkyl for example, two or triphenyl (rudimentary) alkyl [for example benzyl, styroyl, diphenyl-methyl, trityl etc.] etc.

Suitable " acyl group " comprises lower alkane acyl group [formyl radical for example; ethanoyl; propionyl; caproyl; valeryl etc.]; one (or two or three) halos (rudimentary) alkanoyl [chloracetyl for example; trifluoroacetyl group etc.]; elementary alkoxy carbonyl [methoxycarbonyl for example; ethoxy carbonyl; tert-butoxycarbonyl; tert-pentyloxy carbonyl; hexyloxy carbonyl etc.]; formamyl; aroyl [benzoyl for example; toluyl; naphthoyl etc.]; aryl (rudimentary) alkanoyl [phenyl acetyl for example; phenyl propionyl etc.]; aryloxycarbonyl [phenyloxycarbonyl for example; naphthyloxy carbonyl etc.]; aryloxy (rudimentary) alkanoyl [phenoxy group ethanoyl for example; phenoxy group propionyl etc.]; aryl is glyoxyl-based, and [for example phenyl is glyoxyl-based; naphthyl is glyoxyl-based etc.]; optional aryl (rudimentary) alkoxy carbonyl that is replaced by suitable substituents [benzyloxycarbonyl for example; styroyl oxygen base carbonyl; to nitro benzyloxycarbonyl etc.] etc.

The preferred embodiment of " amino protecting group " comprises aryl (rudimentary) alkyl and acyl group, and more preferably aryl (rudimentary) alkyl, lower alkane acyl group and elementary alkoxy carbonyl particularly preferably are one, two or triphenyl (C ₁-C ₆) alkyl, C ₁-C ₆Alkanoyl and (C ₁-C ₆) alkoxy carbonyl..

The preferred embodiment of " amino of protection " comprises aryl (rudimentary) alkylamino and acyl amino, and more preferably aryl (rudimentary) alkylamino, lower alkane acyl amino and elementary alkoxy carbonyl amino particularly preferably are one, two or triphenyl (C ₁-C ₆) alkylamino, C ₁-C ₆Amino and (the C of alkanoyl ₁-C ₆) alkoxycarbonyl amino.

The preferred embodiment of " guanidine radicals of protection " comprises acyl group guanidine radicals (an acyl group guanidine radicals and diacyl guanidine radicals) for example 2,3-two [(rudimentary) alkoxy carbonyl] guanidine radicals [for example 2,3-two (tert-butoxycarbonyl) guanidine radicals], wherein 2,3-two [(C ₁-C ₆) alkoxy carbonyl] guanidine radicals is preferred.

Suitable " hydroxyl of protection " in " hydroxyl of protection (rudimentary) alkyl " comprises acyloxy, aryl (rudimentary) alkoxyl group etc.Suitable " acyl group " part in " acyloxy " comprises lower alkane acyl group [for example formyl radical, ethanoyl, propionyl, caproyl, valeryl etc.], (or two or three) halos (rudimentary) alkanoyl [for example chloracetyl, trifluoroacetyl group etc.], elementary alkoxy carbonyl [for example methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, tert-pentyloxy carbonyl, hexyloxy carbonyl etc.], formamyl etc.Suitable " aryl (rudimentary) alkyl " part in " aryl (rudimentary) alkyl oxy " comprises one, two or triphenyl (rudimentary) alkyl [for example benzyl, styroyl, diphenyl-methyl, trityl etc.] etc.

Suitable " carboxyl of protection " comprises esterifying carboxyl group etc., the specific examples of esterifying carboxyl group comprises elementary alkoxy carbonyl [methoxycarbonyl for example, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, tert-butoxycarbonyl, pentyloxy carbonyl, hexyloxy carbonyl, 1-cyclopropyl ethoxy carbonyl etc.], it can be replaced by suitable substituents, lower alkane acyloxy (rudimentary) alkoxy carbonyl [acetoxyl group methoxycarbonyl for example for example, the propionyloxy methoxycarbonyl, the butyryl acyloxy methoxycarbonyl, valeryl Oxymethoxy carbonyl, the new pentane acyloxy methoxycarbonyl, 1-acetoxyethoxy carbonyl, 1-propionyloxy ethoxy carbonyl, 2-propionyloxy ethoxy carbonyl, hexylyloxy methoxycarbonyl etc.], lower alkyl alkylsulfonyl (rudimentary) alkoxy carbonyl [for example 2-methylsulfonyl ethoxy carbonyl etc.] or (or two or three) halos (rudimentary) alkoxy carbonyl [2-iodine ethoxy carbonyl for example, 2,2,2-trichlorine ethoxy carbonyl etc.]; Lower alkanols allyloxycarbonyl [for example vinyl oxygen base carbonyl, allyl group oxygen base carbonyl etc.]; Low-grade alkynyl oxygen base carbonyl [for example ethynyl oxygen base carbonyl, proyl oxygen base carbonyl etc.]; Aryl (rudimentary) alkoxy carbonyl [for example benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 4-nitro benzyloxycarbonyl, styroyl oxygen base carbonyl, trityl oxygen base carbonyl, diphenyl-methyl oxygen base carbonyl, two (p-methoxy-phenyl) methoxycarbonyl, 3 that can have suitable substituents, 4-dimethoxy benzyloxycarbonyl, 4-hydroxyl-3,5-two-tertiary butyl benzyloxycarbonyl etc.]; Can have the aryloxycarbonyl [for example phenyloxycarbonyl, 4-chlorophenoxy carbonyl, tolyloxy carbonyl, 4-tertiary butyl phenyloxycarbonyl, xylyloxy carbonyl, sym-trimethylbenzene oxygen base carbonyl, cumenyl oxygen base carbonyl etc.] of suitable substituents etc.

The preferred embodiment of " carboxyl of protection " comprises elementary alkoxy carbonyl and aryl (rudimentary) alkoxy carbonyl, the wherein (C that can have suitable substituents ₁-C ₆) alkoxy carbonyl is preferred.

Suitable " leavings group " comprises halogen [for example chlorine, bromine, iodine etc.] or acyloxy for example aryl-sulfonyl oxygen [for example phenylsulfonyloxy, tosyloxy etc.], low alkyl group sulfonyloxy [for example mesyloxy etc.], lower alkane acyloxy [for example acetoxyl group, propionyloxy etc.] etc.

Suitable " negatively charged ion " comprises formate, acetate moiety, trifluoroacetic acid root, maleate, tartrate anion, methanesulfonate, Phenylsulfonic acid root, tosylate, chlorion, bromide anion, iodide ion, sulfate radical, bisulfate ion, phosphate radical etc.

The suitable pharmacologically acceptable salt of The compounds of this invention [I] is conventional non-toxic salt, and for example comprise the salt or the acid salt that form with alkali, for example for example an alkali metal salt [for example sodium salt, sylvite etc.], alkaline earth salt [for example calcium salt, magnesium salts etc.], ammonium salt of the salt that forms with mineral alkali; The salt that forms with organic bases, for example organic amine salt [for example trismethylamine salt, triethyl amine salt, pyridinium salt, picoline salt, ethylate salt, triethanolamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt etc.]; Inorganic acid addition salt [for example hydrochloride, hydrobromate, vitriol, hydrosulfate, phosphoric acid salt etc.]; Organic carboxyl acid or sulfonic acid addition salt [for example formate, acetate, trifluoroacetate, maleate, tartrate, Citrate trianion, fumarate, mesylate, benzene sulfonate, tosylate etc.]; The salt that ethyl and alkalescence or acidic amino acid [for example arginine, aspartic acid, L-glutamic acid etc.] form.

The preferred embodiment of cephem compounds of the present invention is represented by general formula as described below [I].

(1) formula [I] compound or pharmaceutically acceptable salt thereof, wherein

R ¹Be low alkyl group or hydroxyl (rudimentary) alkyl, and

R ²Be hydrogen or amino protecting group, perhaps

R ¹With R ²Be bonded together and form low-grade alkylidene;

R ³Be hydrogen;

A is

Wherein X is O or NH;

R ⁷Be hydrogen or amino protecting group;

R ⁹Be amino amino or protection; And

P is 0,1 or 2.

(2) compound or pharmaceutically acceptable salt thereof of (1), wherein R above ⁵Be hydrogen.

(3) formula [I] compound or pharmaceutically acceptable salt thereof, wherein

R ²Be hydrogen, aryl (rudimentary) alkyl or acyl group, perhaps

R ⁵It is the carboxyl of carboxyl or esterification;

R ⁶Be amino or acyl amino;

R ⁷Be hydrogen, low alkyl group or acyl group; And

R ⁹Be amino, one or two (rudimentary) alkylamino, acyl amino, guanidine radicals, acyl group guanidine radicals or saturated 3-8 unit heterocyclic radical, described heterocyclic radical contains 1-4 nitrogen-atoms, and optional by amino or acyl amino replacement.

(4) compound or pharmaceutically acceptable salt thereof of (3) above, wherein

R ¹Be low alkyl group or hydroxyl (rudimentary) alkyl, and

R ²Be hydrogen, aryl (rudimentary) alkyl or acyl group, perhaps

R ¹With R ²Be bonded together and form low-grade alkylidene;

R ⁵It is the carboxyl of carboxyl or esterification;

R ⁶Be amino or acyl amino;

R ⁷Be hydrogen or acyl group; And

R ⁹Be amino or acyl amino.

(5) compound or pharmaceutically acceptable salt thereof of (4) above, wherein

R ¹Be low alkyl group or hydroxyl (rudimentary) alkyl, and

R ²Be hydrogen, aryl (rudimentary) alkyl, lower alkane acyl group or elementary alkoxy carbonyl, perhaps

R ¹With R ²Be bonded together and form low-grade alkylidene;

R ⁵Be carboxyl or elementary alkoxy carbonyl;

R ⁶Be amino, lower alkane acyl amino or elementary alkoxy carbonyl amino;

R ⁷Be hydrogen, lower alkane acyl group or elementary alkoxy carbonyl; And

R ⁹Be amino, lower alkane acyl amino or elementary alkoxy carbonyl amino.

(6) compound or pharmaceutically acceptable salt thereof of (5) above, wherein

R ¹Be C ₁-C ₆Alkyl or hydroxyl (C ₁-C ₆) alkyl, and

R ²Be hydrogen, one, two or triphenyl (C ₁-C ₆) alkyl, C ₁-C ₆Alkanoyl or (C ₁-C ₆) alkoxy carbonyl, perhaps

R ¹With R ²Be bonded together and form C ₁-C ₆Alkylidene group;

R ⁵Be carboxyl or (C ₁-C ₆) alkoxy carbonyl;

R ⁶Be amino, C ₁-C ₆Amino or (the C of alkanoyl ₁-C ₆) alkoxycarbonyl amino; And

R ⁷Be hydrogen, C ₁-C ₆Alkanoyl or (C ₁-C ₆) alkoxy carbonyl; And

R ⁹Be amino, C ₁-C ₆Amino or (the C of alkanoyl ₁-C ₆) alkoxycarbonyl amino.

(7) compound or pharmaceutically acceptable salt thereof of (5) above, wherein

R ¹Be low alkyl group or hydroxyl (rudimentary) alkyl, and

R ²Be hydrogen, perhaps

R ¹With R ²Be bonded together and form low-grade alkylidene;

R ⁵It is carboxyl;

R ⁶Be amino;

R ⁷Be hydrogen or lower alkane acyl group; And

R ⁹Be amino.

(8) compound or pharmaceutically acceptable salt thereof of (7) above, wherein

R ¹Be C ₁-C ₆Alkyl or hydroxyl (C ₁-C ₆) alkyl, and

R ²Be hydrogen, perhaps

R ¹With R ²Be bonded together and form C ₁-C ₆Alkylidene group;

R ⁵It is carboxyl;

R ⁶Be amino;

R ⁷Be hydrogen or C ₁-C ₆Alkanoyl; And

R ⁹Be amino.

(9) formula [I] compound or pharmaceutically acceptable salt thereof, wherein

R wherein ⁴Be selected from

-NH-A-(NH) _m-(CH ₂) _q-(CH ₂) _p-R ¹⁴，

R wherein ⁷, A, m, p and q define in the formula [I] respectively as mentioned,

R ¹⁴Be the amino of amino, one or two (rudimentary) alkylaminos or protection,

R ¹⁵Be the guanidine radicals of guanidine radicals or protection, and

R ¹⁶Be 3-8 unit heterocyclic radical, described heterocyclic radical contains 1-4 nitrogen-atoms, and optional quilt amino amino or protection replaces.

(10) formula [I] compound or pharmaceutically acceptable salt thereof, wherein

R wherein ⁴Be selected from

Wherein

P is 0,1 or 2,

Q is 0 or 1,

R ⁷Be hydrogen or amino protecting group, and

R ⁹Be amino amino or protection.

(11) compound or pharmaceutically acceptable salt thereof of (10) above, wherein

R ⁷Be hydrogen, lower alkane acyl group or elementary alkoxy carbonyl; And

R ⁹Be amino, lower alkane acyl amino or elementary alkoxy carbonyl amino.

(12) compound or pharmaceutically acceptable salt thereof of (11) above, wherein

R ⁷Be hydrogen, C ₁-C ₆Alkanoyl or (C ₁-C ₆) alkoxy carbonyl; And

(13) compound or pharmaceutically acceptable salt thereof of (11) above, wherein

R ⁷Be hydrogen or lower alkane acyl group; And

R ⁹Be amino.

(14) compound or pharmaceutically acceptable salt thereof of (13) above, wherein

R ⁷Be hydrogen or C ₁-C ₆Alkanoyl; And

R ⁹Be amino.

Below explain in detail the method for preparing The compounds of this invention.

Method 1

Compound [I] or its salt can be by making compound [II] or its at the reactive derivatives on the amino or its salt and compound [III] or its reactive derivatives or its reactant salt on carboxyl.

The reactive derivatives on amino of suitable compound [II] comprising: schiff's base type imino-or its tautomerism enamine type isomer, its by with compound [II] and carbonyl compound for example reaction such as aldehyde, ketone form; The silyl derivative, its by with compound [II] and silyl compound for example reactions such as two (trimethyl silyl) ethanamide, one (trimethyl silyl) ethanamide [for example N-(trimethyl silyl) ethanamide], two (trimethyl silyl) urea form; By what compound [II] and phosphorus trichloride or phosgene reaction were formed.

The suitable salt of compound [II] and reactive derivatives thereof can referring to exemplified for compound [I] those.

The reactive derivatives on carboxyl of suitable compound [III] comprises carboxylic acid halides, acid anhydrides, activatory acid amides and activatory ester.The suitable example of reactive derivatives can be an acyl chlorides; Acylazide; With for example mixed acid anhydride of following acid: the phosphoric acid of replacement [for example dialkyl group phosphoric acid, phosphenylic acid, diphenylphosphoric acid, dibenzyl phosphoric acid, halophosphoric acid etc.], dialkyl group phosphoric acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl sulfonic acid [for example methylsulfonic acid etc.], aliphatic carboxylic acid [for example acetate, propionic acid, butyric acid, isopropylformic acid, PIVALIC ACID CRUDE (25), valeric acid, isovaleric acid, 2 Ethylbutanoic acid, trichoroacetic acid(TCA) etc.] and aromatic carboxylic acid [for example phenylformic acid etc.]; Symmetric anhydride; Imidazoles, dimethyl pyrazole, triazole or tetrazolium activatory acid amides with imidazoles, 4-replacement; Activatory ester [for example cyano methyl ester, methoxymethyl ester, dimethylimino methyl [(CH ₃) ₂N ⁺=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, five chlorophenyl ester, methylsulfonyl phenylester, phenylazo phenyl ester, phenyl thioester, p-nitrophenyl thioester, p-methylphenyl thioester, carboxyl methyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester etc.]; Or the ester that forms with N-oxy-compound [for example N, N-dimethyl hydroxyl amine, 1-hydroxyl-2-(1H)-pyridone, N-hydroxy-succinamide, N-hydroxyphthalimide, N-hydroxyl-1H-benzotriazole etc.].Can come randomly from them, to select these reactive derivatives according to the type of compound used therefor [III].

The suitable salt of compound [III] and reactive derivatives thereof can referring to exemplified for compound [I] those.

This reaction is carried out in common solvent usually, described solvent is for example water, alcohol [for example methyl alcohol, ethanol etc.], acetone, dioxane, acetonitrile, chloroform, methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), ethyl acetate, N, dinethylformamide, pyridine or do not bring any other organic solvent of disadvantageous effect to reaction.These conventional solvents can also be to use with the form of mixtures of water.

In this reaction, when compound [III] used with free acid form or its salt form, this reaction was preferably carried out in the presence of conventional condensing agent, and described condensing agent is N for example, N '-dicyclohexylcarbodiimide; N-cyclohexyl-N '-morpholino ethyl carbodiimide; N-cyclohexyl-N '-(4-diethylamino cyclohexyl) carbodiimide; N, N '-diethyl carbodiimide; N, N '-DIC; N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide; N, N '-carbonyl-two-(glyoxal ethyline); Pentamethylene ketene-N-cyclohexyl imines; Diphenylethlene ketone-N-cyclohexyl imines; Oxyethyl group acetylene; 1-alkoxyl group-1-vinylchlorid; Trialkyl phosphite; The Tripyrophosphoric acid ethyl ester; The Tripyrophosphoric acid isopropyl esters; Phosphoryl chloride (phosphoryl chloride); Phosphorus trichloride; Thionyl chloride; Oxalyl chloride; Halo formic acid lower alkyl esters [for example Vinyl chloroformate, isopropyl chlorocarbonate etc.], triphenylphosphine; 2-ethyl-different  the azoles of 7-hydroxy benzo  salt; The different  azoles  oxyhydroxide of 2-ethyl-5-(a sulfo group phenyl) molecule inner salt; 1-(to the chlorobenzene sulfonyloxy)-6-chloro-1H-benzotriazole; By with N, reaction such as dinethylformamide and thionyl chloride, phosgene, superpalite, phosphoryl chloride and the so-called Vilsmeier reagent of preparation; Or the like.

This reaction also can be carried out in the presence of mineral alkali or organic bases, and described alkali is for example alkali metal hydrocarbonate, three (rudimentary) alkylamine, pyridine, N-(rudimentary) alkyl morpholine, N, N-two (rudimentary) alkyl benzyl amine etc.

Temperature of reaction is not crucial, and this reaction is usually carried out being cooled under the warm situation.

Method 2

Compound [Ib] or its salt can react by the elimination of compound [Ia] or its salt being carried out amino protecting group and make.

Eliminate reaction according to ordinary method for example hydrolysis etc. carry out.

This hydrolysis comprises that preferably in alkali or acid Lewis acid carries out under existing.

Suitable alkali comprises mineral alkali and organic bases for example basic metal [for example sodium, potassium etc.], alkaline-earth metal [for example magnesium, calcium etc.], its oxyhydroxide or carbonate or supercarbonate, trialkylamine [for example Trimethylamine, triethylamine etc.], picoline, 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicylo [2.2.2] octane, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene etc.

Suitable acid comprises organic acid [for example formic acid, acetate, propionic acid, trichoroacetic acid(TCA), trifluoroacetic acid etc.] and mineral acid [for example hydrochloric acid, Hydrogen bromide, sulfuric acid, hydrogenchloride, hydrogen bromide etc.].

Use Lewis acid for example the elimination that waits of three halogenated acetic acids [for example trichoroacetic acid(TCA), trifluoroacetic acid etc.] react and preferably in the presence of positively charged ion trapping agent [for example methyl-phenoxide, phenol etc.], carry out.

This reaction is usually at solvent for example water, alcohol [for example methyl alcohol, ethanol etc.], methylene dichloride, tetrahydrofuran (THF), its mixture or do not bring to reaction in the presence of any other solvent of disadvantageous effect and carry out.Liquid base or acid also can be used as solvent.

Method 3-(i)

Compound [VIII] or its salt can be by making compound [VI] or its salt and compound [VII] or its reactant salt.

The suitable salt of compound [VI], [VII] and [VIII] can referring to exemplified for compound [I] those.

This reaction can be at solvent for example water, phosphate buffered saline buffer, acetone, chloroform, acetonitrile, oil of mirbane, methylene dichloride, ethylene dichloride, methane amide, N, dinethylformamide, methyl alcohol, ethanol, ether, tetrahydrofuran (THF), methyl-sulphoxide or do not bring in any other solvent of disadvantageous effect to reaction and carry out preferably carry out in having strong polar solvent.In the middle of solvent, hydrophilic solvent can be to use with the form of mixtures of water.When compound [VII] when being liquid, it also can be used as solvent.

Preferably for example mineral alkali such as alkali metal hydroxide, alkaline carbonate, alkali metal bicarbonates and organic bases for example carry out in the presence of trialkylamine etc. at alkali in this reaction.

Temperature of reaction is not crucial, and this reaction is carried out under room temperature, warm or heating condition usually.This reaction is preferably carried out in the presence of alkali metal halide [for example sodium iodide, potassiumiodide etc.], alkali metal thiocyanate [for example Sodium Thiocyanate 99, potassium sulfocyanate etc.] etc.

Negatively charged ion Z ^Can be negatively charged ion, and can convert it into other negatively charged ion by ordinary method derived from leavings group Y.

Method 3-(ii)

Compound [I] or its salt can react by the elimination of compound [VIII] or its salt being carried out carboxyl-protecting group and make.

Eliminating reaction can carry out according to the mode that is similar to the reaction in the aforesaid method 2, and therefore, employed reagent and reaction conditions (for example solvent, temperature of reaction etc.) can be referring in the method 2 those.

Method 4

Compound [Id] or its salt can react by the elimination of compound [Ic] or its salt being carried out hydroxyl protecting group and make.

The suitable method of carrying out this elimination reaction comprises ordinary method for example hydrolysis, reduction etc.

(i) for hydrolysis:

Hydrolysis comprises that preferably in alkali or acid Lewis acid carries out under existing.

(ii) for reduction:

Reduction is carried out in a usual manner, comprises chemical reduction and catalytic reduction.

Be used to carry out chemical reduction suitable to go back original reagent be metal [for example tin, zinc, iron etc.] or metallic compound [for example chromium chloride, chromium acetate etc.] and the combination of organic acid or mineral acid [for example formic acid, acetate, propionic acid, trifluoroacetic acid, tosic acid, hydrochloric acid, Hydrogen bromide etc.].

The appropriate catalyst that is used for catalytic reduction is a for example platinum catalyst [platinized platinum for example of conventional catalyst, spongy platinum, platinum black, colloidal state platinum, platinum oxide, platinum filament etc.], palladium catalyst [palladium sponge for example, palladium black, palladous oxide, palladium carbon, pallamine, with barium sulfate is the palladium of carrier, with the barium carbonate palladium of carrier etc.], nickel catalyzator [reduced nickel for example, nickel oxide, Raney nickel etc.], cobalt catalyst [for example reduces cobalt, Raney cobalt etc.], iron catalyst [reduced iron for example, the interior iron of Ruan etc.], copper catalyst [is for example gone back native copper, copper in Ruan, U11man copper etc.] etc.

Reduction usually at the conventional solvent that does not bring disadvantageous effect to reaction for example water, methyl alcohol, ethanol, propyl alcohol, N, is carried out in dinethylformamide or its mixture.

In addition, when the above-mentioned acid of using in chemical reduction was liquid, they also can be used as solvent.

In addition, the suitable solvent that uses in catalytic reduction can be above-mentioned solvent and other conventional solvent for example ether, dioxane, tetrahydrofuran (THF) etc. or its mixture.

Work as R ⁶When being protect amino, R ⁶In amino protecting group can by ordinary method for example hydrolysis eliminate.

Below explain in detail method A and the B that is used to prepare initial compounds.

Method A-(i)

Compound [XII] or its salt can be by making compound [X] or its salt and compound [XI] or its reactant salt.

This reaction can be carried out according to the mode that is similar to the reaction among the aforesaid method 3-(i), and therefore, employed reagent and reaction conditions (for example solvent, temperature of reaction etc.) can be referring among the method 3-(i) those.

Method A-(ii)

Compound [II] or its salt can be by carrying out R with compound [XII] or its salt ¹¹And R ¹³In amino protecting group and R ¹²In the elimination of carboxyl-protecting group react and make.

This reaction can be carried out according to the mode that is similar to the reaction in the aforesaid method 2, and therefore, employed reagent and reaction conditions (for example solvent, temperature of reaction etc.) can be referring in the method 2 those.

Method B

Compound [VI] or its salt can be by making compound [XIII] or its at the reactive derivatives on the amino or its salt and compound [XIV] or its reactive derivatives or its reactant salt on carboxyl.

Eliminating reaction can carry out according to the mode that is similar to the reaction in the aforesaid method 1, and therefore, employed reagent and reaction conditions (for example solvent, temperature of reaction etc.) can be referring in the method 1 those.

Compound by the aforesaid method acquisition can be sent out by for example grinding of ordinary method, recrystallization, column chromatography, redeposition waits and separates and purifying.

It should be noted that, compound [I] and other compound can comprise one or more steric isomers of existing owing to unsymmetrical carbon and two keys for example optically active isomer and geometrical isomer, and isomer that all are such and composition thereof all is included in the scope of the present invention.

The compounds of this invention [I] and pharmacologically acceptable salt thereof comprise solvate [for example forgiving compound (for example hydrate etc.)].

The compounds of this invention [I] and pharmacologically acceptable salt thereof are new, and show high antimicrobial acivity, suppress multiple pathogenic microbes, comprise the growth of Gram-positive and gram-negative micro-organism, and can be used as biocide.

In order to prove the purposes of The compounds of this invention [I], the test data of the MIC (minimum inhibition concentration) about representative The compounds of this invention is described below.

Testing method

Measure anti-microbial activity by twice agar plate dilution process as described below.

With the overnight culture (10 of each test microbes strain of ring in trypticase-soybean broth ⁶Viable cell/ml) go up line at the heart infusion agar (HI-agar) of the representative test compounds that contains gradient concentration is measured the minimum inhibition concentration of representing with μ g/ml (MIC) 37 ℃ of cultivations after 20 hours.

Test compounds

Compound (a): 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[7-(the amino propionamido of 3-)-2,3-dihydro-5-(1H-imidazo [1,2-b] pyrazoles subbase)] methyl-3-cephem-4-formate (embodiment 3)

Compound (b): 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[3-amino-4-(the amino propionamido of 3-)-2-methyl isophthalic acid-pyrazoles subbase] methyl-3-cephem-4-formate (embodiment 4)

Compound (c): 7 β-[(Z)-2-(5-amino-1; 2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[3-amino-4-(glycyl) amino-2-methyl-1-pyrazoles subbase] methyl-3-cephem-4-formic acid hydrosulfate (embodiment 6)

Compound (d): 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-amino-4-[3-(2-amino-ethyl) urea groups]-2-methyl isophthalic acid-pyrazoles subbase } methyl-3-cephem-4-formic acid hydrosulfate (embodiment 7)

Compound (e): 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-(3-amino-4-guanidine radicals-2-methyl isophthalic acid-pyrazoles subbase) methyl-3-cephem-4-formic acid hydrosulfate (embodiment 11)

Ceftazime

Test result

The test microbes strain	Test compounds	MIC(μg/ml)
The test microbes strain	Test compounds	MIC(μg/ml)	Pseudomonas aeruginosa (Pseudomonas aeruginosa) FP 1380	(a)	2
(b)	1			(a)	2
(b)	1	(c)		2
(d)	2	(c)		2
(d)	2	(e)		1
Ceftazime	128	(e)		1

For the treatment administration, The compounds of this invention [I] and pharmacologically acceptable salt thereof can use with the form of conventional medicine preparation, described preparation contain as the described compound of active ingredient and with its blended pharmaceutically acceptable carrier, for example be suitable for the organic or inorganic solid or the liquid excipient of oral, parenteral or outside administration.Pharmaceutical preparation of the present invention can be solid form, for example tablet, granula, pulvis, capsule, or liquid form for example solution, suspension, syrup, emulsion, lemonade etc.

If necessary, in above-mentioned preparation, can comprise auxiliary substance, stablizer, wetting agent and other typical additives for example lactose, citric acid, tartrate, stearic acid, Magnesium Stearate, terra alba, sucrose, W-Gum, talcum powder, gelatin, agar, colloid, peanut oil, sweet oil, cacao butter, ethylene glycol etc.

The dosage of compound [I] can change, and also depend on patient age, the kind of physical appearance, disease type, the compound [I] used etc.The dosage that can be administered to the patient is generally 1mg-4 every day, 000mg or even more.Can use average single dose to treat the disease that is infected by pathogenic microbes for about 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg The compounds of this invention [I].

Provide following preparation example and embodiment and illustrate the present invention in more detail.

Preparation example 1

To (Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl) [(2-tert.-butoxy-1,1-dimethyl-2-oxo oxyethyl group) imino-] acetate (5g) is at tetrahydrofuran (THF) (80ml) and N, add the solution of two (trimethyl silyl) sodium amide (8.33g) in tetrahydrofuran (THF) (12ml) in the solution in the mixture of dinethylformamide (20ml), this mixture was stirred 15 minutes.At the ice-cooled solution of the two carbonic acid tert-butyl esters (3.3g) in tetrahydrofuran (THF) (20ml) that in this reaction mixture, adds down, this mixture was stirred 3 hours down ice-cooled.In this reaction mixture, add ethyl acetate, this mixture is washed with 10% aqueous potassium hydrogen sulfate, use phosphate buffered saline buffer (pH 6.86) washing then.Isolate organic layer, use anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates is developed with Di Iso Propyl Ether, and vacuum-drying, obtained (Z)-2-{5-[(tert-butoxycarbonyl) amino]-1,2,4-thiadiazoles-3-yl } [(2-tert.-butoxy-1,1-dimethyl-2-oxo oxyethyl group) imino-] acetate (3.10g).

IR(KBr) 3191.6，2981.4，1714.4，1550.5，1153.2，1000.9cm ^-1

¹H-NMR(DMSO-d ₆)δ1.37(9H，s)，1.45(6H，s)，1.50(9H，s)，12.7(1H，s)

ESI-MS：m/z＝429(M-H)

Preparation example 2

With N, the mixture of dinethylformamide (0.648ml) and phosphoryl chloride (0.781ml) was stirring at room 30 minutes.In this mixture, add tetrahydrofuran (THF) (4ml) and (Z)-2-{5-[(tert-butoxycarbonyl at 4 ℃) amino]-1,2,4-thiadiazoles-3-yl } [(2-tert.-butoxy-1,1-dimethyl-2-oxo oxyethyl group) imino-] acetate (3g), with this reaction mixture stirring at room 1 hour.During this time, 7 beta-aminos-3-chloromethyl-3-cephem-4-formic acid diphenyl-methyl ester hydrochloride (3g) and the mixture of N-(trimethyl silyl) ethanamide (8.72g) in tetrahydrofuran (THF) (15ml) is warm to obtain settled solution.This solution is cooled to-20 ℃ then, is added in the activatory acid solution that obtains above.This reaction mixture was stirred 1 hour at-10 ℃-0 ℃, pour in the mixture of ethyl acetate and water.Isolate water layer, with organic layer salt water washing, with anhydrous magnesium sulfate drying and filtration.With the filtrate vacuum concentration, pass through silica gel chromatography, with hexane/ethyl acetate (3: 2) wash-out, obtained 7 β-[(Z)-2-(5-tert-butoxycarbonyl amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester (4.79g).

IR(KBr) 2981.4，1793.5，1720.2，1524.8，1371.1，1247.7，1151.3cm ^-1

¹H-NMR(DMSO-d ₆)δ1.39(6H，s)，1.48(3H，s)，1.50(6H，s)，3.58(1H，d，J＝18.3Hz)，3.76(1H，d，J＝18.3Hz)，4.44(2H，s)，5.29(1H，d，J＝5.0Hz)，6.01(1H，dd，J＝8.6，5.0Hz)，6.97(1H，s)，7.2-7.6(10H，m)，9.65(1H，d，J＝5.0Hz)，12.7(1H，s)

ESI-MS：m/z＝849(M+Na)

Preparation example 3

In the 5-amino-solution of 1-methylpyrazole (5g) in ethanol (50ml), add Isopentyl nitrite (6.92ml) at 4 ℃, add 20% hydrochloric acid (5) then.With this reaction mixture refluxed 2 hours, and be cooled to room temperature.In this reaction mixture, add Di Iso Propyl Ether (50ml), this mixture was stirred 0.5 hour.Collect formed precipitation by filtering, and vacuum-drying, 5-amino-1-methyl-4-nitroso-group pyrazoles (3.53g) obtained.

¹H-NMR(DMSO-d ₆)δ3.51(3H，s)，8.07(2H，brs)，8.51(1H，s)

APCI-MS：m/z＝127(M+H)

Preparation example 4

Under nitrogen atmosphere, in the 5-amino-1-methyl-solution of 4-nitroso-group pyrazoles (1g) in water (40ml), add the vitriol oil (0.423ml) and palladium carbon (0.3g).This mixture stirring is spent the night.This reaction mixture is filtered, and with the filtrate vacuum concentration.In resistates, add Virahol, and collect formed precipitation, obtained 4,5-diaminostilbene-methylpyrazole vitriol (1.71g) by filtering.

¹H-NMR(DMSO-d ₆)δ3.54(3H，s)，7.19(1H，s)

ESI-MS：m/z＝113(M+H)

Preparation example 5

Ice-cooled down to 1,1 '-add N-(2-amino-ethyl) t-butyl carbamate (9.61g) in the suspension of carbonyl dimidazoles (9.73g) in dehydration chloroform (72ml), with this mixture stirring at room 1 hour.Add N-ethyl diisopropyl amine (14.22g) and 4 in this reaction mixture, 5-diaminostilbene-methylpyrazole vitriol (10.51g) stirs this mixture 15 hours at 50 ℃.By removing by filter insolubles.In filtrate, add chloroform (200ml) and 5% sodium bicarbonate aqueous solution (100ml).Isolate organic layer, with the mixed extractant solvent of water layer with chloroform and methyl alcohol (4: 1).Organic layer is merged, use anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates with ethyl acetate development and vacuum-drying, has been obtained 5-amino-4-(3-{2-[(tert-butoxycarbonyl) amino] ethyl } urea groups)-1-methylpyrazole (14.0g), be solid.

¹H-NMR(DMSO-d ₆)δ1.38(9H，s)，2.96-2.98(2H，m)，3.03-3.07(2H，m)，3.50(3H，s)，4.81(2H，br)，5.92(1H，br)，6.80(1H，br)，6.96(1H，s)，7.18(1H，br)

Embodiment 1

To 7 β-[(Z)-2-(5-tert-butoxycarbonyl amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester (500mg) is at N, add sodium iodide (100mg) in the solution in the dinethylformamide (1.0ml), with this mixture stirring at room 30 minutes.In this reaction mixture, add 5-amino-4-(3-{2-[(tert-butoxycarbonyl) amino] ethyl } urea groups)-1-methylpyrazole (216mg) is at N, the solution in the dinethylformamide (1.0ml).Whole mixture was stirred 4 hours at 32 ℃.In the gained reaction mixture, add ethyl acetate (50ml) and water (50ml).Isolate water layer, organic layer with 10% trifluoroacetic acid sodium water solution and salt water washing, is also filtered with anhydrous sodium sulfate drying.With the filtrate vacuum concentration to about 5ml.Concentrated solution is poured in the Di Iso Propyl Ether (75ml), and collected formed precipitation, vacuum-drying by filtering.In the solution of gained solid in methylene dichloride (1.8ml), add methyl-phenoxide (0.6ml) and trifluoroacetic acid (1.2ml).Gained solution stirring at room 4 hours, and is poured in the Di Iso Propyl Ether (80ml).Collect formed precipitation by filtering, and vacuum-drying, crude product (380mg) obtained, by using preparative high-performance liquid chromatographic (HPLC) purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 30ml.Concentrated solution is adjusted to about pH 3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (Mitsubishi Chemical Corporation) purifying, with 30% 2-aqueous propanol solution wash-out.With the elutriant vacuum concentration to about 30ml, and freeze-drying, obtained 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-amino-4-[3-(2-amino-ethyl) urea groups]-2-methyl isophthalic acid-pyrazoles subbase } methyl-3-cephem-4-formate (21mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.52(3H，s)，1.53(3H，s)，3.12(2H，t，J＝5.7Hz)，3.22(1H，d，J＝17.9Hz)，3.49(1H，d，J＝17.9Hz)，3.46(2H，t，J＝5.7Hz)，3.71(3H，s)，4.95(1H，d，J＝15.6Hz)，5.15(1H，d，J＝15.6Hz)，5.25(1H，d，J＝4.6Hz)，5.84(1H，d，J＝4.6Hz)，7.89(1H，s)

Preparation example 6

To 5-amino-4-(3-{2-[(tert-butoxycarbonyl) amino] ethyl urea groups)-add trityl group chlorine (669mg) in 1-methylpyrazole (597mg) and the solution of triethylamine (243mg) in methylene dichloride (10ml), with this mixture stirring at room 19 hours.This reaction mixture is washed with 10% aqueous citric acid solution, salt solution and saturated sodium bicarbonate aqueous solution successively.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates is developed with ethyl acetate, has been obtained 4-(3-{2-[(tert-butoxycarbonyl) amino] ethyl } urea groups)-1-methyl-5-trityl group amino-pyrazol (640mg), be solid.

¹H-NMR(DMSO-d ₆)δ1.38(9H，s)，2.70(3H，s)，2.94-2.96(2H，m)，2.99-3.01(2H，m)，5.68(1H，brs)，5.96(1H，br)，6.78(1H，br)，6.85(1H，br)，7.00(1H，s)，7.13-7.15(6H，m)，7.24-7.28(9H，m)

Preparation example 7

To 7 β-[(Z)-2-(5-amino-1; 2; 4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-(pH 7,500ml) solution in and three capryloyl ammonio methacrylates (6.67g) at the 0.05mol phosphate buffered saline buffer to add sodium iodide (61.8g) in the 3-chloromethyl-3-cephem-solution of 4-formic acid benzhydryl ester (60g) in toluene (600ml).With this mixture stirring at room 15 hours.This reaction mixture is added in the mixture of ethyl acetate and water.With organic layer water and salt water washing, use dried over mgso then.Filter out sal epsom, with filtrate evaporated under reduced pressure to 255g.Concentrated solution is poured in the Di Iso Propyl Ether (2L).Collect formed precipitation by filtering, and it is dry, obtained 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester (59.4g).

¹H-NMR (DMSO-d ₆) δ 1.39 (9H, s), 1.46 (6H, s), 3.57 and 3.87 (2H, ABq, J=18.0Hz), 3.76 (3H, s), 4.30 (2H, bs), 5.25 (1H, d, J=4.9Hz), 5.94 (1H, dd, J=4.9,8.7Hz), 6.95 (1H, bs), and 7.15-7.60 (10H, m), 8.17 (2H, bs), 9.53 (1H, d, J=8.7Hz)

Embodiment 2

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester (810mg) is at N, add N-(trimethyl silyl) ethanamide (656mg) in the solution in the dinethylformamide (2.4ml), with this mixture stirring at room 30 minutes.In this reaction mixture, add 4-(3-{2-[(tert-butoxycarbonyl) amino] ethyl } urea groups)-the 1-methyl-solution of 5-trityl group amino-pyrazol (640mg) in methylene dichloride (10ml).With whole mixture stirring at room 26 hours.In the gained reaction mixture, add ethyl acetate (50ml) and water (50ml).Isolate water layer, organic layer with 10% trifluoroacetic acid sodium water solution and salt water washing, is also filtered with anhydrous sodium sulfate drying.With the filtrate vacuum concentration to about 5ml.Concentrated solution is poured in the Di Iso Propyl Ether (80ml), collected formed precipitation by filtering, and vacuum-drying.In the solution of gained solid in methylene dichloride (2.38ml), add methyl-phenoxide (0.79ml) and trifluoroacetic acid (1.58ml).Gained solution stirring at room 4 hours, and is poured in the Di Iso Propyl Ether (80ml).Collect formed precipitation by filtering, and vacuum-drying, crude product (635mg) obtained, by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 30ml.Concentrated solution is adjusted to about pH3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (Mitsubishi Chemical Corporation) purifying, with the aqueous solution wash-out of 30% 2-propyl alcohol.With the elutriant vacuum concentration to about 30ml, and freeze-drying, obtained 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-amino-4-[3-(2-amino-ethyl) urea groups]-2-methyl isophthalic acid-pyrazoles subbase } methyl-3-cephem-4-formate (54mg), be amorphous solid.

Preparation example 8

Down to 2, add saltpetre (111g) in the solution of 3-dihydro-1H-imidazo [1,2-b] pyrazoles (120g) in sulfuric acid (500ml) ice-cooled.With this mixture stirring at room 48 hours.This reaction mixture is added in the ice (2.0kg).Collect this crystalline residue by filtering, and vacuum-drying, having obtained 7-nitro-2,3-dihydro-1H-imidazo [1,2-b] pyrazoles (132g) is solid.

¹H-NMR(DMSO-d ₆)δ4.05-4.09(2H，m)，4.17-4.20(2H，m)，7.82(1H，s)，7.97(1H，br)

Preparation example 9

With 7-nitro-2, the suspension of 3-dihydro-1H-imidazo [1,2-b] pyrazoles (97g) in the mixed solvent of sulfuric acid (34ml) and water (2000ml) was handled 4 days under nitrogen atmosphere with 10% palladium carbon (10g) in room temperature.After the catalyzer filtration, with the filtrate vacuum concentration.Develop resistates with methyl alcohol, and vacuum-drying, having obtained 7-amino-2,3-dihydro-1H-imidazo [1,2-b] pyrazoles vitriol (90.2g) is solid.

¹H-NMR(DMSO-d ₆)δ3.87-3.90(2H，m)，4.07-4.10(2H，m)，7.28(1H，s)

Preparation example 10

To 7-amino-2, add N-[3-(tert-butoxycarbonyl amino)-propionyloxy in 3-dihydro-1H-imidazo [1,2-b] pyrazoles vitriol (2.22g) and the solution of N-ethyl diisopropyl amine (2.84g) in methylene dichloride (70ml)] succinimide (3.15g).With this mixture stirring at room 4 hours.This reaction mixture is washed with saturated sodium bicarbonate aqueous solution,, filter and vacuum concentration the organic layer anhydrous magnesium sulfate drying.With this oily resistates silica gel chromatography,, obtained 7-[3-(tert-butoxycarbonyl amino) propionyl with 5% methyl alcohol/chloroform wash-out] amino-2,3-dihydro-1H-imidazo [1,2-b] pyrazoles (2.2g) is solid.

¹H-NMR(CDCl ₃)δ1.44(9H，s)，2.52(2H，t，J＝6.0Hz)，3.36-3.47(2H，m)，3.96(2H，t，J＝8.2Hz)，4.18(2H，t，J＝8.2Hz)，5.16(1H，br)，7.16(1H，s)，7.90(1H，br)

Embodiment 3

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[7-(the amino propionamido of 3-)-2,3-dihydro-5-(1H-imidazo [1,2-b] pyrazoles subbase)] methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-tert-butoxycarbonyl amino-1; 2; 4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester and 7-[3-(tert-butoxycarbonyl amino) propionyl] amino-2; 3-dihydro-1H-imidazo [1; 2-b] pyrazoles makes in the mode identical with embodiment 1, is amorphous solid.

¹H-NMR(D ₂O)δ1.51(3H，s)，1.52(3H，s)，2.83(2H，t，J＝6.4Hz)，3.26(1H，d，J＝17.9Hz)，3.53(1H，d，J＝17.9Hz)，3.31(2H，t，J＝6.4Hz)，4.15(2H，t，J＝8.7Hz)，4.33(1H，q，J＝8.7Hz)，4.42(1H，q，J＝8.7Hz)，4.95(1H，d，J＝15.1Hz)，5.03(1H，d，J＝15.1Hz)，5.25(1H，d，J＝5.0Hz)，5.84(1H，d，J＝5.0Hz)，8.06(1H，s)

Preparation example 11

[2-(5-amino-1-methyl isophthalic acid H-pyrazoles-4-base formamyl) ethyl] t-butyl carbamate

This title compound is by 4,5-diaminostilbene-methylpyrazole vitriol and N-[3-(tert-butoxycarbonyl amino) propionyloxy] succinimide obtains in the mode identical with preparation example 10.

¹H-NMR(DMSO-d ₆)δ1.38(9H，s)，2.35(2H，t，J＝7.1Hz)，3.18(2H，q，J＝7.1Hz)，3.50(3H，s)，4.90(2H，s)，6.83(1H，t，J＝7.1Hz)，7.14(1H，s)，9.06(1H，s)

AP-MS：m/z＝283

Preparation example 12

2-[1-methyl-5-(trityl amino)-1H-pyrazoles-4-base formamyl] and ethyl } t-butyl carbamate

This title compound is to be obtained in the mode identical with preparation example 6 by [2-(5-amino-1-methyl isophthalic acid H-pyrazoles-4-base formamyl) ethyl]-t-butyl carbamate.

¹H-NMR(DMSO-d ₆)δ1.39(9H，s)，2.08(2H，t，J＝7.1Hz)，2.71(3H，s)，3.04(2H，q，J＝7.1Hz)，5.57(1H，s)，6.72(1H，t，J＝7.1Hz)，7.1-7.4(16H，m)，8.25(1H，s)

Embodiment 4

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[3-amino-4-(the amino propionamido of 3-)-2-methyl isophthalic acid-pyrazoles subbase] methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-tert-butoxycarbonyl amino-1; 2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-)-kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester and { 2-([1-methyl-5-(trityl amino)-1H-pyrazoles-4-base formamyl] ethyl } t-butyl carbamate obtain in the mode identical with embodiment 1.

¹H-NMR(D ₂O)δ1.53(6H，s)，2.89(2H，t，J＝6.5Hz)，3.20and 3.47 (2H，ABq，J＝18Hz)，3.34(2H，t，J＝6.5Hz)，3.75(3H，s)，4.99 and 5.21(2H，ABq，J＝16Hz)，5.25(1H，d，J＝4.8Hz)，5.85(1H，d，J＝4.8Hz)，8.02(1H，s)

ESI-MS：m/z＝674(M+Na)

Preparation example 13

At 4 ℃ to 1; add 4 in 3-two (the tert-butoxycarbonyl)-solution of 2-(trifluoromethyl sulfonyl) guanidine (22.3g) in methylene dichloride (100ml); 5-diaminostilbene-methylpyrazole vitriol (10g) and triethylamine (33.2ml), with this mixture in stirred overnight at room temperature.This reaction mixture is poured in the mixture of ethyl acetate and water.Isolate water layer, with organic layer salt water washing, with anhydrous magnesium sulfate drying and filtration.With the filtrate vacuum concentration.Concentrated solution is poured in the acetonitrile, collected formed precipitation by filtering, and vacuum-drying, obtained 5-amino-4-[2 ', 3 '-two (tert-butoxycarbonyl) guanidine radicals]-1-methylpyrazole (11.62g).

¹H-NMR(DMSO-d ₆)δ1.37(9H，s)，1.50(9H，s)，3.52(3H，s)，5.14(2H，s)，7.11(1H，s)，9.14(1H，s)，11.5(1H，s)

Preparation example 14

4-[2 ', 3 '-two (tert-butoxycarbonyl) guanidine radicals]-1-methyl-5-(trityl amino) pyrazoles

This title compound is by 5-amino-4-[2 ', 3 '-two (tert-butoxycarbonyl) guanidine radicals]-the 1-methylpyrazole makes in the mode identical with preparation example 6.

¹H-NMR(DMSO-d ₆)δ1.37(9H，s)，1.50(9H，s)，2.85(3H，s)，5.88(1H，s)，7.17(1H，s)，7.21(15H，m)，8.85(1H，s)，11.2(1H，s)

ESI-MS：m/z＝597(M+H)

Embodiment 5

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-(3-amino-4-guanidine radicals-2-methyl isophthalic acid-pyrazoles subbase) methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester and 4-[2 ', 3 '-two (tert-butoxycarbonyl) guanidine radicals]-1-methyl-5-(trityl amino) pyrazoles makes in the mode identical with embodiment 1.

¹H-NMR (DMSO-d ₆) δ 1.53 (6H, s), 3.25 and 3.57 (2H, ABq, J=18Hz), 3.75 (3H, s), 5.00 and 5.18 (2H, ABq, J=15Hz), 5.27 (1H, d, J=4.9Hz), 5.85 (1H, d, J=4.9Hz), 8.05 (1H, s)

Preparation example 15

Down to 4, add 2-[(2 in the 5-diaminostilbene-suspension of methylpyrazole vitriol (305g) in tetrahydrofuran (THF) (3.05L), 5-dioxo-1-pyrrolidyl ice-cooled) the oxygen base]-2-oxoethyl t-butyl carbamate (415g).In this mixture, drip diisopropyl ethyl amine (556ml) being lower than under 10 ℃ the temperature.With this mixture in stirred overnight at room temperature.Add salt solution and saturated sodium bicarbonate aqueous solution in gained solution, (3.0L) extracts this mixture with ethyl acetate.Water layer is extracted 2 times with tetrahydrofuran (THF)/ethyl acetate=1/1 (3.0L).With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates is developed with Di Iso Propyl Ether (1.0L), and vacuum-drying, obtained 2-[(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino]-2-oxoethyl t-butyl carbamate (307g).

IR(KBr)3440，3349，1670，1631，1525，1276，1163，1074，1014，860，791cm ^-1

¹H-NMR(DMSO-d ₆)δ1.39(9H，s)，3.44(3H，s)，3.64(2H，d，J＝5.9Hz)，4.91(2H，brs)，6.97(1H，t，J＝5.9Hz)，7.15(1H，s)，9.09(1H，brs)

Preparation example 16

To 2-[(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino]-2-oxoethyl t-butyl carbamate (307g) is at N, adds trityl group chlorine (334g) in the solution in the dinethylformamide (1.5L).In this mixture, drip triethylamine (318ml).With this mixture stirring at room 1 hour.This reaction mixture is dissolved in the ethyl acetate.With this solution water successively, 10% aqueous citric acid solution, water and salt water washing.With the extraction liquid anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates is developed with acetonitrile (1.5L), and vacuum-drying, obtained 2-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-2-oxoethyl t-butyl carbamate (468g).

IR(KBr)3336，3280，1724，1683，1599，1234，939，704cm ^-1

¹H-NMR(DMSO-d ₆)δ1.38(9H，s)，2.73(3H，s)，3.38(2H，d，J＝5.8Hz)，5.58(1H，s)，6.94(1H，t，J＝5.8Hz)，7.11-7.35(15H，m)，7.21(1H，s)，8.31(1H，s)

ESI-MS：m/z＝512.3(M+H ⁺)

Embodiment 6

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester (489g) is at N, adds sodium iodide (102g) in the solution in the dinethylformamide (1.4L).In stirring at room after 1 hour, with 2-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-2-oxoethyl t-butyl carbamate (383g) is added in this mixture.Continuation was stirred 24 hours at 37 ℃.The gained mixture is poured in the water, and used ethyl acetate extraction.With organic layer water successively, 10% sodium thiosulfate solution, salt solution and 10% sodium trifluoroacetate solution washing, use dried over mgso, filter and vacuum-evaporation.Resistates is dissolved in the ethyl acetate (3.5L), this drips of solution is added in the Di Iso Propyl Ether (36L).By filtering collecting precipitation.Filter cake is washed with Di Iso Propyl Ether, and vacuum-drying.

Gained solid (700g) is dissolved in the diamino methane (1.4L), in this solution, adds methyl-phenoxide (700ml) and trifluoroacetic acid (2.1L) successively., after 4 hours this reaction mixture is poured in the Di Iso Propyl Ether (30L) in stirring at room.By filtering collecting precipitation.The gained solid is washed with Di Iso Propyl Ether, and vacuum-drying.Crude product is dissolved in the water (3.5L), with the pH regulator to 7.0 of 28% ammonia soln this solution.Filter out insolubles, with the pH regulator to 1 of concentrated hydrochloric acid with filtrate.Filter out insolubles once more.Filtrate is composed purifying in the enterprising circumstances in which people get things ready for a trip of Diaion  HP-20, with 20% 2-aqueous propanol solution wash-out.The elutriant vacuum concentration to about 3.0L, will be added in this concentrated solution in the solution in the 2.0M sulfuric acid (102ml).With this mixture freeze-drying, obtained crude product.

By preparation HPLC purifying crude product (pH 7.0 phosphate buffered saline buffers and acetonitrile), and the elutriant vacuum concentration that will contain required product is to about 6L.With concentrated hydrochloric acid concentrated solution is adjusted to about pH 1, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 purifying, with the aqueous solution wash-out of 20% 2-propyl alcohol.The elutriant vacuum concentration to about 550ml, and is added to 2.0M sulfuric acid (54.5ml) in this concentrated solution.In this mixture, drip acetonitrile (880ml), with this mixture in stirred overnight at room temperature.In this mixture, add acetonitrile (200ml), with this mixture stirring at room 2 hours.Collect the gained white crystal by filtering; wash with 25% acetonitrile solution; and drying under reduced pressure; obtained 7 β-[(Z)-2-(5-amino-1; 2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[3-amino-4-(glycyl) amino-2-methyl-1-pyrazoles subbase] methyl-3-cephem-4-formic acid hydrosulfate (72.5g).

IR(KBr)1778，1700，1653，1525，1149，1111，617cm ^-1

¹H-NMR (D ₂O) δ 1.61 (6H, s), 3.22 and 3.45 (2H, ABq, J=17.8Hz), 3.73 (3H, s), 4.03 (2H, s), 5.05 and 5.27 (2H, ABq, J=15.8Hz), 5.25 (1H, d, J=4.8Hz), 5.87 (1H, d, J=4.8Hz), 8.09 (1H, s)

ESI-MS：m/z＝638.2(M+H ⁺)

Embodiment 7

With 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-amino-4-[3-(2-amino-ethyl) urea groups]-2-methyl isophthalic acid-pyrazoles subbase } methyl-3-cephem-solution of 4-formate (36g) in water is by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 1.5L.With concentrated hydrochloric acid concentrated solution is adjusted to about pH 1, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (6L) purifying, with the aqueous solution wash-out of 20% 2-propyl alcohol.The elutriant vacuum concentration to about 800ml, is added 2M sulfuric acid (17ml).With the freeze-drying of gained solution, obtained vitriol, be amorphous powder (23.6g).

With this powder dissolution in water (71ml) and ethanol (57ml).After adding crystal seed (310mg), form the white solid precipitation, this mixture was stirred 1 hour.With the mixture that added ethanol (47ml) and water (37ml) in 30 minutes, with 20 minutes adding ethanol (33ml).Then with this slurries restir 1.5 hours.By filtering collecting precipitation, with ethanol/water (60ml/20ml) and ethanol (60ml) washing, dry, obtained 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-amino-4-[3-(2-amino-ethyl) urea groups]-2-methyl isophthalic acid-pyrazoles subbase } methyl-3-cephem-4-formic acid hydrosulfate, be crystal (17.3g).

IR(KBr)3353，3183，1778，1652，1558，1403，1321，1143，1118，99，619cm ^-1

¹H-NMR(D ₂O)δ1.61(6H，s)，3.10-3.55(6H，m)，3.71(3H，s)，5.02 and 5.23(2H，ABq，J＝16.7Hz)，5.25(1H，d，J＝4.9Hz)，5.87(1H，d，J＝4.9Hz)，7.91(1H，s)

ESI-MS：m/z＝667(M+H ⁺)

The X-ray powder diffraction is analyzed (by Rigaku X-ray

Ray diffraction systems MultiFlex)

2 θ intensity

8.0 1286

12.7 586

13.8 423

16.1 618

18.9 520

20.4 748

21.5 667

22.4 1058

23.3 944

24.0 618

25.5 813

26.7 472

27.9 537

28.5 455

31.3 390

X-ray: Cu/40kV/30mA

Preparation example 17

5-amino-1-ethyl-4-nitroso-group pyrazoles

This title compound is to be made in the mode identical with preparation example 3 by 5-amino-1-ethyl pyrazoles.

¹H-NMR(DMSO-d ₆)δ1.21(3H，t，J＝7.1Hz)，3.93(2H，q，J＝7.1Hz)，7.04 and 8.53(1H，s)，8.10 and 8.15(1H，brs)

APCI-MS：m/z＝141(M+H) ⁺

Preparation example 18

4,5-diaminostilbene-ethyl pyrazoles vitriol

This title compound is to be made in the mode identical with preparation example 4 by 5-amino-1-ethyl-4-nitroso-group pyrazoles.

¹H-NMR(D ₂O)δ1.36(3H，t，J＝7.3Hz)，4.10(2H，q，J＝7.3Hz)，7.77(1H，s)

ESI-MS：m/z＝127(M+H) ⁺

Preparation example 19

5-amino-4-[3-(tert-butoxycarbonyl amino) propionyl amino]-1-ethyl pyrazoles

This title compound is by 4, and 5-diaminostilbene-ethyl pyrazoles vitriol makes in the mode identical with preparation example 15.

¹H-NMR(DMSO-d ₆)δ1.24(3H，t，J＝7.2Hz)，1.37(9H，s)，2.35(2H，t，J＝7.1Hz)，3.18(2H，dt，J＝7.1，7.1Hz)，3.85(q，J＝7.2Hz)，4.88(2H，brs)，6.75-6.90(1H，m)，7.17(1H，s)，9.05(1H，brs)

APCI-MS：m/z＝298(M+H) ⁺

Preparation example 20

4-[3-(tert-butoxycarbonyl amino) propionyl amino]-1-ethyl-5-trityl group amino-pyrazol

This title compound is by 5-amino-4-[3-(tert-butoxycarbonyl amino) propionyl amino]-1-ethyl pyrazoles makes in the mode identical with preparation example 16.

¹H-NMR(DMSO-d ₆)δ0.88(3H，t，J＝7.2Hz)，1.39(9H，s)，2.02(2H，t，J＝7.1Hz)，2.95-3.20(4H，m)，5.59(1H，brs)，6.60-6.75(1H，m)，7.10-7.35(16H，m)，8.04(1H，brs)

ESI-MS：m/z＝540(M+H) ⁺，562(M+Na) ⁺

Embodiment 8

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[3-amino-4-(the amino propionyl amino of 3-)-2-ethyl-1-pyrazoles subbase] methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-amino-1; 2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester and 4-[3-(tert-butoxycarbonyl amino) propionyl amino]-1-ethyl-5-trityl group amino-pyrazol obtains in the mode identical with embodiment 1.

IR(KBr)3415，1763，1658，1598，1529，1402，1361cm ^-1

¹H-NMR (D ₂O) δ 1.33 (3H, t, J=7.2Hz), 1.53 (6H, s), 2.89 (2H, t, J=6.5Hz), 3.17 and 3.49 (2H, ABq, J=17.7Hz), 3.34 (2H, t, J=6.5Hz), 4.28 (2H, q, J=7.2Hz), 5.05 and 5.16 (2H, ABq, J=15.4Hz), 5.26 (1H, d, J=4.8Hz), 5.85 (1H, d, J=4.8Hz), 8.03 (1H, s)

Preparation example 21

2-[(5-amino-1-ethyl-1H-pyrazoles-4-yl) amino]-2-oxoethyl t-butyl carbamate

¹H-NMR(DMSO-d ₆)δ1.21(3H，t，J＝7.2Hz)，1.39(9H，s)，3.64(2H，d，J＝6.0Hz)，3.86(2H，d，J＝7.2Hz)，4.88(2H，brs)，6.90-7.00(1H，m)，7.17(1H，s)，9.06(1H，brs)

ESI-MS：m/z＝284(M+H) ⁺，306(M+Na) ⁺

Preparation example 22

2-{[1-ethyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-2-oxoethyl t-butyl carbamate

This title compound is by 2-[(5-amino-1-ethyl-1H-pyrazoles-4-yl) amino]-2-oxoethyl t-butyl carbamate makes in the mode identical with preparation example 16.

¹H-NMR(DMSO-d ₆)δ0.88(3H，t，J＝7.2Hz)，1.38(9H，s)，3.16(2H，q，J＝7.2Hz)，3.31(2H，d)，5.59(1H，brs)，6.80-6.95(1H，m)，7.10-7.40(16H，m)，8.03(1H，brs)

ESI-MS：m/z＝526(M+H) ⁺，548(M+Na) ⁺

Embodiment 9

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[3-amino-4-(glycyl) amino-2-ethyl-1-pyrazoles subbase] methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester and 2-{[1-ethyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-2-oxoethyl t-butyl carbamate obtains in the mode identical with embodiment 1.

¹H-NMR (D ₂O) δ 1.33 (3H, t, J=7.2Hz), 1.53 (6H, s), 2.89 (2H, t, J=6.5Hz), 3.17 and 3.49 (2H, ABq, J=17.7Hz), 4.00 (2H, s), 4.28 (2H, q, J=7.2Hz), 5.06 and 5.17 (2H, ABq, J=15.4Hz), 5.27 (1H, d, J=4.8Hz), 5.85 (1H, d, J=4.8Hz), 8.07 (1H, s)

Preparation example 23

5-amino-4-[2 ', 3 '-two (tert-butoxycarbonyl)-guanidine radicals]-1-ethyl pyrazoles

This title compound is by 1,3-two (tert-butoxycarbonyl)-2-(trifluoromethyl sulfonyl) guanidine and 4, and 5-diaminostilbene-ethyl pyrazoles vitriol makes in the mode identical with preparation example 13.

¹H-NMR(DMSO-d ₆)δ1.22(3H，t，J＝7.1Hz)，1.37(9H，s)，1.50(9H，s)，3.88(2H，d，J＝7.1Hz)，5.12(2H，brs)，7.14(1H，s)，9.16(1H，brs)，11.51(1H，brs)

ESI-MS：m/z＝369(M+H) ⁺

Preparation example 24

4-[2 ', 3 '-two (tert-butoxycarbonyl) guanidine radicals]-1-ethyl-5-trityl group amino-pyrazol

This title compound is by 5-amino-4-[2 ', 3 '-two (tert-butoxycarbonyl) guanidine radicals]-1-ethyl pyrazoles makes in the mode identical with preparation example 16.

¹H-NMR(DMSO-d ₆)δ0.86(3H，t，J＝7.1Hz)，1.38(9H，s)，1.49(9H，s)，5.85(1H，brs)，7.10-7.30(16H，m)，8.80(1H，brs)，11.14(1H，brs)

ESI-MS：m/z＝611(M+H) ⁺，633(M+Na) ⁺

Embodiment 10

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[3-amino-2-ethyl-4-guanidine radicals-1-pyrazoles subbase] methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester and 4-[2 ', 3 '-two (tert-butoxycarbonyl) guanidine radicals]-1-ethyl-5-trityl group amino-pyrazol makes in the mode identical with embodiment 1.

IR(KBr)3437，1760，1658，1625，1406，1065cm ^-1

¹H-NMR(D ₂O)δ1.35(3H，t，J＝7.3Hz)，1.53(6H，s)，3.26and 3.61(2H，ABq，J＝17.8Hz)，4.29(2H，q，J＝7.3Hz)，5.06 and 5.17(2H，ABq，J＝15.7Hz)，5.29(1H，d，J＝4.8Hz)，5.85(1H，d，J＝4.8Hz)，8.06(1H，s)

Embodiment 11

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester (500g) is at N, add 4-[2 ', 3 '-two (tert-butoxycarbonyl) guanidine radicals in the suspension in the dinethylformamide (2.5L)]-1-methyl-5-trityl group amino-pyrazol (419g) and with this mixture stirring at room 16 hours.This reaction mixture is added in the mixture of ethyl acetate and water.With organic layer water, salt solution and 10% sodium trifluoroacetate solution washing, use dried over mgso then.Filter out sal epsom, with filtrate evaporated under reduced pressure to 3.3kg.Concentrated solution is poured in the Di Iso Propyl Ether (33L), and collected formed precipitation by filtering, and vacuum-drying.

In the solution of gained solid in methylene dichloride (1500ml), add methyl-phenoxide (500ml) and trifluoroacetic acid (1500ml).Gained solution stirring at room 4 hours, and is poured in the Di Iso Propyl Ether.Collect formed precipitation by filtering, and vacuum-drying.Crude product is dissolved in the water (3.5L), with the pH regulator to 7.0 of 28% ammonia soln with this solution.Filter out insolubles, with the pH regulator to 1 of concentrated hydrochloric acid with filtrate.Filter out insolubles once more.Filtrate is composed purifying in the enterprising circumstances in which people get things ready for a trip of Diaion  HP-20, with 20% 2-aqueous propanol solution wash-out.With the elutriant vacuum concentration to about 3.0L.In concentrated solution, add 2.0M sulfuric acid (150ml), and, obtained crude product this mixture freeze-drying.By using the preparation HPLC purifying crude product (pH7.0 phosphate buffered saline buffer and acetonitrile) of ODS post.The elutriant vacuum concentration that will contain required product is to about 6L.With concentrated hydrochloric acid concentrated solution is adjusted to about pH 1, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 purifying, with 30% 2-aqueous propanol solution wash-out.With the elutriant vacuum concentration to about 1.5L.In concentrated solution, add 2.0M sulfuric acid (60ml), and with this mixture freeze-drying, obtained 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-(3-amino-4-guanidine radicals-2-methyl isophthalic acid-pyrazoles subbase) methyl-3-cephem-4-formic acid hydrosulfate (48.5g).

IR(KBr)1776，1714，1677，1651，1402，1112cm ^-1

¹H-NMR (D ₂O) δ 1.61 (6H, s), 3.28 and 3.58 (2H, ABq, J=17.8Hz), 3.74 (3H, s), 5.15 and 5.23 (2H, ABq, J=15.7Hz), 5.27 (1H, d, J=4.8Hz), 5.88 (1H, d, J=4.8Hz), 8.07 (1H, s)

ESI-MS：m/z＝623.2(M+H ⁺)

Preparation example 25

Ice-cooled following to 4, add N-ethyl diisopropyl amine (2.1ml) and N-[3-(tert-butoxycarbonyl amino) propionyloxy in the 5-diaminostilbene-suspension of (2-hydroxyethyl) pyrazoles vitriol (2.4g) in methylene dichloride (40ml)] succinimide (2.3g), with this mixture stirring at room 6 hours.In this reaction mixture, add salt solution (40ml) and saturated sodium bicarbonate aqueous solution (20ml), with this mixture with the mixture of ethyl acetate and 2-propyl alcohol (3: 1,60ml) extract.With the organic layer anhydrous sodium sulfate drying, filter and vacuum concentration.Develop resistates with ether, obtained 5-amino-4-[3-(tert-butoxycarbonyl amino) propionyl]-amino-1-(2-hydroxyethyl) pyrazoles (1.65g), be solid.

¹H-NMR(DMSO-d ₆)δ1.38(9H，s)，2.35(2H，t，J＝7.3Hz)，3.16-3.20(2H，m)，3.62-3.65(2H，m)，3.90(2H，t，J＝6.0Hz)，4.85(2H，brs)，4.92(1H，t，J＝5.0Hz)，6.84(1H，t，J＝5.5Hz)，7.20(1H，s)，9.09(1H，brs)

Embodiment 12

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[3-amino-4-(the amino propionamido of 3-)-2-(2-hydroxyethyl)-1-pyrazoles subbase] methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-tert-butoxycarbonyl amino-1; 2; 4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-)-kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester and 5-amino-4-[3-(tert-butoxycarbonyl amino) propionyl] amino-1-(2-hydroxyethyl) pyrazoles makes in the mode identical with embodiment 1, is amorphous solid.

¹H-NMR(D ₂O)δ1.51(6H，s)，2.88(2H，t，J＝6.4Hz)，3.15(1H，d，J＝17.9Hz)，3.48(1H，d，J＝17.9Hz)，3.32(2H，t，J＝6.4Hz)，3.88(2H，t，J＝4.8Hz)，4.39(1H，dt，J＝16.5Hz，4.8Hz)，4.42(1H，dt，J＝16.5，4.8Hz)，5.06(1H，d，J＝15.1Hz)，5.11(1H，d，J＝15.1Hz)，5.25(1H，d，J＝5.0Hz)，5.83(1H，d，J＝5.0Hz)，8.05(1H，s)

Preparation example 26

Down to 4-formyl radical-4,5,6, the 7-tetrahydro-pyrazole also adds saltpetre (111g) in the solution of [1,5-a] pyrimidine (1.51g) in sulfuric acid (7.5ml) ice-cooled.With this mixture stirring at room 17 hours.This reaction mixture is added in the ice (100g).Collect this crystalline residue by filtering, and vacuum-drying, having obtained 3-nitro-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine (0.63g) also, is solid.

¹H-NMR(DMSO-d ₆)δ2.00-2.05(2H，m)，3.30-3.36(2H，m)，3.99(2H，t，J＝6.0Hz)，7.85(1H，s)，7.89(1H，s)

Preparation example 27

With 3-nitro-4,5,6, the 7-tetrahydro-pyrazole also the solution of [1,5-a] pyrimidine (1.68g) in the mixture of sulfuric acid (0.6ml), acetate (100ml) and water (10ml) with 10% palladium carbon (0.5g) under nitrogen atmosphere in room temperature treatment 6 days.After the catalyzer filtration, with the filtrate vacuum concentration.Develop resistates with ethanol, and vacuum-drying, having obtained 3-amino-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine vitriol (2.3g) also, is solid.

¹H-NMR(DMSO-d ₆)δ1.97-2.01(2H，m)，3.22(2H，t，J＝5.0Hz)，3.98(2H，t，J＝6.0Hz)，7.22(1H，s)

Preparation example 28

To 3-amino-4; 5,6,7-tetrahydro-pyrazole also [1; 5-a] add 1,3-two (tert-butoxycarbonyl)-2-(trifyl) guanidine (3.91g) in pyrimidine vitriol (2.96g) and the solution of N-ethyl diisopropyl amine (3.88g) in methylene dichloride (70ml).With this mixture stirring at room 150 minutes.This reaction mixture is washed with saturated sodium bicarbonate aqueous solution.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates by silica gel chromatography, with 2% methyl alcohol/chloroform wash-out, has been obtained 3-[2,3-two (tert-butoxycarbonyl) guanidine radicals]-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine (3.4g) also, is solid.

¹H-NMR(CDCl ₃)δ1.48(9H，s)，1.52(9H，s)，2.12-2.14(2H，m)，3.33-3.37(2H，m)，4.08(2H，t，J＝6.0Hz)，6.17(1H，brs)，7.16(1H，s)，9.87(1H，brs)，11.39(1H，brs)

Embodiment 13

To 7 β-[(Z)-2-(5-tert-butoxycarbonyl amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester (1.0g) is at N, add sodium iodide (181mg) in the solution in the dinethylformamide (2.0ml), with this mixture stirring at room 30 minutes.In this reaction mixture, add 3-[2,3-two (tert-butoxycarbonyl) guanidine radicals]-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine (571mg) and methylene dichloride (2.0ml) also.With whole mixture stirring at room 7 hours.In this reaction mixture, add ethyl acetate (100ml) and water (50ml).Isolate water layer, organic layer with 10% trifluoroacetic acid sodium water solution and salt water washing, is also filtered with dried over sodium sulfate.With the filtrate vacuum concentration to about 5ml.Pour concentrated solution into Di Iso Propyl Ether (150ml), collect formed precipitation by filtering, and vacuum-drying.

In the solution of gained solid in methylene dichloride (3.0ml), add methyl-phenoxide (1.0ml) and trifluoroacetic acid (2.0ml), with this mixture stirring at room 4 hours.This reaction mixture is poured in the Di Iso Propyl Ether (150ml), collected formed precipitation by filtering, and vacuum-drying, crude product (570mg) obtained, by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 30ml.Concentrated solution is adjusted to about pH 3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (Mitsubishi Chemical Corporation) purifying, with 30% 2-aqueous propanol solution wash-out.With the elutriant vacuum concentration to about 30ml, and freeze-drying, obtained 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[3-guanidine radicals-4,5,6,7-tetrahydrochysene-1-pyrazolo [1,5-a] pyrimidine subbase] methyl-3-cephem-4-formate (51mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.52(3H，s)，1.53(3H，s)，2.05-2.25(2H，m)，3.26(1H，d，J＝17.4Hz)，3.56(1H，d，J＝17.4Hz)，3.30-3.45(2H，m)，4.15(2H，t，J＝6.0Hz)，4.93(1H，d，J＝15.6Hz)，5.15(1H，d，J＝15.6Hz)，5.25(1H，d，J＝4.8Hz)，5.84(1H，d，J＝4.8Hz)，7.99(1H，s)

Preparation example 29

To 7-amino-2; 3-dihydro-1H-imidazo [1; 2-b] add 1,3-two (tert-butoxycarbonyl)-2-(trifyl) guanidine (10.18g) in pyrazoles vitriol (4.4g), 4-(dimethylamino) pyridine (244mg) and the solution of triethylamine (8.10g) in chloroform (45ml).With this mixture stirring at room 2 hours.This reaction mixture is washed with 10% aqueous citric acid solution, salt solution and saturated sodium bicarbonate aqueous solution successively.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates is developed with Di Iso Propyl Ether, has been obtained 7-[2,3-two (tert-butoxycarbonyl) guanidine radicals]-2,3-dihydro-1H-imidazo [1,2-b] pyrazoles (4.6g) is solid.

¹H-NMR(CDCl ₃)δ1.49(9H，s)，1.52(9H，s)，3.97-4.01(2H，m)，4.21(2H，t，J＝7.8Hz)，5.30(1H，brs)，7.19(1H，s)，9.86(1H，brs)，11.32(1H，brs)

Embodiment 14

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[7-guanidine radicals-2,3-dihydro-5-(1H-imidazo [1,2-b] pyrazoles subbase)] methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-tert-butoxycarbonyl amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-)-kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester and 7-[2,3-two (tert-butoxycarbonyl) guanidine radicals]-2,3-dihydro-1H-imidazo [1,2-b] pyrazoles makes in the mode with embodiment 13, is amorphous solid.

¹H-NMR(D ₂O)δ1.51(3H，s)，1.52(3H，s)，3.35(1H，d，J＝17.9Hz)，3.61(1H，d，J＝17.9Hz)，4.19(2H，t，J＝8.7Hz)，4.37(1H，q，J＝8.7Hz)，4.47(1H，q，J＝8.7Hz)，5.00(1H，d，J＝15.1Hz)，5.04(1H，d，J＝15.1Hz)，5.26(1H，d，J＝4.8Hz)，5.84(1H，d，J＝4.8Hz)，8.13(1H，s)

Preparation example 30

In the solution of 5-amino-1-(2-hydroxyethyl) pyrazoles (6.35g) in the mixed solvent of ethanol (25ml) and concentrated hydrochloric acid (0.035ml), drip Isopentyl nitrite (7.03g).With this mixture stirring at room 17 hours.Collect this crystalline residue by filtering, and vacuum-drying, obtained 5-amino-1-(2-hydroxyethyl)-4-nitroso-group pyrazoles (4.0g), be solid.

¹H-NMR(DMSO-d ₆)δ3.68(2H，t，J＝5.5Hz)，3.94(2H，t，J＝5.5Hz)，4.89(1H，br)，8.06(2H，br)，8.53(1H，s)

Preparation example 31

With the solution of 5-amino-1-(2-hydroxyethyl)-4-nitroso-group pyrazoles (97g) in the mixed solvent of sulfuric acid (34ml) and water (2000ml) with 10% palladium carbon (10g) under nitrogen atmosphere in room temperature treatment 4 days.After the catalyzer filtration, with the filtrate vacuum concentration.Develop resistates with methyl alcohol, and vacuum-drying, having obtained 4,5-diaminostilbene-(2-hydroxyethyl) pyrazoles vitriol (90.2g) is solid.

¹H-NMR(DMSO-d ₆)δ3.66(2H，t，J＝5.5Hz)，3.95(2H，t，J＝5.5Hz)，7.25(1H，s)

Preparation example 32

To 4; add 4-(dimethylamino) pyridine (2.54g), triethylamine (116ml) and 1 in the 5-diaminostilbene-suspension of (2-hydroxyethyl) pyrazoles vitriol (50.0g) in chloroform (500ml), 3-two (tert-butoxycarbonyl)-2-(trifyl) guanidine (106g).This mixture was stirred 2 hours under reflux state.After cooling on the ice bath, with this reaction mixture water successively, 4% aqueous citric acid solution, water and sodium bicarbonate aqueous solution washing.With the organic layer dried over sodium sulfate, filter and vacuum concentration.With the mixed solvent development of resistates, obtained 5-amino-4-[2,3-two (tert-butoxycarbonyl) guanidine radicals with ethyl acetate (50ml) and ether (200ml)]-1-(2-hydroxyethyl) pyrazoles (50g), be solid.

¹H-NMR(CDCl ₃)δ1.47(9H，s)，1.53(9H，s)，3.28(1H，br)，4.02-4.05(4H，m)，4.65(2H，br)，7.22(1H，s)，9.85(1H，br)，11.55(1H，br)

Embodiment 15

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[3-amino-4-guanidine radicals-2-(2-hydroxyethyl)-1-pyrazoles subbase] methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-tert-butoxycarbonyl amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-)-kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester and 5-amino-4-[2,3-two (tert-butoxycarbonyl) guanidine radicals]-1-(2-hydroxyethyl) pyrazoles makes in the mode with embodiment 13, is amorphous solid.

¹H-NMR(D ₂O)δ1.52(3H，s)，3.21(1H，d，J＝17.9Hz)，3.59(1H，d，J＝17.9Hz)，3.90(2H，t，J＝4.8Hz)，4.35-4.50(2H，m)，5.07(1H，d，J＝14.9Hz)，5.11(1H，d，J＝14.9Hz)，5.28(1H，d，J＝5.0Hz)，5.84(1H，d，J＝5.0Hz)，8.09(1H，s)

Preparation example 33

To 7-[2,3-two (tert-butoxycarbonyl) guanidine radicals]-2, add trityl group chlorine (1.67g) in the solution of 3-dihydro-1H-imidazo [1,2-b] pyrazoles (1.83g) in pyridine (10ml).This mixture was stirred 5 hours at 50 ℃.After the cooling, chloroform (50ml) is added in this reaction mixture, this mixture is washed with 10% aqueous citric acid solution, salt solution and saturated sodium bicarbonate aqueous solution successively.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates by silica gel chromatography, with 2% methyl alcohol/chloroform wash-out, has been obtained 7-[2,3-two (tert-butoxycarbonyl) guanidine radicals]-1-trityl group-2,3-dihydro-1H-imidazo [1,2-b] pyrazoles (1.57g) is solid.

¹H-NMR(CDCl ₃)δ1.47(9H，s)，1.48(9H，s)，3.50(2H，t，J＝7.8Hz)，3.92(2H，t，J＝7.8Hz)，7.07-7.26(10H，m)，7.53-7.54(6H，m)，8.34(1H，brs)，11.12(1H，brs)

Embodiment 16

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester (819mg) is at N, add N-(trimethyl silyl) ethanamide (656mg) in the solution in the dinethylformamide (2.4ml), with this mixture stirring at room 30 minutes.In this reaction mixture, add 7-[2,3-two (tert-butoxycarbonyl) guanidine radicals]-1-trityl group-2,3-dihydro-1 H-imidazo [1,2-b] pyrazoles (730mg).With whole mixture stirring at room 6 hours.In the gained reaction mixture, add ethyl acetate (100ml) and water (50ml).Isolate water layer, organic layer with 10% trifluoroacetic acid sodium water solution, 10% sodium thiosulfate solution and salt water washing, is also filtered with dried over sodium sulfate.With the filtrate vacuum concentration to about 5ml.Pour concentrated solution into Di Iso Propyl Ether (120ml), and collect formed precipitation by filtering, and vacuum-drying.

In the solution of gained solid in methylene dichloride (2.0ml), add methyl-phenoxide (0.67ml) and trifluoroacetic acid (1.34ml), with this mixture stirring at room 4 hours.Pour this reaction mixture into Di Iso Propyl Ether (120ml).Collect formed precipitation by filtering, and vacuum-drying, crude product (430mg) obtained, by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 30ml.Concentrated solution is adjusted to about pH 3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (Mitsubishi Chemical Corporation) purifying, with the aqueous solution wash-out of 30% 2-propyl alcohol.With the elutriant vacuum concentration to about 30ml, and freeze-drying, obtained 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[7-guanidine radicals-2,3-dihydro-5-(1H-imidazo [1,2-b] pyrazoles subbase)] methyl-3-cephem-4-formate (20.4mg), be amorphous solid.

Preparation example 34

To 1,1 '-add N-(3-aminopropyl) t-butyl carbamate (2.30g) in the suspension of carbonyl dimidazoles (1.94g) in methylene dichloride (20ml), with this mixture stirring at room 1 hour.Add N-ethyl diisopropyl amine (2.56g) and 4 in this reaction mixture, 5-diaminostilbene-methylpyrazole vitriol (2.10g) stirs this mixture 3 days at 30 ℃.With this reaction mixture vacuum concentration.Resistates by silica gel chromatography, with 6% methyl alcohol/chloroform wash-out, has been obtained 5-amino-4-(3-{3-[(tert-butoxycarbonyl) amino] propyl group } urea groups)-1-methylpyrazole (1.75g), be solid.

¹H-NMR(DMSO-d ₆)δ1.37(9H，s)，1.43-1.49(2H，m)，2.89-2.93(2H，m)，2.98-3.01(2H，m)，3.50(3H，s)，4.79(2H，br)，5.85(1H，br)，6.77(1H，br)，6.96(1H，s)，7.12(1H，br)

Embodiment 17

To 7 β-[(Z)-2-(5-tert-butoxycarbonyl amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester (1.0g) is at N, add sodium iodide (199mg) in the solution in the dinethylformamide (2.0ml), with this mixture stirring at room 30 minutes.In this reaction mixture, add 5-amino-4-(3-{3-[(tert-butoxycarbonyl) amino] propyl group } urea groups)-1-methylpyrazole (415mg), whole mixture was stirred 24 hours at 32 ℃.In the gained reaction mixture, add ethyl acetate (50ml) and water (50ml).Isolate water layer, organic layer with 10% trifluoroacetic acid sodium water solution and salt water washing, is also filtered with anhydrous sodium sulfate drying.With the filtrate vacuum concentration to about 5ml.Concentrated solution is poured in the Di Iso Propyl Ether (100ml), and collected formed precipitation by filtering, and vacuum-drying.In the solution of gained solid in methylene dichloride (3.6ml), add methyl-phenoxide (1.2ml) and trifluoroacetic acid (2.4ml).Stirring at room 4 hours, and pour gained solution into Di Iso Propyl Ether (100ml).Collect formed precipitation by filtering, and vacuum-drying, crude product (939mg) obtained, by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 30ml.Concentrated solution is adjusted to about pH 3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (Mitsubishi ChemicalCorporation) purifying, with 30% 2-aqueous propanol solution wash-out.With the elutriant vacuum concentration to about 30ml, and freeze-drying, obtained 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-amino-4-[3-(3-aminopropyl) urea groups]-2-methyl isophthalic acid-pyrazoles subbase } methyl-3-cephem-4-formate (53mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.52(3H，s)，1.53(3H，s)，1.85-1.88(2H，m)，3.03(2H，t，J＝8Hz)，3.22(2H，t，J＝18Hz)，3.26(2H，t，J＝7Hz)，3.49(1H，d，J＝18Hz)，3.72(3H，s)，4.96(1H，d，J＝15Hz)，5.16(1H，d，J＝15Hz)，5.25(1H，d，J＝5Hz)，5.84(1H，d，J＝5Hz)，7.88(1H，s)

Preparation example 35

Ice-cooled down to 1,1 '-add N-(2-amino-ethyl) t-butyl carbamate (1.11g) in the suspension of carbonyl dimidazoles (973mg) in methylene dichloride (10ml), with this mixture stirring at room 2 hours.Add N-ethyl diisopropyl amine (1.28g) and 3-amino-4,5,6 in this reaction mixture, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine vitriol (1.18g) also, and this mixture was stirred 6 hours at 50 ℃.With the salt water washing of this reaction mixture.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates by silica gel chromatography, with 5% methyl alcohol/chloroform wash-out, has been obtained 3-(3-{2-[(tert-butoxycarbonyl) amino] ethyl } urea groups)-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine (150mg) also, is solid.

¹H-NMR(CDCl ₃)δ1.43(9H，s)，2.11-2.16(2H，m)，3.22-3.35(6H，m)，4.09(2H，t，J＝7Hz)，4.69(1H，br)，5.14(2H，br)，5.69(1H，br)，7.17(1H，s)

Embodiment 18

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-[3-(2-amino-ethyl) urea groups]-4,5,6,7-tetrahydrochysene-1-pyrazolo [1,5-a] pyrimidine subbase } methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-tert-butoxycarbonyl amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-)-kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester and 3-(3-{22-[(tert-butoxycarbonyl) amino] ethyl } urea groups)-4,5,6,7-tetrahydro-pyrazole also [1,5-a] pyrimidine makes in the mode identical with embodiment 17, is amorphous solid.

¹H-NMR(D ₂O)δ1.52(3H，s)，1.53(3H，s)，2.09-2.21(2H，m)，3.13(2H，t，J＝6Hz)，3.24(1H，d，J＝18Hz)，3.35-3.52(5H，m)，4.12-4.15(2H，m)，4.88(1H，d，J＝16Hz)，5.13(1H，d，J＝16Hz)，5.25(1H，d，J＝5Hz)，5.85(1H，d，J＝5Hz)，7.83(1H，s)

Preparation example 36

Ice-cooled down to 1,1 '-add 0-[2-(tert-butoxycarbonyl amino) ethyl in the suspension of carbonyl dimidazoles (973mg) in methylene dichloride (10ml)] oxyamine (1.11g), with this mixture stirring at room 2 hours.Add N-ethyl diisopropyl amine (1.28g) and 4 in this reaction mixture, 5-diaminostilbene-methylpyrazole vitriol (1.05g) stirs this mixture 4 hours under reflux state.With the salt water washing of this reaction mixture.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates by silica gel chromatography, with 10% methyl alcohol/chloroform wash-out, has been obtained 5-amino-4-(3-{2-[(tert-butoxycarbonyl) amino] oxyethyl group } urea groups)-1-methylpyrazole (255mg), be solid.

¹H-NMR(DMSO-d ₆)δ1.38(9H，s)，3.19-3.20(2H，m)，3.51(3H，s)，3.72(2H，t，J＝6Hz)，4.86(2H，br)，6.95(1H，br)，7.06(1H，s)，8.02(1H，brs)，9.15(1H，brs)

Embodiment 19

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-amino-4-[3-(2-amino ethoxy) urea groups]-2-methyl isophthalic acid-pyrazoles subbase } methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-tert-butoxycarbonyl amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-)-kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester and 5-amino-4-(3-{2-[(tert-butoxycarbonyl) amino] oxyethyl group }-urea groups)-the 1-methylpyrazole makes in the mode identical with embodiment 17, is amorphous solid.

¹H-NMR(D ₂O)δ1.52(3H，s)，1.53(3H，s)，3.21(1H，d，J＝18Hz)，3.33(2H，t，J＝5Hz)，3.47(1H，d，J＝18Hz)，3.74(3H，s)，4.17(2H，t，J＝5Hz)，4.99(1H，d，J＝15Hz)，5.17(1H，d，J＝15Hz)，5.26(1H，d，J＝5Hz)，5.86(1H，d，J＝5Hz)，7.93(1H，s)

Preparation example 37

Ice-cooled down to 1,1 '-add N-(2-amino-ethyl) t-butyl carbamate (1.92g) in the suspension of carbonyl dimidazoles (1.95g) in methylene dichloride (20ml), with this mixture stirring at room 2 hours.Add N-ethyl diisopropyl amine (2.59g) and 7-amino-2 in this reaction mixture, the 3-dihydro-1 h-pyrazole is [1,2-b] pyrimidine vitriol (2.22g) also, with this mixture stirring at room 16 hours.In this reaction mixture, add trityl chloride (9.0g) and triethylamine (3.0g).With this mixture stirring at room 24 hours.This reaction mixture is washed with 10% aqueous citric acid solution, salt solution and saturated sodium bicarbonate aqueous solution.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates by silica gel chromatography, with 3% methyl alcohol/chloroform wash-out, has been obtained 7-(3-{2-[(tert-butoxycarbonyl) amino] ethyl } urea groups)-2,3-dihydro-1-trityl Mi Dingbing [1,5-a] pyrazoles (150mg) is solid.

¹H-NMR(CDCl ₃)δ1.43(9H，s)，3.19(4H，br)，3.69(1H，brs)，3.78-3.85(4H，m)，4.51(1H，br)，5.07(1H，br)，7.20(1H，s)，7.26-7.34(9H，m)，7.46-7.47(6H，m)

Embodiment 20

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-)-kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester (820mg) is at N, add N-(trimethyl silyl) ethanamide (656mg) in the solution in the dinethylformamide (2.4ml), with this mixture stirring at room 30 minutes.In this reaction mixture, add 7-(3-{2-[(tert-butoxycarbonyl) amino] ethyl } urea groups)-2,3-dihydro-1-trityl Mi Dingbing [1,5-a] pyrazoles (700mg), whole mixture stirring at room 6 hours, is added ethyl acetate (50ml) and water (50ml) in the gained reaction mixture.Isolate water layer, organic layer with 10% trifluoroacetic acid sodium water solution and salt water washing, is also filtered with anhydrous sodium sulfate drying.With the filtrate vacuum concentration to about 5ml.Pour concentrated solution into Di Iso Propyl Ether (120ml), and collect formed precipitation by filtering, and vacuum-drying.In the solution of gained solid in methylene dichloride (3.0ml), add methyl-phenoxide (1.0ml) and trifluoroacetic acid (2.0ml).Stirring at room 4 hours, and pour gained solution into Di Iso Propyl Ether (120ml).Collect formed precipitation by filtering, and vacuum-drying, crude product (830mg) obtained, by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 30ml.Concentrated solution is adjusted to about pH 3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (Mitsubishi Chemical Corporation) purifying, with the aqueous solution wash-out of 30% 2-propyl alcohol.With the elutriant vacuum concentration to about 30ml, and freeze-drying, obtained 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{7-[3-(2-amino-ethyl) urea groups]-2,3-dihydro-5-(1H-imidazo [1,2-b] pyrazoles subbase) } methyl-3-cephem-4-formate (28.5mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.53(3H，s)，1.54(3H，s)，3.14(2H，t，J＝6Hz)，3.29(1H，d，J＝18Hz)，3.49(2H，t，J＝6Hz)，3.57(1H，d，J＝18Hz)，4.16(2H，t，J＝9Hz)，4.31-4.45(2H，m)，4.94(1H，d，J＝15Hz)，5.02(1H，d，J＝15Hz)，5.27(1H，d，J＝5Hz)，5.85(1H，d，J＝5Hz)，7.95(1H，s)

Preparation example 38

Ice-cooled down to 1,1 '-add dewatering solution in the chloroform (10ml) of N-(2-hydroxyethyl) t-butyl carbamate (1.92g) in the suspension of carbonyl dimidazoles (2.0g) in dehydration chloroform (30ml).With this mixture stirring at room 1 hour.In this reaction mixture, add N-ethyl diisopropyl amine (2.2ml) and 4,5-diaminostilbene-methylpyrazole vitriol (2.58g), with this mixture stirring at room 17.5 hours.In this reaction mixture, add trityl chloride (3.42g) and triethylamine (1.25g).With this mixture stirring at room 2 hours.This reaction mixture is washed with 10% aqueous citric acid solution, salt solution and saturated sodium bicarbonate aqueous solution.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates by silica gel chromatography, with 5% methyl alcohol/chloroform wash-out, has been obtained 4-{[2-(tert-butoxycarbonyl amino) ethoxy carbonyl] amino }-5-(trityl amino)-1-methylpyrazole (1.91g), be solid.

¹H-NMR(CDCl ₃)δ1.46(9H，s)，2.89(3H，s)，3.30-3.36(2H，m)，4.03-4.07(2H，m)，4.37(1H，brs)，4.75(1H，br)，5.42(1H，br)，7.17-7.30(16H，m)

Embodiment 21

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-amino-4-[(2-amino ethoxy carbonyl) amino]-2-methyl isophthalic acid-pyrazoles subbase } methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester and 4-{[2-(tert-butoxycarbonyl amino) ethoxy carbonyl] amino }-5-(trityl amino)-1-methylpyrazole obtains in the mode identical with embodiment 20, is amorphous solid.

¹H-NMR(D ₂O)δ1.53(3H，s)，1.54(3H，s)，3.18(1H，d，J＝18Hz)，3.30-3.38(2H，m)，3.43(1H，d，J＝18Hz)，3.71(3H，s)，4.37-4.40(2H，m)，4.97(1H，d，J＝15Hz)，5.18(1H，d，J＝15Hz)，5.24(1H，d，J＝5Hz)，5.83(1H，d，J＝5Hz)，7.95(1H，s)

Preparation example 39

To 7-amino-2, add N-[2-(tert-butoxycarbonyl amino) acetoxyl group in 3-dihydro-1H-imidazo [1,2-b] pyrazoles vitriol (1.42g) and the solution of N-ethyl diisopropyl amine (2.73g) in methylene dichloride (50ml)] succinimide (1.90g).With this mixture stirring at room 22 hours.This reaction mixture is washed with saturated sodium bicarbonate aqueous solution, with the organic layer drying, filter and vacuum concentration with anhydrous magnesium sulfate.By silica gel chromatography oily resistates,, obtained 7-[2-(tert-butoxycarbonyl amino) ethanoyl with 5% methyl alcohol/chloroform wash-out] amino-2,3-dihydro-1H-imidazo [1,2-b] pyrazoles (1.07g) is solid.

¹H-NMR(CDCl ₃)δ1.47(9H，s)，3.89(2H，d，J＝5.5Hz)，3.97(2H，dt，J＝2.7，7.3Hz)，4.18(2H，t，J＝7.3Hz)，4.55(1H，br)，5.22(1H，br)，7.16(1H，s)，7.95(1H，br)

Embodiment 22

To 7 β-[(Z)-2-(5-tert-butoxycarbonyl amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester (1.0g) is at N, add sodium iodide (181mg) in the solution in the dinethylformamide (2.0ml), with this mixture stirring at room 30 minutes.In this reaction mixture, add 7-[2-(tert-butoxycarbonyl amino) ethanoyl] amino-2,3-dihydro-1H-imidazo [1,2-b] pyrazoles (421mg).Whole mixture was stirred 3 hours at 30 ℃.In the gained reaction mixture, add ethyl acetate (100ml) and water (50ml) is isolated water layer, organic layer with 10% trifluoroacetic acid sodium water solution and salt solution, is used anhydrous sodium sulfate drying, and filter.With the filtrate vacuum concentration to about 5ml.Concentrated solution is poured in the Di Iso Propyl Ether (150ml), collected the gained precipitation by filtering, and vacuum-drying.In the solution of gained solid in methylene dichloride (3.0ml), add methyl-phenoxide (1.0ml) and trifluoroacetic acid (2.0ml).Gained solution stirring at room 4 hours, and is poured in the Di Iso Propyl Ether (150ml).Collect formed precipitation by filtering, and vacuum-drying, crude product (830mg) obtained, by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 30ml.Concentrated solution is adjusted to about pH 3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (Mitsubishi ChemicalCorporation) purifying, with 30% 2-aqueous propanol solution wash-out.With the elutriant vacuum concentration to about 30ml, and freeze-drying, obtained 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[7-(2-glycyl amino)-2,3-dihydro-5-(1H-imidazo [1,2-b] pyrazoles subbase)] methyl-3-cephem-4-formate (20.8mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.51(3H，s)，1.52(3H，s)，3.26(2H，d，J＝18Hz)，3.54(2H，d，J＝18Hz)，3.97(2H，s)，4.16(2H，t，J＝9Hz)，4.35(1H，q，J＝9Hz)，4.44(1H，q，J＝9Hz)，4.97(2H，d，J＝15Hz)，5.04(2H，d，J＝15Hz)，5.25(1H，d，J＝4Hz)，5.84(1H，d，J＝4Hz)，8.10(1H，s)

Preparation example 40

Ice-cooled following to 4,5-diaminostilbene-(2-hydroxyethyl) pyrazoles vitriol (1.20g) and N-[2-(tert-butoxycarbonyl amino) acetoxyl group] add N-ethyl diisopropyl amine (2.1ml) in the suspension of succinimide (1.35g) in methylene dichloride (20ml), with this mixture stirring at room 17 hours.With this reaction mixture water (40ml), saturated sodium bicarbonate aqueous solution (40ml) and salt solution (40ml) washing.With the organic layer anhydrous sodium sulfate drying, filter and vacuum concentration.With this oily resistates silica gel chromatography,, obtained 5-amino-4-[2-(tert-butoxycarbonyl amino) ethanoyl with 10% methyl alcohol/chloroform wash-out] amino-1-(2-hydroxyethyl) pyrazoles (1.20g), be solid.

¹H-NMR(CDCl ₃)δ1.46(9H，s)，3.89-3.90(4H，m)，4.00-4.04(2H，m)，4.26(2H，br)，5.51(1H，br)，7.17(1H，s)，8.06(1H，br)

Embodiment 23

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[3-amino-4-(2-glycyl amino)-2-(2-hydroxyethyl)-1-pyrazoles subbase] methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-tert-butoxycarbonyl amino-1; 2; 4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-)-kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester and 5-amino-4-[2-(tert.-butoxy amino) ethanoyl] amino-1-(2-hydroxyethyl) pyrazoles makes in the mode identical with embodiment 22, is amorphous solid.

¹H-NMR(D ₂O)δ1.52(6H，s)，3.15(2H，d，J＝18Hz)，3.48(2H，d，J＝18Hz)，3.88(1H，dt，J＝16Hz)，4.02(2H，s)，4.42(1H，dt，J＝16.5Hz)，5.07(2H，d，J＝15Hz)，5.13(2H，d，J＝15Hz)，5.27(1H，d，J＝5Hz)，5.84(1H，d，J＝5Hz)，8.09(1H，s)

Preparation example 41

To 3-amino-4,5,6, the 7-tetrahydro-pyrazole also adds N-[2-(tert-butoxycarbonyl amino) acetoxyl group in [1,5-a] pyrimidine vitriol (2.96g) and the solution of N-ethyl diisopropyl amine (2.59g) in methylene dichloride (70ml)] succinimide (2.72g).With this mixture stirring at room 14 hours.This reaction mixture is washed with saturated sodium bicarbonate aqueous solution.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.This resistates by silica gel chromatography, with 6% methyl alcohol/chloroform wash-out, has been obtained 3-[2-(tert-butoxycarbonyl amino) ethanoyl] amino-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine (2.4g) also, is solid.

¹H-NMR(CDCl ₃)δ1.46(9H，s)，2.08-2.12(2H，m)，3.29-3.32(2H，m)，3.90(2H，br)，4.07(2H，t，J＝6.0Hz)，5.00(1H，br)，5.38(1H，br)，7.12(1H，s)，8.11(1H，br)

Embodiment 24

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[3-(2-glycyl amino)-4,5,6,7-tetrahydrochysene-1-pyrazolo [1,5-a] pyrimidine subbase] methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-tert-butoxycarbonyl amino-1; 2; 4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-)-kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester and 3-[2-(tert-butoxycarbonyl amino) ethanoyl] amino-4; 5; 6; 7-tetrahydro-pyrazole also [1,5-a] pyrimidine makes in the mode identical with embodiment 22, is amorphous solid.

¹H-NMR(D ₂O)δ1.52(3H，s)，1.53(3H，s)，2.05-2.25(2H，m)，3.21(2H，d，J＝18Hz)，3.45(2H，d，J＝18Hz)，3.30-3.45(2H，m)，4.00(2H，s)，4.10-4.25(2H，m)，4.92(2H，d，J＝15Hz)，5.17(2H，d，J＝15Hz)，5.24(1H，d，J＝5Hz)，5.84(1H，d，J＝5Hz)，7.97(1H，s)

Preparation example 42

To 3-amino-4,5,6, the 7-tetrahydro-pyrazole also adds N-[3-(tert-butoxycarbonyl amino) propionyloxy in [1,5-a] pyrimidine vitriol (4.44g) and the solution of N-ethyl diisopropyl amine (3.88g) in methylene dichloride (100ml)] succinimide (4.29g).With this mixture stirring at room 6 hours.This reaction mixture is washed with saturated sodium bicarbonate aqueous solution.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.This resistates by silica gel chromatography, with 5% methyl alcohol/chloroform wash-out, has been obtained 3-[3-(tert-butoxycarbonyl amino) propionyl] amino-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine (2.4g) also, is solid.

¹H-NMR(CDCl ₃)δ1.43(9H，s)，2.08-2.13(2H，m)，2.52(2H，t，J＝6.0Hz)，3.32(2H，t，J＝5.0Hz)，3.43-3.46(2H，m)，4.07(2H，t，J＝6.0Hz)，5.12(1H，br)，5.23(1H，br)，7.13(1H，s)，7.97(1H，br)

Embodiment 25

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-[3-(the amino propionamido of 3-)-4,5,6,7-tetrahydrochysene-1-pyrazolo [1,5-a] pyrimidine subbase] methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-tert-butoxycarbonyl amino-1; 2; 4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-)-kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester and 3-[3-(tert-butoxycarbonyl amino) propionyl] amino-4; 5; 6; 7-tetrahydro-pyrazole also [1,5-a] pyrimidine makes in the mode identical with embodiment 22, is amorphous solid.

¹H-NMR(D ₂O)δ1.51(3H，s)，1.52(3H，s)，2.05-2.25(2H，m)，2.85(2H，t，J＝7Hz)，3.20(2H，d，J＝18Hz)，3.44(2H，d，J＝18Hz)，3.30-3.45(2H，m)，3.31(2H，t，J＝7Hz)，4.05-4.20(2H，m)，4.91(2H，d，J＝16Hz)，5.16(2H，d，J＝16Hz)，5.23(1H，d，J＝5Hz)，5.84(1H，d，J＝5Hz)，7.92(1H，s)

Preparation example 43

Being lower than under 10 ℃ the temperature, in the 5-amino-solution of 1-methylpyrazole (100g) in water (700ml), add concentrated hydrochloric acid (86ml) and the solution of Sodium Nitrite (63.9g) in water (200ml).This reaction mixture was stirred 30 minutes at 5 ℃.By filtering the solid of collecting precipitation, drying has obtained 5-amino-1-methyl-4-nitroso-group pyrazoles (117g).

¹H-NMR(DMSO-d ₆)δ3.52 and 3.59(3H，s)，7.22 and 8.51(1H，s)，8.17 and 8.51(1H，brs)

Preparation example 44

In the suspension of 5-amino-1-methyl-4-nitroso-group pyrazoles (117g), add sulfuric acid (91g) and 10% palladium carbon (58g).With the hydrogenation 10 hours under gasbag pressure of this mixture.This reaction mixture is filtered, with the filtrate vacuum concentration.Adding Virahol (2.3L) in concentrated solution stirs this mixture 1 hour.By filtering the solid that collecting precipitation goes out, drying has obtained 4,5-diaminostilbene-methylpyrazole vitriol (158g)

¹H-NMR(D ₂O)δ3.74(3H，s)，7.80(1H，s)

Preparation example 45

To 4, the 5-diaminostilbene-solution of methylpyrazole vitriol (158g) in water (1.1L) is neutralized to pH6.9 with the 4N aqueous sodium hydroxide solution, adds dioxane (474ml) in this solution.Being lower than under 10 ℃ the temperature, in the gained mixture, drip phenyl chloroformate (124g), with the 4N aqueous sodium hydroxide solution pH of this mixture is remained on 6.9 simultaneously.This reaction mixture was stirred 1 hour.By filtering the solid that collecting precipitation goes out, drying has obtained 5-amino-1-methyl-4-phenyloxycarbonyl amino-pyrazol (155g).

¹H-NMR(DMSO-d ₆)δ3.52(3H，s)，5.00(2H，brs)，7.10-7.50(6H，m)，8.93(1H，brs)

Preparation example 46

Add triethylamine (67g) and trityl group chlorine (185g) in room temperature to the suspension of 5-amino-1-methyl-4-phenyloxycarbonyl amino-pyrazol (153.8g) in tetrahydrofuran (THF) (1L).This mixture was stirred 6.5 hours.In this mixture, add heptane (2.6L), this mixture was stirred 1 hour.By filtering the solid that collecting precipitation goes out, with heptane-Di Iso Propyl Ether (1: 1) wash-out.Crude product is suspended in the water (3L), suspension was stirred 1 hour.By solid collected by filtration, drying has obtained 1-methyl-4-phenyloxycarbonyl amino-5-trityl group amino-pyrazol (253.6g).

¹H-NMR(DMSO-d ₆)δ2.74(3H，s)，5.57(1H，brs)，7.00-7.50(21H，m)，8.12(1H，brs)

Preparation example 47

To 1-methyl-4-phenyloxycarbonyl amino-5-trityl group amino-pyrazol (253.6g) at N, be added in N, triethylamine (59.5g) in the dinethylformamide (254ml) and N-(2-amino-ethyl) t-butyl carbamate (94.2g) in the suspension in the dinethylformamide (1.5L).This mixture was stirred 5 hours, pour in the water (10.6L).These slurries were stirred 1 hour.By filtering the solid that collecting precipitation goes out, and dry, obtained crude product.Crude product is suspended in N, in the dinethylformamide, this suspension was heated 20 minutes under reflux state.With 4 hours this suspension is cooled to room temperature.By solid collected by filtration,, obtained 4-[N-(2-tert-butoxycarbonyl amino-ethyl) formamyl amino with acetonitrile washing and dry]-1-methyl-5-trityl group amino-pyrazol (261.2g).

¹H-NMR(DMSO-d ₆)δ2.69(3H，s)，2.90-3.05(4H，m)，5.69(1H，brs)，5.91-6.01(1H，m)，6.74-6.81(1H，m)，6.87(1H，brs)，7.00(1H，s)，7.10-7.30(15H，m)

Preparation example 48

Ice-cooled following to (Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-add salt of wormwood (113g) and methylsulfonyl chloride (126ml) in 2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) solution of acetate (319g) in N,N-dimethylacetamide (1.5L).This mixture was stirred 2 hours at 10 ℃.This reaction mixture is added in the mixture of ethyl acetate and water.With organic layer water and salt water washing, obtained the activatory acid solution.On the other hand, down the suspension of 7 beta-aminos-3-chloromethyl-3-cephem-4-formic acid 4-methoxy-benzyl ester hydrochloride (300g) in the mixture of water (1L) and ethyl acetate (1L) is adjusted to pH 6 with triethylamine ice-cooled.At 10 ℃, in stirring the activatory acid solution that in the gained mixture, obtains above the dropping down.Continuation was stirred 1.5 hours at 5-10 ℃, with triethylamine the pH of this reaction mixture was remained on 6 simultaneously.With isolated organic layer water and salt water washing, and vacuum-evaporation.Pour concentrated solution into Di Iso Propyl Ether (15L), and by filtering the formed precipitation of collection, and it is dry, obtained 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-chloromethyl-3-cephem-4-formic acid 4-methoxy-benzyl ester (495.7g).

¹H-NMR(DMSO-d ₆)δ1.39(9H，s)，1.44(6H，s)，3.45-3.70(2H，m)，3.76(3H，s)，4.46 and 4.54(1H，ABq，J＝16Hz)，5.10-5.28(2H+1H，m)，5.90(1H，dd，J＝4.9，8.5Hz)，6.94(2H，d，J＝8.7Hz)，7.36(2H，d，J＝8.7Hz)，8.18(2H，brs)，9.52(1H，d，J＝8.5Hz)

Embodiment 26

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-chloromethyl-3-cephem-4-formic acid 4-methoxy-benzyl ester (150g) is at N, add 1 in the solution in the dinethylformamide (400ml), 3-two (trimethyl silyl) urea (225g) stirs this mixture 30 minutes.Potassiumiodide (51.2g) is added in this solution, this mixture was stirred 30 minutes.

At 78 ℃ with 4-[N-(2-tert-butoxycarbonyl amino-ethyl)-formamyl amino]-1-methyl-5-trityl group amino-pyrazol (147g) is dissolved in N, in the dinethylformamide (650ml), this solution is cooled to 45 ℃.This solution is added in the above 7 β that obtain-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-chloromethyl-3-cephem-4-formate.This reaction mixture was stirred 18.5 hours at 35 ℃, pour in the mixture of ethyl acetate (2L), water (1.8L) and 20% sodium chloride aqueous solution (150ml).With the mixture washing of organic layer with 10% sodium thiosulfate solution (375ml) and 20% sodium chloride aqueous solution (375ml).Organic layer is used 10% sodium trifluoroacetate solution washing 3 times (750ml * 3) successively, wash with 20% sodium chloride aqueous solution (750ml).With the organic layer vacuum concentration, filter out sedimentary 4-[N-(2-tert-butoxycarbonyl amino-ethyl) formamyl amino]-1-methyl-5-trityl group amino-pyrazol.With the volume of the further vacuum concentration of filtrate to about 600ml.This solution is added in the Di Iso Propyl Ether, this suspension was stirred 1 hour.Collect the gained solid by filtering, and dry.This solid is dissolved in the methylene dichloride (669ml).In this solution, add methyl-phenoxide (223ml) and trifluoroacetic acid (669ml).This reaction mixture was stirred 4 hours, and pour in the Di Iso Propyl Ether.Collect gained solid and dry by filtering.This solid suspension in water, is being lower than under 10 ℃ the temperature with the pH regulator to 7 of ammonia soln with this suspension.Filter out formed precipitation.With concentrated hydrochloric acid filtrate is acidified to pH 1 being lower than under 10 ℃ the temperature, and filters out formed precipitation.At the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (11L) purifying, with the aqueous solution wash-out of 20% 2-propyl alcohol.The elutriant vacuum concentration to about 3.5L, is added 2M sulfuric acid (51ml).With this mixture freeze-drying, obtained crude product (72.2g).

With the preparation HPLC purifying of crude product (3g) by use ODS post.The elutriant vacuum concentration that will contain required product.With concentrated hydrochloric acid concentrated solution is adjusted to about pH 1, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (400mL) purifying, with the aqueous solution wash-out of 20% 2-propyl alcohol.The elutriant vacuum concentration to about 73ml, is added 2M sulfuric acid (1.5ml).This mixture further is evaporated to volume is approximately 12.5ml, add entry (6ml).After adding crystal seed (10mg), formed the white solid precipitation, with this mixture stirring at room 1 hour.This mixture was stirred 13 hours at 5 ℃.5 ℃ with adding 2-propyl alcohol (20ml) in 20 minutes, with these slurries stirring at room 4 hours.With adding 2-propyl alcohol (20ml) in 30 minutes, with slurries stirring at room 3 hours.Precipitate by solid collected by filtration; and it is dry; obtained 7 β-[(Z)-2-(5-amino-1; 2; 4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-amino-4-[N-(2-amino-ethyl) formamyl amino]-2-methyl isophthalic acid-pyrazoles subbase } methyl-3-cephem-4-formic acid hydrosulfate (1.51g), be crystal.

Preparation example 49

With 4, the 5-diaminostilbene-suspension of methylpyrazole vitriol (20g) in triethylamine (29.2ml) stirred 10 minutes in 0 ℃.The mixture of diacetyl oxide (9.87ml) and formic acid (7.96ml) was stirred 30 minutes at 40 ℃, be cooled to 0 ℃, be added drop-wise in the above-mentioned solution at 0 ℃.Whole mixture was stirred 2 hours at 0 ℃.In this mixture, add salt solution, extract whole mixture with tetrahydrofuran (THF).With the organic layer dried over mgso, and reduction vaporization, having obtained N-(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) methane amide crude product, it need not be further purified and be directly used in next step.

Preparation example 50

N-(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) methane amide crude product (13.33g) is dissolved in N, in the dinethylformamide (130ml).In this solution, add trityl chloride (29.2g), triethylamine (66.3ml) and 4-dimethylaminopyridine (465mg), this mixture was stirred 5 hours at 60 ℃.In this reaction mixture, add entry, with whole mixture ethyl acetate extraction.With organic layer water and salt water washing, and use dried over mgso.With solvent removed under reduced pressure, obtained white solid.This solid with ethyl acetate/Di Iso Propyl Ether (1: 1) development, has been obtained N-[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] methane amide (19.18g).The NMR data of this compound show and have rotational isomer.

¹H-NMR (DMSO-d ₆) δ 2.76 and 2.92 (3H, s), 5.56 and 5.84 (1H, s), 7.0-7.4 (16H, m), 7.66 (1H, d, J=1.7Hz), 8.3-8.4 (1H, m)

ESI-MS：m/z＝405.2(M+Na) ⁺

Preparation example 51

At 0 ℃ under stirring, to N-[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] methane amide (3.825g) is at N, adds sodium hydride (264mg, 60% oil suspension) in the solution in the dinethylformamide (66ml).This mixture was stirred 15 minutes at 0 ℃.In this mixture, be added in N, (3-bromopropyl) t-butyl carbamate of the N-in the dinethylformamide (10ml) (2.62g) and sodium iodide (1.65g).This mixture is warmed to room temperature, and stirred 2 hours.Add 10% aqueous potassium hydrogen sulfate (5ml), with this mixture ethyl acetate extraction.With organic layer water and salt water washing, and use dried over mgso.With solvent removed under reduced pressure; by silica gel chromatography purifying resistates; with dichloromethane/ethyl acetate (4: 1) wash-out, obtained 3-{N-formyl radical-N-[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } the propyl carbamic acid tert-butyl ester (2.714g).The NMR data of this compound show and have rotational isomer.

¹H-NMR(DMSO-d ₆)δ1.37 and 1.39(9H，s)，2.6-2.9(6H，m)，2.89(3H，s)，5.34 and 6.01(1H，s)，6.6-6.9(1H，m)，7.0-7.4(15H，m)，7.5-7.6(1H，m)，7.95(1H，s)

ESI-MS：m/z＝562.3(M+Na) ⁺

Embodiment 27

7 β-[(Z)-2-(5-amino-1; 2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-amino-4-[N-(3-aminopropyl)-N-formyl radical amino]-2-methyl isophthalic acid-pyrazoles subbase } methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-amino-1; 2; 4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester and 3-{N-formyl radical-N-[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } the propyl carbamic acid tert-butyl ester obtains in the mode identical with embodiment 1, and the NMR data of this compound show and have rotational isomer.

¹H-NMR(D ₂O)δ1.53(6H，s)，1.7-2.1(2H，m)，2.9-3.9(9H，m)，4.97 and 5.20(2H，ABq，J＝15.2Hz)，5.26(1H，d，J＝4.8Hz)，5.84(1H，d，J＝4.8Hz)，8.0-8.3(2H，m)

Embodiment 28

Room temperature to 7 β-[(Z)-2-(5-amino-1; 2; 4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-)-kharophen]-3-{3-amino-4-[N-(3-aminopropyl)-N-formyl radical amino]-2-methyl isophthalic acid-pyrazoles subbase } add concentrated hydrochloric acid (0.176ml) in the methyl-3-cephem-suspension of 4-formate (140mg) in methyl alcohol (2.6ml), this mixture was stirred 6.5 hours.In this reaction mixture, add sodium bicarbonate (177mg), by preparation HPLC this mixture of purifying (ODS post, acetonitrile/phosphate buffered saline buffer (pH 7)=5: 95).The elutriant evaporation that will contain required product is used the dilute hydrochloric acid acidifying to remove acetonitrile, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 purifying, with the aqueous solution wash-out of 20% 2-propyl alcohol.With the elutriant concentrating under reduced pressure, and freeze-drying, obtained 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-amino-4-[(3-aminopropyl) amino]-2-methyl isophthalic acid-pyrazoles subbase } methyl-3-cephem-4-formate (39mg).

¹H-NMR(D ₂O)δ1.52-1.54(6H，m)，1.95(2H，tt，J＝7.3Hz，7.3Hz)，3.0-3.2(4H，m)，3.16 and 3.38(2H，ABq，J＝17.7Hz)，3.68(3H，s)，4.89 and 5.11(2H，ABq，J＝15.6Hz)，5.22(1H，d，J＝4.8Hz)，5.83(1H，d，J＝4.8Hz)，7.59(1H，s)

ESI-MS：m/z＝636.3(M-H) ^-

Preparation example 52

2-{N-formyl radical-N-[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } the ethyl carbamic acid tert-butyl ester

This title compound is by N-[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] methane amide and N-(2-bromotrifluoromethane) t-butyl carbamate make in the mode identical with preparation example 51.

IR(KBr) 1709，1670，1170，704cm ^-1

¹H-NMR (DMSO-d ₆) δ 1.35 and 1.36 (9H, s), 2.65 and 2.75 (3H, s), 2.73-2.90 (4H, m), 5.45 and 6.02 (1H, s), 6.78 and 6.88 (1H, t-like), 7.05-7.30 (15H, m), 7.31 and 7.57 (1H, s)

ESI-MS：m/z＝426.3(M+H ⁺)，548.3(M+Na ⁺)

Embodiment 29

7 β-[(Z)-2-(5-amino-1-2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-amino-4-[N-(2-amino-ethyl)-N-formyl radical amino]-2-methyl isophthalic acid-pyrazoles subbase } methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-amino-1; 2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-chloromethyl-3-cephem-4-formic acid benzhydryl ester and 2-{N-formyl radical-N-[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } the ethyl carbamic acid tert-butyl ester obtains in the mode identical with embodiment 1.

IR(KBr)1770，1675，1653，1597cm ^-1

¹H-NMR (DMSO-d ₆) δ 1.53 (6H, s), 3.12-3.78 (4H, m), 3.77and 3.78 (3H, s), 3.86-3.96 (2H, m), 5.00 and 5.19 (2H, ABq, J=15.2Hz), 5.28 (1H, d, J=4.8Hz), 5.86 (1H, d, J=4.8Hz), 8.15 and 8.18 (1H, s), 8.19 and 8.33 (1H, s)

ESI-MS：m/z＝652.2(M+H ⁺)

Embodiment 30

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-amino-4-[(2-amino-ethyl) amino]-2-methyl isophthalic acid-pyrazoles subbase } methyl-3-cephem-4-formate

This title compound be by 7 β-[(Z)-2-(5-amino-1; 2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-amino-4-[N-(2-amino-ethyl)-N-formyl radical amino]-2-methyl isophthalic acid-pyrazoles subbase } methyl-3-cephem-4-formate makes in the mode identical with embodiment 28.

IR(KBr)1770，1651，1593cm ^-1

¹H-NMR(DMSO-d ₆)δ1.53(3H，s)，1.59(3H，s)，3.13-3.26(4H，m)，3.26 and 3.39(2H，ABq，J＝17.8Hz)，3.68(3H，s)，4.87 and 5.11(2H，ABq，J＝15.7Hz)，5.25(1H，d，J＝4.8Hz)，5.84(1H，d，J＝4.8Hz)，7.63(1H，s)

ESI-MS：m/z＝622.2(M-H ^-)

Preparation example 53

To 1-methyl isophthalic acid H-pyrazoles-4, add triethylamine (117ml) in the suspension of 5-diamines vitriol (86g) in tetrahydrofuran (THF) (1.3L), then with (2S)-4-[(tert-butoxycarbonyl) amino]-2-hydroxybutyric acid (82.5g) is added in this mixture.At ice-cooled I-hydroxybenzotriazole (58.3g) and N-(3-the dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (82.7g) of in this mixture, adding down.With this reaction mixture stirring at room 8 hours.In this reaction mixture, add ethyl acetate (1.3L), saturated sodium bicarbonate aqueous solution and sodium-chlor, this mixture was stirred 30 minutes.Isolate organic layer, water layer is extracted 6 times with ethyl acetate (1.0L).With the extraction liquid anhydrous magnesium sulfate drying, filter and vacuum concentration.By the silica gel chromatography resistates, with ethyl acetate/tetrahydrofuran (THF) (1/1) wash-out, obtained (3S)-4-[(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino]-3-hydroxyl-4-oxo butyl } t-butyl carbamate (69.5g).

¹H-NMR(CDCl ₃)δ1.43(9H，s)，1.6-1.9(1H，m)，1.9-2.2(1H，m)，3.1-3.3(1H，m)，3.3-3.5(1H，m)，3.65(3H，s)，4.20(1H，dd，J＝3.6，6.6Hz)，4.7-5.3(4H，m)，7.24(1H，s)，8.58(1H，s)

[α] ²⁰ _D(c＝1.05，CHCl ₃)＝-27.06°

Preparation example 54

To (3S)-and 4-[(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino]-3-hydroxyl-4-oxo butyl } t-butyl carbamate (68.51g) is at N, adds chlorine triphenyl methane (67g) in the solution in the dinethylformamide (350ml).In this mixture, drip triethylamine (67ml).With this mixture stirring at room 12 hours.This reaction mixture is dissolved in the methylene dichloride (2L).With this solution water successively and salt water washing.With the extraction liquid anhydrous sodium sulfate drying, filter and vacuum concentration.Develop resistates with acetonitrile, and vacuum-drying, obtained ((3S)-3-hydroxyl-4-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-4-oxo butyl) t-butyl carbamate (64g).

¹H-NMR(CDCl ₃)δ1.46(9H，s)，1.3-1.6(1H，m)，1.8-2.1(1H，m)，2.95(3H，s)，2.9-3.2(1H，m)，3.3-3.6(1H，m)，3.95(1H，m)，4.53(1H，d，J＝4.5Hz)，4.74(1H，s)，4.92(1H，brs)，7.1-7.3(15H，m)，7.39(1H，s)，7.73(1H，s)

ESI-MS：m/z＝638.2(M+H+Na ⁺)

[α] ²⁰ _D(c＝1.025，CHCl ₃)＝-36.5°

Embodiment 31

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-chloromethyl-3-cephem-4-formic acid 4-methoxy-benzyl ester (130g) is at N, add 1 in the solution in the dinethylformamide (400ml), 3-two (trimethyl silyl) urea (195g), with this mixture stirring at room 30 minutes.In this solution, add potassiumiodide (44.4g), with this mixture stirring at room 30 minutes.In this reaction mixture, add ((3S)-3-hydroxyl-4-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-4-oxo butyl) t-butyl carbamate (106g), stir whole mixture 22 hours at 35 ℃.In this reaction mixture, add ethyl acetate (1.7L), with this mixture water (1.6L), 10% trifluoroacetic acid sodium water solution (650ml * 3) and salt solution (650ml) washing, with dried over mgso and filtration.With the filtrate vacuum concentration to about 1L.Concentrated solution is poured in the Di Iso Propyl Ether (3L), and collected formed precipitation by filtering, and vacuum-drying.In the solution of this solid in methylene dichloride (660ml), add methyl-phenoxide (220ml) and trifluoroacetic acid (660ml).Gained solution stirring at room 4 hours, and is poured in the Di Iso Propyl Ether (7L).Collect formed precipitation by filtering, and vacuum-drying, crude product (156.2g) obtained.Crude product is dissolved in the water (3.5L).This solution is adjusted to about pH 3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (Mitsubishi Chemical Corporation) purifying, with 20% 2-aqueous propanol solution wash-out.The elutriant vacuum concentration to about 1.5L, is added 2M aqueous sulfuric acid (33.18ml).With this mixture freeze-drying.Freeze dried product (40g) is dissolved in the phosphate buffered saline buffer (pH 7), by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 30ml.Concentrated solution is adjusted to about pH 3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (Mitsubishi ChemicalCorporation) purifying, with 10% 2-aqueous propanol solution wash-out.The elutriant vacuum concentration to about 1L, is added 2M aqueous sulfuric acid (13.59ml).With the freeze-drying of gained solution; obtained 7 β-[(Z)-2-(5-amino-1; 2; 4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{3-amino-4-[((2S)-4-amino-2-maloyl group) amino]-2-methyl isophthalic acid-pyrazoles subbase } methyl-3-cephem-4-formic acid hydrosulfate (20.82g), be amorphous solid.

¹H-NMR(D ₂O)δ1.61(6H，s)，1.9-2.4(2H，m)，3.20(1H，d，J＝17.6Hz)，3.0-3.3(2H，m)，3.45(1H，d，J＝17.6Hz)，3.74(3H，s)，4.47(1H，dd，J＝4，6.3Hz)，5.06(1H，d，J＝15.7Hz)，5.25(1H，d，J＝4.8Hz)，5.28(1H，d，J＝15.7Hz)，5.87(1H，d，J＝4.8Hz)，8.07(1H，s)

Preparation example 55

To 1-methyl-N ⁵-trityl-1H-pyrazoles-4 adds triethylamine (0.627ml) and diethyl squarate (0.858ml) in the solution of 5-diamines (1.60g) in ethanol (50ml), with this mixture stirring at room 22 hours.In this reaction mixture, add ethyl acetate (200ml) and hexane (100ml) with this solution water successively, 5% aqueous citric acid solution and salt water washing.With the organic layer anhydrous sodium sulfate drying, filter and vacuum concentration.This crystalline residue is washed with ether, and vacuum-drying, obtained 3-oxyethyl group-4-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-3-cyclobutene-1,2-diketone (1.45g) is solid.

¹H-NMR(CDCl ₃)δ1.42(3H，br)，2.99(3H，s)，4.41(1H，brs)，4.69(2H，q，J＝7.2Hz)，6.40(1H，br)，7.13-7.35(16H，m)

Preparation example 56

To 2-aminoethylamino t-butyl formate (288mg) and 3-oxyethyl group-4-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-3-cyclobutene-1, add triethylamine (0.209ml) in the solution of 2-diketone (718mg) in ethanol (20ml), this mixture was stirred 4 hours under reflux state.In this reaction mixture, add ether and hexane.Collect this crystalline deposit by filtering, and vacuum-drying, obtained 2-[(2-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-3,4-dioxo ring but-1-ene-1-yl) amino] the ethyl carbamic acid tert-butyl ester (830mg), be solid.

¹H-NMR(CDCl ₃)δ1.40(9H，s)，3.07-3.28(5H，m)，3.38-3.67(2H，m)，4.53-4.84(1H，br)，4.84(1H，br)，7.15-7.22(6H，m)，7.23(1H，s)，7.22-7.34(9H，m)

Embodiment 32

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester (901mg) is at N, add N-(trimethyl silyl) ethanamide (720mg) in the solution in the dinethylformamide (1.8ml), with this mixture stirring at room 1 hour.In this reaction mixture, add 2-[(2-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-3,4-dioxo ring but-1-ene-1-yl) amino] the ethyl carbamic acid tert-butyl ester (682mg) is at N, solution in the dinethylformamide (6.3ml) stirs whole mixture 7 hours at 35-40 ℃.In the gained reaction mixture, add ethyl acetate, sedimentation and filtration is come out.With filtrate water successively and salt water washing, with anhydrous sodium sulfate drying and filtration.Filtrate is concentrated into about 5ml.Concentrated solution is poured in the Di Iso Propyl Ether (80ml), and collected formed precipitation by filtering, and vacuum-drying.In the solution of gained solid in methylene dichloride (2.6ml), add methyl-phenoxide (0.88ml) and trifluoroacetic acid (2.6ml).Gained solution stirring at room 3 hours, and is poured in the Di Iso Propyl Ether (80ml).Collect formed precipitation by filtering, and vacuum-drying, crude product (580mg) obtained, by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 30ml.Concentrated solution is adjusted to about pH 3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (Mitsubishi ChemicalCorporation) purifying, with 30% 2-aqueous propanol solution wash-out.With the elutriant vacuum concentration to about 10ml, and freeze-drying, obtained 3-{[3-amino-4-({ 2-[(2-amino-ethyl) amino]-3,4-dioxo-1-cyclobutene-1-yl } amino)-2-methyl isophthalic acid-pyrazoles subbase] methyl }-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate (22mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.53(3H，s)，1.54(3H，s)，3.26-3.36(1H，m)，3.27(2H，t，J＝5.7Hz)，3.58-3.69(1H，m)，3.74(3H，s)，3.86-4.03(2H，m)，4.93(1H，d，J＝14.5Hz)，5.10(1H，d，J＝14.5Hz)，5.29(1H，d，J＝4.3Hz)，5.83(1H，d，J＝4.3Hz)，7.99(1H，s)

Preparation example 57

To 3-amino propyl amino t-butyl formate (366mg) and 3-oxyethyl group-4-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-3-cyclobutene-1, add triethylamine (0.195ml) in the solution of 2-diketone (670mg) in ethanol (30ml), this mixture was stirred 3 hours under reflux state.In this reaction mixture, add ether (40ml) and hexane (10ml).Collect this crystalline deposit by filtering, and vacuum-drying, obtained 3-[(2-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino-3,4-dioxo-1-cyclobutene-1-yl) amino] propyl group } t-butyl carbamate (788mg), be solid.

¹H-NMR (CDCl ₃) δ 1.43 (9H, s), 1.67 (2H, quintet, J=5.5Hz), 3.15 (2H, q, J=5.5Hz), 3.17 (3H, s), 3.60 (2H, q, J=5.5Hz), 4.82 (1H, brs), 4.86 (1H, t, J=5.5Hz), 5.44 (1H, br), 5.86 (1H, br), 7.13-7.33 (15H, m), 7.17 (1H, s)

Embodiment 33

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester (819mg) is at N, add N-(trimethyl silyl) ethanamide (656mg) in the solution in the dinethylformamide (1.6ml), with this mixture stirring at room 40 minutes.In this reaction mixture, add 3-[(2-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino-3,4-dioxo-1-cyclobutene-1-yl) amino] propyl group) t-butyl carbamate (637mg) is at N, solution in the dinethylformamide (3.2ml) stirs whole mixture 3.5 hours at 35-40 ℃.In the gained reaction mixture, add ethyl acetate (60ml), filter out precipitation.With this filtrate water successively (50ml * 2) and salt solution (50ml) washing, with anhydrous sodium sulfate drying and filtration.With the filtrate vacuum concentration to about 8ml.Concentrated solution is poured in the Di Iso Propyl Ether (80ml), and collected formed precipitation by filtering, and vacuum-drying.In the solution of gained solid in methylene dichloride (2.4ml), add methyl-phenoxide (0.80ml) and trifluoroacetic acid (1.6ml).Gained solution stirring at room 3 hours, and is poured in the Di Iso Propyl Ether (80ml).Collect formed precipitation by filtering, and vacuum-drying, crude product (565mg) obtained, by using the preparation HPLC purifying of ODS post, with the mixture wash-out of acetonitrile and phosphate buffered saline buffer (pH 5.5).The elutriant vacuum concentration that will contain required product is to about 20ml.By using the preparation HPLC purifying of ODS post, will be with the fraction vacuum concentration of 8% acetonitrile/0.01M hydrochloric acid wash-out to about 10ml, and freeze-drying, obtained 3-{[3-amino-4-({ 2-[(3-aminopropyl) amino]-3,4-dioxo-1-cyclobutene-1-yl } amino)-2-methyl isophthalic acid-pyrazoles subbase] methyl }-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate tri hydrochloride (34mg), be amorphous solid.

¹H-NMR (D ₂O) δ 1.62 (6H, s), 2.02 (2H, quintet, J=7.3Hz), 3.09 (2H, t, J=7.3Hz), 3.32 (1H, d, J=17.5Hz), and 3.54-3.65 (1H, m), 3.67-3.78 (2H, m), 3.75 (3H, s), 4.93-5.23 (2H, m), 5.30 (1H, d, J=4.5Hz), 5.86 (1H, d, J=4.5Hz), 7.99 (1H, s)

Preparation example 58

Ice-cooled down to 1,1 '-(1,2-dioxo-1,2-ethane two bases) two-1H-imidazoles (761mg) is at N, adds 1-methyl-N in the solution in the dinethylformamide (8ml) ⁵-trityl-1H-pyrazoles-4,5-diamines (709mg), with this mixture stirring at room 30 minutes.In this reaction mixture, add 2-aminoethylamino t-butyl formate (1.28g) at N, the solution in the dinethylformamide (2ml), with this mixture stirring at room 27 hours.In this reaction mixture, add ethyl acetate (50ml).Filter out post precipitation, with filtrate water successively, 5% aqueous citric acid solution and salt water washing.With the organic layer anhydrous sodium sulfate drying, filter and vacuum concentration.With the mixed solvent washing of crystalline residue with ether and ethyl acetate; and vacuum-drying; obtained 2-[(2-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino-2-oxo ethanoyl) amino] ethyl } t-butyl carbamate (823mg), be solid.

¹H-NMR(CDCl ₃)δ1.43(9H，s)，2.97(3H，s)，3.31(2H，q，J＝5.5Hz)，3.43(2H，q，J＝5.5Hz)，4.53(1H，s)，4.84(1H，brs)，7.10-7.30(15H，m)，7.47(1H，s)，7.67(1H，brs)，8.20(1H，brs)

Embodiment 34

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-chloromethyl-3-cephem-4-formic acid 4-methoxy-benzyl ester (618mg) is at N, add N-(trimethyl silyl) ethanamide (656mg) in the solution in the dinethylformamide (1.5ml), with this mixture stirring at room 40 minutes.In this solution, add potassiumiodide (232mg), with this mixture stirring at room 35 minutes.In this reaction mixture, add { 2-[(2-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-2-oxo ethanoyl) amino] ethyl } t-butyl carbamate (626mg) is at N; solution in the dinethylformamide (3ml) stirs whole mixture 24 hours at 35-40 ℃.In the gained reaction mixture, add ethyl acetate (50ml), with this solution water successively (50ml * 2), 10% trifluoroacetic acid sodium water solution (50ml * 2) and salt solution (50ml) washing, with anhydrous sodium sulfate drying and filtration.With the filtrate vacuum concentration to about 10ml.Concentrated solution is poured in the Di Iso Propyl Ether (60ml), and collected formed precipitation by filtering, and vacuum-drying.In the solution of this solid in methylene dichloride (2.9ml), add methyl-phenoxide (0.95ml) and trifluoroacetic acid (2.9ml).Stirring at room 4 hours, and pour gained solution into two and propyl ether (60ml).Collect formed precipitation by filtering, and vacuum-drying, crude product (770mg) obtained, by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 30ml.Concentrated solution is adjusted to about pH3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (Mitsubishi Chemical Corporation) purifying, with 30% 2-aqueous propanol solution wash-out.With the elutriant vacuum concentration to about 10ml; and freeze-drying; obtained 3-{[3-amino-4-({ 2-[(2-amino-ethyl) amino]-2-oxo ethanoyl } amino)-2-methyl isophthalic acid-pyrazoles subbase] methyl }-7 β-[(Z)-2-(5-amino-1; 2; 4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate (31mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.52(3H，s)，1.53(3H，s)，3.20(1H，d，J＝18.0Hz)，3.24(2H，t，J＝6.0Hz)，3.45(1H，d，J＝18.0Hz)，3.66(2H，t，J＝6.0Hz)，3.75(3H，s)，5.02(1H，d，J＝15.5Hz)，5.21(1H，d，J＝15.5Hz)，5.25(1H，d，J＝5.0Hz)，5.85(1H，d，J＝5.0Hz)，8.14(1H，s)

Preparation example 59

In [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] phenyl carbamate (711mg) and the solution of 3-azetidinyl t-butyl carbamate acetate (418mg) in methylene dichloride (8ml), add N-ethyl diisopropyl amine (0.62ml), this mixture was stirred 16 hours under reflux state.In this reaction mixture, add methylene dichloride, this solution is used 10% aqueous citric acid solution, 10% aqueous sodium hydroxide solution and salt water washing successively.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Mixed solvent development resistates with ethyl acetate and hexane has obtained [1-({ [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl)-3-azetidinyl] t-butyl carbamate (735mg), is solid.

¹H-NMR(CDCl ₃)δ1.47(9H，s)，2.92(3H，s)，3.56(2H，dd，J＝7.5，5.0Hz)，4.02(2H，dd，J＝7.5，7.5Hz)，4.42(1H，brs)，4.71(1H，s)，4.74(1H，s)，4.94(1H，brs)，7.18-7.21(7H，m)，7.25-7.32(9H，m)

Embodiment 35

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester (819mg) is at N, add N-(trimethyl silyl) ethanamide (655mg) in the solution in the dinethylformamide (2.4ml), with this mixture stirring at room 30 minutes.In this reaction mixture, add [1-({ [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl)-3-azetidinyl] t-butyl carbamate (553mg) at N, solution in the dinethylformamide (3ml), and whole mixture stirring at room 3 hours, was stirred 1 hour at 50 ℃ then.In the gained reaction mixture, add ethyl acetate (50ml) and water (50ml).Isolate water layer, with organic layer water and salt water washing, with anhydrous magnesium sulfate drying and filtration.With the filtrate vacuum concentration to about 5ml.Concentrated solution is poured in the Di Iso Propyl Ether (80ml), and collected formed precipitation by filtering, and vacuum-drying.In the solution of gained solid in methylene dichloride (2.1ml), add methyl-phenoxide (0.7ml) and trifluoroacetic acid (2.1ml).Gained solution stirring at room 4.5 hours, and is poured in the Di Iso Propyl Ether (80ml).Collect formed precipitation by filtering, and vacuum-drying, obtained crude product (521mg), it by using the preparation HPLC purifying of ODS post, is used the mixture wash-out of acetonitrile and phosphate buffered saline buffer (pH 5.5).The elutriant vacuum concentration that will contain required product is to about 20ml.With the preparation HPLC purifying of concentrated solution by use ODS post, will be with the fraction vacuum concentration of 7% acetonitrile/0.01M hydrochloric acid wash-out to about 10ml, and freeze-drying, obtained 3-[(3-amino-4-{[(3-amino-1-azetidinyl) carbonyl] amino }-2-methyl isophthalic acid-pyrazoles subbase) methyl]-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate tri hydrochloride (22mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.62(3H，s)，1.63(3H，s)，3.25(1H，d，J＝17.9Hz)，3.50(1H，d，J＝17.9Hz)，3.72(3H，s)，4.14(2H，dd，J＝9.6，4.4Hz)，4.25(1H，tt，J＝7.8，4.6Hz)，4.46(2H，dd，J＝9.6，7.8Hz)，5.08(1H，d，J＝15.6Hz)，5.24(1H，d，J＝15.6Hz)，5.27(1H，d，J＝4.6Hz)，5.88(1H，d，J＝4.6Hz)，7.91(1H，s)

Preparation example 60

In [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] phenyl carbamate (2.18g) and the 3-amino-solution of 1-azetidine t-butyl formate (793mg) in methylene dichloride (20ml), add N-ethyl diisopropyl amine (1.07ml), this mixture was stirred 40 hours under reflux state.In this reaction mixture, add methylene dichloride, this solution is used 10% aqueous citric acid solution, 10% aqueous sodium hydroxide solution and salt water washing successively.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates by silica gel chromatography, with 10% ethanol/methylene wash-out, has been obtained 3-[({[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl) amino]-1-azetidine t-butyl formate (1.52g), be solid.

¹H-NMR(CDCl ₃)δ1.44(9H，s)，3.03(3H，s)，3.59(2H，dd，J＝9.2，5.0Hz)，4.17(2H，dd，J＝9.2，7.8Hz)，4.39-4.43(3H，m)，4.64(1H，brs)，7.18-7.21(6H，m)，7.27(1H，s)，7.29-7.32(9H，m)

Embodiment 36

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-chloromethyl-3-cephem-4-formic acid 4-methoxy-benzyl ester (1.48g) is at N, add N-(trimethyl silyl) ethanamide (1.42g) in the solution in the dinethylformamide (3.0ml), with this mixture stirring at room 30 minutes.In this solution, add potassiumiodide (504mg) and with this mixture stirring at room 30 minutes.In this reaction mixture, add 3-[({[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl) amino]-1-azetidine t-butyl formate (1.20g) is at N, solution in the dinethylformamide (2.2ml) stirs whole mixture 16 hours at 50 ℃.In the gained reaction mixture, add ethyl acetate (200ml),, use anhydrous sodium sulfate drying, and filter this solution water successively (50ml), 10% trifluoroacetic acid sodium water solution (50ml * 2) and salt solution (50ml) washing.With the filtrate vacuum concentration to about 10ml.Concentrated solution is poured in the Di Iso Propyl Ether (160ml), and collected formed precipitation by filtering, and vacuum-drying.In the solution of this solid in methylene dichloride (8.64ml), add methyl-phenoxide (2.88ml) and trifluoroacetic acid (8.64ml).Gained solution stirring at room 3 hours, and is poured in the Di Iso Propyl Ether (160ml).Collect formed precipitation by filtering, and vacuum-drying, obtained crude product (2.22g), it by using the preparation HPLC purifying of ODS post, is used the mixture wash-out of acetonitrile and phosphate buffered saline buffer (pH5.5).The elutriant vacuum concentration that will contain required product is to about 20ml.With the preparation HPLC purifying of concentrated solution by use ODS post, will be with the fraction vacuum concentration of 8% acetonitrile solution wash-out to about 20ml, and freeze-drying, obtained 3-[(3-amino-4-{[(3-azetidinyl amino) carbonyl] amino }-2-methyl isophthalic acid-pyrazoles subbase) methyl]-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate (220mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.50(3H，s)，1.51(3H，s)，3.20(1H，d，J＝17.6Hz)，3.47(1H，d，J＝17.6Hz)，3.70(3H，s)，4.18(2H，dd，J＝11.2，7.6Hz)，4.31(2H，dd，J＝11.2，8.3Hz)，4.68(1H，tt，J＝8.3，7.6Hz)，4.94(1H，d，J＝15.6Hz)，5.15(1H，d，J＝15.6Hz)，5.23(1H，d，J＝4.8Hz)，5.83(1H，d，J＝4.8Hz)，7.87(1H，s)

Preparation example 61

In [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] phenyl carbamate (786mg) and the solution of 3-pyrrolidyl t-butyl carbamate (373mg) in methylene dichloride (6ml), add N-ethyl diisopropyl amine (0.43ml), this mixture was stirred 10 hours under reflux state.This reaction mixture is washed with 10% aqueous citric acid solution, salt solution and saturated sodium bicarbonate aqueous solution successively.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration, obtained [1-({ [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl)-3-pyrrolidyl] t-butyl carbamate (730mg), be solid.

¹H-NMR(CDCl ₃)δ1.48(9H，s)，1.82-1.88(1H，m)，2.12-2.18(1H，m)，2.89(3H，s)，2.89-3.03(1H，m)，3.20-3.30(2H，m)，3.38-3.43(1H，m)，4.22(1H，br)，4.69(1H，br)，4.88(1H，brs)，4.96(1H，brs)，7.18-7.27(16H，m)

Embodiment 37

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester (819mg) is at N, add N-(trimethyl silyl) ethanamide (655mg) in the solution in the dinethylformamide (2.4ml), with this mixture stirring at room 30 minutes.In this reaction mixture, add [1-({ [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl)-3-pyrrolidyl] t-butyl carbamate (567mg) at N, the solution in the dinethylformamide (3.0ml).With whole mixture stirring at room 3 hours.In the gained reaction mixture, add ethyl acetate (100ml) and water (50ml).Isolate water layer, organic layer is used 10% trifluoroacetic acid sodium water solution, 10% sodium thiosulfate solution and salt water washing successively, with dried over sodium sulfate and filtration.With the filtrate vacuum concentration to about 2.5ml.Pour concentrated solution into Di Iso Propyl Ether (80ml), and collect formed precipitation by filtering, and vacuum-drying.In the solution of gained solid in methylene dichloride (2.55ml), add methyl-phenoxide (0.85ml) and trifluoroacetic acid (2.55ml), with this mixture stirring at room 3 hours.Pour this reaction mixture into Di Iso Propyl Ether (80ml), and by the formed precipitation of filtration collection, and vacuum-drying, obtained crude product (608mg), it by using the preparation HPLC purifying of ODS post, is used the mixture wash-out of acetonitrile and phosphate buffered saline buffer (pH 5.5).The elutriant vacuum concentration that will contain required product is to about 20ml.Preparation HPLC by using the ODS post is with this concentrated solution desalination, the fraction vacuum concentration that will elute with 7% acetonitrile/0.01M hydrochloric acid is to about 10ml, and freeze-drying, obtained 3-[(3-amino-4-{[(3-amino-1-pyrrolidyl) carbonyl] amino }-2-methyl isophthalic acid-pyrazoles subbase) methyl]-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate tri hydrochloride (31mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.61(3H，s)，1.61(3H，s)，2.13-2.27(1H，m)，2.39-2.54(1H，m)，3.29(1H，d，J＝18.1Hz)，3.51(1H，d，J＝18.1Hz)，3.55-3.68(3H，m)，3.73(3H，s)，3.80(1H，dd，J＝11.5，6.0Hz)，4.01-4.11(1H，m)，5.20(1H，d，J＝16.0Hz)，5.24(1H，d，J＝16.0Hz)，5.28(1H，d，J＝4.8Hz)，5.89(1H，d，J＝4.8Hz)，7.91(1H，s)

Preparation example 62

In [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] phenyl carbamate (711mg) and the 3-amino-solution of the 1-pyrrolidinecarboxylic acid tert-butyl ester (372mg) in methylene dichloride (15ml), add N-ethyl diisopropyl amine (0.51ml), this mixture was stirred 17 hours under reflux state.This reaction mixture is washed with 10% aqueous citric acid solution, salt solution and saturated sodium bicarbonate aqueous solution successively.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates by silica gel chromatography, with 10% ethanol/methylene wash-out, has been obtained 3-[({[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl) amino]-the 1-pyrrolidinecarboxylic acid tert-butyl ester (511mg), be solid.

¹H-NMR(CDCl ₃)δ1.46(9H，s)，1.66-1.74(1H，m)，2.04-2.11(1H，m)，2.97(3H，s)，3.05-3.11(1H，m)，3.30-3.43(2H，m)，3.53-3.58(1H，m)，4.16-4.23(2H，m)，4.45(1H，brs)，4.74(1H，br)，7.18-7.20(6H，m)，7.28-7.30(10H，m)

Embodiment 38

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester (707 mg) is at N, add N-(trimethyl silyl) ethanamide (566mg) in the solution in the dinethylformamide (2.1ml), with this mixture stirring at room 30 minutes.In this reaction mixture, add 3-[({[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl) amino]-the 1-pyrrolidinecarboxylic acid tert-butyl ester (490mg) is at N, the solution in the dinethylformamide (2.0ml).With whole mixture stirring at room 3 hours.In the gained reaction mixture, add ethyl acetate (100ml) and water (50ml).Isolate water layer, organic layer is used 10% trifluoroacetic acid sodium water solution, 10% sodium thiosulfate solution and salt water washing successively, with dried over sodium sulfate and filtration.With the filtrate vacuum concentration to about 3ml.Concentrated solution is poured in the Di Iso Propyl Ether (80ml), and collected formed precipitation by filtering, and vacuum-drying.In the solution of gained solid in methylene dichloride (1.83ml), add methyl-phenoxide (0.61ml) and trifluoroacetic acid (1.83ml), with this mixture stirring at room 5 hours.This reaction mixture is poured in the Di Iso Propyl Ether (80ml), and collected formed precipitation by filtering, and vacuum-drying, crude product (440mg) obtained, by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 30ml.Concentrated solution is adjusted to about pH3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (Mitsubishi Chemical Corporation) purifying, with 30% 2-aqueous propanol solution wash-out.With the elutriant vacuum concentration to about 30ml, and freeze-drying, obtained 3-[(3-amino-2-methyl-4-{[(3-pyrrolidyl amino) carbonyl] amino }-1-pyrazoles subbase) methyl]-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate (18mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.54(3H，s)，1.55(3H，s)，2.00-2.10(1H，m)，2.30-2.40(1H，m)，3.23(0.5H，d，J＝17.9Hz)，3.24(0.5H，d，J＝17.9Hz)，3.27-3.34(1H，m)，3.34-3.43(1H，m)，3.45-3.57(3H，m)，3.72(3H，s)，4.36-4.46(1H，m)，4.95(0.5H，d，J＝15.1Hz)，4.96(0.5H，d，J＝15.6Hz)，5.17(1H，d，J＝15.6Hz)，5.26(1H，d，J＝5.0Hz)，5.85(1H，d，J＝5.0Hz)，7.88(1H，s)

Preparation example 63

To { 2-[({[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl) amino]-ethyl } add the solution of 4M hydrogenchloride in dioxane (50ml) in the solution of t-butyl carbamate (10.8g) in methyl alcohol (50ml).With this mixture stirring at room 3 hours.With the solvent vacuum concentration, and with resistates with ethyl acetate development and vacuum-drying, obtained N-(2-amino-ethyl)-N '-(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) urea tri hydrochloride (5.6g), be solid.

¹H-NMR(DMSO-d ₆)δ2.84-2.87(2H，m)，3.30(2H，brs)，3.71(3H，s)，6.57(1H，br)，7.91(1H，s)，8.05(4H，br)，8.55(1H，br)

Preparation example 64

In N-(2-amino-ethyl)-N '-(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) urea tri hydrochloride (3.1g) and the solution of triethylamine (4.6g) in chloroform (100ml), add the two tert-butyl esters (5.9g) of ({ [(trifluoromethyl) alkylsulfonyl] imino-}-methylene radical) two carboxylamines.With this mixture stirring at room 90 minutes.This reaction mixture is washed with 10% aqueous citric acid solution, salt solution and saturated sodium bicarbonate aqueous solution successively.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates is developed with ethyl acetate, obtained the two tert-butyl esters (4.3g) of ((Z)-{ [2-({ [(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino] carbonyl } amino)-ethyl] amino } methylene radical) two carboxylamines, be solid.

¹H-NMR(DMSO-d ₆)δ1.39(9H，s)，1.48(9H，s)，3.18(2H，q，J＝6.0Hz)，3.35(2H，br)，3.49(3H，s)，4.77(1H，brs)，6.05(1H，br)，6.97(1H，s)，7.19(1H，brs)，8.36(1H，t，J＝5.5Hz)，11.49(1H，brs)

Preparation example 65

In the two tert-butyl esters (2.2g) of ((Z)-{ [2-({ [(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino] carbonyl } amino)-ethyl] amino } methylene radical) two carboxylamines and the solution of triethylamine (0.6g) in chloroform (30ml), add trityl chloride (1.7g), with this mixture stirring at room 14 hours.This reaction mixture is washed with 10% aqueous citric acid solution, salt solution and saturated sodium bicarbonate aqueous solution successively.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates is developed with ethyl acetate, obtained [(Z)-(2-[({[I-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl) amino]-ethyl } amino) methylene radical] the two tert-butyl esters (1.9g) of two carboxylamines, be solid.

¹H-NMR(DMSO-d ₆)δ1.39(9H，s)，1.47(9H，s)，2.72(3H，s)，3.09-3.10(2H，m)，3.31-3.34(2H，m)，5.69(1H，s)，6.10(1H，br)，6.77(1H，brs)，7.02(1H，s)，7.14-7.16(6H，m)，7.22-7.27(9H，m)，8.36(1H，t，J＝5.5Hz)，11.51(1H，brs)

Embodiment 39

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester (820mg) is at N, add N-(trimethyl silyl) ethanamide (656mg) in the solution in the dinethylformamide (1.4ml), with this mixture stirring at room 30 minutes.In this reaction mixture, add [(Z)-(2-[({[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl) amino] ethyl } amino) methylene radical]-the two tert-butyl esters (820mg) of two carboxylamines and N, dinethylformamide (2.0ml).With whole mixture stirring at room 3 hours.In the gained reaction mixture, add ethyl acetate (100ml) and water (50ml).Isolate water layer, organic layer is used 10% trifluoroacetic acid sodium water solution, 10% sodium thiosulfate solution and salt water washing successively, with dried over sodium sulfate and filtration.With the filtrate vacuum concentration to about 5ml.Concentrated solution is poured in the Di Iso Propyl Ether (120ml), and collected formed precipitation by filtering, and vacuum-drying.In the solution of gained solid in methylene dichloride (3.0ml), add methyl-phenoxide (1.0ml) and trifluoroacetic acid (2.0ml), with this mixture stirring at room 4 hours.Pour this reaction mixture into Di Iso Propyl Ether (100ml), and collect formed precipitation by filtering, and vacuum-drying, crude product (740mg) obtained, by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 30ml.Concentrated solution is adjusted to about pH 3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (Mitsubishi ChemicalCorporation) purifying, with the aqueous solution wash-out of 30% 2-propyl alcohol.With the elutriant vacuum concentration to about 30ml, and freeze-drying, obtained 3-{[3-amino-4-({ [(2-GE) amino] carbonyl } amino)-2-methyl isophthalic acid-pyrazoles subbase] methyl }-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate (70mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.55(3H，s)，1.56(3H，s)，3.24(1H，d，J＝17.6Hz)，3.28-3.40(4H，m)，3.52(1H，d，J＝17.6Hz)，3.73(3H，s)，4.97(1H，d，J＝15.4Hz)，5.16(1H，d，J＝15.4Hz)，5.27(1H，d，J＝4.8Hz)，5.84(1H，d，J＝4.8Hz)，7.87(1H，s)

Preparation example 66

To [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] phenyl carbamate (950mg) and (3S)-and add N-ethyl diisopropyl amine (390mg) in the solution of 3-pyrrolidyl t-butyl carbamate (560mg) in methylene dichloride (20ml), this mixture was stirred 23 hours under reflux state.This reaction mixture is washed with 10% aqueous citric acid solution, salt solution and saturated sodium bicarbonate aqueous solution successively.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates is passed through silica gel chromatography, with 4% methyl alcohol/chloroform wash-out, obtained [(3S)-and 1-({ [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl)-3-pyrrolidyl] t-butyl carbamate (680mg), be solid.

Embodiment 40

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester (820mg) is at N, add N-(trimethyl silyl) ethanamide (656mg) in the solution in the dinethylformamide (2.4ml), with this mixture stirring at room 30 minutes.In this reaction mixture, add [(3S)-and 1-({ [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl)-3-pyrrolidyl] t-butyl carbamate (680mg).With whole mixture stirring at room 3 hours.In the gained reaction mixture, add ethyl acetate (80ml) and water (50ml).Isolate water layer, organic layer is used 10% trifluoroacetic acid sodium water solution, 10% sodium thiosulfate solution and salt water washing successively, with dried over sodium sulfate and filtration.With the filtrate vacuum concentration to about 5ml.Concentrated solution is poured in the Di Iso Propyl Ether (120ml), and collected formed precipitation by filtering, and vacuum-drying.In the solution of gained solid in methylene dichloride (3.0ml), add methyl-phenoxide (1.0ml) and trifluoroacetic acid (2.0ml), with this mixture stirring at room 4 hours.Pour this reaction mixture into Di Iso Propyl Ether (100ml), and collect formed precipitation by filtering, and vacuum-drying, crude product (690mg) obtained, by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 30ml.Concentrated solution is adjusted to about pH 3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (MitsubishiChemical Corporation) purifying, with 30% 2-aqueous propanol solution wash-out.With the elutriant vacuum concentration to about 30ml, and freeze-drying, obtained 3-{[3-amino-4-({ [(3S)-3-amino-1-pyrrolidyl] carbonyl } amino)-2-methyl isophthalic acid-pyrazoles subbase] methyl }-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate (60mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.52(6H，s)，2.13-2.27(1H，m)，2.38-2.53(1H，m)，3.20(1H，d，J＝17.4Hz)，3.46(1H，d，J＝17.4Hz)，3.54-3.67(3H，m)，3.73(3H，s)，3.79(1H，dd，J＝11.5，6.0Hz)，4.00-4.10(1H，m)，4.97(1H，d，J＝15.4Hz)，5.16(1H，d，J＝15.4Hz)，5.25(1H，d，J＝4.8Hz)，5.83(1H，d，J＝4.8Hz)，7.85(1H，s)

Preparation example 67

To [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] phenyl carbamate (950mg) and (3R)-and add N-ethyl diisopropyl amine (390mg) in the solution of 3-pyrrolidyl t-butyl carbamate (560mg) in methylene dichloride (20ml), this mixture was stirred 23 hours under reflux state.This reaction mixture is washed with 10% aqueous citric acid solution, salt solution and saturated sodium bicarbonate aqueous solution successively.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates is passed through silica gel chromatography, with 4% methyl alcohol/chloroform wash-out, obtained [(3R)-and 1-({ [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl)-3-pyrrolidyl] t-butyl carbamate (700mg), be solid.

Embodiment 41

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester (820mg) is at N, add N-(trimethyl silyl) ethanamide (656mg) in the solution in the dinethylformamide (2.4ml), with this mixture stirring at room 30 minutes.In this reaction mixture, add [(3R)-and 1-({ [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl)-3-pyrrolidyl] t-butyl carbamate (680mg).With whole mixture stirring at room 3 hours.In the gained reaction mixture, add ethyl acetate (80ml) and water (50ml).Isolate water layer, organic layer is used 10% trifluoroacetic acid sodium water solution, 10% sodium thiosulfate solution and salt water washing successively, with dried over sodium sulfate and filtration.With the filtrate vacuum concentration to about 5ml.Concentrated solution is poured in the Di Iso Propyl Ether (120ml), collected formed precipitation by filtering, and vacuum-drying.In the solution of gained solid in methylene dichloride (3.0ml), add methyl-phenoxide (1.0ml) and trifluoroacetic acid (2.0ml), with this mixture stirring at room 4 hours.This reaction mixture is poured in the Di Iso Propyl Ether (100ml), and collected formed precipitation by filtering, and vacuum-drying, crude product (760mg) obtained, by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 30ml.Concentrated solution is adjusted to about pH 3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (MitsubishiChemical Corporation) purifying, with the aqueous solution wash-out of 30% 2-propyl alcohol.With the elutriant vacuum concentration to about 30ml, and freeze-drying, obtained 3-{[3-amino-4-({ [(3R)-3-amino-1-pyrrolidyl] carbonyl } amino)-2-methyl isophthalic acid-pyrazoles subbase] methyl)-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate (68mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.52(6H，s)，2.13-2.27(1H，m)，2.38-2.53(1H，m)，3.20(1H，d，J＝17.6Hz)，3.47(1H，d，J＝17.6Hz)，3.56-3.66(3H，m)，3.73(3H，s)，3.79(1H，dd，J＝11.0，6.0Hz)，4.00-4.10(1H，m)，4.96(1H，d，J＝15.1Hz)，5.15(1H，d，J＝15.1Hz)，5.26(1H，d，J＝4.8Hz)，5.83(1H，d，J＝4.8Hz)，7.84(1H，s)

Preparation example 68

To (5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) phenyl carbamate (1.86g) and (3S)-and add N-ethyl diisopropyl amine (3.1g) in the 1-benzyl-solution of 3-pyrroles's alkanamine (2.0g) in chloroform (50ml), this mixture was stirred 19 hours under reflux state.With this reaction mixture vacuum concentration, obtained (S)-5-amino-4-[3-(1-benzyl-3-pyrrolidyl) urea groups]-1-methyl isophthalic acid H-pyrazoles crude product, be solid.Under nitrogen atmosphere, the solution of crude product in acetate was handled 24 hours with palladium black (3ml) in room temperature.After catalyzer filtered,, and resistates is dissolved in the saturated sodium bicarbonate aqueous solution (100ml) the filtrate vacuum concentration.In this solution, add the solution of the two carbonic acid tert-butyl esters (5.0g) in tetrahydrofuran (THF) (40ml), with this mixture stirring at room 5 hours.With this reaction mixture of chloroform extraction.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Develop resistates with ether, obtained (3S)-3-({ [(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino] carbonyl } amino)-1-pyrrolidinecarboxylic acid tert-butyl ester (1.9g), be solid.

¹H-NMR(DMSO-d ₆)δ1.40(9H，s)，1.70-1.76(1H，m)，1.95-2.02(1H，m)，3.01-3.05(1H，m)，3.24-3.34(2H，m)，3.38-3.45(1H，m)3.50(3H，s)，4.06-4.11(1H，m)，4.78(2H，brs)，6.19(1H，brs)，6.97(1H，s)，7.09(1H，brs)

Preparation example 69

In (3S)-3-({ [(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino] carbonyl } amino)-1-pyrrolidinecarboxylic acid tert-butyl ester (1.8g) and the solution of N-ethyl diisopropyl amine (720mg) in chloroform (50ml), add trityl chloride (1.6g), with this mixture stirring at room 28 hours.This reaction mixture is washed with 10% aqueous citric acid solution, salt solution and saturated sodium bicarbonate aqueous solution successively.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates by silica gel chromatography, with 3% methyl alcohol/chloroform wash-out, has been obtained (3S)-3-[({[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl) amino]-the 1-pyrrolidinecarboxylic acid tert-butyl ester (1.7g), be solid.

Embodiment 42

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester (820mg) is at N, add N-(trimethyl silyl) ethanamide (656mg) in the solution in the dinethylformamide (2.4ml), with this mixture stirring at room 30 minutes.In this reaction mixture, add (3S)-3-[({[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl) amino]-the 1-pyrrolidinecarboxylic acid tert-butyl ester (680mg).With whole mixture stirring at room 3 hours.In the gained reaction mixture, add ethyl acetate (80ml) and water (50ml).Isolate water layer, organic layer is used 10% trifluoroacetic acid sodium water solution, 10% sodium thiosulfate solution and salt water washing successively, with dried over sodium sulfate and filtration.With the filtrate vacuum concentration to about 5ml.Concentrated solution is poured in the Di Iso Propyl Ether (120ml), and collected formed precipitation by filtering, and vacuum-drying.In the solution of gained solid in methylene dichloride (3.0ml), add methyl-phenoxide (1.0ml) and trifluoroacetic acid (2.0ml), with this mixture stirring at room 5 hours.This reaction mixture is poured in the Di Iso Propyl Ether (100ml), and collected formed precipitation by filtering, and vacuum-drying, crude product (870mg) obtained, by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 30ml.Concentrated solution is adjusted to about pH 3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (MitsubishiChemical Corporation) purifying, with the aqueous solution wash-out of 30% 2-propyl alcohol.With the elutriant vacuum concentration to about 30ml, and freeze-drying, obtained 3-{[3-amino-2-methyl-4-({ [(3S)-3-pyrrolidyl amino] carbonyl }-amino)-1-pyrazoles subbase] methyl }-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-)-kharophen]-3-cephem-4-formate (68mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.52(3H，s)，1.53(3H，s)，2.00-2.09(1H，m)，2.28-2.38(1H，m)，3.22(1H，d，J＝17.4Hz)，3.29(1H，dd，J＝12.4，4.6Hz)，3.34-3.42(1H，m)，3.44-3.54(3H，m)，3.71(3H，s)，4.36-4.43(1H，m)，4.95(1H，d，J＝15.6Hz)，5.15(1H，d，J＝15.6Hz)，5.25(1H，d，J＝4.6Hz)，5.84(1H，d，J＝4.6Hz)，7.87(1H，s)

Preparation example 70

To the 4-[(tert-butoxycarbonyl) amino] add in the suspension of butyric acid (2.13g) in methylene dichloride (40ml) I-hydroxybenzotriazole (HOBT) (1.41g) and N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (WSCD HCl) (3.65g), this mixture was stirred 1 hour.In this solution, add 1-methyl isophthalic acid H-pyrazoles-4,5-diamines vitriol (2g) and N, N-diisopropyl ethyl amine (3.32ml).This reaction mixture was stirred 18 hours.In gained solution, add salt solution and saturated sodium bicarbonate aqueous solution, with this mixture ethyl acetate extraction.Water layer is extracted 2 times with tetrahydrofuran (THF)/ethyl acetate=1/1.With the extraction liquid anhydrous magnesium sulfate drying, filter and vacuum concentration.In resistates, add pyridine (40ml), add chlorine triphenyl methane (5.3g) then.This mixture was stirred 6 hours at 65 ℃.This mixture is dissolved in the ethyl acetate.With this solution water successively, 10% aqueous citric acid solution, water and salt water washing.With the extraction liquid anhydrous magnesium sulfate drying, filter and vacuum concentration.Resistates is passed through silica gel chromatography, with 60% ethyl acetate/dichloromethane wash-out, obtained (4-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-4-oxo butyl) t-butyl carbamate (2.01g).

¹H-NMR(CDCl ₃)δ1.44(9H，s)，1.67(2H，tt，J＝6.7，6.7Hz)，1.92(2H，t，J＝6.7Hz)，2.90(3H，s)，3.09(2H，dt，J＝6.7，6.7Hz)，4.50(1H，s)，4.71(1H，t，J＝6.7Hz)，6.53(1H，s)，7.0-7.35(16H，m)，7.56(1H，s)

Embodiment 43

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-iodomethyl-3-cephem-4-formic acid benzhydryl ester (2g) is at N, add N-(trimethyl silyl) ethanamide (1.77g) in the solution in the dinethylformamide (6ml), with this mixture stirring at room 30 minutes.In this reaction mixture, add (4-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-4-oxo butyl) t-butyl carbamate (1.98g), stir whole mixture 30 hours at 35 ℃.In the gained reaction mixture, add ethyl acetate, with this solution water successively, 10% trifluoroacetic acid sodium water solution and salt water washing, with dried over mgso and filtration.With the filtrate vacuum concentration to about 25ml.Concentrated solution is poured in the Di Iso Propyl Ether (150ml), collected formed precipitation by filtering, and vacuum-drying.In the solution of this solid in methylene dichloride (5ml), add methyl-phenoxide (1.5ml) and trifluoroacetic acid (5ml).Gained solution stirring at room 4 hours, and is poured in the Di Iso Propyl Ether.Collect formed precipitation by filtering, and vacuum-drying, crude product (1.2g) obtained.Crude product is dissolved in phosphate buffered saline buffer, and (pH 6.86,10ml) and in the mixture of saturated sodium bicarbonate aqueous solution, by using the preparation HPLC purifying of ODS post.The elutriant vacuum concentration that will contain required product is to about 20ml.Concentrated solution is adjusted to about pH 3 with concentrated hydrochloric acid, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (Mitsubishi ChemicalCorporation) purifying, with the aqueous solution wash-out of 20% 2-propyl alcohol.The elutriant vacuum concentration to about 30ml, is added 2M aqueous sulfuric acid (72ml).With this mixture freeze-drying; obtained 3-({ the amino butyryl radicals of 3-amino-4-[(4-) amino]-2-methyl isophthalic acid-pyrazoles subbase } methyl)-7 β-[(Z)-2-(5-amino-1; 2; 4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formic acid hydrosulfate (113mg), be amorphous solid.

¹H-NMR(D ₂O)δ1.61(6H，s)，2.01(2H，tt，J＝7.6，7.6Hz)，2.58(2H，t，J＝7.6Hz)，3.07(2H，t，J＝7.6Hz)，3.23(1H，d，J＝18Hz)，3.45(1H，d，J＝18Hz)，3.72(3H，s)，5.06(1H，d，J＝15.7Hz)，5.25(1H，d，J＝4.8Hz)，5.28(1H，d，J＝15.7Hz)，5.87(1H，d，J＝4.8Hz)，8.03(1H，s)

Preparation example 71

(5-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-5-oxo amyl group) t-butyl carbamate

This title compound is by the 5-[(tert-butoxycarbonyl) amino] valeric acid to be to make in the mode identical with preparation example 70.

¹H-NMR(CDCl ₃)δ1.43(9H，s)，1.2-1.6(4H，m)，1.90(2H，t，J＝7.0Hz)，2.90(3H，s)，3.09(2H，dt，J＝7.0，7.0Hz)，4.52(1H，s)，4.61(1H，t，J＝7.0Hz)，6.28(1H，s)，7.0-7.35(16H，m)，7.59(1H，s)

Embodiment 44

3-(the amino pentanoyl of 3-amino-4-[(5-) amino]-2-methyl isophthalic acid-pyrazoles subbase } methyl)-7 β-[(Z)-2-(5-amino-1; 2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formic acid hydrosulfate

This title compound be by (5-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-5-oxo amyl group) t-butyl carbamate makes in the mode identical with embodiment 43.

¹H-NMR(D ₂O)δ1.61(6H，s)，1.65-1.8(4H，m)，2.50(2H，m)，3.02(2H，m)，3.23(1H，d，J＝18Hz)，3.45(1H，d，J＝18Hz)，3.72(3H，s)，5.06(1H，d，J＝15.7Hz)，5.25(1H，d，J＝4.8Hz)，5.28(1H，d，J＝15.7Hz)，5.87(1H，d，J＝4.8Hz)，8.02(1H，s)

Preparation example 72

To 1-methyl-N ⁵-trityl-1H-pyrazoles-4 adds 4-{[(2 in the solution of 5-diamines (4g) in methylene dichloride (100ml), 5-dioxo-1-pyrrolidyl) the oxygen base] carbonyl }-1-piperidine acid tert-butyl ester (4.05g), this mixture was refluxed 72 hours.With this reaction mixture water successively, 10% aqueous citric acid solution, water and salt water washing.With the extraction liquid anhydrous magnesium sulfate drying, filter and vacuum concentration, obtained 4-({ [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl)-1-piperidine acid tert-butyl ester (1.806g).

¹H-NMR(CDCl ₃)δ1.3-1.9(14H，m)，1.5-1.8(2H，m)，2.95(3H，s)，4.10(2H，m)，4.36(1H，s)，6.53(1H，s)，7.0-7.35(16H，m)，7.68(1H，s)

Embodiment 45

3-(3-amino-2-methyl-4-[(4-piperidino carbonyl) amino]-1-pyrazoles subbase } methyl)-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate

This title compound is to be made in the mode identical with embodiment 36 by 4-({ [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl)-1-piperidine acid tert-butyl ester.

¹H-NMR(D ₂O)δ1.57(6H，s)，1.8-2.3(4H，m)，2.7-3.6(7H，m)，3.72(3H，s)，5.06(1H，d，J＝15.7Hz)，5.25(1H，d，J＝4.8Hz)，5.28(1H，d，J＝15.7Hz)，5.87(1H，d，J＝4.8Hz)，8.01(1H，s)

Preparation example 73

To 3-[N-(tert-butoxycarbonyl)-N-methylamino] add HOBT (3.33g) and WSCHCl (6.29g) in the suspension of propionic acid (3.33g) in methylene dichloride (33ml) and tetrahydrofuran (THF) (33ml), this mixture was stirred 1 hour.In this solution, add 1-methyl isophthalic acid H-pyrazoles-4,5-diamines vitriol (3.45g) and N, N-diisopropyl ethyl amine (11.4ml).With this reaction mixture in stirred overnight at room temperature.In gained solution, add salt solution, with tetrahydrofuran (THF)/ethyl acetate=1/1 extraction.With the extraction liquid anhydrous magnesium sulfate drying, filter and vacuum concentration, obtained N-{3-[(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino]-the 3-oxopropyl }-the N-methyl carbamic acid tert-butyl ester, be oily matter (2.4g).This product need not be further purified and be directly used in the next step.

Preparation example 74

To N-{3-[(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino]-the 3-oxopropyl }-the N-methyl carbamic acid tert-butyl ester (4.88g) is at N, adds trityl chloride (6.86g), triethylamine (6.86ml) and 4-dimethylaminopyridine (80mg) successively in the solution in the dinethylformamide (50ml).With this mixture in stirred overnight at room temperature.In the gained mixture, add ethyl acetate, water (3 times) and salt water washing.With the organic layer anhydrous magnesium sulfate drying, filter and vacuum concentration.With resistates by silica gel chromatography, obtained N-methyl-N-(3-[[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-the 3-oxopropyl) t-butyl carbamate (4.20g), be amorphous solid.

IR(KBr)1659，1587，1491，1446，1173，1151，762，739，708cm ^-1

¹H-NMR(DMSO-d ₆)δ1.40(9H，s)，2.12(2H，t，J＝7.4Hz)，2.74(3H，s)，2.74(3H，s)，3.24(2H，t，J＝7.4Hz)，5.58(1H，s)，7.13-7.40(16H，m)，8.30(1H，s)

Embodiment 46

3-[(3-amino-2-methyl-4-{[3-(methylamino) propionyl] amino }-1-pyrazoles subbase) methyl]-7 β-[(Z)-2-(5-amino-1; 2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate

This title compound be by N-methyl-N-(3-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-the 3-oxopropyl) t-butyl carbamate makes in the mode identical with embodiment 32, is amorphous solid.

IR(KBr)1770，1664，1599，1531，1400，1360cm ^-1

¹H-NMR(D ₂O)δ1.53(6H，s)，2.77(3H，s)，2.92(2H，t，J＝6.5Hz)，3.19 and 3.45(2H，ABq，J＝17.7Hz)，3.74(3H，s)，5.00 and 5.21(2H，ABq，J＝15.4Hz)，5.25(1H，d，J＝4.8Hz)，5.85(1H，d，J＝4.8Hz)，8.02(1H，s)

ESI-MS 666.3(M+H ⁺)

Preparation example 75

3-{[5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino] carbonyl }-1-azetidine t-butyl formate

This title compound be by 1-(tert-butoxycarbonyl }-3-azetidine formic acid makes in the mode identical with preparation example 73, is oily matter.This product need not be further purified and be directly used in the next step.

Preparation example 76

3-({ [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl)-1-azetidine t-butyl formate

This title compound is 3-{[(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino] carbonyl }-1-azetidine t-butyl formate makes in the mode identical with preparation example 74, is amorphous solid.

IR(KBr)3367，3321，1701，1662，1489，1414，1144，766，704cm ^-1

¹H-NMR(DMSO-d ₆)δ1.39(9H，s)，2.75(3H，s)，2.97-3.05(1H，m)，3.63-3.70(2H，m)，3.82-3.90(2H，m)，5.57(1H，s)，7.10-7.33(16H，m)，8.41(1H，s)

ESI-MS 560.3(M+Na ⁺)

Embodiment 47

3-(3-amino-4-[(3-azetidinyl carbonyl) amino]-2-methyl isophthalic acid-pyrazoles subbase } methyl)-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate

This title compound is to be made in the mode identical with embodiment 32 by 3-({ [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl)-1-azetidine t-butyl formate, is amorphous solid.

IR(KBr)1768，1663，1624，1605，1406，1362cm ^-1

¹H-NMR (D ₂O) δ 1.53 (3H, s), 1.53 (3H, s), 3.19 and 3.50 (2H, ABq, J=17.7Hz), 3.82-3.98 (1H, m), 4.31-4.35 (4H, m), 4.49 and 5.20 (2H, ABq, J=15.3Hz), 5.25 (1H, d, J=4.8Hz), 5.85 (1H, d, J=4.8Hz), 8.04 (1H, s)

ESI-MS 664.2(M+H ⁺)

Preparation example 77

N-{2-[(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino]-the 2-oxoethyl }-the N-methyl carbamic acid tert-butyl ester

This title compound is to be made in the mode identical with preparation example 73 by [N-(tert-butoxycarbonyl)-N-(methyl) amino] acetate, is oily matter.This product need not be further purified and be directly used in the next step.

Preparation example 78

N-methyl-N-(2-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-the 2-oxoethyl) t-butyl carbamate

This title compound is by N-{2-[(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino]-the 2-oxoethyl }-the N-methyl carbamic acid tert-butyl ester makes in the mode identical with preparation example 74, is white solid.The NMR data of this compound show and have rotational isomer.

¹H-NMR (DMSO-d ₆) δ 1.32 and 1.39 (9H, s), 2.72 and 2.77 (3H, s), 3.52 and 3.61 (2H, brs), 5.61 (1H, s), 7.13-7.33 (16H, m), 8.20 and 8.30 (1H, brs)

ESI-MS 548.3(M+Na ⁺)

Embodiment 48

3-[(3-amino-2-methyl-4-{[(methylamino) ethanoyl] amino }-1-pyrazoles subbase) methyl]-7 β-[(Z)-2-(5-amino-1; 2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate

This title compound be by N-methyl-N-(2-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-the 2-oxoethyl) t-butyl carbamate makes in the mode identical with embodiment 32, is amorphous solid.

IR(KBr)1770，1657，1601，1400，1362cm ^-1

¹H-NMR (D ₂O) δ 1.53 (6H, s), 2.82 (3H, s), 3.18 and 3.45 (2H, ABq, J=17.7Hz), 3.74 (3H, s), 4.08 (2H, s), 5.00 and 5.20 (2H, ABq, J=15.3Hz), 5.25 (1H, d, J=4.8Hz), 5.84 (1H, d, J=4.8Hz), 8.05 (1H, s)

ESI-MS 652.2(M+H ⁺)

Preparation example 79

N-(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) ethanamide

This title compound is to be made in the mode identical with preparation example 73 by (1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) acetate, is solid.

¹H-NMR(DMSO-d ₆)δ3.55(3H，s)，4.36(2H，s)，4.91(2H，brs)，7.14(1H，s)，7.85-8.02(4H，m)，9.48(1H，s)

ESI-MS 322.2(M+Na ⁺)

Preparation example 80

2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-N-[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] ethanamide

This title compound is to be made in the mode identical with preparation example 74 by N-(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) ethanamide, is solid.

¹H-NMR(DMSO-d ₆)δ2.70(3H，s)，4.12(2H，s)，5.41(1H，s)，7.12-7.33(16H，m)，7.85-7.95(4H，m)，8.93(1H，s)

ESI-MS 564.3(M+Na ⁺)

Preparation example 81

In room temperature hydrazine monohydrate (1.46ml) is added to 2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-and N-[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] in the solution of ethanamide (5.42g) in ethanol (108ml) and tetrahydrofuran (THF) (54ml), this mixture was stirred 2 hours at 70 ℃.This reaction mixture is cooled to 0 ℃, and by removing by filter insolubles.With the filtrate vacuum concentration.Resistates is developed with Di Iso Propyl Ether, collected by filtering, and vacuum-drying, obtained 2-amino-N-[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] ethanamide (3.37g), be solid.This product need not be further purified and be directly used in the next step.

Preparation example 82

To 2-amino-N-[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] add the two tert-butyl esters (2.35g) of ({ [(trifluoromethyl) alkylsulfonyl] imino-} methylene radical)-two carboxylamines and triethylamine (2.5ml) in the solution of ethanamide (2.47g) in tetrahydrofuran (THF) (50ml), with this mixture stirring at room 30 minutes.This reaction mixture is poured in the mixture of ethyl acetate and water.Isolate water layer, with organic layer salt water washing, with anhydrous magnesium sulfate drying and filtration.With the filtrate vacuum concentration.By the silica gel chromatography concentrated solution, obtained (E)-[(2-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-the 2-oxoethyl) amino] methylene radical }-the two tert-butyl esters (3.25g) of two carboxylamines, be amorphous solid.

¹H-NMR(DMSO-d ₆)δ1.38(9H，s)，1.49(9H，s)，2.75(3H，s)，3.79(2H，d，J＝4.7Hz)，5.47(1H，s)，7.12-7.33(16H，m)，8.55(1H，t，J＝4.7Hz)，8.61(1H，s)，11.43(1H，s)

ESI-MS 676.3(M+Na ⁺)

Embodiment 49

3-(3-amino-4-[(guanidine radicals ethanoyl) amino]-2-methyl isophthalic acid-pyrazoles subbase } methyl)-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate

This title compound is by { (E)-[(2-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-2-oxoethyl) amino] methylene radical } the two tert-butyl esters of two carboxylamines make in the mode identical with embodiment 32, are amorphous solid.

¹H-NMR (D ₂O) δ 1.53 (6H, s), 3.20 and 3.48 (2H, ABq, J=17.6Hz), 3.75 (3H, s), 4.21 (2H, s), 5.00 and 5.20 (2H, ABq, J=15.3Hz), 5.26 (1H, d, J=4.8Hz), 5.85 (1H, d, J=4.8Hz), 8.02 (1H, s)

ESI-MS 678.2 (M-H ⁺) (bearing)

Embodiment 50

Under ice-cooled; to 3-({ the amino propionyl of 3-amino-4-[(3-) amino]-2-methyl isophthalic acid-pyrazoles subbase } methyl)-7 β-[(Z)-2-(5-amino-1; 2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-add azomethine acid ethyl ester hydrochloride salt (658mg) and salt of wormwood (1.106g) in the solution of 3-cephem-4-formate (652mg) in water (30ml) and acetonitrile (3ml).After 3 hours, add 1N HCl 5 ℃ of stirrings with this reaction mixture that neutralizes.Gained solution is passed through preparation HPLC purifying; mixture wash-out with phosphate buffered saline buffer (pH 5.5) and acetonitrile; elutriant is composed purifying in the enterprising circumstances in which people get things ready for a trip of Diaion  HP-20 (MitsubishiChemical Corporation); freeze-drying; obtained 3-({ 3-amino-4-[(3-guanidine radicals propionyl) amino]-2-methyl isophthalic acid-pyrazoles subbase } methyl)-7 β-[(Z)-2-(5-amino-1; 2; 4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate (23mg), be the amorphous thing.The NMR data of this compound show and have rotational isomer.A kind of main isomer is only described.

IR(KBr)1770，1714，1668，1653，1456，1400，1360cm ^-1

¹H-NMR(D ₂O)δ1.53(6H，s)，2.85(2H，t，J＝6.4Hz)，3.19and 3.46(2H，ABq，J＝17.7Hz)，3.65(2H，t，J＝6.4Hz)，5.00 and 5.21(2H，ABq，J＝15.2Hz)，5.26(1H，d，J＝4.8Hz)，5.85(1H，d，J＝4.8Hz)，7.80(1H，s)，8.01(1H，s)

ESI-MS 677.2 (M-H ⁺) (bearing)

Preparation example 83

To 1-methyl isophthalic acid H-pyrazoles-4, add WSCD HCl (3.83g) and N in the solution that is stirring of 5-diamines vitriol (2.1g) and 3-oxyethyl group-3-oxo propionic acid (1.32g) in methylene dichloride (10ml) and tetrahydrofuran (THF) (10ml), N-diisopropyl ethyl amine (6.96ml), and this mixture stirred spend the night.Removal of solvent under reduced pressure, this comprises 3-[(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino]-the thick resistates of 3-oxo ethyl propionate need not be further purified and be directly used in the next step.

Preparation example 84

To comprise 3-[(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino]-the thick resistates of 3-oxo ethyl propionate is dissolved in N, in the dinethylformamide (20ml), under agitation adds trityl chloride (5.52g) and triethylamine (4.14ml).Water (10ml) stopped reaction is spent the night in this mixture stirring.With whole mixture ethyl acetate extraction, with extraction liquid water and salt water washing, with dried over mgso and concentrating under reduced pressure, obtained the oily resistates, by the silica gel chromatography purifying, with methylene dichloride-ethyl acetate (2: 3) wash-out, obtained 3-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-3-oxo ethyl propionate (1.23g).

ESI-MS 491.2[M+Na] ⁺(just), 467.3[M-H] ^-(bearing)

¹H-NMR(DMSO-d ₆)δ1.18(3H，t，J＝7.1Hz)，2.75(3H，s)，3.04(2H，s)，4.07(2H，q，J＝7.1Hz)，5.55(1H，s)，7.1-7.4(16H，m)，8.54(1H，s)

Preparation example 85

To 3-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino-add 1N aqueous sodium hydroxide solution (3.1ml) in the solution of 3-oxo ethyl propionate (1.3g) in tetrahydrofuran (THF) (30ml), with this mixture stirring at room 3 hours.Vacuum is removed tetrahydrofuran (THF), with rare citric acid with this resistates acidifying.By filter collecting formed precipitation, and drying under reduced pressure, obtained 3-{ (1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-3-oxo propionic acid (1.22g).

ESI-MS 463.2[M+Na] ⁺(just),

¹H-NMR(DMSO-d ₆)δ2.74(3H，s)，2.95(2H，s)，5.56(1H，s)，7.0-7.4(16H，m)，8.54(1H，s)，12.0-13.0(1H，brs)

Preparation example 86

To 3-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino-add WSCD HCl (522mg) in 3-oxo propionic acid (600mg) and the suspension of (2-amino-ethyl) t-butyl carbamate (240mg) in tetrahydrofuran (THF) (12ml) and methylene dichloride (6ml), with whole mixture in stirred overnight at room temperature.In this reaction mixture, add entry (3ml), with whole mixture ethyl acetate extraction.With extraction liquid water and salt water washing, use dried over mgso.With solvent evaporation; obtained thick resistates; it is developed with Di Iso Propyl Ether-ethyl acetate (2: 1), obtained 2-[(3-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino-3-oxo propionyl) amino] ethyl } t-butyl carbamate (537mg).

ESI-MS 604.9[M+Na] ⁺(just),

¹H-NMR(DMSO-d ₆)δ1.38(9H，s)，2.74(3H，s)，2.85(2H，s)，2.9-3.2(4H，m)，5.61(1H，s)，6.7-6.9(1H，m)，7.0-7.4(16H，m)，8.0-8.1(1H，m)，8.63(1H，s)

Embodiment 51

3-{[3-amino-4-(the 3-[(2-amino-ethyl) amino]-3-oxo propionyl } amino)-2-methyl isophthalic acid-pyrazoles subbase] methyl }-7 β-[(Z)-2-(5-amino-1; 2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate

This title compound is by { 2-[(3-{[I-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-3-oxo propionyl) amino] ethyl } t-butyl carbamate makes in the mode identical with embodiment 34.

ESI-MS 731.2[M+Na] ⁺(just),

¹H-NMR (D ₂O) δ 1.53 (6H, s), 3.1-3.3 (2H, m), 3.19 and 3.44 (2H, ABq, J=17.7Hz), 3.54 (2H, s), and 3.5-3.7 (2H, m), 3.74 (3H, s), 5.00 and 5.22 (2H, ABq, J=15.5Hz), 5.25 (1H, d, J=4.7Hz), 5.86 (1H, d, J=4.8Hz), 8.05 (1H, s)

Preparation example 87

In the solution that stirring of 3-amino-2 hydroxy propanoic acid (2.1g) in tetrahydrofuran (THF) (30ml) and water (30ml), add the 1N aqueous sodium hydroxide solution with this solution is alkalized (pN=9).In this mixture, add the two carbonic acid tert-butyl esters (4.36g), this mixture stirring at room 4 hours, is remained on the pH of mixture between 8.5 and 9.0.Whole mixture is washed with ether., saturated with 10% aqueous potassium hydrogen sulfate with sodium-chlor with water layer acidifying (pH=2), use ethyl acetate extraction.With sal epsom with the extraction liquid drying.With solvent removed under reduced pressure, obtained the 3-[(tert-butoxycarbonyl) amino]-2 hydroxy propanoic acid (3.96g).

ESI-MS 228.2[M+Na] ⁺(just),

¹H-NMR(DMSO-d ₆)δ1.37(9H，s)，3.0-3.8(3H，m)，3.9-4.1(1H，m)，6.5-6.8(1H，m)

Preparation example 88

To the 3-[(tert-butoxycarbonyl) amino]-add HOBT (1.59g) and WSCD HCl (3.01g) in the solution of 2 hydroxy propanoic acid (1.61g) in methylene dichloride (8ml) and tetrahydrofuran (THF) (8ml), with this mixture stirring at room 1 hour.This solution is cooled to 0 ℃, adds 1-methyl isophthalic acid H-pyrazoles-4,5-diamines vitriol and N, N-diisopropyl ethyl amine (4.1ml).With this mixture stirring at room 8 hours.Removal of solvent under reduced pressure, obtained 3-[(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino]-2-hydroxyl-3-oxopropyl } the t-butyl carbamate crude product, it need not be further purified and be directly used in next reaction.

Preparation example 89

(2-hydroxyl-3-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-the 3-oxopropyl) t-butyl carbamate

This title compound be by 3-[(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl) amino]-2-hydroxyl-3-oxopropyl t-butyl carbamate makes in the mode identical with preparation example 84.

ESI-MS 564.3[M+Na] ⁺(just),

¹H-NMR(DMSO-d ₆)δ1.39(9H，s)，2.7-2.9(1H，m)，2.83(3H，s)，3.1-3.4(1H，m)，3.7-3.9(1H，m)，5.79(1H，d，J＝5.3Hz)，5.98(1H，s)，6.5-6.7(1H，m)，7.1-7.4(16H，m)，8.36(1H，s)

Embodiment 52

3-(3-amino-4-[(3-amino-2-hydroxyl propionyl) amino]-2-methyl isophthalic acid-pyrazoles subbase } methyl)-7 β-[(Z)-2-(5-amino-1; 2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate

This title compound be by (2-hydroxyl-3-{[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-the 3-oxopropyl) t-butyl carbamate makes in the mode identical with embodiment 32.

¹H-NMR (D ₂O) δ 1.49 (6H, s), 3.1-3.6 (4H, m), 3.76 (3H, s), 4.6-4.7 (1H, m), 5.02 and 5.21 (2H, ABq, J=15.4Hz), 5.26 (1H, d, J=4.8Hz), 5.86 (1H, d, J=4.8Hz), 8.05 (1H, s)

Preparation example 90

In 2-(4, the 5-diaminostilbene H-pyrazol-1-yl) suspension of ethanol vitriol (5g) in methylene dichloride (50ml), add triethylamine (6.38ml) at 0 ℃, this mixture was stirred 10 minutes at 0 ℃.The mixture of diacetyl oxide (2.16ml) and formic acid (1.74ml) was stirred 30 minutes at 40 ℃, be cooled to 0 ℃, be added drop-wise in the above-mentioned solution at 0 ℃.Whole mixture was stirred 2 hours at 0 ℃.In this mixture, add salt solution, extract whole mixture with tetrahydrofuran (THF).With the extraction liquid drying, and reduction vaporization has obtained [5-amino-1-(2-hydroxyethyl)-1H-pyrazoles-4-yl] methane amide crude product with sal epsom, and it need not be further purified and be directly used in next reaction.

Preparation example 91

[1-(2-hydroxyethyl)-5-(trityl amino)-1H-pyrazoles-4-yl] methane amide

This title compound is to be prepared in the mode identical with preparation example 84 by [5-amino-1-(2-hydroxyethyl)-1H-pyrazoles-4-yl] methane amide.The NMR data of this compound show and have rotational isomer.

¹H-NMR (DMSO-d ₆) δ 3.10 (2H, t, J=6.2Hz), 3.3-3.5 and 3.4-3.6 (2H, m), 4.89 and 5.06 (1H, t, J=5.1Hz), 5.77 and 6.07 (1H, s), 7.1-7.4 (16H, m), 7.58 and 8.07 (1H, s), 7.58 (1H, s)

Preparation example 92

Under nitrogen gas stream in room temperature to [1-(2-hydroxyethyl)-5-(trityl amino)-1H-pyrazoles-4-yl] methane amide (2g) at N, add sodium hydride (213mg in the solution that is stirring in the dinethylformamide (30ml), 60% oil suspension), whole mixture was stirred 20 minutes at 0 ℃.In above-mentioned solution, add (3-bromopropyl) t-butyl carbamate (1.27g) at N, solution in the dinethylformamide (10ml) and sodium iodide (799mg), and this mixture stirred spend the night.Add 10% aqueous potassium hydrogen sulfate (5ml), with whole mixture ethyl acetate extraction.With extraction liquid water and salt water washing, use dried over mgso.With solvent removed under reduced pressure; obtained oily matter; by the silica gel chromatography purifying, with methylene dichloride-ethyl acetate (2: 1) wash-out, obtained (3-{N-formyl radical-N-[1-(2-hydroxyethyl)-5-(trityl amino)-1H-pyrazoles-4-yl] amino } propyl group) t-butyl carbamate (1g).The NMR data of this compound show and have rotational isomer.

ESI-MS 592.3[M+Na] ⁺(just),

¹H-NMR (DMSO-d ₆) δ 1.37 and 1.38 (9H, s), 2.7-3.5 (10H, m), 4.80 and 4.88 (1H, t, J=5.0Hz), 5.52 ﹠amp; 6.06 (1H, s), 6.5-6.9 (1H, m), 7.0-7.4 (16H, m), 7.52 (1H, s)

Embodiment 53

3-(3-amino-4-[N-(3-aminopropyl)-N-formyl radical amino]-2-(2-hydroxyethyl)-1-pyrazoles subbase } methyl)-7 β-[(Z)-2-(5-amino-1; 2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate

This title compound is to be made in the mode identical with embodiment 32 by (3-{N-formyl radical-N-[1-(2-hydroxyethyl)-5-(trityl amino)-1H-pyrazoles-4-yl] amino } propyl group) t-butyl carbamate.

ESI-MS 694.2[M-H] ^-(bearing)

¹H-NMR(D ₂O)δ1.53(6H，s)，1.7-2.1(2H，m)，2.9-3.1(2H，m)，3.1-3.8(4H，m)，3.8-4.0(2H，m)，4.3-4.6(2H，m)，4.8-5.2(2H，m)，5.29(1H，d，J＝4.8Hz)，5.85(1H，d，J＝4.7Hz)，8.0-8.3(2H，m)

Embodiment 54

Room temperature to 3-({ 3-amino-4-[N-(3-aminopropyl)-N-formyl radical amino]-2-(2-hydroxyethyl)-1-pyrazoles subbase } methyl)-7 β-[(Z)-2-(5-amino-1; 2; 4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]]-add concentrated hydrochloric acid (0.125ml) in the 3-cephem-suspension that is stirring of 4-formate (100mg) in methyl alcohol (1.4ml), this mixture was stirred 6.5 hours.In above-mentioned solution, add sodium bicarbonate (109mg), by this mixture of preparation HPLC purifying (ODS post; Acetonitrile: phosphate buffered saline buffer (pH7)=5: 95).The elutriant evaporation that will contain required product with its acidifying, is composed purifying in the enterprising circumstances in which people get things ready for a trip of Diaion  HP-20 (Mitsubishi Chemical Corporation), with the aqueous solution wash-out of 20% 2-propyl alcohol with dilute hydrochloric acid to remove acetonitrile.With the elutriant concentrating under reduced pressure, and freeze-drying, obtained 3-({ 3-amino-4-[(3-aminopropyl) amino]-2-(2-hydroxyethyl)-1-pyrazoles subbase } methyl)-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate (18mg).

ESI-MS 666.2[M-H] ^-(bearing)

¹H-NMR (DMSO-d ₆) δ 1.53 (6H, s), 1.96 (2H, tt, J=7.5Hz), 3.0-3.2 (4H, m), 3.13 and 3.43 (2H, ABq, J=17.6Hz), 3.87 (2H, t, J=4.8Hz), 4.2-4.4 (2H, m), 4.87 and 5.03 (2H, ABq, J=15.2Hz), 5.24 (1H, d, J=4.8Hz), 5.83 (1H, d, J=4.8Hz), 7.64 (1H, s)

Preparation example 93

At 0 ℃, to N-[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl]-2-(trityl amino) ethanamide (2g) is at N, stirring in the dinethylformamide (20ml) adds sodium hydride (245mg in the solution, 60% oil suspension), this mixture was stirred 30 minutes, be warmed to room temperature simultaneously.This mixture is cooled to 0 ℃, adds methyl-iodide (1.3g).With whole mixture in stirred overnight at room temperature.Add entry (5ml), with whole mixture ethyl acetate extraction.With organic layer water and salt water washing, use dried over mgso.With solvent removed under reduced pressure, obtained N-methyl-N-[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl]-2-(trityl amino) ethanamide (2.05g).

ESI-MS 690.3[M+Na] ⁺(just),

¹H-NMR(DMSO-d ₆)δ1.99(3H，s)，2.3-2.8(3H，m)，2.52(3H，s)，5.44(1H，s)，6.85(1H，s)，6.9-7.5(30H，m)

Preparation example 94

At 0 ℃ lithium aluminium hydride (455mg) is added in the tetrahydrofuran (THF) (40ml) lentamente, this mixture was stirred 20 minutes.In this mixture, add N-methyl-N-[1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl at 0 ℃]-2-(trityl amino) ethanamide (2g), whole mixture was stirred 2 hours, be warmed to room temperature simultaneously, refluxed then 2 hours.In this mixture, add Sodium Fluoride (2.51g) and water (862mg), and with whole mixture stirring at room 30 minutes.Filter out precipitation, filtrate decompression is concentrated, obtained thick resistates, by chromatography purification (silica gel; Ethyl acetate: methylene dichloride=1: 10), obtained N ⁴, 1-dimethyl-N ⁵-trityl-N ⁴-[2-(trityl amino) ethyl]-1H-pyrazoles-4,5-diamines (740mg).

ESI-MS 676.2[M+Na] ⁺(just),

¹H-NMR(DMSO-d ₆)δ1.7-2.0(2H，m)，1.98(3H，s)，2.2-2.4(1H，m)，2.6-2.8(2H，m)，2.81(3H，s)，5.24(1H，s)，7.00(1H，s)，7.0-7.5(30H，m)

Embodiment 55

3-(3-amino-4-[N-(2-amino-ethyl)-N-methylamino]-2-methyl isophthalic acid-pyrazoles subbase } methyl)-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate

This title compound is by N ⁴, 1-dimethyl-N ⁵-trityl-N ⁴-[2-(trityl amino) ethyl]-1H-pyrazoles-4, the 5-diamines makes in the mode identical with embodiment 32.

ESI-MS 636.2[M-H] ^-(negative)

¹H-NMR (D ₂O) δ 1.60 (6H, s), 2.60 (3H, s), 3.0-3.2 (4H, m), 3.19 and 3.39 (2H, ABq, J=17.7Hz), 3.67 (3H, s), 4.87 and 5.20 (2H, ABq, J=15.8Hz), 5.22 (1H, d, J=4.9Hz), 5.85 (1H, d, J=4.7Hz), 7.90 (1H, s)

Preparation example 95

In [1-(2-fluoro ethyl)-1H-pyrazoles-5-yl] methane amide (15.7g) solution in methyl alcohol (78ml), add concentrated hydrochloric acid (21ml) in room temperature.This reaction mixture was stirred 3.5 hours, and vacuum-evaporation.Resistates is dissolved in the ethyl acetate, washs with sodium bicarbonate aqueous solution.With the organic layer dried over mgso, vacuum concentration has obtained 1-(2-fluoro ethyl)-1H-pyrazoles-5-amine (12g).

¹H-NMR(DMSO-d ₆)δ4.15(2H，dt，J＝25.2，5.1Hz)，4.66(2H，dt，J＝47.2，5.1Hz)，5.1(2H，brs)，5.27(1H，d，J＝1.7Hz)，7.06(1H，d，J＝1.7Hz)

Preparation example 96

In 1-(2-the fluoro ethyl)-1H-pyrazoles-solution of 5-amine (12g) in ethanol (30ml), add concentrated hydrochloric acid (70mg) and Isopentyl nitrite (10.9g).This reaction mixture was stirred 2 hours at 25-38 ℃.Di Iso Propyl Ether and hexane are added in this reaction mixture, gained oily matter is passed through silica gel chromatography (ethyl acetate: hexane=1: 2 → 1: 1 → 2: 1 → 1: 0), obtained 1-(2-fluoro ethyl)-4-nitroso-group-1H-pyrazoles-5-amine (4.8g).

¹H-NMR (DMSO-d ₆) δ 4.10-4.90 (4H, m), 7.09 and 8.59 (1H, s), 8.20 and 8.26 (1H, brs)

Preparation example 97

In the solution of 1-(2-fluoro ethyl)-4-nitroso-group-1H-pyrazoles-5-amine (4.8g) in water (30ml) and methyl alcohol (30ml), add sulfuric acid (2.98g) and 10% palladium carbon (2.5g), with the hydrogenation 7.5 hours under gasbag pressure of this mixture.This reaction mixture is filtered via bed of diatomaceous earth, and with the filtrate vacuum concentration.In resistates, add the 2-propyl alcohol,, obtained 1-(2-fluoro ethyl)-1H-pyrazoles-4,5-diamines vitriol (7g) by filtering collecting precipitation.

¹H-NMR(D ₂O)δ4.25-4.95(4H，m)，7.66(1H，s)

Preparation example 98

Ice-cooled following to 1-(2-fluoro ethyl)-1H-pyrazoles-4, add { 3-[(2 in the solution of 5-diamines vitriol (3g) in tetrahydrofuran (THF) (30ml), 5-dioxo-1-pyrrolidyl) oxygen base]-the 3-oxopropyl } t-butyl carbamate (3.9g) and N, N-diisopropyl ethyl amine (3.5g).With this reaction mixture stirring at room 2 hours.Add sodium bicarbonate aqueous solution and sodium-chlor, this mixture is extracted (3 times) with ethyl acetate-tetrahydrofuran (THF).With the organic layer dried over mgso, and vacuum concentration.With resistates by silica gel chromatography (ethyl acetate → ethyl acetate: ethanol=8: 1), obtained (3-{[5-amino-1-(2-fluoro ethyl)-1H-pyrazoles-4-yl] amino }-the 3-oxopropyl) t-butyl carbamate (2.3g).

¹H-NMR(DMSO-d ₆)δ1.38(9H，s)，2.36(2H，t，J＝7.1Hz)，3.10-3.27(2H，m)，4.16(2H，dt，J＝25.5，5.0Hz)，4.67(2H，dt，J＝47.2，5.0Hz)，5.27(2H，brs)，6.75-6.90(1H，m)，7.23(1H，s)，9.08(1H，brs)

Preparation example 99

Room temperature to (3-{[5-amino-1-(2-fluoro ethyl)-1H-pyrazoles-4-yl] amino }-the 3-oxopropyl) t-butyl carbamate (2.3g) is at N, adds triethylamine (1.48g), 4-dimethylaminopyridine (35.6mg) and trityl chloride (2.2g) in the solution in the dinethylformamide (12ml).This reaction mixture was stirred 2 hours, add entry.With this mixture ethyl acetate extraction, with organic layer water and sodium chloride aqueous solution washing.With the organic layer dried over mgso, and vacuum concentration.Add acetonitrile, by filtering collecting precipitation, obtained (3-{[1-(2-fluoro ethyl)-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-the 3-oxopropyl) t-butyl carbamate (2g).

¹H-NMR(DMSO-d ₆)δ1.39(9H，s)，2.05(2H，t，J＝7.2Hz)，3.00-3.08(2H，m)，3.23(2H，dt，J＝25.3，5.1Hz)，4.41(2H，dt，J＝47.1，5.1Hz)

Embodiment 56

3-(the amino propionyl of 3-amino-4-[(3-) amino]-2-(2-fluoro ethyl)-1-pyrazoles subbase } methyl)-7 β-[(Z)-2-(5-amino-1; 2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate

This title compound be by (3-{[1-(2-fluoro ethyl)-5-(trityl amino)-1H-pyrazoles-4-yl] amino }-the 3-oxopropyl) t-butyl carbamate prepares in the mode identical with embodiment 38.

¹H-NMR(D ₂O)δ2.89(2H，t，J＝6.5Hz)，3.22(1H，d，J＝9.2Hz)，3.34(1H，t，J＝6.5Hz)，3.50(1H，d，J＝9.2Hz)，4.55-4.95(4H，m)，5.08(2H，brs)，5.26(1H，d，J＝4.9Hz)，5.84(1H，d，J＝4.9Hz)，8.09(1H，s)

Preparation example 100

1-methyl-7-nitroso-group-1H-imidazo [1,2-b] pyrazoles

This title compound is to be prepared in the mode identical with preparation example 96 by 1-methyl isophthalic acid H-imidazo [1,2-b] pyrazoles.

¹H-NMR(DMSO-d ₆)δ3.93(1H，s)，7.48(1H，m)，7.92(1H，m)，9.03(1H，s)

Preparation example 101

1-methyl isophthalic acid H-imidazo [1,2-b] pyrazoles-7-amine vitriol

This title compound is to be prepared in the mode identical with preparation example 97 by 1-methyl-7-nitroso-group-1H-imidazo [1,2-b] pyrazoles.

¹H-NMR(DMSO-d ₆)δ3.73(3H，s)，7.24(1H，m)，7.62(2H，m)

Preparation example 102

The two tert-butyl esters of { (Z)-[(1-methyl isophthalic acid H-imidazo [1,2-b] pyrazoles-7-yl) amino] methylene radical } two carboxylamines

This title compound is to be prepared in the mode identical with preparation example 64 by 1-methyl isophthalic acid H-imidazo [1,2-b] pyrazoles-7-amine vitriol.

¹H-NMR(DMSO-d ₆)δ1.34(9H，s)，1.52(9H，s)，3.61(3H，s)，7.14(1H，m)，7.42(1H，m)，7.52(1H，m)

Embodiment 57

7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-{[7-guanidine radicals-1-methyl-5-(1H-imidazo [1,2-b] pyrazoles subbase)] methyl }-3-cephem-4-formate

This title compound is to be made in the mode identical with embodiment 43 by the two tert-butyl esters of { (Z)-[(1-methyl isophthalic acid H-imidazo [1,2-b] pyrazoles-7-yl) amino] methylene radical } two carboxylamines.

¹H-NMR(D ₂O)δ1.51(6H，s)，3.40(2H，m)，3.85(3H，s)，5.15-5.30(3H，m)，5.83(1H，d，J＝4.8Hz)，7.49(1H，d，J＝2.2Hz)，8.02(1H，d，J＝2.2Hz)，8.27(1H，d，J＝1.0Hz)

IR(KBr)3400，3392，1770，1672，1606，1531cm ^-1

Preparation example 103

3-[(1-methyl isophthalic acid H-imidazo [1,2-b] pyrazoles-7-yl) amino]-the 3-oxopropyl } t-butyl carbamate

This title compound is by 1-methyl isophthalic acid H-imidazo [1,2-b] pyrazoles-7-amine vitriol and 3-[(tert-butoxycarbonyl) amino] propionic acid makes in the mode identical with preparation example 70.

¹H-NMR(DMSO-d ₆)δ1.43(9H，s)，2.61(2H，m)，3.49(2H，m)，3.65(3H，s)，7.22(1H，m)，7.26(1H，m)，7.44(1H，m)

Embodiment 58

3-(the amino propionyl of 7-[(3-) amino]-1-methyl-5-(1H-imidazo [1; 2-b] the pyrazoles subbase) methyl)-7 β-[(Z)-2-(5-amino-1; 2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formate

This title compound be by 3-[(1-methyl isophthalic acid H-imidazo [1,2-b] pyrazoles-7-yl) amino]-the 3-oxopropyl t-butyl carbamate makes in the mode identical with embodiment 43.

¹H-NMR(D ₂O)δ1.50(6H，s)，2.97(2H，d，J＝6.5Hz)，3.36(2H，d，J＝6.5Hz)，3.4(2H，m)，3.81(3H，s)，5.15-5.30(3H，m)，5.82(1H，d，J＝4.8Hz)，7.44(1H，d，J＝2.2Hz)，7.98(1H，d，J＝2.2Hz)，8.11(1H，d，J＝1.0Hz)

IR(KBr)3401，1770，1666，1606，1525cm ^-1

Preparation example 104

At N, add triethylamine (1.08g) and the 1-piperazinecarboxylic acid tert-butyl ester (1.99g) in the suspension in the dinethylformamide (32ml) to [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] phenyl carbamate (4.6g).This reaction mixture was stirred 3 hours, and pour in the water.With this mixture of ethyl acetate extraction, with the organic layer vacuum concentration.Resistates is passed through silica gel chromatography (ethyl acetate → ethyl acetate: ethanol=20: 1), obtained 4-({ [1-methyl-5-(trityl amino)-IH-pyrazoles-4-yl] amino } carbonyl)-1-piperazinecarboxylic acid tert-butyl ester (4.7g).

¹H-NMR(CDCl ₃)δ1.46(9H，s)，2.90(3H，s)，3.05-3.25(4H，m)，3.30-3.45(4H，m)，4.76(1H，brs)，5.34(1H，brs)，7.10-7.30(16H，m)

Embodiment 59

To 7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-tert-butoxycarbonyl-1-methyl ethoxy imino-) kharophen]-3-chloromethyl-3-cephem-4-formic acid 4-methoxy-benzyl ester (2g) is at N, add 1 in the solution in the dinethylformamide (6ml), 3-two (trimethyl silyl) urea (3g), and with this reaction mixture stirring 30 minutes.Potassiumiodide (680mg) is added in this solution, this mixture was stirred 30 minutes.4-({ [1-methyl-5-(trityl amino)-1H-pyrazoles-4-yl] amino } carbonyl)-1-piperazinecarboxylic acid tert-butyl ester (2g) is added in this solution.This reaction mixture was stirred 23 hours at 25 ℃, and pour in the mixture of ethyl acetate-water-20% sodium chloride aqueous solution.With the mixture washing of organic layer with 10% sodium thiosulfate solution and 20% sodium chloride aqueous solution.Organic layer with 10% sodium trifluoroacetate solution washing 2 times, is washed with 20% sodium chloride aqueous solution then.Organic layer vacuum concentration to volume is about 10ml.Concentrated solution is added in the Di Iso Propyl Ether, this suspension was stirred 1 hour.Collect gained solid and dry by filtering.Solid is dissolved in the methylene dichloride (6ml).In this solution, add methyl-phenoxide (2ml) and trifluoroacetic acid (6ml).This reaction mixture was stirred 4 hours, and pour in the Di Iso Propyl Ether.Collect gained solid and dry by filtering.With the preparation HPLC purifying of this solid by use ODS post.The elutriant vacuum concentration that will contain required product.With concentrated hydrochloric acid concentrated solution is adjusted to about pH 1, at the enterprising circumstances in which people get things ready for a trip spectrum of Diaion  HP-20 (Mitsubishi Chemical Corporation) purifying, with 20% 2-aqueous propanol solution wash-out.With the elutriant vacuum concentration, add 2M sulfuric acid.With this mixture freeze-drying, obtained 3-({ 3-amino-2-methyl-4-[(1-piperazinyl carbonyl) amino]-1-pyrazoles subbase } methyl)-7 β-[(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(1-carboxyl-1-methyl ethoxy imino-) kharophen]-3-cephem-4-formic acid hydrosulfate (679mg).

¹H-NMR(D ₂O)δ1.60(6H，s)，3.20(2H，d，J＝17.7Hz)，3.25-3.45(4H，m)，3.45(1H，d，J＝17.7Hz)3.72(3H，m)，3.75-3.85(4H，m)，5.00(1H，d，J＝15.7Hz)，5.24(1H，d，J＝15.7Hz)，5.25(1H，d，J＝4.8Hz)，5.86(1H，d，J＝4.8Hz)，7.89(1H，s)

The application is based on October 30th, 2002 in No.2002952355 number application of Australia's submission and in the No.2003904813 number application that on September 4th, 2003 submitted to, and its content is incorporated herein by reference.

Claims

1. formula [I] compound or pharmaceutically acceptable salt thereof:

Wherein

R ¹Be C ₁-C ₆Alkyl, hydroxyl C ₁-C ₆Alkyl or halo C ₁-C ₆Alkyl, and

R ²Be hydrogen, C ₆-C ₁₂Aryl C ₁-C ₆Alkyl or acyl group, described acyl group is selected from C ₁-C ₆Alkanoyl, one or two or three halo C ₁-C ₆Alkanoyl, C ₁-C ₆Alkoxy carbonyl, formamyl, be selected from benzoyl, toluyl and naphthoyl aroyl, be selected from the aryl C of phenyl acetyl and phenyl propionyl ₁-C ₆Alkanoyl, be selected from phenyloxycarbonyl and naphthyloxy carbonyl aryloxycarbonyl, be selected from the aryloxy C of phenoxy group ethanoyl and phenoxy group propionyl ₁-C ₆Alkanoyl, to be selected from phenyl aryl glyoxyl-based and that naphthyl is glyoxyl-based glyoxyl-based and be selected from benzyloxycarbonyl, styroyl oxygen base carbonyl and to the optional substituted aryl C of nitro benzyloxycarbonyl ₁-C ₆Alkoxy carbonyl, perhaps

R ¹With R ²Be bonded together and form C ₁-C ₆Alkylidene group or C ₂-C ₆Alkenylene;

R ³Be hydrogen or C ₁-C ₆Alkyl;

R ⁴Be

Wherein

A is

Wherein X is O or NH,

R ⁷Be hydrogen, C ₁-C ₆Alkyl, C ₆-C ₁₂Aryl C ₁-C ₆Alkyl or acyl group, described acyl group is selected from C ₁-C ₆Alkanoyl, one or two or three halo C ₁-C ₆Alkanoyl, C ₁-C ₆Alkoxy carbonyl, formamyl, be selected from benzoyl, toluyl and naphthoyl aroyl, be selected from the aryl C of phenyl acetyl and phenyl propionyl ₁-C ₆Alkanoyl, be selected from phenyloxycarbonyl and naphthyloxy carbonyl aryloxycarbonyl, be selected from the aryloxy C of phenoxy group ethanoyl and phenoxy group propionyl ₁-C ₆Alkanoyl, to be selected from phenyl aryl glyoxyl-based and that naphthyl is glyoxyl-based glyoxyl-based and be selected from benzyloxycarbonyl, styroyl oxygen base carbonyl and to the optional substituted aryl C of nitro benzyloxycarbonyl ₁-C ₆Alkoxy carbonyl,

R ⁸Be hydrogen or hydroxyl,

R ⁹Be amino, one or two C ₁-C ₆Alkylamino, C ₆-C ₁₂Aryl C ₁-C ₆Alkylamino or be selected from C ₁-C ₆Alkanoyl amino and C ₁-C ₆The acyl amino of alkoxycarbonyl amino, guanidine radicals, be selected from single C ₁-C ₆Alkoxy carbonyl guanidine radicals and two C ₁-C ₆The acyl group guanidine radicals of alkoxy carbonyl guanidine radicals or saturated 3-8 unit heterocyclic radical, described heterocyclic radical contains 1-4 nitrogen-atoms, and optional by amino, C ₆-C ₁₂Aryl C ₁-C ₆Alkylamino or be selected from C ₁-C ₆Alkanoyl amino and C ₁-C ₆The acyl amino of alkoxycarbonyl amino replaces,

K, m, n and q are 0 or 1 independently, and

P is 0,1,2 or 3;

R ⁵Be carboxyl or esterifying carboxyl group, esterifying carboxyl group is selected from C ₁-C ₆Alkoxy carbonyl, C ₁-C ₆Alkanoyloxy C ₁-C ₆Alkoxy carbonyl, C ₁-C ₆Alkane alkylsulfonyl C ₁-C ₆Alkoxy carbonyl, one or two or three halo C ₁-C ₆Alkoxy carbonyl, C ₂-C ₆Alkenyloxy carbonyl, C ₂-C ₆Alkynyloxy base carbonyl, be selected from benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 4-nitro benzyloxycarbonyl, styroyl oxygen base carbonyl, trityl oxygen base carbonyl, diphenyl-methyl oxygen base carbonyl, two (p-methoxy-phenyl) methoxycarbonyl, 3,4-dimethoxy benzyloxycarbonyl and 4-hydroxyl-3, the aryl C of the optional replacement of 5-two-tertiary butyl benzyloxycarbonyl ₁-C ₆Alkoxy carbonyl and be selected from the aryloxycarbonyl of the optional replacement of phenyloxycarbonyl, 4-chlorophenoxy carbonyl, tolyloxy carbonyl, 4-tertiary butyl phenyloxycarbonyl, xylyloxy carbonyl, sym-trimethylbenzene oxygen base carbonyl and cumenyl oxygen base carbonyl; And

R ⁶Be amino or C ₆-C ₁₂Aryl C ₁-C ₆Alkylamino or be selected from C ₁-C ₆Alkanoyl amino and C ₁-C ₆The acyl amino of alkoxycarbonyl amino.

2. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein

R ¹Be C ₁-C ₆Alkyl or hydroxyl C ₁-C ₆Alkyl, and

R ²Be hydrogen, C ₆-C ₁₂Aryl C ₁-C ₆Alkyl or acyl group as defined in claim 1, perhaps

R ¹With R ²Be bonded together and form C ₁-C ₆Alkylidene group;

R ³Be hydrogen;

A is

Wherein X is O or NH;

R ⁷Be hydrogen, C ₆-C ₁₂Aryl C ₁-C ₆Alkyl or acyl group as defined in claim 1;

R ⁹Be amino or C ₆-C ₁₂Aryl C ₁-C ₆Alkylamino or acyl amino as defined in claim 1; And

P is 0,1 or 2.

3. the compound or pharmaceutically acceptable salt thereof of claim 2, wherein R ⁸Be hydrogen.

4. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein

R ⁵Be carboxyl or esterifying carboxyl group as defined in claim 1;

R ⁶Be amino or acyl amino as defined in claim 1;

R ⁷Be hydrogen, C ₁-C ₆Alkyl or acyl group as defined in claim 1; And

R ⁹Be amino, one or two C ₁-C ₆Alkylamino, acyl amino as defined in claim 1, guanidine radicals, acyl group guanidine radicals as defined in claim 1 or saturated 3-8 unit heterocyclic radical; described heterocyclic radical contains 1-4 nitrogen-atoms, and optional by the amino or replacement of acyl amino as defined in claim 1.

5. the compound or pharmaceutically acceptable salt thereof of claim 4, wherein

R ¹Be C ₁-C ₆Alkyl or hydroxyl C ₁-C ₆Alkyl, and

R ¹With R ²Be bonded together and form C ₁-C ₆Alkylidene group;

R ⁵Be carboxyl or esterifying carboxyl group as defined in claim 1;

R ⁶Be amino or acyl amino as defined in claim 1;

R ⁷Be hydrogen or acyl group as defined in claim 1; And

R ⁹Be amino or acyl amino as defined in claim 1.

6. the compound or pharmaceutically acceptable salt thereof of claim 5, wherein

R ¹Be C ₁-C ₆Alkyl or hydroxyl C ₁-C ₆Alkyl, and

R ²Be hydrogen, C ₆-C ₁₂Aryl C ₁-C ₆Alkyl, C ₁-C ₆Alkanoyl or C ₁-C ₆Alkoxy carbonyl, perhaps

R ¹With R ²Be bonded together and form C ₁-C ₆Alkylidene group;

R ⁶Be carboxyl or C ₁-C ₆Alkoxy carbonyl;

R ⁶Be amino, C ₁-C ₆Alkanoyl amino or C ₁-C ₆Alkoxycarbonyl amino;

R ⁷Be hydrogen, C ₁-C ₆Alkanoyl or C ₁-C ₆Alkoxy carbonyl; And

R ⁹Be amino, C ₁-C ₆Alkanoyl amino or C ₁-C ₆Alkoxycarbonyl amino.

7. the compound or pharmaceutically acceptable salt thereof of claim 6, wherein

R ¹Be C ₁-C ₆Alkyl or hydroxyl C ₁-C ₆Alkyl, and

R ²Be hydrogen, perhaps

R ¹With R ²Be bonded together and form C ₁-C ₆Alkylidene group;

R ⁵It is carboxyl;

R ⁶Be amino;

R ⁷Be hydrogen or C ₁-C ₆Alkanoyl; And

R ⁹Be amino.

8. the compound or pharmaceutically acceptable salt thereof of claim 1,

R wherein ⁴Be selected from

R wherein ⁷, A, m, p and q respectively as defined in claim 1,

R ¹⁴Be amino, one or two C ₁-C ₆Alkylamino, C ₆-C ₁₂Aryl C ₁-C ₆Alkylamino or be selected from C ₁-C ₆Alkanoyl amino and C ₁-C ₆The acyl amino of alkoxycarbonyl amino,

R ¹⁵Be guanidine radicals or be selected from single C ₁-C ₆Alkoxy carbonyl guanidine radicals and two C ₁-C ₆The acyl group guanidine radicals of alkoxy carbonyl guanidine radicals, and

R ¹⁶Be the first heterocyclic radical of saturated 3-8, described heterocyclic radical contains 1-4 nitrogen-atoms, and optional by amino, C ₆-C ₁₂Aryl C ₁-C ₆Alkylamino or be selected from C ₁-C ₆Alkanoyl amino and C ₁-C ₆The acyl amino of alkoxycarbonyl amino replaces.

9. the compound or pharmaceutically acceptable salt thereof of claim 1,

R wherein ⁴Be selected from

Wherein

P is 0,1 or 2,

Q is 0 or 1,

R ⁷Be hydrogen, C ₆-C ₁₂Aryl C ₁-C ₆Alkyl or acyl group as defined in claim 1, and

R ⁹Be amino or C ₆-C ₁₂Aryl C ₁-C ₆Alkylamino or acyl amino as defined in claim 1.

10. the compound or pharmaceutically acceptable salt thereof of claim 9, wherein

R ⁷Be hydrogen, C ₁-C ₆Alkanoyl or C ₁-C ₆Alkoxy carbonyl; And

R ⁹Be amino, C ₁-C ₆Alkanoyl amino or C ₁-C ₆Alkoxycarbonyl amino.

11. the compound or pharmaceutically acceptable salt thereof of claim 10, wherein

R ⁷Be hydrogen or C ₁-C ₆Alkanoyl; And

R ⁹Be amino.

12. the method for preparation formula [I] compound or its salt:

Wherein

R ²Be hydrogen or C ₆-C ₁₂Aryl C ₁-C ₆Alkyl or acyl group, described acyl group is selected from C ₁-C ₆Alkanoyl, one or two or three halo C ₁-C ₆Alkanoyl, C ₁-C ₆Alkoxy carbonyl, formamyl, be selected from benzoyl, toluyl and naphthoyl aroyl, be selected from the aryl C of phenyl acetyl and phenyl propionyl ₁-C ₆Alkanoyl, be selected from phenyloxycarbonyl and naphthyloxy carbonyl aryloxycarbonyl, be selected from the aryloxy C of phenoxy group ethanoyl and phenoxy group propionyl ₁-C ₆Alkanoyl, to be selected from phenyl aryl glyoxyl-based and that naphthyl is glyoxyl-based glyoxyl-based and be selected from benzyloxycarbonyl, styroyl oxygen base carbonyl and to the optional substituted aryl C of nitro benzyloxycarbonyl ₁-C ₆Alkoxy carbonyl, perhaps

R ³Be hydrogen or C ₁-C ₆Alkyl;

R ⁴Be

Wherein

A is

Wherein X is O or NH,

R ⁷Be hydrogen, C ₁-C ₆Alkyl or C ₆-C ₁₂Aryl C ₁-C ₆Alkyl or acyl group, described acyl group is selected from C ₁-C ₆Alkanoyl, one or two or three halo C ₁-C ₆Alkanoyl, C ₁-C ₆Alkoxy carbonyl, formamyl, be selected from benzoyl, toluyl and naphthoyl aroyl, be selected from the aryl C of phenyl acetyl and phenyl propionyl ₁-C ₆Alkanoyl, be selected from phenyloxycarbonyl and naphthyloxy carbonyl aryloxycarbonyl, be selected from the aryloxy C of phenoxy group ethanoyl and phenoxy group propionyl ₁-C ₆Alkanoyl, to be selected from phenyl aryl glyoxyl-based and that naphthyl is glyoxyl-based glyoxyl-based and be selected from benzyloxycarbonyl, styroyl oxygen base carbonyl and to the optional substituted aryl C of nitro benzyloxycarbonyl ₁-C ₆Alkoxy carbonyl,

R ⁸Be hydrogen or hydroxyl,

K, m, n and q are 0 or 1 independently, and

P is 0,1,2 or 3;

R ⁵Be carboxyl or esterifying carboxyl group, esterifying carboxyl group is selected from C ₁-C ₆Alkoxy carbonyl, C ₁-C ₆Alkanoyloxy C ₁-C ₆Alkoxy carbonyl, C ₁-C ₆Alkane alkylsulfonyl C ₁-C ₆Alkoxy carbonyl or one or two or three halo C ₁-C ₆Alkoxy carbonyl, C ₂-C ₆Alkenyloxy carbonyl, C ₂-C ₆Alkynyloxy base carbonyl, be selected from benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 4-nitro benzyloxycarbonyl, styroyl oxygen base carbonyl, trityl oxygen base carbonyl, diphenyl-methyl oxygen base carbonyl, two (p-methoxy-phenyl) methoxycarbonyl, 3,4-dimethoxy benzyloxycarbonyl and 4-hydroxyl-3, the aryl C of the optional replacement of 5-two-tertiary butyl benzyloxycarbonyl ₁-C ₆Alkoxy carbonyl and be selected from the aryloxycarbonyl of the optional replacement of phenyloxycarbonyl, 4-chlorophenoxy carbonyl, tolyloxy carbonyl, 4-tertiary butyl phenyloxycarbonyl, xylyloxy carbonyl, sym-trimethylbenzene oxygen base carbonyl and cumenyl oxygen base carbonyl; And

R ⁶Be amino, C ₆-C ₁₂Aryl C ₁-C ₆Alkylamino or be selected from C ₁-C ₆Alkanoyl amino and C ₁-C ₆The acyl amino of alkoxycarbonyl amino,

Described method comprises

1 with [II] compound or its reactive derivatives or its salt on amino

R wherein ¹, R ², R ³And R ⁴Define the preceding as this claim respectively,

With formula [III] compound or its reactive derivatives or its reactant salt on carboxyl

R wherein ⁵And R ⁶Define the preceding as this claim respectively,

With acquisition formula [I] compound or its salt:

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶Define the preceding as this claim respectively,

Perhaps

2 carry out the elimination reaction of the protecting group on the amino with formula [Ia] compound or its salt:

R wherein ¹, R ², R ³, R ⁵, R ⁶, R ⁷, R ⁸, A, k, m, n, p and q define the preceding as this claim respectively, and R ⁹A is C ₆-C ₁₂Aryl C ₁-C ₆Alkylamino or be selected from C ₁-C ₆Alkanoyl amino and C ₁-C ₆The acyl amino of alkoxycarbonyl amino, be selected from single C ₁-C ₆Alkoxy carbonyl guanidine radicals and two C ₁-C ₆The acyl group guanidine radicals of alkoxy carbonyl guanidine radicals or saturated 3-8 unit heterocyclic radical, described heterocyclic radical contain 1-4 nitrogen-atoms and by C ₆-C ₁₂Aryl C ₁-C ₆Alkylamino or be selected from C ₁-C ₆Alkanoyl amino and C ₁-C ₆The acyl amino of alkoxycarbonyl amino replaces,

Acquisition formula [Ib] compound or its salt:

R wherein ¹, R ², R ³, R ⁵, R ⁶, R ⁷, R ⁸, A, k, m, n, p and q define the preceding as this claim respectively, and R ⁹B is amino, guanidine radicals or the first heterocyclic radical of the saturated 3-8 by amino replacement that contains 1-4 nitrogen-atoms,

Perhaps

3 with formula [VI] compound or its salt

R wherein ⁵And R ⁶Define R respectively the preceding as this claim ¹⁰Be as the esterifying carboxyl group of this claim, and Y is leavings group in preceding definition,

React with formula [VII] compound or its salt:

Acquisition formula [VIII] compound or its salt:

R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁶And R ¹⁰Define Z respectively the preceding as this claim ^Be negatively charged ion,

Formula [VIII] compound or its salt is carried out the elimination reaction of esterifying carboxyl group protecting group,

Acquisition formula [I] compound or its salt:

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶Define the preceding as this claim respectively.

13. pharmaceutical composition, described composition comprise claim 1 compound or pharmaceutically acceptable salt thereof and with its blended pharmaceutically acceptable carrier.

14. the compound or pharmaceutically acceptable salt thereof of claim 1 is used for the treatment of application in the medicine of infectious diseases in preparation.